FIREFISH hits milestone with risdiplam for progressive neuromuscular disorder in infants

In part 2 of the open-label FIREFISH study evaluating infants with type 1 spinal muscular atrophy (SMA), more infants on risdiplam met motor milestones and showed improvements in motor function compared with those seen in historical cohorts.

In type 1 SMA, several motor developmental milestones are not achieved, and motor function dwindles following diagnosis. [Neuromuscul Disord 2016;26:754-759; Neurology 2014;83:810-817; Ann Neurol 2017;82:883-891] “[Moreover,] the majority of untreated infants do not survive beyond 2 years of age,” said the researchers.

None of the 41 infants (median age at enrolment 5.3 months, 54 percent female) enrolled in the study were able to sit without support at baseline. [N Engl J Med 2021;385:427-435]

“After 12 months of treatment, 12 infants were able to sit without support for at least 5 seconds, a milestone not attained in this … progressive neuromuscular disease characterized by an onset at ≤6 months, an inability to sit without support, and deficient levels of survival of motor neuron (SMN) protein,” they said. “[T]he percentage was significantly higher than the performance criterion of 5 percent from natural-history data (p<0.001).”

Compared with historical controls, there were significantly greater fractions of infants treated with risdiplam who had a CHOP-INTEND* score of ≥40 (56 percent vs 17 percent), an increase of at least 4 points from baseline CHOP-INTEND score (90 percent vs 17 percent), a HINE-2** motor milestone response (78 percent vs 12 percent), and an event-free survival*** (85 percent vs 42 percent; p<0.001 for all).

“[Higher CHOP-INTEND and HINE-2] scores indicate better motor function … [Infants who] were event-free … were classified as having a motor-milestone response at month 12 than in historical cohorts,” the researchers noted.

Forty-eight serious adverse events (AEs) were reported, the most common being pneumonia (n=13), bronchiolitis, respiratory failure, and hypotonia (n=2 each). Three infants had fatal respiratory complications, which are typical of type 1 SMA. Ophthalmologic testing did not reveal risdiplam-associated retinal toxicities – an effect seen in monkeys at higher risdiplam exposures. [J Med Chem 2018;61:6501-6517]

In the dose-finding part 1 of the trial, risdiplam led to an increased expression of SMN protein. [N Engl J Med 2021;384:915-923] Based on these findings, risdiplam was given at a dose of 0.2 mg/kg/day in infants >5 months of age. For infants <5 months, treatment was initiated at a dose of 0.04 or 0.08 mg/kg/day and adjusted to 0.2 mg/kg/day, generally within 1–3 months following treatment initiation and review of pharmacokinetic data. Infants who were able to swallow received the drug orally, while those unable to swallow received it as a bolus via a feeding tube.

The other two FDA-approved therapies for SMA – nusinersen and onasemnogene abeparvovec-xioi – have been tied to improvements in motor and survival outcomes in individuals with type 1 SMA. [N Engl J Med 2017;377:1723-1732; N Engl J Med 2017;377:1713-1722] However, these findings cannot be compared against the current observations owing to differences in study cohorts, designs, treatment durations, and standards of care and available therapies at the time of study initiation.

“[Nonetheless, our findings show that] oral risdiplam treatment over a period of 12 months in patients with type 1 SMA resulted in higher percentages of infants who met motor milestones, survived without need for ventilation, and showed improvements in motor function than the percentages in natural-history cohorts,” said the researchers. Larger and longer studies are warranted to ascertain the long-term effects of risdiplam in this patient setting.

A long-term open-label study is ongoing, as well as studies evaluating the potential of risdiplam in pre-symptomatic infants, SMA patients who have received other therapies, and in type 2 or 3 SMA.