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 22^nd 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.

Emil

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.
MRCC-UX001-00059
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.

Symposium Summary of the Neuromuscular Disease Foundation

"Success is not final, failure is not fatal, it is the courage to continue that counts".   Winston Churchill

Globally we will cure GNEM

It has never before been attempted to gather researchers and GNE Myopathy (GNEM) patients on such a large scale under one roof to discuss and examine the available research on this rare disease. However, the Neuromuscular Disease Foundation (NDF) has now successfully conducted  and completed this in an exemplary manner.  The focus for the 2-day Symposium was to bring together scientists and patients from around the globe in an effort to explore every angle of a cure  for GNEM. A wealth of information about GNEM was presented, and I can only attempt to summarize a very small part of the entire Symposium here.

The presentations by GNEM scientists were intense, packed  with scientific findings, research, patients stories, exercises, and descriptions of adaptive resources.  For more detailed information and accompanying videos, please visit the NDF Facebook page and web site.  Please refer to the links at the end of this summary for additional information.

Lale' Welsh, CEO of the NDF  commenced the Symposium by welcoming the patients, their caregivers, besides scientists who came from all over the world. Immediately following the introductions, we were off delving into two full days of rigorous scientific data. Patients thereafter were able to have their questions answered face-to-face by the researchers.
Symposium Day 1

1.  Dr. Mansbach, Vice President of clinical development from Ultragenyx, stated that he was very saddened by the lack of success of the Phase 3 Sialic Acid trial, which was the last step before regulatory approval. Unfortunately, they were not able confirm the data they showed in Phase 2 of this study.  Since it is necessary to show the FDA that the placebo control group versus the group on Sialic Acid  demonstrated insignificant benefit, making this the end of the road for the development of this compound. He further stated that it is important to try.  Even though this door may be closing, there are other groups that may be able to build upon what has been learned through this trial.  Dr. Mansbach further explained the details on how they designed the Phase 3 Sialic Acid trial and and how the endpoints were tested.

2.  Dr. Lochmuller from Newcastle, United Kingdom, discussed the online monitoring program for GNEM patients he and his team continue to conduct.  It includes a Disease Monitoring Program (DMP) platform where patients can log into their medical file to answer a battery of questions at regular intervals. There is no treatment associated with this program, although they are learning about the most common GNEM mutations that are characteristic in certain groups.  Dr. Lochmuller further mentioned that if we can understand the "modifier gene" we may be able to design a effective GNEM treatment.

3.  Dr. Nishino from Japan presented information on GNEM that was derived from the Japanese population.  In Japan there are 188 registered GNEM patients.  Common mutations within the Japanese group are V603L and D207V.  This latter mutation is in some cases mild or asymptomatic in patients.  Dr. Nishino theorized that there are other options for treating GNEM, such as bone marrow or liver transplant although these are not very easy, practical or even viable to accomplish.

4.  Dr. Rosenbaum from Israel (who identified the GNE gene) mentioned that the precise mechanism of the pathway of the GNE gene and its "interactors" are not yet fully understood.  Even though GNEM is a mono-genetic disease, she stated that we need to understand if and how it is interacts with other genes. She implied that we need diverse research to bring about more understanding of the GNE gene.  Many proteins interact with the GNE gene, thus making the GNE protein problematic to work with.

5.  Dr. Huizing from the National Institutes of Health (NIH) reported that they have been following:

• 54 GNEM patients in the Natural History study program for the past 6 years and thought that this study had valuable data in terms of how GNEM progresses, how muscles function in regards to different mutations.
•  The Sialic Acid synthesis pathway has been well studied.
•  Dr. Carrillo, from the NIH, and her team have come to understand that chronological age is not equal to "Disease Age." Dr. Carrillo and her team have designed a "Disease Progression Model" to assess the Disease Age of each patient they study. As a patient, I see other patients of the same age, I  notice differences in their strengths and their mobility.  This will be a very helpful and standardized tool to give all of us an idea of  what stage we are in the disease process.
• It has been suggested that perhaps patients who have both mutations on the kinase domain, ManNAc may be more effective
• ManNAc is a neutral sugar that is slowly released into the blood stream.  It is easily taken up and sialylated, and thus it could still be present in the blood 48 hours after dosing.
• The NIH plans on starting a multicenter  Phase 3 ManNAc trial on 50 patients later this year. For this study patients will need to be off of Sialic Acid, ManNAc, or any other pertinent medications. Patients will need to pass a Quantitative Muscle Assessment (QMA).  To participate in this upcoming trial, please monitor this site to see when recruitment will begin. Link to monitor for the upcoming ManNAc trial.

6.  Dr. Hegde from Perkin Elmer, Atlanta Georgia, presented her ongoing research on the analysis of various genes and her observation is that GNEM is under-diagnosed and may as well have other genes that interfere and or interact with the GNE gene.  This is an area that she intends to investigate as she partners with the Jain Foundation to study muscular dystrophy.

7.  Dr. Shin from Pusan Nat'l University, Yangsan Hospital, South Korea, presented a short piece on how the South Korean GNEM patients are getting organized to increase the Korean peoples' awareness of  GNEM. There are approximately 50 known patients in his south Korea. (Note: for several years I have been sending emails to neurologists in Korea, China, and other countries, asking them if they know of any GNEM patients, and if so to have them contact me. Finally, I was able to meet a doctor studying GNEM and a patient from South Korea.  Our next frontier is China!

8.  A Panel  led by Doctors Argov, Huizing Shieh, Rufibach, Mansbach Mozaffar, and Shin.  GNEM patients, family members, and caregivers were able to ask various questions from the panel ranging from stem cell therapy to various clinical trials.

