22 research outputs found
P.025 Efficacy and safety results of the avalglucosidase alfa phase 3 COMET trial in participants with late-onset Pompe disease (LOPD)
Background: Phase 3 COMET trial (NCT02782741)
compares avalglucosidase alfa (n=51) with alglucosidase alfa (n=49) in
treatment-naïve LOPD. Methods: Primary objective:
determine avalglucosidase alfa effect on respiratory muscle function.
Secondary/other objectives include: avalglucosidase alfa effect on
functional endurance, inspiratory/expiratory muscle strength, lower/upper
extremity muscle strength, motor function, health-related quality of life,
safety. Results: At Week 49, change (LSmean±SE) from
baseline in upright forced vital capacity %predicted was greater with
avalglucosidase alfa (2.89%±0.88%) versus alglucosidase alfa
(0.46%±0.93%)(absolute difference+2.43%). The primary objective, achieving
statistical non-inferiority (p=0.0074), was met. Superiority testing was
borderline significant (p=0.0626). Week 49 change from baseline in 6-minute
walk test was 30.01-meters greater for avalglucosidase alfa (32.21±9.93m)
versus alglucosidase alfa (2.19±10.40m). Positive results for
avalglucosidase alfa were seen for all secondary/other efficacy endpoints.
Treatment-emergent adverse events (AEs) occurred in 86.3% of avalglucosidase
alfa-treated and 91.8% of alglucosidase alfa-treated participants. Five
participants withdrew, 4 for AEs, all on alglucosidase alfa. Serious AEs
occurred in 8 avalglucosidase alfa-treated and 12 alglucosidase alfa-treated
participants. IgG antidrug antibody responses were similar in both. High
titers and neutralizing antibodies were more common for alglucosidase alfa.
Conclusions: Results demonstrate improvements in
clinically meaningful outcome measures and a more favorable safety profile
with avalglucosidase alfa versus alglucosidase alfa.
Funding: Sanofi Genzym
Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension
OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo
O.23 A novel desmin mutation causes autosomal recessive limb girdle muscular dystrophy without features of myofibrillar myopathy
Novel <em>SBF2</em> mutations and clinical spectrum of Charcot-Marie-Tooth neuropathy type 4B2
Myophosphorylase (Pygm) Mutations Determined By Next Generation Sequencing In A Cohort From Turkey With Mcardle Disease
This study aimed to identify PYGM mutations in patients with McArdle disease from Turkey by next generation sequencing (NGS). Genomic DNA was extracted from the blood of the McArdle patients (n = 67) and unrelated healthy volunteers (n = 53). The PYGM gene was sequenced with NGS and the observed mutations were validated by direct Sanger sequencing. A diagnostic algorithm was developed for patients with suspected McArdle disease. A total of 16 deleterious PYGM mutations were identified, of which 5 were novel, including 1 splice-site donor, 1 frame-shift, and 3 non-synonymous variants. The p.Met1Val (27-patients/11-families) was the most common PYGM mutation, followed by p.Arg576* (6/4), c.1827+7A>G (5/4), c.772+2_3delTG (5/3), p.Phe710del (4/2), p.Lys754Asnfs (2/1), and p.Arg50* (1/1). A molecular diagnostic flowchart is proposed for the McArdle patients in Turkey, covering the 6 most common PYGM mutations found in Turkey as well as the most common mutation in Europe. The diagnostic algorithm may alleviate the need for muscle biopsies in 77.6% of future patients. A prevalence of any of the mutations to a geographical region in Turkey was not identified. Furthermore, the NGS approach to sequence the entire PYGM gene was successful in detecting a common missense mutation and discovering novel mutations in this population study. (C) 2017 Elsevier B.V. All rights reserved.Wo
Efficacy and Safety of Avalglucosidase Alfa in Patients with Late-Onset Pompe Disease after 97 Weeks: A Phase 3 Randomized Clinical Trial
Importance: In the previously reported Comparative Enzyme Replacement Trial With neoGAA Versus rhGAA (COMET) trial, avalglucosidase alfa treatment for 49 weeks showed clinically meaningful improvements in upright forced vital capacity (FVC) percent predicted and 6-minute walk test (6MWT) compared with alglucosidase alfa. Objective: To report avalglucosidase alfa treatment outcomes during the COMET trial extension. Design, Setting, and Participants: This phase 3 double-blind randomized clinical trial with crossover in the extension period enrolled patients 3 years and older with previously untreated late-onset Pompe disease (LOPD) between November 2, 2016, and February 10, 2021, with primary analysis after 49 weeks. Patients were treated at 55 referral centers in 20 countries. Efficacy outcomes were assessed at 97 weeks and safety outcomes to last follow-up, with data cutoff at February 10, 2021. Data were analyzed from May to June 2021. Interventions: Random assignment (1:1) to receive 20 mg/kg of avalglucosidase alfa or alglucosidase alfa by intravenous infusion every other week for 49 weeks; thereafter, all patients received 20 mg/kg of avalglucosidase alfa every other week. Main Outcomes and Measures: The primary outcome was the least squares (LS) mean change from baseline in FVC percent predicted. Secondary outcomes included the LS mean change from baseline in 6MWT, muscle strength, motor function, quality of life, and disease biomarkers. Safety and tolerability were also assessed. Results: Of 100 participants from the double-blind treatment period, 95 entered the extension period. Of these, 51 (54%) were men, and the mean (range) age was 48.3 (10-79) years. At the start of this study, mean upright FVC percent predicted was similar between treatment arms, and 6MWT distance was greater in the avalglucosidase alfa arm. From baseline to week 97, LS mean (SE) FVC percent predicted increased by 2.65 (1.05) for those who continued avalglucosidase alfa and 0.36 (1.12) for those who switched to avalglucosidase alfa. The LS mean (SE) 6MWT distance increased by 18.60 (12.01) m and 4.56 (12.44) m, respectively. For participants who switched to avalglucosidase alfa, FVC percent predicted remained stable (LS mean [SE] change from week 49 to 97, 0.09 [0.88]) and 6MWT distance improved (LS mean [SE] change from week 49 to 97, 5.33 [10.81] m). Potentially treatment-related adverse events were reported in 29 patients (56.9%) who continued avalglucosidase alfa and in 25 patients (56.8%) who switched. Conclusions and Relevance: In this randomized clinical trial extension, maintenance of positive clinical outcomes was demonstrated for patients continuing avalglucosidase alfa treatment and, to a lesser extent, patients who switched from alglucosidase alfa. No new safety concerns were observed. Trial Registration: ClinicalTrials.gov Identifier: NCT02782741