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. 2025 Aug 16;272(9):581. doi: 10.1007/s00415-025-13266-y

Efficacy and safety of avalglucosidase alfa in patients with late-onset Pompe disease after 145 weeks of treatment during the COMET trial

Priya S Kishnani 1,✉, Jordi Díaz-Manera 2, Sergey Illarioshkin 3, Ans T van der Ploeg 4, Paula R Clemens 5,6, John W Day 7, Antonio Toscano 8, Hani Kushlaf 9, Shafeeq Ladha 10, Shahram Attarian 11, Gerson Carvalho 12, Anna Kostera-Pruszczyk 13, Sevim Erdem-Özdamar 14, Ozlem Goker-Alpan 15, Tahseen Mozaffar 16, Volker Straub 2, Mark Roberts 17, Kristina An Haack 18, Olivier Huynh-Ba 18, Swathi Tammireddy 19,20, Magali Periquet 19,20, Nathan Thibault 19,20, Tianyue Zhou 19,20, Mazen M Dimachkie 21, Benedikt Schoser, the COMET Investigator Group22
PMCID: PMC12357813  PMID: 40817977

Abstract

Background and objectives

In the COMET trial, avalglucosidase alfa treatment for late-onset Pompe disease was safe, tolerable and associated with stabilization or improvement in disease parameters through 97 weeks. We report outcomes in the trial extension through 145 weeks of treatment.

Methods

In this phase 3, double-blind, randomized trial, participants with previously untreated late-onset Pompe disease were randomly assigned to receive 20 mg/kg avalglucosidase alfa or alglucosidase alfa every other week for 49 weeks; thereafter, all patients received 20 mg/kg avalglucosidase alfa every other week. For this analysis, efficacy was assessed at 145 weeks and safety to last follow-up (data cutoff: March 11, 2022).

Results

Of 100 participants in the double-blind treatment period, 95 entered the open-label extension, and 88 completed ≥ 145 weeks of treatment. At study start, the mean upright FVC percent predicted was similar between treatment arms, and 6MWT distance was greater in the avalglucosidase alfa arm. From baseline to week 145, the LS mean (SE) FVC percent predicted increased by 1.38 (1.22) in the avalglucosidase alfa arm and 1.25 (1.34) in the switch arm. The LS mean (SE) 6MWT distance walked increased by 20.65 (9.60) m and 0.29 (10.42) m, respectively. Potentially treatment-related adverse events were reported in 27 patients (53%) in the avalglucosidase alfa arm and 25 patients (57%) in the switch arm. Anti-drug antibodies declined over time in both arms.

Conclusions

In this randomized clinical trial extension, positive clinical outcomes were maintained for patients taking avalglucosidase alfa for up to 145 weeks with no new safety concerns.

Trial registration

ClinicalTrials.gov, NCT02782741, https://clinicaltrials.gov/ct2/show/NCT02782741. Registration date: 2016-05-23; Date of first patient enrolled: 2016-11-02.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00415-025-13266-y.

Keywords: Late-onset Pompe disease, Acid α-glucosidase deficiency, Avalglucosidase alfa, Alglucosidase alfa

Introduction

Pompe disease is an autosomal recessive neuromuscular disorder caused by a deficiency of the enzyme, acid α-glucosidase (GAA), in affected patients. As GAA breaks down glycogen in lysosomes, GAA deficiency leads to glycogen build-up in muscle, resulting in progressive muscle weakness, respiratory dysfunction, and functional disabilities [1, 2]. Pompe disease has a broad clinical spectrum and varies in time of symptom onset and rate of progression [3–6]. Infantile-onset Pompe disease (IOPD), the more severe form, is characterized by cardiomyopathy in children up to 1 year of age. Disease progression is rapid, and without treatment, these children usually die by 1–2 years of age [2]. Late-onset Pompe disease (LOPD) is characterized by respiratory and mobility dysfunction that often leads to the need for respiratory and ambulatory support [4]. Symptom onset can occur at any age, though it most often occurs in adulthood, and the rate of progression is slower. New research on LOPD manifestations identified by newborn screening revealed variable early presentation, including postural and kinematic concerns, increases in creatine kinase and transaminases, and mild feeding/swallowing abnormalities [7].

