The following is a transcript of a telephone interview conducted for the IPA(International Pompe Association) by Kevin O’Donnell of the AGSD-UK (Association for Glycogen Storage Disease-United Kingdom.

Kevin O'Donnell interviewed Paul Kaplan, General Manager of the Genzyme/Pharming Joint Venture, about the current state of the art regarding Genzyme's current ERT (enzyme replacement therapy) project.

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!

Pharming and Genzyme to Start Study for Pompe's Disease

Excerpt from Pharming Press Release--March 30, 2001

LEIDEN, the Netherlands, March 30, 2001 - Pharming Group N.V. announced the start of a Phase II-III clinical trial of an enzyme replacement therapy for Pompe's disease. The trial, under management of the Genzyme-Pharming Alliance LLC, will be conducted at medical centers in Europe and the United States. In this trial, the safety and efficacy of cell-derived recombinant human alpha-Glucosidase will be investigated in patients with the classical infantile form of Pompe's disease.

"The initiation of this trial demonstrates the ongoing progress in the development of a therapy for Pompe's disease and it is an important step towards the market launch of this much-needed product. It is therefore a major event for both the Pompe patient community and the Genzyme-Pharming partnership," said George J.M. Hersbach, Pharming's president and chief executive officer. "This trial will build on the results we have seen to date in the treatment of Pompe patients and we expect that it will provide us with the necessary data to submit the first registration dossier next year, which is according to plan." Genzyme and Pharming continue to have discussions with regulatory authorities regarding a registration dossier based on Phase II-III clinical trial results. Additional data may be required prior to filing a BLA in the USA. Mr. Hersbach adds: "We currently anticipate the first launch of the product for the infantile indication to take place in Europe followed by other geographical areas and other indications."

Pompe's disease is a hereditary, lethal disease caused by a lack of activity of the enzyme alpha-Glucosidase, which is necessary for breaking down glycogen and converting it into glucose, an important energy source for the human body. Patients suffering from Pompe's disease lack the ability to adequately break down glycogen leading to an accumulation of this substance, which results most prevalently in the degradation of skeletal, heart and lung muscle. The disease manifests itself in early or late-onset forms: infants diagnosed with the disease generally die of cardiac failure before reaching 1 year of age. For juvenile Pompe patients, the disease leads to serious motor disabilities, severe respiratory complications and death within two or three decades. An estimated 5,000 - 10,000 people in the Western World are affected by Pompe's disease.

Since 1998, Genzyme and Pharming have been working in partnership to develop a therapy for Pompe's disease. Results from extended and ongoing Phase I-II clinical trials at Duke University Medical Center (Durham, NC, USA), Sophia Children's Hospital (Rotterdam, the Netherlands) and University Hospital Essen (Essen, Germany) with human alpha-Glucosidase suggest that the enzyme may reduce heart size and improve heart and skeletal muscle functions. All nine infants currently under treatment will remain on therapy. They have reached ages varying from 20 to 30 months and are doing well. Results from the Duke-trial were recently published in Genetics and Medicine, whereas the results of the Rotterdam-study were published in The Lancet in July 2000........

Excerpt From Press Release-March 20, 2001

Genzyme General and Pharming Report Publication of Study Results for Pompe Disease Therapy

CAMBRIDGE, MA and LEIDEN,the Netherlands—Genzyme General (Nasdaq: GENZ), a division of Genzyme Corp., and Pharming Group N.V. (AEX: PHAR and EASDAQ: PHAR) announced the publication March 20 in Genetics in Medicine (http://www.wwilkins.com/GIM/we0086-01a.html) of results from the first 12 months of an ongoing Phase 1-2 clinical trial evaluating the safety and efficacy of the enzyme replacement therapy they are developing for Pompe disease.

The open-label trial, conducted at Duke University Medical Center, includes three infants with Pompe disease, a rare genetic disorder caused by the lack of the enzyme alpha-Glucosidase, which is responsible for breaking down glycogen into glucose. Patients with Pompe disease experience severe organ and tissue degradation resulting from the accumulation of glycogen in their heart and skeletal muscles.

