AMDA Pompe’s Disease Conference Call Transcripts

Session # 9
Thursday, January 27th, 2005
Topic: 2nd FDA Teleconference
Speaker: Dr. John Hyde, Medical Team Leader at the FDA

I would like to introduce Dr. John Hyde. He graciously agreed to come and answer all of our questions. I am going to give a little background.

He received his PHD in statistics from Stanford University and got his MD degree from the University of Miami. Dr. Hyde joined the FDA 13 years ago and since then he has been involved in the review and approval of wide range of medical products including drugs for treating addiction disorders, analgesic drugs, arthritis drugs, clinical laboratory devices, and cardiovascular devices. Dr. Hyde is currently the team leader of the vision of therapeutic, biologic and internal medicine products where he has been responsible for over-seeing the review of a variety of biologic products, including those used for treating inborn errors for metabolism. Welcome Dr. Hyde and thank you for taking the time.

Well thank you. Ok there are several questions you supplied, but I thought it would be helpful if I go over just sort of an overview of what the FDA does and the drug approval process, actually the drug development and approval process. I think it will provide sort of background on context and then we can go through those specific questions and then fill in what is missing there.

Q: How big is the FDA facility?

A: There are about 10,000 people. It includes several different sections and it really involves several different aspects of the economy. There’s a center for foods, center for veterinary medicine, center for toxicologic research, a center for devices; it covers everything from Band-Aids to artificial hearts, a center for biologics; which is vaccines, blood banking, gene therapy, and then the center for drugs which is about a third of the FDA personnel, I believe. It is probably the largest center in there.

Most of the people at the FDA, that work here outside Washington, but there is certainly a large number that are in field offices throughout the country; doing inspections or working on enforcement actions.

Before I get started, just an issue about confidentiality. Most industries when they have product ideas or products under development, research consider that to be trade secret information, but because pharmaceutical research and development involves experimenting with human subjects, they are subject to special regulations and a high degree of oversight. So then they are required to submit information that would usually be considered trade secret to the FDA so we can exercise our oversight function, but as sort of a compliment to that we have to keep that information confidential. I’m not allowed to then discuss products that are under review. Some companies make that information public if they choose to, but others keep want to keep it secret for variety reasons and so we have to respect that confidentiality; so I really won’t be able to talk about anything specific that hasn’t been approved.

As we go along, you know there is a lot of lingo and drug development, so if I say anything that is unclear it is perfectly fine to interrupt and ask for a clarification as we go along. I may sort of lapse into the lingo as part of this.

First of all, I will have to simplify things because there are certainly a lot of special cases and exceptions and I can’t go into all the details, but I will try to present a more or less generic scenario for how a drug is developed and what the FDA does during that process. The FDA doesn’t do any of the studies itself. These are really done by the company. They do all the testing of the manufacturing facilities, laboratory studies, animal studies, clinical studies, by themselves. So the FDA doesn’t do any of the drug evaluation per say, but it does review all that material that the companies provide to us. The FDA has it’s hands in it really much of the way and we’re not just sort sitting there waiting for everything to get done and then they submitted to us for an approval really very much involved in many products all the way from the beginning of drug development to the point where it finally gets submitted to us for approval.

If you look at the food and drug law, it starts out by saying you can’t distribute a drug unless it has been approved by the FDA. So then the question is how do you study an unapproved drug, and the law allows for a special exemption, which they call the investigational new drug exemption and it’s called (IND) for short. So I am going to be using that term cause it’s sort of common term the IND. You can sort of think of it as a license to investigate a drug. You don’t get any certificate to hang on the wall, but we just open a file for you, but that is how the drug development is done under an IND, and what it does is lets the company distribute the drug and give it to subjects as long as they follow certain procedures.

Now, large company can have several INDs for different products or sometimes even for the same product if they are looking at it to treat different diseases they’ll have different INDs going, but a small company may just have one for their main product. All studies of the drug, before it gets approved anyway, are done under the IND and the FDA keeps a file on the drug development program and it’s not just a manila folder. We’re talking often volumes and volumes of information that the company will submit during the drug development process.

Now, to get one of these INDs going the company has to submit results of their testing on the product, it covers sort of basically three things, the product manufacturing process, results of any animal studies they’ve done already with the product, and then their proposal for what to do for human studies, and when the FDA gets this information it has 30 days to decide whether it is ok to go ahead with the program or whether they need to put what we call a hold on it. We tell them they can’t start until they either submit certain information or make certain changes to their program. Now this information is usually reviewed by a team of product reviewer who is usually like a PHD chemist or an immunologist, another expert in animal studies, maybe a PHD pharmacologist or a doctor of veterinary medicine or sometimes a physician, and also a doctor that looks at the clinical protocol to evaluate the light of all the other information.

As I have said, the FDA has 30 days to decide that they have to stop the study or actually not start the study, but usually what we’ll try to do is if we see a problem we will try to work with the company and try to get whatever additional information or ask them to change their plan in a way that makes it acceptable. So it is unusual that we would actually have to tell a company not to go forward, but that is an option if we don’t think that it is safe to do so. Now sometimes it is an IND, for a new drug this might be a first time it would actually be used on humans. Sometimes it is a drug that has been used elsewhere before, but sometimes it can be a little scary. The first time it goes into a person you haven’t had that experience before. So we have to rely what we have learned in animal studies to try to decide what’s the safe dose to start out at and what sort of monitoring might be necessary, but I think it is a testament to the system that really misadventures are really exceedingly rare.

Are there any questions up to this point? No.

Ok.

Now the drug is often in this IND phase for many years and people both at the FDA and the drug company may change over that period of time, although, we usually try to keep one person on it so that they are familiar with the product. Now every time a new human study is done with that product a protocol has to be submitted to the FDA and at each point we have the option of deciding if we don’t think that it is safe of putting that study on hold. Usually those studies go through several phases, usually the first studies going to be just like a single dose study to see what happens, starting at very low doses and then going progressively higher looking for any problems with safety, if things look good at that point they may go, that is usually called phase 1 and then the next step is called phase 2 studies, then there they may try to give it for longer periods of time and also try to use it in patients to really see if there is going to be a therapeutic affect. Try to figure out what the best dose is, what the dosing interval and sort of fine tune it, really learn what their drug can do and how best to use it.

That phase may actually last for quite a while for some drugs certainly for common diseases there may be various ways they want to try to investigating it, but for rare diseases where you have only a few patients that stage may be fairly limited and you may want to move more rapidly, on to what is known as phase 3. And phase 3 is when the company is doing really its main studies that would support an application for approval to the FDA and usually what we set up the standard is two well controlled i.e. some important comparative group often a placebo controlled, but other possibilities are used sometimes too with the purpose of demonstrating that it really has a beneficial clinical affect. In further evaluating whatever safety concerns there may be for it, and they really try to get it tested under more or less realistic conditions i.e. not a very select patient population, but you know everybody that might reasonably be treated with it or at least put the population of people the company would hope to have it indicated for.

Q: How does the FDA define an official affect?

A: That varies and for some things it sort of a condition that may affect many other treatments already there is sort of a standard is to what is considered significant or beneficial affect. For other things that are more novel, it can be a little more difficult because there may be no real standards or studies that have been done before that really define what that is. We sort of have the approach would be that we really like to have it be a clinically meaningful affect. So that in most cases showing a laboratory parameter changes something isn’t usually a sufficient indication of benefit. We like to see something that patients can really recognize as being "I’m better in this way or that way." For certain things, like blood pressure treatment though. Blood pressure is used as the indicator of affect, but in that case there is a pretty long track record an established benefit of lowering blood pressure. As we get into areas where less maybe known about it, we usually fall back on stuff that we can talk about clinically. At the same time the company may also be doing additional animal studies, there maybe although human data, human studies are really the most important thing for deciding the safety and effectiveness of a drug. There maybe other questions that we need other animal studies to address like does it cause cancer, what’s the effect on pregnancy those are the things that maybe carried out as animal studies and would still be important things to know.

Q: When is it appropriate to use a surrogate marker, I’m thinking like a clearance of a sub-straight for lysosomal storage disease, is that considered a surrogate marker and is that something that would be considered clinically meaningful or can you assume that if you reduce the amount of sub-straight that it’s going to have a clinically meaningful affect?

A: Not necessarily. Not without some other information I mean if a surrogate marker like that a laboratory test is used for example is used for the basis for approval. We usually like to have it to have a known relationship to some other clinical event like hypertension, lowering blood pressure. You know studies have shown that does have a beneficial affect so in that case we would accept it, for something else a laboratory parameter in an area which we don’t really have much experience, to know. That may well be a good thing, but how does it really carry over into something more tangible there we would have more questions about using something like that.

There are some special accelerated approval processes that do rely more on the surrogate marker rather than the clinical end point.

Q: By clinical end point, do you mean like improvement in respiratory function, or improvement in muscle strength or something like that?

A: Yes, something that can walk farther, something that sort of on the face of it would be an improvement.

Q: So when the company is in there talking with you, do you setup an actual number and say ok you’ve picked your marker if you can improve that by 20% we will approve, but if you can’t improve by 20% we will reject? Or is it kind of more like a negotiation and what you feel like whether it is positive?