Lale' Welsh, CEO NDF, Commences Dinner Celebrations 

9.  At an extensive eloquent dinner served to all attendees on the first day of the Symposium, there were two guest speakers Dr. Kakkis, CEO, of Ultragenyx, and Dr. Jerry Mendel from the Nationwide Childrens Hospital, Columbus, Ohio.

Dr. Kakkis made a conscious choice to come and address our patient community regarding the termination of the Ace-ER (Sialic Acid) trial.  He did not have to come but made the choice to do so any way as he has always had patient well being at the forefront as a therapy for GNEM was being developed. He notified our group that because the Ace-ER trial failed to meets its primary"end points," and further showed no statistical difference between the placebo group and the group taking Ace-ER: they have no other choice but to terminate that study.  There were 89 patients enrolled in this study. Ultragenyx will  continue to support other efforts to find a solution for GNEM.  Currently, they are working on pro-drug program for GNEM which is a version of Sialic Acid that is now in the early stages of a preclinical trial.  

Dr. Mendell outlined the process for applying to the FDA for the pre-IND and IND approval for gene therapy. He further stated that in order to proceed with the gene  therapy process, the following will need to be done:

• One must have good clinical data to show the FDA such as "proof of concept" and "proof of principle."  
• Preclinical data to show the FDA, that there is efficacy in an animal model.
• FDA will then assist the investigators in preparing a delivery scheme to proceed with the chosen form of gene therapy.
• Dr. Mendell is using the mouse model from Dr.Nishino and the transgenic mouse from Dr. Rosenbaum.
• The delivery gene that contains the virus still has to be tested on several hundreds mice and on  non-human primates for toxicology purposes.
• Dr. Mendell also discussed the various vectors, promoters, and systematic delivery methods.
• There is possibility of a ten fold gene expression in the GNE gene using an MCK promoter which could allow the gene expression to persist for over one year.
• To proceed with toxicology tests $300,000 is needed and about $3.5 million would be needed to proceed with GNEM gene therapy trial on humans.

Ms. A. Curran, Certified Patient Advocate, NDF shared her impressive GNEM journey and gave the reason for which she became an advocate.
Ms. Lale' Welsh, CEO, NDF presented 10 certified advocates (from various countries) with awards and pins with the hope that they would return to their respective countries and generate increased awareness of GNEM. 

                               Scientists and doctors enjoying an outdoor lunch at the Symposium.
Symposium Day 2
On Day 2 there were various break out sessions as follow:

1.  Mr. Clements, Monterey Peninsula College, CA, worked with patients, family members, and caregivers on various adaptive exercises.
2.  Dr. Tabibian, NDF Board Member, led the patient group in meditation and nutrition.
3.  Dr. Kubacky, Psy.D met with patients only in a private session to discuss various ways to deal with our disease.
4.  Ms. Gelbard, LSCW and Dr. Rahban, both NDF Board Members led a group consisting of family members and caregivers.
5.  Mr. Loren, NDF Board Member moderated a consortium and data-sharing session with scientists, physicians, industry professionals, and NDF Board Members.
6.  Ms. Curran and  Mrs. Voogel, both NDF Certified Patient Advocates, led a patient-only group where they discussed, shared, and demonstrated various adaptive resources that GNEM patients may find practical and helpful in their activities of daily living.

The NDF 's fourth annual symposium was well attended with approximately 40 GNEM patients, family members, and researchers from more than 15 countries. The NDF has planned for this-one-of- a-kind Symposium for over a year.  There were a variety of complexities to pay attention to in order to assure that all our patients get the appropriate transportation from the airport to the hotel, get accessible rooms, and be able to coordinate with vendors for wheelchairs to name a few of the complexities.

Ms. Curran and Mrs Voogel, NDF Certified Advocates set up a "Whatsapp group" to assist with communication and updates of the Symposium. There was a caregiver liason, Mr. Pizzi who was ready to transport the patients and scientists in a shuttle to the various venues around UCLA campus. 

Seen and experienced from the eyes of a GNEM patient, my takeaway from this Symposium is that I felt that we were united as a GNEM group both, patients and scientists.  We were united in one goal and the goal is a cure for GNE Myopathy. Additionally, I felt that we were very fortunate to have these "Giants" (talented, dedicated scientists) working on our rare disease.  There are more than 7,000 rare diseases and GNEM is getting their attention.  

We have had a minor setback with the termination of the Sialic Acid trial, but setbacks are not failures. It may lead us to a deeper understanding in how the GNE gene works and interacts with our other genes. Let us remind ourselves that we are warriors, everyday warriors.  We face extreme challenges every day  with our physical selves. Our long-term vision must be to find a cure.  We must continue the effort to get patients accurately diagnosed in our communities.  We know we have not yet scratched the surface since, per the NIH calculation, there are approximately 40,000 GNEM patients world wide of which only a small fraction is known to researchers. Strength lies in number and our job is to find these patients.  

I want to thank my extended GNEM family (my beloved GNEM friends, Lale', Nancy, Amy and Jon) for giving me the opportunity to experience your presence at this Symposium.  Without the undying love of a mother for her daughter we would not have the NDF.

We are STRONG just after our exercises, nutrition presentation, and sharing many practical tips. 

For detailed discussion of the Symposium, please visit:
1.  NDF Facebook Page
2.  Curehibm.org

 "There's a silly notion that failure's not an option at NASA. Failure is an option here. If things are not failing, you are not innovating enough." Elon Musk