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Clinical Trial
. 2023 Jun 1;80(6):558-567.
doi: 10.1001/jamaneurol.2023.0552.

Efficacy and Safety of Avalglucosidase Alfa in Patients With Late-Onset Pompe Disease After 97 Weeks: A Phase 3 Randomized Clinical Trial

Priya S Kishnani  1 , Jordi Diaz-Manera  2 , Antonio Toscano  3 , Paula R Clemens  4   5 , Shafeeq Ladha  6 , Kenneth I Berger  7   8 , Hani Kushlaf  9   10 , Volker Straub  2 , Gerson Carvalho  11 , Tahseen Mozaffar  12 , Mark Roberts  13 , Shahram Attarian  14 , Yin-Hsiu Chien  15 , Young-Chul Choi  16 , John W Day  17   18 , Sevim Erdem-Ozdamar  19 , Sergey Illarioshkin  20 , Ozlem Goker-Alpan  21 , Anna Kostera-Pruszczyk  22 , Ans T van der Ploeg  23 , Kristina An Haack  24 , Olivier Huynh-Ba  24 , Swathi Tammireddy  25 , Nathan Thibault  25 , Tianyue Zhou  25 , Mazen M Dimachkie  26 , Benedikt Schoser  27 ; COMET Investigator Group
Collaborators, Affiliations
Clinical Trial

Efficacy and Safety of Avalglucosidase Alfa in Patients With Late-Onset Pompe Disease After 97 Weeks: A Phase 3 Randomized Clinical Trial