A: Well these can often be difficult questions. We usually challenge the company to provide us with information that says "if this improves by 10% improvement that is something that is really meaningful." For example: in certain respiratory testing, at least for certain conditions or for certain diseases an improvement by 10% is something patients can perceive as being better and if that has been established by some other studies then that would be useful information and to use in trying to decide how big an improvement we’ve really think to be something important.

Q: It wouldn’t just be for a few select, it would have to be for an average group? Let’s say 50% of the group increased by 10% to 20% on the respiratory functions, therefore, that is definitely significant and we will move forward?

A: Yes, we like to set those ground rules before they go into the major studies so everybody’s clear on what the expectations are and to the extent we can, we would like to base it on something other than a good feeling about it. If there is evidence from other sorts of studies, that changes of this kind are really meaningful. That is certainly helpful information, but it can be sort of challenging to come up with something.

Q: And would you take previous cases from before and look at that data as well, in conjunction with the one year trial we are looking at? Because there is also an expanded access program currently being done right now and would you look at those patients and include them?

A: Well I am not going to talk about any particular program, but certainly information like I talked about a phase 2 study is where you begin to do some exploratory things to see what the size of the affect of the drug might be and in the context of doing those preliminary studies it well could generate information that will be helpful in setting what the benchmark should be in your pivotal or main studies. It can be a challenge and to some extent its negotiation. We usually sort of put on the company to come back and convince us of whatever targets they are aiming for are going to be meaningful.

Q: And I have a child that he’s 2 ½ and he started at 8 months, since Pompe they usually die before a year, won’t that be a big decision factor too in this particular drug?

A: We try to adapt to whatever the disease situation that is appropriate for that condition. It is hard to speak in generalities I usually have to get down to the specific cases and that depends on what particular aspect of the disease the drug maybe most affective in treating and that maybe the thing to try to focus on when they do the main studies.

Q: Can you talk a little bit about using a placebos and the placebo trial? Initially we were told that wouldn’t be necessary and I don’t know if you can talk about this, but now it seems like a placebo will be initiated for this next late onset trial. Can you talk about that at all?

A: Yes, I will get to that in a little bit and I think when I go through the questions we will go through that a little more too.

Q: Clinically meaningful, do the patients have any role in deciding what is clinically meaningful? Or is it decided by the FDA? Or some other agency?

A: Well, I mean in some cases well established situations there may be sort of excepted standards on what would be. In cases where we need some new information, certainly experience with patients or patient report and that sort of thing could be helpful in trying to set with the standards maybe.

Q: I mean if there is a 5% increase in muscle strength or respiratory function. Would you ever consider that not clinically meaningful? I mean is it a statistical significant increase is that always considered to be meaningful.

A: No, it’s not. Often studies are hard enough to do so that often a statistically significant difference will be large enough to be also clinically significant, but a statistically significant change isn’t necessarily all we would require of a product in general.

Q: What if you saw a change a lot faster than what was planned for the one year extension? What if you saw a significant clinical and statistical change within a four month period and even though the trial was set for one year, would you make a move on it then? And change everything and really review and say my gosh we don’t need to do this for a full year, let’s change it now?

A: Well, there are certainly a variety of possible designs for pivotal studies. Some of them involve interim looks and some of them are set for a fixed period of time. We’ll go and do the study. If there is uncertainty, or a possibility that the effect maybe different or larger, one always hopes better than expected, a study can be designed to actually formally planned to look early with the possibility that we may have more information sooner than we thought and that may be a way to do it, but that usually has to be planned ahead of time because it could be rather difficult then to interpret if it is just something that that cropped up. And things do crop up, and it is hard to really evaluate how unusual that is.

Q: Doctor, can you please speak later on, what the patients can do if anything in the process?

A: Ok, I think that some of the questions touched on that too.

Ok, well then let me continue. We talked about kinds of studies might be done during the IND phase to then get ready for an application. Oh, another thing I want to mention is Fast track, the term fast track sometimes come up, and that is a designation that’s given to an IND and what it is, is a recognition by FDA that the product is showing some promise in treating a significant disease where other options don’t exist. Then the FDA can designate it as a fast track drug and what that does is guarantees a certain level of accessibility to the FDA during the drug development process. Sort of to the matter of course, we will often meet with the companies they will request meetings with us during the drug development and with good cause. We will usually meet with them and discuss with their program. Certainly a fast track designation makes it much more accessible pretty much any good reason and we’ll be happy to discuss things with them and work closely with them if they have that fast track designation also have some implications for how it is treated during the actual application and review later on.

There was a question about who actually does all this work under the IND?

As I mentioned, the FDA isn’t really doing it. The company is really responsible for doing these testing. Sometimes smaller companies may actually kind of farm these things out of. There are agencies that are known as (CRO) Contract Research Organizations, which can do some of the animal studies and actually manage some of the clinical studies. Often they are experienced in doing these things so they may be better than some smaller companies. Although, larger companies usually have the personnel and the expertise to run these things themselves, but even the clinical studies they usually are actually done frequently at academic centers and supervised by academic physicians it may not be on the company payroll, but are done under contract with the company.

Sometimes even common diseases the simple treatments may actually be done by large volume specialists out in the community. The company is always the one that is ultimately responsible for making sure the studies are done according to the planned procedures and done correctly. So the studies are actually completed. The company is ready to submit to the FDA for approval sooner to be New Drug Application (NDA), for biologics the nomenclature is a little different (BLA) Biologics License Application, but the procedure is still pretty much the same either way.

What does the company have to provide then, when they come in for approval?

Officially they have to provide information about the manufacturing process of the final marketed product, things like purity and stability and they need to prove they can make it in the sort of volume they are going to marketing it because usually for the IND phase they are talking about small batches, when they want to get approval they are talking much larger volumes. So there are issues of scale up and can they really do the same thing in a large volume and this isn’t really trivial. I mean especially for biologic products can sort of be kind of hard to make consistently and so it can be a major issue.

And if you have followed the FDA for a while, you may have noticed occasionally you left something, that a great drug comes along and an advisory committee says yes approve it this is good. Then months pass and six months pass and the FDA doesn’t approve it and people say what’s going on here. What well maybe the problem, is there is a problem with the manufacturing and so that can be one of the sticking points everything else is fine. To really make sure that the factory can do things correctly and the processes are correct. Sometimes that’s sort of a major bottle neck and that often something that doesn’t get a lot of publicity and that is something that we as the FDA cannot reveal where the issue is. Sometimes the companies aren’t necessarily forthcoming as to what the problem is, but that is an important aspect of the approval process.

Another part is the information on animal testing as I mentioned, things like carcinogenicity or reproductive toxicity maybe questions still be best answered with animal studies. So then we would still need to see those and significantly see the results of the major clinical studies and actually we want to see the results of all studies. Basically see any information at all that they have that they know about that is relevant at all to the drug really has to be part of that submission and so it is a very all encompassing requirement.

Now the FDA doesn’t just ask for reports, but we really want to see all the data behind them so that means we want to see the datasets, we want to see copies of any report forms that were used, printouts, product test results, and typically we get 10’s to 100’s literally volumes of information or now it is electronic, but it would be the equivalent of that much information so it is really a large body of information that has to be provided to us.

Now what do we do with it, well is sort of similar to when the IND comes in that we get a product specialist, animal specialist, a statistician assigned to it, a medical doctor or maybe a couple of them, so there will be a small team maybe 3-6 not professional individuals that will be looking through all that information. Typically it will be the people who were working on it while it was under an IND because they are familiar with it already so that is the ideal situation, but sometimes a personnel change or depending on what the particular workload demands are somebody else maybe looking at least at parts of that . Now it is all going to be in the same division and usually with the same team so that similar products everybody is going to know about what’s going on. So even if it isn’t exactly the same individual that has been working on it during the IND phase there’s usually still a lot of familiarity with the product by whoever is reviewing it.

The review timelines the current standards are for a standard type of submission the agency likes to get some sort of response either an approval or what we call a complete response a list of all the deficiencies within 10 months and for something that is a priority review which would usually be a product that had a fast track designation or sometimes others that don’t have a fast track designation, but just seem to be turning out particularly well or a significant advance it’s a priority review and we like to get a response within 6 months of the submission.

Q: Do you know if Myozyme is on a fast track at this time doctor?

A: You know I don’t offhand. It seems like it would be a good candidate. I can’t be exactly sure. I would have to check the record. We have several products that are.

Q: So the sixth month either an approval or the deficiency meaning that you need to get back in and run an additional study or something manufacturing or something like that?

A: Yes, it’s our responsibility to say either yes it is approved or to say no I’m sorry I can’t approve it and here are the reasons why and if you address all these reasons then it would be approvable. So we really have to get a complete list of any problems have to be identified by that point of time. We try to be proactive if it is something that is easy enough to fix. We usually try to identify that in the course of the review and give the company an opportunity to fix it. So we just don’t sit there silently for six months and then come up with an answer. It’s usually active and interactive process so that if there is something that doesn’t require a major it’s either something they can do differently just for their information that they didn’t provide originally, something they can change. We try certainly to work with that so we don’t have to go through an additional cycle.

