Orphan Drug Designation
A drug becomes an “orphan” when it receives orphan designation from the Office of Orphan Products Development, FDA. An orphan drug is a drug intended to treat diseases or conditions affecting fewer than 200,000 people per year in the United States. The costs of research and development of an orphan drug may exceed sales of the drug when it is marketed. Therefore, the Orphan Drug Act was passed as an incentive to develop and manufacture drugs that treat rare conditions. Orphan designation qualifies the sponsor to receive certain benefits, such as 7 years marketing exclusivity, from the U.S. Government in exchange for developing the drug. However, the drug must successfully complete the new drug approval process and be approved by the U.S.-FDA before these benefits can be realized. More than one sponsor may receive orphan drug designation of the same drug for the same rare disease or condition. When another sponsor seeks orphan drug designation for a subsequent drug for the same rare disease or condition, an explanation of why the proposed variation may be clinically superior to the first must be made.

Are orphan products approved faster than other drugs?
Historically, the approval time for orphan products as a group has been considerably shorter than the approval time for all drugs. This is due to the fact that many orphan products receive expedited review because they are for serious or life-threatening disease.

How much do orphan drugs cost?
The cost of orphan products is determined by the sponsor of the drug and is not controlled by the FDA. The costs of orphan products vary greatly. Generally, health insurance will pay the cost of orphan products that have been approved for marketing.

The above information is reprinted from the FDA Office of Orphan Products Development: http://www.fda.gov/orphan/index.htm.

Clinical Trials
Testing Drugs in People
by Ken Flieger

“Most of us understand that drugs intended to treat people have to be tested in people. These tests, called clinical trials, determine if a drug is safe and effective, at what doses it works best, and what side effects it causes—information that guides health professionals and, for nonprescription drugs, consumers in the proper use of medicines.

Personal Participation in Clinical Trials
Clinical trials are carried out at major medical research centers such as teaching hospitals, at specialized clinics ....., and even in doctors’ offices. Although they often involve hospitalized patients, many clinical trials are conducted on an outpatient basis, with participants more or less going about their normal activities.

Although investigational drug studies vary widely, some things should be expected by participants in virtually any clinical trial…... Tests to assess disease status might be more frequent. Participants are often required to keep detailed records of their symptoms and follow strict schedules.

Trials in Humans
Phase 1
Number of Patients: 20-100
Length: Several months
Purpose: Mainly safety
Percent of Drugs Successfully Tested*: 70 percent

Phase 2
Number of Patients: Up to several hundred
Length: Several months to 2 years
Purpose: Some short-term safety but mainly effectiveness
Percent of Drugs Successfully Tested*: 33 percent

Phase 3
Number of Patients: Several hundred to several thousand
Length: 1-4 years
Purpose: Safety, dosage, effectiveness
Percent of Drugs Successfully Tested*: 25-30 percent

* For example, of 100 drugs for which investigational new drug applications are submitted to FDA, about 70 will successfully complete phase 1 trials and go on to phase 2; about 33 of the original 100 will complete phase 2 and go to phase 3; and 25 to 30 of the original 100 will clear phase 3 (and, on average, about 20 of the original 100 will ultimately be approved for marketing).

The above information and additional information can be found at the FDA website: http://www.fda.gov/

Additional information on clinical trials for patients with rare disease or conditions is provided by the Office of Rare Diseases of the NIH and can be accessed at the following sites:
http://rarediseases.info.nih.gov/ord/ct-about.html

“Testing Drugs in People” originally appeared in the July-August 1994 FDA Consumer . The companion article “Skeptic’s Guide to Medical Breakthroughs” was taken from the November 1987 FDA Consumer Special Report on New Drug Development in the United States (January 1995). Ken Flieger is a writer in Washington D.C.

Background—Pompe Disease

Pompe disease is one of a family of 40 rare diseases known as lysosomal storage disorders. Pompe disease, also known as acid maltase deficiency or glycogen storage disease type II, is caused by complete or partial deficiency of the enzyme alpha -glucosidase and affects an estimated 5,000-1 0,000 people in the Western world. Another well-known example of a lysosomal storage disorder is Gaucher disease, which is caused by deficiency of the enzyme glucocerebrosidase. For Gaucher disease, there is an existing enzyme replacement therapy, in fact the first such therapy for a lysosomal storage disorder.

Clinical forms of Pompe disease vary according to the age of onset and progression of symptoms. The infantile form appears in the first few months after birth and is characterized by a rapid build-up of glycogen in several tissues, severe muscle weakness, and enlargement of the heart and liver. Respiratory and heart complications often lead to an early death in the first or second year of life.

‘The juvenile form usually begins in early childhood and develops more slowly. It is characterized by progressive muscle weakness, with the respiratory muscles being most critically affected. Patients with this form of the disease usually succumb to respiratory failure before the age of 30.

In the adult form of the disease, symptoms may go undetected until the third to fifth decade of life. Glycogen build-up occurs mainly in skeletal muscle, leading to muscular weakness, particularly in the diaphragm, limb girdle and the trunk. Respiratory complications are the main cause of death.

Alpha-glucosidase production

Pharming has pioneered the production of recombinant human proteins isolated from the milk of transgenic animals. This technology allows for efficient production of complex proteins which may be difficult to produce (technically or economically) by other methods. In the particular case of Pompe disease, Pharming has succeeded in producing the enzyme human alpha-glucosidase at high levels in the milk of transgenic rabbits.

The production of human alpha-glucosidase currently takes place at Pharming’s small scale pilot plant in Geel, Belgium. The pilot plant is capable of producing sufficient alpha-glucosidase for clinical trials. In addition, Pharming is constructing a commercial scale plant for commercial production of the enzyme after product approval. The plant’s completion is expected in the year 2000.

In October 1998, a joint venture was established between Pharming Group, N.V. of the Netherlands and Genzyme Corporation, of Cambridge, Massachusetts for the worldwide development and commercialization of human alpha-glucosidase (the joint venture).

The first steps of human alpha-glucosidase development

The safety and efficacy studies for alpha-glucosidase in animals were concluded with positive results. The study showed that regular intravenous injection of the recombinant human alpha-glucosidase appeared to correct the enzyme deficiency and significantly improve tissue morphology with generally few side effects.

Pharming then proceeded to take human alpha-glucosidase into Phase I clinical trials to test the safety and tolerance of the enzyme in human subjects. Participants in this trial were healthy (adult) volunteers. The study was concluded in the summer of 1998 with encouraging results: human alpha-glucosidase was generally safe and well-tolerated.

It is important to note that these are preliminary results. More studies in patients are needed to confirm these findings before an application seeking marketing approval can be submitted to the Regulatory Authorities.

Human alpha-glucosidase in Phase II clinical trials and beyond

As a first step to test recombinant human alpha-glucosidase in Pompe disease patients, a pilot trial will be carried out at Sophia Children’s Hospital in Rotterdam, under the direction of Pharming/Genzyme LLC. The aim of the study is to assess for the first time the safety and early indications of efficacy of the enzyme in patients. It will be a pilot trial with a limited number of infantile (approximately four) and juvenile patients (approximately three). Dr. Ans van der Ploeg at the Sophia Children’s Hospital in Rotterdam is the principal investigator of the current pilot trial.

Data obtained while the pilot study is in progress will be used to design two larger Phase II/III pivotal trials in the US and Europe. Detailed design of these trials can only be done when data from the pilot trial are available. The goal is to have these studies underway in mid1999.

A relatively limited number of patients will be enrolled in the combined trials which is in line with the limited number of Pompe disease patients overall. It is also due to the fact that Pharming’s pilot plant is not equipped to supply more human alpha-glucosidase than the scheduled trials demand, However, as a testimony of the Pharming/Genzyme LLC’s conviction to the success of these trials, the company is currently constructing a commercial scale plant. Therefore, larger amounts will become available, as market demand increases.

Questions and Answers

1. Have the clinical trials started?

Approval for a small pilot study on 4 infants and 3 juvenile patients was recently received in the Netherlands. The study has begun (January 1999) at the Sophia Children’s Hospital in Rotterdam and inclusion of patients has started. Dr. Ans van der Ploeg is the principal investigator. This study is designed to assess safety and give indications of efficacy of recombinant human alpha-glucosidase in this population.

If successful, data obtained while the pilot trial is in progress will be used to design two larger Phase II/III trials in the US and Europe. Detailed design of these trials can only be done when data from the pilot trial are available. Our goal is to initiate the first of these 2 studies in mid-1999.

2. How can I participate in upcoming additional clinical trials?

Once the protocol and sites have been established, your physician should contact the principal investigator at the participating center to determine whether a patient can participate. Your physician should also inform you about the consequences of trial participation, such as potential side effects, additional examinations, prolonged hospital stay and costs.

3. How are patients selected for these clinical trials?

Before starting clinical trials, the principal investigators and participating institutions will be identified. The investigators will follow a predefined protocol with patient inclusion and exclusion criteria that define patient eligibility for trial participation, as well as the number of patients that can be enrolled. Inclusion or exclusion is determined by a selection committee consisting of several physicians including the primary investigator(s) based on the protocol.

4. What are the inclusion/exclusion criteria for the trials?

The protocols for the Phase II/III clinical trials have not been determined to date as they will be dependent on the results of the Phase II pilot trial in the Netherlands.

5. Who are the principal investigators and institutions in the next trials?

The participating physicians and institutions have not been determined yet. Your local patient organization (AMDA in the U.S.) will be informed on all progress toward trial preparation.

6. How will patients from other countries be able to participate in clinical trials performed in the US and/or Europe?

Your physician should contact the principal investigator(s) at the participating center(s) to understand the inclusion and exclusion criteria for the protocol, and to determine whether a patient might be eligible for participation.

7. What are the starting dates for the trials?

The initial, small pilot study taking place in Rotterdam has begun. Our goal is to implement the next trial in mid-to-late 1999.

8. Will therapy be continued for trial patients after completion?

If the product proves efficacious in the trial, our plan is to continue patient treatment under the Pharming/Genzyme LLC until regulatory approval has been obtained.

9. Is it possible to start treatment for patients concurrently with or after completion of the clinical trial?

Construction of a large scale production plant is underway in Belgium. Until that time, product supply is available from a small pilot plant to support the limited patients that are enrolled in the Phase II/III clinical trials. The large scale production plant is scheduled to be operational around mid-2000. Within the framework set by international legislation and the limits to product supply, the Pharming/Genzyme LLC joint venture will evaluate the possibilities for patient treatment concurrently or after completion of the clinical trial.

10. Has the FDA already given the go-ahead in start clinical trials in the US?

Not at this time. Pharming/Genzyme LLC is working to complete the application to perform the clinical trials in the US (i.e.. the IND, Investigational New Drug Application). The FDA will allow us to start clinical trials only after we have finalized the clinical protocol and submitted it to them for review. In Europe, the required approvals to perform clinical trials must also be obtained.

11. When will the product be approved?

The Pharming/Genzyme LLC is committed to working diligently and thoroughly to develop a safe, efficacious product as quickly as possible. As always, timelines may shift depending upon the outcome of the trials, review time by the FDA in the ‘US and the EMEA in Europe, and production capacity at our manufacturing facilities.

After successful completion of the Phase II/III clinical trials in infants, the Pharming/Genzyme joint venture will apply for product approval for this population. Completion of this clinical trial, assessment of results, filing of the application and review by the FDA may take as long as 12-24 months. In Europe, we must complete a Market Authorization Application with the EMEA, the central European regulatory body, to obtain approval in the member states of the European Union.

A second trial in juvenile patients is planned to start later, and the trial will most likely take longer to complete. Thus, the process until approval for treatment of juvenile patients may take until mid-to-late 2001.

The following status statement was released by Synpac (North Carolina), Inc., on June 30, 1999

Synpac Pharmaceuticals Limited
Cambois, Bedlington, Northumberland NE22 7DB
Tel: (01670) 565656 Fax: (01670) 850571

I.S. Hodgson-Direct Line
Tel: 01670 565539
Fax: 01670 522459

On May 24, 1999, (see press release above article), Duke University announced the start of clinical trials to test the safety and efficacy of recombinant human acid alpha-glucosidase (rhGAA) for the treatment of glycogen storage disease type II (Pompe Disease). The initial study will include up to three infantile patients who meet the inclusion criteria defined in the study protocol. Dr. Y.T. Chen, Chief of Medical Genetics at Duke, is the sponsor of the study. Synpac (N.C.), Inc., is funding the study and has provided the rhGAA.

Because it is known that individuals with Pompe disease lack the acid alpha-glucosidase enzyme, it has been proposed that enzyme replacement therapy with rhGAA would treat the symptoms related to Pompe disease, much like synthetic insulin can treat the symptoms of individuals with insulin dependent diabetes. When rhGAA was administered to an animal model of Pompe disease (Japanese quail that lack the same enzyme and have similar clinical features of Pompe disease), significant improvement in muscle strength was observed after three weeks. It is anticipated that if Pompe patients are treated with a manufactured version of acid alpha- glucosidase (rhGAA), the symptoms of Pompe disease may be alleviated. The current clinical trial is designed to test the safety and effectiveness of this enzyme in humans with Pompe disease.

It is important to note that rhGAA is not designed to be a cure for Pompe disease. Rather it is intended as a therapeutic agent to treat Pompe disease. The rhGAA will be administered intravenously to supplement the body’s insufficient supply of enzyme. It is anticipated that patients will require life long therapy with rhGAA.

Synpac plans to expand the trial to include juveniles and adults and to expand the trials to Europe; however, the timing and design of all phases of the clinical trials depend upon a number of factors including:

Analysis of results from the initial trial.
Questions that this first study is designed to answer include: Is the drug well tolerated? Are there side effects? Is there evidence of clinical benefit? In future studies, data will be generated to determine what the effective dose will be and how frequently it will need to be administered.

Review and permission of regulatory agencies.
The Food and Drug Administration (FDA) must review the drug safety and tolerance data generated during this first phase and grant permission to expand the number patients. All efforts are directed at moving this product through the regulatory requirements as quickly as possible, while assuring the safety and clinical benefit of the product. Advantage will be taken of the provisions for rapid approval through the FDA.

Continued manufacturing success
Manufacturing Plans: Manufacturing efforts must continue to be successful as we expand production to meet anticipated demands. Although the trials have just begun, Synpac has already started developing a full scale manufacturing program to generate a drug supply sufficient for the anticipated market of infants, juveniles, and adults. We anticipate the clinical trials will progress in parallel with the manufacturing efforts to increase supply.

Manufacturing Methods: To manufacture the rhGAA, Synpac is using a Chinese hamster ovary (CHO) cell line, which Dr. Chen’s laboratory at Duke genetically engineered to contain the human GAA gene. As the cells grow in a nutrient rich broth, they secrete the rhGAA enzyme into the broth. The enzyme is then purified from the broth through a series of filtering and sieving devices. CHO cell technology is not new and has been used for many years to manufacture a number of medical products on the market.

Manufacturing Capabilities: Synpac initially produced a preliminary drug supply in a small pilot manufacturing facility. However, Synpac has now moved its manufacturing efforts to an established contractor with large scale manufacturing capabilities. By using a contract manufacturer, Synpac avoids the major investments of both time and costs required to build a manufacturing facility and gains the expertise of a team of scientists who have prior experience manufacturing similar proteins.

“It is our goal to insure a continuous drug supply to all patients enrolled in clinical trials.”

The opening presentation was given by Dr. M.C.B. Loonen. Dr. Loonen served as Head of the Child Neurology Department of the Academic Hospital Rotterdam, the Netherlands, from 1971 until retirement in 1995. Her thesis entitled, “The variability of Pompe’s Disease. A clinical, biochemical and genetic study of glycogen storage disease type 2, or acid maltase deficiency”, appeared in 1979.

Dr. Loonen’s presentation gave a historical overview of Pompe’s disease from it’s initial description by J.C. Pompe, a Dutch pathologist in 1932; the discovery of lysosomes in 1955 by Christian de Duve (et al); the discovery by H. G. Hers (et al) that glycogen storage was caused by the deficiency of the lysosomal enzyme, acid alpha-glucosidase and his unsuccessful attempt at enzyme replacement therapy in 1963; the 1964 demonstration by Baudhuin (et al) which showed that glycogen stored in the liver of Pompe patients was present mainly within the lysosomes. In 1965 it was recognized that there are also “late-onset” forms of Pompe’s disease.

Although presently retired, Dr. Loonen is still involved in the clinical trials for enzyme replacement therapy currently underway at Sophia Children’s Hospital in Rotterdam.

Dr. M.G.E.M. Ausems, Clinical Geneticist and Head of Genetic Counseling in the Department of Medical Genetics, University Medical Center Utrecht, the Netherlands, based her presentation on her publication “The frequency of Glycogen Storage Disease type II in the Netherlands; implications for diagnosis and genetic counseling.” (Ausems MEM, Verbiest J. Herman MMP, it al; Eur J Hum Genet in press).

Since 1995 she has been involved in studies on the frequency of Pompe’s disease and genotype-phenotype correlations of the disease in close collaboration with Dr. Reuser, Dr. van der Ploeg and Prof. Dr. J.H.H. Wokkel, Department of Neurology, University Medical Center Utrecht, the Netherlands.

Dr. Ausems’s data predicts that frequency of GSD II is 1 in 40,000 in the Dutch population as opposed to the frequently quoted figure of 1 in 100,000. A recent study on the carrier frequency by Frank Martiniuk, Ph.D., New York University Medical Center (USA), also indicated a disease frequency of 1 in 40,000, based on his study of the general population in New York (Martiniuk F, Chen A, Mack A et al. Carrier frequency for glycogen storage disease type II in New York and estimates of affected individuals born with the disease. AM J Med Genet 1998; 79:69-72.)

Dr. Ausems concluded, “Our results suggest that the world wide frequency of GSD II must be higher than 1 in 100,000 and that the birth prevalence of adult GSD II is two times higher than that of infantile GSD II.

Prof. Dr. John J. Hopwood, Deputy Head of the Chemical Pathology Services and Head of the Lysosomal Disease Research Unit, Women’s and Children’s Hospital, North Adelaide, South Australia, stressed the importance of joining together all LSD, lysosomal storage disorders (of which there are 40), to broaden the patient base and thereby, bring this category of disorders to the foreground. Based on his research he has found that LSD affects approximately 1 in 5,000.

For over 20 years Dr. Hopwood’s research has been linked to the provision of a diagnostic service and the development of therapy for patients with LSD. Specifically toward GSD II he stated, “We have been developing new methodology to achieve fast, inexpensive and non-invasive procedures for the early detection and diagnosis of GSD II in individuals from newborns to adult populations,” but he went on to say that diagnosis of GSD II using blood samples is complicated by the presence of other alpha-glucosidase activities.

Arnold J.J. Reuser, Ph.D., Associate Professor of Cell Biology, Department of Clinical Genetics, Erasmus University Rotterdam, the Netherlands, also made a historical presentation on Pompe’s disease.

