Researchers conducted a pooled safety analysis of the FIREFISH, SUNFISH, and JEWELFISH studies.
Data from the risdiplam (Evrysdi, PTC Therapeutics) clinical development program suggest that the treatment has a favorable safety profile in spinal muscular atrophy (SMA).
The FIREFISH (NCT02913482), SUNFISH (NCT02908685), and JEWELFISH (NCT03032172) studies all reported no treatment-related safety findings leading to treatment withdrawal. Data from the RAINBOWFISH (NCT03779334), also in the risdiplam clinical development program, was not included in the study.
The studies’ findings were presented at the Muscular Dystrophy Association (MDA) Clinical and Scientific Conference 2021, March 15-18, by first author Laurent Servais, MD, PhD, professor, neuromuscular diseases, MDUK Oxford Neuromuscular Centre.
“Risdiplam is the first oral systemic treatment to have efficacy data in pediatric and adult patients to support its use in SMA and has shown a favorable safety profile across a broad range of patients with SMA. The pooled safety analyses aim to determine the longer-term safety profile of risdiplam in individuals with SMA who have participated in the risdiplam clinical development program studies,” Servais and colleagues wrote.
Servais and colleagues analyzed data from a total of 465 patients enrolled in the program. The overall exposure to risdiplam was 480.9 patient years (PY).
SMA type 1 was present in 77 patients from parts 1 and 2 of the FIREFISH study and the JEWELFISH study. These patients had a median age of 0.56 years (range, 0.2-19.1) at first dose. SMA types 2 and 3 were present in 388 patients from parts 1 and 2 of the SUNFISH study and the JEWELFISH study. These patients were a median age of 12.63 years (range, 2.2-60.9) at first dose.
The rate of adverse events (AEs) per 100 PY was similar across both SMA pools. No AEs related to the treatment resulted in patient withdrawal and most were mild. The most common related AEs were diarrhea in 9 patients, nausea in 7, and rash and headache in 5 each. All but 15 AEs in 11 patients related to treatment resolved. Of all AEs, headache had the highest rate per 100 PY at 55.8, followed by pyrexia (43.2), upper respiratory tract infection (41.6), nasopharyngitis (27.8), and vomiting (22.8). The difference in AE rates between SMA pools were driven by differences in age and disease severity.
Serious AEs (SAEs) were more common in SMA type 1, with a rate of 93.3 per 100 PY, than in types 2 and 3 (25.2 per 100 PY). Overall, the most common SAE was pneumonia in 18 patients with SMA type 1 and 17 with types 2 and 3.
In the SMA type 1 pool, 1 patient had an SAE related to treatment, neutropenia in the context of pneumonia, which resolved. The patient’s dose was not altered. One patient in the type 2 and 3 pool also had a related SAE, supraventricular tachycardia (in the context of hypoxia), which resolved with ongoing risdiplam treatment.
An unrelated SAE, a fatal respiratory tract viral infection, occurred in 1 patient with SMA type 1. A total of 7 patients, all with SMA type 1, died from respiratory complications unrelated to treatment, 6 during the study and 1 after withdrawal.
In both pools, the rate of AEs decreased over time, with the highest rate in the first 6 months of treatment. The SMA type 1 pool had an approximately 3.5-fold higher SAE rate than the other pool, but this rate declined more than 1.5-fold between the first and second 6-month periods. The SAE rate in the type 2 and 3 pool remained more stable.
“Since most reported AEs and SAEs were associated with underlying disease or disease progression, reduction in AE rates may be indicative of the therapeutic benefit of risdiplam treatment, with a marked deviation from the natural course of disease progression. The differences in the AE profile between type 1 and types 2/3 SMA populations appeared to be driven by illnesses and conditions that are common in the respective age groups,” Servais and colleagues concluded.
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