One thing is usually labeling is usually changed in the process of that and there’s usually extensive discussion about what the labeling should be so that we can come to an agreement by that time point.

Now the team is really full time reviewers at the FDA, but they’ve often got other responsibilities too. So it’s not going to be the only thing they are thinking about the entire time because they’re also usually working on other INDs simultaneously. The reviewers go over the study reports, they see if the data really match what is in the case report forms, we reproduce what is in the statistical analysis, often do additional analysis, really decide which of the conclusions we feel are supported and which ones aren’t.

We also have a separate division of scientific investigation. These people actually go out to the study sites, not all of them, but selected sites and do on-site inspections to make sure patients actually existed. You would be amazed what some people try pull even knowing we are looking. It’s rare, but occasionally we do find irregularities. So they go out to the sites to make sure that the records were kept properly, make sure that the data that were actually reported to the datasets and the FDA actually match, what’s in the patient charts, and lab reports. There are also other inspectors that go out to the factories to make sure that the manufacturing processes is what they say it is and that they were keeping proper records and doing the procedures properly. So in short, these applications are given an order of magnitude of more scrutiny than just say a journal article. Submitted to a journal it is pretty much checked for internal consistency and that’s it.

We really go back to the original data we come to an understanding that this study is about as good as you can do just short of actually having done the study ourselves. Sometimes a journal article will come out and everything looks great and the FDA may after looking at all the data actually come to a different conclusion because we have the opportunity to go back to the source. Sort of the end result of all that work is first of all an extensive written report of the findings and that’s the reviews produced by the each of product reviewer, the animal study reviewer, the clinical reviewer, and the statistician and eventually if the product is approved these things are usually posted on the web. So that they are available through the freedom of information, but usually it is easier now to get it done because of the internet. Certain things though, I mean, it isn’t necessarily the complete review because there maybe certain items that are still trade secret information that manufacturing information and occasionally the reviews refer to other unapproved products so that particular part of it won’t be there, but usually you get a pretty in-depth picture of what the reviewers thought about it.

Q: So that is only if there are deficiencies?

A: No, if it is not approved it won’t go out. So it is only if it is approved if it is not approved it remains confidential.

Session # 8
Tursday, October 28, 2004
Topic: Special Needs Trust Funds
Speaker: Theresa Varnet

Bio: Theresa Varnet is an attorney with Spane, Spane and Varnet. She works with trust funds and how to set up a trust fund for our loved ones. Her office is out of Chicago, IL.

I am always glad to share information. I do a lot of training across the country so this is something that I am of used to doing. One of the things is when you have a child who may need government benefits, even if you don’t know for certain that they are going to need government benefits, that you want to do when you set up an estate plan which is a will or a trust. Is to make sure that whatever you set up for your son or daughter doesn’t disqualify them for critically needed benefits and the only way to do that is with something called special needs trust or supplemental needs trust. The beauty of a supplemental needs trust is it can receive anything that anyone in the family wants to leave, whether it is grandparent, an aunt, uncle or friend of the family whatever. Those funds can be held throughout the beneficiary’s lifetime. Supplementing their care, filling in the gap, paying for things the government doesn’t pay for or paying for a higher quality for services that are above and beyond what the government provides. And then when the individual, who is the beneficiary of the trust, passes away, that money goes to charity or wherever it is that the family that set up the trust in the first place says it goes.

So, there’s really a lot of people are afraid to put money in these kinds of trusts because they think the government will get the money when the beneficiary dies, but that’s not the case, it can go to other family members, it can go to other children in the family. Or it is a nice way to leaving a legacy in your child’s name by leaving it to charity.

I would just open questions on any topic at all in terms of funding trusts through wills or life insurance policies or whatever, but that is very basically what you need to know about supplemental needs trusts. They will just receive the inheritance rather than the inheritance going directly to the person with the disability. I should back up and explain; if a person with a disability has more than $2000 in his/her name they will not qualify for a needs based, which is welfare type programs like Medicaid.

Q: Ok can you say that again, I’m sorry.

A: If a person has more than $2000 in his/her name, they will not qualify for any government benefits that are needs based.

Q: So it has to be in the child’s name though? What about if the parent has that?

A: Well if a parent of a child under the age of 18 has assets, the most needs based benefits the parent’s resources are counted. Once the child turns 18, the parent’s assets and income are no longer counted. When most people are thinking about doing the estate plan, they are hoping that they are going to be in their ripe old age of 70 or 80 and their adult disabled child will be 40 or 50. We are talking about adults for the most part. However, even grandparents who want to provide for the children/grandchildren with special needs could leave a special needs trust, but up until the child reaches18 his/her parent couldn’t be the trustee. So you could still have a grandparent doing this for a family and just not putting the money into the parent’s name so that the money wouldn’t count against the handicapped child.

I have a client right now, as a matter of fact, who’s daughter is in her early 30’s and she has a grandson I believe he is 9 or 10 years old and the grandmother has cancer. She wants to provide for her daughter and grandson. She knows that if she leaves money to her daughter, who is poor, her daughter will lose all the government benefits and assistance she is getting for her son, who has a significant disability. So she has set up a special needs trust for the grandson and until her grandson reaches 18. The mother can’t touch the money herself it will be manage by uncle by her brother for the nephew

So you can provide for children as well you just have to be a little more careful on how you set it up.

Has everyone had a chance to read like the basics on my website on the terms of a special needs trust is?

No, I apologize I saw the memo to do that and meant to do that and forgot all about it. I will do that right after the conference.

The only reason I say that is I knew in an hour phone call if we asking any questions that it would be very hard to try to explain what it is. That is why it would be helpful to have it ahead of time. Basically what all it is a way of providing money, an inheritance, for a person who may need government benefits at sometime in their life. The government can’t claim it as a resource because it doesn’t belong to the disabled person. The trust will have language in it like that will say something to this effect "the primary purpose of this trust is to provide those goods and services only that the government doesn’t provide or to provide a higher quality of care than that which government provides." So you get the government’s subsistence level as a base and then the special needs trust comes in with a quality piece.

Q: You said that if the beneficiary of the trust dies, for example this child, was set up for, then the trust can be redirected to other children?

A: Yes. If it’s a third party trust, if the money in the special needs trust does not belong to the handicapped person to begin with, then yes. I am assuming that is what we are talking about here. There is a little known, and I don’t know how long ago habit, because there are people right now in Washington who would like to take this away from us, but if a disabled person is under the age of 65, comes into a win fall from any source via an inheritance, lawsuit settlement, lottery winning whatever,. He/she can take their own money and put it in a trust for themselves it is called special needs trust, but because the trust is funded with their own money it has what is called a payback to the state. In other words, when the handicapped child dies, if there is anything left it goes back to the state. That is what we call a qualified special needs trust. It is used in very rare circumstances.

I didn’t think that was the focus of tonight’s phone call. I though tonight’s call was parents planning with their own money or grandparents planning, but if somebody does have any money in their name from a lawsuit settlement or whatever, there is additional information on my website under OBRA (Omnibus Budget Reconcilate Act) 93 Trust. That type of trust we only use in two circumstances.

Q: Can they use the full trust available to them, or just the interest or just the dividends?

A: Everything of it including the principal. That is up to what we call the settler, the person who creates the trust, but generally a pure special needs trust allows the trustee to dip into the interest as well as the principal. You could limit it if you wanted. If somebody wanted to set aside a nest egg for a disabled grandchild, and then wanted to go to the other grandchildren after the beneficiary died they could just limit it to the income, but there’s no rule about that. Most parents say that the trustee can dip into the income and principal at the trustee sole discretion.

Everyone who has a child with special needs, quite frankly should redo their will and provide this, even if in 20-30 years later it turns out the child doesn’t need benefits. You can always go back in and change your will and leave the money directly to the beneficiary, but I tell people that if they think their child may need government benefits, we don’t have a crystal ball as to when we are going to die. So why not have it set up and that way you can designate you’re IRAs, retirement plans, life insurance policies, whatever so they flow into the special needs trust. Because, God forbid, it does happen early. You’re prepared.

Q: You said that it is not the ownership of the beneficiary, that they are also for eligible for Medicare/Medicaid?

A: Yes, there are basically three types of government benefits. There are your entitlements which Medicare is, your welfare benefits which Medicaid is, and we now have what we call a buy in medicate for people who go to work and lose their Medicaid because they are making too much money, but they are allowed to buy in and that is called a sliding scale C program. So we now have three types of medical coverage in the United States one of which is an entitlement which is Medicare, one of which is welfare which is Medicaid and the third is sliding scale C by that I mean you based pay on your ability to pay and how much you can earn depends upon what state you live in because all the states have adopted different caps.

Here, I’m in Massachusetts right now when Marsha introduced me she said that I was from Illinois. My main practice is in Illinois, but I live in Massachusetts and in Massachusetts you can earn almost $40,000 a year and still be able to buy into Medicaid. In Illinois, the cap is $22,000 a year. So as you can see that is a pretty big difference. So it just depends on which state you are in and all the states you can’t assume what a state does today their going to do tomorrow. The states are in a period major flux so who you have as your Governor, who your state representatives or state senators they make a big difference, it isn’t all just federal.

