Onpattro (patisiran) results in sustained improvements in polyneuropathy, quality of life, and other symptoms among people with familial amyloid polyneuropathy (FAP), while showing an acceptable safety profile, according to a one-year interim analysis from an open-label extension clinical trial.
The study, “Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy: 12-month results of an open-label extension study,” was published in The Lancet Neurology. It was funded by Alnylam Pharmaceuticals, which markets Onpattro.
FAP, also known as hereditary ATTR amyloidosis with polyneuropathy, is caused by mutations in the TTR gene. These mutations lead to the production of faulty TTR proteins, which form toxic deposits in tissues.
An RNA interference (RNAi) therapy, Onpattro is designed to prevent the production of the abnormal form of TTR by blocking its messenger RNA or mRNA. mRNA is the molecule made from the mutated TTR gene that encodes the instructions for making the faulty TTR protein.
Onpattro has been approved to treat adults with FAP in the U.S., Europe, Japan, Canada, Switzerland, and Brazil. These approvals were based on positive results from the global APOLLO Phase 3 clinical trial (NCT01960348), in which participants with FAP were given either Onpattro or a placebo.
Participants who completed APOLLO were eligible to enroll in an ongoing, open-label extension (OLE) study (NCT02510261), in which all patients are being given the active medication. It is administered by infusion into the bloodstream every three weeks, at a dose of 0.3 mg/kg.
This OLE study, planned to continue for a total of five years, also included some participants who had been in a previous Phase 2 extension study (NCT01961921).
Researchers from Alnylam and other institutions now reported data from participants in the OLE who had been treated for at least 12 months (one year). This included 126 participants who had originally been given Onpattro in APOLLO, 38 who had originally been given a placebo in APOLLO, and 25 from the previous extension study.
Most of the participants were white (79%) or Asian (18%), and most were male (74%). These patients had received the medication for a mean of 20.5 months, and the majority (63%) had received all planned doses (the rest missed at least one dose).
“To our knowledge, patients in this study have had the longest treatment duration with an RNAi therapeutic to date,” the researchers wrote.
Among trial participants who had been on Onpattro prior to starting the OLE, the benefits seen in the previous trials were sustained after a year in the extension study. Compared with before they started therapy, mean scores on the modified Neuropathy Impairment Score +7 (mNIS+7) decreased by four points for those who had been on Onpattro in APOLLO, and by 4.7 points for those who had been in the Phase 2 extension study.
Of note, mNIS+7 is a measure of polyneuropathy, with decreasing scores indicating easing symptoms.
Participants who had been on placebo in APOLLO, who started Onpattro upon enrollment in the OLE, saw their mean mNIS+7 scores decrease by 1.4 points, suggesting a lack of disease progression.
However, scores were still higher than they had been before APOLLO, because participants given a placebo in that trial experienced disease progression during the study. This supports the use of Onpattro in earlier stages of the disease, the researchers noted.
Similar trends were seen for measures of quality of life, autonomic function, nutritional status, and disability. Participants who had already been on Onpattro generally maintained their benefits. Those who had been on a placebo experienced some benefits, but their scores were still generally worse than they had been prior to APOLLO.
Among participants who had been on placebo before the OLE, blood TTR levels decreased by a mean of 78.7% after six months on Onpattro.
Of the 211 total participants in the OLE, nearly all (97%) reported at least one adverse event. The most common were mild or moderate infusion reactions, which affected 12% of participants. Such reactions were more common in participants who had previously been on a placebo.
Serious adverse events occurred in 82 participants, including over half of those who had previously been on a placebo. Most of these were heart-related events deemed unrelated to Onpattro treatment. Two participants had serious events that were deemed related to treatment: one instance of abdominal discomfort, and one of systemic inflammatory response syndrome.
There were 23 deaths during the study. All were attributed to the underlying FAP, and most (13) occurred in participants previously on placebo. Statistical analyses indicated that Onpattro treatment significantly reduced mortality rates.
Overall, the findings, “show a continued benefit with patisiran [Onpattro] in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. The current data also underscore the importance of patisiran treatment early in the disease course,” the researchers concluded.
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