Dr. Reuser has been involved in Pompe research since 1973. Throughout the 80s and 90s, he was involved in the biosynthesis and structure of acid alpha-glucosidase, the cloning of the acid alpha-glucosidase gene, mutation analysis, and the development of a mouse model for Pompe’s disease. All of these endeavors have lead to the commencement of clinical trials in enzyme replacement therapy for Pompe’s disease currently in progress at Sophia Children’s Hospital in Rotterdam.

Dr. Reuser joined Professor Hans Buller, director of Sophia Children’s Hospital Rotterdam, and Dr. Ans van der Ploeg, principal investigator, who recently expressed their optimism about the progress of the trial.

Dr. Reuser concluded by “.......highlighting the role of the patients, patient organizations and charities that have kept the ‘process’ alive. Our research team…....has experienced tremendous support…....from patients…....(and) patient organizations and charities (such as), the AGSD (UK), the AMDA (USA), the Prinses Beatrix Fonds and the Sophia Foundation, in particular, .......(who) have made financial contributions to keep us going.” He closed his speech by commending the formation of the IPA.

Dr. Andrea Amalfitano, Duke University Medical Center (USA) made a presentation entitled “Therapy for GSD-II; Enzyme based therapeutics and novel gene therapy approaches.”
(see research from Duke June 25, 1999 & Aug. 3, 1999)

Dr. A.T. van der Ploeg, Sophia Children’s Hospital Rotterdam, The Netherlands, gave her presentation entitled “Enzyme therapy for Pompe’s disease” on the last day of the conference.
see Phase II Juvenile Trials Underway in Netherlands, July 4, 1999

Presentations were also made by industry representatives:

“A Transgenic Approach to Enzyme Replacement Therapy in Pompe Patients” was jointly made by A. Vos, Ph.D., Pharming/Genzyme LLC (Netherlands); J. Dalle, MSc, Pharming NV (Belgium); A. Curtis, MBA, Genzyme Corp (USA).

“The Challenges of rhGAA Manufacture ” was the title of the presentation made by Blythe Devlin,Ph.D., Synpac (N.C.) Inc.

Patient organization presentations included the following:

“Knowledge is power” and “The importance of good information,” Kevin O’Donnell, Ph.D., AGSD (UK);

“Forming a national Pompe group, our experience,” Marylyn House, AMDA (USA);

“The International Pompe Association, position, objectives, policy and activities,” Ysbrand Poortman, VSN (Netherlands); “Developments in the area of Pompe’s disease,” Haske van Veenendal, VSN (Netherlands);

“Funding treatment before the government subsidy approvals,” Robert Morrison, MDA (Australia);

“Legal procedures regarding the International Pompe Association,” Helmut Erny, SHG Glycogenose Deutschland eV(Germany)

Maryze Schoneveld van der Linde, representative of VSN, presented a moving autobiographical portrait of a Pompe patient’s endurance of this progressive debilitating disease. Maryze has struggled with the juvenile form of the disease for over 20 years. She was diagnosed with the disease at the age of 8. Her speech was entitled “From patient initiative to treatment.”

Ria Broekgaarden, VSN, and Randall House, AMDA, co-chaired the second day’s events. Thomas Schaller, SHG Glykogenose Deutschland (Germany) chaired the final day’s session.

A closed session to formulate and discuss IPA objectives was co-chaired by Randall House and Ysbrand Poortman and included only members of patient groups. Mr. House summarized the committee report at the general meeting on the final day.

By way of introduction, how about telling us a little about yourself?
I am the General Manager of the Genzyme/Pharming joint venture – the legal entity set up to develop alpha-glucosidase. I’ve been in the biotechnology industry for about 10 years managing drug development programs at a small company. Prior to that, I was on the faculty of Harvard Medical School and before that, I did post-doctoral training at the Salk Institute in San Diego.

Were you already working for Genzyme or did you join after the project started?
I was recruited specifically for this project and joined Genzyme in July of last year.

I think that many people would be interested to know what the registration process entails – what steps are required and why do we need more trials at all?
PK Approval, whether in the US or Europe or Japan (the major markets), follows a similar course. Drugs must be approved by the relevant Regulatory Authority, which dictates what is required for approval. Basically, there are two standards that must be met before marketing approval is given. A new drug must be shown to be safe and it must be shown to be effective. I think everyone’s common-sense view of safety is a fairly accurate view of what is required in the way of safety. I would add that safety is generally judged in the context of a risk to benefit decision; are the side effects acceptable given the benefit offered by a drug?

The effectiveness standard is perhaps a little more difficult to understand. A claim of effectiveness must be supported with data from clinical trials where the positive effect of drug treatment must be shown not to have occurred by mere chance, that is the positive effect must be statistically significant. Showing statistical significance requires a greater number of patients than have been treated thus far. The exact number is determined (based on mathematical principals) by size of the effect and what is being measured. For example, we know that Pompe patients become weaker over time, losing strength at some rate. More patients would be needed to show statistical significance if a drug just slows this than if a drug caused recovery of strength. This is because the difference between the untreated patient and the treated patient is greater if the drug leads to recovery; there is a greater effect. There are also many types of statistical tests that can be done, some more appropriate than others, and there is always a healthy discussion between companies and regulatory agencies about what is most appropriate given the particular circumstances.

Are the results from the completed infantile trials enough to demonstrate this?
The evidence is compelling to us, in other words we think the data is good enough that we will eventually be able to prove that the drug is effective to the satisfaction of regulatory authorities. However, the data is not yet sufficient to convince them of the drug’s effectiveness. The gold standard is that the test must be of a sufficiently large number of patients to be certain that the observed effect is due to the drug. What’s interesting here is what is ‘sufficiently large’ – it’s an ambiguous term. Genzyme is in negotiations with the Regulatory Authorities on this point. In our judgement, we will need a trial of 10-20 infants.

The case of the juvenile and adult forms is a different issue, for two reasons. First, while serious, regulatory authorities do not view these forms of the disease as immediately life threatening. Second, the presentation of the disease is more varied. That is, patients present at different ages and with different severity of symptoms. For the infantile patients, where exactly the opposite situation prevails, a trial that includes a placebo would be unethical, however this would not be the case for a juvenile/adult trial. This comparison would mean that a larger number of patients were needed. A gold standard of drug development is the use of a placebo, where appropriate, to help meet the burden of statistical significance that I discussed above.

By way of comparison, the recent trial for ERT for Fabry disease had 58 patients, 29 of whom received a placebo. It is important to note, that even though half the patients in this trial received a placebo for the duration of the trial, all patients eventually received the drug. Thus, participation in the trial allowed these patients access to the drug prior to regulatory approval even though some patients received it earlier than others.

There are several hundred patients identified, so recruiting that number shouldn’t be a problem. One objective of maintaining open communication with the patient organisations is to help make sure that we are able to identify the right patients for the trial as quickly as possible.

So in summary, the data so far is encouraging but not enough to convince the regulatory authorities. Genzyme believes in it – that’s why we’re investing money in developing the drug. As I sometimes say: it does work – it’s Genzyme’s job to prove it!

So what are the actual steps that need to be gone through?
The process is similar in the US and Europe. We have now provided very strong data that the treatment is safe, which is the principal goal of initial or first-in-man clinical studies. We are now in Phase II/III where the primary interest is in efficacy, although safety can not be ignored. We will be conducting studies over the next year. When completed, the results will be presented to the EMEA and FDA. They will then review the data. This usually takes 6-8 months but in the case of Pompe’s it could be as short as 3. The agencies will then decide whether to approve the drug. If approved, it can then be prescribed.

It is important to remember that approval is based on the clinical evidence presented and the level of comfort that the regulatory agencies have that the data is applicable to the entire patient population. Thus, our initial clinical trials will be in infantile onset disease patients. Obviously we want to make the drug available for all patients, but the initial regulatory approval may be limited to infant patients. If this is the case, then we will need to present additional data to give the regulatory agencies the evidence they need to grant approval for older patients. Of course, we are being prudent in assuming that data in juvenile/adult patients will be needed and will not wait to be asked for it before testing the drug in this group of patients.

Can patient groups play any part in expediting this process?
Pressure from patient groups can be most useful at the final stage. The agencies may convene a group of experts to evaluate the data and medical need. They often invite patients to make presentations. This is a good point for patients to apply pressure by presenting the impact of the disease on their life and family. If the data is marginal, patient testimony can make the difference. However we are not anticipating that this will be necessary for Pompe’s.

An example of this process is that the Committee for Proprietary Medicinal Products just recommended approval for our drug for Fabry disease in Europe. The EMEA will now review their decision and will hopefully approve the drug.

Another place patient groups might expedite the process is in being advocates in the legislative process. Local laws dictate the drug approval process. The Orphan Drug Act in the US and similar laws in Europe have created a process by which drugs for small and life threatening diseases, such as Pompe’s, can be developed and approved more rapidly than for traditional drugs. These laws are often developed with the assistance of patient groups.

In what way can patient groups become involved in the process earlier?
I think the most significant way will be with our patient registry, which we expect to announce this summer. This will be different from the existing identification registries, held by various laboratories and groups. The existing registries are relatively small compared to what we are planning. We have set up similar registries for Gaucher and Fabry disease. It will consist of an ongoing assessment of individual patients via their physicians. It will look at the progression of the disease and its effect on a whole range of parameters and in a very consistent way. We hope eventually to include all Pompe’s patients. Patient groups can make physicians aware of this registry and persuade them to join. It will be an open resource for the medical community. It will help us to figure out how to design future trials. We will make an announcement about the registry as soon as more information is available

Will this data be available to, for example, Novazyme?
Not directly. The data will be available to physicians involved in the registry. It will be a resource for the medical community. As with our other registries, physicians in the registry will be able to publish their research using data derived from the registry, and this will be publicly available to all interested parties. I would anticipate however, that it may be a year or more before there is enough data to warrant a scientific publication. There will, of course, be a restriction on patient identity, in order to preserve confidentiality.

Will there be any other restrictions on physicians regarding the data? Will they need to sign any sort of non-disclosure agreement?
I don’t know the details. I don’t have a direct role in setting these up.

Going back to the registration process, how long do you think it will be before submission?
We will initiate trials in infantile patients first, as this is the best opportunity to demonstrate a large and very compelling effect, as they are a very homogeneous group. Also, because more drug is needed than was anticipated a few years ago, and we need to develop production facilities for quite large amounts of drug, which takes time, starting trials in the smallest patients is most effective use of the currently limited supply. In the longer term, it is our intention to make the drug available to all patients.

Are you proceeding with getting a full-scale production plant on-line?
It would be an imprudent business decision to build a manufacturing facility prior to approval because a plant can cost several hundred million dollars and there is a risk that it might not get approved, however, we must also anticipate the time involved in getting a plant approved and merge that into our development plans. I am confident that the drug will get approved, but this is obviously not a guarantee. Our job is to balance the risks. Obviously if we don’t have sufficient manufacturing capacity in place at the time the drug is approved, we would lose sales, but if we have an over-capacity, we might be taking resources away from other important programs. Based on industry norms and our past experience, we believe that we are at an appropriate scale for the current stage of clinical development.

What effect will this have on the timescale for registration?
Surprisingly little since both the registration and manufacturing plant processes are parallel efforts with similar timescales. On the clinical side, it will take several months to enrol the patients. This is will likely take longer for infants since at the time the trial starts, the patients may not have been diagnosed…perhaps several months. Then there is the treatment period. For infants, the patients will be treated for 12 months. We don’t yet know for juveniles. Finally, several months will be needed to verify and evaluate the data and prepare the registration dossier. The industry average is about 6 months, but could be shorter here. Realistically, it will probably be 18-24 months until infantile data can be submitted, if it is sufficiently strong to support approval, although we are looking at ways to shorten even this. It may be longer for juvenile/adult patients – we don’t know how long yet.

So we should add the time taken by the regulatory authority to the two years?
That’s right. Typically, approval takes 6-12 months following submission, but for orphan drugs there are mechanisms to reduce this. I would think 6 months should be an upper limit for Pompe’s, but again, this is not entirely within our control.

Assuming the drug us then given approval, how long until it becomes generally available?
We expect to have the drug will be available for distribution the day approval is given. As a practical matter, patients would probably be treated within 2-4 weeks of approval, possibly earlier.

What about the availability of the drug prior to approval, for compassionate use?
That’s tough to answer. My personal view is that it would be hard for the regulatory authorities to deny treatment to certain groups of patients prior to approval.

What ‘certain group’ might be eligible for compassionate use?
Those in a life-threatening situation. For example, a 3 month old with cardiomyopathy – probably yes - a 40 year old with muscle weakness – probably not. However, that is my own view; every case will be evaluated on its own merit.

Compassionate use can’t be guaranteed but we’d hope to be able to obtain permission for it in at least the most serious situations. However, we do not have drug available today.

At which stage will it become possible?
It is a possibility at each stage along the way. If there is drug beyond what is needed to supply the trials, we could make a case to the regulatory authorities. It is they who decide if compassionate use is allowed. That won’t happen this year but possibly next year. However it won’t be an open door.

Is there a patient group role here?
That’s a tough one. There’s a fine line between making a case heard and just annoying the regulatory authorities. It’s important that Genzyme maintains good relations with the regulatory authorities and is not seen to be encouraging pressure since this could ultimately slow the approval process.

The further along we are, the more data we have, the easier it will be to obtain approval from them but it will be on a case-by-case basis.

Is enzyme availability a bottleneck to compassionate use?
At the moment, yes. We would like to enrol more patients now if we could. There is enough enzyme for the planned trials but supplies beyond that needed for the trials won’t be available until next year at the earliest. As you know, there have been a few problems along the way. One lot of drug had to be rejected for use in the trials, which was bad luck.

To go back to compassionate use, what would be the actual steps that a patient would need to take, if enzyme was available?
The request would need to come from the physician to Genzyme. We would then make a case to the relevant regulatory authority. However, we would first look at the likelihood of gaining permission for what would be, at that time, an unproven product. We might use an independent board of physicians to help make this determination. We would also need to make sure that there was enough enzyme to continue to supply the patient with drug. In a life-threatening situation, regulatory authorities can turn around requests quite quickly. Genzyme has a lot of experience in that kind of thing.

Are there mechanisms other than compassionate use whereby the drug could be made available?
There’s conditional approval, which was used with, for example, AIDS drugs. In that case, Approval is given on less data than would otherwise be the case. However, there is still a need to show effect on some measurable outcome for Approval. Do the benefits outweigh the risks? Is there a safety hazard? If not then there is scope for compassionate use on a case-by-case basis.

What are the steps involved in increasing enzyme production?
When you first try to make a drug like alpha-glucosidase, you might prepare it on a scale of a few mL. You might then scale the process to 500 to 1000 mL. This is a scale that is common size in a laboratory environment and gives you enough drug to do some preliminary experiments in mice. Depending on your diligence and luck it might take a few weeks to get sufficiently pure material to test in animals.

However in order to make drug for clinical trials you need to get well beyond this. The initial step in scaling to a commercial manufacturing process would require 50 or 100L tanks. This gets to be some pretty serious equipment, sort of like a beer brewery on steroids! Now you’re at the point where every aspect of the process is controlled, for example the amount of nutrients added to the vessel and the rate at which they are added. One reason for applying such control is so that you can optimise the process; your goal is to get the maximum amount of drug from the minimum amount of effort and materials…this reduces your cost. Every time you produce drug in one of these controlled vessels, you are essentially running an experiment, and of course you need to run it many times to systematically test all the parameters and make sure that your results are reproducible, that is that you have control of the process. Once you have optimised the process at one scale then you move it to the next scale and repeat the process of optimisation. However, you at least use what you learn from the smaller scale. You also have to remember that process contains multiple steps, both growing the cells and purifying the enzyme, each of which must be evaluated at each scale is not just the process of growing cells. A typical scaling process would go from tens of litres to hundreds and finally to thousands, which is the scale that Cerezyme is manufactured at.

Each time we move to the next stage in the scaling process, we need to check the product to make sure that it is the same. This is not a trivial problem. We need to make sure that the structure, activity, shelf life, and lack of contaminants, to name just a few parameters, are the same. It’s very time and labour intensive and takes several months to a year for each stage. Things don’t always work the way you want them to and occasionally you run into resource constraints that aren’t within your control, for example having an appropriately qualified batch of a particular raw materials.

Can you say what scale production is at now?
We’re about midway along the process. We have gone through several rounds of scaling. We have enough enzyme to support the trial patients for the foreseeable future, but as I said earlier, the dose is higher than we expected and this means that the drug we have can’t go to as many patients as we would like. We will scale the process for the number of patients we think we will have at launch. The 2,000 L fermenters are an important resource within the company and their usage needs to be planned years in advance. We will make a judgement as to the best use of resources.

Are you able to say what the problem was with the rejected batch of enzyme?
Not specifically. All drugs, whether experimental or commercial, need to be manufactured to pre-set specifications, or they must be rejected. We set specifications that it needed to meet and it didn’t meet one of them. The problem was unexpected, but not unknown. We have now corrected the problem. I can’t say any more than that.

What is the current state of the infantile trials?
The initial data from both the Duke and Rotterdam trials have been published. All patients continue to receive the drug. The Rotterdam patients are now aged from 2.5 to nearly 3. The Duke patients range from 1.5 to 2 years. All would have died before 1 year of age, so the trial has had a profound impact. In both trials, one child has done very well, others less so.

One reason for these differences in response to drug might be in the enzyme status of the individual patients. Infantile onset disease results from nearly complete loss of alpha-glucosidase (as opposed to juvenile and adult onset disease where there is only a partial loss of enzyme). You can get to a complete loss either by not having it produced, or by having a normal amount enzyme that is completely inactive, or by some combination of these two. Biochemically you have the same problem, an inability to clear glycogen from muscle. However, immunologically, these two states are completely different. In patients with no enzyme, the patients’ immune system recognises the drug as a foreign substance and attempts to remove it, much like our immune systems respond to the flu virus. In patients with some protein but no activity, the immune system does not see the drug as a foreign substance (since there is already some present) and therefore does not attempt to reject it. We refer to these two states as CRIM negative (no enzyme) and CRIM positive (some enzyme). The patients who did very well in both trials were CRIM positive. The patients who did more poorly were CRIM negative. In the short term, there may be a problem for treating CRIM negative infants, but we are now working on methods to prevent or overcome the antibody response. In any case, we think that only about half of infants are CRIM negative. Further, by definition, juveniles and adults are all CRIM positive, so we think that they will not attempt to reject the drug. It is worth noting that we don’t necessarily need to prove that the drug is effective in treating CRIM negative infants, although we will need to include them in clinical trials.

Are you concerned by the differences between the US and Dutch trials?
Given the differences in design and analysis, we believe that the data is equivalent. However there is not enough to convince the Regulatory Authorities.

What are the results of the juvenile trial?
Data from the ongoing treatment of juvenile patients with alpha-glucosidase at Rotterdam are encouraging. Publication of those results will be the responsibility of Dr. van der Ploeg. While I cannot reveal the results, you should take note that Genzyme and Pharming are continuing to invest considerable resources in the program. If the data were not encouraging we might not take such a step. We have every confidence that ERT will be a successful therapeutic option for Pompe’s disease.

