Article

Expanded Data From FIREFISH Published, Risdiplam Continues to Improve SMA Outcomes

Author(s):

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

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).

READ MORE: Botox Label Expanded to Include 8 New Muscles for Upper Limb Spasticity Treatment

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.

REFERENCES
1. Darras BT, Masson R, Mazurkiewicz-Beldzinska M, Rose K, et al. Risdiplam-treated infants with type 1 spinal muscular atrophy versus historical controls. NEJM. Published online July 29, 2021. doi: 10.1056/NEJMoa2102047
2. Genentech’s Evrysdi continues to improve motor function and survival in babies with type 1 spinal muscular atrophy (SMA). News release. Genentech. April 15, 2021. Accessed July 29, 2021. https://www.biospace.com/article/releases/genentech-s-evrysdi-continues-to-improve-motor-function-and-survival-in-babies-with-type-1-spinal-muscular-atrophy-sma-/
3. Darras BR, Baranello G, Boespflug-Tanguy O, et al. FIREFISH Part 1: 24-month safety and exploratory outcomes of risdiplam in infants with Type 1 spinal muscular atrophy (SMA). Presented at: MDA Clinical and Scientific Conference 2021; March 15-18.

Newsletter

Keep your finger on the pulse of neurology—subscribe to NeurologyLive for expert interviews, new data, and breakthrough treatment updates.

Related Videos
Cassandra Moore, MPH, CPH
Sam Hooshmand, DO
Funke Afolabi-Brown, MD, FAASM
Brenda L. Wong, MD
Kevin Sheth, MD
Kevin Swong, MD
© 2025 MJH Life Sciences

All rights reserved.