Alnylam nears FDA filing for 4th RNAi therapy vutrisiran after late-stage data back use in protein misfolding disorder
With three approved RNAi therapeutics already on the market, Alnylam has secured its place as the leader in that rare disease-focused field. Now, a fourth candidate is rapidly approaching regulators’ desks, and Alnylam hopes it will complement another of its drugs targeting a rare protein misfolding disorder.
On Thursday, Alnylam unveiled data from its open-label Phase III Helios-A study showing vutrisiran topped a historical placebo control in reducing the symptoms of polyneuropathy tied to transthyretin-mediated (ATTR) amyloidosis from baseline after nine months of treatment. On several secondary endpoints, including changes in quality of life and patient gait speed, vutrisiran also beat out historical placebo.
The 164-patient trial randomized patients 3:1 on either a once-quarterly, subcutaneous 25mg dose of vutrisiran for 18 months or 0.3mg of Onpattro (patisiran), Alnylam’s approved RNAi therapy for ATTR. The study’s primary endpoint judged patients’ baseline changes against a historical placebo recorded during Onpattro’s pivotal Phase III Apollo study.
Alnylam plans to submit a new drug application for vutrisiran with the FDA in early 2021 and stands ready to launch by early 2022. The company will then follow that with filings in other countries, including Brazil and Japan, and then in the EU after obtaining results of the Helios-A study’s 18-month analysis. That filing could come later this year.
Alnylam CEO John Maraganore told Endpoints News the company decided on the Helios-A trial design after consultation with the FDA, which decided it was unethical to enroll a new placebo control arm given the deleterious effects of the disease and consistent placebo data from four other late-stage trials Alnylam has run in the disorder.
“There is complete confidence that if a patient’s left untreated with this disease, they will inextricably decline with a very defined rate of disability,” Maraganore said. “It is just absolutely unethical to do another placebo-controlled study.”
Alnylam reported two deaths in the vutrisiran arm of Helios-A, both of which investigators didn’t tie to treatment. One of those patients died of Covid-19 during treatment, Maraganore said, and another died after forming an iliac artery occlusion following pneumonia. That patient contracted pneumonia back in December 2019, and Maraganore said Alnylam couldn’t confirm whether it was actually another novel coronavirus case.
“Whether it was Covid or not, we don’t know,” he said.
There were also two cases of severe side effects an investigator tied to vutrisiran, Alnylam said, which included dyslipidemia with urinary tract infection. Maraganore said those side effects are also common for untreated patients with ATTR amyloidosis, and Alnylam did not flag any new safety concerns in the late-stage study.
As it angles for a second treatment targeting polyneuropathy tied to ATTR, Alnylam is also pursuing both Onpattro and vutrisiran in ATTR with cardiomyopathy, potentially expanding both drugs’ small patient pools. As a good sign for the Helios-B study for vutrisiran in that indication, the therapy showed a significant benefit over placebo in terms of reducing a key cardiac biomarker known as NT-proBNP. Helios-B was initiated in late 2019 and is currently enrolling at sites around the world.
Maraganore touted the first Helios study’s data as “spectacular” and as a sign of more to come.
“What this really promises to do is really significantly expand our leadership and overall opportunity in ATTR space staring with polyneuropathy,” he said.