What about the Essen trial?
That trial is not as far along. The oldest child is just over 1 year old and the data is being analysed, however it appears to be similar to the other trials. There is one other patient. It is the fact that we have seen a remarkably consistent story in three separate studies that has convinced Genzyme to continue investing heavily in the drug.

Are the Essen patients receiving the rabbit enzyme?
Yes.

Didn’t the Rotterdam trial show that antibody response had no effect on the efficacy of the enzyme?
That was the conclusion published in the Lancet article, but there is some disagreement here. The problem is that we can’t compare the data directly – antibody response was measured in a different way in each case. We are looking at designing an experiment to see if the antibody response is the same with the rabbit and CHO forms of the enzyme. It could be a moot point because we may have a lot of other data by the time that is done – however we recognise that it needs to be done.

What is the current position with the rabbit enzyme?
Genzyme/Pharming have decided to develop the CHO product, primarily on the basis of manufacturing considerations. We don’t believe that we can make enough of the rabbit enzyme – the number of rabbits needed would be enormous perhaps tens or hundreds of thousands. Choosing to go to another animal, say goats or cows, might take 6-8 years to yield an approvable drug. In the final analysis, the cost of manufacture and the time needed to develop a sufficiently large production capacity, as well as regulatory considerations lead us conclude that CHO is the way to go. The decision is made much easier by the fact that the clinical data is comparable for the two drugs.

I know that there was a lot of consternation and frustration on the part of patients who have wondered why we chose to abandon what appears to be a successful product in favour of an unproven one. I want to emphasise that our decisions were made on the basis of information that we could not reveal at the time. When the decision was made, we believed the two programs to be roughly at the same stage of development. Nothing that has happened since the decision was made changes my belief that it was the correct one. I want to assure everyone that we are committed to developing and making available to all patients as quickly as possible a treatment for Pompe’s disease.

Will the rabbit enzyme continue to be made?
It will be made for as long as necessary. New patients will receive CHO drug, and our goal is to transfer patients receiving the rabbit drug to the CHO enzyme. However, if it is not possible to transfer one or more patients for some reason, then we will continue to produce the rabbit enzyme.

So Genzyme undertake to continue to provide rabbit enzyme to a small number of patients indefinitely, if need be?
Yes. We would have an ethical duty to do so. For example, we still have a small number of Gaucher patients on Ceredase, manufactured from placentas, rather than Cerezyme, which is CHO produced. It certainly isn’t cost-effective but we think it’s the right thing to do.

What are your plans for transition?
We hope to begin transitioning patients at the end of the year, depending on the availability of the CHO enzyme. It isn’t linked to approval of the CHO enzyme.

Does Genzyme have further plans for transgenic development – perhaps through Genzyme Transgenics?
No, not at this time. I indicated previously our reasons for our decision. Despite the name, Genzyme only owns 20% of Genzyme Transgenics and so has little influence on what they develop.

In summary, are you confident that the CHO enzyme is as good as the rabbit one?
We believe that the CHO product will have the same the same therapeutic effect as the rabbit one.

What is the timetable for future trials?
The new infantile trial will start within days. There will be a public announcement within a couple of weeks. The trial will be multicentre – one US location and two in Europe.

Why are there two sites in Europe and only one in the US?
Logistical reasons. In the US it is easier to move patients around, everyone speaks the same language. For example, none of the Duke study patients are at Duke any more; they are being treated by their ‘home’ physician. That is more difficult in Europe, therefore there is more than one centre.

Are the trials only open to patients from the country concerned?
The trials are open to anyone in the world. Once patients are identified, they will be seen at the most appropriate centre.

What about the costs of participating in a trial?
We will pay for clinical trial costs. This is typical for any clinical trial. That should not be a concern for participants in any trial.

I’m also thinking of things like living expenses, airfares etc.
There are charities which can help with things like airfares. This should not be an issue that concerns participants. Without tying Genzyme in to an open-ended guarantee, I can tell you that what needs to be done, will be done.

As you know, there is an active group of patients in Australia who have put a lot of effort into making a case for that country to be a site for clinical trials. Is this a possibility?
We have made no final decisions about the location of juvenile/adult onset disease trials. There are many criteria for selecting a clinical trial location. In the end however, patients will be included in the clinical trial if they meet the inclusion criteria no matter where they live. To paraphrase a somewhat overused expression, if the trial doesn’t come to the patient, we will get the patient to the trial. No patient will be excluded for personal financial reasons.

What is the procedure for enrolling a patient in the trial?
Once a clinical trial starts, information on patients who are potentially eligible for that trail will be forwarded to one of the centers where the trial is being conducted. The principal investigator at that center will then determine whether the patient is likely to meet the inclusion criteria for the trial. The investigator will then contact the patient’s physician, if appropriate.

So it is the local centres that will make the decisions?
Yes. Genzyme facilitates this, but the decisions are local.

How about trials for late onset-disease patients?
We aim to start these early next year. We have no further information yet. We are convening experts to advise us on a protocol, which will then be reviewed by the Regulatory Agencies.

Do you envisage them including adult as well as juvenile cases?
I don’t know. The terms juvenile-onset and adult-onset are a matter of convenience, not necessarily an accurate medical distinction. As a general comment, in developing a drug a sponsor walks a fine line. The sponsor wants to conduct a trial in a sub-group with homogeneous presentation, so as to minimise the number of patients needed to show an effect of treatment, but at the same time wants to avoid getting approval only for that sub-group. The younger the patient group, the more homogeneous the disease presentation. Our goal is broad approval for all patients.

It is also possible that we might be given conditional approval for a sub-group, say adult patients. In this case, we might need to provide data beyond approval, a condition that would probably not restrict availability of the drug to patients.

Is Novazyme a threat to Genzyme?
We view Novazyme as a challenge, not a threat. If Novazyme has a better product than we do and can get it approved faster than we can then we deserve to be beaten to and in the market and patients will get the best product. We don’t intend to let this happen

Is Novazyme the reason for the delays in your product?
Novazyme’s presence in this arena really has no bearing on how we are developing our product or the timing. We believe that our strategy will lead to the development of an effective therapy for Pompe disease that can be made available to all patients. If anything, they should spur us to move faster.

Why is development of the drug taking longer than was initially said would be the case?
It’s partly because things have not gone as well as predicted at times. There have been manufacturing problems as I have said. Also, I think that there have been times in the past when some unrealistic expectations have been set; sometimes due to statements that we have made, but occasionally because we all want to believe that the end of a long research program is at hand. I’ve tried hard not to set unrealistic expectations now. Finally, I think we’ve learned a lot as we’ve advanced the program into clinical testing. While I don’t believe that anyone’s faith has been shaken in the value of ERT for Pompe, it is clear that it’s a little more difficult that we first thought.

To get back to Novazyme, will you do a Synpac-like deal with then?
Even if I knew the answer to the question, I couldn’t tell you.

Dr. Amalfatano was the first author on the paper describing the results of the CHO clinical trial. Does this mean that he has been taken off the gene therapy program?
Dr. Amalfatano continues to work on gene therapy for Pompe disease in addition to his involvement in the ERT trial. As with many other medical center based physicians, Dr. Amalfatano has both patient care duties and the responsibility for running a research laboratory.

What is the status of the gene therapy program?
Gene therapy as a disease treatment for all diseases has proven to be far more difficult than was first envisioned. It is interesting that for the past 15 years, a gene-based disease therapy has always been about 5 years distant. The problems that all gene-therapists have had to overcome include maintaining expression of the gene at therapeutic levels for an extended time and preventing an immune response to the gene delivery system. Unfortunately, these problems remain, not just for Pompe, but for all gene-therapy based approaches to disease management.

Once these problems are worked out in the laboratory, any gene-based therapy will require clinical trials that will take an additional 3-5 years to complete. I have no doubt that gene therapy/gene repair will eventually find its way to the treatment of chronic diseases, but it would be shear speculation to say when and for what diseases.

How do you view your relationship with the patient organisations?
Beginning last fall, I started to have a monthly teleconference with the IPA. I believe that is a useful mechanism for updating the patient community with the latest news. I believe that a version of minutes from these meetings will be made generally available through GSDNet. In addition, I hope to meet members of the various patient organizations from time to time to talk about the program

We see the IPA, and by extension, the member organizations, as forum for communicating with patients, finding out about the needs and concerns of patients, and assisting in recruitment of patients into clinical trials. If we are successful in our goal of developing a therapy for Pompe disease, then the importance of this forum will increase both for patients and the companies.

How many people at Genzyme are involved in this project?
I could tell you how many people at Genzyme are involved in this project, but it would have little meaning since it has no context. Frankly, the number changes from week to week as different events occur. The short answer is that this program has the highest priority at Genzyme and we have enough people working on this to ensure it’s timely success. Having fewer would limit our progress, having more would be superfluous.

Who are the key players in this project?
Within Genzyme, I serve as the focal point for all Pompe related activities at the company. I have a dual role, that of general manager of the Genzyme/Pharming Joint Venture and that of program advocate within Genzyme. In the former capacity, I coordinate all activities of the program, both internal and external, to make sure that the program is driving forward. In the latter capacity, I work with other program managers to make sure that sufficient resources are available for all programs in a timely manner. Other people that you have met in recent months, Jan van Heek Gene Williams, and Tanja Braakman, for example participate in the program as their expertise is needed, some much more frequently than others.

As far as far as outsiders are concerned, we continue to work with Drs. Reuser, Chen, and van der Ploeg. Clearly these physician/scientists are the thought leaders in the Pompe field; they have had the most patient experience and have amassed a considerable amount of background data on the disease that is useful in designing clinical studies that will lead to product approval.

In addition, we work with other physicians and scientists, either regularly or intermittently, as we need their expertise to drive the program forward. Some of these people serve as clinical consultants, others, such as Dr. Amalfatano, conduct basic research.

Finally, as I mentioned, we are planning to initiate an international registry of Pompe patients. The purpose of the registry is to gather data on the natural course of Pompe disease by looking at all Pompe patients. This is a significant advance over existing registries that are more geographically restricted. Moreover, the registry will gather data in a standardized way for a very large number of patients, which is in contrast to the medical literature, where each published study looks at a small number of patients in a different way.

A number of well known physicians who treat patients with Pompe disease will be involved in entering medical and quality of life data on individual patients (confidentially of course) on a regular basis. These physicians will then be in a position to conduct epidemiological research on the data. We expect that this patient registry will serve as resource to physicians and scientists who will seek to improve the effectiveness of ERT as well as develop second and future generation therapies for Pompe disease.

I’d like to close by recording my thanks to you for making time in your busy schedule for this interview and for your full and open answers. I am sure the patient community will read it with great interest.

And AMDA wants to thank Kevin O’Donnell for giving his time and energy once again to promote the Pompe cause. Thank you Kevin!

What makes Novazyme different?
The people, culture and philosophy. We are a science-driven, patient-focused organization. The patient is at the center of everything we do.

We’re a glycobiology company. We manipulate carbohydrate structures - for example the sugar chains on enzymes, which can be 50% of the volume of the active enzyme. In order to treat lysosomal storage diseases (LSDs), we need to be able to mimic the carbohydrate structure of the natural enzyme.

Novazyme’s expertise in this area stems from over 8 years of research by Dr. William Canfield at the University of Oklahoma.

The carbohydrate chains on lysosomal enzymes target the enzymes to the cells that need it most (heart and muscle). Phosphorylating those carbohydrates is the signal that tells the cell to transport the enzyme inside the lysosomes.

CHO (Chinese hamster ovary) cells, commonly used in cell culture, have a tendency to modify carbohydrate chains in a way that significantly reduces the efficacy of the finished enzyme. They tend to add complex carbohydrate chains rather than the mannose-6-phosphate residues needed as markers for the lysosomes.

Novazyme is modifies the CHO product to make it more natural.

How important is this tendency of CHO cells to add complex carbohydrates? Hasn’t the CHO product used in the Duke trial worked well?
The standard in-vitro assay used to measure enzyme uptake may give an exaggerated figure - because it doesn’t account for the way the liver can soak up that enzyme when it is introduced to the body. Based on a comparable enzyme we have produced, we estimate that less than 1% of the enzyme used in the Duke trial is phosphoryated.

What’s the evidence for the efficacy of the Novazyme product?
Animal studies carried out at Oklahoma and by Dr. Barry Byrne at the University of Florida indicate that normal enzyme activity could be restored to one year-old Pompe’s mice with just one injection of our enzyme. It also clears massive amounts of glycogen from the muscle cells after just 6 hours. This is a finding that we have repeated several times.

The high activity of the enzyme means that we may be able to achieve the above result with a lower dose of enzyme than with either the CHO or transgenic products. Our dosage in mice was 0.3mg/kg. The equivalent for the Duke CHO enzyme is 10 mg/kg and for the transgenic enzyme 40 mg/kg.

Once enzyme activity is replaced, glycogen is cleared from the muscles and muscle strength is restored. We have measured muscle strength by an electrical method that allows us to compare the strength of treated and untreated muscle in mice.

This last finding is very important because it suggests that muscles may recover after the glycogen is cleared. The big question now is, can this be replicated in humans?

What are your plans for clinical trials?
We intend to start a clinical trial towards the end of 2001. It will involve affected children and take place at three different centers in the USA Florida, NIH Bethesda, Philadelphia). The trial will be designed so that we can rapidly expand to international centers and to pivotal Phase III as soon as possible.

How many children will you be including and what will be the criteria for inclusion?
The trial will include 12-18 children. Our approach to inclusion will be different to that taken in other trials. We will take profoundly ill children and attempt to make them better.

Just to be clear, by ‘profoundly ill’ do you mean children who are already showing symptoms of Pompe’s and who may be, for example, ventilator dependent?
The two things we want our trials to do are to contribute to science and to help patients. We will therefore be looking at patients with symptoms and will not be excluding children on ventilators. We will be looking for children who have the cardinal manifestations of the disease - cardiac dysfunction (which we believe is in all types, not just the infantile, though not in the form of cardiomyopathy), pulmonary involvement and musculo-skeletal disorder. It doesn’t matter which age the children are, as long as they meet the criteria. However, we don’t know what the exact criteria will be until we meet with the FDA.

Will the trial be restricted to children in the USA?
The trial will be open to all children who meet the trial criteria, anywhere in the world. We believe that costs should not be something that families should have to worry about, so we will meet all traveling and accommodation expenses, and also compensate for loss of earnings.

Will any of the children on the trial be given a placebo?
No. We are looking for a striking improvement that will demonstrate the efficacy of the treatment. We are looking to reverse the disorder, not just halt decline. We believe that we understand enough about the disease to be able to show change without comparison to a placebo. We also think that it would be unethical to bring children into the trial - perhaps involving a great deal of domestic upheaval - and give them a placebo.

So what are the next steps after that initial trial - will you be extending to other sub-types?
We don’t believe that there are sub-classes of Pompe’s - what we have is a continuum. However patients can be grouped into distinct populations and we will hold pivotal phase III trials aimed at those populations. We are currently in discussion with the regulatory agencies to that effect.

The big distinction is between CRIM (cross-reactive immunological material) -ve individuals and CRIM +ves. All those with the classical infantile form are CRIM -ve, meaning that they may produce antibodies against alpha-glucosidase. It is possible that the lower dosages needed with our enzyme may help reduce this problem.

The target for the start of wider trials is mid 2002. Our intention is to run different trials in parallel. We are looking worldwide for trial sites, including Australia and Europe.

What is the bottleneck for progress?
We need commercial grade material for phase III and we are looking at options for this. We may decide to manufacture in-house. All of these things are progressing in parallel - we are not waiting for the results of Phase I/II before making progress with Phase III.

When do you think you will be able to complete the registration process?
The best case for approval is mid-2003. This is a challenging target. However building a company from scratch in a year was equally challenging - and we did it!

What about pricing? The high cost of ERT is a concern for many people.
Our philosophy on pricing is that the patient is at the center. The cost will reflect the burden of the disease. We recognize that this is a life-saving technology and our intention is that it will be fairly priced relative to other products in this area. This will be partly due to the low dosages required.

Our philosophy is that no patient should be deprived of this drug because they can’t afford it.

What about the developing world?
We will look at ways of tackling the problem of provision in the developing world. To be honest, we would love to have that problem. Our core philosophy of providing the best drug to as many patients as quickly as possible applies with equal vigor to all patients, regardless of geography.

We are determined to retain our patient focus, despite the competing pressures of Wall Street, the regulatory authorities etc. That is why we have appointed Julie Anne Smith as Senior Director with responsibility for Patient Advocacy.

What is your attitude to the patient groups?
Our philosophy is to be open and honest and to build a partnership. We have already spoken directly to over 100 patients. If there is any change in the timetable we’ve outlined in this interview, you’ll hear it first from us.

Our focus is that it will be great to treat 12-18 kids - but what we need to do is to treat 12-18 hundred kids.

How independent is Novazyme? Is there any chance that you will ‘do a Synpac’?
We will do whatever gets our treatment to as many patients as possible, as fast as possible. At the moment, we’ve considered whether that could best be done as part of a collaboration and have come to the view that, in fact, the best way is to be independent. However, that decision is constantly being re-evaluated against our patient-centered philosophy.

Although 95% of our efforts are currently directed at Pompe’s, we have plans for other products. We are also developing treatments for other LSDs - MSP I, Gaucher, and Fabry disease.

Gaucher disease? You’re really planning to compete with Genzyme’s big product?
The decision isn’t driven by a desire to go head to head with Genzyme. We believe that we have a product which will be an improvement on Cerezyme (the Genzyme ERT for Gaucher) and which may help patients with difficulties that product does not help.

What’s your biggest problem at present?
Our biggest challenge is putting all the parallel strands together and holding them together. Four months ago we didn’t have a manufacturing plant. Now we have a state of the art plant, operators, a GMP (good manufacturing practice) team etc.

We believe that we may well have the “Holy Grail” necessary to effectively treat this horrid disease. We believe that we can beat Nature. But now we have to deliver it to patients. We are a 80-person company going at 100 miles per hour, trying to satisfy our Directors, Wall Street, the regulators - while all the time keeping our patient focus.

What effect does John Crowley’s background have on the company?
John Crowley’s background undoubtedly helps in retaining and strengthening focus. We want to help not just Megan and Patrick but the thousands of children like them.

We have a regular ‘Lunch and Learn’ feature where we bring in patients to talk to the staff here about their experience of Pompe’s and that also helps to retain the patient focus.

For the record though, Megan and Patrick Crowley will not necessarily take part in the first clinical trial. John Crowley is standing aside from that process.

That means that we are not letting up from our drive to make the enzyme as widely available as possible, as quickly as possible. We will be looking to set up an expanded access program [AKA compassionate use - KO’D] as early as possible in the trials. Participants would need to follow the established treatment protocol and their data could therefore contribute to the approval process.

Thank you for the open way you have approached these discussions and for the time you have devoted to them. We look forward to working with you in the future.

And AMDA wants to thank Kevin O’Donnell for giving his time and energy once again to promote the Pompe cause. Thank you Kevin!

