The recent and (mostly) surprise FDA rejection of Alnylam Pharmaceuticals’ RNAi drug Onpattro for patients with a rare genetic heart condition was a knock to the company’s market plans, and CEO Yvonne Greenstreet said she was “extremely disappointed with the outcome.”
The regulator denied approval despite a positive vote from an independent medical advisory committee earlier this year, saying in a complete response letter that Alnylam did not demonstrate clinically meaningful results in patients with cardiomyopathy of ATTR amyloidosis.
On an investor call this week, Greenstreet, a PharmaVoice 100 honoree, questioned the FDA’s decision to rule against the advisory committee in rejecting Onpattro, which was previously approved for patients with nerve damage from the same genetic disease called ATTR amyloidosis.
Looking ahead, some of the takeaways from Greenstreet’s call provide insight into Alnylam leadership’s views on the decision and where the company goes from here.
“Despite the existence of an FDA-approved therapeutic to treat this disease, there is a significant unmet need, as there are patients that continue to experience decline in their functional capacity and quality of life, as well as patients that cannot access the available therapy.”
The Pfizer treatments Vyndaqel and Vyndamax, both forms of the drug tafamidis, received approval in 2019 for patients with cardiomyopathy caused by ATTR amyloidosis, which is a potentially fatal disease that affects daily living through shortness of breath, fatigue and diminished exercise tolerance. Greenstreet emphasized that patients still need more options.
The CEO pointed to reasons she found the rejection surprising, including earlier consultation with the FDA that lined up the functional measure of a six-minute walk test as the primary endpoint of the late-stage trial.
Prior to the rejection, the advisory committee voted 9-3 in favor of Onpattro’s benefits outweighing the potential risks. Furthermore, the complete response letter did not cite safety as a concern.
The butting heads of industry leaders and regulatory decision makers when it comes to acceptable endpoints, particularly for rare diseases and patients with few other treatment options, neither begins nor ends with Alnylam. Experts have been pushing for regulatory clarity for years.
“It does not make sense for us to invest further in additional development to enable commercialization of [Onpattro] in cardiomyopathy.”
Despite the positive outcome of the phase 3 trial in cardiomyopathy, the regulatory decision has caused Alnylam to stop seeking further indications for Onpattro in the disease, Greenstreet said. Instead, the company will look deeper into its pipeline and embrace its “next generation” of treatments including Amvuttra, which has already been approved for the polyneuropathy of hATTR amyloidosis.
Results from a late-stage study of Amvuttra are expected in early 2024, giving Alnylam a potential foothold in the cardiomyopathy space that slipped through the company’s fingers this time around. Greenstreet pointed out that Amvuttra’s study is “approximately twice as large and three times longer than” Onpattro’s study, which sets the company up for another round with regulators. The study focuses on “hard outcomes” like death and hospitalization rather than the quality-of-life outcomes of the previous study.
Greenstreet also said that the setback has not caused the company to walk away from the long-term goal set out in 2021 to achieve profitability by the end of 2025 with six or more marketed products and half a million drugs sold. The goal would put Alnylam in the top five biotechs by market capitalization, according to former CEO John Maraganore at the time.
“We see evidence of separation favoring the [Onpattro] arm and emerging over time with longer follow up and greater event accumulation — thus it's possible that the benefits of RNAi-mediated silencing of TTR may be maintained or even grow over time.”
Greenstreet conveyed the confidence in Alnylam’s overall platform, which uses RNA interference — the winner of a 2006 Nobel Prize — to turn off specific genes that cause disease. In fact, she said the platform could show longer-lasting results that didn’t come through in the Onpattro study.
She said being a platform company allows Alnylam to pivot after this unexpected turn of events to bring forward a new wave of therapies quickly.