Duchenne Research Update: October 2016

When I first joined the Duchenne community in 2009 at Children’s National Medical Center, I remember thinking that I was walking into a critical juncture in Duchenne history. There were three compounds in the clinic (drisapersen, ataluren, and eteplirsen aka Exondys 51) with more waiting in the wings to go into clinical trials, a drug development/regulatory landscape primed for rare disease drug development and, perhaps the most important piece, an engaged community of patients and families ready to roll up their sleeves and disrupt the process to create momentum.  


As I sit to write this research roundup I realize it was not only a critical juncture, but the beginning of a new era in drug development. While we are not there yet, we are certainly in the midst of a dynamic, active research and development cycle with many opportunities being explored. 


So much has happened in recent weeks in the Duchenne space that it is hard to keep up. While approvals and partnerships and regulatory actions have dominated the press, there is still a lot of pre-clinical and early stage clinical research happening behind the scenes, with great potential. 

Here Is a Summary of What Is Going On:


First US Approval of a Duchenne Therapy

Sarepta Therapeutics received accelerated approval for Exondys 51 on September 19, 2016, with post regulatory commitments spelled out in the approval letter

For those US patients amendable to an exon 51 skip you can contact SareptAssist for questions about access. If you are uncertain if you or your child is amenable to exon skipping, visit Decode Duchenne for free genetic testing and counseling.


Sarepta Collaborations

Sarepta recently announced two partnerships to broaden their portfolio of Duchenne therapeutic options. One partnership is with Catabasis who is pursuing an NF-kB inhibitor program (a protein that is activated in Duchenne and drives inflammation and fibrosis, muscle degeneration and suppresses muscle regeneration). The other is a licensing agreement with Summit Therapeutics, the developer of ezutromid, a utrophin modulator. Utrophin is a naturally occurring protein that is functionally and structurally similar to dystrophin.  


Sarepta is expected to file an application for Exondys 51 in the European Union (EU) soon, but will have to resolve the patent issues with BioMarin to have the freedom to commercialize it there. 


The Essence trial, for those amenable to exon 45 or 53 skips, has enrolled its first patients and is underway.


Under Review at FDA

Deflazacort, Marathon Pharmaceutical's product, is under review at the FDA and a decision is expected sometime in February 2017. In the meantime, their expanded access program is underway. We look forward to more updates from Marathon in the coming weeks.


PTC Therapeutics holds a conditional approval for Translarna (ataluren) in the EU but received a refusal to file (RTF) letter in the US in February. Just this week, we learned that the FDA denied PTC first appeal of the RTF. As we understand it, this is a process and may involve additional appeals. PPMD will be meeting with PTC to better understand the communications that transpired between the agency and the company and how we as a community can support this process moving forward.

In the meantime, a paper in PNAS was just published on the mechanism of action. They also recently published compelling pulmonary data in non-ambulatory patients


Additionally, PPMD has been collecting patient experience data from those who have been on Translarna. Please take this survey if you have been in a clinical trial or are currently on drug.


PPMD continues to urge the FDA to give Translarna a full review and to conduct an advisory committee meeting.  


Request by FDA for More Data

Santhera Pharmaceuticals submitted briefing documents and a meeting request to the FDA to discuss the filing of a New Drug Application (NDA)  under the Subpart H Accelerated Approval framework for Raxone in non-glucocorticoid treated patients. The FDA said they wanted to see trial results of their Phase 3 trial in glucocorticoid treated patients before deciding. This could potentially delay an approval for 3 years. The Phase 3 trial, called SIDEROS, is currently recruiting participants.

Last year PPMD conducted a patient preference study around pulmonary outcomes in Duchenne. We found that patients and caregivers are willing to accept risk and burden in order to achieve pulmonary benefit., and that a drug like Santhera’s Idebenone presents a favorable choice for a potential treatment. PPMD shared these results with the FDA and we have also expressed the frustration of our community regarding the decision not to let Santhera file for accelerated approval. Read the report.


