Moment of truth for Sarepta and Myonexus

A limb girdle muscular dystrophy gene therapy Sarepta licensed last year faces its first clinical test.

The third pillar of Sarepta’s plan to dominate the treatment of muscular dystrophy will soon face its first clinical test. Sometime this quarter the first clinical study of MYO-101, a gene therapy against limb girdle muscular dystrophy type 2E licensed from Myonexus Therapeutics last May, will yield results.

The placebo-controlled study aims to enrol nine subjects, but the upcoming interim look concerns the first three dosed since October. There had been hopes that the interim data would be revealed at Sarepta’s JP Morgan conference presentation, and the fact they were not caused a minor market wobble. Still, there is all to play for, and chances of success look reasonably high.

The first three subjects will have been given MYO-101 at a 5x1013vg/kg dose, and if this is successful the next six-patient cohort can start dosing at 2x1014vg/kg, with three subjects in the active group and three in control; the trial has a crossover design.

Genetically distinct

Limb girdle muscular dystrophy (LGMD) is a group of inherited muscular dystrophies that is distinct in origin from the Duchenne variety. There are numerous different types of LGMD, and the fact that each has a specific genetic cause makes them particularly amenable for treatment with gene therapies.

LGMD type 2E is an autosomal recessive disorder whose basis is a mutation in the SGCB gene, leading to insufficient production of its product, beta-sarcoglycan. As MYO-101 aims to deliver this gene the key data point investors will be looking for is expression of beta-sarcoglycan in muscle fibres; Goldman Sachs reckon expression in 20% of fibres in muscle biopsies would represent a robust result.

Bulls will hope for a repeat of the market euphoria that erupted when Sarepta revealed clinical data on the first three subjects treated with an in-house gene therapy, rAAVrh74.MHCK7.micro-dystrophin (Sarepta investors party like it’s 2015, 19 June 2018). This is the second pillar of Sarepta’s muscular dystrophy strategy, the first being its marketed exon-skipping drug, Exondys 51.

The microdystrophin project and MYO-101 both use an AAVrh74 vector, something that should increase confidence in the latter. On the other hand, MYO-101 comprises the full-length SGCB gene, whereas the microdystrophin therapy contains a truncated version because the full dystrophin-coding gene is too big to fit inside an AAV vector.

It is hoped that expression of beta-sarcoglycan will be sufficient. For now the only guide for investors is Myonexus’s highly positive findings in a mouse model.


Comparisons with microdystrophin gene therapies are also relevant in light of the troubles faced by a competitor, Solid Biosciences: its DMD gene therapy SGT-101 was briefly put on clinical hold after the first patient dosed at 5x1013vg/kg was hospitalised with a decreased platelet count and evidence of complement activation, issues that the group now reckons it can manage.

Obviously, investors will pay close attention to MYO-101’s safety profile, too. MYO-101 subjects were dosed a week apart, with each subsequent patient receiving the therapy if tolerability in the previous one had been acceptable; the fact that three subjects could apparently be dosed with no issues reported is thus another positive sign.

The upcoming data also represent a make-or-break test of Myonexus, a private startup founded in 2017 that Sarepta has an exclusive option to acquire. The MYO-101 clinical trial is Myonexus’s first ever, and the company appears to have benefited from just one equity investment, raising $2.5m of seed financing in December 2017.

As such the $60m it got up front from Sarepta in May was a significant windfall. Sarepta investors will soon find out whether this was money well spent.

Project Gene therapy  Study design Trial ID
MYO-101 scAAVrh74.MHCK7.hSGCB Placebo-controlled crossover in 9 limb girdle muscular dystrophy type 2E subjects NCT03652259

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