Link to the article

Genzyme Corp. and privately held Novazyme Pharmaceuticals Inc. today announced a definitive merger agreement under which Novazyme will be acquired by Genzyme and operate as part of Genzyme General . Genzyme expects that the acquisition will significantly advance its leadership position in the development of enzyme replacement therapies for lysosomal storage disorders, a group of genetic diseases caused by the absence of certain cellular enzymes.

Novazyme has developed a series of novel protein engineering technologies that have been shown in pre-clinical studies to greatly enhance the targeting and uptake of replacement enzymes. Genzyme believes that these technologies could potentially lead to improved, second-generation versions of its marketed products and optimal first-generation products for the treatment of various lysosomal storage disorders. Novazyme’s technologies may also have application for developing advanced monoclonal antibodies and gene therapies.

The most advanced of Novazyme’s product candidates is NZ-1001, an enzyme replacement therapy for Pompe disease that is on track to enter clinical trials by the end of 2001. The product—a highly phosphorylated and properly glycosylated form of recombinant human alpha-Glucosidase—has demonstrated encouraging results in pre-clinical studies. Genzyme will move forward aggressively with the development of NZ-1001, while it simultaneously completes the ongoing Phase 2 clinical trial of its own enzyme replacement therapy for Pompe disease, being developed in collaboration with Pharming Group N.V.

Novazyme has a strong proprietary position covering its products and technologies, with patents pending in the United States and worldwide.

“The acquisition of Novazyme is consistent with our commitment to develop the best possible products for patients,” said Henri A. Termeer, chairman and chief executive officer of Genzyme. “Novazyme has created a promising protein technology platform that complements our own and that could have a profound impact on our efforts to develop improved therapies for patients with lysosomal storage disorders.”

John F. Crowley, president and chief executive officer of Novazyme, said: “Novazyme and Genzyme have a shared vision of bringing the very best medicine to very sick patients as quickly as possible. Genzyme’s infrastructure, resources, and extensive experience in the area of genetic disorders can powerfully support and accelerate the development of our technology and products. This merger is an important event for patients, provides an excellent return for our shareholders, and further advances our mission.”

Terms of the Agreement

Under terms of the agreement, Genzyme will acquire Novazyme for $137.5 million, payable in shares of Genzyme General stock. Novazyme shareholders are also eligible to receive two subsequent payments totaling $87.5 million, payable in stock, contingent on U.S. marketing approval for the first two products employing certain of Novazyme’s technologies.

The boards of directors of Genzyme Corp. and Novazyme have approved the transaction, which is subject to customary closing conditions. The transaction is expected to close in the third quarter.

The acquisition of Novazyme will be accounted for as a purchase transaction and may result in a one-time charge for in-process research and development. Genzyme General expects the transaction to have an impact of approximately $.03 (excluding amortization) on its earnings-per-share for 2001, reflecting the issuance of approximately 2.5 million new shares at closing and an expected increase in research and development spending of approximately $7 million. Genzyme now anticipates earnings in the range of $1.12 - $1.17 per share for the year, compared to previous guidance of $1.15 - $1.20 per share. The total number of Genzyme General shares outstanding is expected to increase to approximately 211 million by the end of this year.

Novazyme’s laboratories, offices and manufacturing facility will remain in operation following the completion of the merger. John Crowley, Novazyme’s president and chief executive officer, has agreed to serve as a senior vice president of Genzyme Therapeutics and will assume overall responsibility for the company’s Pompe disease programs. He will continue to serve as president of Novazyme, a wholly owned subsidiary of Genzyme. William Canfield, M.D., Ph.D., Novazyme’s founder, chairman and chief scientific officer, has accepted the position of senior vice president for glycobiology and will continue to lead a first-class team of approximately 70 scientists located at Novazyme’s Oklahoma City facilities, which will serve as a glycobiology center of excellence for Genzyme.

In addition to its pipeline and proprietary technology platform, Novazyme has assets that include important intellectual property; approximately $5 million in cash; laboratory facilities; and a 3,000-square-foot cGMP manufacturing plant.

Protein Remodeling and Lysosomal Storage Disorders

Lysosomal storage disorders are caused by a deficiency of one or more enzymes responsible for the breakdown of lipids or other molecules in the cells. Molecules that are normally broken down into smaller building blocks instead accumulate inside a compartment of the cell called the lysosome, affecting the cell’s overall functioning. Novazyme’s products in development are based on the company’s proprietary technologies for the targeted delivery of the missing enzymes critical for the treatment of lysosomal storage disorders.

Under the direction of Dr. Canfield, one of the world’s leading glycobiologists, Novazyme has developed methods for modifying recombinantly produced enzymes to enhance their uptake by the body. The ability to target lysosomal enzymes to affected cells is enhanced by a carbohydrate structure with two or more phosphates attached to each enzyme. Addition of these phosphates enables the lysosomal enzyme to interact efficiently with receptors on cells that target them to the lysosome. Since this receptor is present on most human cells, this modification should enable the enzymes to enter cells throughout a patient’s body.

By increasing the phosphorylation of lysosomal enzymes and allowing them to be taken up more efficiently by the cells, these technologies could potentially lead to products with dramatic advantages over first-generation therapies in development.

Genzyme was the first to successfully employ protein remodeling technology in the 1980s when it used a different process to produce Ceredase® (alglucerase) and Cerezyme® (imiglucerase for injection) for Type 1 Gaucher disease. The products are, respectively, natural and recombinant forms of glucocerebrosidase for which the glycosylation of the enzyme has been modified so that it is mannose terminated and therefore more easily recognized and taken up by the macrophage cells that accumulate lipids. Applying Novazyme’s technology to create highly phosphorylated glucocerebrosidase, could represent a next-generation version of Cerezyme.

Genzyme General develops and markets therapeutic products and diagnostic products and services. Genzyme General has five therapeutic products on the market and a strong pipeline of products in development focused on the treatment of genetic disorders and other chronic debilitating diseases with well-defined patient populations. Genzyme General is a division of the biotechnology company Genzyme Corporation.

Novazyme is a pharmaceutical company developing biotherapies for the treatment of lysosomal storage disorders. These biotherapies are based on Novazyme’s proprietary technologies for the targeted delivery of the missing enzymes critical for the treatment of these diseases. The technologies were developed by William M. Canfield, M.D., Ph.D., in his laboratories at the University of Oklahoma Health Sciences Center. Dr. Canfield, formerly an associate professor of medicine at the university, founded Novazyme in 1999. Dr. Canfield currently serves as the company’s chairman and chief scientific officer. Novazyme’s headquarters are located in Oklahoma City, Oklahoma and its business and executive offices are located in Princeton, NJ….......

In the near term, the acquisition of the Geel facility is intended to allow Genzyme to assume control over the production of the transgenic enzyme and secure its supply to nine patients with Pompe disease participating in the extension of a clinical trial. Genzyme has been solely funding the production of the enzyme since Pharming Group sought receivership.

In the longer term, this acquisition will broaden Genzyme’s worldwide manufacturing infrastructure by providing the company with a biopharmaceutical production facility located in continental Europe. Genzyme is in the midst of a comprehensive program to substantially expand manufacturing capacity to support the strong growth of existing products and the launch of products within its development pipeline. The company plans to significantly expand protein production capacity in Geel and begin full manufacturing operations there in 2003. As a result, Genzyme has suspended plans to construct a recombinant protein production facility adjacent to its Framingham, Massachusetts, campus. Genzyme intends to retain all of the full-time employees of Pharming N.V.

“We believe this is a positive resolution to what has been a difficult situation,” said Jan van Heek, executive vice president of Genzyme Corp. “Most importantly, this acquisition helps ensure that patients will continue to receive the transgenic product. At the same time, it will allow us to establish a new protein manufacturing facility much sooner than we had planned. We are eager to begin integrating the Geel facility with our existing and planned operations.”

Genzyme Corporation is a biotechnology company that develops and markets products and services designed to address unmet medical needs.

This press release contains forward-looking statements, including statements about: the anticipated benefits of the acquisition of the Geel facility; expectations concerning Genzyme’s ability to produce transgenic enzyme; plans for the Geel facility and the employees; and product development plans. Actual results may materially differ due to numerous factors, including without limitation: the content and timing of filings with and decisions by courts and other authorities; access to materials supplied by third parties; the results of feasibility studies, product development efforts and clinical studies; the ability to manufacture sufficient quantities of product in a timely manner; and the risks and uncertainties described in reports filed by Genzyme Corporation with the Securities and Exchange Commission under the Securities Exchange Act of 1934, as amended, including without limitation Exhibit 99.2 to Genzyme’s 2000 Annual Report on Form 10-K, as amended.

Genzyme® is a registered trademark of Genzyme Corporation. All rights reserved.

1. Finalize the universal patient questionnaire to be distributed in the near future by the IPA to all member organizations throughout the world.

This questionnaire is a long-time endeavor by leading researchers in the Pompe field. It will serve a two-fold purpose:

A. To identify and classify Pompe patients worldwide
B. To serve as an independent patient database

This database will safeguard patient confidentiality, but will also allow accessibility to data by corporations, physicians, and medical facilities working towards treatments for Pompe’s disease.

2. Compassionate (or humanitarian) use will be discussed. The objective is to set up criteria for making enzyme replacement therapy available to patients before market approval is obtained.

Availability of enzyme is the critical issue in this agenda—how to make the currently produced enzymes available to more patients in the shortest possible time. This matter (expanded production) will be a major point of discussion with Genzyme representatives at this meeting.

3. Current results from the ongoing clinical trials (CHO and transgenic) and the current timetable for initiation of new CHO trials will be discussed.

4. Collaboration between IPA and Genzyme to release research and development information on a quarterly basis to patient organizations.

5. Expense of enzyme replacement therapy (when marketed) will be discussed—how to insure that the cost will not prohibit any patient from receiving treatment.

Be assured that patient organizations through the IPA are working with Genzyme as well as with Pompe researchers to continue to push for safe, effective, and timely treatment for all patients with Pompe’s disease.

Best Regards,
Randall House
President, IPA

1. Communications—Kevin O’Donnell, Alan Muir, Marylyn House
 
2. Patient Organizations—Maryze Schoneveld, Marylyn House
 
3. Legal Issues—Helmut Erny, Ria Broekgaarden
 
4. Financial Budget and Sponsoring—Randall House, Helmut Erny
 
5. Scientific/Industrial Contacts—Randall House, Bob Morrison, Ria Broekgaarden

Issues discussed were:

1. Expansion of the existing trials
2. New trials
3. Product supply
4. Compassionate/humanitarian use
 
5. Product registration
 
6. Reimbursement

Timetable of future events. Genzyme has agreed to supply IPA with a detailed progress report on a quarterly basis.

IPA Patient Questionnaire*:

The IPA patient questionnaire will be ready for distribution to the member organizations by the end of the month. Accurate translation of the questionnaire and how to safeguard patient confidentiality was discussed. The first versions for distribution to patients will be available in English and Dutch.

*The purpose of the questionnaire is to gather data in order to classify patients by onset, symptoms, muscle strength, respiratory functions, family history, progression of the disease, mutation, etc. Patient confidentiality will be maintained by a coding system which will allow the IPA to provide equal access of statistical data to researchers, medical institutions, and corporations involved in Pompe research and treatment.

The information on the questionnaire will help researchers learn more about the progression of the disease in order to “fit” patients into categories based on similarities. This will help researchers determine the “path” of illness and the progression of the disease and thereby maximize the efficiency of ERT and future treatments. Participation or non-participation in the questionnaire study will in no way influence a patients participation in clinical trials for Pompe’s disease.

The questionnaire was developed mainly through the endeavors of Dr. C. Loosen, M.D., Ph.D., Rotterdam, The Netherlands. Dr. Loonen, a pediatric neurologist, is an expert in the field. She has been involved in Pompe research for over 30 years and has published numerous articles on the disease.

 

Following is a summary of the meeting—February 18-19, 2002
by Alan Muir (ASGD-UK):

The IPA (International Pompe Association) meeting of February 18-19, 2002, was chaired by Randall House (AMDA-US). Those present were: Allan Muir (AGSD-UK), Ria Broekgaarden (VSN), Maryze Schoneveld (VSN), Anton Hammink (VSN), Helmut Erny (SHG Glydogenose Deutschland e.V.). The secretary was Paula Waddell, (VSN). Bob Morrison (AMDA-Australia) joined the meeting via telephone hook-up.

The main points of the two days were as follows:

1. The IPA (International Pompe Association) constitution was agreed to by those present. Board members were nominated and executive positions filled. Ria Broekgaarden will organize the signing of the constitution and other managerial matters.
2. The IPA (International Pompe Association) membership now extends to 27 countries headed by interested groups/persons who represent some 680 Pompe’s patients worldwide.
3. The questionnaire, to be used for compiling the Pompe’s Registry, has been completed and agreed to by professionals, expert in the Pompe field. It now needs to be translated into the appropriate languages before being issued to the support groups for distribution to patients.

During the evening of the 18th, Dr. Ans van der Ploeg and Dr. Arnold Reuser were invited to talk about the on-going clinical trials, and Dr. Patrick Cabri, Genzyme Europe, gave a presentation on the ERT registration process in Europe.

Dr. van der Ploeg had little additional news from the current trials in Rotterdam. She did, however, say that ERT should not be considered alone in the treatment of Pompe’s. For good recovery, it must be part of a good rehabilitation program including physiotherapy and other practical training. She added that keeping as healthy as possible prior to ERT is also important; the therapy is most effective with those patients least affected.

Dr. Cabri, Genzyme-Europe, provided the following information:

1. Dr. Cabri described the procedure for achieving drug approval in Europe by the EMEA, the European Agency for the Approval of Medicinal Products. A dossier is currently being compiled from all the research and trials and will (soon?) be submitted. Approval will take at least 12 months. The dossier will be presented for scientific scrutiny to 15 countries. After approval through EMEA, Genzyme must seek national approval (in Europe). This can take 1 to 24 months. It is important that the national government offices be aware of the drug before its submission to save valuable time.
 
2. Compassionate use was discussed, and Dr. Cabri stated that once ERT is licensed (this is prior to universal marketing of the drug) for use in a country, it will be up to a patient’s physician to apply for the drug on compassionate grounds. However the acceptance criteria is likely to be quite harsh (e.g. must be life-threatening situation). Genzyme is currently working on a development plan - which includes proposals for compassionate use. An announcement on this is expected ‘soon’.
   
3. Approval by the US-FDA was also brought up. Basically the same timetable should apply for the approval process in the US. Genzyme is working towards approval in the US and Europe simultaneously.
   
4. Availability of the ERT is likely to be another issue as there is currently a worldwide shortage of fermenters. Production facilities in the US have room for expansion, but many other orphan drugs in development will be competing for their use—short term (next 5 years). This is a real problem, but it is being aggressively addressed by Genzyme.

Dear Friends,

On Saturday, March 9th, 2002, I will be speaking at the VSN (The Dutch Muscular Dystrophy Association, Vereniging Spierziekten Nederland) Annual Patient Conference in The Netherlands. At the conference I will provide a general overview of Genzyme, focusing on our plans to move forward with the development of ERT (Enzyme Replacement Therapy) for Pompe disease. In an effort to keep you informed I would like to share with you some of the highlights of my presentation.

First, thank you for your patience over the last six months as we have made dramatic and significant advancements in the Pompe development program. Genzyme has fundamentally reorganized the structure, organization and leadership of Genzyme’s global Pompe efforts. Twelve key members from the executive teams of Genzyme and Novazyme (a fully owned subsidiary of Genzyme as of 11/15/01) have formed the PLT (Pompe Leadership Team), chaired by John Crowley. We have engaged the best and the brightest individuals in the PLT to move this program forward as quickly as possible. The PLT sets the strategic direction and is responsible for making operational decisions with respect to all aspects of the Pompe program, including: pre-clinical, manufacturing, clinical, regulatory, and business, along with input from Genzyme’s senior executives.

We truly believe that 2002 will finally mark the year of change for the future of Pompe patients worldwide.

In the past, one of the vexing problems has been limited supply of the protein for ERT. We have made significant improvements in both the quantity and quality of enzyme production over the past months. We have transitioned all enzyme production into Genzyme’s own manufacturing facilities and have much more control over enzyme quality, consistency and quantity. We are confident that our manufacturing process changes will ensure adequate product supply in the future.

We will soon be meeting with the regulatory authorities to discuss specific details of the next clinical studies of our CHO cell line product in different patient groups. The specific numbers of patients and inclusion criteria have not yet been presented to the regulatory authorities and therefore, are not yet finalized. Presently, we plan that this will be a multi-center, international trial, with sites in both Europe and the United States.

We will disclose more details about the inclusion criteria, specific timeline and overall design of the trial when we receive approval from the regulatory authorities. We anticipate enrolling patients into the new trials as soon as we conclude our discussions with the regulatory authorities.

Please note that the safety and efficacy of our CHO cell line ERT for Pompe disease has not yet been established in large clinical studies. As part of this aggressive development plan we plan to accumulate a strong package of pre-clinical and clinical evidence to present to the regulatory authorities in the future.

In closing, I would like to emphasize that our goal is to have both an approved and reimbursed product available to all patients around the world. To achieve this task we need to work together to generate a greater awareness about the life-threatening affects of Pompe disease.

Many patients ask what they can do to help. My response is to ask you to work within your local areas to generate public interest stories focused on Pompe. The more we can raise awareness and recognition of Pompe disease. There is still much work to be done, but by working together we can ensure that the future for individuals and families affected by Pompe will be bright.

At this time I respectfully ask for your continued patience for several more weeks until our discussions with the regulatory authorities are concluded. At that time we will share with you the approved clinical path forward for 2002. In the meantime please direct any questions you may have to Sara Den Besten, Senior Manager of Patient Advocacy (email: sdenbesten@novazyme.com - phone: (609) 683 – 4400 x119).

Sincerely,

Jan van Heek
Executive Vice President, Therapeutics and Genetics
Genzyme Corporation

(Released March 5, 2002)

Mr. van Heek was unable to attend the VSN Conference on March 9, 2002, as initially planned. Philippe van Holle and Dr. Cabri addressed the group in his absence.

To accelerate the progression to regulatory approval for multiple Pompe disease indications, Genzyme recently conducted a comprehensive, blinded pre-clinical analysis comparing all four Pompe enzymes. The analysis showed that Genzyme’s internally developed CHO product, when compared with the Synpac enzyme, provided a similarly robust response profile in terms of glycogen clearance. Due to the significantly greater production yields of the Genzyme CHO enzyme, it offers the clearest and most efficient pathway to commercialization based on both clinical and manufacturing considerations. Genzyme expects to meet soon with U.S. and European regulatory authorities to outline a plan for the clinical development of this product, and it expects to initiate trials in infantile and delayed-onset Pompe patients in the second half of this year. Genzyme plans to initiate pivotal trials for this product by the end of the year.

John Crowley, senior vice president of Genzyme Therapeutics and general manager of Genzyme’s Pompe programs, said: “The robust response associated with CHO enzyme therapy we’ve seen in clinical trials to date has been encouraging. This shift to the internal Genzyme CHO product will help ensure timely availability of significant drug supply for clinical and commercial use. Importantly, by producing this product entirely at our own facilities, Genzyme will be able to leverage its expertise in large scale manufacturing
of enzyme replacement therapies.”

