Patisiran Shows Long-Term Benefit in Hereditary ATTR With Polyneuropathy

Long-term treatment with patisiran (Onpattro) led to modest changes for people with hereditary transthyretin amyloidosis (hATTR) with polyneuropathy, data from a global open-label extension (OLE) of two trials showed.

Of 138 patients who completed the 5-year study, polyneuropathy disability scores remained stable in 55.5% and improved in 9.5%, reported David Adams, MD, PhD, of the Université Paris-Saclay in France, and co-authors.

At year 5, polyneuropathy severity — assessed by Neuropathy Impairment Scores (NIS), which can range from 0-244 — changed by an average of 10.9 points from OLE baseline on measures of muscle weakness, reflexes, and sensation, the researchers said in JAMA Neurology. In comparison, the NIS of the placebo group had worsened by 25.4 points during the 18-month parent study.

Nutritional status also improved at 5 years, as did quality of life and functional measures.

The analysis presents the longest-term data on patisiran for hATTR with polyneuropathy to date, Adams and colleagues said. It’s also the longest study of an RNA interference (RNAi) drug for any disease.

“These results highlight the importance of initiating early treatment for hATTR and the potential of RNAi therapeutics in medicine,” they wrote.

Hereditary transthyretin amyloidosis is a rapidly progressive disease caused by a mutation in the TTR gene that results in the buildup of misfolded transthyretin protein, leading to amyloid deposits in the heart, gastrointestinal tract, and peripheral nerves. Life expectancy is a median of 4.7 years after hATTR with neuropathy is diagnosed, less in hATTR patients with cardiomyopathy.

Patisiran targets and silences specific messenger RNA, potentially blocking the production of transthyretin protein before it’s made. In 2018, the FDA approved patisiran to treat hATTR with polyneuropathy. In 2023, the agency declined to expand its indication to include wild-type or hereditary ATTR cardiomyopathy.

The 5-year OLE analysis included patients from the phase III APOLLO randomized trial and a phase II OLE trial. It enrolled people in 19 countries between July 2015 and August 2017, and followed them until November 2022.

Of 212 hATTR patients who completed the parent studies, 211 enrolled in the current OLE, and 138 completed it. Participants received 0.3 mg/kg of intravenous patisiran once every 3 weeks for up to 5 years. Mean age of participants was about 61 at the OLE baseline, and 74% of participants were men.

At year 5, nutritional status — assessed by the modified body mass index (mBMI), calculated as weight in kilograms divided by height in meters squared times serum albumin in grams per liter — increased by 46.4. After starting patisiran in the global OLE, the APOLLO placebo group recovered more than half of the mBMI lost during the phase III trial.

Norfolk Quality of Life-Diabetic Neuropathy scores improved by 4.1 points at 5 years, a 94% slower rate of worsening compared with the placebo group during the parent study, the researchers pointed out. Rasch-Built Overall Disability Scale scores changed by -3.7 points, an 89% reduction in worsening rates compared with the APOLLO placebo group.

More than one in five (22.3%) patients had adverse events that led to study withdrawal. The most common treatment-related adverse events were infusion-related reactions in 16.1%.

Overall, 41 patients (19.4%) died during the study. No deaths were attributed to the study drug.

“The parent studies enrolled patients who had polyneuropathy as the predominant disease manifestation, but cardiovascular causes of death were common,” Adams and co-authors noted. “Nearly all patients who initially present with polyneuropathy will develop a mixed phenotype with cardiomyopathy within 8 years.”

Survival rates were higher in people who received patisiran in the parent studies compared with those who received placebo first, then switched to patisiran. Mortality rates per 100 patient-years were 12.8 in the APOLLO placebo group, 3.3 in the APOLLO patisiran group, 1.7 in the phase II OLE patisiran group, and 4.4 in the current OLE population.

The findings are descriptive due to the study’s open-label nature and its lack of randomization and a placebo comparator. The results are susceptible to survivorship bias, Adams and co-authors acknowledged. Selection bias also may have influenced results.