Anybody have any questions for Theresa?

Q: How old are your children? I have a daughter with special needs, but she is now 21. I don’t think that she would come under this at all anymore. Of course, it is something that would have been beneficial.

A: Why wouldn’t she come under these programs now that she is 21 your income wouldn’t be counted now. You income wouldn’t be counted now. She should be getting SSI and Medicaid right now. Is she? No. Is she working? No She is in school. Ok if she has a disability that prevents her from working and here is the definition that social security uses, if you have a mental or physical impairment that prevents you from being gainfully active, then you are entitled to SSI. SSI will give you approximately $550 a month plus Medicaid which pays for your prescriptions, your co-pays and everything, and if she is not working. Do you have group health insurance? For yourself. We have a personal policy. Not a group policy. Well if anyone is lucky enough to have a group policy. Then that group policy will pay for that child forever. My daughter is 37 and she is still covered under my husband’s health insurance policy. She’s got the best of all worlds. She has Medicare because she’s worked and paid into social security. She got Medicaid because she is also still poor since she only earns $6,000 a year. Because she is what we call a Disable Adult Child (DAC), she is eligible to stay under my husband’s insurance. So we have all three coverages for her. So it provides an excellent health insurance. A lot of people think once the child moves out of the home they can never claim them on their health insurance. My daughter lives in a home of her own, but because she was disabled prior to the age of 22 and she is incapable of gainful activity we can still cover her under our plan. That is true for most group insurance policies. So your child who is 21, if you have a personal plan unfortunately it will stop covering her probably when she ages out of school, but she still should be eligible for SSI and Medicaid because your income and assets would not count anymore

Q: Excuse me I have one question on that. Is there like an income limit for the child once their over 21 and you want to cover the on your group insurance? Is there a limit to what they can earn?

A: As long as they are getting SSI, they are eligible for your group health insurance because SSI is what we call primafacia evidence that their incapable for gainful activity. Now SSI generally looks at whether or not the individual can earn more than $810 a month. Now it gets more complicated than that because there is something called impairment related work expenses. So I have a client who is earning over $1,000 a month, but he has to pay for a medication that costs him $400 a month that Medicaid won’t pay for. So if you minus the $400 from the earnings of $1,100, he has less than the $810 countable income because it is call impairment related work expenses you can deduct them. So it comes down to $810 a month of countable income and then he qualifies. So I hate to say it is just $810 a month because a person might have some deductions and they could earn more, but it’s a good deal if your child works. Like my daughter works part-time, she works three days a week and its just perfect for her it’s just enough that she gets enjoyment and pleasure out of her job and yet not enough that she loses very important government benefits.

That is the best of both worlds between the public and the private that come together then you are covered on all basis. But a lot of people don’t know that their adult children can continue to be covered if their income earnings are low.

I didn’t know that and kind of wondered what would happen when he ever gets past that age.

It is only an issue if you have group health insurance, and you do have to notify your insurance carrier within nine months of them aging off the program. You can’t wait until the last minute to tell them.

Q: Special needs trust set up to help them with their needs and then let’s say gene therapy or something came along that made them basically normal, what would happen to the special needs trust?

A: Well if the parents are still alive when the restoration occurred, and what I am referring to the restoration is that even though you still have a disability you are able to function normally and go on and have a pretty normal life. The parents of course could change their will if they chose to and leave the money outright to the person with special needs. If the parents have already died, and the trust let’s say has $100,000 - $200,000 in it or whatever, and then 10 years after the parent died there’s this wonderful cure which the trust can pay for by the way, because government benefits don’t always pay for cutting edge medical treatment. So the trust pays for the cure and now the person is cured and they can work. Unfortunately you cannot put a restoration clause in a trust, you cannot say if the person is disabled the money is protected and they cannot get at it, but if they are ever cured they can have the money outright. Because that is considered against public policy it’s sort of an insult to the taxpayer. So I am afraid it would have to stay in the trust, but that’s not bad because if you suddenly been cured and go out and work and you are earning $30,000-$40,000 a year. How nice to have a trust that can provide you with another $10,000-$20,000 a year in benefits. So the trust is still there throughout the person’s lifetime. They just, unfortunately, can’t have control over it, but it can certainly be used to enhance welfare of your life and supplement whatever income their getting instead of supplementing their benefits.

So it could continue to pay for normal medical expenses?

It could pay for everything, if they are not getting government benefits. It could pay for medical expenses, it can pay for a housekeeper to come in so they don’t have to worry about housework, if they own a home they can pay to have a landscaper to take care of the property, it can pay for maintenance costs on their home, it can pay for them to take a vacation once or twice a year, it can pay for whatever it is they need help with. So the money isn’t going to be wasted. The only insult of it is the disabled person, who is now restored doesn’t have control over the inheritance his parents left him/her. So they might be a little insulted by that, but that is a small price to pay to preserve eligibility for government benefits just in case.

Thanks.

Nothing’s worse than and especially this current administration in Washington wants to put Medicaid in the form of block grants. If that ever happens, there will be waiting lists for Medicaid. So you can imagine how terrible it would be if a person had Medicaid and that was paying their medical bills and then Larry dies leaving that disabled child $50,000, therefore, they lost their Medicaid and if this administration has its way and we have waiting lists for Medicaid that person is going to be in a worse off position. Because right now until once you spend your money back down under $2,000 you go right back on Medicaid, but if we ever have waiting lists, which we’re anticipating will be the situation, that person will be far worse off because if they need to wait a year or two or three before they get back on Medicaid. That $50,000 has left them worse off. That’s why these trusts, I think, are going to be even more important in the future than they are now.

Q: What are typical costs for establishing a trust?

A: Well I can’t say for different parts of the country, I’ll tell you what our firm charges both in Massachusetts and Illinois and it gives you something to measure it by. Although, I have seen law firms charge three and four times what I charge. We charge for two wills, which is what we call nero wills, the mother and father leave everything to each other and when both parents die it goes to the kids, but the share that goes to the child with the special need. Goes to a stand a lone special needs trust. We charge $1,400 for that and that includes two wills, one special needs trust and two powers of attorney to health care and property for the mother and father. What those are, are two forms that say if the parents are ever incompetitant they designate someone they trust to be in charge of their affairs. I am a firm believer that everyone should have powers of attorney. So for the $1,400. Now if they are lucky enough to have the state tax problem it is more expensive than that. Seeing as that most people don’t have the state tax problem that is why I quoted the $1,400. Most law firms if the family doesn’t have the whole thing will let them go on a budget plan of some kind so they can pay it off. I have some people paying me as little as $75 a month and that’s all they can afford. You just do it and put it aside when they finish paying for it then you mail it to them. And that way, God forbid, in the mean time if they die, they haven’t died without a will and a trust it’s done. But you can compare that to local of that $1,400 the special needs trust is $800, so it is basically $600 for the two will and the powers of attorney for health care and property.

Are all of your children up there like teenagers or are they all over the place in age?

I don’t have any children. I guess I am a special needs child because I am 34. Ok anyone who is over the age of 18, everyone should have a power of attorney because none of knows what tomorrow’s going to bring and if we should be unconscious or unable to handle our affairs. It is good to designate someone that we have confidence in that we trust to manage our affairs to make health care decisions for us, to manage our funds for us. And if you just sign a power of attorney, then whoever you pick has that power. If you should become ill and there is no one there to sign. Someone has to become your guardian and that can be very expensive and very intrusive. Along with wills and special needs trusts I always recommend to people that the do powers of attorney as well. It’s just an alternative to guardianship you will never need a guardianship if you have a power of attorney.

Q: I don’t get SSI, but I qualify for it. If my parents died and left me and left me a lot of money, that would cause me a problems right?

A: Right so you should talk to your parents about leaving a special needs trust for you and that way you get the best of both worlds. What the government gives us is minimal and frankly we can’t expect the taxpayers to give high quality of care. All they are required to give by law is give us is a subsistence level of care. Nobody wants to subsist, if you can you want to have a higher quality of life and that’s the beauty of the special needs trust. It basically allows our parents to provide for us just like they do while they are alive. You know how parents can help you out a lot while they are alive they just dip into their pocket and do it. Well, when they are dead they can leave a special needs trust to do the same thing.

That makes sense.

So it’s a nice way of parents providing for their children from the grave. I always tell people that I am a control freak I like idea of my money doing what I want it to do after I have died. It gives me some control over my money even long after I am gone.

Q: Special needs trust can be set up for people long after people over 18 years of age?

A: You can set up a special needs trust for anyone regardless of their age. I trust stuff when Jennifer, my daughter is now 37, but I set up her trust when she was only 9 . Because I didn’t know when I was going to die and fortunately I haven’t needed it yet, but it is there. Our life insurance policy, our pension everything flows into the trust. Jennifer personally gets nothing, but the trust gets everything and that allows her to live independently. Right now she lives in a home of her own that we bought for her and when we die the home that we bought for her will be owned by the special needs trust. So she will continue to be able to live in that home rent free plus the trust will pay all the taxes on the home, maintenance home, it will pay for her to have extras, a car, insurance on the care, maintenance on the car, whatever she needs the trust will pay for it.