The first enzyme replacement therapy for Pompe disease, alglucosidase alfa (Myozyme/Lumizyme, Sanofi, Cambridge, Mass., USA), has been approved for the long-term treatment of patients with Pompe disease in many countries since 2006 [8, 9]. Although the lives of patients with IOPD have been extended by alglucosidase alfa and respiratory and motor function have generally improved or stabilized in patients with either IOPD or LOPD, some patients have experienced clinical decline or sub-optimal treatment response while receiving alglucosidase alfa [10–16]. A longitudinal Pompe Registry analysis showed both a benefit of alglucosidase alfa treatment on FVC trajectory in LOPD for at least 13 years (compared with natural history data) and some lung function decline for most individuals 5 years after initiating treatment [17]. To address this unmet need, avalglucosidase alfa, a recombinant human GAA, has been engineered with 7 synthetic bis-M6P-containing hexasaccharides, resulting in approximately ≈ 15-fold greater mannose-6-phosphate (M6P) content compared with alglucosidase alfa [18, 19], thereby increasing M6P receptor-mediated uptake, a primary pathway for cellular uptake and trafficking to the lysosome [20]. Avalglucosidase alfa (Nexviazyme®/Nexviadyme®, Sanofi, Cambridge, Mass., USA) is approved in several countries for IOPD and/or LOPD, including in the European Union for all patients with Pompe disease and the United States for patients with LOPD ≥ 1 year of age [8, 21].

Outcomes up to 97 weeks in the phase 3, double-blind COMET trial (NCT02782741) comparing avalglucosidase alfa vs alglucosidase alfa in treatment-naïve participants with LOPD were published previously [22, 23]. During the 49-week, double-blind treatment period, avalglucosidase alfa treatment resulted in a trend toward greater improvements in forced vital capacity (FVC), 6-min walk test (6MWT) and other respiratory and motor outcomes, and a slightly more favorable safety profile compared with alglucosidase alfa [22]. In the first 48 weeks of the open-label extension period in which all participants received avalglucosidase alfa, participants who switched from alglucosidase alfa to avalglucosidase alfa maintained stability on these parameters during their first 48 weeks of avalglucosidase alfa treatment [23]. Participants on avalglucosidase alfa for all 97 weeks maintained improvements from baseline in respiratory function, motor function, muscle strength, and health-related quality of life [23]. In both treatment groups, no new safety concerns were observed during the additional 48 weeks of treatment and there were no safety- or immunogenicity-related concerns among those who had switched from alglucosidase alfa to avalglucosidase alfa [23].

Here, we report long-term efficacy and safety outcomes after 145 weeks of treatment in the COMET trial.

Methods

Study design

COMET was a phase 3, multicenter, multinational, randomized trial that compared the efficacy and safety of intravenous avalglucosidase alfa to alglucosidase alfa [22, 23]. Participants were enrolled between November 2, 2016, and February 10, 2021, at 55 centers in 20 countries. In the double-blind treatment period, treatment-naïve participants with LOPD were randomized 1:1 to receive 20 mg/kg of either avalglucosidase alfa or alglucosidase alfa by intravenous infusion every other week for 49 weeks [22]. After the double-blind treatment period, participants entered the open-label extension period, in which all participants received 20 mg/kg of avalglucosidase alfa every other week for up to a total of 289 weeks [23]. Participants who received avalglucosidase alfa in the double-blind treatment period continued this treatment (avalglucosidase alfa arm) and participants who had initially received alglucosidase alfa switched to avalglucosidase alfa (switch arm) (Online Resource 1). At the data cutoff (March 11, 2022), participants had received 145 weeks or more of treatment; participants in the avalglucosidase alfa arm had been receiving avalglucosidase alfa for 145 weeks and participants in the switch arm had been receiving avalglucosidase alfa for 96 weeks. Efficacy outcomes are reported through week 145. Safety data are reported until the last follow-up, which extends beyond 145 weeks for participants enrolled earlier.

Standard protocol approvals, registrations, and patient consents

Informed consent was obtained from participants prior to study-related procedures. The study protocol was reviewed and approved by the appropriate ethics committee or institutional review board governing each participating site and conducted in accordance with the Declaration of Helsinki and the International Council for Harmonisation guidelines for Good Clinical Practice [22]. The COMET trial (NCT02782741) is registered on ClinicalTrials.gov: https://clinicaltrials.gov/ct2/show/NCT02782741.

Participants

Detailed participant inclusion and exclusion criteria have been published [22]. In brief, study participants were ≥ 3 years old with an LOPD diagnosis confirmed by GAA enzyme deficiency from any tissue source and/or two confirmed GAA pathogenic variants and no prior treatment with alglucosidase alfa or any investigational therapy for Pompe disease. Key exclusion criteria were Pompe disease-specific cardiac hypertrophy, invasive ventilation (non-invasive ventilation was permitted), wheelchair dependence, and prior or current use of immune tolerance induction therapy.

