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#apaperaday: Draft Guidance for Industry Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, and Related Dystrophinopathies – Developing Potential Treatments for the Entire Spectrum of Disease

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Draft Guidance for Industry Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, and Related Dystrophinopathies – Developing Potential Treatments for the Entire Spectrum of Disease

Today’s pick was again premium confetti material according to Yuzu. It is from @journal_nd by McDonald et al on the updated draft guidance for dystrophinopathy therapy development for Industry. This effort included many people including me 😀 DOI: 10.3233/JND-230219

The most important changes are new therapies that are now approved (exon skipping, gene therapy), the focus also on treating heart pathology and the shift of developing treatments only for Duchenne to developing treatments for dystrophinopathies (the whole spectrum).

The update involved a large group of patient representatives, clinicians, researchers who working in different working groups and included zoom meetings and many rounds of editing (at least for my working group :). Authors here provide an executive summary.

The whole document is provided as a supplement. Authors stress that we should shift from Duchenne, Becker and female cardiomyopathy to dystrophinopathies as with better care the historical difference (wheelchair <12 years Duchenne, ambulant >16 Becker) no longer applies.

Also there is more focus on female dystrophinpathy patients, who used to be called symptomatic carriers (focus on carrier, not the fact that they had symptoms, which is not right).

There are new therapies approved now based on surrogate endpoints. The patient community stresses the need for confirmatory studies to show the clinical impact of the treatments and urges companies to perform these studies in a timely fashion.

The paper provides a summary on key topics:

A. Patient engagement and patient experience: there is more data now on patient and caregiver preferences, that facilitates focusing on clinical meaningfulness of therapies. Also a community advisory board exists to guide industry.

B. Diagnosis criteria: This stresses mentioning a spectrum of dystrophinopathies rather than Duchenne/Becker/Female dystrophinopathy. Biopsies are sometimes needed in trials, but generally not for diagnosis. New born screening is needed now that therapies are approved in USA.

C. Natural history: This is now better understood with different trajectories for subgroups, and loss of milestones, but also trajectories for outcome measures used in trials.

D. Outcome measure selection: information is now available on clinical meaningfulness. Furthermore, outcome measure analysis at baseline allow including patients most likely to show therapeutic effects and upper limb functions are now available and used in trials.

E. Biomarkers: for dystrophin both the amount and the distribution is relevant information.Biopsies should be minimized (the number and amount) as they are burdensome. Magnetic resonance can be used to study muscle quality. Biomarkers in the blood are still exploratory and more work is needed.

F. Trial design: Most innovative designs can be used to reduce the number of patients and make results more informative. Steroids are standard of care so most treatments are tested on top of steroids. There are now also trials in Becker patients. Not mentioned here but important to note: at the @Parent_Project meeting Eugenio Mercuri presented on the trial results of the givinostat trial. This was a 72 weeks placebo controlled trial that showed significant differences on the primary and secondary endpoints. However… Eugenio presented that they have now done an analysis: what if the trial had lasted only for 48 weeks? Then they would NOT have been able to detect a significant difference. This underlines the need for long trials in Duchenne even though this increases the burden.

G. Cardiomyopathy: A new section, because there are now more therapeutic developments to treat heart pathology in both early and late stage dystrophinopathy. More work is needed for biomarkers and reaching consensus and studying natural history (current focus of @DuchenneUK)

H. Gene therapy: This is another new section, now that gene therapy trials are ongoing and a gene therapy product is approved. The challenges are outlined: the abundance of muscle mass and the size of the dystrophin protein code.

The draft guidance stresses the need to study and monitor the immune response to the gene therapy. Furthermore, there should be even more focus on measuring clinical benefit as repeat treatment for now is not possible.

A massive amount of work – I was only a small piece in one working group. I commend the leaders who coordinated this work (herding cats!) and finalized the guidance document and also provided this executive summary.