Q: If she had a Great aunt or something, who left her money could she leave that money to the trust you’ve established or would she have to make her own?

A: No you can’t take your own money and put it into a third party special needs trust. Ordinarily if it is left to the person that needs government benefits, they’ll lose their government benefits, but there is that special type of special needs trust I mentioned earlier. The qualified one that you can take your money and put it into, but when you die the state gets every penny. It doesn’t go to your wife or your children or where you want it to go.

Q: I wondered if there were two benefactors or let’s say a mother and father divorced and were separately leaving things to the special needs person?

A: They could leave it to the same trust if they wanted to. What they shouldn’t do is leave it to the disabled individual because he or she can’t turn around and plunk it into the trust.

But once this trust is established it is an entity?

Think of it as an empty cookie jar waiting for the cookie.

Like all your relatives if you let them know, could leave, if they were going to leave you anything could leave it to the trust instead.

That way you get the best of both worlds because you can get the SSI and Medicaid or whatever you are entitled to and then afterward after your parents died. That trust is funded and then you can go to the trustee of trust and say hey my refrigerator worn out and I need a new refrigerator or my television needs replacing or I need a new car or my car needs new tires and I don’t have the money to pay for it.

And you don’t have to be rich. I have a client who has less than $30,000 in a trust that was left to her by her parents. That’s all her parents had to leave her was $30,000 and what it does is she lives on SSI, Medicaid, and Medicare and what we do is pay her train pass every month which cost $80 and we pay her cable tv and that’s all we pay. But it allows her to not worry about how she’s going to have enough money to pay for a train pass and cable TV would be a luxury that she wouldn’t be able to afford otherwise. So you don’t have to be rich to do a special needs trust. $30,000 to leave your child isn’t exactly a rich parent, but most of us have that much to leave our children when we die, because even if you sell a house full of furniture and a car, you can usually leave your child $30,000. People shouldn’t think these trusts are for rich people because they are not.

Q: You talked about the $1,400 to establish the trust and things. How much is it for an ongoing maintenance? Is it the law firm that is the trustee or do you designate someone?

A: It depends if the family has somebody that they trust and confidence in, the other family members should be the trustee. It could be an Aunt or Uncle, Brother or sister there’s lots of non-profit agencies across the country who will serve as trustees for special needs trusts.

So any costs that would be associated would determine who the trustee then. The cost obviously if you are going to have a lawyer or a bank be the trustee, you need at least a quarter of a million to make it worth while, but if you are talking about a family of siblings being a trustee. I even have some cases where adult children of the disabled person is the trustee. I even have some individuals with physical disabilities who have adult children, they might be in their 50’s and 60’s and they have 30 year old children. So their children would be the trustee of their parent’s trust. So there is no one person that can serve as a trustee anyone who is good with money and is trustworthy that’s what you need, they can be trustee. It is no different than balancing a checkbook I mean you do have to follow a few other rules you have the wear with all to balance a checkbook you can be taught to be a trustee.

Q: As I understand it the parents establish this trust for their child, they could say in their will that if this child passes it can go to the other children or charity. And if the beneficiary out lives the parents and there are no other children, where happen to the money in the trust?

A: A properly written trust will always have a remainder mand, in other words, it will always say if it doesn’t say then you will have to look at your state law. And most state law say then it goes to the heirs at law of the settler and not the beneficiary. Some people can leave the beneficiary what we call a limited power appointment to say where the money goes. The reason the limited power of appointment is important is that you don’t want a general power of appointment because a general power of appointment the state will say if you can say it can go anywhere then you have to say it comes back to the state if we are helping you. If you do give the beneficiary the power to say where it goes, limit it so that it doesn’t go back to the state, remainder mand is just a legal term that says where the money goes if the disabled person dies.

Q: What states do you all live in are you all over the place?

A: I live in Iowa, Virginia, Texas, anywhere else.

Iowa has some wonderful programs and Iowa pays for programs very differently. They have a county system for paying so you want to be sure that you whatever special needs trust you write conforms to the county rules as well as the federal and state rules.

Virginia has some non-profit agencies that will serve as trustees of the special needs trust so if you didn’t have a family member you could turn to some non-profits. I think the arch serves as trustee.

Texas there are several good lawyers that do these things so if you didn’t know somebody out there I could refer you to one.

Session # 7
Tuesday, August 31, 2004
Topic: Gene Therapy
Speaker: Dr. Barry Byrne

Paul Kessler and I began to study the approach to treating inherited muscles diseases and we really took a fairly broad view that one could use the concept of gene transfer as well as stem cell therapies for inherited muscle diseases. That really was our very first proposal in that area, to a local foundation in Maryland which funded our initial work. That initially led us to the finding that we felt we could demonstrate that it was possible to restore alpha glucosidase activity in tissue culture cells. So the first work was invitro, as it is called or in tissue culture using an adenovirus to carry the gene for human acid alpha glucosidase back into the cells that were deficient in the protein.

What was the departure for us was the work that was done with another kind of viral gene transfer age called Adeno Associated virus (AAV). This was actually another part of my background in my graduate training so this was a great opportunity to return to that very basic virology work that I had done before.

What we found with AAV was that it went in as a vehicle to bringing the gene back into the cells. It had an unusual property in muscle cells. The DNA which was carried by the virus actually lasted in the muscle cells for (as in the initial experiment), as long as we carried out the experiments.

That was a new finding in the field of gene therapy. There had not previously been any sustained gene transfer with the DNA virus that infected non-dividing cells which was the case here. That initial work used a marker gene and was not a study done in Pompe’s disease, but it was done to lay down the foundation that we had hoped to do for acid alpha glucosidase activity. So that was the start of an area of investigation about gene transfer into muscle cells which has really grown substantially over the years.

This all started in early 1995, and in the 10 years that has gone by, we have put a lot of effort into evaluating how AAV is introduced into muscle, how the transferred gene stays in muscle cells, and whether this approach would be feasible for children with Pompe’s disease. As clinicians, caring for kids with inherited muscle diseases, particularly ones that affect the heart has always been our goal.

When I moved from Baltimore to Florida, it was with the intention that we would build a gene therapy center. This center would be focused on what some people call translational research. This is the kind of applied science that would bring the basic investigations to the clinic. So our center has focused on that goal and invested in facilities which could make clinical material for human studies. As well as provide the support necessary to get protocols through the regulatory review process to get the approvals needed in order to conduct these clinical trials.

So there is a multi-level approach to doing these studies, starting with the basic science which is combined with a good idea on how to proceed to attack a problem. Designing the proof of concept studies that demonstrate the usefulness of a given approach and then importantly demonstrating that that approach is safe and effective are some of the criteria by which the FDA judges these studies. That is what we have done since I’ve come to Florida in 1997.

We finally reached that goal in one disease model, a form of inherited emphysema, with a lot of help from the Alfa-1-Foundation. We have been able to start a phase one trial of gene transfer into muscle, very much the same approach we anticipate using in Pompe’s disease, for an inherited protein deficiency called Alpha-1-Antitrypsin deficiency. Three subjects have actually enrolled in the first trial.

There are almost sixty subjects now in a human study that have been evaluated for gene transfer for cystic fibrosis. Several patients with a type of muscular dystrophy (limb girdle muscular dystrophy), have also been studied and we are hoping to continue this work.

So that is the history of what we have been doing. I would be happy to answer questions about any specific aspects, from basic science issues, to the process of getting a program through the FDA and into the clinic, and how those studies are evaluated clinically for safety and efficacy.

I could talk about any one of these specific areas, but of course, many of the things we do in science is when we answer one question it raises two more questions and we keep finding new things about this disease. Certainly we feel like we have learned a lot from the animal models we have generated in close collaboration with Anita Rabin, back when we first started this work we felt this was a critical component. Both our lab and Nita’s lab are in collaboration together to make knock out constructs which generated the mice we use today to study gene transfer in Pompe’s disease. They are not entirely indicative of what we would expect in human subjects, but it has been very helpful to get a glimpse as to what can be expected after certain approaches to treatment of the disease.

Questions & Answers

Q: Mr. Byrnes from what you describe in your comments, is it my understanding that this is strictly for kids? You don’t have any programs for adults?

A: The Alpha-1-Antitrypson deficiency trial is actually for only adult subjects. The initial studies are aimed at looking at a single site of injection of AV that would lead to secretion of the protein from that site and how the therapeutic affects the rest of the body. This may be an approach which seems to work quite well in Alpha 1 disease. We had some success in hemophilia and it actually was our initial thought about how it might be approached in adults or younger patients with Pompe’s. I think the immunology in Pompe’s disease is a little more complicated than some of these other diseases except maybe hemophilia.

One of the challenges we see to this approach is the production of antibodies against the protein. So one of the reasons we’re focusing on the younger patient population is that we see less immune resistance to the protein when high levels are generated. The same affect would not be as great in adult patients with some protein that is really only partially defective. But right now we felt like the most pressing medical need was in the infant population who would benefit from systemic gene transfer.

Adult patients are not off the list, but with the approach we are contemplating right now would focus on the smallest kids first.

