“The positive outcome of this trial is an important milestone for people with type 2 or 3 SMA, too many of whom remain untreated,” Levi Garraway, MD, PhD, said in a press release. Garraway is Roche’s chief medical officer and head of global product development.
SMA is caused by mutations in the SMN1 gene, which leads to a reduction in the load of 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.
Risdiplam — developed by Roche and Genentech in collaboration with PTC Therapeutics and the SMA Foundation — is an oral therapy designed to boost the ability of the SMN2 gene to produce a functional SMN protein not only in motor neurons, but also throughout the body.
The two-part, placebo-controlled, multi-center, Phase 2/3 SUNFISH clinical trial (NCT02908685) is evaluating the safety and effectiveness of risdiplam (given once a day) in SMA type 2 or 3 patients aged 2 to 25 years.
SUNFISH Part 1 was designed to determine the best dose of risdiplam for the second part of the study. It assessed the safety, tolerability, pharmacokinetics (uptake, distribution, and elimination in the body), and pharmacodynamics (effects on the body) of several doses of risdiplam for 12 weeks in 51 patients both ambulatory (able to walk) and non-ambulatory (cannot walk).
Part 2 is evaluating the safety and effectiveness of the selected dose for 24 months in 180 non-ambulatory patients. Its primary goal is to assess whether risdiplam induced greater improvements in motor function — measured through the Motor Function Measure-32 (MFM32) scale — than a placebo after one year of treatment.
The MFM32 scale is a validated 32-item test to detect motor function changes in a broad range of patients with neuromuscular diseases, including SMA, and where higher scores 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.
After either part of the study, participants will be able to continue treatment with the selected dose during an open-label extension phase.
Previous results from Part 1 showed that risdiplam led to a median two-fold increase in blood SMN protein levels after four weeks of treatment — which was sustained for at least a year — and to clinically meaningful motor improvement (assessed with the MFM32 scale) compared with the natural history of the disease.
Now, Genentech announced that Part 2 met its primary goal, with participants showing improvements in motor function after one year of treatment with risdiplam, compared with a placebo.
The interim data also confirmed the consistent safety profile of risdiplam in previous trials, with no new adverse side effects identified. To date, there have been no treatment-related adverse events leading to treatment discontinuation in any risdiplam trial.
“SUNFISH is the largest placebo-controlled study ever undertaken in type 2 or 3 SMA patients. We thank the SMA community for their partnership and look forward to sharing these results with regulators and bringing risdiplam to people living with this condition,” Garraway said.
The company also plans to present detailed SUNFISH Part 2 data at an upcoming medical congress.
In addition to SUNFISH, another Phase 2/3 trial (FIREFISH, NCT02913482) and two still-recruiting Phase 2 studies (JEWELFISH, NCT03032172, and RAINBOWFISH, NCT03779334) are evaluating the effectiveness of risdiplam in people with SMA types 1 (pre-symptomatic and symptomatic), 2, and 3.
Risdiplam is being studied in a broad real-world spectrum of people living with SMA, from birth to 60 years old, including patients previously treated with other SMA-targeting therapies.