Patients in the study have been receiving intravenous infusions of recombinant human alpha-Glucosidase purified from CHO cells for over 18 months. Because infants with Pompe disease generally die of cardiac failure before reaching 12 months of age, one of the study’s primary end points was heart-failure-free survival at 1 year of age. Given the limited life-expectancy of infants with this disease, no placebo control was employed. All three infants passed the critical age of 1 year. All currently remain on therapy and have reached the ages of 20 months, 22 months, and 26 months. (Pompe disease also manifests itself in late-onset forms, and can also be fatal for those who develop symptoms as juveniles.)

Trial results indicate that the enzyme replacement therapy may be able to reduce heart size and improve cardiac function. Left ventricular mass measurements decreased during therapy for the two patients who began the trial with increased left ventricular mass and severe cardiomyopathy. Both patients had left ventricular masses reduced to between 60-70 percent of baseline pre-treatment levels. These decreases suggest an overall reduction in heart size, a finding that was confirmed with chest X-ray images. Improved cardiac function has been sustained in all three patients in the trial.

Improvements in skeletal muscle function were also observed, although the significance and extent of these improvements have been more variable than with those in cardiac function. One patient showed marked improvement and currently has normal muscle tone and strength, as well as normal neurological and motor development evaluations. Muscle biopsies confirmed that significant reductions in glycogen accumulation occurred in one patient after enzyme replacement therapy. Initial improvements in two patients declined coincidental with a rise in antibody titers.

Study results indicated that recombinant human alpha-Glucosidase was generally well tolerated. Two patients experienced mild infusion reactions consisting of fever and rash. These reactions have been easily managed with routine pre-treatment medication. All hematological, liver and renal function parameters have remained in the normal range throughout the therapy period for all patients.

“Based on the encouraging results of this trial, we will begin very shortly a Phase 2-3 clinical trial for infants with Pompe disease,” said Henri A. Termeer, chairman and chief executive officer of Genzyme Corp. “We hope to subsequently expand this trial to include patients with later-onset forms of the disease. We are optimistic that this next study will demonstrate in a broader group of patients the positive impact of enzyme replacement therapy on Pompe disease.”

Genzyme and Pharming have been working in partnership to develop a treatment for Pompe disease since 1998. George J.M. Hersbach, president and chief executive officer of Pharming, adds: “Today’s clinical results publication is a welcome and exciting confirmation of the earlier published results in the Lancet of July 2000 on our jointly sponsored clinical studies of transgenic human alpha-Glucosidase at the Sophia Children’s Hospital in Rotterdam, The Netherlands, and similar studies at the University Hospital of Essen, Germany.” ......

Excerpt From Press Release--October 5, 2000

Genzyme General and Pharming Group Report Results From First Two Clinical Trials for Pompe Disease


Genzyme General and Pharming Group N.V., announced today that results from the first two clinical trials ever conducted for Pompe disease were presented this week at the American Society of Human Genetics (ASHG) meeting in Philadelphia. Genzyme and Pharming are working in partnership to develop a treatment for Pompe disease and are associated with both clinical studies.

There is currently no effective therapy for patients who have Pompe disease, a rare and fatal genetic disorder caused by the lack of the lysosomal enzyme alpha-Glucosidase, which breaks down glycogen into glucose. The accumulation of glycogen in the heart and skeletal muscles of patients results in severe organ and tissue degradation. Pompe disease manifests itself in early or late-onset forms. Infants generally die before reaching 12 months of age, and the disease is typically fatal for those who develop symptoms as juveniles. Pompe disease affects an estimated 5,000-10,000 people in the developed world.

“The very encouraging clinical results achieved in both of these studies give us tremendous confidence about moving forward to complete the development of the first treatment for patients who are suffering from Pompe disease,” said Henri A. Termeer, chairman and chief executive officer of Genzyme Corp. “These results reveal the great progress that has been made and give us hope that a therapy for all patients with this devastating disease will be available in the near future.”

