Vutrisiran, an siRNA for ATTR-CM, Meets Primary Endpoint in HELIOS-B

A randomized, clinical trial testing vutrisiran, a small-interfering RNA (siRNA) therapy for the treatment of cardiomyopathy resulting from transthyretin amyloidosis (ATTR-CM), has met its primary endpoint, according to an announcement from Alnylam Pharmaceuticals today.

In the HELIOS-B study, 655 patients with ATTR-CM treated subcutaneously with vutrisiran every 3 months had a significant 28% lower risk of all-cause mortality and recurrent cardiovascular events when compared with placebo-treated patients at 36 months. For 395 patients not on background tafamidis (Pfizer), a Food and Drug Administration-approved treatment for ATTR-CM, there was a significant 33% lower risk of the primary endpoint compared with placebo.

All-cause mortality, a secondary outcome assessed at 42 months, was reduced by 36% in the overall population and by 35% in those taking vutrisiran alone (P = 0.025 and P < 0.05, respectively). Other outcomes, including changes from baseline in a 6-minute walk test, quality of life assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ), and NYHA functional class, also significantly improved with vutrisiran.

ATTR-CM is inherited as an autosomal dominant trait caused by mutations in the transthyretin gene (TTR) or by deposits of wild-type transthyretin proteins. Hereditary ATTR amyloidosis affects roughly 50,000 globally whereas wile-type ATTR amyloidosis affects between 200,000 and 300,000 people. In HELIOS-B, investigators randomized patients with both wild-type and hereditary ATTR-CM and a medical history of heart failure.

Pushkal Garg, MD, Alnylam’s chief medical officer, who presented the topline results to financial analysts this morning, said they were “thrilled” with the study outcome, noting the treatment cleared “an extraordinary high bar for efficacy.” They were also pleased to see that the medication provided additional benefit when given to tafamidis-treated patients.

“These remarkable results of vutrisiran in a contemporary population of patients with ATTR cardiomyopathy—with clinical benefits seen on every single one of this rigorous set of endpoints—highlight the power of the RNAi mechanism of action and suggest that vutrisiran has the potential to become the new standard of care in ATTR cardiomyopathy,” said Garg.

Vutrisiran (Amvuttra) is currently approved for the treatment of polyneuropathy associated with hereditary transthyretin-mediated amyloidosis, and Garg said the safety seen in patients with ATTR-CM was consistent with the therapy’s established profile. The rates of adverse events and serious adverse events, including those that led to drug discontinuation, were similar in the vutrisiran and placebo study arms, the company reported.

Alnylam has already submitted the trial results to the European Society of Cardiology (ESC) for consideration as a late-breaking clinical trial at the ESC Congress later this summer. They are also moving toward filing a new drug application with US regulators in late 2024 and will be using their priority review voucher to accelerate the review process.

Cost Could Be an Issue

Back in 2019, the FDA approved two formulations of Pfizer’s transthyretin “stabilizer” tafamidis (Vyndaqel and Vyndamax) for ATTR-CM, making it the only therapy approved at the time for this condition. Pfizer, however, was slammed for listing the drug price at $225,000 per year. Doctors accused the company of “price gouging,” noting that many seniors had out-of-pocket costs running upwards of $1,000 to $2,000 per month if they received no financial support. Studies also showed that the price, which made it the most expensive cardiovascular medication in history, far exceeded commonly accepted thresholds for affordability.

Whether vutrisiran for ATTR-CM will face the same outcry remains to be seen. When approved in 2022 to treat polyneuropathy associated with hereditary transthyretin-mediated amyloidosis, vutrisiran was granted regulatory orphan drug status, whereupon Alnylam set its price at roughly $460,000 per year.  

Earlier this year, Alnylam suffered a setback when the FDA chose not to expand the indication for patisiran, another siRNA, for the treatment of ATTR-CM. Like vutrisiran, patisiran is approved for the treatment of polyneuropathy in hereditary transthyretin-mediated amyloidosis. That decision was a bit of a surprise as the FDA’s Cardiovascular and Renal Drugs Advisory Committee supported the expanded indication. Following the agency’s complete response letter, Alnylam announced they wouldn’t pursue patisiran for the expanded ATTR-CM indication.