Prosensa’s future hangs in the balance after the damaging phase III failure of its lead exon-skipping project, drisapersen, but at least for now the group can count on the support of its partner GlaxoSmithKline.
Still, a key decision looms: the UK company is expected to complete its analysis of the failed trial by the year end. Prosensa’s chief executive, Hans Schikan, remains upbeat, saying he sees a “very committed Glaxo”, as well as highlighting its partner’s options on other pipeline assets. But the loss of the Glaxo deal cannot be ruled out, and would represent a serious strike two for Prosensa.
“Glaxo is in the driver’s seat, and we are fully supporting them,” the chief executive tells EP Vantage. Among Prosensa’s other exon-skipping assets are no fewer than five projects that, like drisapersen, target Duchenne muscular dystrophy, and Glaxo has a potential interest in this pipeline too.
Drisapersen specifically targets Duchenne caused by a genetic deletion at exon 51, and it was these patients that were recruited into the failed Demand 3 trial. Each of the six earlier-stage pipeline projects targets less common but still possibly significant genetic subtypes of Duchenne.
|Beyond drisapersen – Prosensa's Duchenne pipeline|
|Project||Genetic deletion||Duchenne patients affected||Status||GSK involvement?|
|Drisapersen||Exon 51||13%||Failed ph III||Licensed to GSK|
|PRO044||Exon 44||6%||Ph I/II||Worldwide option|
|PRO045||Exon 45||8%||Ph I||Option on either PRO045 or PRO053|
|PRO053||Exon 53||8%||Ph I|
|PRO052||Exon 52||4%||Preclinical||Option on either PRO052 or PRO055|
“It’s striking that we have so many different compounds, all for Duchenne,” says Mr Schikan. However, much rests on the analysis of Demand 3, and Glaxo must consider whether this study failed on account of a design flaw or whether there were issues that cast a doubt over Prosensa’s technology as a whole.
In the latter scenario there would be little reason for the UK group to persevere with the deal.
Indeed, one unavoidable conclusion is that the exon-skipping approach as a whole is flawed, and this fear has not been allayed by Prosensa’s rival Sarepta being hit by US FDA doubts over a study of its own project, eteplirsen (Sarepta’s bubble bursts, November 12, 2013).
While Mr Schikan will not speculate on the outcome of Glaxo’s analysis, he is prepared to offer at least one hypothesis for the failure of Demand 3.
Unlike the broadly positive Demand 2 and 5 studies, Demand 3 did not have patients’ ability to rise from the floor as one of its inclusion criteria, he says. “The phase III could therefore have included boys who were more progressed in the disease.”
Study endpoints are another increasingly unclear area, but, although the FDA has questioned the value of the six-minute walk test, Mr Schikan remains confident about this metric. Nevertheless, he says he is now considering additional measures, including upper limb movement, imaging and measuring renal abnormalities.
“It’s a shifting area, and we are active in it,” he states.
These considerations aside, the most contentious issue remains Sarepta’s suggestion that increases in dystrophin production – which the group was able to correlate with eteplirsen’s activity – might have served as a surrogate endpoint and thus allowed an accelerated approval in Duchenne.
Ironically, it was partly Prosensa’s failure that scuppered Sarepta’s chances here, since Demand 2 had seen some increases in dystrophin production, but these were not generally correlated with patients’ functional changes.
As such Mr Schikan pulls no punches as to the relevance of showing dystrophin production, stating: “It’s an interesting biomarker from a pharmacokinetic point of view, but from a surrogate endpoint view less relevant.”
He also believes that his company’s measurement of it, via an automated method, was less prone to error than Sarepta’s, which relied more on an operator’s assessment of staining in fibres.
It will be interesting to see how the dystrophin issue plays out, and the analyses from Demand 3 have still not been released. Neither has anything been said about drisapersen’s prized US breakthrough therapy designation, which some have suggested should be rescinded after the pivotal study failure.
Mr Schikan confirms that Prosensa has discussed the matter with Glaxo, but will not comment on “any interaction between Glaxo and the FDA”.
With the risk of a key partner pulling the plug on his company’s lead project, Mr Schikan clearly has bigger fish to fry.