A low-key breakthrough in spinal muscular atrophy

It is one thing for a company to keep a low profile and rein in expectations, but another entirely for it to play down what looks like a potentially game-changing advance in a currently untreatable rare disease.

Yet this is what the private French company Trophos seems to have done in reporting topline data from olesoxime’s pivotal trial in spinal muscular atrophy (SMA). The study actually confirms olesoxime as the most advanced SMA project in development, and sets it up for imminent US and European filings (see table).

The company this week said that olesoxime had shown a beneficial effect in maintaining motor function versus placebo in the trial, but omitted to reveal vital details, providing no numerical or statistical data. To hardened biotech watchers, used to companies touting non-significant or data-mined results, this looked like a classic case of vagueness being used to mask a failed study.

However, this was not the case. “The primary endpoint (outcome) is statistically significant, according to the generally accepted rates for clinical trials,” Trophos confirmed to EP Vantage. “The data from this phase II/III study are sufficient to support registration in both US and EU. The application will be submitted as soon as possible.”

This puts olesoxime ahead of its nearest SMA competitor, Isis Pharmaceuticals’ ISIS-SMNRx, which might start phase III this summer, and Novartis’s BVS857, which only recently began phase II (Proof of concept for Isis puts ball in Biogen’s court, February 24, 2014).

Current treatments for SMA, a genetic, muscle-wasting disorder, are purely symptomatic, and the pipeline of industry projects is small. In addition to those below, several investigator-sponsored trials are ongoing; established drugs like AbbVie’s Depakote have also been studied, but no active trials are under way.

Clinical projects for spinal muscular atrophy
Project Company Pharmacology class Status Trial ID
Olesoxime Trophos Mitochondrial pore modulator Phase II/III NCT01302600
ISIS-SMNRx Isis/Biogen Idec Muscular atrophy antisense Phase II NCT01839656
BVS857 Novartis Unknown Phase II NCT02024932
SMN2 Roche/PTC Therapeutics Muscular atrophy agent Phase I NCT01910168
RG3039 Repligen/Pfizer DcpS inhibitor Phase I

One problem with an unmet disease is selecting an appropriate endpoint. There is no FDA-validated endpoint since no SMA treatment has been approved, but Trophos says the motor function measure (MFM) scale is accepted by both the US and EU regulators. 

Competitors have measured muscle function, power and volume. Isis, for instance, has looked at muscle function as measured by the Hammersmith motor scale – a secondary endpoint in the olesoxime study that Trophos says was also met.

The Trophos study’s sole primary endpoint used MFM to assess loss of neuromuscular function, and this was prevented for two years in the olesoxime arm, while placebo recipients declined more quickly, the French company said. Detailed results, including absolute numerical changes and a statistical analysis, will be presented at scientific conferences.

The trial had surprisingly broad recruitment criteria: it comprised 165 patients between three and 25 years of age, some of whom were non-ambulatory, but the rest of whom could walk. This is despite SMA having distinct classifications according to age of onset, meaning that the study risked being thwarted by misrepresentation of disease types across the active and placebo arms.

But Trophos said it was important to have a representative sample of the overall patient population. Either way, it said that in addition to filing it would discuss the results with some of the potential partners that had expressed earlier interest in olesoxime.

The project had been licensed to Actelion, along with an option to buy Trophos in its entirety, but this was canned when a phase III trial in amyotrophic lateral sclerosis failed. It seems that SMA has given it, and Trophos, a second lease of life.

To contact the writer of this story email Jacob Plieth in London at jacobp@epvantage.com or follow @JacobEPVantage on Twitter

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