Patisiran Met Primary Endpoints in Phase 3 Hereditary ATTR (hATTR) Amyloidosis


Alnylam Therapeutics expects to file for a New Drug Application in late 2017.

mutation, Hereditary ATTR (hATTR) Amyloidosis, patisiran

The APOLLO phase 3 study of ALN-TTR02 (patisiran), an investigational RNAi therapeutic being developed for patients with hereditary ATTR (hATTR) amyloidosis with polyneuropathy, demonstrated topline results, reported Sanofi and Alnylam Therapeutics.

Patisiran met its primary efficacy endpoint and all secondary endpoints with high statistical significance.

“We believe the very encouraging APOLLO data demonstrate the potential for investigational atisiran to help improve the lives of hereditary ATTR amyloidosis polyneuropathy patients,” Akshay Vaishnaw, MD, PhD, executive vice president of Alnylam R&D, said.

The primary endpoint for the study focused on the change from baseline in the modified neuropathy impairment score (mNIS+7) at 18 months. The key secondary endpoint was improvement in quality of life assessed by the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QOL-DN).

Other secondary endpoints included measures of motor strength assessing muscle strength (NIS W), disability through the Rasch-built Overall Disability Scale (R-ODS), gait speed through a 10 meter walk test, nutritional status through the modified body mass index (mBMI) scale, and autonomic symptoms through a questionnaire (COMPASS 31).

Exploratory endpoints included assessment of cardiac function in patients with evidence of cardiac involvement at baseline, as well as measures of dermal amyloid burden and nerve fiber density in skin biopsies.

Patisiran uses the body’s natural processes to lower the levels of the TTR protein that causes TTR amyloidosis. It’s designed to target and silence specific messenger RNA, potentially blocking the production of TTR protein before it’s made.

The APOLLO phase 3 study enrolled 225 hATTR amyloidosis patients with polyneuropathy, comprised of 39 genotypes, at 44 study sites, in 19 countries around the world.

The trial is a randomized, double blind, placebo-controlled study evaluating the efficacy and safety of patisiran in hATTR amyloidosis patients with polyneuropathy.

Eligible patients include those 18—85 years old with hATTR amyloidosis, a documented TTR mutation, an investigated-estimated survival greater than 2 years, an NIS of 5–130, a polyneuropathy disability (PND) score less than or equal to IIIb and adequate biochemical liver function.

Patients were randomized 2:1 to patisiran or a placebo. Patisiran was administered intravenously at 0.3 mg/kg once every 3 weeks for 18 months, over 70 minutes.

At 18 months, the mean change from baseline in mNIS+7 was significantly lower in the patisiran group versus placebo. Patients in the patisiran group experienced improved quality of life versus the placebo, as assessed by Norfolk QOL-DN.

All other 5 secondary endpoints demonstrated statistically significant favorable differences versus placebo.

Both groups had similar frequencies of adverse effects — 96.6% for the patisiran arm and 97.4% for the placebo arm, and serious adverse effects, 36.5% and 40.3%, respectively.

The frequency of deaths in the study was also similar both the patisiran and placebo arms, 4.7% and 7.8%.

Patisiran treatment was associated with fewer discontinuations from treatment versus the placebo, 7.4% and 37.7%, and discontinuations from treatment due to adverse effects, 4.7% and 14.3%.

Based on the positive results, Alnylam expects to file its first New Drug Application (NDA) in late 2017, along with the first marketing authorization application in early 2018.

Nearly all eligible patients who completed APOLLO rolled over to the APOLLO-Open Label Extension (OLE) study, continuing to receive patisiran.

The safety and efficacy of patisiran have not yet been evaluated by the US Food and Drug Administration (FDA).

A press release was made available.

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