- Alnylam Pharmaceuticals, Inc. still is not sure what factors led to a higher number of patient deaths in the treatment group of a Phase 3 study testing its experimental drug revusiran in hereditary ATTR amyloidosis.
- The RNA interference (RNAi) specialist discontinued further development of revusiran last October after a review found an imbalance in the number of deaths between those patients receiving the drug and those receiving placebo.
- A subsequent investigation into the deaths and a 3-month safety follow-up turned up no clear answers, although Alnylam found no evidence of drug-related cardiotoxicity. The biotech suggested that lower-than-expected mortality on the placebo arm could have contributed to the observed imbalance.
Alnylam's announcement last October of its decision to halt development of revusiran immediately led to questions about the safety of its GalNAc delivery platform and its overall approach to RNAi therapeutics. Shares in the Cambridge biotech fell nearly 50% in value on the news.
At the time, Alnylam said a review by the study's monitoring committee found no evidence of drug-related neuropathy but showed the benefit-risk profile no longer supported dosing. Analysis by Alnylam uncovered the reported "imbalance of mortality" but didn't uncover a potential cause.
Ten months later, the company still has no single answer for what contributed to the higher number of patient deaths, but offered up new details on the study.
Alnylam noted the treatment arm had a greater proportion of patients who were over the age of 75. Yet, adjusting for age in models did not sufficiently explain the higher number of deaths, the company said.
After ruling out cardiotoxicity and pharmacodynamic/pharmacokinetic-related toxicity, Alnylam suggested a lower-than-expected mortality raised the risk of a chance imbalance in mortality for the relatively small study.
Interestingly, the dosing regimen for revusiran meant that annualized exposure levels to the drug were significantly higher than for other programs using the GalNAc conjugate platform.
No read through
Even though Alnylam has since restored confidence in its pipeline, the company made clear it felt the investigation into revusiran raised no red flags for other programs.
"Importantly, we continue to remain confident that the findings with revusiran, a first-generation GalNAc-conjugate do not read through to the rest of our GalNAc platform and we believe recently reported data from across our pipeline continue to strengthen this confidence," said company CEO John Maraganore on an August 9 earnings call with analysts.
That pipeline continues to advance. Phase 3 results from the APOLLO study of patisiran in ATTR amyloidosis are expected in the coming weeks. Strong data from that study would support a filing for approval in the U.S. by year-end, Alnylam said.
If successful with patisiran, Alnylam would be on track to hit its goal of becoming a multi-product commercial-stage company by the end of 2020.
Elsewhere, Alynlam recently launched a Phase 3 study of its hemophilia drug fituisran and plans to push another RNAi therapeutic for acute hepatic prophyrias into late-stage testing later this year.