Last month, PPMD convened a day and half meeting – Inflammation in Duchenne: Current and New Treatment Strategies – to bring academic and clinical researchers together to discuss advancements that could be made by treating inflammation in Duchenne.

I had the pleasure of attending this workshop and wanted to share insights and next steps from the meeting. This is my first official post for PPMD having just recently joined the PPMD team.

Current landscape of inflammation in Duchenne

As you know, Duchenne is a disease characterized by a lack of dystrophin, which leads to muscle weakness and degeneration. The absence of dystrophin in muscle cells causes membrane instability and the release of various compounds outside the cell. These compounds initiate an immune response and, eventually, a state of chronic inflammation. For the two days of this workshop, Duchenne was approached as a chronic inflammatory disease with a focus on the best methods to address the role inflammation plays in the disease.

A Steering Committee, consisting of a number of researchers and clinicians, worked with PPMD to put together the agenda. The committee included:

• Jim Tidball, PhD (University of California, Los Angeles)
• Kanneboyina Nagaraju, DVM, PhD (Binghamton University)
• Basil Petrof, MD, FRCPC (McGill University Health Centre – Research Institute)
• Denis Guttridge, PhD (Medical University of South Carolina)
• Elizabeth McNally, MD (Northwestern University)
• Tom Cheever, PhD (NIH-NIAMS)
• Abby Bronson, MBA (PPMD)

The opening discussions helped set the stage for our current understanding of inflammation in Duchenne and described some of the outstanding issues that need to be resolved in order to provide the best care. The presentations spanned a wide variety of topics in inflammation and immune response, yielding fruitful discussions between presenters and audience members.

Some of the heavily discussed ideas from the opening talks included:

• Due to the small patient population in Duchenne, we need to strive to make more human samples (blood and tissue) available and optimize our pre-clinical models to expedite drug discovery and development.
• The immune response has both positive and negative side-effects in Duchenne, so it is important that treatment be focused on targeting specific aspects of the immune response rather than a broad immunosuppression approach.
• Treatment with steroids, typically prednisone or deflazacort, is the recommended standard of care in Duchenne, but further investigation into the best dose and treatment regimen (daily vs weekend dosing) are still needed.
• Genetic variation in patients, outside of the mutation causing Duchenne, can have an effect on disease progression and steroid efficacy. Furthering our understanding of an individual’s genotype will aid clinicians in providing personalized care.

Inflammatory drugs on the horizon

A primary goal of the meeting was to discuss potential therapies that were outside of the steroid standard of care. A number of industry sponsors and researchers were present to provide updates on these novel anti-inflammatory therapies:

• Edasalonexent (CAT-1004) from Catabasis is a novel, investigation drug that inhibits nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-kb), a protein complex that plays a key role in inflammation. By targeting NF-kb specifically, edasalonexent can potentially mimic the benefits of steroids without the side effects. Data was presented showing Duchenne boys treated with edasalonexent had similar MRI results as Duchenne boys on steroids. The growth patterns for those treated with edasalonexent didn’t have the characteristic steroid side-effects (weight gain, height stunting). Catabasis is currently enrolling a Phase 3 trial, PolarisDMD (NCT03703882).
• Vamorolone (VBP15) from Reveragen is a first-in-class steroidal drug. Utilizing a novel molecule and mechanism, this therapy is also able to specifically inhibit NF-kb. VBP15 is a compound that should repress inflammation like a steroid without generating the negative side effects associated with steroids. Reveragen is currently enrolling a Phase2b trial (NCT03439670).
• MNK-1411 (cosyntropin) from Mallinckrodt is a synthetic form of adrenocorticotropic hormone (ACTH), a naturally occurring hormone. The slow release of MNK-1411 should stimulate the adrenal cortex to increase the body’s production of cortisol, a naturally occurring corticosteroid, which could reduce muscle inflammation. They are currently enrolling a Phase 2 trial (NCT03400852).
• Jill Rafael-Fortney, PhD, shared insights on spironolactone, a steroid that targets different receptors than prednisone. Drugs in the same class as spironolactone are often used in treating heart failure and show reductions in mortality and morbidity. Pre-clinical research has shown it has the potential to improve heart and skeletal muscle function, with lower negative side-effects compared to glucocorticoids. Kevin Flannigan, MD, at Nationwide Children’s is currently enrolling an open label study comparing efficacy in motor function between spironolactone and prednisolone (NCT03777319).

