High-Dose Risdiplam Results in High Percentage of Event-Free Infants With SMA


The high-dose cohort in part 1 of the FIREFISH study also showed that more than 50% of infants could sit without support and more than 90% could feed orally.

Basil T. Darras, MD, associate neurologist-in-chief; chief, division of clinical neurology; and director, Neuromuscular Center and Spinal Muscular Atrophy Program, Boston Children’s Hospital

Basil T. Darras, MD

New data from part 1 of the FIREFISH study (NCT02913482) of risdiplam (Evrysdi; PTC Therapeutics) in infants with symptomatic type 1 spinal muscular atrophy (SMA) show that in the 0.2 mg/kg daily high-dose cohort B (n = 17), 88% of infants were event-free after 24 months.

Additionally, 59% (n = 10) of those infants were able to sit without support for at least 5 seconds, as measured by the Gross Motor Scale of Bayley Scales of Infant & Toddler Development Edition 3 (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.

Of 14 infants with the data available at month 24, 93% (n = 13) of infants were alive and able to feed orally. As well, 100% (n = 14) maintained the ability to swallow, of which 86% (n = 12) were able to feed exclusively orally.

The data from 21 patients in cohort B of part 1 were presented in a poster by Basil T. Darras, MD, associate neurologist-in-chief; chief, division of clinical neurology; and director, Neuromuscular Center and Spinal Muscular Atrophy Program, Boston Children’s Hospital, at the Muscular Dystrophy Association (MDA) Clinical and Scientific Conference 2021, March 15-18. Cohort A consisted of 4 patients treated with low-dose risdiplam.

As of the March 3, 2020 data cutoff, all 21 infants in cohort B had experienced at least 1 adverse event (AE) and 71% (n = 15) had experienced at least 1 serious AE, which the authors noted were “reflective of underlying disease.” Notably, the serious AEs decline from 20 in the first 12 months to 10 in the second 12 months, with the incidence of them declining by roughly 50% between the 2 periods.

No risdiplam-associated ophthalmologic findings were observed after 24 months of treatment, and 29% (n = 6) of infants did not require hospitalization—defined as hospital admission lasting 1 or more nights—up to Month 24.

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The most common AEs reported were pyrexia in 71% (n = 15); upper respiratory tract infection 52% (n = 11); cough and vomiting in 33% each (n = 7 for both); and diarrhea and respiratory tract infection in 29% each (n= 6 for both). The most common serious AEs were pneumonia in 24% (n = 5), followed by acute respiratory failure, respiratory distress, respiratory tract infection, and viral respiratory tract infection in 10% each (n = 2 for all).

The second part of the FIREFISH study consists of the efficacy and safety analysis of the dose selected in this first part, which also includes an open-label extension, in 41 patients. The second part is open-label treatment for 24 months, after which patients can participate in a 36-month open-label extension. At baseline, the high-dose cohort (65% [n = 11] female) had a median Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) score of 24.0 (range, 16–34) and a Hammersmith Infant Neurological Examination-2 (HINE-2) score of 1.0 (0–2).

Treatment with risdiplam also resulted in continued motor milestone gains, as measured by HINE-2, in the cohort between months 12 and 24. At both 12 and 24 months, 77% (n = 13) of patients achieved head control—of those, 12% were wobbling and 65% maintained constant upright control at month 24, compared to 24% and 53%, respectively, at month 12. As well, 70% (n = 12) of infants were able to roll at month 24 compared to 59% at month 12. Specifically, at month 24, 29% could roll supine to prone, 6% from prone to supine, and 35% could roll to the side. At 12 months, those percentages were 12%, 18%, and 29%, respectively.

“At Month 24, 76% (13/17) of infants responded to treatment using the HINE-2 scale and pre-specified response criteria,” Darras et al. wrote.

Sitting was achieved by 71% of the cohort at month 24, compared to 59% at month 12. Of those, 18% could do pivots, 35% could sit stable, and 18% could sit with props at month 24. At 12 months, no patients could sit with pivots, while 35% could sit stable, 18% with props, and 12% with support at the hips. Additionally, 30% of the cohort at month 24 could stand (6% with support; 24% which could support their weight) compared to just 6% at month 12 (6% which could support their weight).

In total, Darras et al. noted that fatal events were reported in 2 infants in the cohort. “Fatal cardiac arrest and respiratory failure on study Day 236 in [a] female infant aged 7 months at enrollment on concurrent night ventilation (BiPAP for <16 hours per day) in the context of suspected aspiration,” and “Respiratory tract infection with onset on study Day 386 in [a] female infant aged 5 months and 3 weeks at enrollment. In the absence of fever and due to moderate symptomatology (nasal congestion and labored breathing) which seemed to improve, the infant was not hospitalized and died 1 day after onset of respiratory tract infection,” they wrote.

An additional infant (age 3 months and 3 weeks at enrollment) died roughly 3.5 months after treatment discontinuation on Day 585, due to cardiac arrest and hypoxia in the context of pneumonia. As well, 2 more patients were censored because they were younger than 30 months of age as of the data cut-off.

For more coverage of MDA 2021, click here.

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.
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