Onpattro Prevents Function Decline, Boosts Life Quality in Phase 3 Study

Alnylam to seek US approval this year for ATTR amyloidosis with cardiomyopathy

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Onpattro (patisiran), a widely approved treatment for familial amyloid polyneuropathy (FAP), preserved functional ability and improved life quality for people with a related form of heart disease called transthyretin-mediated (ATTR) amyloidosis with cardiomyopathy.

That’s according to top-line results from the Phase 3 APOLLO-B clinical trial, which tested the therapy’s safety and efficacy.

Alnylam Pharmaceuticals, the company that sells Onpattro, is planning to apply for U.S. approval of therapy for ATTR amyloidosis with cardiomyopathy later this year.

“We believe the totality of the APOLLO-B study results provides a compelling clinical profile of [Onpattro] for patients and families living with ATTR amyloidosis with cardiomyopathy, a fatal, multi-system disease,” Pushkal Garg, MD, chief medical officer at Alnylam, said in a press release.

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ATTR amyloidosis are a group of disorders in which a protein called transthyretin forms toxic clumps in body tissues. This can result in nerve damage, which is typically seen in FAP, and it may also cause cardiomyopathy, a form of heart disease characterized by the heart’s muscles becoming weakened and enlarged.

“The cardiac manifestations associated with ATTR amyloidosis can have a devastating impact on patients’ lives and current treatment options are limited,” said Mathew Maurer, MD, a professor at Columbia University Irving Medical Center.

“With the rapidly progressive nature of the disease, there is a significant need for treatments like [Onpattro], which has the potential to be a new option for patients and physicians to treat the cardiomyopathy of ATTR amyloidosis,” Maurer said.

Onpattro in APOLLO-B clinical trial

Alnylam sponsored the Phase 3 APOLLO-B clinical trial (NCT03997383), which enrolled 360 participants at 69 sites across 21 countries to evaluate Onpattro in adults with ATTR amyloidosis-related cardiomyopathy.

Participants were randomly assigned to receive Onpattro (0.3 mg/kg) or a placebo, given every three weeks for a year via infusion into the bloodstream. Those who completed the yearlong study had the option to continue into an open-label extension, in which all patients are being treated with Onpattro — and monitored for long-term outcomes.

The study’s main goal was to assess the effect of treatment on physical function, measured based on the distance that patients could walk in six minutes, called the 6-MWT test. After a year, the median 6-MWT distance decreased by 8.15 meters (about 27 feet) from baseline, or the study’s start, in patients on Onpattro. That compared with a drop of 21.345 meters, or 70 feet, from baseline in the placebo group.

The median difference between the groups — 14.7 meters, or nearly 50 feet, favoring Onpattro — was statistically significant, meeting the trial’s main goal.

“It was encouraging to see the impact of [Onpattro] on functional capacity in the study, as the change from baseline in 6-MWT for [Onpattro]-treated patients was in the range of the approximately 5 meter decline typically seen in healthy older adults over a 12-month period,” Garg said.

Average scores on the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) — a measure of life quality tailored for people with heart disease — increased (improved) slightly, by 0.3 points, in patients after one year on Onpattro. By contrast, patients given the placebo experienced an average decrease of 3.4 points, a significant difference of 3.7 points favoring Onpattro.

“Health status and quality of life in [Onpattro]-treated patients was maintained relative to baseline, which is another important aspect of the potential benefit that [Onpattro] treatment may provide to patients,” Garg said.

Mean levels of NT-proBNP, a marker of heart damage, were around 20% lower in patients treated with Onpattro than in those given a placebo. Additionally, Onpattro significantly lowered transthyretin levels in the blood by a mean of 87% after one year.

“The results of the APOLLO-B Phase 3 study are impressive, as I believe they underscore the potential for [Onpattro] to provide a benefit on functional capacity and quality of life in patients living with ATTR amyloidosis with cardiomyopathy. Furthermore, these results were seen after only 12 months of treatment,” Maurer said.

Measures of mortality, hospitalization rates, and cardiac events (e.g., heart attack) generally tended to favor Onpattro, but differences from the placebo were not statistically significant. Mortality efficacy analyses did not count deaths from COVID-19, though they counted heart transplant as equivalent to death. By this definition, there were four deaths (2.2%) in the Onpattro group and 10 (5.6%) in the placebo group.

Onpattro was generally well-tolerated, with most reported adverse events (side effects) being mild or moderate in severity. The most common treatment-emergent adverse events included infusion-related reactions, joint pain, and muscle spasms. In total, five patients in the Onpattro arm and eight in the placebo arm died over the course of the study.

“With these results, we can take another important step forward towards delivering a potential new treatment to the patients who need it, assuming favorable regulatory review,” Garg said.