On Eve of Big Data Reveal, Patient Death Stalls Alnylam Hemophilia Drug

Xconomy Boston — 

After years of ups and downs, RNA interference is as close as it’s ever been to producing its first drug. But the field’s roller coaster ride hit another bump this morning: Alnylam Pharmaceuticals is suspending development of an experimental hemophilia drug after a patient in a clinical trial died from brain swelling.

It’s a setback for Cambridge, MA-based Alnylam (NASDAQ: ALNY), which has already started a Phase 3 study of the drug, fitusiran. Alnylam has been hoping fitusiran might be a new, long-lasting therapeutic option to help hemophilia patients prevent dangerous bleeds. But the program’s future is now up in the air. Alnylam said the death was “possibly related” to fitusiran, so it is stopping all studies, including the Phase 3 program, until it figures out what happened and develops a risk mitigation strategy.

Alnylam executive vice president of R&D Akshay Vainshaw said in a statement that the company aims to restart the trials “as early as late 2017” after speaking with regulators. The company, in the statement, said it plans to keep developing fitusiran given “overall consideration of fitusiran’s benefit-risk profile.” It also, separately, announced that a different drug, givosiran, is heading to Phase 3 testing for a rare metabolic disease. Investors sent shares down more than 12 percent in pre-market trading on Wednesday nonetheless. As Leerink Partners analyst Paul Matteis wrote, even should Alnylam resume clinical testing of fitusiran, its “commercial opportunity may now be limited given the risk-averse nature of the hemophilia patient population.”

The news is troubling for Alnylam at a critical time. The company is preparing to reveal, this month, the most important data in its existence: Phase 3 data on patisiran, a drug for the rare nerve disease familial amyloid polyneuropathy which has a chance, if successful, to become the first commercialized RNAi therapy ever. Yet it has now had to either suspend or scrap multiple drugs in its pipeline due to unexpected safety problems. Last year, for instance, it ended development of a revusiran, a drug that, like fitusiran, was also in Phase 3 testing. Another drug, ALN-AAT, was scrapped due to worrisome signs in an early trial.

More broadly, the latest news shows that, despite all the progress that has been made with RNAi—a method of switching off a gene so it can’t make a potentially harmful protein—questions still remain. RNAi’s history has a dramatic series of twists and turns, largely due to solving the technical challenge of getting large RNAi molecules to their targets. But improvements in delivery methods over the past several years have put them on the precipice of actual medicines. Those improvements, and other technological advances, were part of the reason Craig Mello, who won a Nobel Prize in 2006 for co-discovering RNAi, told Xconomy this week that “the hard work has been done, or a lot of it.”

Both patisiran and fitusiran are part of a wide-ranging alliance between Alnylam and Sanofi. The two split rights to both drugs.

Here’s more, meanwhile, on the long saga of RNAi, and Alnylam’s place in it.