Prosensa's muscular dystrophy programme 'back on track'

At the start of the year, prospects for Prosensa's Duchenne muscular dystrophy (DMD) drug drisapersen looked decidedly shaky, with GlaxoSmithKline giving up on the project after lacklustre pivotal trial results.

Six months on and after extensive discussions with the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), the Dutch company is gearing up to file for accelerated approval of drisapersen in the US, followed by submission in the EU within the next few months.

The company has also secured a valuable funding stream - worth €5 million - from medical charity CureDuchenne that will support the drisapersen programme as well as other drug candidates in Prosensa's pipeline.

"It has been an amazing journey," according to Prosensa's chief executive Hans Schikan. "We have learned a tremendous amount that enables us to better understand both the natural history of DMD as well as put the vast dataset we have into context."

Drisapersen is one of several DMD drugs in the pipeline designed to induce 'skipping' of an exon when the dystrophin sequence on DNA is transcribed to RNA. The aim is to produce a smaller but semi-functional form of the dystrophin protein that is abnormal in DMD that can help restore some muscle function.

Transferring rights back from GSK was a mammoth task involving the retrieval of more than 350,000 clinical trial files, but the process allowed the company to take stock and review its dataset for drisapersen, which is the largest in DMD spanning 300 patients and 450 treatment years.

Prosensa's longest trial showed that over three-and-a-half years, boys with DMD who were treated with drisapersen showed a decline of 25 metres in the six-minute walk test, the standard measure for new treatments for the progressive muscle wasting disease. Typically DMD patients lose 120 metres on the walk test over a two-year period.

The results of the company's first placebo-controlled study were positive, but a second trial suggested the effect observed was much smaller, with a 10 metre difference between the drug and placebo after 48 weeks.

After re-evaluating the data, it seems that "the phase 3 trial may have failed the drug rather than the drug failing the trial," said Schikan, who added that when the trial began in 2010 much less was known about the natural history of DMD.

The size of the study perhaps contributed to its downfall, as the boys enrolled at baseline were a very mixed group compared to those in the smaller placebo-controlled trial. Specifically, they tended to be older and performed worse on muscle function tests on enrolment.

"Based on our analysis we believe that early intervention in this disease may delay progression of DMD," said Schikan, who believes it will be possible to secure approval with the current data on the proviso that two post-approval studies are carried out.

One study should compare the therapy to a treatment with a similar mechanism of action but which targets a different exon to drisapersen, which skips exon 51. A second open-label trial will compare boys treated with the drug to the natural history of the disease, and is already fully-enrolled.

The CureDuchenne funding will help progress Prosensa's second exon-skipping therapy PRO044 through a Phase II extension study and into a Phase III trial which may serve as the active control confirmatory study.

One of the most encouraging things in the last few months has been the response of the regulatory authorities, who recognise the "degree of urgency" felt by patients and their carers as drisapersen and other new drugs emerge to fill the therapeutic void in DMD, said Schikan.

A key highlight has been the conditional approval of PTC Therapeutics' Translarna (ataluren) for DMD patients with so-called nonsense mutations in the dystrophin gene by the EMA, and with other drugs such as Sarepta Therapeutics' eteplirsen and Santhera's Catena/Raxone (idebenone) also nearing regulatory filings it is a " monumental time for all stakeholders in this space", he added.

"It's clear that patients, families, clinicians, and patients and placebo group voices have been heard loud and clear and - for the first time - we are in an environment where there is very real hope."