Upcoming events – Voyager’s gene therapy data and Sarepta’s FDA meeting

Welcome to your weekly digest of approaching regulatory and clinical readouts. In the first quarter Voyager Therapeutics will report additional early data from its Parkinson’s disease gene therapy VY-AADC01, its lead project, which lost Sanofi as a partner last year.

Meanwhile, Sarepta plans to meet the US FDA this quarter to discuss a potential accelerated approval for its new Duchenne muscular dystrophy (DMD) candidate golodirsen. The company will have to hope that a recent safety scare in its phase III trial will not make the agency more cautious.

Onwards Voyage

12-month data are due shortly from the highest dose in Voyager’s open-label phase 1b trial, which has three doses and five patients in each cohort. Subjects have advanced Parkinson’s disease and are 40 to 70 years old.

VY-AADC01 contains the gene encoding AADC, an enzyme that converts levodopa to dopamine, and is designed as an add-on to levodopa. It was administered as a single transfrontal infusion under MRI guidance to the putamen, the region of the brain associated with impaired motor function.

Voyager reported 12-month data with the lower two doses last year. In the mid-dose cohort there was a four-hour increase in diary on-time without dyskinesia, a 54% decrease in off-time and a 56% reduction in UPDRS-III motor scores while on medication. Worryingly, the lowest dose showed an increase in UPDRS-III motor scores, and will not be used in subsequent trials.

There were no vector-related serious adverse events. One patient experienced a pulmonary embolism and related heart arrhythmia, most likely related to immobility during the surgical procedure, which can take 8-10 hours. After deep vein thrombosis prophylaxis was added no subsequent events were observed.

A month after the initial results were released partner Sanofi walked away from the project; while Voyager stated that it didn’t want to share US rights, it could also be possible that Sanofi had seen something in the data that investors had not (Sanofi decides against its first gene therapy voyage, October 21, 2017).

Voyager plans to dose patients in a placebo-controlled phase II/III programme in the second quarter. The phase II portion in 30 patients is 80% powered to detect a two-hour difference in on-time. Morgan Stanley analysts put forward the possibility of accelerated approval assuming a robust treatment effect.

The phase III component in 100 patients is >90% powered for a 1.5-hour difference, offering a back-up if phase II only demonstrates a numerical improvement.

Golo goal

Approval of Sarepta’s golodirsen would broaden the number of addressable Duchenne patients: the company’s currently approved drug, Exondys 51, targets the 13% of patients treatable with exon 51 skipping, while golodirsen takes aim at the 8% of patients amenable to exon 53 skipping.

Phase I/II dystrophin data suggest that golodirsen is more effective than Exondys 51, fuelling hopes that an early approval could be on the cards (Sarepta hopes to pull off the same trick twice, September 6, 2017).

The FDA did nothing to dash these hopes with last week’s guidance on DMD, citing dystrophin as a potential surrogate endpoint for accelerated approval. This merely appears to strengthen the agency’s previous stance – it gave Exondys 51 the nod despite questionable dystrophin data – but sent Sarepta’s share price up 5%.

It is unclear what accelerated approval would mean for the ongoing placebo-controlled phase III Essence trial of golodirsen; if the project gets the go-ahead before this completes, patients might not want to risk receiving placebo. If this trial is disrupted it could have a knock-on effect on Sarepta’s exon 45 skipping project casimersen/SRP-4045, which is being evaluated in a separate treatment arm in Essence.

The trial has already had its issues: treatment at UK sites was halted after a case of rhabdomyolysis (Sarepta contains UK study halt, for now, February 9, 2018). Sarepta played down the adverse event, pointing out that the patient had resumed treatment and dosing had not stopped in other countries. The trial is still blinded, and it is not known in which arm the affected patient was.

With the FDA apparently increasingly comfortable with dystrophin as an endpoint, perhaps only fears over safety could prompt the agency to wait for the Essence data before giving golodirsen the nod.

To contact the writers of this story email Joanne Fagg or Madeleine Armstrong in London at [email protected] or follow @ByJoFaggor @ByMadeleineA on Twitter