On Tuesday, Y.T. Chen, M.D., Ph.D., of Duke University presented results from an ongoing Phase 1-2 study being conducted at Duke Medical Center, in which three infants with Pompe disease have received enzyme replacement therapy for over one year. The patients have been receiving intravenous infusions of a recombinant form of the enzyme human alpha-Glucosidase produced in CHO cells.

The preliminary results from the trial indicate that the product is capable of improving cardiac and skeletal muscle functions. In two patients, left ventricular mass measurements decreased during therapy. The infants have each passed the critical age of one year (currently 15-, 17-, and 20-months old) and continue to show improved cardiac function, thus averting the progressive cardiomyopathy and heart failure that normally lead to death prior to age one in untreated patients.

Improvements of skeletal muscle functions have also been noted, although the significance and extent have been more variable than with improvements in cardiac function. One patient showed marked improvement and currently has normal muscle tone and strength, as well as normal neurological and motor development evaluations. Muscle biopsies confirmed that significant reductions in glycogen accumulation occurred in one patient after enzyme replacement therapy. The study data showed that the CHO-cell product was generally well tolerated.*see Excerpt of Chen's Presentation that follows

Also at the ASHG (American Association of Human Genetics) meeting in Philadelphia (10-3-00), Dr. Ans T. van der Ploeg of Sophia Children’s Hospital in Rotterdam presented the results from a 36-week Phase 2 clinical trial of transgenic human alpha-Glucosidase. The trial results were published in The Lancet in July. The study was sponsored by Genzyme and Pharming.

In the trial, four infants with Pompe disease ranging in age from 2.5 to 8 months received weekly infusions of transgenic human alpha-Glucosidase. The starting dose was 15-20 milligrams of enzyme per kilogram of body weight. The dose was later increased to 40 mg/kg.

Results showed that transgenic human alpha-Glucosidase lowered lysosomal glycogen storage and improved tissue morphology. Total tissue glycogen content did not change. Skeletal muscle and strength improved, most significantly for the patient who had the least severe disease at the start of treatment. This infant reached milestones that are beyond expectations for a patient with the disease, including crawling and standing with the support of one arm at the age of 12 months. Improvements in motor function were also observed for all patients.

The most prominent effect of treatment was on the heart. By 36 weeks, cardiac size had decreased significantly to less than 30 percent of baseline. Left-ventricular posterior-wall thickness and left-ventricular mass index decreased in all patients.

All patients remain on therapy and have been treated for over a year. Adverse events such as fever, rashes, and flushing were transient and manageable by adaptation of the infusion rate and premedication.

Patient enrollment in the clinical trial evaluating the use of transgenic alpha-Glucosidase has been completed. All patients will continue to receive treatment with the transgenic product and will have the option of transitioning to the CHO-cell derived product.

Earlier this year, Genzyme obtained exclusive, worldwide rights from Synpac (North Carolina) Inc. to develop and commercialize the human alpha-Glucosidase product derived from CHO cells, shifting its focus from the development of human alpha-Glucosidase produced in the milk of transgenic rabbits. The decision to pursue the CHO-cell product was based on manufacturing considerations. Genzyme and Pharming believe that the CHO-derived product can be scaled to commercial production levels, qualified for use, and made accessible to patients faster than the transgenic product. This decision was not based on efficacy or safety concerns with either product. Clinical results obtained to date suggest that the CHO-derived and transgenic products show comparable clinical effects.

Genzyme and Pharming plan to initiate a second clinical trial of the CHO-cell product by the end of 2000 in patients with infantile-onset Pompe disease. The companies are currently in discussions with the U.S. Food and Drug Administration on the design of the trial, which is expected to involve medical centers in both the United States and Europe. Further details will be announced later this fall once the trial’s protocol has been finalized.. . . . . . . . .
- - - - - - - - - - - - - - - - - - - - -

Excerpt from presentation of Y.T. Chen ,M.D. Ph.D. (Duke University) at ASHG meeting (10-3-00)

Chen focused on the phase I/II trials underway at Duke with 3 IIa infants. Average age at diagnosis is 5 months and survival thereafter is 3 1/2 months on average, with a range of 0-9 months. Very few baby's survive a year. Recombinant enzyme from CHO cells (5 mg/kg twice weekly) has been given for more than a year to these 3 infants, now aged 20, 17, and 15 months. Symptoms, signs of allergy, liver/kidney/blood toxicity followed. The only adverse event so far has been an allergic reaction during infusion of the enzyme that was treated with benadryl and did not interfere with the trials.

