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Alnylam changes analysis plan for key Amvuttra heart trial, jolting investors

2024-02-15

临床3期

If the HELIOS-B trial returns positive results, Alnylam's Amvuttra may challenge Pfizer's blockbuster tafamidis franchise in ATTR-CM.

Changing a clinical trial’s statistical analysisAlnylamn tAmvuttraof a readout? TPfizerexactly what Alnylam just did for a closely watched study of its next-generation RNA interference therapy Amvuttra in a rare heart disease.

Alnylam’s announcement about changes to the phase 3 HELIOS-B trial triggered a 8% decline in the company’s stock price Thursday morning. HELIOS-B is on the top of investors’ minds given the bloAmvuttra markerare heart diseaserpinned by a patient population that’s about 10 times larger than Amvuttra’s existing nervous system indication.

Alnylamal is testing Amvuttra in transthyretin amyloHELIOS-Bomyopathy (ATTR-CM) and was originally expected to report results early this HELIOS-Bw, after multiple tweaks to how the drug’s efficacy will be measured, Alnylam is pushing the readout to late June or early July.Amvuttra

During a Thursday conAmvuttracalltransthyretin amyloid cardiomyopathy (ATTR-CM)tors that the changes reflect the company’s confidence in Amvuttra, and that Alnylam has “enhanced the study” to enable “the best demonstration” of Amvuttra’s impact across the ATTR-CM population.

“For us, it’s important to make surAlnylamd as much information as we possibly could prior to making any changes before database lock andAmvuttra] to make sAlnylamt we consulted with the FDA and other health authorities,” GreenAmvuttraaid of the adjustments.

Despite those assurances, Alnylam’s last-minute changes suggested to investors that the company may have some concerns that Amvuttra might not live up to expectations under the original tFDAl design.

In the updated plan, invesAlnylams will evaluate Amvuttra’s ability to improve cardiovascular outcomes compared with placeboAmvuttrae final patient reaches 33 months of treatment. This adds three months of treatment compared with the original trial design.

The additional three months of follow-up will givAmvuttraudy more statistical power to show a significant benefit for Amvuttra, Alnylam’s chief medical officer, Pushkal Garg, M.D., said on the call.

“This is an important change as these three additional months of observation constitute a short but meaningful prolongAmvuttraring the critical late part of the study, which is when we expect to see the greatest number of outcome events happening in the placebo arm,” Garg added.

Previously, Amvuttra’s predecessor, Onpattro, failed to gain FDA approval in ATTR-CM based on results from the shorter APOLLO-B study. In an open-label extension phase at 24 months and beyond, the drug began to show greater benefits.

Besides the Amvuttraree months, AlnyOnpattrow Amvuttra plan will analyze a suATTR-CMof patients who received the drug as a monotherapy, in parallel with an evaluation of the overall trial population.

Under certain statistical scenarAlnylame studyAmvuttraield a positive result even if only the monotherapy subgroup meets the statistical significance bar. Monotherapy patients make up about 60% of the trial population, according to Alnylam.

The issue here centers on Pfizer’s tafamidis, known commercially as Vyndaqel and Vyndamax, which Amvuttra aims to challenge in ATTR-CM. In the previous APOLLO-B trial, Onpattro didn’t show much benefit in patients who were already oAlnylamidis.

Not pairing well with tafaPfizercoutafamidisroblem, because analystsVyndaqeljecteVyndamaxh battleAmvuttrae road for Alnylam in ATTR-CMging Pfizer. Meanwhile, a combinatOnpattrooach offers another opportunity entirely.tafamidis

During Thursday’s calltafamidisknowledged that the changes to HELIOS-B were made based on lessons from APOLLO-B and Alnylamng data from thePfizer.” He argued that the additional Amvuttra monotherapy analysis isn’t an indicator of any lack of confidence in the overall population, but that it allows Alnylam to “demonstrate the true impact” of Amvuttra as a standalone treatment, which will be relevant to patients and physicians, Garg said.

“Existing [reimbursement] plan restrictions and prior precedent suggests that for the next several years, the market is expected to be primarily monotherapy driven,” he explainedAmvuttra Amvuttra

What’s more, Alnylam also streamlined HELIOS-B’s secondary endpoints to now only include a six-minute walk test, a patient-reported questionnaire score called KCCQ-OS, all-cause mortality and change from baseline in NYHA Class, which is a measurement of heart function.

All these changes were made in consultation with the FDA, Garg said, and the agency was “supportive of this approach, particularly as it relates to the handling of the primary endpoint.” Several analysts on Thursday’s call remarked that the new analysis “makes a lot of sense.”

If HELIOS-B is eventually successful, Alnylam plans tFDAile for an approval in late 2024.

Despite questions about Alnylam’s moveAlnylamsts at William Blair said they still believe HELIOS-B will be positive because of Amvuttra’s RNA-silencing mechanism.

“We view the extension aAlnylamge to the statistical plan to be a prudent adjustment to improve the probability of success, andAmvuttraclinical trials in TTR-cardiomyopathy certainly point toward longer trials as beneficial to yield drug effect sizes,” the William Blair team said in a Thursday note to clients.

HELIOS-B is a go-big-or-go-home event for Alnylam’s ATTR franchise after the Onpattro rejection. Onpattro and Amvuttra, in their existing ATTR-polyneuropaTTR-cardiomyopathyought in $254 million in sales in the fourth quarter, good for 10% sequential growth compared with the third quarter.

By comparison, Pfizer’s tafamidis family gAlnylamp $961 million in sales thanks to continued growOnpattroTR-CMAmvuttra ATTR-polyneuropathy

Editor's Note: Pfizerorytafamidis updated with a comment from Willaim Blair.ATTR-CM