Rare Disease Report

NDA Filing for Promising RNAi Therapy for Amyloidosis Expected Soon

SEPTEMBER 20, 2017
James Radke
The Phase 3 clinical trial testing patisiran to treat ATTR amyloidosis with polyneuropathy has met its primary endpoint.

Based on the results, the sponsors of the drug—Alnylam Pharmaceuticals and Sanofi Genzyme—expect to submit regulatory filings shortly. A New Drug Application (NDA) is expected to be filed in late 2017 and a Marketing Authorization Application for Europe will be filed soon thereafter.

ATTR amyloidosis is a progressive genetic disease resulting in the misfolding of transthyretin (TTR) proteins, which, in turn, creates amyloid fibrils that deposit in different organs.

In ATTR amyloidosis with polyneuropathy, the amyoid deposits affect the peripheral or autonomic nerves. Common symptoms with ATTR amyloidosis with peripheral neuropathy may include numbness, tingling, pain, weakness, and loss of sensations. Common symptoms with ATTR amyloidosis with autonomic neuropathy may include postural hypotension, urinary retention, impotence, body temperature irregularities, and gastrointestinal problems.

In the Phase 3, APOLLO trial, 225 ATTR amyloidosis patients with polyneuropathy were randomized 2:1 to patisiran (0.3 mg/kg every 3 weeks) or placebo for 18 months.

The primary endpoint was change from baseline in the modified neuropathy impairment score (mNIS+7) and the study observed a very significant improvement in the mNIS+7 scores (P < .00001).

Patisiran is an RNA interference (RNAi) drug. It essentially blocks the production of mutated mRNA being produced in patients with HHT amyloidosis and thereby reduced the accumulation misfolded TTR proteins.

While exact numbers have not yet been provided, Akshay Vaishnaw, M.D., Ph.D, vice president of R & D at Alnylam noted in a webcast this morning that mean and median mNIS scores in the patisiran treated group reached negative values, indicating that the drug is effective in reducing neuropathy. Several secondary endpoints measuring quality of life, disability, body mass index, walking and gait speed, were also significantly improved in the patisiran treated group.

The drug was well-tolerated with only 7.4% of patients discontinuing treatment due to the adverse events (AE). In the placebo group, 37.7% discontinued treatment.

The most common AEs seen more frequently with patisiran compared with placebo were peripheral edema (29.7% vs. 22.1%, respectively) and infusion-related reactions (18.9% vs. 9.1%, respectively).

The Phase 3 APOLLO data is the first trial to reach this level of clinical development and the company is justifiably pleased.

In a news release, 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.”

Dr. Vaishnaw, added, “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.”

Pending regulatory approvals, Alnylam will commercialize patisiran in the U.S., Canada and Western Europe and Sanofi Genzyme will commercialize the product elsewhere.

Elias Zerhouni, M.D., President, Global R&D, Sanofi said, “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.”

Wall Street seems happy with the news today, too. Investors who took a hit earlier this month when Alnylam’s clinical program for hemophilia was suspended will be excited to hear that Alnylam stock has risen 40% since this new information was released.

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