Data from the FIREFISH (NCT02913482), SUNFISH (NCT02908685), and JEWELFISH (NCT03032172) clinical trials were presented at the 24th International Annual Congress of the World Muscle Society, held Oct. 1-5, in Copenhagen, Denmark.
“We are excited that risdiplam has the potential to enter the market with a best-in-class profile for patients with all types of SMA,” Stuart W. Peltz, PhD, CEO of PTC Therapeutics, said in a press release.
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 in motor neurons.
Data from Part 1 (dose escalation study) of the open-label, Phase 2/3 FIREFISH trial (NCT02913482) showed that after 16 months of treatment, 14 of the 17 infants (82%) — all receiving the dose selected for the second part of the trial — had a CHOP INTEND score of 40 or greater. CHOP-INTEND, a measure for assessing motor skills of SMA type 1 infants, uses a 0–64-point scale, in which higher scores indicate better motor function. A score of 40 or greater is rarely observed in untreated infants.
Altogether, the Phase 2/3 FIREFISH trial involved 21 babies with SMA type 1. The latest results showed 86% (18 out of 21) of the infants were alive (the three deaths were unrelated to treatment), and none required tracheostomy or permanent ventilation.
Part 2 of the FIREFISH study, which recruited 41 additional type 1 SMA infants, will evaluate the safety and effectiveness of the selected dose of risdiplam for 24 months, and is expected to be concluded by September 2020.
The two-part, double-blind, placebo-controlled Phase 2/3 SUNFISH clinical trial (NCT02908685) is evaluating the safety and effectiveness of risdiplam in SMA type 2 or 3 patients between 2 and 25 years old.
Results from the first part of the study — which investigated the best dose of risdiplam — showed that treatment led to a median two-fold increase in blood SMN protein levels after four weeks of treatment. The increase was sustained for at least one year.
Independent of age or disease severity, participants showed clinically meaningful motor improvements — assessed by increases of at least three points on the Motor Function Measure-32 scale — compared with the natural history of the disease.
SUNFISH Part 2, which is set to be completed in July 2020, is evaluating the safety and effectiveness of the selected dose of risdiplam for 24 months, in 180 already enrolled participants.
Patients in the second part of the FIREFISH or SUNFISH studies will be allowed to continue treatment during an open-label extension study.
The open-label Phase 2 JEWELFISH trial (NCT03032172), which is still recruiting at locations in the U.S. and Europe, is evaluating the safety and tolerability of risdiplam in up to 180 SMA type 2 or 3 patients, ages 6 months to 60 years. Participants in this trial must have been previously treated with Spinraza (nusinersen), Zolgensma (onasemnogene abeparvovec-xioi), or olesoxime.
Interim data from 45 participants showed that risdiplam led to a sustained, greater than two-fold increase in median SMN protein over 12 months of treatment.
To date, risdiplam has been well-tolerated at all dose levels and in all clinical studies, with no treatment-related withdrawals.
“These data continue to demonstrate the disease-modifying properties of risdiplam across a broad range of ages and infants receiving the drug are continuing to experience improved motor outcomes,” Peltz said.
The safety and effectiveness of risdiplam also is being evaluated in up to 25 presymptomatic SMA type 1 babies, up to 6 weeks old, in the open-label, international, multi-center Phase 2 RAINBOWFISH study (NCT03779334). That trial, which is still recruiting, enrolled its first patient in August. More information on trial sites and contacts is available here.