Applying the win ratio method in clinical trials of orphan drugs: an analysis of data from the COMET trial of avalglucosidase alfa in patients with late-onset Pompe disease.

"Declarations Ethics approval and consent to participateThe COMET study protocol was approved by the ethics committees or institutional review boards of the participating centers and carried out in accordance with the Declaration of Helsinki and the International Council for Harmonisation guidelines for Good Clinical Practice. Written informed consent was obtained from participants before any study-related procedures. Consent for publicationNot applicable. Competing interestsMB reports receiving speaker honoraria from Sanofi Genzyme, Amicus, Biogen, UCB Pharma, and ITF Pharma; advisory board activities for Sanofi-Genzyme, Amicus, Pharnext, and Biogen; and financial research support from Sanofi-Genzyme and Löwenstein Medical. KIB reports board membership for AskBio, Sanofi Genzyme, Spark Therapeutics, and Takeda; and receiving consulting Fees from Amicus Therapeutics, AskBio, Sanofi Genzyme, Spark Therapeutics, Takeda, and Inventiva Pharma. JDM reports advisory board membership for Sanofi, Sarepta, Amicus, Audentes, and Lupin; consulting fees from Spark Therapeutics, Sanofi, Audentes, and Lupin; contracted research with Spark Therapeutics, Sanofi, Audentes, and Boehringer Ingelheim; intellectual property rights/patent with Boehringer Ingelheim; and travel expenses from Sanofi, Pfizer, and Amicus. MMD serves or recently served as a consultant for Amazentis, ArgenX, Catalyst, Cello, Covance/Labcorp, CSL-Behring, EcoR1, Janssen, Kezar, Medlink, Momenta, NuFactor, Octapharma, Priovant, RaPharma/UCB, Roivant Sciences Inc, Sanofi Genzyme, Shire Takeda, Scholar Rock, Spark Therapeutics, Abata/Third Rock, UCB Biopharma and UpToDate. MMD also received research grants or contracts or educational grants from Alexion, Alnylam Pharmaceuticals, Amicus, Biomarin, Bristol-Myers Squibb, Catalyst, Corbus, CSL-Behring, FDA/OOPD, GlaxoSmithKline, Genentech, Grifols, Kezar, Mitsubishi Tanabe Pharma, MDA, NIH, Novartis, Octapharma, Orphazyme, Ra Pharma/UCB, Sanofi Genzyme, Sarepta Therapeutics, Shire Takeda, Spark Therapeutics, The Myositis Association, UCB Biopharma/RaPharma, Viromed/Healixmith & TMA. AH and NT are employees and stockholders of Sanofi. LRF was an employee of Sanofi at the time of study conduct and holds stock in Sanofi; he is currently an employee of Aixial, a CRO working with Sanofi. PS, JI, and JJC are employed by Evidera, a consultancy that received funding from Sanofi for the work reported here. Competing interests MB reports receiving speaker honoraria from Sanofi Genzyme, Amicus, Biogen, UCB Pharma, and ITF Pharma; advisory board activities for Sanofi-Genzyme, Amicus, Pharnext, and Biogen; and financial research support from Sanofi-Genzyme and Löwenstein Medical. KIB reports board membership for AskBio, Sanofi Genzyme, Spark Therapeutics, and Takeda; and receiving consulting Fees from Amicus Therapeutics, AskBio, Sanofi Genzyme, Spark Therapeutics, Takeda, and Inventiva Pharma. JDM reports advisory board membership for Sanofi, Sarepta, Amicus, Audentes, and Lupin; consulting fees from Spark Therapeutics, Sanofi, Audentes, and Lupin; contracted research with Spark Therapeutics, Sanofi, Audentes, and Boehringer Ingelheim; intellectual property rights/patent with Boehringer Ingelheim; and travel expenses from Sanofi, Pfizer, and Amicus. MMD serves or recently served as a consultant for Amazentis, ArgenX, Catalyst, Cello, Covance/Labcorp, CSL-Behring, EcoR1, Janssen, Kezar, Medlink, Momenta, NuFactor, Octapharma, Priovant, RaPharma/UCB, Roivant Sciences Inc, Sanofi Genzyme, Shire Takeda, Scholar Rock, Spark Therapeutics, Abata/Third Rock, UCB Biopharma and UpToDate. MMD also received research grants or contracts or educational grants from Alexion, Alnylam Pharmaceuticals, Amicus, Biomarin, Bristol-Myers Squibb, Catalyst, Corbus, CSL-Behring, FDA/OOPD, GlaxoSmithKline, Genentech, Grifols, Kezar, Mitsubishi Tanabe Pharma, MDA, NIH, Novartis, Octapharma, Orphazyme, Ra Pharma/UCB, Sanofi Genzyme, Sarepta Therapeutics, Shire Takeda, Spark Therapeutics, The Myositis Association, UCB Biopharma/RaPharma, Viromed/Healixmith & TMA. AH and NT are employees and stockholders of Sanofi. LRF was an employee of Sanofi at the time of study conduct and holds stock in Sanofi; he is currently an employee of Aixial, a CRO working with Sanofi. PS, JI, and JJC are employed by Evidera, a consultancy that received funding from Sanofi for the work reported here."

"Funding The COMET trial and the analysis reported here were funded by Sanofi."

"Data from COMET were reanalyzed with the win ratio approach to assess the overall effect of treatment on the primary endpoint (FVC % predicted) and the key secondary endpoint (6MWT). Details of the COMET trial design were published previously []. Briefly, this was a phase 3, randomized, double-blind trial that took place at 55 sites across 20 countries. Eligibility for COMET required a diagnosis of LOPD confirmed by acid alpha-glucosidase enzyme deficiency, two confirmed pathogenic GAA gene variants, or both; age ≥ 3 years; no previous treatment with Pompe-specific enzyme replacement therapy; and the ability to perform repeated FVC measurements of 30–85% predicted and walk ≥ 40 m without stopping or assistance. Patients were excluded if they required invasive ventilation or were wheelchair-dependent. COMET consisted of a 49-week double-blind primary analysis treatment period followed by an open-label extended treatment period. During the double-blind treatment period, participants were randomly allocated (1:1) to intravenous AVA or ALG, both administered at a dose of 20 mg/kg. FVC % predicted was calculated as the ratio of the actual to the predicted upright forced vital capacity for each participant based on their sex, race, age, and height. 6MWT distance was defined as the distance walked, in meters, over a span of 6 min."