Long-term treatment with Onpattro (patisiran) safely and effectively halts or reverses disease progression in people with familial amyloid polyneuropathy (FAP), final data from a two-year Phase 2 trial show.
The study “A phase II, open-label, extension study of long-term patisiran treatment in patients with hereditary transthyretin-mediated (hATTR) amyloidosis,” was published in the Orphanet Journal of Rare Diseases.
FAP, also known as hereditary ATTR (hATTR) amyloidosis, is caused by mutations in the transthyretin (TTR) gene that results in the production of a faulty TTR protein. This leads to the formation and buildup of damaging TTR clumps in tissues, mainly the nerves, heart, kidneys, and eyes.
The most common symptoms of FAP are peripheral neuropathy — a loss of nerve function in the periphery of the body, including the feet, legs, hands, and arms — and autonomic neuropathy, which refers to damage to the nerves that control involuntary bodily functions such as heart rhythm, blood pressure, temperature control, and digestion.
Onpattro, an RNA interference therapy developed by Alnylam Pharmaceuticals, is designed to prevent the production of the abnormal protein by blocking TTR’s messenger RNA, the molecule generated from DNA that is used as a template in protein production.
As such, the therapy is expected to help reduce the accumulation of the harmful aggregates and ease FAP-related symptoms.
Onpattro’s safety and effectiveness was extensively evaluated in several clinical trials, including the APOLLO study, which showed that 18 months of treatment halted or reversed nerve dysfunction, and improved quality of life in most of enrolled patients.
This study enrolled 27 of 29 FAP patients who completed a Phase 2 trial (NCT01617967) designed to evaluate Onpattro’s safety and pharmacological profile.
During the extension study, Onpattro was administered directly into the bloodstream every three weeks for two years. Its main goal was to evaluate Onpattro’s long-term safety and tolerability.
Secondary goals included measures of TTR levels in the blood, and changes in nerve damage-related symptoms using the modified Neuropathy Impairment Score + 7, quality of life via the EuroQOL-5-dimension 5-level, motor function, and nutritional status.
Exploratory goals looked disease severity — using the FAP stage and polyneuropathy disability score — and patient-reported autonomic symptoms, as well as heart parameters in those with heart involvement.
Participants’ median age was 64 (range 29–77). Most patients had a medical history of gastrointestinal or kidney disorders, while 12 (44%) showed walking difficulties due to nerve damage.
A total of 25 people completed the extension trial; it ended in August 2016. The other two died of causes unrelated or unlikely to be related to treatment before its completion.
Results showed that Onpattro was generally well-tolerated, even in patients with heart or kidney involvement, and the safety profile was consistent with that seen in the APOLLO study. No new safety concerns were reported.
Most of the reported adverse effects were mild to moderate in severity, with flushing and infusion-related reactions as the most common (22% each). None of the serious (26%) and severe (19%) side effects were considered related to treatment. Onpattro-related side effects did not lead to treatment discontinuations.
Onpattro led to a fast and robust drop, by a mean of about 82%, in TTR blood levels, which was sustained across the two-year period. Notably, this resulted in a stopping or reversion of nerve damage, with 19 patients (70%) showing less nerve damage-related symptoms.
Quality of life, motor function, autonomic symptoms and disease severity all also showed stability throughout the trial. Heart parameters also remained stable in affected patients, as opposed to what is typically seen in untreated patients with heart involvement.
“In summary, these results demonstrate that long-term treatment with patisiran [Onpattro] had an acceptable benefit:risk profile, and provide further data that it may halt or reverse neuropathy progression as well as have beneficial effects on QOL [quality of life], physical functioning, autonomic symptoms, and activities of daily living by reducing TTR levels,” the researchers wrote.
Data also revealed that Onpattro leads to therapeutic benefits in a broad range of FAP patients, including those with heart involvement.
All 25 people who completed the extension trial chose to enter a global extension study (NCT02510261), which will continue to collect data on Onpattro’s long-term safety and effectiveness for an additional five years.
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