Changing a clinical trial’s statistical analysis plan on the cusp of a readout? That’s exactly 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 blockbuster market opportunity underpinned by a patient population that’s about 10 times larger than Amvuttra’s existing nervous system indication.
The trial is testing Amvuttra in transthyretin amyloid cardiomyopathy (ATTR-CM) and was originally expected to report results early this year. Now, after multiple tweaks to how the drug’s efficacy will be measured, Alnylam is pushing the readout to late June or early July.
During a Thursday conference call, Alnylam CEO Yvonne Greenstreet assured investors 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 sure we had as much information as we possibly could prior to making any changes before database lock and also […] to make sure that we consulted with the FDA and other health authorities,” Greenstreet said 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 trial design.
In the updated plan, investigators will evaluate Amvuttra’s ability to improve cardiovascular outcomes compared with placebo when the 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 give the study 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 prolongation during 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 extra three months, Alnylam’s new Amvuttra plan will analyze a subgroup of patients who received the drug as a monotherapy, in parallel with an evaluation of the overall trial population.
Under certain statistical scenarios, the study could yield 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 on tafamidis.
Not pairing well with tafamidis could be a problem, because analysts had projected a tough battle down the road for Alnylam in challenging Pfizer. Meanwhile, a combination approach offers another opportunity entirely.
During Thursday’s call, Garg acknowledged that the changes to HELIOS-B were made based on lessons from APOLLO-B and “emerging data from the field.” 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 explained.
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 to file for an approval in late 2024.
Despite questions about Alnylam’s move, analysts at William Blair said they still believe HELIOS-B will be positive because of Amvuttra’s RNA-silencing mechanism.
“We view the extension and change to the statistical plan to be a prudent adjustment to improve the probability of success, and recent clinical 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-polyneuropathy indication, brought 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 ginned up $961 million in sales thanks to continued growth in ATTR-CM.
Editor's Note: The story has been updated with a comment from Willaim Blair.