They have been measuring heart and lung function, muscle strength, motor development, and urine/plasma oligosaccharide levels.

By echocardiogram, the volume of the left ventricle has increased steadily (reflecting smaller muscle size) over three months to normal and stayed normal. The left ventricle mass has fallen steadily over the year in all three babies. The size of the hearts on X-ray has gone from very large to borderline large in two and from moderately large to normal in one. Heart function is normal in all three.

As for muscle strength, two showed improvement to near-normal levels over 3 months, then had declines to previous levels as their bodies made antibodies to the enzyme. The third's muscle strength climbed into the normal range (to the 50th percentile) and remains there. He has no antibodies and evidence of an enzyme precursor in his cells that may prevent him from responding with antibodies to the administered enzyme.

Microscopic examination of his muscle fibers is normal now.

Response to therapy may depend on stage of the disease and whether or not one makes antibody.

The older brother of the third patient died at nine months of age. This baby walked at 12 months of age, has normal developmental milestones, and was shown riding his toy bike as an active toddler.

- - - - - - - - - - - - - - - - - - - - -

Earlier this year, Genzyme obtained exclusive, worldwide rights from Synpac (North Carolina) Inc. to develop and commercialize the human alpha-Glucosidase product derived from CHO cells, shifting its focus from the development of human alpha-Glucosidase produced in the milk of transgenic rabbits. The decision to pursue the CHO-cell product was based on manufacturing considerations. Genzyme and Pharming believe that the CHO-derived product can be scaled to commercial production levels, qualified for use, and made accessible to patients faster than the transgenic product. This decision was not based on efficacy or safety concerns with either product. Clinical results obtained to date suggest that the CHO-derived and transgenic products show comparable clinical effects.

Genzyme and Pharming plan to initiate a second clinical trial of the CHO-cell product by the end of 2000 in patients with infantile-onset Pompe disease. The companies are currently in discussions with the U.S. Food and Drug Administration on the design of the trial, which is expected to involve medical centers in both the United States and Europe. Further details will be announced later this fall once the trial's protocol has been finalized . . . . . . . . .

- - - - - - - - - - - - - - - - - - - - -

Statement from Genzyme and Pharming

Genzyme Corporation and it's development partner, Pharming N.V., are committed to providing an effective and practical therapy for Pompe disease that can be made available to the greatest number of patients in the shortest possible time. As part of this commitment, the companies desire to maintain open communications with the patient community. Genzyme and Pharming will work with the IPA and other patient advocacy groups to disseminate accurate information concerning clinical development of this therapy in a timely manner.

During the spring of 2000, Genzyme and Pharming shifted the focus of their development work away from drug purified from the milk of transgenic rabbits to drug produced in cultured Chinese hamster ovary (CHO) cells. This decision was not based upon safety or efficacy concerns with either product. Results obtained so far suggest that the transgenic and CHO-derived drugs show comparable clinical effects, however there have not yet been enough patients treated with either product for a regulatory agency to evaluate its safety and effectiveness for approval.

The switch to developing the CHO-derived product was based on manufacturing considerations. Genzyme and Pharming believe that the CHO-derived product can be scaled to commercial production levels, qualified for use, and made accessible to patients considerably faster than the transgenic product.

That said, why have Genzyme and Pharming stated that there is only limited drug availability at present? There are three answers to this question. First, it was not known until patients were initially treated that a larger amount of drug than anticipated would be required. As a result of the higher than expected material requirement, it was necessary to secure additional resources to produce larger amounts of enzyme. Second, there is a limited worldwide supply of the equipment necessary to produce these large amounts of enzyme. Finally, the task of preparing large quantities of a purified enzyme is complex and time consuming. At each step it is necessary to ensure that the product is comparable in terms of its identity, performance, and shelf life. Genzyme and Pharming are working diligently to develop large scale manufacturing capabilities to provide an adequate supply of the medication.

