Sarepta caused excitement last year with data from its first Duchenne muscular dystrophy gene therapy candidate. But with results only available in a handful of patients so far, there is still a chance for other players to make a mark in this space.
Step forward Solid Biosciences. The company is hoping to put its controversial IPO and clinical hold behind it with the first clinical data on its own DMD gene therapy project, SGT-001, due this month – but a previous safety issue could come back to haunt it.
|NPV as % of mkt cap||473%|
|Event||Preliminary phase I/II data|
Solid is to report results soon from the first six subjects in the phase I/II Ignite DMD study. But any concerns about small patient numbers should be tempered slightly by the fact that Solid’s trial has a placebo arm – unlike Sarepta’s study, whose update last June involved just three DMD youngsters with no control group (Sarepta investors party like it’s 2015, 19 June 2018).
As such, Solid’s initial data will come from three patients receiving SGT-001 and three age-matched placebo controls. The trial is designed so the latter can switch to the gene therapy after 12 months.
It might be difficult to draw conclusions from the available data: Solid’s trial includes both ambulatory children and non-ambulatory adolescents, who are at different stages of disease. Currently each arm of the study includes two children and one adolescent.
Both SGT-001 and Sarepta’s lead DMD gene therapy – known as rAAVrh74.MHCK7.micro-dystrophin – are designed to increase the production of microdystrophin, a shorter version of the dystrophin protein that is missing in DMD patients.
Solid believes its gene therapy construct could have an edge. The group’s chief executive, Ilan Ganot, told attendees at the JP Morgan conference earlier this month that SGT-001 is the only project to include a neuronal nitric oxide synthase (nNOS) binding domain, “just like full-length dystrophin”. The binding of nNOS to dystrophin is thought to increase the blood supply to muscle cells, so SGT-001 could allow greater improvements to muscle function than other gene therapies, Solid contends.
The company will have to prove this in the clinic. The primary efficacy endpoint of Ignite DMD is change from baseline in microdystrophin protein in muscle biopsies, measured using both Western blot and immunofluorescence. Solid is starting with a 5x1013vg/kg dose of SGT-001, at which it hopes to see microdystrophin expression levels of 10% or higher, Solid executives said at JP Morgan.
This might not be enough to topple Sarepta. Updated data from four patients treated with rAAVrh74.MHCK7.micro-dystrophin, presented at the World Muscle Society meeting in October, showed microdystrophin levels, as measured by Western blot, of 74% using a method developed by Sarepta and 96% using a method from Nationwide Children’s Hospital.
Cross-trial comparisons should always be treated with caution, but this one could be particularly tricky because the companies are likely using different assays to measure microdystrophin expression, Goldman Sachs analysts noted. Furthermore, Sarepta is using a higher dose of rAAVrh74.MHCK7.micro-dystrophin, 2x1014vg/kg.
Solid could up the dose of SGT-001, but will need to tread carefully: the clinical hold on SGT-001 was triggered after the first patient given SGT-001, at 5x1013vg/kg, was hospitalised with a decreased platelet count and evidence of complement activation.
The hold was lifted in June and Solid believes it has found a way to manage these issues involving steroids, additional monitoring and the use of Alexion’s Soliris to treat complement activation.
Indeed, the next two patients also experienced platelet decreases but these were resolved after following the new protocol – although Solid has not said whether these subjects received Soliris. Alexion's drug would be an expensive rescue therapy, particularly on top of the cost of the gene therapy itself (Gene therapy: how much will it cost patients?, 22 January 2019).
Solid’s chief medical officer, Jorge Quiroz, brushed off any concerns, saying the decreases in platelet count “seem to be a more generic effect with AAV administration”.
“Because the construct is differentiated and it’s so powerful in preclinical models, we’d like to hope it doesn’t take a lot of it to get great function,” said Mr Ganot, although he added that durability would also be an important concern as the company decided on its next steps.
Pfizer also has a DMD gene therapy candidate, PF-06939926, originally developed by Bamboo Therapeutics, in a phase I trial. But for now, the company that Solid needs to beat is Sarepta.