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Press Release from Ultragenyx Regarding Termination of the Sialic Acid (Ace-ER) trial and Some Frequently Asked Questions About the Ace-ER trial

Hope is in our GNE gene!      
Friends, I know many of us are sad with the outcome and termination of the SA-ER study. We must continue on and put our best effort into supporting other therapies, such as the upcoming ManNAc trial (NIH), gene therapy (Dr. Mendell/NDF), and other possible treatments.  Perhaps the prodrug Ultragenyx is working on will prove successful.

Following on from the press release issued by Ultragenyx on August the 22nd regarding the results of the Phase 3 Study (Click for press release)Dr Emil Kakkis M.D., Ph.D., the Chief Executive Officer at Ultragenyx would like to share the following letter with all of the GNEM –DMP registry participants.
 If you have any questions please do get in touch by emailing  hibm@treat-nmd.eu or Nicole.oconnor@ncl.ac.uk and we will try to help. Alternatively, you could consult with your Doctor.
To read the letter from Dr. Kakkis, please click here.  
Finally, thank you for continuing to participate in the registry!
Best wishes,
GNE Myopathy team

Findings of the UX001-CL301Clinical Trial

Dear GNE Myopathy Patient Community,
We announced very disappointing news from our Phase 3 study of UX001 (Ace-ER) which failed to demonstrate efficacy in treatment of GNE myopathy. We did not confirm the benefit in maintaining the arm strength of subjects treated with Ace-ER as we had expected from our Phase 2 study. If there was any effect, it was small and the other endpoints did not provide any supporting evidence for efficacy. Safety was acceptable as previously observed. We can tell that the patients were taking the drug by their serum sialic acid levels. I believe the Ultragenyx clinical team designed and conducted a high-quality study but the treatment effect was unfortunately, not confirmed.
We have been looking at why it did not work and there is no perfect answer. It is clear that the patients included in this study were stronger at baseline but this is what we planned by our inclusion criteria to include people with more muscle to lose, based on our Phase 2 data. These Phase 3 patients did not decline quite as fast as expected but they did still decline in arm strength and Ace-ER had no significant effect. There may be other smaller differences between the studies, but those differences alone cannot fully account for the lack of efficacy in stabilizing the patients. The phase 2 study was small and the Phase 3 study much larger, so it is a better dataset to make conclusions. Without a pathway forward for the product to approval and no positive results, we had to terminate the program and focus on other things at the company.
For patients in our studies or on compassionate use, we are most heartbroken that we cannot offer even a modest therapy for them and that their future now depends on other research work that is ongoing. We will manage this transition graciously to avoid a precipitous stop. We know this is a shocking moment for patients on our studies and for those who feel the drug is helping them. For patients not already on Ace-ER, we cannot initiate new therapy. Whether on Ace-ER or not, the GNE myopathy patient community needs to not lose faith in research but participate in other clinical studies to help get an effective treatment approved. Patients will likely have to be off Ace-ER to participate in other clinical studies.
While we were unable to get Ace-ER to approval, we did contribute to the field and this is very important in the development of any therapy. GNE myopathy is a more widely known disease now among people other than doctors and patients. It is being diagnosed more often with the diagnosis program we supported. We established and made available new methods and endpoints for measuring muscle strength and GNE myopathy patient function as well as gained acceptance for those endpoints from a regulatory standpoint. FDA and EMA know the disease now and a regulatory pathway now exists. Our
DMP natural history study data are very valuable and as planned, all of our data will be available for others doing research on the disease through our relationship with TREAT-NMD. Finally, we will continue our research work to develop a better replacement therapy in our sialic acid prodrug program. If we can demonstrate it has substantial efficacy in animal models then perhaps we can come back to the clinic at some point in the future. We don’t know when that will be but the work is ongoing. In the meantime, we are hoping to see patients participate in other clinical programs and fight this disease everywhere, every day, and all the time, until a solution is found.
Thank you for all you do.


