Risdiplam Continues to Show Promise for Treating SMA, Data Show

Risdiplam continues to sustain high levels of the SMN protein and improve motor function in children and young adults with spinal muscular atrophy (SMA) types 2 and 3, two-year data from the first part of the SUNFISH trial show.

It also safely and effectively raises SMN levels in patients previously treated with other disease-modifying therapies, according to preliminary one-year data from the JEWELFISH trial, which has completed enrollment.

“These 24-month exploratory data are important as they are consistent with the medically meaningful results we saw after one year in Part 2 of the SUNFISH study, designed to represent a broad, real-world SMA population,” Levi Garraway, MD, PhD, Roche’s chief medical officer and head of global product development, said in a press release.

“We are also encouraged to see an increase in SMN protein levels across both the SUNFISH Part 1 and JEWELFISH studies. These data reinforce the potential of risdiplam to make a real difference in the lives of the many people living with SMA,” he added.

These findings were recently presented at the Cure SMA Annual Conference which was held virtually.

Risdiplam — developed by Roche and Genentech in collaboration with PTC Therapeutics and the SMA Foundation — is an oral liquid therapy designed to boost SMN production, which is impaired in SMA patients.

SMN, a protein present in virtually every cell in the body, is involved in several cellular processes and essential for motor neuron and muscle health.

Risdiplam is under regulatory review for the treatment of all SMA types in eight countries, including the U.S., where a decision is expected on or before Aug. 24. Filing of a similar marketing application to the European Medicines Agency may be imminent.

The two-part, multicenter, placebo-controlled Phase 2/3 SUNFISH study (NCT02908685) is evaluating the safety and effectiveness of risdiplam (given once a day) in SMA type 2 or 3 patients, ages 2 to 25 years.

Part 1 determined the best risdiplam dose — focusing on achieving a sustained twofold increase in SMN levels — for the second part of the study in 51 ambulatory (able to walk) and non-ambulatory patients, some with scoliosis or joint contractures.

After the 12-week, dose-finding stage, all patients were moved to the therapeutic dose.

Previous Part 1 data showed that risdiplam led to a median twofold increase in SMN blood levels after four weeks of treatment, which was sustained for at least a year. It also resulted in clinically meaningful motor improvements (assessed with the Motor Function Measure-32 or MFM32 scale), compared with the natural course of the disease.

MFM32 is a validated test to measure motor skills — from sitting, standing, and walking to use of hands and fingers — across a range of patients with neuromuscular diseases, including SMA.

Newly-presented two-year data showed that risdiplam resulted in sustained SMN levels and in significantly greater motor improvements (by a mean of 3.99 points in MFM32), compared with SMA’s natural course.

These findings were consistent with one-year data from SUNFISH Part 2 in 180 non-ambulatory patients showing that MFM32 changes were significantly greater (by a mean of 1.55 points) in risdiplam-treated patients than in those on placebo, meeting the trial’s primary goal.

Part 1’s most frequently reported adverse events included fever (55%), cough (35%), vomiting (33%), upper respiratory tract infections (31%), cold (24%), and sore throat (22%). Pneumonia (5%) was the most common serious adverse event.

The open-label Phase 2 JEWELFISH trial (NCT03032172) is assessing risdiplam’s safety, tolerability, pharmacokinetics (uptake, distribution, and elimination in the body), and pharmacodynamics (its effects on the body) in type 1, 2, and 3 SMA patients, ages 6 months to 60 years, who were previously treated with other SMA therapies.

Among the 174 patients enrolled, 84 were previously treated with Genentech’s investigational compounds (including olesoxime), 76 with Spinraza (by Biogen), and 14 with the gene therapy Zolgensma (by Novartis).

Data from the 18 patients who already completed one year of treatment demonstrated a median twofold increase in SMN protein levels. The most common adverse events were upper respiratory tract infections (13%), headache (12%), fever (8%), diarrhea (8%), common cold (7%), and nausea (7%).

No treatment discontinuations due to risdiplam-related side effects were reported in either trial. The therapy’s safety profile in JEWELFISH was similar to that reported in other risdiplam trials of patients not previously treated with an SMA-targeting therapy.

These findings are “clinically meaningful with a favorable safety profile,” reinforcing “the potential of risdiplam as a differentiated, oral therapy to improve motor function for children and adults with SMA,” Stuart Peltz, PhD, PTC’s co-founder and CEO, said in a separate press release.

“We anticipate that risdiplam will be a new and meaningful at-home treatment for a broad range of people affected by this devastating disease,” he added.

A separate risdiplam trial, called RAINBOWFISH (NCT03779334), is still enrolling newborns up to 6 weeks old with a genetic diagnosis of SMA but no evidence of symptoms at a dozen sites across eight countries, including the U.S.