Higher percentages of infants were event-free and were classified as having a motor-milestone response at month 12 than in historical cohorts.
Basil Darras, MD
Researchers from the FIREFISH clinical trial (NCT02913482), which evaluated risdiplam (Evrysdi; PTC Therapeutics), an FDA-approved treatment for spinal muscular atrophy (SMA), have published additional data from part 2 of the study.1 All told, 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.
Lead author Basil Darras, MD, director, Neuromuscular Center and Spinal Muscular Atrophy Program, Boston’s Children’s Hospital, and colleagues originally published 2-year data from the study in April 2021, which indicated that the treatment had a significant impact on the primary end point. The milestone of being able to sit without support for at least 5 seconds at month 12 was met by 29% (12 of 41) of participants, significantly higher than the performance criteria of 5% from natural-history data (P <.001).2
Key secondary end points included a score of 40 or higher on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), an increase of at least 4 points from baseline in the CHOP-INTEND score, a motor-milestone response as measured by Section 2 of the Hammersmith Infant Neurological Examination (HINE-2), and survival without permanent ventilation. These performance criteria were the upper limits of the 90% confidence intervals for natural-history data from 40 infants with type 1 SMA.1
After 12 months of treatment 56% (95% CI, 40-72; n = 23) of infants had a CHOP-INTEND score of 40 or higher, as compared with the performance criterion of 17% (P <.001). Additionally, 90% (95% CI, 77-97; n = 37) of the cohort had at least a 4-point increase from baseline in such scores, as compared with the performance criterion of 17% (P <.001).
Classification of having a HINE-2 motor-milestone response was identified in 78% (95% CI, 62 to 89; n = 32) of infants on risdiplam, compared with the performance criterion of 12% (P <.001). At month 12, 85% (95% CI, 70-93; n = 35) of infants were event-free in comparison to the natural history criterion of 42% (P <.001). Event-free survival was defined as being alive without the use of permanent ventilation. This included tracheostomy or bilevel positive airway pressure for at least 16 hours per day continuously for 3 weeks or continuous intubation for 3 weeks, in the absence of, or after the resolution of, an acute reversible event.
Exploratory analysis of the blood SMN protein concentration showed that the median concentration at baseline was 2.91 ng/mL (range, 0.42-4.51). At 17 weeks, investigators noticed that the blood SMN protein concentration increased to its highest median value of 6.75 ng/mL (range, 1.03-9.83). Notably, the median value at 12 months was 5.17 ng/mL (range, 0.76-9.39).
A total of 254 adverse events (AEs) and 48 serious AEs were recorded among the study population. The most common AEs included upper respiratory tract infection (68%), pneumonia (39%), and pyrexia (39%), followed by constipation (20%), diarrhea (10%), and maculopapular rash (10%). Previously reported data showed that between the first and second 12-month periods of FIREFISH part 2, the incidence of serious pneumonia declined by approximately 3-fold.2
Three infants had fatal respiratory complications that investigators concluded are characteristic of type 1 SMA. Notably, ophthalmologic assessments did not show risdiplam-associated retinal toxic effects.
Results from part 1 of the FIREFISH study of risdiplam published in March 2021 showed that in the 0.2 mg/kg daily high-dose cohort B (n = 17), 88% of infants were event-free after 24 months.3 Additionally, 59% (n = 10) of those infants were able to sit without support for at least 5 seconds, as measured by the BSID-III scores at 24 months, an improvement from 41% (n = 7) at 12 months. All 7 of the infants achieving that milestone at 12 months maintained it by 24 months.
Risdiplam received FDA approval for the treatment of SMA in adults and children 2 months of age and older in August 2020. To date, the drug has been approved in 39 countries and submitted in a further 33 countries.