After giving the go-ahead to Sarepta’s Exondys 51 on questionable data, the FDA might have a hard time denying accelerated approval for the group’s new Duchenne muscular dystrophy (DMD) candidate, golodirsen. The exon 53-skipping project has reported phase I/II dystrophin data that appear, on the face of it, to be better than those that took Exondys 51 to the market.
However, perhaps this is not saying much: there were serious questions over the reliability of the Exondys 51 data, and its eventual approval had much to do with pressure from patient groups in the absence of other options for the disease. Now the FDA has set this precedent it might have to continue with its lenient stance, especially as the rest of the late-stage DMD pipeline is looking sparse (see table below).
Exondys 51 is used in the approximately 13% of patients with a mutation of the DMD gene that is amenable to exon 51 skipping. The company has made no secret of its desire to expand its DMD franchise to include the full spectrum of patients, and the latest results with golodirsen could take it a step closer to this goal.
The project, also known as SRP-4053, addresses another 8% of DMD patients. Sarepta also has an exon 45-skipping project, SRP-4045, targeting another 8%.
Both golodirsen and SRP-4045 are in a phase III study, Essence, in which they are administered to patients amenable to exon 53 and exon 45 skipping, respectively. The primary endpoint is change in six-minute walk test, and results are due in 2019.
Sarepta hopes it will not have to wait that long to get golodirsen on the market; it has indicated that it will ask the FDA whether it can seek accelerated approval on the latest data. The group’s shares were trading 11% higher this morning.
However, accelerated approval for golodirsen would complicate the ongoing placebo-controlled Essence trial, which is possibly the most rigorous that Sarepta has conducted so far. Presumably it would be impossible to continue recruiting patients into the golodirsen arm – surely none would want to risk getting a placebo – robbing physicians, patients and regulators of the chance to scrutinise a much more thorough test of Sarepta's exon skipping approach.
This would be a sound reason for the FDA to decide to wait for the Essence data before making a decision on golodirsen – a move that would also go some way to answering criticism over how it handled the approval of Exondys 51.
Sarepta is hoping the phase I/II results are good enough to convince the agency to act quicker. The data come from the 25-patient 4053-101 study, which included an initial placebo-controlled dose-titration phase in 12 patients, followed by an open-label portion during which 25 patients were treated with golodirsen for 48 weeks.
Mean dystrophin protein, measured using muscle biopsy, rose from 0.095% of normal at baseline to 1.019% of normal at 48 weeks, a 10.7 fold increase. And all 25 participants had an increase in skipping exon 53 over baseline levels, as measured by RT-PCR, according to Sarepta, although it did not give more detailed data.
On first glance, the dystrophin response appears better than that seen in Study 3 of Exondys 51. In 12 evaluable patients baseline levels of 0.16% of normal rose to 0.44% of normal after 48 weeks, a 2.8 fold increase, enough to win approval (Sarepta, patients win – but what of regulatory oversight?, September 19, 2016).
Looking at the remaining pipeline of DMD projects, the FDA will find little to stay its hand. The most advanced is PTC’s nonsense mutation-directed therapy, Translarna, which the company has filed with the FDA “under protest” and is due to go in front of an advisory committee on September 28.
Although Translarna has been available in Europe since 2014, hopes for FDA approval are low, given the agency’s previous refusal to consider the application. The regulator was unconvinced that the data presented supported effectiveness and issued a refuse to file letter in early 2016; Translarna has two failed phase III studies under its belt but hopes to win approval based on sub-group analyses.
The only other product in a robust pivotal trial is the HDAC inhibitor givinostat, which is being tested in a global, randomised, double-blind, placebo-controlled phase III trial that is seeking to recruit 213 ambulant patients. Results are unlikely to emerge until 2020, and the mechanism is far from proven in DMD.
Other projects are much earlier stage. So whether the FDA approves golodirsen sooner or later, Sarepta looks likely to own this therapy area for the foreseeable future.
|The Duchenne muscular dystrophy pipeline|
|Exondys 51||Sarepta||Exon 51 skipping (~13% of patients)||Approved US|
|Emflaza||PTC Therapeutics||All||Approved US|
|Translarna||PTC Therapeutics||Nonsense mutation (~13% of patients)||Approved EU/FDA adcom Sept 28/PDUFA Oct 24|
|Raxone||Santhera||All||Filed EU/PIII US|
|SRP-4045/SRP-4053||Sarepta||Exon 45 & 53 skipping (both ~8% of patients)||Phase III|
|NS-065||Nippon Shinyaku||Exon 53 skipping||Phase II|
|DS-5141||Daiichi Sankyo||All||Phase I/II|
|Myostatin adnectin||Bristol-Myers Squibb||All||Phase I/II|