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August 3, 2022 07:00 AM EDTUpdated 07:40 AM R&DPharma
Alnylam heralds PhIII APOLLO-B win on way to creating an ‘industry leading TTR franchise’
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Alnylam $ALNY has laid claim to a major success in Phase III, with its RNAi drug patisiran hitting the primary endpoint in its APOLLO-B study for ATTR amyloidosis with cardiomyopathy, one of the most important pivotal trials to read out this year.
Shares of the big biotech soared 46% ahead of the bell, after starting the day with a market cap of $17 billion.
This is a topline readout only, with no details on the precise data comparison for the primary endpoint of change from baseline in the 6-Minute Walk Test at 12 months compared to the placebo arm. That’s still some weeks away, reserved for a conference. But the p-value hit 0.0162, while a key secondary on the quality of life also weighed in on the positive side of the stat boundary at 0.0397. And that sets the stage for a quick march to the FDA in search of a 2023 market launch.
There is a caveat, though, with the drug failing the secondary composite endpoint of “all-cause mortality, frequency of cardiovascular events, and change from baseline in 6-MWT over 12 months compared to placebo.” That prevented further endpoint analysis, but didn’t stop Alnylam CEO Yvonne Greenstreet from flagging a landmark win.
“Really, the study met all of its major objectives,” Greenstreet tells me. “We achieved a statistically significant improvement in the 6-Minute Walk Test compared to placebo. That was the primary endpoint. And in the first secondary endpoint, a statistically significant improvement in the quality of life as measured by the KCCQ. So we’ve delivered what we set out to do here. And I think what’s also important to comment on is the safety. I mean, the safety data were really encouraging, and we were particularly encouraged by the numeric reduction in mortality with patisiran compared to placebo.”
On safety, five patients (2.8%) on patisiran and eight patients (4.5%) on placebo died.
It’s hard to overestimate the importance of this study for Alnylam. By the biotech’s reckoning, it marks the boundary line for creating an “industry leading TTR franchise, which currently includes Onpattro and Amvuttra for the polyneuropathy of hereditary ATTR amyloidosis.”
“We believe these data take us one step closer to achieving our Alnylam P5x25 vision of becoming a leading biopharma company,” Greenstreet says.
The study has frozen some analysts in the headlights of the oncoming data, with dire notes in the wake of a BridgeBio disaster on the same target marking the sharply higher risk of failure at Alnylam. The SVB team recently called this one “the most divisive and closely watched catalyst in our coverage universe.” According to their own analysis, it would take a minimum 14-meter improvement over baseline in the 6MWT to hit significance here.
BridgeBio shares go into meltdown mode as their lead PhIII drug implodes at the finish line
BridgeBio set the stage for a tense showdown at Alnylam late last year with its stunning failure, which eviscerated its market cap and raised questions about the disease and how it’s treated. That failure, SVB noted a few days ago, fueled “controversy by calling into question (1) the validity of 6MWT as an endpoint in TTR-CM and (2) whether differences in the TTR-CM population since the ATTR-ACT study of tafamidis were under appreciated at the time of trial design, powering assumptions for APOLLO-B. Investor sentiment shifted further to skepticism when IONS expanded study size and increased duration in CARDIO-TTRansform.”
Alnylam execs are shrugging that all off now, pointing to a string of successes in the clinic that made them confident they could score here.
“I think these results really validate the hypothesis that TTR silencing with an RNAi therapeutic is effective in treating the cardiomyopathy of ATTR amyloidosis,” notes Greenstreet. “And I think a lot of people have obviously been focused on our second study, which is vutrisiran in the HELIOS-B study in patients with wild-type and hereditary cardiomyopathy. And I think these data give us even greater confidence in the outcome of that study.”
“We, after discussion with regulators,” she adds, “would plan to submit an sNDA by the end of this year, and that would mean a launch in 2023. And of course, launch in the US, but in other markets as well.”
CMO Pushkal Garg says he doesn’t know exactly why the BridgeBio study failed. But he feels confident in their own work.
First and foremost, we think we identified the right patient population to enroll based on all the learnings in the field. We rigorously ascertained the sites and we had extensive sort of work done to make sure we were executing this study flawlessly. We designed the study, from the populations of patients, between hereditary and wild-type, between TAF experienced and TAF naive. All of these things to really optimize the sweet spot in terms of patients who we thought, on placebo, were likely to progress, and on drug, were most likely to benefit….
I personally believe that a silencing mechanism, based on what we’ve seen in neuropathy, where we halt and reverse the disease, is likely to track very well into the cardiomyopathy….
I think an important point is this is an increasingly commonly recognized cause of heart failure. 20% or more of patients with heart failure with preserved ejection fraction probably have ATTR amyloidosis, and diagnosis is now increasing because of the availability of technician scans, noninvasive methods.
Alnylam’s shares closed Tuesday just under $142 a share, down 18% year-to-date — not a terrible track record in what has been a catastrophic year for many public biotechs. But they’ll end the day at a much higher mark than that.