As a result of this decision, Genzyme will not proceed with further clinical development of the CHO therapy licensed from Synpac. Genzyme will continue to supply product to patients participating in the extensions of clinical trials of this product, as it has with patients receiving the transgenic enzyme, until they can be transitioned to the Genzyme CHO product. Genzyme will proceed with the pre-clinical development of Novazyme’s NZ-1001 as a potential next-generation therapy for Pompe disease. Novazyme’s novel carbohydrate engineering technologies-intended to enhance the targeting and uptake of replacement enzymes-will continue to serve as a central part of Genzyme’s efforts to develop improved second-generation versions of its marketed products and optimal products for the treatment of other lysosomal storage disorders.

Link to complete press release

Genzyme representatives included Jan van Heek, Executive Vice President; John Crowley, Senior Vice President of Therapeutics and General Manager of the Pompe Program; and numerous senior executives involved in pre-clinical, clinical, manufacturing, science, operations, product development, and patient advocacy.

We were extremely pleased with the extent of the information shared and with Genzyme’s candor in the dialogue that transpired.  Although the bulk of the information shared was highly confidential, we think it is important to provide you with a summary of what we have learned.

The following information was presented at the meeting:

Over the last 6 months, Genzyme has conducted comprehensive, blinded studies both in-house and in collaboration with independent investigators.  All four of the existing Pompe enzymes were placed into a comparative study.  The study included: the transgenic enzyme developed in joint venture with the Pharming Group N.V., which began in 1998; the CHO enzyme licensed from Synpac in 2000; the enzyme obtained in the Novazyme acquisition in 2001; and the internally produced CHO enzyme, that Genzyme began developing last year.

Each enzyme was analyzed and compared. Data derived from these studies showed that the highest degree of glycogen clearance in the muscle cells was achieved with the CHO enzyme. This was substantiated at various dosages. Results were extremely comparable between the original CHO enzyme, licensed from Synpac, and the new CHO enzyme, produced in-house by Genzyme. Results showed that in glycogen clearance, there was a very similar, robust response between the two products.

In addition, the data suggests that there is a high correlation between reduction in glycogen content and response to the introduction of ERT. The data derived from these studies will further support the filings with the regulatory authorities and continue to build upon what is already understood about Pompe and the potential benefits of ERT.

The results in the comparative studies have also supported Genzyme’s decision to shift further development from the Synpac CHO product to its own internally produced CHO derived enzyme. This step will allow Genzyme not only to gain better control of production but is also expected to yield more mature enzyme in a shorter period of time.  Shifting to the Genzyme produced CHO should ultimately lead to an increased supply of the drug, thus pursing best path forward for clinical and commercial use.

Genzyme’s development of the Novazyme NZ-1001 product, as a potential next-generation therapy for Pompe’s disease, is proceeding and continues to be in pre-clinical development.  It is intended that Novazyme’s science, which focuses on targeting and uptake of enzyme, will continue to serve as a central component in the efforts to develop improved second-generation versions of the Pompe ERT, improve upon some of their current marketed products, as well as help to develop new therapies for the treatment of additional lysosomal storage disorders.

To date Genzyme has been able to produce only enough enzyme for those patients participating in the current clinical studies.  Genzyme’s Vice President of Manufacturing presented the plan for up-scaling the production of enzyme to provide enough product to support additional clinical studies and to work toward the goal of an expanded access program for patients severely affected and who do not meet future trial criteria.

To date enzyme has been produced in several 90-liter bioreactors and is currently being up-scaled into 160 liter bioreactors.  Genzyme has purchased a 2000-liter bioreactor (in excess of $5 million-US) which should be online by the end of the year.  In 2003 they will have a second 2000-liter bioreactor producing enzyme.  It is important to point out that each time production is up-scaled into a larger bioreactor, Genzyme must demonstrate to the regulating authorities that the new process does not change the make-up of the enzyme; thus, increasing supply is a timely process.

Genzyme will continue to supply the Synpac CHO product to patients participating in the extension of clinical trials of this product as it has done with patients receiving the transgenic enzyme. Eventually, all study participants will be transitioned to the Genzyme produced CHO enzyme.  This will occur only after additional laboratory testing is done to determine safety and equivalency of dosage, and after in-depth discussions with each patient’s physicians has been completed.

Genzyme also presented their clinical trial plan, designed to be the swiftest path forward to obtaining approval and bringing treatment to patients worldwide. The initiation of clinical trials will depend on the success of their production efforts and on the approval by the regulating authorities. They are anticipating the launch of several overlapping trials in the second half of 2002.

They are planning on conducting extended and pivotal infantile trials, as well as trials including delayed onset patients (patients not diagnosed with the classical infantile form of Pompe). If approved, the future trials will be utilizing the Genzyme internal CHO enzyme. They are planning for the studies to be conducted in several centers between the US and Europe.  The inclusion criteria has not yet been finalized, and will not be considered finalized – and therefore made public - until regulatory approval to begin enrollment has been granted.  This is because, that until approval is granted to begin enrollment, every detail regarding their plan is up for discussion and could possibly need to be altered to comply with regulatory concern.

At the conclusion of these meetings, all of us in attendance felt that there had been much accomplished in the last several months.  We also believe that Genzyme is doing everything in their power to develop ERT as quickly as possible.  What we have learned is that there are so many more factors in developing an ERT than we previously recognized.  Although it seems like a long waiting period, right now, for the next set of studies, it should bring an approved treatment to all patients in an overall shorter amount of time.

We recognize the importance of the comprehensive studies conducted by Genzyme in order to compare all forms of Pompe enzymes.  Data shared with us, that was derived from this study, substantiates Genzyme’s claim that they are pursuing the most efficient pathway to commercialization. This is based not only on manufacturing considerations, but on clinical analysis as well. This most important data will hopefully expedite both ERT and reimbursement approval.

In moving forward, we will continue to develop the Pompe public awareness program that is so important and about which many of you have voiced concerns. We are working to develop a plan of action for the IPA and our member organizations. We will share more detailed information on this front when the plan is more refined (in the next several weeks).  In addition, we will continue to keep the dialogue open with Genzyme through the bi-monthly teleconferences and will provide you with updates of those conversations.

We all agree that this meeting was a step forward in working together for what we all desire most….a safe, effective, and rapid treatment for all Pompe patients.

Read complete article on the IPA web site.

Q: What is the status of the Pompe program?

Genzyme has made strong progress within its Pompe disease program since its decision earlier this year to move forward with an internally developed product candidate.  In November, we filed an IND with the FDA for the first of several planned clinical studies, marking a significant milestone in our Pompe program.  We share with patients and their families a tremendous sense of urgency to begin clinical studies of Genzyme’s recombinant human acid alpha-Glucosidase (rhGAA), so that we can move toward the goal of making a treatment broadly available.  Our discussions with regulatory authorities to date have been positive, and we are optimistic that they will support us in moving this process forward expeditiously.  The Pompe program is currently Genzyme’s largest research and development initiative.

Q: When will new clinical trials begin?

Enrollment is expected to begin by the end of this year in the first of several planned clinical trials evaluating the use of rhGAA to treat infantile-onset Pompe disease. Patients up to three years old with the infantile-onset form of the disease will be included in this study. A second trial is expected to begin in the second quarter of 2003 and will focus on patients less than six months old with the most severe infantile-onset form of Pompe disease, in which infants generally die before the age of one year. The studies—to be conducted at medical centers in the United States, Europe, and Asia once we receive the necessary regulatory and IRB approvals—will focus on the effect of treatment on patient survival, as well as other factors such as respiratory function, cardiac status, motor development, and safety.  Clinical studies for patients with late-onset Pompe disease are expected to begin once a sufficient supply of clinical trial material is available.

Q: Are you able to make product available for compassionate use?

Sufficient quantities of Genzyme rhGAA are currently available to conduct the two planned infantile studies.  In addition, patients now receiving either transgenic rhGAA or rhGAA licensed from Synpac (North Carolina) Inc. are scheduled to transition to Genzyme rhGAA next year.  Genzyme has held discussions with regulatory authorities regarding the current limitations on product supply and the urgent needs of Pompe patients.  Until adequate product inventory exists, priority must be given to maintaining patients who are currently on therapy and to conducting the clinical studies necessary to secure product registrations worldwide.  Only with this focus can treatment be made available as quickly as possible to patients who need it.

Q: How is product manufacturing going?

Genzyme has successfully initiated production of rhGAA in its development-and pilot-scale manufacturing facilities in Framingham, Massachusetts.  In addition, Genzyme is now working to complete the installation of commercial-scale bioreactors at its Allston Landing manufacturing facility in Boston to provide capacity for rhGAA production in the longer term.

Q: When do you expect to seek product registration?

Genzyme is continuing its discussions with regulatory authorities in Europe regarding the content and timing of a marketing authorization application. These discussions have not yet been held with regulatory authorities in the United States or other countries.

Q: Have there been program management changes?

A: Yes.  John Crowley, senior vice president, Genzyme Therapeutics, and general manager of the Pompe program, is leaving the company to spend more time with his family, particularly his children, both of whom suffer from Pompe disease.  Mr. Crowley came to Genzyme in 2001 following Genzyme’s acquisition of Novazyme Pharmaceuticals Inc., where he was president and chief executive officer.  He will continue to work with Genzyme as a consultant. Frank Ollington, Ph.D., senior vice president, Genzyme Therapeutics, has assumed management responsibility for the Pompe program. Frank has held a number of important leadership positions in his 14 years with Genzyme.  He directed the start-up of the Allston Landing manufacturing plant, served as president of the Genzyme Pharmaceuticals business unit and senior vice president of corporate operations, and chaired the steering committee overseeing the development of Aldurazyme® (laronidase), a product under development for the treatment of the genetic disorder MPS 1.

This document contains forward-looking statements that are subject to risks and uncertainties that could cause actual results to differ materially from those projected in these forward-looking statements including, among others, the risks and uncertainties described in reports filed by Genzyme Corporation with the Securities and Exchange Commission under the Securities Exchange Act of 1934, as amended, including without limitation Exhibit 99.2 to Genzyme’s 2001 Annual Report on Form 10-K, as amended.  These statements speak only as of the date of this document.  Genzyme® is a registered trademark of Genzyme Corporation.  Aldurazyme® is a registered trademark of BioMarin/Genzyme LLC.  All rights reserved.

The trial is the first of two studies Genzyme expects to conduct this year involving patients with the infantile-onset form of Pompe disease, in which symptoms manifest themselves during the first year of life.  The trial (known as study 1702) will include up to 16 children between the ages of six months and three years.  It is being conducted at medical centers in the United States and Europe.

A second trial (known as study 1602) is scheduled to begin this spring, and will include up to 16 infants younger than six months of age at the time of their first infusion.  Genzyme expects to complete enrolment in both studies this year.  The studies will focus on the effect of Myozyme on patient survival, as well as other factors such as respiratory function, cardiac status, motor development, and safety.  Genzyme expects to pursue product registrations globally based on results from these trials and previous studies of enzyme replacement therapy for Pompe disease.

“We are moving forward with sense of urgency to complete these studies,” said Henri A. Termeer, chairman and chief executive officer of Genzyme Corp. “This is a devastating disease, and we are committed to doing all that is necessary to bring forward a safe and effective treatment for patients.”

About Pompe disease

Pompe disease is a rare and fatal genetic disorder caused by a deficiency of the lysosomal enzyme acid alpha- Glucosidase, which is responsible for breaking down glycogen within cells.  Pompe disease shares a common element of muscle wasting with more than 40 different muscle diseases, often called muscular dystrophies.  There is currently no treatment available for this disease, which affects several thousand people worldwide.  Pompe disease ranges from a rapidly fatal infantile-onset form with severe cardiac involvement to a more slowly progressive adult-onset form.

Genzyme General develops and markets therapeutic products and diagnostic products and services.  Genzyme General has five therapeutic products on the market and a strong pipeline of therapeutic products in development focused on the treatment of genetic diseases and other chronic debilitating disorders with well-defined patient populations.  Genzyme General is a division of Genzyme Corp.

This press release contains forward-looking statements, including statements about: planned clinical trials for a potential therapy for Pompe disease, including the anticipated timing and design of trials; plans regarding submissions to regulatory authorities; and manufacturing plans and expectations.  These statements are subject to risks and uncertainties that could cause actual results to differ materially from those projected in these forward-looking statements.  These risks and uncertainties include, among others: the receipt of IRB approvals for clinical trials and the timing thereof; enrolment rates for clinical trials; the efficacy and safety of Genzyme rhGAA in humans and the actual timing and final design of clinical trials; the results of pre-clinical and clinical studies; the actual timing and content of submissions to and decisions made by regulatory authorities concerning the Pompe product candidate and facilities, including the nature and extent of data required for marketing applications; the results and timing of qualifying runs at facilities; the ability to manufacture sufficient quantities of product for development activities (including without limitation extension studies and expanded access arrangements) and to do so in a timely and cost-efficient manner; and the risks and uncertainties described in reports filed by Genzyme with the Securities and Exchange Commission under the Securities Exchange Act of 1934, as amended, including without limitation Exhibit 99.2 to Genzyme’s 2001 Annual Report on Form 10-K, as amended.  Genzyme General Division common stock is a series of common stock of Genzyme Corporation.  Therefore, holders of Genzyme General Division common stock are subject to all of the risks and uncertainties described in the those reports.  We caution investors not to place undue reliance on the forward-looking statements contained in this press release.  These statements speak only as of the date of this press release, and we undertake no obligation to update or revise the statements. Genzyme® is a registered trademark of Genzyme Corporation. All rights reserved.

Genzyme expects to complete enrollment in both studies this year and to apply for marketing approvals for Myozyme in 2004 based on results from these trials, and on previous studies of enzyme replacement therapy for Pompe disease.

Both studies involve patients with the infantile-onset form of Pompe disease, in which symptoms manifest themselves during the first year of life. The 1602 trial announced today will examine the effect that Myozyme has at different doses on patient survival and on clinical factors such as respiratory function, and cardiac and muscle function. Infants with the most severe form of Pompe disease rarely survive more than one year without treatment. By contrast, the patients enrolled in the 1702 study announced in March span a broader range of symptoms and severity. Genzyme intends to use the results of these two trials to support global product registrations of Myozyme.

“The start of this clinical trial marks another important step toward the development of a safe and effective treatment for children with this devastating disorder,” said Richard Moscicki, MD, Genzyme’s chief medical officer and senior vice president of medical, clinical, and regulatory affairs. “We are enormously conscious that for these children, time is of the essence. We are continuing to work diligently with our clinical investigators and regulatory authorities to bring this important therapy to patients as quickly as possible.”

Both studies initiated this year are multi-center, international trials involving treatment sites in the United States and Europe. The 1602 study will also include a treatment site in Taiwan, where the disease is more prevalent.

About Pompe Disease

Pompe disease is a rare and sometimes fatal muscle disease caused by an inherited deficiency of the enzyme acid alpha-glucosidase (GAA), which is responsible for breaking down glycogen within specialized compartments called lysosomes in cells. Pompe disease ranges from a rapidly fatal infantile-onset form with severe cardiac involvement to a more slowly progressive late-onset form primarily affecting skeletal muscle. There is currently no therapeutic treatment available for the disease, which affects an estimated several thousand people worldwide.

Genzyme General develops and markets therapeutic products and diagnostic products and services. Genzyme General has six therapeutic products on the market and a strong pipeline of therapeutic products in development focused on the treatment of genetic diseases and other chronic debilitating disorders with well-defined patient populations. Genzyme General is a division of Genzyme Corp.

This press release contains forward-looking statements, including statements about: plans concerning clinical trials for a potential therapy for Pompe disease, including the anticipated timing and design of trials; estimates concerning the Pompe patient population; plans regarding submissions to regulatory authorities; and the potential future availability of a therapy for Pompe disease. These statements are subject to risks and uncertainties that could cause actual results to differ materially from those projected in these forward-looking statements. These risks and uncertainties include, among others: the receipt of IRB approvals for clinical trials and the timing thereof; enrollment rates for clinical trials; the actual efficacy and safety of rhGAA in humans and the actual timing of clinical trials; the results of pre-clinical and clinical studies; the actual timing and content of submissions to and decisions made by regulatory authorities concerning the Pompe product candidate and facilities, including the nature and extent of data required for marketing applications; the results and timing of qualifying runs at facilities; the ability to manufacture sufficient quantities of product for development activities (including without limitation extension studies and expanded access arrangements) and to do so in a timely and cost-efficient manner; the accuracy of Genzyme’s information concerning the Pompe patient population; and the risks and uncertainties described in reports filed by Genzyme with the Securities and Exchange Commission under the Securities Exchange Act of 1934, as amended, including without limitation Exhibit 99.2 to Genzyme’s 2002 Annual Report on Form 10-K, as amended. Genzyme General Division common stock is a series of common stock of Genzyme Corporation. Therefore, holders of Genzyme General Division common stock are subject to all of the risks and uncertainties described in the those reports. We caution investors not to place undue reliance on the forward-looking statements contained in this press release. These statements speak only as of the date of this press release, and we undertake no obligation to update or revise the statements. `

View the complete conference details at this web site.

View complete conference summary here.

The EMEA’s Committee for Human Medicinal Products is expected to issue an opinion on the Myozyme application within one year, and a decision by the European Commission is anticipated early in 2006.

“Pompe disease takes a devastating toll on patients and their families,” said Henri A. Termeer, chairman and chief executive officer of Genzyme. “We have proceeded with a great sense of urgency to develop a product that we hope and believe will finally give them a chance. We are enormously grateful to everyone who has contributed so much to get us to this point, and we are working diligently to begin the approval process for Myozyme in other parts of the world next year.”

Myozyme has received orphan medicinal product designation, which applies to treatments for diseases that affect fewer than 5 in 10,000 people in the European Union. Approved orphan medicinal products are granted market exclusivity for 10 years.

Genzyme is seeking approval for Myozyme’s use as a long-term enzyme replacement therapy for all patients with a confirmed diagnosis of Pompe disease, defined as alpha-glucosidase deficiency. Genzyme’s marketing application for Myozyme contains results from several clinical trials, including interim data from the ongoing study AGLU-01702, which is evaluating the use of Myozyme in severely affected children between 6 months and 3 years of age. One-year results from AGLU-01702 will become available during the application-review process, as will interim data from the ongoing study AGLU-01602, which is fully enrolled and includes children younger than 6 months of age with the classical infantile-onset form of Pompe disease.

Nearly 100 Pompe patients are currently receiving Myozyme in clinical studies, through Genzyme’s expanded access program, or through pre-approval access mechanisms sponsored by governments in several European countries.

“This is a very hopeful moment for people with Pompe disease in Europe,” said Ria Broekgaarden, of the Dutch Pompe patient organization VSN (Vereniging Spierziekten Nederland) and secretary of the International Pompe Association. “Patients urgently need treatment, and we will continue to advocate on their behalf.”

