Onpattro slows FAP progression over five years in extension study
Researchers: Results underscore importance of early treatment
Five years of treatment with Onpattro (patisiran) slowed disability progression and maintained quality of life for people with familial amyloid polyneuropathy (FAP) in a long-term clinical trial, a study shows.
Although Onpattro can help delay FAP progression, “patients tend not to recover function that is lost before starting treatment,” the researchers wrote. Also, patients who started Onpattro in the original trial before entering the long-term study had better outcomes and survival than those first assigned to a placebo who switched to the therapy in the long-term trial.
“These results highlight the importance of initiating early treatment,” the researchers wrote.
The study, “Five-Year Results With Patisiran for Hereditary Transthyretin Amyloidosis With Polyneuropathy A Randomized Clinical Trial With Open-Label Extension,” was published in JAMA Neurology. It was funded by Alnylam Pharmaceuticals, Onpattro’s developer.
FAP is a genetic disorder wherein mutations in the TTR gene lead to an abnormal form of transthyretin (TTR), a protein that forms toxic clumps that accumulate mainly in the nerves outside the brain and spinal cord, causing damage.
Onpattro is an approved FAP treatment that’s classified as a gene silencer and works by reducing the production of the abnormal TTR protein. Given by infusion into the bloodstream every three weeks, it exerts its effects via RNA interference, a technology that targets the intermediary RNA molecule that’s made when the gene is read to produce the protein.
Benefits of early Onpattro treatment
Approvals of Onpattro in the U.S. and other countries were based mainly on data from a Phase 3 clinical trial called APOLLO (NCT01960348), which tested it against a placebo in more than 200 adults with FAP. After 18 months, or about 1.5 years, Onpattro-treated patients had significantly less nerve damage and related disability than those given a placebo.
Patients who completed the placebo-controlled APOLLO study or earlier Phase 2 open-label extension (OLE) studies of Onpattro had the option to enter into a five-year OLE study (NCT02510261). The study included 211 patients: 49 in the APOLLO placebo group, 137 in the APOLLO Onpattro group, and 25 in Phase 2 OLE Onpattro groups. All were treated with Onpattro and monitored for long-term outcomes, Five years of follow-up was completed by 138 participants.
“Here, we present the final results from the global OLE study, the longest experience to date of a TTR gene silencer in adults with [FAP], in which some patients received [Onpattro] for up to [seven] years,” the researchers wrote.
Five-year data showed that patients’ polyneuropathy disability score, a measure of disability based on walking skills, was sustained in 55.5% of evaluable patients and improved in 9.5% of patients compared with the start of the global OLE study.
Long-term mortality in the overall population was lower than expected from natural history and much lower among patients receiving early treatment in the parent studies, underscoring the adverse impact of delaying treatment
By the end of the OLE study, only nine patients required a wheelchair to get around, four of whom already needed a wheelchair at the study’s start. Also, 46% of the patients could still walk unaided and 47.4% needed an aid like a cane or crutches to walk.
Average scores on the Neuropathy Impairment Score (NIS), a measure of disability related to nerve damage, worsened by an average of 10.9 points during the five-year extension study. To put that in perspective, in patients given a placebo during APOLLO, this score worsened by 25.4 points over 1.5 years, suggesting a slowing in NIS worsening by roughly 87% when these patients switched to Onpattro in the OLE study.
Measures of disease progression
Scores on the Norfolk QOL-DN, a measure of life quality, worsened by 4.1 points over five years, while patients in the APOLLO placebo group showed a score worsening of 19.8 points over 1.5 years, suggesting a 94% slower worsening rate with Onpattro.
Other measures of functional ability, along with nutrition, generally showed similar trends.
“Across multiple measures, the APOLLO placebo group experienced substantial disease progression over 18 months while receiving placebo, which was [lessened] over [five] years of [Onpattro] treatment,” the researchers wrote. “The phase 2 OLE and APOLLO [Onpattro] groups, which received [Onpattro] for up to [seven] years, demonstrated the greatest benefit and sustained clinical stability.”
Forty-one patients (19.4%) died during the study. Statistical analyses showed that a higher FAP stage (reflecting worse disability) and starting Onpattro treatment later, at entry in the OLE study, were each significantly associated with a five times higher chance of death during the OLE study.
“Long-term mortality in the overall population was lower than expected from natural history and much lower among patients receiving early treatment in the parent studies, underscoring the adverse impact of delaying treatment,” the scientists wrote.
No new safety issues were noted during the extension study. The most common side effect was infusion reactions.
“In a disease characterized by unrelenting decline, the results depict the long-term clinical stability afforded by TTR reduction and the long-term safety of [Onpattro] treatment,” and provide “compelling evidence for the capacity of [Onpattro] treatment to improve survival,” the researchers wrote.
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