PTC’s confirmatory Duchenne data resurrect US hopes

Real-world data on Translarna look good, but with a failed confirmatory trial and a troubled history US approval is far from guaranteed.

Welcome to PTC Therapeutics’ world, where nothing is straightforward. After failing to convince the FDA to approve its Duchenne muscular dystrophy drug Translarna five years ago the company is gearing up to try again, but success is far from guaranteed.

PTC’s previous attempts relied on post-hoc data dredges from two failed trials, which the FDA strenuously rejected. So the company went away and conducted a larger, placebo-controlled study focusing on the subgroups that had previously performed strongly. That strategy backfired, it was revealed today, although the company is still claiming a win.

That trial was Study-041, and to be eligible boys had to be able to walk at least 150 metres in six minutes. 359 were enrolled, and given either Translarna or placebo, with the primary endpoint, the six minute walk test, conducted after 72 weeks. However, the primary analysis was conducted only in those who could walk at least 300 metres at baseline, and took at least five seconds to stand up from lying down, characteristics that PTC said were, in previous trials, associated with a strong response to Translarna.

Not so this time. The trial found no statistical difference between the treatment and control arms in this group, with the change from baseline in the 6MWD coming in at only an eight metre difference, generating a p value of 0.36. This makes the trial a technical bust.

Ironically, the subgroup that PTC had previously focused on in its attempts to win over the FDA – boys with a 6MWD of 300-400 metres at baseline, did show a nominally significant difference. As did the intent to treat population – a much larger cohort – and it is this data that PTC focused on today when presenting the data to analysts.

 Study-041  (NCT03179631)
  ITT population 6MWD 300m – 400m 6MWD 300m and ≥5 sec supine to stand*
  Translarna Pbo Diff Translarna Pbo Diff Translarna Pbo Diff
N 183 176   86 83   92 93  
Chg** in 6MWD (m) -53 -67.4 14.4 (nominal p= 0.0248) -55.8 -80 24.2 (nominal p= 0.0310) -81.8 90.1 8.3 (p= 0.3626)
*Primary analysis population. **Change from baseline. Source: Company presentation. 

True, regulators tend to like to see data on an ITT basis. And the win here is impressive, if one believes previous explanations for trial failures in this space. PTC, and others developers working in DMD, have claimed that teasing out a drug’s benefit is hard in the heterogeneous DMD population, with mixed abilities in terms of ambulation and rates of decline.

Study-041 was designed to support full European approval, and it seems likely that this will be granted. But going by past experience the FDA is likely to prove much harder to convince. The company said talks will be sought to discuss a possible path towards another filing. 

Real world

What might make PTC’s case stronger is real-world data it has been collecting for European regulators, which granted Translarna conditional approval in 2014. The company has been submitting annual reports to the EMA from a registry called Stride, and the latest cut, encompassing 288 patients, was also presented today.

This proves that Translarna is preserving ambulation and pulmonary function, PTC says. Patients in the registry retained the ability to walk for 5.4 years longer than in natural history studies. It also showed a 1.8 year delay in decline in lung function, which is a predictor of mortality.

A 15% share price jump today suggests investors hold out some hope for a different outcome in the US this time around, but once again PTC's package will be far from straightforward.

Timeline of Translarna's development
Aug 2014 Translarna conditionally approved in EU
Dec 2014 PTC begins FDA submission for Translarna
Jan 2016 PTC completes FDA submission
Feb 2016 PTC receives refuse-to-file letter from FDA
Mar 2017 FDA acknowledges the filing over protest of PTC's NDA
Sep 2017 Adcom votes against Translarna
Oct 2017 PTC receives CRL for Translarna
Source: company releases. 

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