Alnylam and Sanofi today reported successful Phase III results for their rare disease RNA interference (RNAi) candidate patisiran, saying the treatment showed “highly significant” improvement in transthyretin-related hereditary amyloidosis (hATTR) patients with polyneuropathy.
In the Phase III APOLLO trial, patisiran met its primary efficacy endpoint of change from baseline in the modified neuropathy impairment score (mNIS+7) at 18 months and met all six of the study’s secondary endpoints, the companies said. APOLLO’s 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 III results for an RNAi therapeutic, marking the potential arrival of an entirely new class of medicines,” Alnylam CEO John Maraganore, Ph.D., said in a statement. “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.”
Investors appeared to share Dr. Maraganore’s enthusiasm, as Alnylam shares jumped 38% in trading this morning, to $103.74 as of 10:18 a.m., from yesterday’s closing price of $75.04
Based on APOLLO’s positive results, the companies added, Alnylam expects to file its first New Drug Application (NDA) later this year, and its first Marketing Authorisation Application in Europe shortly thereafter—while Sanofi Genzyme is preparing for regulatory filings for patisiran in Japan, Brazil, and other countries, beginning 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 elsewhere in the world.
APOLLO enrolled 225 hATTR amyloidosis patients with polyneuropathy, representing 39 genotypes, at 44 study sites in 19 countries—making it the largest randomized study ever completed in this disease, according to Alnylam and Sanofi. 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.
The mean change from baseline in mNIS+7 seen in APOLLO was significantly lower in patisiran patients compared with patients randomized to placebo. And the mean and median changes in mNIS+7 impairment scores for patisiran both achieved negative values, indicating improvement overall, and in the majority of patients, compared with baseline, Alnylam and Sanofi said.
Meeting Secondary Endpoints
The companies added that patisiran patients also showed improvement in quality of life compared to placebo, as assessed by Norfolk QOL-DN—with the treatment generating negative values in the mean and median changes in QOL scores for patisiran, indications of improvement overall and in most patients, compared with baseline.
In addition to favorable Norfolk QOL-DN scores, patisiran showed positive results in the study’s five other secondary endpoints. These include: NIS-W, the subdomain of mNIS+7 that assesses 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 intended to assess autonomic symptoms.
The study also showed patisiran with safety profile results the companies called “encouraging,” including:
- Similar frequencies of adverse events (AEs) in the patisiran and placebo arms (96.6% and 97.4%, respectively) and serious adverse events (36.5% and 40.3%, respectively).
- Similar frequency of deaths in the patisiran and placebo arms (4.7% and 7.8%, respectively).
- Fewer discontinuations from patisiran treatment (7.4%) compared with placebo (37.7%), and fewer discontinuations due to AEs from patisiran treatment (4.7%) than placebo (14.3%).
However, AEs reported in greater than 10% of patients and seen more frequently with patisiran than with placebo included peripheral edema (29.7% vs. 22.1%) and infusion-related reactions (18.9% vs. 9.1%), both of which were generally mild-to-moderate in severity.
Full results from APOLLO—including data from an exploratory analysis of a subgroup of patients with cardiac involvement—are set to be presented at the 1st European ATTR Amyloidosis Meeting for Patients and Doctors, to be held November 2 in Paris.
Nearly all eligible patients who completed APOLLO have rolled over to the APOLLO-Open Label Extension study and continue to receive patisiran, the companies said.
Patisiran is the only investigational medicine in Alnylam’s pipeline that employs a lipid nanoparticle (LNP) formulation— a small interfering RNA encapsulated in an LNP—and is administered via intravenous infusion.
“The APOLLO data suggest that patisiran could help improve the lives of people living with hATTR with polyneuropathy, a patient population in urgent need of additional treatment options,” added Elias Zerhouni, M.D., Sanofi’s president, global R&D. “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.”