Genzyme and Pharming plan to initiate a clinical trial by the end of 2000 in a limited number of patients with infantile onset Pompe disease, pending the outcome of ongoing discussions with the US Food and Drug Administration and the successful production of the drug for the clinical trial. The trial is expected to involve centers in both the US and Europe. Following enrollment of the patients with infantile onset disease, Genzyme and Pharming are planning to expand patient enrollment to involve a larger number of patients in order to supplement the initial data and support the use of the product in older patients. Further details of the trial, including the enrollment criteria and the clinical centers where it will be conducted will be made publicly available once the details have been finalized.

We remain committed to making new therapies available to Pompe patients as rapidly as possible, and look forward to working with patient associations to keep you up to date on our progress.

Paul L. Kaplan, Ph.D., M.B.A.
Senior Director of Program Management
Genzyme (www.genzyme.com)

Results of First 36 Weeks of Treatment in Infants in Netherlands Published

The Lancet--July 29, 2000

Recombinant human alpha-glucosidase from rabbit milk in Pompe patients
Lancet 2000; 356: 397-398
Hannerieke Van den Hout, Arnold J J Reuser, Arnold G Vulto, M Christa B Loonen, Adri Cromme-Dijkhuis, Ans T Van der Ploeg

Following is a short summary of the information published:

The results of the effects of the enzyme, human acid alpha-glucosidase, on four infantile Pompe patients was described by Ans Van der Ploeg, M.D, Ph.D., et al, in this issue of The Lancet Interactive. It documented the successful treatment of 4 babies with the infantile form of Pompe's disease who were treated with recombinant human alpha-glucosidase from the milk of transgenic rabbits. The results showed that there was uptake of the enzyme in skeletal muscle and the muscle function was stimulated. The treatment reduced heart size, improved heart function and condition, and seemed to be responsible for the prolonged lives of the four babies in the clinical trial.

Pompe's disease is a fatal muscle disease caused by the lack or deficiency of the lysosomal enzyme acid alpha-glucosidase (acid maltase). The infantile form of the disease is usually fatal within the first year of life. All four babies in the trial passed this critical one year juncture.

The report covered the first 36 weeks of the infantile clinical trial which began in January 1999, and is still ongoing in the Netherlands at Sophia Children's Hospital, an affiliate of Erasmus University, Rotterdam.

Genzyme General Obtains Rights to
Pompe Disease Therapy from Synpac

Genzyme and Pharming to Fund Commercialization

Cambridge, Mass., USA, Durham, N.C., USA, and Leiden, the Netherlands, April 19, 2000 -

Genzyme General and Synpac (North Carolina) today announced an agreement under which Genzyme will obtain exclusive, worldwide rights to develop and commercialize Synpac’s Pompase™ enzyme replacement therapy for Pompe disease, a lethal, hereditary muscle disorder. In a partnership, Pharming and Genzyme announced their intention to share equally in the program and the funding for the commercialization of Pompase™.

Genzyme will make a $19.5 million initial payment to Synpac, and Pharming will issue a convertible note to Genzyme for an aggregate principal amount of $10 million. Other terms of the agreement were not disclosed. Genzyme and Pharming expect to initiate pivotal clinical trials of Pompase in the second half of this year.

Pompase is a recombinant form of the enzyme human alpha-Glucosidase produced in mammalian cell culture using Synpac's CHO cell line licensed from Duke University. An initial clinical trial of the product was completed in 1999. Three infants with Pompe disease received treatment with Pompase for three months, and all patients remain on therapy. Results of the trial, which was conducted under the supervision of Dr. Y.T. Chen at Duke Medical Center, recently have been submitted for publication.