Throughout the day there were a number of thoughtful dialogues between the participants in the workshop. While everyone is hopeful for the success of dystrophin replacement therapies, such as exon skipping and gene therapy, there is still time before they will be widely available. One of the more thoughtful discussions focused on how we can prepare for dystrophin restoration therapies, with three main goals:

• Researchers and clinicians need to focus on optimizing muscle cell integrity and regeneration while inhibiting fibrosis (scarring) until dystrophin restoration therapies are widely available.
• Optimizing conditions in the body to make gene therapies more successful are key goals as we look to the future.
• Dystrophin restoration is not a cure, but it will lead to greatly improved quality of life for people with Duchenne, mimicking the slower disease progression of Becker muscular dystrophy. With that in mind, more research will need to focus on ways to improve treatment of Becker.

Learning from other pediatric diseases

Looking to other diseases that share similar manifestations as Duchenne provides a pathway for identifying therapeutics that could be brought into the Duchenne disease space.

Overviews and treatment of Juvenile Dermatomyositis and Myositis, both of which are inflammatory muscle diseases, were presented. Similar points were made in both presentations with lessons that can be adapted in the treatment of Duchenne.

• Both diseases have a number of biomarkers that provide valuable information to clinicians about disease progression and potential treatment.
  • For Duchenne, we have a need to validate clinical biomarkers for numerous aspects of the disease, including disease progression, predictive markers for drug efficacy, prognostic markers for predicting risk of incidence, safety markers for drug tolerance, and surrogate endpoints that could allow for faster drug approval.

• Treatment of these diseases do not have a one size fits all drug; different subsets of patients require different drugs. For Myositis, a single drug is typically efficacious in only 30-40% of the population.
  • As previously mentioned, consideration for genetic effectors that impact disease progression and response to therapeutics should be incorporated into treatment decisions.

The insights from other diseases continued by looking at different classes of drugs that could be co-opted to treat Duchenne. Drugs that are either FDA approved or have strong pre-clinical data targeting different parts of the inflammation pathway were presented. These drugs would require further pre-clinical investigation in Duchenne models, but could allow for faster approval if they are shown to confer benefits to Duchenne patients.

A final talk was shared by Dr. Lee Sweeney, head of PPMD’s Scientific Advisory Committee, in which he stated the importance of testing novel therapeutics alongside glucocorticoids in pre-clinical models. Due to the prevalence of steroid usage in people with Duchenne, even those in trials, it is important that the field identifies the possible interactions or influences that steroids may have on a drug’s efficacy.

Closing remarks

To conclude the meeting was a summary of ideas of where the field should focus efforts, centering around:

• Further investigation of steroid dosing, both in dosage amount and regimen
• Identification of our best candidate biomarkers for validation
• Improve access to biological samples for researchers, through a biobank
• Introduce drugs that have been approved for other diseases with inflammatory features into the Duchenne space

For those that were unable to attend the meeting, there will be a scientific, in-depth write-up of the meeting coming in 2019. In the immediate future, the planning committee, organizers, and members of the FDA will be reconvening in early 2019 to discuss a plan of action to tackle the ideas discussed at the meeting.

It is our hope to share some of our successes at a subsequent meeting in a year’s time. Continuing to hold inflammation specific workshops will allow us to identify and resolve barriers to providing the best treatment for those with Duchenne muscular dystrophy.

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Meet Eric Camino, PhD

Prior to joining the PPMD team, I spent time at Nationwide Children’s Hospital working on clinical trials for Duchenne. While at Nationwide, I had the great fortune to work for Dr. Jerry Mendell and a number of other fantastic providers on the PPMD sponsored Carrier Study. Working on the Carrier Study afforded me the opportunity to meet a number of amazing mothers committed to furthering research in Duchenne. I look forward to interacting with more families throughout the coming year.