Safety and efficacy of avalglucosidase alfa versus alglucosidase alfa in patients with late-onset Pompe disease (COMET): a phase 3, randomised, multicentre trial.

BACKGROUND

Pompe disease is a rare, progressive neuromuscular disorder caused by deficiency of acid α-glucosidase (GAA) and accumulation of lysosomal glycogen. We assessed the safety and efficacy of avalglucosidase alfa, a recombinant human GAA enzyme replacement therapy specifically designed for enhanced mannose-6-phosphate-receptor targeting and enzyme uptake aimed at increased glycogen clearance, compared with the current approved standard of care, alglucosidase alfa, in patients with late-onset Pompe disease.

METHODS

We did a randomised, double-blind, phase 3 trial at 55 sites in 20 countries. We enrolled individuals (aged ≥3 years) with enzymatically confirmed late-onset Pompe disease who had never received treatment. We used a centralised treatment allocation system to randomly allocate participants to either avalglucosidase alfa or alglucosidase alfa. Participants and investigators were unaware of their treatment allocation. The primary outcome measure was change from baseline to week 49 in upright forced vital capacity percent (FVC%) predicted. We used a hierarchical fixed sequential testing strategy, whereby non-inferiority of avalglucosidase alfa compared with alglucosidase alfa was assessed first, with a non-inferiority margin of 1·1. If non-inferiority was seen, then superiority was tested with a 5% significance level. The key secondary objective was effect on functional endurance, measured by the 6-minute walk test (6MWT). Safety was assessed, including treatment-emergent adverse events and infusion-associated reactions. The modified intent-to-treat population was the primary analysis population for all efficacy analyses. The safety population was the analysis population for safety analyses. This trial is registered with ClinicalTrials.gov, NCT02782741. We report results of the 49-week primary analysis period.

FINDINGS

Between Nov 2, 2016, and March 29, 2019, 100 participants were randomly allocated avalglucosidase alfa (n=51) or alglucosidase alfa (n=49). Treatment with avalglucosidase alfa resulted in a least-squares mean improvement in upright FVC% predicted of 2·89% (SE 0·88) compared with 0·46% (0·93) with alglucosidase alfa at week 49 (difference 2·43% [95% CI -0·13 to 4·99]). Non-inferiority was shown because the lower bound of the 95% CI for the difference far exceeded the predefined non-inferiority margin but did not exclude 0 (p=0·0074). Superiority was not reached (p=0·063), so formal testing was stopped, as per the testing hierarchy. Improvements were also seen in the 6MWT with avalglucosidase alfa compared with alglucosidase alfa, with greater increases in distance covered (difference 30·01 m [95% CI 1·33 to 58·69]) and percent predicted (4·71% [0·25 to 9·17]). Treatment-emergent adverse events potentially related to treatment were reported in 23 (45%) of 51 participants in the avalglucosidase alfa group and in 24 (49%) of 49 in the alglucosidase alfa group, and infusion-associated reactions were reported in 13 (26%) participants in the avalglucosidase alfa group and 16 (33%) in the alglucosidase alfa group. Of the five trial withdrawals, all in the alglucosidase alfa group, four were due to adverse events, including two infusion-associated reactions. Serious treatment-emergent adverse events were reported in eight (16%) participants who received avalglucosidase alfa and in 12 (25%) who received alglucosidase alfa. One participant treated with alglucosidase alfa died because of acute myocardial infarction determined to be unrelated to treatment. Antidrug antibody responses were similar in both groups. High and persistent titres (≥12 800) and neutralising antibodies were more common with alglucosidase alfa (in 16 [33%] participants) than with avalglucosidase alfa (ten [20%]).

INTERPRETATION

We consider that this study provides evidence of clinically meaningful improvement with avalglucosidase alfa therapy over alglucosidase alfa in respiratory function, ambulation, and functional endurance, with no new safety signals reported. An open-label extended-treatment period is ongoing to confirm the long-term safety and efficacy of avalglucosidase alfa, with the aim for this therapy to become the new standard treatment in late-onset Pompe disease.

FUNDING

Sanofi Genzyme.