"These agreements are consistent with Genzyme's, Pharming's and Synpac's commitment to develop the most effective treatment possible for patients with Pompe disease", said Henri A. Termeer, chairman and chief executive officer of Genzyme Corp, "We believe Pompase holds great promise for these patients, and we will move rapidly to accelerate its development.'

Leslie Koo, chairman of Synpac, said:"Genzyme is a recognized leader in the development of therapies for rare genetic disorders. We believe that their expertise, commitment and substantial global resources provide the best opportunity to make this therapy available to patients with Pompe disease as quickly as possible.'

Pharming's president and chief executive officer George J.M. Hersbach commented on the agreement: 'For Pharming this is a unique opportunity to combine its technology with that of other fascinating developments, both scientifically and business wise. This will ensure that in the end, Pompe patients will receive the best therapy. Both Genzyme and Pharming will significantly strengthen their positions in the development of a therapy for this serious disease, and will continue to equally share costs and profits."

Genzyme General and Pharming plan to equally fund the commercialization of Pompase and share in the program accordingly. The companies established a joint venture in 1998 to develop human alpha-Glucosidase as an enzyme replacement therapy for Pompe disease. In late 1999, Pharming completed a 36-week phase II clinical trial with transgenic human alpha-Glucosidase at the Sophia Children's Hospital in Rotterdam, the Netherlands under the supervision of Dr. A.T. van der Ploeg, and the results have been submitted for publication. A phase II clinical trial evaluating the use of human alpha-Glucosidase in infants is ongoing in Essen, Germany. All patients currently on treatment with transgenic human alpha-Glucosidase will continue to receive this product.

Pompe disease is caused by the lack of alpha-Glucosidase activity, an enzyme involved in the breakdown of glycogen into glucose, a primary source of energy for the human body. Patients suffering from this disease show accumulation of glycogen in various tissues, resulting most prevalently in degradation of skeletal, heart and lung muscles. Pompe disease can manifest itself in early and late onset forms. Infants suffering from Pompe disease generally die before reaching 12 months of age. The clinical appearance of the disease varies from rapid progress and cardiac involvement in the infantile form to slow progress and severe respiratory complications in the later onset forms. Pompe disease affects an estimated 5,000 - 10,000 people in the developed world.

The agreement between Genzyme and Synpac is subject to clearance under the Hart-Scott-Rodino Anti-Trust Improvements Act and customary closing conditions. The agreement between Genzyme and Pharming is subject to receipt of corporate approvals.

Genzyme General develops and markets therapeutic products and diagnostic products and services. Genzyme General has three therapeutic products on the market and a strong pipeline of products in development focused on the treatment of rare genetic diseases. A division of the biotechnology company Genzyme Corp., Genzyme General has its own common stock intended to reflect its value and track its economic performance.

Pharming Group N.V. focuses on the development, production and commercialization of human therapeutic proteins using the company's proprietary technology. Pharming's portfolio comprises products for (rare) genetic disorders, surgical and traumatic bleeding, infectious and inflammatory diseases, tissue and bone repair and blood-related disorders. The company has operations in Belgium, Finland, the Netherlands and the USA,

Synpac (North Carolina), Inc. is a drug development company located in Research Triangle Park.

Pharming
Health Care Products

Pharming B.V.
Niels Bohrweg 11-13
2333 CA Leiden
The Netherlands

Pharming's first Phase II clinical trial for Pompe's disease finalised, showing survival, skeletal muscle regeneration and overall improvement of heart and lung functions

Leiden, the Netherlands, March 15, 2000

The bio-pharmaceutical company Pharming Group N.V. (Pharming) of Leiden, the Netherlands (AEX, EASDAQ: PHAR), in conjunction with its joint venture partner, Genzyme General of Cambridge, MA, USA (NASDAQ: GENZ) has finalised with positive results its first Phase II clinical study with transgenic recombinant human alpha-Glucosidase. The study was a single centre open label Phase II study in infantile Pompe patients, performed at the Sophia Children's Hospital in Rotterdam, the Netherlands, with Dr Ans van der Ploeg, pediatrician and a world expert on Pompe's disease, as principal investigator. Pompe's disease is a hereditary, lethal muscle disorder, for which until now there has been no therapy. The human alpha-Glucosidase for the clinical trial in Rotterdam has been produced in the milk of Pharming's transgenic rabbits at its plant in Geel, Belgium.

