Shares in Alnylam went into freefall yesterday after the US biotech revealed it was stopping development of its lead pipeline drug revusiran.
A phase III trial of revusiran in the rare disease hereditary ATTR amyloidosis with cardiomyopathy – which can cause nerve and heart damage – showed that more patients died on the drug than on placebo, although Alnylam is at a loss to explain the finding.
All told, there were 18 deaths out of 206 patients in the ENDEAVOUR trial, but Alnylam has yet to reveal how many occurred in each arm.
The revelation is a big blow to Alnylam and also its co-development partner Sanofi’s rare disease subsidiary Genzyme, which has rights to the drug in outside North American and Western Europe. Analysts have previously suggested the drug could top $1bn in sales by 2023.
Revusiran works via a mechanism called RNA interference, and is designed to switch off the production of specific proteins. It blocks the production of prealbumin from the TTR gene, which when faulty leads to amyloid deposits in various tissues including the heart. Patients with hereditary ATTR amyloidosis and cardiomyopathy generally die within 2.5 to 5 years of diagnosis.
Reports of worsening nerve damage in a phase III trial of revusiran prompted Alnylam to suspend the trial and have the data monitoring committee take a close look at the blinded data. The imbalance in patient deaths between the group was discovered, and a decision taken to halt the trial.
“We have stopped all dosing and are actively monitoring patients across revusiran studies to ensure their safety,” said Alnylam’s chief executive John Maraganore, who added the company would now work hard to try to understand the reasons behind the findings.
“Given the lack of available treatment options for patients suffering from this devastating disease, we remain committed to serving the needs of the ATTR amyloidosis community.”
Shares in the company fell more than 40% yesterday as news of the setback emerged, and Alnylam will now have to concentrate its efforts on patisiran, another RNAi drug in phase III testing to halt the progression of neuropathy in patients with hereditary ATTR amyloidosis.
That is a very different patient population from the cardiomyopathy group, who tend to be frailer and often have concomitant illnesses and medication use.
On a conference call, Alnylam’s chief medical officer Akshay Vaishnaw said there is a fundamental difference between revusiran and patisiran – and indeed other candidates in its pipeline – as patients on revusiran have a much higher annualised exposure to the drug. Dosing is between 12 to 30 times higher than for the seven other candidates it has in clinical trials, he noted.
“Patisaran is a completely different molecule and has a different approach for delivery [and] we have been encouraged by the safety data we’ve seen in the phase II open-label study to date,” said Maraganore.