Alnylam has offered a closer look at the data that could support Onpattro’s quest to expand into a rare heart disease. While an approval looks likely, some industry watchers have raised fresh doubts about the drug’s commercial opportunity in its potential fight against Pfizer.
In patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM), Onpattro showed benefits against placebo on several exploratory endpoints, such as change on the cardiac stress test called NT-proBNP. The drug also bested placebo on a myocardial injury biomarker called troponin I plus some heart ultrasound imaging markers.
But critics zeroed in on a subgroup analysis released at the Heart Failure Society of America’s annual meeting Friday. The findings raised doubts about whether Onpattro can challenge Pfizer’s blockbuster tafamidis franchise of Vyndaqel and Vyndamax, some analysts said.
While Onpattro showed a statistically significant benefit in slowing disease progression as measured by the six-minute walk test—the phase 3 APOLLO-B trial’s primary endpoint—the result appeared to be driven by those who hadn’t received Pfizer’s Vyndaqel/Vyndamax. In fact, in that patient subgroup, the control group performed slightly better on the walk test than Onpattro takers did.
Within the key secondary endpoint of health status and quality of life, as measured by a questionnaire called KCCQ-OS, Onpattro demonstrated a very small advantage over placebo among patients with baseline Vyndaqel/Vyndamax use.
What’s more, reductions in serious cardiovascular events in the overall group appeared to be driven primarily by patients who were previously on tafamidis, Berenberg analyst Zhiqiang Shu, Ph.D., pointed out in a Monday note. In the entire trial population, Onpattro failed to show a statistically significant edge over placebo at 12 months when measuring the composite endpoint of all-cause deaths, cardiovascular events and change in the six-minute walk test.
The subgroup analyses “confirm that [Onpattro] is no better than tafamidis,” Shu said. Assessing how Onpattro works in patients who progressed from tafamidis is “key for us to assess the commercial potential of Onpattro,” he said. The analyst predicts the Alnylam drug will be “a marginal product” for ATTR-CM.
Still, even considering the results, the trial’s primary investigator told Shu that he’s willing to potentially prescribe Onpattro in ATTR-CM under favorable pricing and payer coverage, the analyst wrote.
In a separate note from SVB Securities, analysts there also argued Onpattro could win an FDA approval next year based on the APOLLO-B results but said that “investors will continue to question the degree of switching from tafamidis to [Onpattro].”
The debate will likely continue into 2024, when Alnylam is expected to report top-line data for its newer ATTR drug Amvuttra in ATTR-CM from the HELIOS-B trial, the SVB team said.
But as Berenberg’s Shu sees it, Onpattro’s APOLLO-B results indicate increased risk to Amvuttra’s HELIOS-B because the two drugs showed “high similarity” in reducing the TTR protein. To add more uncertainty to the upcoming Amvuttra readout, HELIOS-B enrolled 50% of patients who took Vyndaqel/Vyndamax at baseline, versus 30% in APOLLO-B.
Further, disease progression on Vyndaqel/Vyndamax was not a requirement for HELIOS-B, so patients had less severe disease in the Amvuttra study.
But RBC Capital Markets' Luca Issi, Ph.D., struck a more positive tone. In a Friday note, the analyst suggested that HELIOS-B is likely to succeed given it’s larger and longer than the APOLLO-B study.
Even if the trial is positive, Shu said, “what ultimately drives real-world use is clear clinical benefit in segment(s) of patients.”