Normal levels

After 36 weeks in the study, the four included infantile patients have reached the age range of 12 to 17 months, which is well beyond the mean age of survival in untreated infantile Pompe patients. Repeated muscle biopsies demonstrated that the transgenic recombinant enzyme is taken up by the main target tissue, skeletal muscle, reaching normal levels of alpha-Glucosidase activities, which are comparable to healthy individuals. In the skeletal muscle tissue, the enzyme shows to be active, since on histological evaluation, lysosomal glycogen storage decreased and muscle regeneration was observed.

The most prominent effect was seen on the heart. In untreated patients, the left ventricular posterior wall thickness increases over time as the disease progresses. After start of treatment, the slope of left ventricular posterior wall thickness versus time changed significantly for all four patients, This was in-line with a concomitant significant decrease of left ventricular mass index (a measure for the dimension of the left ventricle) over time, with the largest improvement to less than 30% of the baseline value at the beginning of the study. In addition, symptoms of cardiac instability diminished in all patients,

The treatment appears to have an effect on respiratory function. The two patients included prior to 3 months of age did not become dependent on artificial ventilation and currently they are treated as outpatients, receiving their weekly treatment on a day care basis.

Objective

The objective of this clinical study was to obtain data of safety and efficacy of alpha-Glucosidase. Following a two-week baseline period, four patients were included and treated for 36 weeks for a total of 144 infusions. Patients were started at a dose of 15 and 20 mg/kg per week while during the study, based or monitoring of muscle tissue activity levels, the dose was increased to 40 mg/kg in a once a week intravenous infusion. The enzyme was generally well tolerated, Adverse events reported were fever, malaise, erythematous rash, sweating, hypoxia, flushing and tachycardia. These events were transient and could be well managed. No changes were found in routine hematology and clinical chemistry and no changes in blood pressure during or after infusion were observed.

Skeletal muscle function and strength improved in all patients, with one patient reaching development milestones which are beyond normal observations for untreated patients with infantile Pompe's disease. Generally the increase in muscle function was best observable in the strength of the arms. Long term follow-up will be needed to assess the final outcome: safety, efficacy and impact on quality of life for these children and their respective families.

Critical breakthrough

"Of course we will not draw final conclusions at this stage of our clinical studies, but the results so far have exceeded our initial expectations", says George J.M. Hersbach, president and chief executive officer of Pharming. "For myself, as president of this company, it is really moving and exciting at the same time to hear that one of the infants in the trial can even walk now without help of its parents. Pharming will supply the four children with its human alpha-Glucosidase to continue treatment. To stay alive, the children need life-long treatment." George Hersbach adds that the results in Rotterdam represent a critical breakthrough for Pharming, and the medical world as a whole. The study lends weight to the idea that using transgenic animals to produce critical human proteins is an effective way of combating some of the most difficult-to-treat illnesses,"

Filing beginning 2001

A few months ago a second Phase II clinical trial was started simultaneously by the same investigation team at the Sophia Children's Hospital in Rotterdam, in which three juvenile Pompe patients are involved, who are treated with Pharming's transgenic recombinant alpha-Glucosidase. The first results of that trial are expected to be available before this summer. A Phase 1 infantile clinical trial has been set up recently by the Pharming / Genzyme joint venture in Essen, Germany. With further positive results, regulatory filing for alpha- Glucosidase for the first treatment of Pompe's disease might be possible beginning of 2001 envisioning market launch mid 2001.

In October 1998 Pharming and Genzyme formed a joint venture to develop enzyme replacement therapy for the lysosomal storage disorder Pompe's disease.

Pharming focuses on the development, production, and worldwide commercialisation of human therapeutic proteins, produced at high levels in the milk of transgenic animals that have been created using the company's proprietary technology....