Q: I have a daughter who has the disorder, she is 13, and I would like to know how many more clinical trials that might be coming up for her age. And also how many more trials before the drug can be on the market as an approved drug?

A: A general background on drug approval. It doesn’t matter whether they are protein drugs or gene drugs. This is a very long process which first establishes safety then demonstrates some critical endpoints or outcomes of the treatment as to whether the drugs are effective.

So it depends on what part of the disease a person is addressing, which would influence what is on the label for so-called release or availability of the drug. This is a very long process and so far no approaches using gene therapy have been licensed or have passed the final stage of testing.

One point I might raise about the older patient, particularly in the age range of late childhood to early adulthood, since respiratory muscle weakness seems to be one of the predominant features of the disease in this population. One of the things we have contemplated, however, it is not on the docket for immediate testing is the following. We have recently published a paper about gene transfer to the diaphragm. The diaphragm is a restricted muscle group which we feel would be very responsive to the gene transfer approach and that improvement in diaphragm strength and function may be sufficient to meliorate a lot of the symptoms in the older patient and avoid the potential for toxicity related to this approach.

Q: I have a 9 year old son, is in the Expanded Access Program at University of Alabama, Birmingham, and we go every two weeks to have enzyme replacement therapy (ERT). Will ERT be a requirement before they are allowed to come into a trial for the polymer gel?

A: Now that is a very good question. Sometimes clinical studies are designed to develop a clear cut difference between one therapy over another. I think that gene transfer approaches, particularly for subjects who are already in clinical studies, have the potential to enhance these. The initial feeling is that there would not necessarily be an exclusive treatment for one over the other. If someone can distinguish the effects of one approach apart from the other approach, then that is one of the challenges looking at specific outcome measurements.

Q. My child like so many that are on ERT is vent dependent 24/7, and has been since 1998. We haven’t seen any changes in the ventilator use in the current study, but we’re very young into it as he is only on his 12th treatment. We’ve seen a tremendous change in his heart, in his general health and well being, and he just feels better. Since his heart involvement was pretty serious, his blood pressure has been stabilized, but we haven’t gotten so far into the study as to see any changes with the ventilator yet.

A. I think you bring up an important point, since there was a lot of focus on categorizing the disease into different bins, if you will, or certain types of the disease. I think our team feels pretty confident that what we are seeing is the spectrum of the disease from very severe early on-set disease, to very mild late-onset disease. It tends to correlate with the degree of enzyme activity, but we also feel that there are other factors which influence the severity of the disease in different organs systems. So it used to be thought that a child as old as 9 actually didn’t have any heart involvement related to the disease, but it is clear now that that can be the case.

Q: How unique is your approach to that of Dr. Amalfitano’s? You are directly targeting muscle and Dr. Amalfitano is targeting liver which leads to uptake by muscle. Do you see any particular advantage to targeting muscle directly?

A: There are two different vectors in use in those studies that are directed at the liver. We had done some early peripheral concept studies with adeno viruses and it has generally been found in the field that while there can be persistence of the targeted cells that there is the potential at least, and this has been improved upon over the years in terms of the inflammatory response to the vector itself. And that certainly has been the case with the work the Duke Group had in improving those vectors, but there has not been an example like AAV in any other class of virus other than the retro viruses for the persistence of expression. Our feeling is that the inherited diseases which are going to have a life long manifestation should use an approach of gene transfer which is going to be the most likely persistent and lead to the least inflammatory response.

Now the question then is why treat muscles with specific gene therapy as opposed to secretions from the liver. I think the liver has several advantages as does the muscles, so ideally one could utilize both platforms to achieve a correction. The focusing only on liver is very much like the protein transfer studies that are on going and we have seen in our own lab the same consequences of infused protein and the antibody production against the protein. When the protein is made within the cell which needs that protein to traffic properly to the lysosome, the interference of antibody does not occur within a cell itself. So although the potential for antibodies to help eliminate cells that are damaged and exposed their insides to the circulation, a cell that is functioning properly, that has cell specific genetic correction responds quite well to that approach. So that would be part of the rationale for treating muscle directly and to circumvent what were left and the antibody responses.

Q: What needs to happen for this to enter clinical trials? What is the major hurdle that you are facing?

A: The steps required to proceed through the early proof of concept studies is to have a discussion with the FDA about a clinical proposal and then to actually execute that clinical proposal. It requires we choose a single agent for study (we always seems to be making slight improvements in the construct that expresses the gene), and I think we have finally selected one that meets all of our requirements. And then selecting the way in which it will be delivered and the doses it would be delivered at. Sometimes it is a little difficult to predict how the dose used in mice would translate to bigger folks, but once that is established then in working with the FDA a plan is established for the safety studies that are required.

We are fortunate that our center has been designated as one of five sites in the country that is supported by the National Center Research Resources part of the NIH core group that provides funding to clinical research centers. The program called the National Gene Vector Laboratories (NGVL) supports these five sites for vector production and toxicologic studies. So we expect to utilize that mechanism in order to get funding to proceed with the safety studies.

The NGVL also provides funding required in order to make clinical grade material for our improved clinical plan. That would be the very next step after getting the toxicology studies completed, which we have now done for three different programs both in muscle diseases and eye diseases. Finally, we have to get the permission through our institution to do the clinical study.

Q: Dr. Amalfitano said that he was pretty close to a critical threshold of toxicity for the doses that would be required for his approach to gene therapy. Are you having the same problem with your approach?

A: We have not found that yet in the toxicology studies we have done for the existing trials. We use a safety margin of 10 times the top dose in the study to see whether we can generate toxicities related to the vector itself. What we have attempted to do in those studies is to make a worse case scenario by giving the vector, instead of just into the muscle; we can make one group of animals receive a dose into the vein so that it theoretically goes everywhere. However, we haven’t identified systemic toxicities related to that, other than one example which was presented at the Recombinant DNA Advisory committee meeting. When we presented the data a few months ago one of the questions that came up was, what is the consequence of getting the vector everywhere in the body, in such a way, that in males or females there would be positivity of the vector in germ cells or gonatal tissue (that would be eggs or sperm).

Those studies are most easily conducted by looking at contamination of sperm by the DNA. That’s something that the FDA would not want to allow unless this risk was justified by a certain benefit. We’ve done studies with several types of AAV and actually are conducting a large longitudinal study that will look at several generations of animals to see whether having the vector in that fluid, results in the gene being transferred from one generation to the next. We have actually never been able to demonstrate that, but we need to prove that point conclusively to the FDA. So, that is the only toxicity we’ve observed and it has never resulted in any adverse affects that we can find. So we will keep looking. The group here has done very well to meet the challenge of manufacturing the clinical grade material in order to reach a dose that will actually matter. You have to be able to make enough of it and it is something we have devoted a lot of effort to do. We will be using a new manufacturing method that was developed just for the purpose of making more vector in an economical fashion.

Q: Can you talk a little bit more down the line, what therapy will be like? Is this therapy once a year, or once a month and how do you see this process occurring? Will it be used with ERT too?

A: Yes that is a good question. All of our gene transfer with AAV studies that have been done thus far, have been single dose experiments. There is a group here studying Parkinson’s disease in which the gene transfer is done in the appropriate region of the brain. It’s a single dose. We found that in cells that don’t divide like the brain, the muscle, and the eye, that it is not necessary to give another dose of material to get any sustained expression. Depending on the clinical trail design, a single dose administration and then following subjects over time.

Q: As far as the funding goes, do you see any problems with funding down the road for the studies that you have? Are you funded well enough?

A: For many of the rare diseases we really rely on the cooperation of the various organizations as well as the rare disease entity within the NIH and the FDA. Then specific agencies within the NIH that have an interest in pediatric diseases, such as the Child Health Agency, and the Heart, Lung and Blood Institute have been supporting our work for a number of years because of the focus on heart disease. Traditionally two other agencies NIAMS and NIMDS have been supportive with the muscular dystrophies. The MDA has been supportive since the initial part of this work had a very intense focus on gene transfer for muscular dystrophies both limb girdle and Duchene muscular dystrophy.

Q: So, as far as funding goes it’s not really blocking your findings as you go forward with a clinical trial. Do you see anything as far as a certain avenue you want to approach, or a certain type of virus that you like and want to use, and can you see implementing it in a clinical trial in the future? If so, how long and what timeframe would you be able to implement something?

A: The clinical studies that have been done thus far with AAV have had a good safety profile. So as long as we design studies which help answer some of the basic questions that are good science then we expect the NIH will get behind those too, since they continue to be supportive of gene transfer studies in general. This has been the focused of a lot of different review groups within the NIH and there is considerable expertise in that. The funding for this approach can utilize both public and private sources and it’s a fairly expensive proposition even just to test the safety studies that are required by the FDA. We need to utilize all the resources that are out there, but I think the good news for rare diseases, is the voice of the organizations have been heard both in congress and the NIH who listens very carefully to the appropriations committee that decides their funding level. Efforts by the MDA and other rare disease organizations and NORD in particular has, I think been heard, we’ve see a lot of initiatives coming out of the NIH soliciting proposals related to rare diseases and I think this is a good thing.

