Risdiplam, Potential Oral Therapy for All SMA Types, Granted Priority FDA Review

The U.S. Food and Drug Administration (FDA) accepted Genentech‘s application requesting approval for risdiplam, its potential oral treatment for all types of spinal muscular atrophy (SMA), and gave it priority review.

An agency decision is expected on or before May 24, 2020.

If approved, risdiplam would become the second disease-modifying SMA therapy that works by increasing the ability of the SMN2 gene to produce functional SMN protein that’s essential to muscle health.

But risdiplam is an orally administered liquid — unlike Spinraza (nusinersen), an SMN2 splicing therapy by Biogen that became the first targeted SMA to win FDA approval in late 2016. As such, it could become the first “at-home” treatment for SMA patients, Genentech said in a press release.

It is being developed by Roche and Genentech (a member of the Roche group), in collaboration with PTC Therapeutics and the SMA Foundation.

Risdiplam’s approval request is supported by data from the ongoing FIREFISH and SUNFISH trials, which are treating SMA type 1, 2, and 3 patients between the ages of 1 month and 25 years.

“The FIREFISH and SUNFISH trials were designed to represent the real world spectrum of people living with SMA and include many people previously underrepresented in clinical trials,” said Levi Garraway, MD, PhD, Roche’s chief medical officer and head of Global Product Development.

“We look forward to working closely with the FDA to explore broad access to risdiplam for all individuals in the community who might benefit,” Garraway added.

In the open-label and two-part Phase 2/3 study called FIREFISH (NCT02913482), 21 type 1 infants ages 1–7 months were given various doses of risdiplam to find the best dose in part one; 14 of the 17 who received what became the optimal dose showed a CHOP INTEND score of 40 or greater after 16 months of treatment, researchers reported at an October science conference. Treatment was also found to be safe and well-tolerated.

CHOP-INTEND, a measure of motor skills for SMA type 1 infants, works on a 0 to 64-point scale with higher scores indicating better motor function. A score of 40 or greater is rarely observed in untreated SMA infants.

An additional 41 type 1 infants were enrolled for part two of FIREFISH, and were treated with risdiplam for up to 24 months. This trial is expected to finish in September 2020, and includes an open-label and long-term extension study.

SUNFISH (NCT02908685) is a two-part, double-blind, and placebo-controlled Phase 2/3 trial in children and young adults (ages 2–25 ) with type 2 or 3 SMA. Part one, in 51 ambulatory (able to walk) and non-ambulatory (cannot walk) patients, established the best safe dose for its second part.

Results released in May also showed that treatment with risdiplam led to a more than two-fold increase in median SMN protein blood levels after four weeks, which was sustained for one year. Meaningful gains in motor abilities were likewise evident.

Part 2 is evaluating the safety and effectiveness of the optimal dose over 24 months of treatment in 180 non-ambulatory patients.

It recently met its primary goal of improvements in motor function — measured through the Motor Function Measure-32 (MFM32) scale — in treated patients compared to those given a placebo after one year.

The MFM32 scale is a validated 32-item test of motor function changes in a broad range of people with neuromuscular diseases, including SMA. Higher scores again indicate better motor function. An increase of at least three points on the MFM32 scale, which is rarely seen in SMA’s natural history, is considered clinically meaningful.

Risdiplam’s safety profile in SUNFISH was consistent with other studies, and no patients have withdrawn from any risdiplam trial due to its side effects or other treatment-related safety concerns, Genentech said.

Two Phase 2 trials — JEWELFISH (NCT03032172) and RAINBOWFISH (NCT03779334) — are also evaluating risdiplam’s effectiveness in SMA types 1, 2, and 3. Both these studies are still recruiting; more information for JEWELFISH (ages 6 months to 60 years, and previously treated with an SMA therapy) is available here, and for RAINBOWFISH (presymptomatic up to 6 weeks old) here.

SMA is caused by mutations in the SMN1 gene, which leads to insufficient levels of the survival motor neuron (SMN) protein. A second survival motor neuron gene (SMN2), with an identical sequence, can ease the damage done by the mutation, but only to a very limited degree. This gene produces a shorter and unstable protein in nature.

Risdiplam, a small molecule given orally as a systemwide treatment, is an SMN2-directed splicing modifier designed to improve that gene’s ability to produce functional SMN protein in motor neurons and throughout the body.

Spinraza works much the same way, and is given as an intrathecal injection into the spinal cord. Treatment is once every four months after an initial loading dose.

The FDA grants priority review to a potential therapy it considers as having the potential to significantly improve the safety and effectiveness of the treatment, prevention, or diagnosis of a serious disease.

Risdiplam was named an orphan drug by the FDA in January 2017, and placed on a fast track in April 2017, both designations intend to assist and speed its development and possible approval.

Genentech will be responsible for marketing risdiplam in the U.S. should the FDA favor its approval.