PHARMING
Health Care Products

Pharming B.V.
Niels Bohrweg 11-13
2333 CA Leiden
the Netherlands

Pharming and Genzyme Form Joint Venture
to Develop Treatment for Pompe's Disease

Leiden, the Netherlands/Cambridge, Mass., October 14, 1998--Pharming Group N.V. (Easdaq: PHAR), the Netherlands biopharmaceutical company, and the American biotechnology company Genzyme General (Nasdaq: GENZ), has created a joint venture to develop and commercialize worldwide the enzyme human alpha-glucosidase as a treatment for Pompe's disease, a lethal lysosomal storage disorder.

Based on the results of Pharming's phase I clinical trial conducted to assess safety, tolerability and pharmacokinetics of human alpha-glucosidase in healthy volunteers, Genzyme and Pharming expect to commence phase II/III clinical trials by the end of 1998. In September 1996, Pharming received orphan drug designation for human alpha-glucosidase by the US Food and Drug Administration (FDA), potentially giving the company a seven year market exclusivity in the US following FDA approval.

Under the joint venture agreement, Genzyme will pay the first US $14 million of costs of the product development program. Thereafter, costs and revenues will be 50/50 shred. Upon first approval by the FDA of human alpha-glucosidase, Genzyme will make an additional payment to Pharming of US $7 million. A management team consisting of an equal number of representatives from both companies will manage the joint venture. In July of this year Genzyme also made an equity investment in Pharming of US $14 million.

"The new agreement further validates Pharming's technology," says George J.M. Hersbach, president and chief executive officer of Pharming. "The joint venture links Genzyme's marketing experience to Pharming's proprietary technologies and product development capabilities and will enable us to accelerate the process of bringing a therapy for Pompe's disease to market." Pharming has additional products for genetic disorders in the pipeline, including products for other lysosomal storage disorders.

Pompe's disease is one of a family of 40 rare diseases known as lysosomal storage disorders. Genzyme's Cerezyme® and Ceredase® enzyme replacement therapies are the only effective treatments for Gaucher's disease, one of these disorders. Cerezyme and Ceredase--Genzyme's lead products, had combined sales in 1997 of US $333 million.

When the two companies first announced their intention to form a joint venture in July this year, Henri A. Termeer, president and chief executive officer of Genzyme Corp, said that Genzyme is convinced that transgenic technology holds great potential for producing proteins to treat enzyme deficiencies underlying lysosomal storage disorders. Termeer further expressed Genzyme's great enthusiasm about working with Pharming to develop a potentially life-saving treatment.

Pompe's disease, also known as acid maltase deficiency or glycogen storage disorder type II, is caused by a complete or partial deficiency of the enzyme human alpha-glucosidase. The disease results in a build up of glycogen in various muscles and organs of the body, leading to fatal muscle degeneration. Pharming and Genzyme General believe administration of human alpha-glucosidase to patients suffering from Pompe's disease could alleviate or eliminate symptoms.

Under the program of the joint venture, collaborations with patient organizations and clinicians will be continued and intensified. In the USA, the Acid Maltase Deficiency Association (AMDA)* represents all US patients suffering from Pompe's disease. AMDA offers support and information services to patients and their relative and also maintains a patient registry which will be used to notify patients and their physicians of approaching therapy. The Netherlands Association for Neuromuscular Disease* in the Netherlands (VSN) and the Association for Glycogen Storage Disease* in the United Kingdom are equally involved and also maintain registries for patients in their countries. Similar organizations that have been established in other countries may also be involved. Pompe's disease affects an estimated 5,000-10,000 people in the Western world.

Genzyme recently formed a joint venture with BioMarin Pharmaceutical, Inc., to develop alpha-L-iduronidase as a treatment for Hurler's syndrome, another lysosomal storage disorder. In addition, Genzyme is conducting a phase I/II clinical trial of alpha-galactosidase as a treatment for Fabry's disease. The company is also investigating gene therapy approaches to treating lysosomal storage disorders.

Pharming focuses on the development , production and worldwide commercialization of human therapeutic proteins, produced at high levels in the milk of transgenic animals that have been created using the company's proprietary technology.