FDA Issues Complete Response Letter for Onpattro in Heart Failure Indication

The FDA has issued a complete response letter (CRL) for Alnylam Pharmaceuticals’ supplemental new drug application (sNDA) for Onpattro (patisiran) to treat patients with cardiomyopathy of transthyretin-mediated (ATTR) amyloidosis. Regulators said that the clinical meaningfulness of Onpattro’s in this indication was not supported by the data.

ATTR amyloidosis is a rare, progressive, debilitating disease caused by misfolded transthyretin proteins that accumulate as amyloid fibrils in multiple tissues including the nerves, heart, and gastrointestinal tract. In cardiomyopathy, the heart loses its ability to pump blood.

The complete response letter does not impact Onpattro’s current indication: treating patients withpolyneuropathy of hereditary ATTR amyloidosis, which affects the peripheral nerves. It generated $558 million in revenue in 2022. Its wholesale acquisition cost is $9,785 per vial.

Related: FDA Advisory Committee Backs Use of Onpattro in Heart Failure Indication

Last month, the FDA’s Cardiovascular and Renal Drugs Advisory Committee (CRDAC) voted 9 to 3 in support of Onpattro despite questions about its benefit. Many committee members felt the data from the APOLLO-B study were marginally positive. Those who voted yes said more options for rare diseases are needed. Only one treatment is available to treat cardiomyopathy in ATTR: Pfizer’s Vyndamax (tafamidis).

The FDA in a briefing document indicated that there was no evidence of treatment effect in patients who were also taking Vyndamax. FDA officials the analysis of these patients did not provide evidence for or against treatment effect. Regulators pointed out the study was not powered to provide conclusions about these patients.

Alnylam officials said the company will no longer pursue Onpattro for this indication. The company will instead on focus on Amvuttra (vutrisiran), an RNAi therapeutic in a phase 3 trial (HELIOS-B) to treat patients with cardiomyopathy of ATTR amyloidosis.

Yvonne Greenstreet, MBChB

“While we had very much hoped for an approval on Onpattro would have represented the first step to help this underserved population, but with vutrisiran and the HELIOS-B study serving as a very important next step and with the top-line read out of HELIOS-B expected in early 2024, it does not make sense to conduct further additional development of patisiran in cardiomyopathy,” Yvonne Greenstreet, MBChB, CEO of Alnylam Pharmaceuticals, said in a call with analysts.

She said the HELIOS-B study was designed and powered with patients similar to those in the APOLLO-B on the composite outcome of all-cause mortality and recurrent cardiovascular events over 30 to 36 months

Amvuttra is already available on the market and was approved in July 2022 to treat patients with polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. hATTR amyloidosis is a rare, inherited, rapidly progressive, and fatal disease. In this indication, Amvutta was approved based on nine-month data from the HELIOS-A study.

"The next step in our journey will be achieving positive results with the HELIOS-B phase 3 study of vutrisiran where we are leveraging over a decade of experience in ATTR amyloidosis and building on the growing body of data that gives us confidence of success,” Greenstreet said.

Beyond vutrisiran, the company is also studying the potential of ALN-TTRsc04 to treat patients with ATTR amyloidosis, which may allow for greater TTR knockdown and once-annual dosing.