Dalia Moawad, MD, Executive Director, Head of Neurological Rare Diseases, Medical Affairs at Genentech, discusses 3-year data from the FIREFISH study of risdiplam (Evrysdi) in infants with spinal muscular atrophy (SMA) type 1.
SMA is a rare inherited neuromuscular disorder caused by an inadequate level of the survivor motor neuron (SMN) protein due to mutations in the SMN1 gene. The absence of the SMN protein leads to cellular imbalances in motor neurons that in turn causes the motor neuron endplates to not properly connect to muscle and the motor neurons die.
As Dr. Moawad explains, FIREFISH is a phase 2/3, 2-part, multicenter, open-label trial of risdiplam in infants 2 to 7 months of age with infantile-onset SMA. Part 1 of this study was designed to be a dose-finding study for risdiplam. The results of part 1 were published last year in the New England Journal of Medicine. In part 2 of the FIREFISH study, participants receive risdiplam once daily at the dose defined in Part 1 for 24 months at which point they entered a 3-year open-label extension phase and continue to receive risdiplam at the same dose. The primary endpoint of part 2 was the percentage of infants sitting without support for at least 5 seconds as assessed by the BSID-III gross motor scale at Month 12.
Recently, 3-year data was announced from the open-label extension period, demonstrating that infants treated with risdiplam maintained or continued to improve in their ability to sit without support between 24-36 months. Among infants with an available assessment treated with risdiplam (n=48), 32 infants maintained and 4 gained the ability to sit without support for at least 5 seconds since month 24, as assessed by the Gross Motor Scale of the BSID-III. Additionally, 20 infants maintained and 15 gained the ability to sit without support for at least 30 seconds. No infant who gained the ability to sit without support lost this ability after 3 years of treatment. The majority of infants treated with risdiplam maintained the ability to feed orally and swallow up to month 36.
Most infants treated with risdiplam continued to improve or maintain measures of the Hammersmith Infant Neurological Examination 2 (HINE-2) between 24-36 months, including being able to hold their heads upright (36 maintained, 3 gained, none lost the ability since month 24), pivot while sitting (15 maintained, 11 gained, none lost the ability), stand with support (6 maintained, 5 gained, 1 lost the ability) and walk while holding on (1 maintained, 2 gained, none lost the ability).
The most common adverse events (AEs) were pyrexia (60%), upper respiratory tract infection (57%), pneumonia (43%), constipation (26%), nasopharyngitis (24%), diarrhea (21%), rhinitis (19%), vomiting (19%) and cough (17%). The most common serious AEs were pneumonia (36%), respiratory distress (10%), viral pneumonia (9%), acute respiratory failure (5%) and respiratory failure (5%). The rate of all AEs continued to decrease over time. Moreover, all AEs reported were reflective of the underlying disease and there were no treatment-related AEs leading to withdrawal or treatment discontinuation. The rate of hospitalizations decreased from 1.24 hospitalizations per patient year over 12 months to 0.70 hospitalizations over 36 months. No additional deaths occurred from the primary analysis of FIREFISH to the data cut-off (November 23, 2021) and an estimated 91% of infants (n=58) treated with risdiplam were alive after three years of treatment.
To learn more about SMA, visit our SMA Learning Page here.