Wave crashes again – this time on toxicity concerns

A run of bad news leaves investors questioning Wave Life Sciences’ ability to deliver on its promises.

The bad news just keeps coming for Wave Life Sciences, and yesterday it was its Duchenne muscular dystrophy candidate suvodirsen that triggered a 28% share price fall. Investors appeared to react badly to the news of adverse events seen at the higher doses of survodirsen in a phase I trial and the decision to take some of the lower doses of the exon-skipping treatment into phase II/III trials.

Wave’s choice raised concerns as to whether the quantities selected would be high enough to demonstrate a therapeutic effect. With this second clinical disappointment in as many weeks following the delay to its Huntington’s disease candidates, questions are now being asked about management’s ability to execute.

How low can you go?

Reporting the phase I trial data, Wave said that 0.5-10mg/kg suvodirsen doses were all well tolerated in the 36-patient trial, with headache, fever and vomiting being the main adverse events seen at up to 5mg/kg.

What spooked investors was that adverse events at 7mg/kg and 10mg/kg, though similar to those in lower doses, were more severe. It was also unclear from the study if the more severe adverse events seen in the higher dosing cohorts would be repeated every time the drug was administered, a factor that might be of concern to doctors and patients.

The unveiling of the details of a 150-patient Dystance 51 phase II/III trial at the same time as the phase I results did little to halt the share price slide. Most of the worry was due to concerns that the chosen doses of 3mg/kg and 4.5mg/kg doses – equivalent to 5mg/kg in phase I – might be too low to show effectiveness, especially as Sarepta Therapeutic's own exon-skipper drisapersen was dosed at 6mg/kg in clinical trials.

Wave has repeatedly pointed to its expertise in stereochemistry and said differences in the chemical structure of the two compounds might allow lower dosing. It should also be cautioned that cross-trial comparisons might not be ideal when it comes to determining potential efficacy.

Also ran… and ran…

But even before yesterday’s phase I results there had been concerns that Wave, which has significantly lagged Sarepta, could see itself fall even further behind in the Duchenne race.

Much will now be riding on the mid-year readout of the ongoing open-label extension trial. This study will not only deliver an interim analysis of dystrophin expression, but importantly uses 3mg/kg and 4.5mg/kg doses, giving an early insight into Wave’s decision to use these in Dystance 51, whose results are due in the second half.

A positive outcome, however, might not be much help in lifting the shares in the longer term, as suvodirsen is unlikely to be launched before 2021, and the advent of gene therapy products in Duchenne might make Wave’s exon-skipping treatments obsolete.

This latest batch of bad news came only a week after the stock fell 19% when Wave admitted that slower recruitment levels would delay results for its Huntington’s disease programmes WVE-120101 and WVE-120102 until the second half of 2019. The two events have seen Wave’s market cap fall from $1.4bn to yesterday's close of $836m.

And, while the two events are not related, the questions around the group’s ability to deliver clinically and strategically mean that any further missteps might be punished even more harshly.  

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