Risdiplam Succeeds in Treating Type 1 Babies with FIREFISH Meeting Main Goal, Genentech Says

Genentech announced, without providing details, positive topline results from the pivotal second part of its FIREFISH clinical trial of risdiplam, now before the U.S. Food and Drug Administration for approval.

The company said in its release that risdiplam demonstrated statistically significant and medically meaningful motor milestone improvement in infants with type 1 SMA, meeting the study’s primary endpoint or goal of sitting upright without support.

Risdiplam’s use also did not raise new safety issues or cause anyone to withdraw from the trial.

If approved by the FDA, risdiplam would be the first oral and “at home” treatment for spinal muscular atrophy (SMA), and the second to work by boosting the ability of the SMN2 gene to produce the functional SMN protein essential to muscle health.

The FIREFISH study (NCT02913482) is evaluating risdiplam, given as a liquid, to infants ages 1 to 7 months old with type 1 SMA. The study consists of two parts.

Part 1 assessed risdiplam’s safety in 21 babies, and determined the proper dosage for part 2. Part 2 is looking at efficacy in another 41 infants, with a primary goal of a significant percentage being able to sit without support for at least five seconds after 12 months of treatment, as determined by the Gross Motor Scale of the Bayley Scales of Infant and Toddler Development — Third Edition (BSID-III).

Secondary measures in part 2 will include, after two years of treatment, measures of blood levels of the SMA protein, and changes in motor function (a measure of muscle health) using the BSID-III and other standard tests.

This trial is expected to largely finish in November, and includes an open-label and long-term extension study.

Genentech intends to detail data from the FIREFISH study at an upcoming medical conference.

Infants with type 1 SMA have poor muscle tone and experience difficulties moving, swallowing, and breathing. Most do not live past age 2, usually because of respiratory failure.

Risdiplam — developed by Roche and Genentech in collaboration with PTC Therapeutics and the SMA Foundation — is 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.

Because risdiplam is taken orally, it can be easily taken at the home with minimal assistance. This is in contrast to Spinraza (nursinersen), one of the two currently approved medications for SMA, which has a similar mechanism of action to risdiplam but is administered as an injection into the spinal fluid of the lower back.

“This large, global trial confirms the efficacy of risdiplam in an advanced and difficult-to-treat population, including many infants whose disease had already progressed significantly before starting treatment,” Levi Garraway, MD, PhD, Genentech’s chief medical officer and head of Global Product Development, said in a press release.

A number of other clinical trials are also investigating risdiplam in other SMA patient populations.

SUNFISH (NCT02908685) is a two-part Phase 2/3 study assessing motor function improvement in people 2 to 25 years old with type 2 or 3 SMA.

Part 1 was designed to determine the best dose of risdiplam for SUNFISH’s second part. 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 ambulatory (able to walk) and non-ambulatory patients.

Part 2, evaluating the safety and effectiveness of the selected dose for 24 months in 180 non-ambulatory patients, also met its primary goal, Genentech said in its release. That endpoint is the change from the study’s start (baseline) to one year of treatment in Total Motor Function Measure 32 (MFM-32) scores, measures focused on upper and lower limb strength, and hand, finger and neck muscle strength.

As with FIREFISH, Genentech plan to report detailed data from this trial’s second part at an upcoming medical conference.

JEWELFISH (NCT03032172) is an open-label Phase 2 exploratory trial to assess the safety, tolerability, and pharmacokinetics/pharmacodynamics in people with SMA type 1, 2 or 3, ages 6 months to 60 years, who have been previously treated with Spinraza, the gene therapy Zolgensma (onasemnogene abeparvovec-xioi), or olesoxime. Recruitment for JEWELFISH is ongoing, but nearing completion. More information can be found here.

RAINBOWFISH (NCT03779334) is an open-label Phase 2 trial investigating risdiplam’s efficacy, safety, pharmacokinetics/pharmacodynamics in babies from birth to 6 weeks of age at first dose, who are genetically diagnosed with SMA but not yet showing symptoms. This study is actively recruiting. More information can be found here.

To date, more than 400 people have been treated with risdiplam across all these studies, with no reported treatment-related safety issues, Genentech said.

An early access program for risdiplam has begun in Europe for people with SMA type 1. An access program for those with type 2 is expected to open in Europe later this year.

A decision on risdiplam’s approval in the United States is expected from the U.S. Food and Drug Administration on or before May 24.