Informations de copyright

Copyright © 2021 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests SA received reimbursement for attending symposia and other expenses. KB has served on advisory boards for Sanofi Genzyme, AskBio, Spark Therapeutics, and Takeda; and received consultant fees from Sanofi Genzyme, Amicus Therapeutics, AskBio, Spark Therapeutics, Takeda and Valerion. Y-HC has received research support, consulting fees, reimbursement for attending symposium and other expenses, and fees for non-continuing medical education or continuing education services from Sanofi Genzyme. PRC has served as a member of the Pompe Registry North American Advisory Board and undertaken contracted research for Amicus, Sanofi Genzyme, Spark, ReveraGen Biopharma, and NS Pharma. She has been a consultant for Roche and Epirium. She has received travel funding from Roche, Spark, and NS Pharma. JWD has received consulting fees from Audentes, Biogen;, Ionis Pharmaceuticals, Cytokinetics, Pfizer, AveXis, Roche/Genentech Pharmaceuticals, AMO Pharmaceuticals, and Sarepta Therapeutics; and has undertaken contracted research for Biogen, Ionis Pharmaceuticals, Cytokinetics, Roche Pharmaceuticals, AveXis, Sanofi- Genzyme, Sarepta Therapeutics, and Scholar Rock. JD-M has served as a consultant or speaker for Sanofi Genzyme, Lupin, Sarepta, and PTC Therapeutics; and received research support from Boehringer Ingelheim and Sanofi Genzyme. MMD has served as a consultant forArgenX, Catalyst, Cello, CSL Behring, EcoR1, Kezar, Momenta, NuFactor, Octapharma, RaPharma/UCB, RMS Medical, Sanofi Genzyme, Shire Takeda, Spark Therapeutics, and UCB Biopharma; and has received grants from Alexion, Alnylam Pharmaceuticals, Amicus, BioMarin, Bristol-Myers Squibb, Catalyst, Corbus, CSL Behring, US Food and Drug Administration/Office of Orphan Products Development, Genentech, GlaxoSmithKline, Grifols, Kezar, Mitsubishi Tanabe Pharma, Muscular Dystrophy Association, US National Institutes of Health (NIH), Novartis, Octapharma, Orphazyme, Ra Pharma/UCB, Sanofi Genzyme, Sarepta Therapeutics, Shire Takeda, Spark Therapeutics, UCB Biopharma, Viromed/Healixmith, and TMA. SE-O has served on advisory boards for Sanofi Genzyme. OG-A has served on advisory boards for Amicus, BioMarin, Sanofi, and Takeda; served on speaker's bureau for Sanofi and Takeda; received consulting fees from Amicus, BioMarin, Sanofi Genzyme, Shire Human Genetics Therapies, and Takeda; and undertaken contracted research for Amicus, Freeline, Genentech, Protalix, Sangamo, Sanofi, and Takeda. SI has received honoraria from Actelion, Boehringher Ingelheim, Ever Pharma, Merz Pharma, Servier, Takeda, and Teva. PSK has served on advisory boards for Amicus, Baebies, and Sanofi Genzyme; received consulting fees from Amicus, AskBio, Sanofi Genzyme, and Vertex; undertaken contracted research for Amicus, Sanofi Genzyme, and Valerion; received honoraria from Amicus, AskBio, Sanofi Genzyme, and Vertex; received travel expenses from Amicus and Sanofi Genzyme; and has ownership interests in AskBio and Baebies. HK has served on advisory boards for Alexion, Catalyst Pharmaceuticals, PTC therapeutics, and Sanofi Genzyme; and is on the speaker's bureau of Akcea, Catalyst Pharmaceuticals, and Sanofi Genzyme. SL has served on advisory boards and speaker's bureau, received consulting fees, and undertaken contracted research for Sanofi Genzyme. TM has served on advisory boards for Amicus, Biomarin, Idera, Novartis, Sanofi Genzyme, Ultragenyx, and received travel subsidies and honoraria for related activities; has served as a consultant to NuFactor, Sarepta Therapeutics, and Walgreens, and received travel subsidies and honoraria; served on the speaker's bureau for Sanofi Genzyme and Grifols and received travel subsidies and honoraria for these; and received research funding from Alexion, Alnylam, Amicus, Baxter, Bio-Blast, Biogen, Biomarin, CSL Behring, Sanofi Genzyme, Grifols, GlaxoSmithKline, Idera, ISIS Pharmaceuticals, NIH, Novartis, and Ultragenyx. MR has received research support from Amicus; received consulting fees, honoraria, and travel reimbursement from Sanofi Genzyme, BioMarin, and Amicus; has received royalties from NIH; is a member of a speaker's bureau for NIH; and is a member of the Pompe Registry Scientific Advisory Board. BS has served within the last 3 years on advisory boards for Amicus Therapeutics, Audentes Therapeutics, Dyne, Lupin, Nexien, Sanofi Genzyme, Spark, and UCB; undertaken contracted research for Amicus, Greenovation Biopharm, and Sanofi Genzyme; received honoraria from Alexion and Kedrion; and travel expenses from Kedrion and Sanofi Genzyme. VS has received consulting fees from AveXis, Exonics Therapeutic, Roche, Sanofi Genzyme, and Sarepta Therapeutics; received honoraria from Sanofi Genzyme; and undertaken contracted research from Sanofi Genzyme and Ultragenyx. AT has received reimbursement for participation either as a speaker for lectures and symposia or as a Pompe Registry board member from Sanofi Genzyme. ATvdP provided consulting services, participated in advisory board meetings, and received grants for pre-marketing studies and research from industries (eg, Sanofi Genzyme, Biomarin, and Amicus, etc) via agreements between Erasmus MC and the industries. KAH and her spouse, CH, OH-B, JJ, NT, and TZ are employees of Sanofi Genzyme. All other authors declare no competing interests.