Wave Life Sciences is well behind its Duchenne muscular dystrophy rival Sarepta in getting an exon-skipping therapy to market, and earlier phase I data with Wave's suvodirsen raised doubts over whether it would ever catch up.
Wave has a chance to make amends in the fourth quarter, when it is due to report dystrophin data from an open-label extension trial. The company is confident that suvodirsen can outperform Sarepta’s similarly acting Exondys 51 and set up a filing for US accelerated approval.
Going the Dystance?
Notably, the company is already starting its confirmatory trial for suvodirsen; the 150-patient Dystance 51 study will look at clinical outcomes and dystrophin levels with suvodirsen versus placebo.
Sarepta recently drew criticism for not yet having started enrolling patients in its confirmatory trial of Exondys 51, despite the therapy getting accelerated approval in 2016, and perhaps Wave wants to avoid a similar backlash.
Wave’s chief executive, Paul Bolno, told Vantage that he “wanted to send a message to regulators that we’re committed to running the confirmatory study”. Interestingly, Dystance 51’s placebo arm comprises a mixture of actual patients and historical control data to address ethical issues with running placebo-controlled studies in rare diseases, and Wave has made much of the FDA's blessing.
However, Dystance 51 is not due to complete until 2021. In the meantime, Wave’s hopes for its wholly owned project hinge on the upcoming dystrophin expression data at 22 weeks, measured via biopsy, from the open-label extension of its phase I trial. Wave expects 37 patients to complete the open-label portion, and will release results from “the vast majority” of these, according to a spokesperson.
DMD is caused by an absence of dystrophin, and an increase in this protein is thought by some to show that therapy is working as intended.
Exondys’s accelerated approval was based on a small, 0.28% rise in dystrophin, as per its label. Mr Bolno says Wave aims for a 5-10% increase at least, as measured by Western blot, although he hopes for an even higher result.
His confidence is driven by Wave's project being more specific and stereopure, versus Sarepta’s stereorandom approach. Suvodirsen and Exondys are both antisense oligonucleotides targeting patients with a mutation amenable to exon 51 skipping, equating to around 13% of the DMD population.
Wave so far has not managed to convince investors. Its stock is down 46% this year to date.
An update from suvodirsen’s phase I trial in April did not include any dystrophin measurements, but raised questions over toxicity with higher doses (Wave crashes again – this time on toxicity concerns, April 17, 2019). Wave is focused on lower doses in the open-label extension and phase III Dystance 51 trials.
Mr Bolno is adamant that there will still be a place for exon-skipping DMD treatments even if gene therapies make it to market. He pointed out that exon skippers can be dosed repeatedly, and added that it was still unclear what clinical benefit was conferred by the microdystrophin used in gene therapies.
Though excitement over DMD gene therapies is building, data are so far only available in a handful of patients, and recent safety scares show that there is still some way to go.
Despite the lack of clinical backing so far, Mr Bolno said he would be "very surprised" if suvodirsen did not show an improvement in dystrophin. Even if it does, failure to meet the 10% target could be a disaster for Wave, given the competition.
|The DMD landscape|
|Project||Company||Description||Status||2024e sales ($m)|
|SRP-9001||Sarepta Therapeutics||Microdystrophin gene therapy||Phase II (NCT03769116)||2,352|
|Exondys 51||Sarepta Therapeutics||Exon 51 skipping antisense||Approved in US||502|
|Vyondys 53 (golodirsen)||Sarepta Therapeutics||Exon 53 skipping antisense||FDA complete response letter, Aug 2019||360|
|Casimersen||Sarepta Therapeutics||Exon 45 skipping antisense||Phase III (NCT02500381)||277|
|Translarna||PTC Therapeutics||Transcription modulator||Approved in EU||268|
|Suvodirsen||Wave Life Sciences||Exon 51 skipping antisense||Phase II/III (NCT03907072)||235|
|Edasalonexent||Catabasis Pharmaceuticals||NF-kB inhibitor||Phase III (NCT03703882)||227|
|NS-065||Nippon Shinyaku||Exon 53 skipping antisense||Phase III (NCT04060199)||194|
|Emflaza||PTC Therapeutics||Corticosteroid||Approved in US||144|
|SGT-001||Solid Biosciences||Microdystrophin gene therapy||Phase I/II (NCT03368742)||131|