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Alnylam Scraps RNAi Drug After Safety Problems, Shares Plunge

Xconomy Boston — 

Alnylam Pharmaceuticals has gone through more than a decade of twists and turns, trying to become the first company to bring an RNA interference drug, a method of “silencing” disease-causing genes, to market. And while the Cambridge, MA, company still may achieve that goal, it suffered a big setback this afternoon as safety concerns have caused it to scrap a once-promising drug.

Alnylam (NASDAQ: ALNY) said in a statement late Wednesday that it has discontinued development of a drug called revusiran, one of the two most advanced RNAi drugs in the company’s pipeline. Alnylam had been testing revusiran in a Phase 3 trial of patients with a form of the rare disease transthyretin (TTR) amyloidosis, but that effort has abruptly ended due to safety problems. The news has no impact on the development of patisiran, the company’s other drug in Phase 3 testing, Alnylam said.

In its announcement, Alnylam said that reports of worsening nerve pain in an ongoing Phase 2 extension study led the company to convene an ad hoc meeting with an independent data monitoring committee this week. The committee then unblinded its ongoing Phase 3 placebo-controlled study, named Endeavour, and reviewed the data.

The committee determined that “the risk-benefit profile for revusiran no longer supported continued dosing,” and worse, the company subsequently found after taking a more detailed look that there was an “imbalance” between the number of patients on Alnylam’s drug who had died, and those on placebo. Alnylam has stopped all three studies of revusiran, which include two Phase 2 trials and the late-stage Endeavour study.

The news immediately triggered a massive sell-off of Alnylam shares, which plunged more than 40 percent in after-market trading on Wednesday, from a $70.30 close to $39.85 as of 6:48 pm ET. Alnylam shares haven’t closed below $50 a share since mid-2013.

On a conference call with analysts Wednesday evening, Alnylam CEO John Maraganore (pictured) and chief medical officer Akshay Vainshaw said that 18 patients in the Phase 3 revusiran study had died. They wouldn’t say exactly how many of those patients were on revusiran compared to placebo, though Maraganore said it wasn’t “18 to zero.”

Vainshaw said that most of the deaths were “cardiac in nature,” though he noted that that is typical of patients with the form of TTR in the trial. Those patients have what’s known as familial cardiomyopathy, which means the abnormal buildup of amyloid proteins in their body causes damage to the heart, which can often lead to heart failure. Vainshaw said that the patients in Alnylam’s trial were a “sick, older population” taking many other drugs.

Maraganore said that at this point, the company doesn’t have a current explanation for the findings. It has to dig through the data. But he and Vainshaw took pains to distance the safety issues that doomed revusiran from the rest of Alnylam’s experimental drugs. Issues with worsening nerve pain or an imbalance in patient deaths haven’t been seen with these other drugs, they said, and all of the other drug candidates in the company’s pipeline use a different delivery technology.

Patisiran, for instance, is an infusible drug, while revusiran is administered via a subcutaneous injection. And while Alnylam has subsequently developed other drugs taken through an injection just under the skin—including another potential drug for familial cardiomyopathy in Phase 1 testing—they use a different technology that enables the company to deliver the RNAi drugs at a much lower dose than revusiran.

Outside of this instance, Maraganore said, “there is no evidence of a drug-related [nerve pain] signal in our entire safety database.” That includes data on more than 800 treated patients, some of whom have been on Alnylam’s experimental RNAi drugs for as long as 34 months. Alnylam, however, also recently scrapped another experimental RNAi drug, for the rare disease alpha-1 antitrypsin deficiency, after spotting some potential safety problems in a Phase 1 trial.

Maraganore said that despite the revusiran setback, the company still plans to have three drugs on the market by 2020, and noted that it has eight drug candidates in clinical testing.

“This is drug development,” Maraganore said. “These things do happen.”

Still, it’s sobering news for the field of RNAi drug development, which is as close as it’s ever been to an approved drug. RNAi drugs are meant to silence disease-causing genes before they make the proteins that trigger diseases by introducing short, synthetic strands of RNA into cells. RNAi’s history has been a roller coaster, 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, with patisiran and revusiran at the forefront.

Patisiran is being developed for a different form of TTR affecting the nerves. Given today’s news, the Phase 3 trial that’s expected to produce results next year has now become even more critical for Alnylam, which has been amassing the commercial infrastructure needed to prepare to finally begin selling its products.

Here’s more on Alnylam and the ups and downs faced by RNAi drug developers over the years.