IPA Questions to Amicus Therapeutics

Response: 2nd April 2007

1. What are chaperones? Pharmacological chaperones are small molecules that selectively bind to and stabilize proteins in cells, leading to improved protein folding and trafficking, and increased activity.

2. Why are chaperones chosen for a therapeutic approach in Pompe disease? Pompe disease is due to the reduced activity of the enzyme α-glucosidase in the lysosome. Enzymes are specialized proteins. Many of the genetic mutations reported in Pompe disease result in the production of a form of α-glucosidase that is unstable, cannot fold properly and cannot get to the lysosome.

3. What are the working principles of chaperones in Pompe disease? Pompe disease is due to the reduced activity of the enzyme α-glucosidase in the lysosome. Enzymes are specialized proteins. Many of the genetic mutations reported in Pompe disease result in the production of a form of α-glucosidase that is unstable, cannot fold properly and cannot get to the lysosome. The concept behind the pharmacological chaperone approach is to identify a small molecule that can selectively bind to the mutant form of α-glucosidase. This binding interaction would confer stability; enhance trafficking out of the endoplasmic reticulum and to the lysosome, where α-glucosidase would function to breakdown substrate. This is a theoretical approach with a mechanism of action that has not been proven for Pompe disease.

4. Which chaperones to be used for Pompe disease therapy? Amicus Therapeutics is exploring the use of AT2220 as a pharmacological chaperone for Pompe disease. We have conducted preclinical work on this molecule and submitted an IND application to the FDA. This experimental drug is currently in phase 1, whereby healthy, adult volunteers consent to take the experimental drug. The primary endpoint of this phase 1 trial is safety.

5. To what part of the Pompe population is chaperone therapy expected
to be beneficial? The answer to this question is unknown at this time. We will gather this data over time as the human clinical trials involving individuals with Pompe disease are conducted. Individuals who make some active α-glucosidase which can be enhanced by AT2220 are expected to benefit.

6. Is the chaperone technique suitable for all the different DNA
mutations, or is a specific approach needed? Amicus is exploring the use of AT2220 for treatment of Pompe disease. The experimental drug is targeted to α-glucosidease, not to an individual mutation. Continued experimentation will reveal the range of mutations that result in altered forms of α-glucosidase that respond to AT2220. It is expected that response to AT2220 will vary across mutations and that some will not respond at. For example, it is likely that a deletion mutation will result in the production of no active α-glucosidase and therefore not respond to AT2220.

7. Will chaperones replace or support enzyme replacement therapy? Currently ERT is the only approved treatment for Pompe disease. It is unknown the future role pharmacological chaperones will play in the treatment options of individuals with Pompe disease.

8. Will there be non-responders to chaperone therapy? If so, for what
reasons? Great question and certainly an important one in the Pompe patient community, given their experience with ERT thus far. As applied to pharmacological chaperone therapy, non-responder takes on multiple meanings. On a cellular level, we refer to the response of α-glucosidase activity to exposure with AT2220; i.e. does the naturally reduced activity of the enzyme increase after exposure with AT2220. As mentioned previously, mutations causing Pompe disease will result in α-glucosidase enzyme with reduced activity. Some mutations will cause the production of α-glucosidase that will not respond to enhancement by AT2220. We are currently studying the response of α-glucosidase to AT2220 in cells obtained via a blood draw from individuals with Pompe disease. Functional response, as defined by the effects AT2220 on the organ systems involved in Pompe disease, is unknown. This is data only obtained through clinical research trials involving individuals with Pompe disease.

9. What is the timeframe for therapy development (clinical studies)? Phase 1 clinical trials involving healthy volunteers are on-going and will be conducted throughout the better part of 2007. If the data from phase 1 support a phase 2 clinical trial, we expect to initiate phase 2 clinical trials by the end of 2007 or the beginning of 2008.

10. When is chaperone therapy expected to be available? We cannot speculate at this time, but we hope the process will take 5-7 years.

11. Where will the clinical studies take place? US only? Europe? Germany? (Why is Germany mentioned separately?) We are currently speaking to key thought leaders in Pompe disease both in the US and ex-US to determine the design of the clinical studies as well as the location of the phase 2 clinical trials. If you have recommendations of physicians with whom we ought to speak we are happy to receive them.

12. Has contact with physicians or clinical centers already been established in the US and Europe? If so, which centres and why. We are beginning to reach out to key scientific and medical thought leaders in Pompe disease across the US and internationally. We welcome suggestions and recommendations. Many relationships have been established through our research involving other lysosomal storage disorders. For example, current members of our MAB include Dr. Thomas Voight, Dr. Marc Patterson, Dr. Barry Byrne, Dr. Pram Mistry, and Dr. Dominque Germaine.

13. Who will be recruited for clinical studies? Will it be patients not receiving ERT or will patients be required to stop ERT? If the latter, for how long? The inclusion and exclusion criteria for the phase 2 clinical studies involving individuals with Pompe disease have not been determined at this point. Again, we are actively discussing these studies with the key physicians and scientists in Pompe disease. The trials will be posted publicly on www.clinicaltrials.gov and interested participants should speak with the investigators conducting the trial as to the specifics of the eligibility criteria.

14. What age groups will be studied? This is an extremely sensitive topic, given the many significant medical and psychosocial issues present across the clinical spectrum of infantile, juvenile, and late-onset Pompe disease communities. It is most likely the case that the earliest studies will involve adults with Pompe disease. Again, the protocols have not been designed and the plan for all clinical trials determined, so eligibility criteria cannot be commented upon at this time.

15. What are the expected costs and benefits of the therapy? Another very important question. We are early in the drug development process and have not assigned costs or determined potential benefits. As we move through the development process and closer to a commercial product, we will have a better idea of the costs. Benefits will be determined by clinical trials.

16. How can IPA and national patient groups support Amicus? Amicus is committed to transparent communication, supporting the disease communities and their families, and to building a strong Patient Advocacy program. We want to establish a relationship with the organizations representing the Pompe community in order to learn about the needs of the community, so that we can begin to build services and programs that meet the stated needs. We would like to have the relationship built on trust and a mutual sharing of information. We would like support from the patient organizations in the form of dissemination of information to the broad Pompe community involving physicians, patients, and families. We are excited to move forward with a Pompe program, but feel strongly that we must do so with caution when communicating to the patient community. We do not want to raise false hopes and unrealistic expectations. Many of the questions above reflect experience with current therapy either as a marketed product or as a late-stage investigational drug. We are very early in the drug development process and cannot speculate as to any effects AT2220 may or may not have on individuals with Pompe disease. Our work thus far has focused on cells and animals. We look forward to our continued progress in the drug development process and look forward to your support as we move through the process of evaluating the pharmacological chaperone approach to treatment. We also look forward to meeting with the leadership of the IPA.