Risdiplam Demonstrates Long-Term Success in Infants With SMA
The findings were consistent with the drug's previously reported safety profile and no new safety signals were observed.
Stuart Peltz, PhD
PTC Therapeutics announced that treatment with its investigational, orally administered survival motor neuron-2 (SMN2) splicing modifier, risdiplam (Evrysdi), is associated with continued improvement and achievement of motor milestones in patients aged 2 months and older with spinal muscular atrophy (SMA) over a 2-year period.1
The data from Part 1 of the ongoing FIREFISH study (NCT02913482), which were presented at the 25th International Annual Congress of the World Muscle Society (WMS), showed that 88% of infants (17 of 21) treated with the therapeutic dose of risdiplam were alive and required no permanent ventilation at 2 years.
“The results from the long-term FIREFISH trial demonstrate that SMA patients continue to improve in motor function and gain additional developmental milestones,” Stuart Peltz, PhD, chief executive officer, PTC Therapeutics, said in a statement.
Patients also achieved multiple major milestones throughout the study. The ability to sit without support for at least 5 seconds, as measured by the Gross Motor Scale of the Bayley Scales of Infant and Toddler Development–Third Edition (BSID-III), was achieved in 41% (7 of 17) of patients at 1 year and 59% (10 of 17) of patients at 2 years. Upright head control was achieved by 53% (9 of 17) and 65% (11 of 17) of patients at 1 and 2 years, and the ability to turn over was reported in 12% and 29% of patients at 1 and 2 years, respectively.
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Other additional milestones including standing while supporting weight or with support were observed in 6% (1 of 17) and 30% (5 of 17) of patients at 1 and 2 years, respectively. A Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) score of 40 points or more was recorded in 59% (10 of 17) of patients at 1 year and 71% (12 of 17) of patients at 2 years.
“In addition, the results further validate the safety and durable efficacy profile of Evrysdi and reinforce the continued benefit of the therapy. Since its approval in August, Evrysdi has demonstrated a strong commercial launch signifying the need for an oral treatment for SMA patients, especially one that can be taken at home amidst the global pandemic,” Peltz added.
Safety findings for risdiplam were consistent with its previously reported safety profile and no new safety signals were identified. The most common adverse events (AEs) included pyrexia (71%), upper respiratory tract infection (52%), cough (33%), vomiting (33%), diarrhea (29%), and respiratory tract infection (29%). Pneumonia was the most serious AE, occurring in 24% of patients. Notably, to date, there have been no drug-related safety findings leading to withdrawal from any study.
Of the 14 infants alive at 2 years, 100% maintained the ability to swallow and 93% (13 of 14) were able to feed orally. Of the 17 infants treated with the therapeutic dose, 2 experienced fatal complications of their disease at 8 and 13 months of treatment and 1 infant was withdrawn from the study and died 3.5 months later. Investigators deemed that none of these were related to treatment with risdiplam.
FIREFISH is an open-label, 2-part clinical trial in infants with Type 1 SMA. Part 1 was a dose-escalation study with the primary objective of assessing the safety profile of risdiplam and determining the dose for Part 2. Part 2 is a single-arm study of risdiplam in 41 infants with Type 1 SMA treated for 2 years followed by an open-label extension. At the time of analysis, the youngest infant was 28.4 months and the oldest was 45.1 months old. The median age at enrollment was 6.3 months.
Data from Part 2 of the study were announced in April and demonstrated a significant increase in achieved motor milestones in infants with Type 1 SMA aged 1 to 7 months after 12 months of treatment. Using the BSID-III, 12 infants (29%) sat without support for 5 seconds by the end of month 12, a milestone typically not reached in the natural history of Type 1 SMA (P <.001).
The data, which were accepted for presentation to the American Academy of Neurology (AAN) 2020 Annual Meeting, showed that 18 (43.9%) infants were able to hold their head upright, 13 (31.7%) were able to roll to the side, and 2 (4.9%) were able to stand with support, as measured by the Hammersmith Infant Neurological Examination 2 (HINE-2). A maintained ability to swallow at 12 months was observed in 36 (95%) patients, while 34 (89%) were able to feed orally.2
Risdiplam received FDA approval for the treatment of SMA in August 2020, the first SMA therapy indicated for at-home oral administration of a liquid formulation in patients 2 months and older. The agency’s decision was based on the findings of the FIREFISH and SUNFISH (NCT02908685) studies, both of which demonstrated the efficacy of the SMN2-directed RNA splicing modifier in this patient population.3
The therapy is currently being evaluated in 4 multi-center trials in people with SMA, including FIREFISH, SUNFISH, JEWELFISH (NCT03032172), and RAINBOWFISH (NCT03779334).