Genzyme anticipates submitting a marketing application for Myozyme in the United States in the middle of 2005. Applications in Japan and other countries will follow the U.S. submission. The company continues to make a significant investment in the development of Myozyme, which is its largest research and development project. Genzyme is currently conducting an observational study for patients with the late-onset form of Pompe disease and plans to initiate a placebo-controlled treatment study for late-onset patients next year. The company has also established a registry designed to improve knowledge about Pompe disease by documenting the natural course of the disease, disease management approaches and clinical outcomes. All patients are eligible to participate in the registry through their treating physicians. Genzyme is also engaged in a substantial expansion of manufacturing capacity for Myozyme at its facilities in both the United States and Europe.

About Pompe disease

Pompe disease is an inherited muscle disease that affects fewer than 10,000 people worldwide. The disease is caused by a deficiency of an enzyme known as acid alpha-glucosidase. This deficiency leads to the excessive accumulation of glycogen in the body, particularly in the muscles. Pompe disease manifests as a broad spectrum of clinical symptoms with varying rates of disease progression. Infantile-onset patients present in the first months of life with an enlarged heart and skeletal and respiratory muscle weakness, and most die from cardiac or respiratory complications by one year of age. Late-onset patients may present with muscle or respiratory weakness anytime during childhood or adulthood, and disease progression is less rapid. Late-onset patients often require mechanical ventilation for breathing assistance and mobility aids such as canes, walkers or wheelchairs. Late-onset patients will experience a shortened lifespan due to progressive respiratory failure. Pompe disease belongs to a family of approximately 40 rare inherited diseases known as lysosomal storage disorders.

About Genzyme

Genzyme Corporation is a global biotechnology company dedicated to making a major positive impact on the lives of people with serious diseases. The company’s broad product portfolio is focused on rare genetic disorders, renal disease, osteoarthritis and immune-mediated diseases, and includes an industry-leading array of diagnostic products and services, and sophisticated biomaterials. Genzyme’s commitment to innovation continues today with research into novel approaches to cancer, heart disease, and other areas of unmet medical need. Approximately 7,000 Genzyme employees in offices around the globe serve patients in more than 80 countries.

Safe-Harbor Statement

This press release contains forward-looking statements, including statements about: the potential receipt of marketing approval for Myozyme in Europe; regulatory plans and expected timelines, including without limitation the expected timing of an opinion from the Committee for Human Medicinal Products and a decision from the European Commission; the expected timing of regulatory submissions in the United States, Japan and other countries; clinical trial plans; and estimates concerning the Pompe patient population. These statements are subject to risks and uncertainties that could cause actual results to differ materially from those projected in these forward-looking statements. These risks and uncertainties include, among others: the actual timing and content of submissions to and decisions made by the Committee for Human Medicinal Products, the European Commission and other regulatory authorities regarding marketing authorization applications for Myozyme and the labeling for Myozyme; the actual timing and results of clinical trials of Myozyme; the ability to manufacture sufficient quantities of product for development and commercialization activities and to do so in a timely and cost efficient manner; the accuracy of the company’s information about the Pompe patient population; and the risks and uncertainties described in reports filed by Genzyme with the Securities and Exchange Commission. Please see the disclosure under the heading “Factors Affecting Future Operating Results” in the Management’s Discussion and Analysis of Financial Condition and Results of Operations section of Genzyme’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2004 for a more complete discussion of these and other risks. Genzyme cautions investors not to place substantial reliance on the forward-looking statements contained in this press release. These statements speak only as of the date of this press release, and Genzyme undertakes no obligation to update or revise the statements.

Genzyme® and Myozyme® are registered trademarks of Genzyme Corporation. All rights reserved.

Media Contact:
Bo Piela
671-768-6579

Investor Contact:
Sally Curley
617-768-6140

“The results are extremely encouraging and confirm our plan to submit a BLA in the middle of this year,” said Richard A. Moscicki, senior vice president and chief medical officer for Genzyme Corp. “This analysis will allow us to seek U.S. approval for Myozyme as quickly as we had expected and to supplement our previously filed European marketing application with data from the pivotal study. We have proceeded with a great sense of urgency throughout the development of Myozyme, given the devastating nature of Pompe disease.”

The pivotal trial, known as AGLU01602, includes 18 patients with infantile-onset Pompe disease. These patients were enrolled in the trial and began receiving Myozyme by 6 months of age. Because of the rapidly progressive and fatal nature of infantile-onset Pompe disease, outcomes for these patients are being compared with a matched historical cohort rather than a placebo cohort.

The study’s primary endpoint is the proportion of patients treated with Myozyme who are alive and free of invasive ventilator support at 18 months of age, compared with the proportion of patients who were alive at 18 months of age in the historical cohort (2 percent). Results for the primary endpoint will be known this summer, when patients will have completed 52 weeks of treatment.

By 12 months of age, 89 percent of patients treated with Myozyme (16 of 18) were alive and free of invasive ventilator support compared with 17 percent of patients who were alive at 12 months of age in the historical cohort. This result meets a secondary efficacy endpoint and indicates the trial will very likely meet its primary endpoint.

The interim analysis also found the following:

• All patients treated with Myozyme showed a reversal in cardiomyopathy, a condition in which the heart muscle becomes enlarged and heart function is impaired. This reversal was measured by decreases in left ventricular mass index from baseline.
• 72 percent of patients treated with Myozyme demonstrated gains in motor development as measured by the Alberta Infant Motor Scale.
• All patients evaluated demonstrated gains in cognitive, language and personal/social skills from baseline.
• 83 percent of patients developed antibodies to Myozyme and 44 percent experienced infusion associated reactions.

Genzyme will submit data from study AGLU01602 to the European Medicines Agency, which is reviewing a marketing authorization application (MAA) for Myozyme filed in December 2004. The agency’s Committee for Human Medicinal Products is expected to make a decision on the application later this year. The MAA contains data from other studies, including AGLU01702, which enrolled patients with infantile-onset Pompe disease who were older than those in AGLU01602 and whose disease was more advanced.

Genzyme is pursuing approval for Myozyme’s use as a long-term enzyme replacement therapy for all patients with a confirmed diagnosis of Pompe disease, defined as acid alpha-glucosidase deficiency. There is currently no approved treatment for the disease. More than 100 patients are now receiving Myozyme in clinical studies, through Genzyme’s expanded access program, or through pre-approval mechanisms sponsored by governments in several European countries. The Myozyme program is Genzyme’s largest research and development initiative.

About Pompe disease

Pompe disease is an inherited, progressive muscle disease that affects fewer than 10,000 people worldwide. The disease is caused by a deficiency of an enzyme known as acid alpha-glucosidase. This deficiency leads to the excessive accumulation of glycogen in the body, particularly in the muscles. Pompe disease manifests as a broad spectrum of clinical symptoms with varying rates of disease progression. Infantile-onset patients present in the first months of life with an enlarged heart and skeletal and respiratory muscles weakness, and most die from cardiac or respiratory complications by one year of age. Late-onset patients may present with muscle or respiratory weakness anytime during childhood or adulthood, and disease progression is less rapid. Late-onset patients often require mechanical ventilation for breathing assistance and mobility aids such as canes, walkers or wheelchairs. Late-onset patients will experience a shortened lifespan due to progressive respiratory failure. Pompe disease belongs to a family of approximately 40 rare inherited diseases known as lysosomal storage disorders.

About Genzyme

One of the world’s leading biotechnology companies, Genzyme is dedicated to making a major positive impact on the lives of people with serious diseases. Founded in 1981, Genzyme has grown from a small start-up to a diversified enterprise with annual revenues exceeding $2 billion and more than 7,000 employees in locations spanning the globe. With many established products and services helping patients in more than 80 countries, Genzyme is a leader in the effort to develop and apply the most advanced technologies in the life sciences. The company’s products and services are focused on rare inherited disorders, kidney disease, orthopaedics, cancer, transplant and immune diseases, and diagnostic testing. Genzyme’s commitment to innovation continues today with a substantial development program focused on these fields as well as heart disease and other areas of unmet medical need.

This press release contains forward-looking statements, including statements about clinical trial results, regulatory plans and expected timelines for Myozyme, including the completion of the AGLU-01602 trial and the timing thereof, the submission of a BLA to the FDA and the timing thereof, and the expected timing of a decision from the Committee for Human Medicinal Products on Genzyme’s MAA. These statements are subject to risks and uncertainties that could cause actual results to differ materially from those projected in these forward-looking statements. These risks and uncertainties include, among others: the actual timing and content of submissions to and decisions made by the US and EU regulatory authorities regarding marketing authorization applications for Myozyme; the actual timing and final results of the Myozyme clinical trials; and the risks and uncertainties described in reports filed by Genzyme with the Securities and Exchange Commission. Please see the disclosure under the heading “Factors Affecting Future Operating Results” in the Management’s Discussion and Analysis of Financial Condition and Results of Operations section of Genzyme’s Annual Report on Form 10-K for the year ended December 31, 2004 for a more complete discussion of these and other risks. Genzyme cautions investors not to place substantial reliance on the forward-looking statements contained in this press release. These statements speak only as of the date of this press release, and Genzyme undertakes no obligation to update or revise the statements.

Genzyme® and Myozyme® are registered trademarks of Genzyme Corporation. All rights reserved.

Media Contact
Bo Piela
617-768-6579

Investor Contact
Sally Curley
617-768-6140

View complete summary here.

The BLA contains data from several clinical trials, including the pivotal study AGLU01602, which Genzyme reported today met its primary endpoint. This trial enrolled 18 patients with infantile-onset Pompe disease who began receiving Myozyme by six months of age. Outcomes for these patients were compared with a historical cohort, rather than a placebo cohort, because of the rapidly progressive and fatal nature of infantile-onset Pompe disease.

All patients treated with Myozyme were alive at 18 months of age, compared with two percent of patients who were alive at this age in the historical cohort. The primary endpoint for the study was the proportion of patients treated with Myozyme who were both alive and free of invasive ventilator support at 18 months of age, compared with the proportion of patients in the historical cohort who were alive at 18 months of age. Eighty-three percent of patients treated with Myozyme (15 of 18) were both alive and free of invasive ventilator support at this age, compared with two percent of patients in the control group who were alive.

“This is a very exciting and hopeful moment for Pompe patients and their families,” said Henri A. Termeer, chairman and chief executive officer of Genzyme. “Myozyme could be available in the United States and Europe by the early part of next year and in other parts of the world relatively soon afterward.”

Genzyme will submit results from study AGLU01602 to the European Medicines Agency, which is reviewing a marketing authorization application for Myozyme filed in December 2004. The company anticipates submitting a marketing application for Myozyme in Japan later this year.

Genzyme is seeking approval for Myozyme’s use as a long-term enzyme replacement therapy for all patients with a confirmed diagnosis of Pompe disease, defined as a deficiency of the enzyme acid alpha-glucosidase. There is currently no approved treatment for the disease. Myozyme has received orphan drug designation in the United States, which would convey a seven-year period of market exclusivity if the product is approved. Orphan drug designations have also been granted in the European Union and Japan.

More than 130 patients are now receiving Myozyme in clinical studies, through Genzyme’s expanded access program, or through pre-approval mechanisms sponsored by governments in several European countries. Genzyme expects to initiate a clinical trial shortly for patients with late-onset Pompe disease. The company recently concluded an observational study involving late-onset patients, which was designed to evaluate appropriate endpoints for a treatment study. The Myozyme program is Genzyme’s largest research and development initiative.

About Pompe disease

Pompe disease is an inherited, progressive muscle disease that affects fewer than 10,000 people worldwide. The disease is caused by a deficiency of an enzyme known as acid alpha-glucosidase. This deficiency leads to the excessive accumulation of glycogen in the body, particularly in the muscles. Pompe disease manifests as a broad spectrum of clinical symptoms with varying rates of disease progression. Infantile-onset patients present in the first months of life with an enlarged heart and skeletal and respiratory muscle weakness, and most die from cardiac or respiratory complications by one year of age. Late-onset patients may present with muscle or respiratory weakness anytime during childhood or adulthood, and disease progression is less rapid. Late-onset patients often require mechanical ventilation for breathing assistance and mobility aids such as canes, walkers or wheelchairs. Late-onset patients will experience a shortened lifespan due to progressive respiratory failure. Pompe disease belongs to a family of more than 40 rare inherited diseases known as lysosomal storage disorders.

About Genzyme

One of the world’s leading biotechnology companies, Genzyme is dedicated to making a major positive impact on the lives of people with serious diseases. Founded in 1981, Genzyme has grown from a small start-up to a diversified enterprise with 2005 revenues expected to exceed $2.6 billion and more than 7,600 employees in locations spanning the globe. With many established products and services helping patients in more than 80 countries, Genzyme is a leader in the effort to develop and apply the most advanced technologies in the life sciences. The company’s products and services are focused on rare inherited disorders, kidney disease, orthopaedics, cancer, transplant and immune diseases, and diagnostic testing. Genzyme’s commitment to innovation continues today with a substantial development program focused on these fields as well as heart disease and other areas of unmet medical need.

This press release contains forward-looking statements, including statements about clinical trial results, regulatory plans and expected timelines for Myozyme, including the submission of the AGLU-01602 trial study report to US and EU regulatory authorities, the submission of a marketing application in Japan and the timing thereof, the anticipated timing of commercial availability of Myozyme, and plans to initiate a clinical trial for late-onset Pompe patients and the timing thereof. These statements are subject to risks and uncertainties that could cause actual results to differ materially from those projected in these forward-looking statements. These risks and uncertainties include the actual timing and content of submissions to and decisions made by the EU, US and Japanese regulatory authorities regarding the marketing authorization applications for Myozyme, Genzyme’s ability to obtain labeling approval of Myozyme for treatment of all Pompe patients on infantile-onset clinical trial data, the timely receipt of pricing and reimbursement approvals in approved countries, the ability to manufacture sufficient quantities of product for development and commercialization activities and to do so in a timely and cost efficient manner, and the risks and uncertainties described in reports filed by Genzyme with the Securities and Exchange Commission. Please see the disclosure under the heading “Factors Affecting Future Operating Results” in the Management’s Discussion and Analysis of Financial Condition and Results of Operations section of Genzyme’s Quarterly Report on Form 10-Q for the period ended March 31, 2005 for a more complete discussion of these and other risks. Genzyme cautions investors not to place substantial reliance on the forward-looking statements contained in this press release. These statements speak only as of the date of this press release, and Genzyme undertakes no obligation to update or revise the statements.

Genzyme® and Myozyme® are registered trademarks of Genzyme Corporation. All rights reserved.

“This is a brief extension of the review period, and we continue to expect that Myozyme will be approved in the United States during the first half of this year,” said Alison Lawton, Genzyme’s senior vice president for regulatory affairs. “We have worked closely with the FDA throughout the review process and are confident the agency recognizes the urgency of making this treatment available to patients.”

Myozyme has been developed for the treatment of Pompe disease, a debilitating, progressive and often fatal muscular disorder. Genzyme submitted a biologics license application for Myozyme in late July. The application was given Priority Review status, which required the FDA to act within six months.

Genzyme is currently engaged in a broad range of activities to prepare for Myozyme’s introduction in the United States and in Europe, where the Committee for Human Medicinal Products is expected to issue an opinion later this month on the marketing authorization application for Myozyme.

Approximately 200 patients in 14 countries are currently receiving Myozyme through clinical trials, expanded access programs, or pre-approval regulatory mechanisms.

About Genzyme

One of the world’s leading biotechnology companies, Genzyme is dedicated to making a major positive impact on the lives of people with serious diseases. This year marks the 25th anniversary of Genzyme’s founding. Since 1981, the company has grown from a small start-up to a diversified enterprise with more than 8,000 employees in locations spanning the globe and 2005 revenues of $2.7 billion. Genzyme has been selected by FORTUNE as one of the “100 Best Companies to Work for” in the United States.

With many established products and services helping patients in more than 80 countries, Genzyme is a leader in the effort to develop and apply the most advanced technologies in the life sciences. The company’s products and services are focused on rare inherited disorders, kidney disease, orthopaedics, cancer, transplant and immune diseases, and diagnostic testing. Genzyme’s commitment to innovation continues today with a substantial development program focused on these fields, as well as heart disease and other areas of unmet medical need.

This press release contains forward-looking statements regarding the expected timing of U.S. and European regulatory action on Myozyme. These statements are subject to risks and uncertainties that could cause actual results to differ materially from those projected. These risks and uncertainties include that the FDA may not approve Myozyme on the timeframe anticipated by Genzyme or at all. Please refer to the risks and uncertainties described in reports filed by Genzyme with the Securities and Exchange Commission under the heading “Factors Affecting Future Operating Results” in the Management’s Discussion and Analysis of Financial Condition and Results of Operations section of Genzyme’s Quarterly Report on Form 10-Q for the period ending September 30, 2005, for a more complete discussion of the risks associated with Genzyme’s business. Genzyme cautions investors not to place substantial reliance on the forward-looking statements contained in this press release. These statements speak only of the date of this press release, and Genzyme undertakes no obligation to update or revise the statements.

Genzyme® and Myozyme® are registered trademarks of Genzyme Corporation. All rights reserved.

“This is an extraordinary moment for Pompe patients and their families,” said Henri A. Termeer, chairman and chief executive officer of Genzyme Corp. “The effort to develop Myozyme has required the enormous commitment of many people throughout Genzyme and across the Pompe community, who have worked with a great sense of urgency and have overcome tremendous challenges. Our focus now is to ensure that Myozyme is available to all patients who need treatment.”

Myozyme has received orphan medicinal product designation in Europe. The orphan medicinal products regulation is designed to encourage the development of treatments for rare disorders such as Pompe disease, for which no therapies have existed previously. Genzyme will introduce Myozyme in Europe on a country-by-country basis, as pricing and reimbursement approvals are obtained.

Ria Broekgaarden, of the Dutch Pompe patient organization VSN (Vereniging Spierziekten Nederland) and secretary of the International Pompe Association, said, “For people with Pompe disease, this is a very important moment in history. The approval of this treatment represents great hope and progress for all Pompe patients, which in turn will give them a new perspective on their future.”

Pompe disease manifests as a broad spectrum of clinical symptoms. All patients typically experience progressive muscle weakness and breathing difficulty, but the rate of disease progression can vary widely depending on the age of onset and the extent of organ involvement. When symptoms appear within a few months of birth, babies frequently display a markedly enlarged heart and die within the first year of life. When symptoms appear during childhood, adolescence or adulthood, patients may experience steadily progressive debilitation and premature mortality due to respiratory failure. They often require mechanical ventilation to assist with breathing and wheelchairs to assist with mobility.

Genzyme began working to develop a treatment for Pompe disease in 1998. In 2003, the company initiated clinical studies of Myozyme, which produced highly encouraging results and formed the basis of the company’s regulatory submissions. In the pivotal clinical study, 83 percent of patients treated with Myozyme were both alive and free of invasive ventilator support at 18 months of age, compared with two percent of patients in the historical cohort. The trial, which met its primary endpoint, enrolled 18 patients with infantile-onset Pompe disease, who began receiving therapy at approximately six months of age. Approximately 39 percent of patients treated with Myozyme developed infusion associated reactions, which were mostly mild to moderate in nature. Two patients experienced serious infusion reactions. One experienced urticaria, the other experienced urticaria, rales, tachycardia, decreased oxygen saturation, bronchospasm, tachypnea, periorbital edema and hypertension.

