Safety and efficacy of avalglucosidase alfa versus alglucosidase alfa in patients with late-onset Pompe disease (COMET): a phase 3, randomised, multicentre trial
Por:
Diaz-Manera, J, Kishnani, PS, Kushlaf, H, Ladha, S, Mozaffar, T, Straub, V, Toscano, A, Van der Ploeg, AT, Berger, KI, Clemens, PR, Chien, YH, Day, JW, Illarioshkin, S, Roberts, M, Attarian, S, Borges, JL, Bouhour, F, Choi, YC, Erdem-Ozdamar, S, Goker-Alpan, O, Kostera-Pruszczyk, A, Haack, KA, Hug, C, Huynh-Ba, O, Johnson, J, Thibault, N, Zhou, TY, Dimachkie, MM, Schoser, B
Publicada:
1 dic 2021
Resumen:
Background Pompe disease is a rare, progressive neuromuscular disorder caused by deficiency of acid ti-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-phosphatereceptor 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 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% (S E 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 3001 in [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 W.2 800) 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 ofclinically meaningful improvement with avalglucosida se 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.
Filiaciones:
Diaz-Manera, J:
Newcastle Univ, John Walton Muscular Dystrophy Res Ctr, Ctr Life, Newcastle Upon Tyne, Tyne & Wear, England
Hosp Santa Creu & Sant Pau, Dept Neurol, Neuromuscular Dis Unit, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Raras CIBERER, Barcelona, Spain
Kishnani, PS:
Duke Univ, Div Med Genet, Dept Pediat, Med Ctr, Durham, NC USA
Kushlaf, H:
Univ Cincinnati, Dept Neurol & Rehabil Med, Cincinnati, OH USA
Univ Cincinnati, Dept Pathol & Lab Med, Cincinnati, OH USA
Ladha, S:
Barrow Neurol Inst, Gregory Fulton ALS & Neuromuscular Ctr, Phoenix, AZ 85013 USA
Mozaffar, T:
Univ Calif Irvine, Dept Neurol, Irvine, CA 92717 USA
Straub, V:
Newcastle Univ, John Walton Muscular Dystrophy Res Ctr, Ctr Life, Newcastle Upon Tyne, Tyne & Wear, England
Toscano, A:
Univ Messina, Dept Clin & Expt Med, Reference Ctr Rare Neuromuscular Disorders, Messina, Italy
Van der Ploeg, AT:
Erasmus MC, Univ Med Ctr, Ctr Lysosomal & Metab Dis, Rotterdam, Netherlands
Berger, KI:
NYU, Grossman Sch Med, Div Pulm Crit Care & Sleep Med, New York, NY USA
Bellevue Hosp, Andre Cournand Pulm Physiol Lab, New York, NY USA
Clemens, PR:
Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA
Dept Vet Affairs Med Ctr, Pittsburgh, PA USA
Chien, YH:
Natl Taiwan Univ Hosp, Dept Med Genet & Pediat, Taipei, Taiwan
Day, JW:
Stanford Univ, Dept Neurol, Stanford, CA 94305 USA
Stanford Univ, Dept Pediat, Stanford, CA 94305 USA
Illarioshkin, S:
Res Ctr Neurol, Moscow, Russia
Roberts, M:
Salford Royal NHS Fdn Trust, Salford, Lancs, England
Attarian, S:
Hop La Timone, Referral Ctr Neuromuscular Dis & ALS, Marseille, France
Borges, JL:
Clin Res Ctr Brazil, Brasilia, DF, Brazil
Bouhour, F:
Hop Neurol, Referral Ctr Neuromuscular Dis, Lyon, France
Choi, YC:
Yonsei Univ, Gangnam Severance Hosp, Coll Med, Seoul, South Korea
Erdem-Ozdamar, S:
Hacettepe Univ, Dept Neurol, Ankara, Turkey
Goker-Alpan, O:
Lysosomal & Rare Disorders Res & Treatment Ctr LD, Fairfax, VA USA
Kostera-Pruszczyk, A:
Med Univ Warsaw, Dept Neurol, Warsaw, Poland
Haack, KA:
Sanofi Genzyme, Shanghai, Peoples R China
Hug, C:
Sanofi Genzyme, Cambridge, MA USA
Huynh-Ba, O:
Sanofi Genzyme, Chilly Mazarin, France
Johnson, J:
Sanofi Genzyme, Cambridge, MA USA
Thibault, N:
Sanofi Genzyme, Cambridge, MA USA
Zhou, TY:
Sanofi Genzyme, Cambridge, MA USA
Dimachkie, MM:
Univ Kansas, Med Ctr, Dept Neurol, Kansas City, KS 66103 USA
Schoser, B:
LMU Klinikum Munchen, Friedrich Baur Inst, Dept Neurol, Munich, Germany
Open Access
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