Assessments

Long-term efficacy assessments were performed at weeks 61, 73, 97, 121, and 145. Respiratory function was measured by upright FVC percent predicted. Pulmonary function was measured locally and evaluated by a central laboratory according to American Thoracic Society (ATS)/European Respiratory Society (ERS) Task Force guidelines [24]. FVC percent predicted values were based on participants’ age, sex, race, and height according to reference equations [25]. Inspiratory and expiratory muscle strength were measured by upright maximum inspiratory pressure (MIP) percent predicted and maximum expiratory pressure (MEP) percent predicted, respectively. Functional endurance was measured by the 6MWT per ATS guidelines [26], and 6MWT percent predicted was calculated based on normal reference equations for the age range of trial participants [27, 28]. Lower extremity muscle strength was measured with hand-held dynamometry (HHD) [29]. Motor function was assessed with the Quick Motor Function Test (QMFT) [30] based on the Gross Motor Function Measure-88 (GMFM-88) [31, 32], and the Gait, Stair, Gower’s Maneuver, and Chair (GSGC) composite score [33]. The Pompe disease biomarkers, urinary hexose tetrasaccharide (HEX4) and serum creatine kinase (CK), were measured. Health-related quality-of-life assessments included the Short Form-12 (SF-12)—Physical Component Summary (PCS) and Mental Component Summary (MCS) scores [34].

Safety was assessed at each visit by collecting reports of adverse events, including infusion-associated reactions (IAR), serious adverse events, and adverse events of special interest (AESI). Immunogenicity was assessed using a tiered bioanalytical strategy and validated assays. IgG anti-drug antibodies (ADAs) were detected using a direct ELISA, confirmed by binding inhibition and titer by ELISA. ADA-positive participants were also evaluated for neutralizing antibodies using inhibition of enzymatic activity and cell-based inhibition of enzyme uptake assays [22].

Statistical analysis

Hypothesis testing was not performed for this analysis of data up to 145 weeks, because all participants received avalglucosidase alfa starting at Week 49. Efficacy end points were analyzed using a mixed model for repeated measures. Least squares (LS) means and standard error (SE) from the mixed model for repeated measures followed the intention-to-treat approach to include data from all participants to address the issue of missing data (assuming data are missing at random). Different covariance matrix structures were used for analysis of the double-blind treatment period vs this analysis of the double-blind and extension periods combined for FVC, MIP, MEP, and 6MWT. An unstructured covariance matrix was used for analyses of the double-blind treatment period. Heterogeneous Toeplitz (heterogeneous variance and a separate correlation for each level of separation between the time points) was used for analysis of FVC, MIP, MEP, and 6MWT in the combined double-blind and extension periods because the model did not converge with the unstructured covariance matrix, as prespecified in the statistical analysis plan. Unstructured covariance matrix was used for analysis of HHD of lower extremities, QMFT, and SF-12 in the combined double-blind and extension periods. Statistical analyses were performed using SAS version 9.4 (SAS Institute).

Data availability

Qualified researchers may request access to patient-level data and related study documents. Patient-level data will be anonymized, and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi’s data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org/.

The study protocol and statistical analysis plan were published and are freely available as open access [23].

Results

Participants

Of 100 participants who enrolled in the double-blind treatment period, 95 completed the double-blind treatment period and entered the open-label extension period, and 88 completed at least 145 weeks of treatment (48 from the avalglucosidase alfa arm [94%] and 40 from the switch arm [82%]) as of the data download on March 11, 2022 (Online Resource 1). During the extension period, 14 participants discontinued (7 from each treatment arm). One additional pediatric participant (age 9 years), who was enrolled directly into the open-label extension to receive avalglucosidase alfa (i.e., not randomized), was excluded from the efficacy analysis.

The mean (SD) duration of exposure to avalglucosidase alfa was 191.45 weeks (SD: 45.35, range: 70.44‒273.50) in the avalglucosidase alfa arm and 138.27 weeks (SD: 53.35, range: 7.83–230.02) in the switch arm. The demographic and clinical characteristics of the COMET population have been published previously [22].

Efficacy

At week 145, the avalglucosidase alfa arm maintained improvements from baseline in LS mean [SE] FVC percent predicted (+ 1.38 [1.22]), MIP percent predicted (+ 7.69 [1.87]) and MEP percent predicted (+ 14.41 [2.73]) (Fig. 1a–c). The switch arm maintained improvements from baseline in FVC percent predicted (+ 1.25 [1.34]) and continued to improve on MIP (+ 9.72 [2.07]) and MEP (+ 15.94 [2.99]) percent predicted. In the switch arm, LS mean (SE) FVC percent predicted increased by + 0.65 (0.94) from week 49 (when those participants switched from alglucosidase alfa to avalglucosidase alfa) to week 145.

Fig. 1.

