The dawn of RNA interference drugs

11 years after Andrew Fire and Craig Mello earned the 2006 Nobel Prize in Physiology or Medicine for their work on RNA interference and 19 years after they actually wrote the paper which earned them the price, the first commercially available therapy based on their groundbreaking work is about to become reality. So just weeks after the first approval of a CAR-T construct by the FDA, another breakthrough technology is about to transform the treatment of genetic disorders.

Alnylam today announced that its investigational RNAi therapeutic called patisiran met all its primary endpoint in a phase III trial which measured modified neuropathy impairment score of patisiran versus placebo in hATTR amyloidosis patients with polyneuropathy. Hereditary transthyretin-mediated (hATTR) amyloidosis is an inherited, progressively debilitating disease caused by mutations in the TTR gene. These mutations cause abnormal amyloid proteins to accumulate and damage body organs and tissue, such as the peripheral nerves and heart. The incidence of the disease is estimated to be between 5 and 13 per million per year. As per press release:

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 5 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.

Given the surprisingly benign side effect profile, it is fair to assume that the in-human proof of concept of the technology has been achieved and that more RNAi treatments will find their way to commercialization in due course. It’s probably just a matter of time until companies like Silence Therapeutics or Arrowhead Pharma come up with their own success stories.