Some Frequently asked Questions about the SA-Er (Ace-ER) Trial

1. Why is the Sialic Acid (Ace-ER) trial terminated?
a. The Phase 3 Ace-ER study enrolled 89 adults with GNEM able to walk > 200 meters in
the six minute walk test. Patients were randomized 1:1 to Ace-ER at a dose of 6g/day or
placebo for 48 weeks.
b. The study did not meet the primary endpoint of demonstrating a statistically significant
improvement in Upper Extremity Composite score (+0.74 kg, p=0.5387) for Ace-ER
treated patients (n=45, -2.25 kg) compared to placebo (n=43, -2.99 kg) patients for the
change from baseline to 48 weeks.
c. There were three pre-specified key secondary endpoints, including the lower extremity
muscle strength composite score as measured by hand-held dynamometry (HHD),
physical functioning using the Mobility domain of the GNE Myopathy-functional activity
scale (GNEM-FAS), and a measure of muscle strength in knee extensors. The study did
not meet any of these key secondary endpoints.
d. The Phase 3 study was appropriately designed and indicates that Ace-ER did not
stabilize this stronger patient population. We would have expected that there would be
an effect in this population where more muscle is remaining to treat.
e. The Phase 2 study was much smaller and did not have a placebo for the full duration of
the study. The EMA reviewed the results of this study and determined that it was not
sufficient for conditional approval .
2. Should I stop the SA-ER tablets immediately?
a. Please talk to your doctor. It is completely up to you if you want to stop immediately.
You do not have to, but you can if you want. In the phase 3 study, Ace-ER (aka sialic acid
extended release) did not show any benefit compared to placebo in stabilizing strength in the upper extremity or improving the other endpoints.
3. Will I experience withdrawal symptoms when I stop ingesting SA-ER?
a. No evidence of withdrawal symptoms have been observed.
4. When will my trial doctor (investigator) contact me?
a. In the next few weeks. You can also reach out to your study team to talk to them sooner.
5. What are the resources available to me during the transition period?
a. We recognize that some patients feel that they are receiving benefit; however, the overall data did not show a benefit compared to the placebo. Given these results,Ultragenyx has made the difficult decision to end the Ace-ER Program and all studies evaluating Ace-ER in GNE Myopathy.
b. For patients currently in studies or on compassionate use, your physician may request access through compassionate use to provide a reasonable transition. This mechanism
requires approvals by the following groups: Principal Study Investigator, IRB
(Institutional Review Board) / EC (Ethics Committee), & country Health Authority.
6. Can my local doctor or PCP (using central IRB) request compassionate use on my behalf or does it have to go through the study investigator?
a. The study investigator should be in agreement about the risk/benefit profile of the study drug but then Ultragenyx could work with the patient’s local neurologist for a compassionate use request.
7. I feel hopeless now as SA-ER was a very promising solution for GNEM, who should I contact for additional resources.
a. Your doctor(s)
b. The NDF has support resources available to support you
c. ManNac trial: Kennan Bradley, MPH is the Clinical Research Coordinator at the NIH for
the ManNac trials. Contact info: Office: 301-827-7746, Cell: 240-461-0725, Fax: 301-402-0006. https://www.genome.gov/27567243/
8. Will you publish data and when, on the findings of phase 3 study?
a.Yes, we will be publishing the results of the studies and working with GNEM researchers (NDF and TREAT-NMD) to make data available.
9. Do you have other substrates you are considering as a trial for GNEM?
a. We have a pro-drug program for GNE myopathy that is in the very early stages of preclinical research.
10. What is the pro-drug you mentioned at the NDF Symposium you are working on? And how will a pro-drug work if you do not have a drug for it to help?
a. Prodrug is a chemically modified version of sialic acid that is designed to improve delivery to muscle.
11. When will this be available as a trial?
a. At this point we do not know if and when it may make it to the clinic
12. Will this pro-drug work in concert with ManNAc?
a. We do not know at this time.
13. Who should I contact if I need more information why SA-ER was terminated?
a. Kim Mooney at 408.981.3526 or kmooney@ultragenyx.com
14. Could my biopsies/data collected by you be shared with researchers working on GNEM?
a. We will work with Treat NMD, our partner that shares in ownership of the data in the
GNEM-DMP to ensure the data will be available to help support development of other
therapies by researchers and companies.
15. How do I get my individual study results?
a. We will share information with each study site on which subjects received active
treatments vs placebo.
b. Please ask your investigator/ study site for study data related to your muscle 
measurements and other data.

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