Search

By the age of 20 years, almost all patients with Duchenne’s or Becker’s muscular dystrophy have experienced dilated cardiomyopathy (DCM), a condition that contributes significantly to their morbidity and mortality. Although studies have shown carvedilol to be an effective therapy for patients with other forms of DCM, few data exist concerning its safety and efficacy for patients with muscular dystrophy. This study aimed to evaluate the safety and efficacy of carvedilol for patients with DCM. A clinical trial at an outpatient clinic investigated 22 muscular dystrophy patients, ages 14 to 46 years, with DCM and left ventricular ejection fraction (LVEF) less than 50%. Carvedilol up-titrated over 8 weeks then was administered at the maximum or highest tolerated dose for 6 months. Baseline and posttreatment cardiac magnetic resonance imaging (CMR), echocardiography, and Holter monitoring were recorded. Carvedilol therapy was associated with a modest but statistically significant improvement in CMR-derived ejection fraction (41% ± 8.3% to 43% ± 8%; p < 0.02). Carvedilol also was associated with significant improvements in both the mean rate of pressure rise (dP/dt) during isovolumetric contraction (804 ± 216 to 951 ± 282 mmHg/s; p < 0.05) and the myocardial performance index (0.55 ± 0.18 to 0.42 ± 0.15; p < 0.01). A trend toward improved shortening fraction, E/E’ ratio, and isovolumetric relaxation time also was observed. Two patients had runs of nonsustained ventricular tachycardia exceeding 140 beats per minute (bpm) before carvedilol administration. Ventricular tachycardia exceeding 140 bpm was not observed after carvedilol therapy. Carvedilol was well tolerated, and no serious adverse events were identified. Carvedilol therapy appears to be safe for patients with DCM secondary to muscular dystrophy and produces a modest improvement in systolic and diastolic function. [ABSTRACT FROM AUTHOR]

ISIS-SMNRx is an antisense oligonucleotide designed to enhance inclusion of SMN2 exon 7 mRNA and increase the amount of functional SMN protein. A first-in-human, open-label, escalating-dose clinical study was conducted to evaluate the safety, tolerability, and pharmacokinetics of ISIS-SMNRx in patients with SMA. A single dose was delivered by intrathecal injection to medically stable SMA patients 2-14 years of age. Four dose levels (1, 3, 6, 9 mg) were examined in cohorts of 6-10 subjects (n=28). Subjects were followed for 29 days or 85 days post-dosing and monitored for drug safety and tolerability. Plasma drug levels were measured over the first 24 hours and CSF drug levels were assessed at 7 or 28 days post-dose. Exploratory endpoints including the Hammersmith Motor Function Scale - Expanded (HFMSE) in all subjects, and electrophysiological measures in cohort 4 only, were performed to gain further experience with these measures. Overall, ISIS-SMNRx was well tolerated in this study. No serious adverse events or dose-limiting toxicities were reported. All adverse events were mild or moderate in severity and none were related to dose level of ISIS-SMNRx. No drug-related changes in neurological exams, CSF laboratory assessments, or systemic evaluations were reported. Intrathecal injections were also well tolerated in SMA children and shown to be feasible. Pharmacokinetics in plasma and CSF indicate that drug levels in SMA patients were dose-dependent; observations were consistent with preclinical data and thus support infrequent administration (i.e. every 6-9 months). Although the study was not designed to provide evidence of functional improvement, an increase in the HFMSE was observed in the highest dose cohort at 3 months (mean increase = 3.1 points or 17.6%; 6/10 subjects with a >4 point change). Results from this study support continued development of ISIS-SMNRx and thus we have initiated multiple-dose clinical studies of ISIS-SMNRx in patients with SMA. [Copyright &y& Elsevier]

Risdiplam (EVRYSDI®) is a centrally and peripherally distributed, oral survival of motor neuron 2 (SMN2) pre-mRNA splicing modifier that has been approved in more than 70 countries worldwide. Safety data were analyzed from four studies within the risdiplam clinical development trial program: FIREFISH (NCT02913482) assesses efficacy, safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of risdiplam in infants with type 1 SMA (aged 1–7 months at enrollment). SUNFISH (NCT02908685) assesses efficacy, safety, tolerability, PK and PD of risdiplam in patients with types 2/3 SMA (aged 2–25 years at enrollment). JEWELFISH (NCT03032172) assesses safety, tolerability, PK and PD of risdiplam in patients with SMA (aged 6 months–60 years at enrollment) who previously received RG7800 (RO6885247), nusinersen (SPINRAZA®), olesoxime or onasemnogene abeparvovec (ZOLGENSMA®). RAINBOWFISH (NCT03779334) assesses efficacy, safety, PK and PD of risdiplam in infants (from birth–6 weeks of age at first dose) with genetically diagnosed and presymptomatic SMA. We have previously reported pooled safety analyses from FIREFISH, SUNFISH and JEWELFISH showing no treatment-related safety findings leading to withdrawal in 465 patients treated with risdiplam for up to 46.9 months (data-cuts: 12 November 2020, 30 September 2020 and 29 January 2021, respectively). The rate of adverse events (AEs) per 100 patient years was comparable across the type 1 and type 2/3 SMA populations. The overall rate of serious AEs was higher in the type 1 SMA population compared with the types 2/3 SMA population. With continued risdiplam treatment, there was a marked decline in SAE rates over time in type 1 SMA. Here we will present updated safety analyses from the risdiplam studies, including safety data from the RAINBOWFISH study. Safety data from across the risdiplam studies will add to the understanding of the long-term safety profile of risdiplam. [ABSTRACT FROM AUTHOR]