Risdiplam safely and significantly improved or stabilized motor function in children and young adults with spinal muscular atrophy (SMA) types 2 and 3, one-year data from the second part of the SUNFISH trial show.
As anticipated by risdiplam’s developers, these benefits were more pronounced in younger patients.
“Risdiplam is the first potential treatment to have pivotal placebo-controlled data in a broad population of patients, including children, teenagers and adults,” Eugenio Mercuri, MD, PhD, the trial’s principal investigator, said in a press release.
“We are very encouraged by the positive results in this broad group of SMA patients, many of whom are under-served and under-represented in clinical trials,” said Levi Garraway, MD, PhD, Roche’s chief medical officer and head of global product development.
The trial’s results, “SUNFISH Part 2: Efficacy and safety of risdiplam (RG7916) in patients with Type 2 or non-ambulant Type 3 spinal muscular atrophy (SMA),” were presented by Mercuri on Wednesday at the 2nd International Scientific and Clinical Congress on Spinal Muscular Atrophy, running Feb. 5–7, in Evry, France.
Risdiplam — developed by Roche and Genentech in collaboration with PTC Therapeutics and the SMA Foundation — is an oral liquid therapy designed to boost the production of SMN, the protein that is missing or produced at severely low levels in SMA patients, primarily in motor neurons but also throughout the body.
The two-part, placebo-controlled and global Phase 2/3 SUNFISH clinical trial (NCT02908685) is evaluating the safety and effectiveness of risdiplam (given orally once a day) in people with type 2 or 3 SMA ages 2 to 25.
After determining the best dose of risdiplam in 51 both ambulatory (able to walk) and non-ambulatory patients (part 1), the study is evaluating the safety and effectiveness of the selected dose for 24 months in 180 non-ambulatory patients (part 2).
With a mean age of 15.5 months at disease onset, 128 (71.1%) of the people in part 2 had been diagnosed with SMA type 2, and 52 (28.9%) with type 3. Scoliosis was present in 66.7%, and about half were male. Patients were randomized to risdiplam (120 people, optimal dose not reported) or a placebo (60) in groups that largely maintained a similar sex and SMA-type ratio.
Part 2’s primary goal (endpoint) is to assess whether risdiplam leads to greater improvements in motor function — measured through the Motor Function Measure-32 (MFM32) scale — compared to placebo after one year of treatment. An increase of at least three points on the MFM32 scale, rarely seen in SMA’s natural history, is considered clinically meaningful.
Secondary goals include the proportion of patients achieving stabilization (defined as a change in MFM32 scores equal to or greater than 0) or improvement (rise in MFM32 scores of at least three points) in motor function. Other functional measures included changes in the Revised Upper Limb Module (RULM) score, the Hammersmith Functional Motor Scale Expanded (HFMSE), and the SMA Independence Scale (SMAIS).
Of note, SMAIS measures the amount of assistance required to complete daily living activities, such as self-feeding, brushing teeth, getting dressed, or writing.
One-year data (cut-off date of Sept. 6, 2019) supported the trial achieving medically meaningful and statistically significant results in primary and main secondary goals.
Patients given risdiplam showed significantly greater improvements in motor function — reflected by significant changes in both the MFM32 and RULM scores — than those on placebo. There was also a numerical tendency favoring risdiplam over placebo in the HFMSE score, but this difference was not statistically significant.
The greatest improvements in motor function, as assessed by the MFM-32 score, were found in the youngest age group (2–5 years old), with 78.1% of risdiplam-treated patients here showing a meaningful improvement, compared with 52.9% of those on placebo, an exploratory subgroup analysis reported.
Among the oldest age group (18–25 years old), a stabilization in motor function was observed in more patients treated with risdiplam (57.1%) than in those on a placebo (37.5%). Since treatment goal in older patients is to stabilize motor function to prevent further disability, these findings are considered relevant.
Risdiplam-treated patients and their caregivers also reported gains in terms of their independence in daily tasks compared to those on placebo (where lesser independence was reported after one year). These tasks include eating a meal using hands, fork or spoon, brushing teeth, and writing or using a pen.
“The data suggest that risdiplam can preserve and potentially enable greater independence through improved motor function in people with type 2 or non-ambulant type 3 SMA,” Mercuri said.
Garraway added that SUNFISH helped the company “understand which measurement scales are the most relevant for patients, as well as the importance of stabilization in people with more established disease.”
Risdiplam’s safety profile was consistent with that reported in previous trials, with no new adverse events reported and a profile similar to that of placebo. The most commonly reported adverse events were upper respiratory tract infection (31.7%), common cold (25.8%), fever (20.8%), and headache (20%).
Serious lower respiratory tract infections occurred in more patients in the risdiplam group than placebo (10% vs. 2%) but were considered unrelated to risdiplam’s use and resolved without any treatment change.
“This was the first clinical study encompassing SMA patients representative of the population that are seen in clinical practice. Together with the positive data from the FIREFISH study in type 1 patients, these data exemplify the potential of risdiplam for all SMA patients,” Stuart W. Peltz, PhD, PTC Therapeutics’ CEO, said in his company’s press release.
The U.S. Food and Drug Administration (FDA) granted priority review to Genentech‘s application seeking risdiplam’s approval as a treatment for all SMA types in November. A decision is expected on or before May 24.
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