Sarepta hopes to pull off the same trick twice


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).

Expanding exons

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.

Faster action?

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 
Project  Company  Amenable  subset  Status 
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 
Givinostat  Italfarmaco  All   Phase III 
TAS-205  Otsuka  All   Phase II 
NS-065  Nippon Shinyaku  Exon 53 skipping  Phase II 
Ezutromid  Summit/Sarepta  All   Phase II 
Domagrozumab  Pfizer  All   Phase II 
Pamrevlumab  Fibrogen  All   Phase II 
Edasalonexent  Catabasis  All   Phase I/II 
CAP-1002  Capricor  All   Phase I/II 
DS-5141  Daiichi Sankyo  All   Phase I/II 
Myostatin   adnectin  Bristol-Myers Squibb  All   Phase I/II 
Trial ID
4053-101 study NCT02310906
Essence NCT02500381

To contact the writer of this story email Madeleine Armstrong or Amy Brown in London at or follow @ByMadeleineA or @ByAmyBrown on Twitter

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