Genzyme recently completed enrollment in its clinical trial involving patients with late-onset Pompe disease. Ninety patients are participating in this international, placebo-controlled study. Currently, more than 270 patients in 30 countries are receiving Myozyme through clinical trials, expanded access programs, or pre-approval regulatory mechanisms.

Genzyme manufactures Myozyme at two facilities in the United States. To ensure that it is able to meet the anticipated demand for the product in Europe and throughout the world, the company expects to also produce Myozyme in the future at its new protein manufacturing facility in Geel, Belgium, and its new fill/finish facility in Waterford, Ireland.

About Pompe Disease

Pompe disease, also known as Acid Maltase Deficiency or Glycogen Storage Disease Type II, is one of more than 40 genetic diseases called lysosomal storage disorders, which are caused by a deficiency or malfunction of specific enzymes found in cell lysosomes. People born with Pompe disease have an inherited deficiency of an enzyme known as acid alpha-glucosidase (GAA). Enzymes, which are protein molecules within cells, trigger biochemical reactions in the body. In a healthy person with normal GAA activity, this particular enzyme would assist in the breakdown of glycogen, a complex sugar molecule stored within a compartment of the cell known as the lysosome. But in Pompe disease, the GAA activity may be dramatically reduced, dysfunctional, or non-existent, resulting in an excessive accumulation of glycogen in the lysosome.

Eventually, the lysosome may become so clogged with glycogen that normal cellular function is disrupted and muscle function is impaired. Although there is glycogen storage in the cells of multiple tissues, heart and skeletal muscles are usually the most seriously affected.

For more information on Pompe disease, please visit http://www.pompe.com/

About Genzyme

One of the world’s leading biotechnology companies, Genzyme is dedicated to making a major positive impact on the lives of people with serious diseases. This year marks the 25th anniversary of Genzyme’s founding. Since 1981, the company has grown from a small start-up to a diversified enterprise with more than 8,000 employees in locations spanning the globe and 2005 revenues of $2.7 billion. Genzyme has been selected by FORTUNE as one of the “100 Best Companies to Work for” in the United States.

With many established products and services helping patients in more than 80 countries, Genzyme is a leader in the effort to develop and apply the most advanced technologies in the life sciences. The company’s products and services are focused on rare inherited disorders, kidney disease, orthopaedics, cancer, transplant and immune diseases, and diagnostic testing. Genzyme’s commitment to innovation continues today with a substantial development program focused on these fields, as well as heart disease and other areas of unmet medical need.

This press release contains a forward-looking statement regarding Myozyme manufacturing. This statement is subject to risks and uncertainties that could cause actual results to differ materially from those projected, including that Genzyme is unable to produce Myozyme at its Geel, Belgium facility or produce it in sufficient quantities to meet demand. Please refer to the risks and uncertainties described in reports filed by Genzyme with the Securities and Exchange Commission under the heading “Factors Affecting Future Operating Results” in the Management’s Discussion and Analysis of Financial Condition and Results of Operations section of Genzyme’s Annual Report on Form 10-K for the year ended December 31, 2005 for a more complete discussion of the risks associated with Genzyme’s business. Genzyme cautions investors not to place substantial reliance on the forward-looking statement contained in this press release. This statement speaks only as of the date of this press release, and Genzyme undertakes no obligation to update or revise the statement.

Genzyme® and Myozyme® are registered trademarks of Genzyme Corporation. All rights reserved.

“This is a special day for people across the Pompe community and at Genzyme, who have worked together for many years and overcome enormous challenges so that patients with this devastating disease now have a chance,” said Henri A. Termeer, chairman and chief executive officer of Genzyme Corp.

The Myozyme label includes the following indication: “Myozyme (alglucosidase alfa) is indicated for use in patients with Pompe disease (GAA deficiency). Myozyme has been shown to improve ventilator-free survival in patients with infantile-onset Pompe disease as compared to an untreated historical control, whereas use of Myozyme in patients with other forms of Pompe disease has not been adequately studied to assure safety and efficacy.”

The product label also includes a boxed warning with information on the potential risk of hypersensitivity reactions associated with Myozyme. The boxed warning states that “Life-threatening anaphylactic reactions, including anaphylactic shock, have been observed in patients during Myozyme infusion. Because of the potential for severe infusion reactions, appropriate medical support measures should be available when Myozyme is administered.” Of the 280 patients who received Myozyme in clinical studies or through expanded access, eight patients (3 percent) experienced severe or significant hypersensitivity reactions. Full prescribing information for the product is available on Genzyme’s Web site.

Pompe disease manifests as a broad spectrum of clinical symptoms. All patients typically experience progressive muscle weakness and breathing difficulty, but the rate of disease progression can vary widely depending on the age of onset and the extent of organ involvement. When symptoms appear within a few months of birth, babies frequently display a markedly enlarged heart and die within the first year of life. When symptoms appear during childhood, adolescence or adulthood, patients may experience steadily progressive debilitation and premature mortality due to respiratory failure. They often require mechanical ventilation to assist with breathing and wheelchairs to assist with mobility.

Genzyme recently completed enrollment in its clinical trial involving patients with late-onset Pompe disease. Ninety patients have been enrolled in this international, placebo-controlled study. Currently, more than 280 patients in 30 countries are receiving Myozyme through clinical trials, expanded access programs, or pre-approval regulatory mechanisms.

Myozyme has received orphan drug designation in the United States, which provides seven years of market exclusivity. The orphan drug law is designed to encourage the development of treatments for rare disorders such as Pompe disease, for which no therapies have existed previously. Genzyme expects to launch Myozyme in the United States within two weeks. Late last month, Myozyme was approved in the European Union.

Because early diagnosis, intervention and treatment are critical in Pompe disease and other lysosomal storage disorders, Genzyme has for the past seven years supported several outside research collaborations to develop new diagnostic technology. This research has led to the recent introduction of an enzyme assay utilizing blood samples that makes it possible to diagnose Pompe patients more rapidly and with a less-invasive procedure. Genzyme will offer this test now through its Genzyme Genetics unit, and the test will also be available through several other clinical laboratories in the United States and elsewhere in the world.

“The journey from development to approval of a therapy for Pompe disease has been a long and winding road, but we are now at a milestone and are thrilled with the outcome,” said Randall H. House, chairman of the International Pompe Association and president of the Acid Maltase Deficiency Association (AMDA), a Pompe patient association in the United States. “Enzyme replacement therapy with Myozyme gives Pompe patients hope.” The AMDA, formed in 1995, has assisted in funding Pompe disease research and promotes public awareness of Pompe disease.

Valerie Cwik, medical director for the Muscular Dystrophy Association, said: “Myozyme is the first treatment for any of the muscle diseases included among the 40 neuromuscular disorders covered by the Muscular Dystrophy Association. This is a great day for people with Pompe disease, and a hopeful moment for the thousands of other people who are affected by the diseases in the MDA program, because it shows that support and research can lead to treatments.” The MDA helped support patients who took part in clinical trials of Myozyme and also sponsored early research in Pompe disease.

Genzyme began working to develop a treatment for Pompe disease in 1998. In 2003, the company initiated a pivotal clinical study of Myozyme that demonstrated the product’s safety and efficacy. In the study, 83 percent of patients treated with Myozyme were both alive and free of invasive ventilator support at 18 months of age. In a natural history study, 2 percent of similar infantile-onset patients were alive at 18 months of age. The pivotal trial enrolled 18 patients with infantile-onset Pompe disease, who began receiving therapy at approximately six months of age. The most common serious adverse events observed in clinical studies of Myozyme, whether or not they were related to the drug, were pneumonia, respiratory failure, respiratory distress, catheter-related infection, respiratory syncytial virus infection, gastroenteritis and fever. Many of these can be complications of Pompe disease.

“We are very proud that we have been able to bring to market four therapies for ultra-orphan diseases where no treatments existed previously,” said Mr. Termeer. “This underscores our fundamental commitment to patients and confirms the productivity of our research efforts. We continue to invest in potential new approaches to treating these diseases.”

Myozyme is the fourth enzyme replacement therapy developed by Genzyme for a rare genetic disease. Genzyme has developed Cerezyme® (imiglucerase for injection) for Type 1 Gaucher disease; Fabrazyme® (agalsidase beta) for Fabry disease; and, in collaboration with BioMarin Pharmaceutical Inc., Aldurazyme® (laronidase) for MPS I. These treatments are currently available to patients throughout the world.

Genzyme currently manufactures Myozyme in the United States. In the future, the company expects to also produce Myozyme at its new protein manufacturing facility in Geel, Belgium, and its new fill/finish facility in Waterford, Ireland, to ensure that it is able to meet the anticipated demand for the product throughout the world.

About Pompe Disease

Pompe disease, also known as Acid Maltase Deficiency or Glycogen Storage Disease Type II, is one of more than 40 genetic diseases called lysosomal storage disorders, which are caused by a deficiency or malfunction of specific enzymes found in cell lysosomes. People born with Pompe disease have an inherited deficiency of an enzyme known as acid alpha-glucosidase (GAA). Enzymes, which are protein molecules within cells, trigger biochemical reactions in the body. In a healthy person with normal GAA activity, this particular enzyme would assist in the breakdown of glycogen, a complex sugar molecule stored within a compartment of the cell known as the lysosome. But in Pompe disease, the GAA activity may be dramatically reduced, dysfunctional, or non-existent, resulting in an excessive accumulation of glycogen in the lysosome.

Eventually, the lysosome may become so clogged with glycogen that normal cellular function is disrupted and muscle function is impaired. Although there is glycogen storage in the cells of multiple tissues, heart and skeletal muscles are usually the most seriously affected.

For more information on Pompe disease, please visit www.pompe.com

For information on Myozyme ordering and support services please call (800) 745-4447 or (617) 768-9000.

About Genzyme

One of the world’s leading biotechnology companies, Genzyme is dedicated to making a major positive impact on the lives of people with serious diseases. This year marks the 25th anniversary of Genzyme’s founding. Since 1981, the company has grown from a small start-up to a diversified enterprise with more than 8,000 employees in locations spanning the globe and 2005 revenues of $2.7 billion. Genzyme has been selected by FORTUNE as one of the “100 Best Companies to Work for” in the United States.

With many established products and services helping patients in more than 80 countries, Genzyme is a leader in the effort to develop and apply the most advanced technologies in the life sciences. The company’s products and services are focused on rare inherited disorders, kidney disease, orthopaedics, cancer, transplant and immune diseases, and diagnostic testing. Genzyme’s commitment to innovation continues today with a substantial development program focused on these fields, as well as heart disease and other areas of unmet medical need.

This press release contains forward-looking statements regarding the anticipated timing of a Myozyme launch, plans to launch a diagnostic test for Pompe disease, and the expected addition of Myozyme manufacturing sites. These statements are subject to risks and uncertainties that could cause actual results to differ materially from those projected, including our ability to successfully identify and market to new patients; the timely receipt of pricing and reimbursement approvals in approved countries; our ability to enter into agreements with our distributors; scientific, technical and manufacturing issues that could prevent the successful launch of the Pompe diagnostic test, the failure of the test to produce diagnostic results as anticipated; the commercial acceptance of the diagnostic test, including the acceptance of the diagnostic test at price levels that are economically viable for Genzyme Genetics; and our ability to produce Myozyme at our Geel, Belgium facility or produce it in sufficient quantities to meet demand. Please refer to the risks and uncertainties described in reports filed by Genzyme with the Securities and Exchange Commission under the heading “Factors Affecting Future Operating Results” in the Management’s Discussion and Analysis of Financial Condition and Results of Operations section of Genzyme’s Annual Report on Form 10-K for the year ended December 31, 2005 for a more complete discussion of the risks associated with Genzyme’s business. Genzyme cautions investors not to place substantial reliance on the forward-looking statements contained in this press release. These statements speak only as of the date of this press release, and Genzyme undertakes no obligation to update or revise the statements.

Genzyme® and Myozyme® are registered trademarks of Genzyme Corporation. All rights reserved.

Download the complete letter on from this page.

As many of you are aware, a standard part of the biologics drug development process is to incrementally scale-up manufacturing capacity as demand for the product increases. During the development of Myozyme®, Genzyme began the manufacturing process using a smaller scale, and has since scaled-up to produce larger quantities of product for
commercial use worldwide.  In addition to the use of this larger scale in multiple clinical trials, we’ve successfully transitioned to commercial use of the larger scale of Myozyme in over 29 countries where we have received regulatory approval.  In the United States, we are still in the process of seeking regulatory approval for use of the larger scale
manufacturing process, as it has taken time to produce the necessary data to support the submission to the FDA.

MTAP, the Myozyme® (alglucosidase alfa) Temporary Access Program, is a clinical program to provide access to Myozyme produced by a larger scale manufacturing process for a limited time until this manufacturing scale is approved by the FDA.  Patients enrolled in MTAP will be provided Myozyme at no cost during the course of the program.  The goals of MTAP are two-fold:  (a) to minimize any potential disruption in the treatment of patients already on therapy; and (b) to ensure that Myozyme is available for new patients who are in the most urgent clinical need. 

CAMBRIDGE, Mass. – Genzyme Corp. (Nasdaq: GENZ) announced today that its Late Onset Treatment Study (LOTS) of Myozyme® (alglucosidase alfa) met its co-primary efficacy endpoints.  The study was undertaken to evaluate the safety and efficacy of Myozyme in juvenile and adult patients with Pompe disease.  Myozyme was first approved in 2006, and the product is now registered in 36 countries. 

In April 2007, Genzyme implemented measures to manage the limited supply of Myozyme® (alglucosidase alfa) in the United States in order to ensure uninterrupted treatment for as many patients as possible.  Since April, both the patient and physician communities have worked diligently to enroll the majority of adults into the Myozyme Temporary Access Program (MTAP) and have greatly reduced the number of individuals at risk of an interruption in treatment.  In spite of this achievement, not enough adults were transitioned into MTAP to ensure that the remaining infants, children and adults would have a steady supply of commercial Myozyme until the larger scale manufacturing process is approved by the FDA. Unfortunately, it is necessary to take immediate additional measures to manage the current limited commercial supply of Myozyme.

We would like to take this opportunity to provide an important update related to Myozyme (alglucosidase alfa) manufacturing in the United States.  The FDA has informed Genzyme of its decision on the application for the larger scale manufacturing process to commercially supply Myozyme in the US.  The FDA has decided that Myozyme produced at the smaller bioreactor scale (160 L) and at the larger scale (2000 L) should be classified as two different products based on a comparison of biochemical characteristics of the product produced at the two scales.  We at Genzyme are disappointed in this decision. Genzyme believes that both products are clinically effective and safe.  The product from the smaller scale was used in the pivotal trials supporting FDA approval of Myozyme.  The product from the larger scale is approved in 41 countries and is currently used to treat approximately 900 patients of all ages throughout the world including the 138 adults in the US who are currently accessing Myozyme through the Myozyme Temporary Access Program (MTAP).

Amicus Therapeutics, a biopharmaceutical company developing small molecule, orally-administered pharmacological chaperones for the treatment of human genetic diseases, today announced that it has initiated a Phase 2 clinical trial of AT2220 (1-deoxynojirimycin HCl), for the treatment of Pompe disease. Amicus will conduct the study in adult Pompe patients in clinical centers throughout North America and Europe. AT2220 is the third compound based on Amicus’ pharmacological chaperone technology platform to enter Phase 2 clinical development.

The US Food and Drug Administration (FDA) held a meeting of its Endocrinologic and Metabolic Drugs Advisory Committee on October 21, 2008 to discuss Genzyme’s Biologics License Application (BLA) for alglucosidase alfa produced at the 2000 L bioreactor scale to treat late-onset Pompe disease in the United States. The Committee voted 16-1 that the Late Onset Treatment Study (LOTS) established the effectiveness of alglucosidase alfa produced at the 2000 L scale for the treatment of patients with late-onset disease.  The majority of the committee members recommended an ‘Accelerated Approval’, which would allow the 2000L to be approved but with the requirement to conduct a verification study of clinical benefit of therapy with alglucosidase alfa.  The committee also recommended that treatment with the 2000 L product should be made available to all patients with late-onset disease, without restrictions based on age. 

The US Food and Drug Administration (FDA) has informed Genzyme that the FDA plans an accelerated approval for alglucosidase alfa produced at the 2000 L bioreactor scale for the treatment of late onset Pompe disease. Prior to approval, the company and the agency first need to agree on the design of a post-approval verification study and the FDA must complete its review of the Risk Evaluation and Mitigation Strategy (REMS), which Genzyme submitted earlier this month. This REMS program is intended to ensure that distribution of the 2000 L product is prescribed and administered to the intended patient population. The FDA has classified this submission as a major amendment to the Biologics License Application (BLA) for alglucosidase alfa produced at the 2000 L scale. Therefore, to provide time to agree on the design of a post-approval verification study and complete the review of the REMS submission, the FDA has changed the Prescription Drug User Fee Action (PDUFA) date to February 28, 2009.  Genzyme will be required to submit the final protocol for the verification study after approval. 

We would like to take this opportunity to provide an important update to the Pompe Community.
The US Food and Drug Administration (FDA) has informed Genzyme that the FDA plans an accelerated approval for alglucosidase alfa produced at the 2000 L bioreactor scale for the treatment of late onset Pompe disease. Prior to approval, the company and the agency first need to agree on the design of a post-approval verification study and the FDA must complete its review of the Risk Evaluation and Mitigation Strategy (REMS), which Genzyme submitted earlier this month. This REMS program is intended to ensure that distribution of the 2000 L product is prescribed and administered to the intended patient population. The FDA has classified this submission as a major amendment to the Biologics License Application (BLA) for alglucosidase alfa produced at the 2000 L scale. Therefore, to provide time to agree on the design of a post-approval verification study and complete the review of the REMS submission, the FDA has changed the Prescription Drug User Fee Action (PDUFA) date to February 28, 2009. Genzyme will be required to submit the final protocol for the verification study after approval.
Genzyme is pleased to have clarity from the FDA on what it will take for alglucosidase alfa produced at the 2000 L to be approved under an accelerated approval. An accelerated approval is not a priority or fast-track review. An accelerated approval is an approval for commercial marketing, but with the requirement to conduct further studies to verify clinical benefit. We will work closely with the FDA to design a post-approval verification study.
Due to our continued state of limited supply, regrettably, MTAP will remain closed to new adult patients throughout this 3 month extension. Upon approval of alglucosidase alfa produced at the 2000 L scale, it is anticipated that new adult patients with late-onset Pompe disease will be able to access product through regular commercial channels. Patients currently enrolled in MTAP can continue in MTAP until the 2000 L scale is approved, at which time we will work to transition MTAP participants to commercial therapy. Alglucosidase alfa produced at the 160 L scale continues to be commercially available for all patients 17 years of age and younger.
Genzyme recognizes the difficulty this delay may cause for some Pompe patients and their families, as well as the physicians managing their care and appreciate your ongoing patience and understanding.