Q: So you are saying positive findings in gene transfer with other diseases could help Pompe disease?

A: Oh absolutely, and by the same token entities that are interested in more common diseases like heart failure will be interested and are interested in the findings from rare disease programs. The advantage in the rare disease studies is that we know the very specific path of the physiology of the disease, we hope, in some of the more complex multi-factorial diseases that affect millions of people like heart failure. It is unclear what the best therapeutic approach is and we know any single gene defects to go after.

Q: Is there a possibility of getting a private corporation involved in helping to fund a clinical trial for Pompe or is it such a rare disease that it would be difficult to find a company that would be interested?

A: No one ever rules out that possibility. There have been various companies that have expressed interest in both lysosomal storage diseases and cardiovascular disease that would theoretically use this as an example, if you will. The economics of it all are complicated and I don’t begin to understand what would make something a successful commercial venture, but I think the science behind it has to be the first motivator. And particularly the fact that we continue to look for successful therapeutic approaches for what is a complex problem.

Q: If I understand what you are saying, the gene therapy would be administered by injection into the muscle?

A: The study we are doing now is establishing the safety of injecting into muscle. However with Pompe disease where multiple muscles are affected we really want an approach that is more systemic in nature and there are various strategies for achieving that. By a publication recently by Dr. Chamberlain’s group, in which they are focusing on Duchene muscular dystrophy used the strategy of AAV gene transfer to muscle, but takes advantage of a unique feature called VEGF which helps get the vector beyond the vasculature of the muscle cells. In other types of AAV, not the types used in that study, the vector seems to do that bit all on its own. So that’s the approach we are contemplating will be most useful in Pompe’s disease. And in conditions where there is mostly heart muscle involvement there are other strategies for delivering the dose to the heart muscle or to the diaphragm or specific muscle groups that might be most effective. But I think the one approach is to try to consider getting all the muscle groups at once.

Q: I was reading today about the Myostatin blockers with mighty mice and that they were seeing that it was making them much stronger. For somebody like me, who is just beginning to have difficulty with walking, would something like that possibly be beneficial to me to have something that might work with the muscles I have and make them stronger?

A: That is a very interesting concept. For those that haven’t followed this, I can give you a smidgeon of background on this protein. Myostatin is part of the family of protein’s that regulate how different organs grow to a certain size. So that muscle mass is controlled by level of Myostatin expression. It influences it in reverse, if you will; more Myostatin makes you smaller and less Myostatin makes more muscle. For some of the diseases where there is an abnormal loss of cells, it may be that Myostatin causes the dividing myoblasts to become myotubes or mature muscle cells. In the case of Acid Maltase Deficiency, those cells would probably be equally affected by glycogen accumulation so it wouldn’t necessarily be a long term benefit to actually promote muscle mass using the precursor cells at a faster rate then one might want. So I don’t think that is probably a good strategy, but it is a very interesting approach to some of the other dystrophies or particularly those people without inherited muscle disease.

Session # 6
Tuesday, June 21, 2004
Topic: The Preventions or Respiratory Complications
Speaker: Dr. John Bach

Let me put this all in perspective. Your condition involves basically muscle weakness and the only way this condition can severely harm or kill anybody is because of the effect of the muscle weakness, in particular the respiratory muscles. Now, sometimes the heart being a muscle can be involved, but it is not nearly involved to any degree like the respiratory muscles in general.

Most people suffer from the involvement of the respiratory muscles.

What are the respiratory muscles? You need to think about 3 groups of muscles:

1. Inspiratory Muscles for breathing
2. Expiratory Muscles for coughing (those are mostly the abdominal and some of the chest muscles)
3. Bulbar Muscles or throat muscles

The throat muscles are largely spared in Pompe’s disease. I don’t know of any patients who have lost the ability to speak, swallow and then can’t protect their airway such that they basically drown in saliva dripping in the airway. This is very different from many other neuromuscular conditions. For example, in Lou Gehrig’s disease, there is a type that is called Bulbar ALS where people can walk around and even play tennis, however, they can’t speak or swallow and eventually they will need to get a tracheostomy tube because they can’t keep the saliva out of their airway.

The good news in Pompe’s disease is that I don’t think this ever happens, so nobody should ever need a tracheostomy tube or even develop respiratory complications if you are properly informed and equipped.

So what does this mean? There are people that get so weak that they really can’t breathe effectively. If they can’t take deep enough breaths the carbon dioxide in the blood goes up and causes many of the following symptoms:

• Morning headaches
• Daytime drowsiness
• Difficulty concentrating
• Depression
• Loss of libido
• Fatigue

Fatigue is the most subtle and the most common symptom of not breathing deeply enough to maintain normal carbon dioxide levels. In fact, for a comparison, it is like walking into a vat of fermenting wine, where the carbon dioxide is so high that it can actually turn off your breathing completely and you stop breathing.

What happens when you don’t breathe deeply enough and your carbon dioxide goes up? Carbon dioxide is acidic. The kidneys have to retain bicarbonate so the blood does not become acidic. We can’t permit the blood to become acidic. So the kidneys retain bicarbonate to neutralize the acid. What that does though is that turns off the brain’s breathing apparatus, so that the brain doesn’t expect to breathe deeply anymore and it is like a bad cycle. The carbon dioxide keeps getting higher and the bicarbonate keeps getting higher, and then what happens one morning is you simply just don’t wake up. This happens to many people with neuromuscular disorders.

What happens even more commonly then that, especially in children, is that they get a cold or bronchitis or RSV. And because their abdominal muscles can be very weak, they may not be able to cough effectively, the sputum lies in the airway and the bacteria multiply causing pneumonia and then they get short of breath and go to the local emergency room and the doctor there gives them oxygen. That turns off their breathing even worse, the carbon dioxide goes even higher and they stop breathing and then they get a tube down their throat to be hooked up to a ventilator.

So, the two ways that people can suffer and die from respiratory muscle weakness is the inability to cough effectively (which is the most common problem resulting in pneumonias), and simply not breathing deeply enough. After we hit 40 we get fewer colds, sometimes only one cold in 5 -10 years, whereas kids get a couple of colds a year. So, usually for children that suffer from neuromuscular disease they usually do ok until they get a bronchitis, and then they get the pneumonia and go into respiratory failure. Where as for older people, they may just gradually develop higher and higher carbon dioxide retention, until they become very symptomatic, and if they are not put on some type of night time ventilatory assistance they can literally not wake up in the morning and become comatose and either be rushed to the hospital or even die that way.

Now the good news is that the throat muscles are rarely affected, if ever affected, to the extent that people need tracheostomy tubes with Pompe’s disease. But people do still get tracheostomy tubes anyway because the doctors often think that the inability to breathe, or inability to cough or clear the airway is an indication for a tracheostomy tube. And this is what you have to understand. I have had many patients who have had no ability to breathe; they have had zero vital capacity for over 50 years.

Vital capacity is where you take as deep a breath as you can and you blow it into a spirometer that just measures the volume of air that you are able to put into your lungs in one deep breath. That is called the vital capacity and most of you have probably had vital capacities measured. For a normal breath, we generally need about 500 to 600 ml of air. If the vital capacity is 600 - 700 ml of air then we can breathe without ventilators ok, although each breath is about 80% of our capacity. It does tend to tire our diaphragms out and so that is when the brain starts to allow us to breathe more shallowly and the carbon dioxide goes up. So many people whose vital capacity of 600 or 700 especially as we get older they may very well be retaining some carbon dioxide at a little higher than normal.

When you cough, an average cough is four times the vital capacity. So, if you have a vital capacity of 1000, they may have a normal carbon dioxide and be able to breath perfectly well. But when they get the flu, the first part of a cough is a deep breath, about 2.5 liters and everybody takes a deep breath when they cough. If you try to cough with your lungs empty, you will see that it is not as effective. So part of the reason the cough becomes less effective is because you can’t take a deep breath.

I’ve had patients over 50 years with a zero vital capacity, which means they cannot breathe a single breath or even 10% of a normal breath, they can’t breathe anything for over 50 years and yet none of them have tracheostomy tubes. They have a little mouth piece by their mouth that is hooked up to a ventilator on the back of their wheelchair or at the bedside, and they get deep breaths through the mouthpiece. The mouth piece is 15 mm and it is not in the mouth, but next to the mouth and they just grab it a couple times a minute to get deep breaths.

Some people with a little bit of vital capacity, they can breath on their own but their voice is very low because they don’t breath to a deep volume to be able to speak loudly and when there is a lot of ambient noise it is impossible to hear them. So, we often get a ventilator like that, put the mouth piece next to their mouth and then they can grab it when they need a deep breath, when they need to raise their voice, or when they need to cough.

Now, one of the things that we teach our patients is air stacking. Air stacking is when the machine delivers a breath and you hold it with your throat and then you let it cycle another breath and you hold it doubling you volume. Then do it again for triple that volume, and you keep going until you fill your lungs with air. Now, this is extremely important because probably most of you understand what range of motion is because many of you are probably seeing physical therapists and they have taught you that if you don’t stretch your ankles, they will get stiff and if you don’t stretch different joints that have some weak muscles, they will get stiff. Well, the same is true for the lungs and the chest wall. If you don’t fill your lungs completely to the predicted inspiratory capacity, then parts of the lungs close down and the chest wall gets stiff. If this problem becomes severe, then you can’t get a real deep breath to cough effectively with, then you may die from a stiff lung.