Priya S Kishnani et al. JAMA Neurol. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Kishnani has received grants from Sanofi Genzyme, Amicus Therapeutics, and Valerion as well as personal fees from Sanofi Genzyme, Amicus Therapeutics, Maze Therapeutics, JCR Pharmaceutical, Vertex, and Asklepios Biopharmaceutical (AskBio) during the conduct of the study; serves on advisory boards for Sanofi Genzyme, Amicus Therapeutics, and Baebies; and holds equity in Asklepios Biopharmaceutical (AskBio), Baebies, and Maze Therapeutics. Dr Diaz-Manera has received grants from Sanofi, Spark, Boehringer Ingelheim, and Audiences as well as personal fees from Sanofi, Amicus, Lupin, Sarepta, and PTC Therapeutics during the conduct of the study. Dr Toscano has received personal fees from Sanofi. Dr Clemens has received grants from Sanofi during the conduct of the study; grants from Amicus, NS Pharma, Spark, ReveraGen Biopharma, National Institutes of Health, and US Food and Drug Administration; institutional funding from Foundation to Eradicate Duchenne; and personal fees from Roche, Epirium, Spark, and NS Pharma outside the submitted work. Dr Ladha has received grants and personal fees from Sanofi outside the submitted work. Dr Berger has received personal fees from Sanofi during the conduct of the study as well as personal fees from Asklepios Biopharmaceutical (AskBio), Spark, Takeda, Amicus, and Valerion outside the submitted work. Dr Kushlaf has received grants from Muscular Dystrophy Association and Healey ALS Platform as well as personal fees from Sanofi, Akcea, Alexion, AstraZeneca, Argenx, Immunovant, UCB, Catalyst Pharmaceuticals, and PTC Therapeutics outside the submitted work. Dr Straub has received grants from Sanofi during the conduct of the study; grants from Astellas Gene Therapy and Ultragenyx; and personal fees from AveXis, Exonics Therapeutic, Roche, Sanofi, and Sarepta Therapeutics outside the submitted work. Dr Mozaffar has received grants from Sanofi, Amicus, Alexion, Alnylam, Baxter, Bio-Blast, Biogen, BioMarin, CSL Behring, Valerion, Spark, Astellas Gene Therapy, Grifols, GlaxoSmithKline, Idera, ISIS Pharmaceuticals, National Institutes of Health, Novartis, and Ultragenyx as well as personal fees from Amicus, BioMarin, Idera, Grifols, Novartis, Sanofi, Ultragenyx, Maze Therapeutics, NuFactor, Sarepta Therapeutics, and Walgreens during the conduct of the study. Dr Roberts has received grants from Amicus; personal fees from Sanofi, BioMarin, NIL, and Amicus; and royalties from NIL. Dr Chien has received grants and personal fees from Sanofi outside the submitted work. Dr Day has received grants from Biogen, Ionis Pharmaceuticals, Cytokinetics, Roche, AveXis, Sanofi, Sarepta Therapeutics, and Scholar Rock as well as personal fees from Audentes, Biogen, Ionis Pharmaceuticals, Cytokinetics, Pfizer, AveXis, Roche/Genentech Pharmaceuticals, AMO Pharmaceuticals, and Sarepta Therapeutics. Dr Erdem-Ozdamar has received personal fees from Sanofi-Genzyme, Pfizer, Biogen, GlaxoSmithKline, CSL Behring, and Alexion outside the submitted work. Dr Illarioshkin has received personal fees from Actelion, Boehringer Ingelheim, Ever Pharma, Merz Pharma, Servier, Takeda, and Teva. Dr Goker-Alpan has received grants from Sanofi-Genzyme during the conduct of the study; grants from Amicus, Freeline, Genentech, Protalix, Sangamo, Sanofi, and Takeda; and personal fees from Sanofi-Genzyme, Amicus, BioMarin, Sanofi, Shire HGT, and Takeda outside the submitted work. Dr Kostera-Pruszczyk has received grants from Sanofi-Genzyme and Biogen; personal fees from Sanofi-Genzyme, Biogen, PTC Therapeutics, Roche, Novartis, Argenx, Takeda, CSL Behring, and UCB; and nonfinancial support from Sanofi-Genzyme, Biogen, PTC Therapeutics, Roche, and CSL Behring outside the submitted work. Dr van der Ploeg has received grants and personal fees from Sanofi-Genzyme paid to his institution during the conduct of the study as well as grants and personal fees from Amicus Therapeutics, Spark, and Denali paid to his institution outside the submitted work. Dr An Haack has a patent for US8759501 issued and a patent for PCT/US2021/037111 pending. Dr Dimachkie has received grants, personal fees, and nonfinancial support from Sanofi during the conduct of the study; grants from Amicus, BioMarin, Spark, Abcuro, Alexion, Alnylam Pharmaceuticals, Bristol Myers Squibb, Catalyst, Corbus, CSL Behring, US Food and Drug Administration/Office of Orphan Products Development, GlaxoSmithKline, Genentech, Grifols, Kezar, Mitsubishi Tanabe Pharma, MDA, National Institutes of Health, Novartis, Octapharma, Orphazyme, Ra Pharma/UCB, Sarepta Therapeutics, Shire Takeda, The Myositis Association, Viromed/Healixmith, and TMA; and personal fees from MDA, Astellas, Spark, Abcuro, Amazentis, ArgenX, Catalyst, Covance/Labcorp, CSL Behring, Cello, Eco-R1, Janssen, Kezar, Medlink, Momenta, NuFactor, Octapharma, Priovant, RaPharma/UCB, RMS Medical, Roivant Sciences, Shire Takeda, Scholar Rock, Abata/Third Rock, UCB Biopharma, and UpToDate outside the submitted work. Dr Schoser has received grants from Amicus as well as personal fees from Sanofi, Amicus, Taysha, Pepgen, Avrobio, Kedrion, Astellas, and Argenx outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Participant Disposition
aOther reasons for discontinuation included patient decision (no reason given; n = 1), difficulty of the visits (n = 1), fear of COVID-19 exposure by coming to clinical site (n = 1), and inability to travel due to COVID-19 (n = 1).
Figure 2.
Figure 2.. Least Squares (LS) Mean Change in Respiratory Function Parameters From Baseline to Week 97
Error bars indicate SEs. FVC indicates forced vital capacity; MEP, maximum expiratory pressure; MIP, maximum inspiratory pressure.
Figure 3.
Figure 3.. Least Squares (LS) Mean Change in Functional Endurance and Motor Function Parameters From Baseline to Week 97
Error bars indicate SEs. 6MWT indicates 6-minute walk test; HHD, hand-held dynamometry; QMFT, Quick Motor Function Test.
See this image and copyright information in PMC

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