Clinical Trials Genzyme/Pharming

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Are the Essen patients receiving the rabbit enzyme?
Yes.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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