Spinal Muscular Atrophy Drug Risdiplam Proves Success in Infants

This article was originally published on NeurologyLive.

PTC Therapeutics shared data from part 1 of the FIREFISH study (NCT02913482) evaluating risdiplam (Evrysdi; PTC Therapeutics) in infants with symptomatic type 1 spinal muscular atrophy (SMA).

Patients treated with risdiplam at 12 months demonstrated significant improvement in survival and developmental milestones, with 19 of 21 (90%) infants able to survive without permanent ventilation and 7 (41%) infants able to sit without support for at least 5 seconds (Gross Motor Scale of Bayley Scales of Infant & Toddler Development Edition 3 [BSID-3]). Increased levels of survival motor neuron (SMN) protein were also observed.

"The positive data published in the New England Journal of Medicine reinforces the benefits of Evrysdi and substantiates over a decade of work building our splicing platform to develop treatments for patients with diseases of high unmet medical need, like SMA," said Stuart W. Peltz, PhD, chief executive officer, PTC Therapeutics, in a statement. "We believe the platform has broad potential for a large number of target genes across many disease areas."

Risdiplam is an SMN2-directed RNA splicing modifier designed to treat SMA caused by mutations in chromosome 5q that lead to SMN protein deficiency. Risdiplam is administered daily at home in liquid form by mouth or feeding tube. It was approved for the treatment of SMA in adults and children 2 months and older in August 2020.

FIREFISH Evaluation in Infants With SMA

FIREFISH is an open label, 2-part clinical trial. In part 1, researchers investigated dose-escalations of risdiplam in 21 infants, 4 of which were in a low-dose cohort treated with a final dose of 0.08 mg per kg per day at month 12, and 17 of which were in a high-dose cohort treated with a final dose of 0.2 mg per kg per day at month 12. The infants had a median age of 6.7 months at enrollment (range, 3.3-6.9). At symptom onset, these infants ranged from 28 days to 3.0 months of age.

The researchers, including first author Giovanni Baranello, MD, PhD, developmental neurology unit, Carlo Besta Neurological Research Institute, Milan, Italy, found that the baseline median SMN protein concentration in the blood increased from 1.31 ng per mL (range, 0.58-4.82) at baseline to 3.05 ng per mL (range, 1.75-5.51) in the low-dose cohort at 12 months. A similar increase was seen in the high-dose cohort, from 2.54 ng per mL (range, 1.10-6.40) at baseline to 5.66 ng per mL (range, 2.66-8.60) at 12 months. These increases are 3.0 times and 1.9 times the baseline values, respectively.

The highest median SMN value of 4.46 ng per mL (range, 2.61-5.55) was seen at 4 weeks in 3 infants in the low-dose cohort, representing a median of 4.5 times (range, 1.2-5.4) the baseline value. In the high-dose cohort, the blood SMN protein concentration increased to its highest median value of 5.87 ng per mL (range, 2.84-8.76) among 17 infants at 4 weeks, which was a median of 2.1 times (range, 0.9-6.5) the baseline value.

Other positive motor milestone achievements included 9 infants (53%) achieving upright head control, 1 infant (6%) being able to stand (Hammersmith Infant Neurological Examination-2), and 11 infants (52%) with a Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders total score of 40 points or higher. In terms of pulmonary function and swallowing, 18 (86%) were able to feed orally, either exclusively or in combination with a feeding tube.

Overall, 202 adverse events (AEs) were reported, 24 of which were serious. Serious AEs included pneumonia, respiratory tract infection, and acute respiratory failure. By the time of publication, 4 infants had died of respiratory complications.

These findings imply that “risdiplam shifts mRNA splicing toward the expression of full-length SMN2 mRNA. It cannot be stated with confidence that there was clinical benefit of the agent because the exploratory clinical end points were analyzed post hoc and can only be qualitatively compared with historical cohorts. Part 2 of the study is ongoing to evaluate the longer-term safety and effect of risdiplam in type 1 spinal muscular atrophy,” Baranello and colleagues concluded.

Ongoing Studies Evaluating Risdiplam in SMA

The second part of FIREFISH is a single-arm study of risdiplam in 41 infants with type 1 SMA treated for 2 years followed by an open-label extension. Enrollment was completed in November 2018. The primary objective was to assess efficacy in BSID-III after 12 months of treatment. The study met its primary end point.

SUNFISH (NCT02908685) is a 2 part, double-blind, placebo-controlled study in people aged 2 to 25 years with type 2 or 3 SMA. Part 1, with 51 participants, determined dosage for part 2, with 180 participants, that evaluated motor function using total score of Motor Function Measure 32 (MFM-32) at 12 months. The study met its primary endpoint.

JEWELFISH (NCT03032172) is an open-label exploratory trial to assess the safety, tolerability, pharmacokinetics and pharmacodynamics in people aged 6 months to 60 years with SMA who have received other investigational or approved SMA therapies for at least 90 days prior to receiving risdiplam. The study has completed recruitment of 174 participants.

RAINBOWFISH (NCT03779334) is an open-label, single-arm, multi-center study. It aims to investigate the efficacy, safety, pharmacokinetics, and pharmacodynamics of risdiplam in babies with genetically diagnosed SMA who are not yet presenting with symptoms, from birth to 6 weeks of age at first dose. The study aims to recruit around 25 participants.