After an investigational BridgeBio drug surprisingly failed a clinical trial that would have set up a fight against Pfizer in a rare heart condition, investors have been worrying about Alnylam because of a similar study design. Now, Alnylam has returned partially successful.
The closely watched Apollo-B trial testing Alnylam’s Onpattro in the heart failure disease of transthyretin-mediated amyloidosis (ATTR) with cardiomyopathy has hit its primary goal, the company said Wednesday. In the phase 3 study, Onpattro takers experienced a bigger improvement in a six-minute walk test at 12 months than the placebo group did.
However, on the objective—and arguably more important—measurement of patients’ outcomes, Onpattro didn’t demonstrate a statistically significant edge over placebo. That composite endpoint looked at all-cause deaths, cardiovascular events and change in the six-minute walk test. Because of that lack of showing, two other secondary endpoints on death rates and hospitalizations in the different patient populations weren’t formally tested.
Still, based on the primary goal win and a separate showing of improvement in quality of life, Alnylam plans to apply for a U.S. approval of Onpattro in ATTR-cardiomyopathy in late 2022, setting up a potential launch in 2023. If approved, the drug would compete with Pfizer’s blockbuster tafamidis franchise—Vyndaqel and Vyndamax—which pulled in $909 million in sales in the U.S. alone last year thanks to a 48% year-over-year growth.
It remains to be seen how regulators will view the Onpattro data, and whether the drug would be competitive on the market if approved. Doctors value patient outcomes results, Mizuho analyst Salim Syed wrote in a July note after a panel discussion featuring four cardiologists.
“[H]ard clinical endpoints such as mortality and hospitalizations are more key, since patients will not rely on [six-minute walk test] performance but on mortality data compared to available treatments when asking their physicians for a better drug for them,” Syed wrote, summarizing the doctors’ position.
The doctors pointed out that even if Onpattro is approved based on the six-minute walk test data, prescriptions would notably increase if the hard outcome data were positive, Syed said.
During an investor call Wednesday morning, Alnylam chief medical officer Pushkal Garg, M.D., blamed the study’s design as well as the trial size and length for the disappointing patient outcomes data.
“Important to note, the study was designed and powered for the six-minute walk test and the [quality of life] endpoints,” Garg said. “Over the size and 12 months duration of the study, we’re not optimized to demonstrate an outcomes benefit, which would have required a significantly larger sample size and a longer study.”
During the call, Alnylam executives kept mum about the exact data, sharing only statistical significance results. The full data will be presented at the upcoming International Symposium on Amyloidosis meeting in September, they said.
Despite the mixed results, Apollo-B can still be counted as a win for Alnylam. The Onpattro readout comes after a surprising phase 3 failure in December by BridgeBio’s acoramidis on the same six-minute walk test. At that time, industry watchers predicted that Apollo-B would likely fail because ATTR-CM patients appeared to be healthier these days compared with historical data that Pfizer used for its approvals, making it difficult to pull off a clear win on the six-minute walk test.
Executives on Wednesday’s call declined to comment on how Apollo-B’s placebo arm fared compared to historical data.
Looking forward, Alnylam could have clearer ATTR-CM outcomes data from arguably the even more important Helios-B trial for freshly FDA-approved Amvuttra. The Amvuttra trial, expected to read out early 2024, is twice as large as Onpattro’s Apollo-B and runs about three times as long, Garg noted.
Currently, both Onpattro and Amvuttra are only allowed in hereditary ATTR-polyneuropathy, which affects peripheral nerves. The global ATTR-CM patient population is estimated to be at over 250,000, according to Alnylam. That’s about five times that of hATTR-PN.
“[T]he purpose of Apollo-B is to gain early access to the CM market for [Onpattro] while Helios-B for [Amvuttra] bakes,” Evercore ISI analysts wrote in a note last week. This early access could mean $1 billion in sales by Evercore’s calculation. Thanks to its under-the-skin formulation, Amvuttra is expected to ultimately eat away Onpattro infusion’s use, the team said.