Onpattro shows benefits for 1.5 years in ATTR cardiomyopathy trial
Therapy seen to slow disability progression in people with ATTR-CM
Treatment with Onpattro (patisiran) for 1.5 years leads to sustained reductions in disability progression among people with ATTR amyloidosis with cardiomyopathy (ATTR-CM), or damage to the heart.
That’s according to interim data from the ongoing open-label extension (OLE) portion of the Phase 3 APOLLO-B clinical trial (NCT03997383). That trial’s initial one-year placebo-controlled portion had shown that Onpattro slowed functional decline and improved patients’ quality of life.
Earlier this year, Alnylam Pharmaceuticals, Onpattro’s developer, applied to the U.S. Food and Drug Administration seeking the expansion of the therapy’s label — which now indicates its use for people with familial amyloid polyneuropathy (FAP) — to include ATTR-CM. A decision is expected in October.
The new study findings were presented at the Annual Congress of the Heart Failure Association of the European Society of Cardiology, held in May both in Prague, Czech Republic, and virtually.
“We are pleased to share encouraging new data from our APOLLO-B OLE study, which we believe continue to support the potential for [Onpattro] to be an important therapeutic option for patients with ATTR amyloidosis with cardiomyopathy,” Rena N. Denoncourt, vice president and TTR franchise lead at Alnylam, said in a company press release, adding, “We remain steadfast in our commitment to bring [Onpattro] to patients with ATTR amyloidosis with cardiomyopathy who currently have limited treatment options.”
Focus of APPOLLO-B study: Adults with ATTR-CM
ATTR amyloidosis are a group of disorders in which a protein called transthyretin (TTR) forms toxic clumps in body tissues. FAP, also called hereditary ATTR amyloidosis with polyneuropathy, is a form of ATTR amyloidosis marked mostly by nerve damage. ATTR-CM, meanwhile, is characterized by heart damage.
Administered via infusions directly into the bloodstream, Onpattro is an RNA interference therapy that works to reduce production of the TTR protein.
The global APOLLO-B study, launched in 2019, enrolled 360 adults with ATTR-CM who were randomly assigned to receive either Onpattro (0.3 mg/kg) or a placebo. The infusions were given once every three weeks for about a year.
The main goal of APOLLO-B was to assess changes in exercise capacity, as measured by the distance patients could walk in six minutes — a common test referred to as 6MWD. Quality of life also was measured, with the use of a standardized tool called the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS).
Those results showed that, after one year, most patients experienced a decline in 6MWD — but that decline was significantly slower for the individuals given Onpattro versus those on the placebo.
Onpattro also was superior to the placebo at significantly preventing life quality worsening. The therapy was associated with a slight improvement in KCCQ-OS scores, whereas patients given the placebo reported notably worsening life quality after one year.
Participants completing that placebo-controlled portion had the option to enroll into the study’s open-label extension, in which all are being treated with Onpattro for up to three additional years.
More benefits seen for ATTR-CM patients always on Onpattro
In a presentation titled “Patisiran Treatment for ATTR Cardiac Amyloidosis: 18-Month Results of the Phase 3 APOLLO-B Study,” researchers shared data covering six months of the OLE. Overall, the data covered 18 months, or 1.5 years, of the trial.
The results showed that, for patients always on Onpattro, the decline in 6MWD remained slow. Specifically, after 1.5 years of treatment, the average 6MWD had declined by 9.2 meters, or a bit longer than 30 feet. That was consistent with one-year findings.
Meanwhile, among patients originally assigned to the placebo, average 6MWD worsened by 25.4 meters, or longer than 83 feet, after a year on the placebo.
For the patients on the placebo, that worsening worked out to more than 12 meters, or about 40 feet, every six months, on average. By comparison, after six months of Onpattro treatment in the OLE, the average 6MWD worsened by just 5.7 meters, or slightly less than 19 feet.
Differences also were substantial for quality of life measures.
The individuals on Onpattro for the entire 1.5 years had their average KCCQ-OS scores increase by 0.2 points, suggesting generally stable life quality. In contrast, life quality scores dropped by 4 points on average among patients originally assigned to the placebo.
Group differences also were seen for levels of markers of heart stress, known as NT-proBNP, and heart injury, or troponin 1. Patients given Onpattro throughout “maintained relatively stable NT-proBNP and troponin  levels” during the study, the researchers wrote. Conversely, those originally on the placebo “showed steadily rising rates of [heart] biomarker levels up to Month 12, which then slowed or stabilised after initiation of [Onpattro].”
Rates of hospitalizations and all-cause mortality also tended to be lower among patients always on Onpattro, though the difference from the placebo did not reach statistical significance. Alnylam stressed that this study was not designed to assess the effect of treatment on these outcomes.
Importance of early treatment start
The therapy’s safety profile “was consistent with previous findings with no new safety concerns identified,” the researchers wrote. The most common treatment-related side effects were infusion-related reactions.
These data, in conjunction with the observed decline in placebo-treated patients during the [placebo-controlled] period, reinforce the importance of early treatment initiation in ATTR amyloidosis.
“The results demonstrate that [blood] TTR reduction with an RNA [interference] therapeutic has the potential to provide sustained clinical benefit through 18 months of treatment,” Denoncourt said.
“These data, in conjunction with the observed decline in placebo-treated patients during the [placebo-controlled] period, reinforce the importance of early treatment initiation in ATTR amyloidosis.”
Researchers also presented results from a posterior analysis of the trial’s placebo-controlled part in a poster titled “Effect of Patisiran Treatment in Patients with hATTR Amyloidosis with Cardiomyopathy and Polyneuropathy: Post-hoc Analysis of the APOLLO-B Study.”
The findings showed that the subgroup of patients with both cardiomyopathy and polyneuropathy — 31 in the Onpattro group and 28 in the placebo group — showed generally similar trends to the total patient population. Overall, the results favored Onpattro.