Sanofi Genzyme, the specialty care global business unit of Sanofi, and Alnylam Pharmaceuticals, the leading RNAi therapeutics company announced that the APOLLO Phase 3 study of patisiran, an investigational RNAi therapeutic being developed for patients with hereditary ATTR amyloidosis with polyneuropathy, met its primary efficacy endpoint and all secondary endpoints. The primary endpoint for the study was 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).

"We are very proud to report the first ever positive Phase 3 results for an RNAi therapeutic, marking the potential arrival of an entirely new class of medicines. This moment is the culmination of a 15-year journey of tireless work by countless contributors who have overcome enormous scientific and business challenges to make RNAi therapeutics a reality," said John Maraganore, Ph.D., Chief Executive Officer of Alnylam. "This is an incredibly exciting milestone for Alnylam and RNAi, and most importantly for patients and their treating physicians and families. We extend our deepest gratitude to all the patients, investigators and study staff who participated in the APOLLO study - they made this important scientific progress possible."

The APOLLO trial enrolled 225 hATTR amyloidosis patients with polyneuropathy, representing 39 genotypes, at 44 study sites in 19 countries around the world. Patients were randomized 2:1 to patisiran or placebo, with patisiran administered intravenously at 0.3 mg/kg once every three weeks for 18 months. For both the mNIS+7 and Norfolk QOL-DN endpoint measures provided below, a lower score indicates a better clinical result.

At 18 months, the mean change from baseline in mNIS+7 was significantly lower in the patisiran group as compared with placebo (p less than 0.00001). The mean and median changes in mNIS+7 impairment scores for patisiran both achieved negative values, indicating an improvement overall and in the majority of patients compared with baseline. Patients in the patisiran group experienced improvement in quality of life compared to placebo, as assessed by the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QOL-DN) (p less than 0.00001).

The mean and median changes in QOL scores for patisiran also both achieved negative values, indicating an improvement overall and in the majority of patients compared with baseline. All five other secondary endpoints also demonstrated statistically significant favorable differences in the patisiran arm compared to placebo (p less than 0.001). These were: NIS-W, the subdomain of mNIS+7 assessing muscle strength; Rasch-built Overall Disability Scale (R-ODS), a patient reported outcome measure of daily living and disability; 10-meter walk test, assessing gait speed; Modified body mass index (mBMI), assessing nutritional status; and COMPASS-31, a questionnaire to assess autonomic symptoms. The overall safety profile of patisiran was encouraging.

The patisiran and placebo arms had similar frequencies of adverse events (AEs) (96.6 percent and 97.4 percent, respectively) and serious adverse events (SAEs) (36.5 percent and 40.3 percent, respectively). The frequency of deaths in the study was similar in the patisiran (4.7 percent) and placebo (7.8 percent) arms. Patisiran treatment was associated with fewer discontinuations from treatment compared with placebo (7.4 percent and 37.7 percent, respectively) and discontinuations from treatment due to AEs (4.7 percent and 14.3 percent, respectively).

AEs reported in greater than 10 percent of patients and seen more frequently with patisiran compared with placebo were peripheral edema (29.7 percent vs. 22.1 percent, respectively) and infusion-related reactions (18.9 percent vs. 9.1 percent, respectively), both of which were generally mild-to-moderate in severity.

"Patients living with hATTR amyloidosis face an inevitable and painful advancement of their debilitating disease," said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President, R&D of Alnylam. "We believe the very encouraging APOLLO data demonstrate the potential for investigational patisiran to help improve the lives of hereditary ATTR amyloidosis polyneuropathy patients. Our immediate objective is now to submit these data to global health authorities."

Based on these positive results, Alnylam expects to file its first New Drug Application in late 2017 and first Marketing Authorisation Application shortly thereafter. Sanofi Genzyme is currently preparing for regulatory filings for patisiran in Japan, Brazil and other countries, to begin in the first half of 2018.  Pending regulatory approvals, Alnylam will commercialize patisiran in the U.S., Canada and Western Europe, with Sanofi Genzyme commercializing the product in the rest of the world.

"This is a significant milestone that supports our belief that RNAi therapeutics have the potential to become an innovative new class of medicines for patients with rare genetic diseases," said Elias Zerhouni, M.D., President, Global R&D, Sanofi. "The APOLLO data suggest that patisiran could help improve the lives of people living with hATTR amyloidosis with polyneuropathy, a patient population in urgent need of additional treatment options. We look forward to working with Alnylam to make patisiran available around the globe as quickly as possible."

Full results, including data from an exploratory analysis of the subgroup of patients with cardiac involvement, will be presented at the 1st European ATTR Amyloidosis Meeting for Patients and Doctors, on November 2,2017 in Paris, France.

APOLLO is the largest randomized study ever completed in this disease. Nearly all eligible patients who completed APOLLO have rolled over to the APOLLO-Open Label Extension (OLE) study and continue to receive patisiran.

The APOLLO Phase 3 study is a randomized, double blind, placebo-controlled, global study designed to evaluate the efficacy and safety of patisiran in hATTR amyloidosis patients with polyneuropathy. The primary efficacy endpoint was change from baseline in the mNIS+7 composite neuropathy impairment score at 18 months. Modified NIS+7 is a composite measure of neurologic impairment that evaluates sensorimotor capabilities, nerve conduction, reflexes, and autonomic function. Secondary endpoints included the Norfolk QOL DN quality of life score as well as measures of motor strength (NIS W), disability (R ODS), gait speed (10 meter walk test), nutritional status (mBMI) and autonomic symptoms (COMPASS 31). Exploratory endpoints included cardiac measures in patients with evidence of cardiac involvement at baseline as well as measures of dermal amyloid burden and nerve fiber density in skin biopsies.