#apaperaday: Clinical potential of microdystrophin as a surrogate endpoint

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled:  Clinical potential of microdystrophin as a surrogate endpoint

Today’s pick is by Boehler et al in World Muscle Society Journal of Neuromuscular Disorders on the potential as microdystrophin to be a surrogate endpoint for Duchenne. DOI: 10.1016/j.nmd.2022.12.007

The paper is co-authored by people from Solid BioSciences which is developing micro-dystrophin gene therapy for Duchenne. However, the paper is very nuanced and generally balanced and gives a very good overview of different perspectives and considerations.

In drug development normally phase 3 trials will have an endpoint that assess whether the candidate treatment leads to clinical benefit. For Duchenne this is based on functional outcome measures. This is very challenging for progressive diseases.

Often it takes over a decade to develop drugs – which is difficult for rare diseases as often there is no alternative treatment available. Surrogate endpoints are objective measures that correlate with or predict clinical benefit.

Surrogate endpoints allow a quicker evaluation. However, they have to be clinically validated: so a study needs to be done to show that a certain change in the surrogate endpoint (e.g. protein level) correlates with a certain change in function.

For rare diseases this is difficult as often there is no effective treatment yet…FDA therefore also accepts surrogate endpoints that are reasonably likely to predict clinical benefit. A Duchenne themed example is of course dystrophin restoration for exon skipping drugs.

Exon skipping aims to restore dystrophin for Duchenne patients. Dystrophins produced are also produced by Becker patients, so their functionality is clinically confirmed. However, Becker patients produce them from birth, while treated Duchenne patients produce them later. Also, so far dystrophin levels produced after exon skipping are lower than those produced by Becker. Authors here focus on whether micro-dystrophin can be a surrogate endpoint. Micro-dystrophin is an engineered dystrophin that fits in adeno associated viral vectors.

They are engineered based on what is known from studying dystrophin mutations that lead to Duchenne, severe and milder Becker. We know actin binding and dystroglycan binding domains are crucial and the C-terminal domain seems to be redundant.

The spectrin repeat is the largest part (encoded by 50/79 exons): it consists of 24 repeats that are similar but also different. Also the way the repeats connect is important. Generally 2 exons encode 1 repeat.

So if a deletion is in-frame but consists of an odd number of exons, remaining repeats will not connect properly (called “out of phase”). Generally speaking Becker patients with out of phase in frame deletions have a more progressive disease than those with in phase deletions.

The microdystrophin is engineered so the repeats are in phase. For exon skipping however whether the repeat is in phase or not is determined by the mutation. So for some patients the dystrophin produced will likely be more functional than others. Using exon skipping dystrophin or microdystrophin as a surrogate endpoint is challenging because it is not yet known how much dystrophin you need. Authors pose that likely you need higher levels for out of phase dystrophins than for in-phase dystrophins.

So far there is little data on this, but the position is interesting and makes sense. Also, it fits with studies in transgenic animals with a dystrophin with a deletion of exon 17-48 (out of phase), where higher dystrophin levels were needed than for full length for benefit. Authors stress that if you want to use dystrophin (skip or micro) as a surrogate endpoint good quantification has to be done, to analyze dystrophin levels (western blotting or mass spec) and dystrophin location (within the fiber and distribution over fibers).

Dystrophin location analysis can reveal whether associated proteins are restored. Authors pose that micro-dystrophin should be predictable for clinical benefit and therefore could be a surrogate marker. However, they stress that the safety aspect needs to be considered too.

Currently placebo controlled trials are ongoing for microdystrophins for Pfizer and Sarepta that assess functional effects. However, these studies take a long time. In parallel, using micro-dystrophin as a surrogate endpoint is being pursued as well. Whether this will be accepted by the FDA remains to be seen. The biggest challenge is that there is no evidence yet that the micro-dystrophins are functional in humans. For exon skipping, Becker patients were clearly showing skipped dystrophins were functional.

On the other hand, the microdystrophin levels that are produced after AAV delivery are much higher than the skip dystrophin levels… We will have to wait and see for the FDA verdict about this. There are arguments for accepting it and for not accepting it.

Regardless the placebo controlled trials are needed – when a surrogate endpoint is used, companies still have to collect additional evidence. So these trials are still useful. Back to the paper: recommended reading! Gives a very nice and nuanced outline of what we know about dystrophin and its functional domains and also clearly specifies which questions are not yet answered and which aspects are as yet controversial.