This Generation of Clinical Trials

The Duchenne community has worked hard to achieve such a rich pipeline of trials that are in the clinic, many of them supported by PPMD in earlier stages. We need to ensure trials are thorough and efficient, determining viability quickly, so that we don’t waste precious time and resources.


While this is not an exhaustive list, it does cover the candidates that are on the horizon. The first two, as mentioned, have partnerships with Sarepta, which will help them financially as they make their way through the riskier part of the development process. 


Visit PPMD's DuchenneConnect for a comprehensive list of all drugs in development.


PPMD Supported Early Stage Research:

PPMD has a long history of funding early-stage, innovative preclinical and clinical research for potential therapies. In the fall of 2015, PPMD opened an RFA and received over 30 applications.

Our Scientific Advisory Committee (SAC) reviewed the applications in early spring of 2016 on technical merit and ability to impact this generation of people with Duchenne, meaning that results could be applied in a meaningful way now. Of the 30 reviewed, four grants have been awarded for research that we believe is compelling and relevant to today’s therapeutic landscape.


Micro-dystrophin and Immune Response

"In silico re-engineered micro-dystrophin - Expanding a novel approach to evade T-cell immune responses in Duchenne patients" - Guy Odom, University of Washington: $50,000 

What drew our SAC to this project was that it addressed a known issue related to gene therapy – the potential for an immune response to the newly created microdystrophin. This project will explore ways to avoid this potential immune response to microdystrophin, by re-engineering it the so that the immune system does not recognize it. The re-engineering will be done using a computational model. The results could also be applied to dystrophin produced from exon skipping which makes this research even more relevant and applicable.


NF-KappaB and Cardiac Function

“NF-kB Function in DMD Cardiomyopathy” - Dennis Guttridge, Nationwide Children’s Hospital: $50,000

Most Duchenne patients develop heart problems so new drugs will have to work by fixing both skeletal and heart muscles. There has been a lot of research on skeletal muscle, but very little is known about a dystrophic heart. This project will focus on a protein called NF-kB, which has been shown to contribute to the degeneration of skeletal muscles and to understand how NF-kB is capable of causing Duchenne hearts to fail. This award will provide additional insight on how NF-kB functions in Duchenne and potentially ways to target this molecule to improve therapy. Several companies are currently studying compunds that target NF-kB and this research could expand our knowledge of potential benefit.


Improving Exon Skipping Efficiency

"Investigation of the efficiency for exon skipping and mode of entry into muscle by antisense constructs of different chemistries" - Terry Partridge, Children’s National Medical Center: $230,000  

Exon-skipping is currently a promising therapeutic for attacking the primary defect behind Duchenne. Indeed, the only approved therapy for Duchenne is based on exon skipping. However, it has been hard to assess how well the technology has worked in coaxing new useful dystrophin to be produced in muscle. This project will characterize the timing, efficiency, and duration of each stage in the process of production of dystrophin by exon skipping. Researchers will test three different agents in two strains of mice in which the same mutation produces two different patterns of disease. The results will be important as exon skipping technologies move forward and could help inform design of optimal regimes of administration of different types of antisense agents.


Quercetin as a Potential Drug for Duchenne

"Quercetin-based therapies with immediate application for dystrophic muscle" - Josh Selsby, Iowa State University: $200,000

Quercetin is a flavanol found in many foods and is a nutritional supplement that some Duchenne patients are currently taking. It is suspected to have a strong effect on heart muscle, along a different pathway than other heart medicines (i.e. ace inhibitors). In this project, quercetin and lisinopril (an ace inhibitor), will be studied together and alone to see if there is a synergistic effect on the heart. This project will shed more light on this compound to determine its potential for cardio-protection and ability to keep muscles healthy. Coming to a conclusive determination of a substance’s usefulness can takes years of studies, in both animals and humans, as our community is well aware of. So this is one more step in understanding quercetins effectiveness and gives us more information about next steps.




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