So, the first goal for everyone is to find out what your vital capacity is. We look at it two ways, the absolute value of it, which could be 1000 ml, and also the percent of what it should be. If the percent of what it should be is less than 70 or 80%, then everybody should be doing range of motion for their lungs and rib cage. To do that is very simple. What you need to get is an ambu bag or manual resuscitator (it is one of those balloon things with a mouthpiece on the end), and you put it in the mouth and you squeeze it and basically inflate the lungs just like you would do to a balloon. You take a deep breath and hold it with you throat, take another deep breath on top of that and we call that air stacking and you air stack up to as much air as you can hold and that stretches out the lungs and the chest wall and keeps them healthy and elastic. Now as the vital capacity goes down further, the most important thing is not the vital capacity while you are sitting, it is the vital capacity when you lie down. In Pompe’s disease there is a tendency for the diaphragm to be involved a little more than the chest wall muscles and that causes the vital capacity to be lower when you are lying down than when you are sitting. In fact the symptoms from that are people can breath ok when sitting but they can’t breathe lying flat. That is very common and that is because of excessive involvement of the diaphragm. That is a very easy thing to take care of. Some of you are using bi-pap and that is ok. However, if the vital capacity is under 70% or so, I don’t recommend bi-pap.

Now, for those of you who do not know what bi-pap is, in the 1970’s, we discovered a disease that can be described a 150 years ago. This is where people have obstructive apnea when they sleep. And they may be very much over weight and not strong enough to move their diaphragm to inflate their lungs. They had C-pap at that time. C-pap stands for continuous positive airway pressure. This is the same as breathing with your head hanging out of a car window going about 50 MPH. It should never be used for anybody with neuromuscular disease because it doesn’t help anyone breathe. It is true that it helps if you have obstructive sleep apnea, but it doesn’t directly rest the muscles or assist the muscles. And for those 500 lb people who still aren’t strong enough to ventilate their lungs they would try C-pap with 50-70 liters of water. It is like exhaling against a tornado. It is like exhaling against a tremendous flow of air that makes it difficult to actually get the air out. It is uncomfortable and it doesn’t do any good. So, Respironics developed the Bi-pap machine and Bi-pap stands for Bi-level positive air pressure. And what that does is a box that pushes out a constant stream of air like C-pap except that you can adjust the pressure separately when you are inhaling and when you are exhaling. If someone gives you air under positive pressure, to your nose and mouth and to your lungs or while you are inhaling it makes it easier to inhale. If they give you positive pressure when you are trying to exhale that makes it more difficult to exhale so you can lower that pressure. So for example you can give an inspiratory pressure of 10 and an expiratory pressure of 4 and then you are actually giving a pressure assist of 6 (10-4=6). Now if I get hit by a truck and become a C-2 quadriplegic and I have a zero vital capacity you are not going to ventilate me or anyone else with a pressure of 6. I would die quickly at that rate, because you need a pressure of 18 to 20 cm of water for normally compliant lungs. So what typically happens to people is that their doctors send them for a sleep study, and that shows that there is some problem with breathing during sleep and they are put on bi-pap. But they are put on Bipap at a lower span (inspiratory pressure of 10, expiratory pressure of 5) that gives them help, that helps them a bit, but as they get weaker, their carbon dioxide goes up anyway, and eventually they will collapse and they are told they need a trach tube which is absolutely wrong. Once they do get a trach tube though and they are hooked up to a different type of ventilator and if you look at the gauge on the ventilator it always reads pressures of 20-30. While obviously if you gave the pressure of 20 or 30 non-invasively through the nose like the bi-pap machine the patient wouldn’t have collapsed in the first place, be intubated and get a trach tube. However, most doctors don’t think of that. They really don’t. It’s incredible how people go from bi-pap and then they develop a cold and can’t cough, they develop pneumonia, develop respiratory failure and then they are told that they need to be trached.

Patients that are sent for pulmonary function tests in laboratories are basically wasting their time and their money. The laboratories are designed for people with lung disease and airway disease. The same thing is true for arterial blood gases. Pompe patients should never need arterial blood gases and what should be done (and what Dr Bach does) is this: They have a little machine called a capnigraph that monitors, or measures, the carbon dioxide level of the air that you exhale from the nose. So we know the carbon dioxide, the oximeter tells the oxygen saturation and a spirometer is needed to measure the vital capacity. But not just when you are sitting, also when you are lying down. When that difference is 7% or less (that is normal), but often when you lie down the vital capacity is half what it is when you are sitting. And even if when you are sitting it is 3000 I can guarantee you pretty much that the vital capacity is less than half that, (and) when you lie down you can’t breathe. Which means you can go to a laboratory and they will find that you have a practically normal vital capacity, but that you can’t breath lying down anyway. So the treatment is to use a ventilator to give nasal ventilation overnight or they can use a lip seal.

Ventilation can be given through the nose or through the mouth. Lip seal ventilation works better than nasal ventilation, but again doctors are not familiar with this. (Through) nasal ventilation the air can go through the nose and leak out of the mouth. Whereas with the lip seal, the air can’t leak out of the mouth and the air doesn’t usually go back up and leak through the nose. Anybody having difficulty with nasal ventilation and if they are still symptomatic there are 2 things to think about:

1. The settings are no good, they are much too low. So if anyone is using nasal ventilation with bi-pap and still feels symptomatic--they may be better but not completely better, may feel tired, etc.--the settings are probably too low. You should be on a span of well over 10. If the e-pap on your machine doesn’t go below 4 then you have to be on an i-pap of 15 or more to get a span of 10 or 11. Number 1 you have to increase that span make that, if you can, 20 i-pap and an e-pap of 2 if you can, if the e-pap can go down that low.
2. The second problem that you have to suspect is excessive leaks out of the mouth. Normally this only happens if people are taking sedatives, narcotics or oxygen.

None of you should be taking oxygen. Oxygen is like putting a Band-Aid on a cancer. The cancer is under-ventilation and airway secretions. If you don’t correct the ventilation and don’t remove secretions when you have them, the thing gets worse, you get worse and you end up going into respiratory failure. Oxygen turns off the brain’s ventilatory drive and turns off the breathing, so it gradually allows the carbon dioxide to get higher and higher. So I’ll tell you right now, nobody should be taking oxygen. If you are taking oxygen it is probably a substitute for good ventilation.

Now let’s talk a little bit about the bi-pap machines. Bi-pap is a pressure cycled ventilator. You adjust the pressure and it delivers air ‘til it feels that pressure then it shuts off. So for example: If you adjust it to 20, it will deliver a volume of air until it feels that pressure of 20 and then if you try to hold that air and try to air stack with it you can’t do it because as soon as it delivers another volume of air it is going to sense the 20 immediately and won’t give any air. So you cannot air stack with a bi-pap machine which is why I never prescribe it for anybody over the age of 5--with the exception of the bulbar ALS patients since they can’t air stack anyway since their throat is too weak. The other type of ventilator which is more appropriate for all of you is a volume-cycle ventilator, where you simply adjust the volume instead of the pressure and the machine doesn’t really care what the pressure is, since it will deliver the volume that you set it at. The main reason why this is more appropriate is because you can air stack, get deeper breaths, cough better and speak louder. The volume-cycle ventilators are quieter, they have more alarms which is not a benefit, since you have to turn them off all of the time, and it is more expensive than bi-pap, which is why everyone likes to use bi-pap. The volume-cycle ventilator is also more comfortable because you don’t have to get e-pap, there isn’t any e-pap, so it is more comfortable, they are more quiet, you can air stack with them and they are very reliable, but they are more expensive than bi-pap.

For anyone who cannot breathe lying flat should be using nasal ventilation or lip seal ventilation from a volume-cycle ventilator ideally. And if the carbon dioxide tends to go up during the daytime, usually people are not symptomatic provided that they are using something at night like some of you are, and that the daytime oxygen saturation is normal. Normal is 95% or more. Remember this, this is very important; the oxygen saturation can only go down below 95 for 3 reasons when you are awake:

1. If the carbon dioxide goes up high the oxygen goes down. This is prevented by getting deep breaths through a mouthpiece using a ventilator.
2. Mucus in the airway, which blocks the lungs respiratory exchange membrane. That causes the oxygen to go down without the carbon dioxide going up. The treatment for that is assisted coughing. If you can’t cough deep enough on your own there is a machine called the cough assist. That machine gives a real deep breath and then the pressure drops from +40 to -40 typically, that causes an effective cough, which clears the airway brings the secretions up, and patients don’t develop pneumonia.
3. If you don’t use the cough assist correctly and you end up with pneumonia or atelectasis. Actually, this is inevitable for everyone because we peak in terms of our strength at the age of 19 and after that we all lose 1% or more liver, kidney, heart and respiratory function. Over 30% of otherwise healthy people die in nursing homes from pneumonia due to just not coughing effectively anymore. If you start off with a condition that