Editor's note: BioPharma Dive, as part of its newly launched Gene Therapy Weekly (subscribe), is taking a closer look at inherited diseases for which researchers are developing genetic medicines. We aim to give a brief overview of the gene therapy pipeline and lay out what could come next for such drugs. This, on Duchenne muscular dystrophy, is our first.

By next year, two companies could have gene therapies for Duchenne muscular dystrophy in late-stage clinical trials. The start of those studies will mark the culmination of years of research, a milestone that could finally put a gene therapy for the debilitating disease within reach.

Both treatments, along with a third a little further behind, hold the potential to change Duchenne's course, driving excitement and hope of a potential breakthrough for patients, most of whom don't have good treatment options.

But the data supporting that promise have come from small, early-stage trials, which compared results to historical controls rather than a placebo. The true effectiveness of these therapies, or how long any benefit will last, remains uncertain — questions that will only be answered by the studies just now getting underway.

Next year, then, could be a defining one for Duchenne gene therapy. Here's where things stand:

How is Duchenne treated now?

Duchenne is a potentially deadly genetic disease that affects some 300,000 people, mostly boys, worldwide. An inherited DNA defect leaves Duchenne patients lacking dystrophin, a critical muscle-protecting protein. Without it, they progressively lose the ability to walk or function independently, often dying at a young age from lung or heart problems.

The only available treatments are steroids like dexamethasone and, for two small subsets of patients, gene-targeting medicines from Sarepta Therapeutics and NS Pharma. At best, these drugs may slow the progression of Duchenne. But neither Sarepta nor NS Pharma have proven that yet. The Food and Drug Administration cleared the therapies after studies of a few dozen boys each showed treatment helped patients produce tiny amounts of dystrophin — sufficient, the companies claimed and the FDA agreed, to possibly help.

Confirmatory tests by Sarepta and by NS Pharma are ongoing, but may not produce results for a few years.

How could gene therapy be used?

Duchenne has long been a prime target for gene therapy, but several tough technical challenges proved difficult to overcome. The dystrophin gene, for instance, is too large to fit into the adeno-associated viruses, or AAVs, commonly used to deliver gene therapies. Researchers also needed to ensure they could get enough gene therapy product into muscle tissue to make an impact.

Instead of using the full dystrophin gene, scientists engineered smaller, modified genes that produce a shortened form of dystrophin meant to function like the real protein. The gene therapies now in testing help patients produce these proteins, dubbed either "micro" or "mini" dystrophin, for potentially many years. These treatments are delivered at high doses, with specific AAVs that are meant to shepherd the genetic instructions through the blood and into various muscles.

Once successfully delivered, the companies hope their treatments could slow or even halt disease progression, giving patients a chance to avoid Duchenne's devastating effects. Both outcomes would be a significant advance, though it's not yet clear whether either is achievable.

Duchenne gene therapy also represents a business opportunity for drugmakers, catalyzing large investments by Pfizer, Roche and other companies. Some analysts have projected billions of dollars in peak sales for Sarepta's experimental gene therapy, a lofty total that would make it among the best-selling rare disease drugs.

Which companies are working on gene therapies?

Three companies — Sarepta, Pfizer and Solid Biosciences — have similar Duchenne gene therapies in human testing.

Sarepta's and Pfizer's are furthest along, with late-stage studies testing commercial-grade products starting soon. Both have produced evidence showing their treatments can help patients produce what appear to be meaningful levels of shortened dystrophin, and that those numbers may translate to better outcomes. Neither have had to halt testing for safety reasons, though Pfizer has seen a couple worrisome incidents in early testing that caused it to modify its study rules.

Select gene therapies for Duchenne muscular dystrophy
Company Gene therapy Development phase Trial number Status
Sarepta SRP-9001 Phase 2 NCT03769116 Data expected early next year; Phase 3 could begin by year end
Pfizer PF-06939926 Phase 1 NCT03362502 Phase 3 could begin by year end
Solid SGT-001 Phase 1/2 NCT03368742 Cleared to resume, new patients to be enrolled early next year
Astellas ASP-0367 Phase 1 NCT04184882 Expected to start in December

SOURCE: Companies, clinicaltrials.gov

Safety concerns have slowed Solid's research, but the FDA last month cleared the company to restart clinical testing. Soon after, Ultragenyx licensed technology from Solid to develop a different variation of Duchenne gene therapy.

Others could soon be in the mix as well. Astellas Pharma has a program that combines elements of gene therapy and the gene-based medicines that have won FDA approval. Recruiting hasn't yet begun for a Phase 1 study.

Editas Medicine, as well as Vertex and CRISPR Therapeutics, have each said they intend to use CRISPR gene editing to spur long-lasting dystrophin production. Neither has advanced beyond preclinical stages.

What's next?

Sarepta expects results from a placebo-controlled, Phase 2 trial early next year in what could be a crucial test for the treatment's potential. Both Sarepta and Pfizer are racing to start their respective Phase 3 studies, which would be the first late-stage tests of a Duchenne gene therapy.

Sarepta has long been in the lead, and CEO Doug Ingram has said the company aims to apply for approval based on the Phase 2 data and an interim look at the Phase 3 study, which it aims to have by the first quarter of 2021.

The FDA recently complicated those plans, however, when it asked Sarepta for an additional lab test before starting the new trial, which threatened to narrow the biotech's lead on Pfizer. Sarepta and the agency hammered out those issues in November and agreed to a much smaller study than originally planned, with dosing expected to begin by the end of 2020. Pfizer, too, plans to start its trial by the end of the year.

Solid, meanwhile, could dose more patients in its early stage study in the first quarter of 2021.



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