Genzyme would like to take this opportunity to provide an update to the Pompe Community.
The US Food and Drug Administration (FDA) held a meeting of its Endocrinologic and Metabolic Drugs Advisory Committee on October 21, 2008 to discuss Genzyme’s Biologics License Application (BLA) for alglucosidase alfa produced at the 2000 L bioreactor scale to treat late-onset Pompe disease in the United States. The Committee voted 16-1 that the Late Onset Treatment Study (LOTS) established the effectiveness of alglucosidase alfa produced at the 2000 L scale for the treatment of patients with late-onset disease. The majority of the committee members recommended an ‘Accelerated Approval’, which would allow the 2000L to be approved but with the requirement to conduct a verification study of clinical benefit of therapy with alglucosidase alfa. The committee also recommended that treatment with the 2000 L product should be made available to all patients with late-onset disease, without restrictions based on age.
The Advisory Panel vote is not an approval of the BLA and the FDA is not obligated to follow the panel’s recommendations. Genzyme has received a Prescription Drug User Fee Action (PDUFA) date from the FDA of November 29, 2008 and anticipates a response from the FDA regarding the approval status of the BLA on or prior to this date. Until Genzyme receives the FDA’s official response, we cannot speculate on the specific details of the approval status of the product produced at the 2000 L scale including the timing of when it will become commercially available, or the exact wording of the indication.
In the meantime, we would like to reiterate the current status of the product supply in the United States. Alglucosidase alfa produced at the 160 L scale continues to be available commercially for all patients 17 years of age and younger. The MTAP program remains closed to new patients at this time. Genzyme will update the community following the official response from the FDA.
Our commitment to provide treatment to all those in need remains unchanged and Genzyme appreciates the support and understanding the Pompe community has demonstrated during this process

Amicus Therapeutics announced today that the Company has suspended enrollment for the Phase 2 clinical trial of its investigational drug AT2220 (1-deoxynojirimycin HCI) for the treatment of Pompe Disease and that it has received verbal notice from the U.S. Food and Drug Administration (FDA) that the trial is on clinical hold. After evaluation of available data the Company plans to work closely with the FDA and if appropriate will amend the Phase 2 protocol with the objective of restarting the trial as expeditiously as possible.

Furthermore, as a result of this approval in Europe, the guidance issued to conserve Myozyme for infants and children is no longer in effect and all adult patients worldwide can immediately resume regular infusion schedules and physicians outside of the United States (US) are now able to initiate therapy for new adult patients.  In addition, due to the high degree of participation throughout the world of adult patients who transitioned to monthly infusions in January and February, we would like to inform the community that Genzyme has not been made aware of any infants or children who missed infusions during this period. Please know that we at Genzyme deeply appreciate your support, engagement, and understanding in managing through this temporary global supply constraint.

FDA Decision on Lumizyme™ (alglucosidase alfa)

 
There is also an important update regarding our application for alglucosidase alfa produced at the 2000 L scale in the United States, which will be known as Lumizyme.  The FDA was unable to approve Lumizyme on February 28th and has outlined, in a complete response letter we received on February 27th, the items that need to be addressed before approval can be granted.  Genzyme and the agency had made substantial progress toward finalizing these items but were not able to complete them before the action date.  Specifically, Genzyme and the FDA must agree on a final design for a verification study to confirm the clinical benefit of alglucosidase alfa produced at the 2000 L scale and on the details of a Risk Evaluation and Mitigation Strategy (REMS) for the product. Genzyme must also address some issues detailed in a separate warning letter that was also received on February 27th and related to observations made by the FDA during an inspection of our Allston Landing, Massachusetts manufacturing facility before approval can be granted. We are confident that all of the information can quickly be assembled and provided to the FDA.  We will be communicating with the FDA this week to start resolving the outstanding issues and will submit a response as soon as possible. 
 
Adult patients in the US currently enrolled in MTAP can continue to receive treatment via this access program and should return to regular bi-weekly infusion schedules now that the supply constraint on the 2000 L product has been resolved.  Due to the supply capacity limitations of Myozyme produced at the 160 L scale, Myozyme in the US will continue to be commercially available only to patients 17 years of age and younger. Upon approval of Lumizyme in the US, it is anticipated that new adult patients with late-onset Pompe disease will be able to access product through regular commercial channels; however, at this time, enrollment in MTAP remains closed to new adult patients. 
 
Although we are disappointed by this additional delay in the approval process, Genzyme now has further clarity from the FDA on which issues remain outstanding.  Our commitment to finding a
sustainable long-term solution for all those in need of therapy remains unchanged and we appreciate the support and understanding the US community has demonstrated during this lengthy process.  We will continue to provide updates to the community as information becomes available. 

Download Press Release here

Genzyme Manufacturing Update

Genzyme invites all patients to participate in a forum to discuss recent FDA reports and media attention related to manufacturing operations in Allston, Massachusetts.

Date: Monday, November 23, 2009
Time: 6:00 PM – 7:00 PM (EST)
US Toll Free: 1‐800‐369‐3331
US Toll: 1‐312‐470‐7363
Passcode: Town Hall

To accommodate the large number of anticipated participants, an operator assistant will help you join the call starting at 5:30pm (EST), and will place you on hold until the teleconference begins.

We also recommend submitting your questions in advance of the call by sending an email to: TownHall@genzyme.com

The Town Hall teleconference will be recorded.

As a guideline we recommend that all patients with Pompe disease are vaccinated against influenza. This applies both to the seasonal influenza as well as for the 2009 flu pandemic (influenza virus A/H1N1 – also called Swine flu, Hog flu, Pig flu or Mexican flu).  It is especially important for patients with reduced lung function to be vaccinated because the H1N1 virus can cause increased breathing difficulties.  In order to maximise your body’s defences we advise Pompe patients to have their vaccinations, if possible, at least to 2 days before or at least 2 days after a Myozyme infusion.

The press release can be found here.

In addition, the AMDA created a one-page fact sheet regarding Pompe disease to help raise awareness of the condition. That fact sheet can be found here.

To read full press release, please click here.

For more information on the approval and how to access treatment, please read the Pompe Program Update.

BioMarin Pharmaceutical Inc. (Nasdaq: BMRN) announced today that it has received orphan drug designation from the U.S. Food and Drug Administration (FDA) for BMN-701, a novel fusion of insulin-like growth factor 2 and alpha glucosidase (IGF2-GAA) in development for the treatment of Pompe disease. An investigational new drug application (IND) for BMN-701 has been submitted, investigational material has been manufactured and a Phase I/II study is expected to start in the first quarter of 2011.

“Receiving orphan drug designation from the FDA for BMN-701 is a significant milestone for our Pompe program. As part of their assessment for designation, the FDA determined that BMN-701 is sufficiently different from alglusidase alfa (Myozyme/Lumizyme) to allow for a unique orphan designation. For this reason, clinical superiority over alglusidase alfa will not be necessary to secure orphan exclusivity for BMN-701,” said Jean-Jacques Bienaime, Chief Executive Officer of BioMarin. “This emphasizes our mission of developing innovative, products for orphan diseases with an unmet medical need. We believe BMN-701 has the potential to possibly deliver more enzyme to lysosomes compared to traditional mannose-6-phosphate targeted approaches using the recently acquired GILT technology.”

Abstract of Dr. Amalfitano’s proposal: Acid Maltase Deficiency (AMD, also known as Pompe Disease), is due to a patient’s inability to produce enough acid alpha glucosidase (GAA).  This results in glycogen accumulation in the patient’s limb muscles, as well as cardiac muscles (in those patients affected by the early age onset (infantile) form of the disease).  Based upon published results using animal models, intravenous infusion of recombinant rhGAA (Myozyme® or Lumizyme®) at current doses is not adequate to provide maximal improvement to so-treated AMD/Pompe patients.  However, current production methods for recombinant proteins such as GAA may not be capable of producing enough GAA enzyme to support higher and more frequent dosing.  Our multiple, previously published studies confirm that a single “Gene Therapy” treatment of most AMD/Pompe patients can potentially overcome this problem, by allowing for high level production of GAA from the livers of AMD/Pompe patients for a continuous period of time (24 hours a day), for >1 year in some of our studies. We propose to now confirm these promising results in larger animal models of AMD/Pompe , so that we can both determine the safety and potential effectiveness of gene therapy for AMD/Pompe in future human trials. The results will power future expanded studies in large animal models, as well help justify human clinical trials in patients affected by AMD/Pompe. 

The AMDA is hosting yet another webinar for the Pompe community on Feb 3, 2011.

Title: Genzyme’s Next Generation Pompe Treatment: Clinical Development Overview
Date:  Thursday, February 3, 2011
Time:  8:00 pm (ET); 7pm (CT); 6pm (MT); 5pm (PT)

Guest Speakers:
Edward Kaye, MD:  Dr Kaye, is currently Group V.P. and Therapeutic Area Head in Clinical Research at Genzyme Corporation where he supervises the clinical research in the lysosomal storage disease programs and in the genetic neurological disorders.

Alison McVie-Wylie, PhD:  Dr McVie-Wylie is the Scientific Director of the Pharmacology and Toxicology group at Genzyme Corporation.  Alison manages a group of scientists who design, execute, interpret and report studies to support preclinical drug development of novel biologic therapeutics.  Alison was the lead Scientist responsible for the preclinical development and licensure of Myozyme.

Registration link for the webinar

I hope you all plan on participating!  Please know that the AMDA will be buying a copy of the webinar and it will be posted onto the AMDA website for those of you unable to participate Feb 3, 2011.

On June 6, 2011 the AMDA will host a webinar on Respiratory Muscle Strength Training in Pompe disease at 12:00pm (ET); 11:00am (CT); 10:00am (MT); 9:00am (PT).

The Guest Speaker is:  Harrison N. Jones, PhD, BRS-S, CCC-SLP, Assistant Professor, Department of Surgery, Division of Speech Pathology & Audiology, Duke University.

Dr. Jones received his PhD from the University of Florida in Rehabilitation Science in 2007. He has been practicing as a speech pathologist for over ten years and continues to spend half his time in the clinic. Dr. Jones has published many peer-reviewed journal articles.  Additionally, he is co-author of the book Dysphagia in Movement Disorders, co-editor of Dysphagia in Rare Conditions, and the author of many book chapters.  His current research program is focused on speech, swallowing, and respiratory disorders in genetic diseases across the lifespan and their rehabilitation via exercise-based, behavioral approaches. Currently funded research projects are focused on adults and children with Down syndrome and Pompe disease.

To register for the webinar, please click here.

Download: Letter to Applicants
Download: Grant Application

PURPOSE
Prior authorization is a common cost containment method used by health plans and insurers that significantly delays medication accessibility for patients and imposes high costs that negatively impact operating margins for health care providers.  SB 866 streamlines the prior authorization process and improves access to prescription drugs by creating a standardized form for providers to use when making a request for prior authorization.

BACKGROUND
Health plans and insurers require physicians to fill out a prior authorization form when the provider prescribes a medicine or treatment not covered by the plan or insurer’s formulary.  Each health plan and insurer has their own forms for prior authorization.

Prior authorization negatively delays and impacts patient care.
·      A recent survey by the American Medical Association found nearly two-thirds of physicians wait several days to receive prior authorization from an insurer.
·      More than half of physicians experience difficulty obtaining approval from health plans and insurers.
·      A survey of pharmacists found that 61% of pharmacists knew of an incident when the requirement for prior authorization adversely affected patient care.

Prior authorization requires providers to spend excessive time on paperwork that could be spent providing patient care.
·      Physicians spend, on average, 20 hours per week handling prior authorizations. Studies show that navigating the managed care maze cost physicians $23.2-31 billion a year.
·      Pharmacists also find prior authorization time consuming, spending an average of 4.6 hours a week on requests.

Public programs must respond timely to prior authorization requests.
Both federal and state law specifies that the state must respond to prescription drug prior authorization requests under Medi-Cal, the state’s Medicaid program, within 24-hours.

SUMMARY

Under current law, health plans and insurers have five business days to respond to a prior authorization request for prescription drugs.  If the patient faces an imminent and serious threat to his/her health, the plan must respond in 72 hours.  Decisions to approve, modify or deny requests must be communicated within 24 hours of the decision.

This bill would:
·      Direct the Departments of Insurance and Managed Health Care to jointly develop a standardized prior authorization form, with input from stakeholders, by July 2012.
·      Specify that the form cannot exceed two pages and must be electronically available and transmittable.
·      Require health plans and insurers to use the standardized form for all prior authorization requests by January 2013.
·      Specify that if a plan or insurer does not use the form or fails to respond within two business days, the prior authorization is deemed granted.  Exempts Medi-Cal managed care plans from the two business day requirement.
·      Exempt physicians or physician groups who have been delegated the financial risk for prescription drugs by a health plan and does not use a prior authorization process from these requirements.

TARGET LEGISLATORS

Bill Berryhill – Stockton CA
State Capitol, Room 3141
Sacramento, CA 95814
916-319-2026
916-319-2126 fax

SERVING: Ceres, Escalon, Manteca, Modesto, Patterson, Ripon, Stockton, Turlock

Connie Conway –  Visalia CA
State Capitol, Room 3104
Sacramento, CA 95814
(916) 319-2034
(916) 319-2134 fax

SERVING: Baker, Barstow, Bishop, Boron, California City, Exeter, Farmersville, Fort Irwin, Independence, Ivanhoe, Landers, Lindsay, Lone Pine, Lucerne Valley, Mojave, Needles, Newberry Springs, North Edwards, Porterville, Rosamond, Springville, Strathmore, Three Rivers, Tulare, Visalia, Woodlake, Yermo

Paul Cook – Yucaipa CA
State Capitol, Room 5164
Sacramento, CA 95814
916-319-2065
916-319-2165 fax

SERVING:  City of Banning, City of Beaumont, City of Big Bear Lake, City of Calimesa, City of Hemet, City of Menifee, City of Moreno Valley, City of Perris, City of San Jacinto, City of Twentynine Palms, City of Yucaipa, City of Yucca Valley, County of Riverside, County of San Bernardino

Nathan Fletcher – San Diego
State Capitol, Room 2111
Sacramento, CA 95814
916-319-2075
916-319-2175 fax

SERVING:  Escondido, Poway, San Diego

Linda Halderman – Clovis / Fresno
State Capitol, Room 4009
Sacramento, CA 95814
(916) 319-2029
(916) 319-2129 fax

SERVING: Clovis, Fresno, Madera, Orange Cove

Brian Jones – La Mesa / San Diego
State Capitol, Room 3149
Sacramento, CA 95814
(916) 319-2077
(916) 319-2177 fax

SERVING: Alpine, Borrego Springs, Bostonia, Casa de Oro - Mount Helix, Crest, El Cajon, Granite Hills, Harbison Canyon, Jamul, La Mesa, Lakeside, Ramona, Rancho San Diego, San Diego, San Diego Country Estates, Santee, Winter Gardens

Jim Nielson – Colusa, Shasta Counties
State Capitol Room #6031
Sacramento, CA 95814
916-319-2002
916-319-2102 fax

SERVING:  Alturas, Anderson, Arbuckle, Biggs, Burney, Chico, Colusa, Corning, Cottonwood, Dorris, Dunsmuir, Durham, Etna, Fall River Mills, Fort Jones, Gerber, Gridley, Live Oak, McArthur, Montague, Mount Shasta, Orland, Red Bluff, Redding, Shasta Lake City, Tehama, Tulelake, Weed, Williams, Willows, Woodland, Yreka, Yuba City

Kristen Olsen - Modesto
State Capitol, 2111
Sacramento, CA 95814
916-319-2025
916-319-2125 fax

SERVING: Angels Camp, Chowchilla, Hughson, Madera, Mammoth Lakes, Mariposa, Modesto, Oakdale, Riverbank, Sonora, Waterford

David Valadao – Hanford
State Capitol, Room #2174
Sacramento, CA 95814
916-319-2030
916-319-2130 fax

SERVING:  Alpaugh, Armona, Arvin, Avenal, Bakersfield, Coalinga, Corcoran, Delano, Earlimart, Goshen, Hanford, Huron, Kettleman City, Kingsburg, Lamont, Laton, Lemoore, Lost Hills, McFarland, Pixley, Poplar-Cotton Center, Richgrove, Riverdale, Shafter, Stratford, Terra Bella, Tipton, Traver, Wasco, Weedpatch

CRANBURY, NJ, US, December 1, 2011 – Amicus Therapeutics, a biopharmaceutical company at the forefront of developing therapies for rare diseases, today announced the initial infusion of the first subject in an open-label Phase 2 drug-drug interaction study (Study 010) of AT2220 (duvoglustat HCl) co-administered with enzyme replacement therapy (ERT) in individuals with Pompe disease.

The purpose of Study 010 is to evaluate whether AT2220, an orally available, investigational pharmacological chaperone owned exclusively by Amicus, can be safely co-administered with the ERT alglucosidase alfa, the only approved therapy for Pompe disease. All subjects will be given a regularly scheduled ERT infusion. One hour prior to the initiation of the next ERT infusion, subjects will receive a single oral dose of AT2220. In Study 010, alglucosidase alfa will be measured in plasma and muscle tissue, with and without AT2220.

John F. Crowley, Chairman and Chief Executive Officer of Amicus Therapeutics said, “ERT is an important first generation treatment that has extended the lives of many individuals living with Pompe disease. We believe that chaperone-ERT co-administration has the potential to improve treatment outcomes for Pompe patients, and we are excited about commencing Study 010. Along with our work in Fabry, the co-administration approach may represent an important expansion of our technology platform into other lysosomal storage diseases where ERT is standard of care.”

In acid alpha-glucosidase (GAA) knock-out mouse models of Pompe disease, AT2220 co- administered with ERT increased ERT activity in plasma and uptake into key tissues, which corresponded with greater reductions in muscle glycogen, compared to ERT alone. Collectively these preclinical data highlight the potential for AT2220 to improve ERT in patients with Pompe disease.

“Results from Study 010, if positive, may form the basis for later stage studies that would allow us to evaluate the effect of AT2220 co-administered with ERT on glycogen reduction and ERT- related toxicity in patients with Pompe disease,” said Pol F. Boudes, Chief Medical Officer of Amicus.

Study Design

Study 010 is a Phase 2 open-label, multi-center study to evaluate the safety and pharmacokinetic (PK) effects of four increasing oral doses of AT2220 co-administered with ERT versus ERT alone in individuals with Pompe disease.

The study will enroll approximately 16 male or female subjects who have been on a stable dose and regimen of ERT for at least three months. All subjects will be given a regularly scheduled ERT infusion. One hour prior to the initiation of the next ERT infusion, subjects will receive a single oral dose of AT2220. Plasma enzyme activity and protein levels will be evaluated during each infusion. Muscle biopsies will be taken seven days after each infusion to measure tissue ERT activity with and without the chaperone, as well as the level of AT2220.
More information about Study 010, including patient eligibility, enrollment requirements and study location sites can be obtained by visiting www.clinicaltrials.gov: NCT1380743 or www.pompestudy.com, calling the patient hotline at 855-POMPE-33 (855-766-7333), or e- mailing inquiries to info@pompestudy.com.