Fig. 1

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Least squares (LS) mean change in respiratory function parameters from baseline to week 145. A Upright FVC percent predicted. B Upright MIP percent predicted. C Upright MEP percent predicted. FVC: forced vital capacity; MEP: maximal expiratory pressure; MIP; maximal inspiratory pressure; SE, standard error. *1 participant’s FVC percent predicted value at week 97 was excluded due to a physiologically implausible change between weeks 73 & 97 and 97 & 121. †4 participants (2 in each group) were excluded from the MIP and MEP percent predicted analyses due to implausible values at baseline

Individual participants’ FVC, MIP and MEP percent predicted data from baseline to week 145 are shown in Online Resource 2.

At week 145, the avalglucosidase alfa arm sustained improvements from baseline in the LS mean (SE) 6MWT distance walked (+ 20.65 [9.60] m, Fig. 2a) and 6MWT percent predicted (+ 3.90 [1.46], Online Resource 3). Switch-arm participants maintained baseline levels on the 6MWT, with LS mean (SE) change from baseline to week 145 of + 0.29 (10.42) meters for distance walked (Fig. 2a) and + 0.54 (1.58) for 6MWT percent predicted (Online Resource 4). Individual participants’ 6MWT distances from baseline to week 145 are shown in Online Resource 4. The HHD lower extremity composite score (+ 177.22 [69.22] and + 154.90 [74.92], Fig. 2b) and QMFT total score in (+ 4.27 (0.80) and + 1.93 (0.90), Fig. 2c) improved from baseline to week 145 in both treatment arms (avalglucosidase alfa arm and switch arm, respectively). The SF-12 PCS score improved from baseline to week 145 in the avalglucosidase alfa arm (LS mean [SE] + 4.07 [0.88]) and the switch arm (LS mean [SE] + 3.83 [0.98]) (Fig. 2d); the SF-12 MCS score remained stable in both arms (Online Resource 5). On the GMFM-88 standing and walking total score and GCSC total score, the avalglucosidase alfa arm maintained improvements and the switch arm remained stable but without improvement (Online Resource 6).

Fig. 2.

Fig. 2

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Least squares (LS) mean change in functional and motor parameters from baseline to week 145. A Six-minute walk test (6MWT). B Lower extremity hand-held dynamometry (HHD). C Quick Motor Function Test (QMFT). D Short-form 12-item (SF-12) physical component summary (PCS). SE: standard error. Note: Two participants in the avalglucosidase alfa arm had unexplained decreases in HHD (lower extremity) composite scores from Week 61 to 73, which contributed substantially to the group LS mean decrease during that time interval. Scores for both participants stabilized following Week 73. No participant- or treatment-related factors were identified as reasons for this decrease

In both the avalglucosidase alfa and switch arms, levels of urinary HEX4 (nmol/mol), a biomarker of glycogen burden, decreased from baseline to week 145 with mean (SD) percent changes of − 53.35 (72.73) and − 48.04 (41.97), respectively (Fig. 3a). Similarly, serum CK, a biomarker that may reflect muscle damage, decreased from baseline to week 145 in both the avalglucosidase alfa and switch arms (percent change − 39.01 [32.41] and − 30.42 [28.41], respectively) (Fig. 3b). Mean HEX4 and CK levels at week 145 were within or near the normal range (Online Resource 7).

Fig. 3.

Fig. 3

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Mean percent change in biomarkers from baseline to week 145. A Urinary hexose tetrasaccharide (HEX4). B Serum creatine kinase (CK). SD: standard deviation

Safety

Adverse events that occurred while participants were receiving avalglucosidase alfa are summarized in Table 1. These include events during the double-blind and extension periods (baseline to week 145 or last follow-up) for the avalglucosidase alfa arm and the extension period only (week 49 to week 145 or last follow-up) for the switch arm. Table 1 shows similar safety profiles for avalglucosidase alfa among participants who were treatment naïve at the start of avalglucosidase alfa treatment and those who switched from alglucosidase alfa to avalglucosidase alfa. Rates of severe adverse events, adverse and serious adverse events related to treatment, adverse events leading to discontinuation, and protocol-defined IARs were similar between the two treatment arms.

Table 1.

Summary of adverse events during avalglucosidase alfa treatment

Avalglucosidase alfa arma
(N = 51)		 Switch arma
(N = 44)
Any adverse event 50 (98) 43 (98)
Adverse events potentially related to treatment 27 (53) 25 (57)
Serious adverse events 18 (35) 12 (27)
Serious adverse events potentially related to treatment 4 (8) 2 (5)
Severe adverse events 12 (24) 10 (23)
Adverse events leading to permanent treatment discontinuationb 2 (4) 3 (7)
Adverse events leading to death 0 1 (2)c
Protocol-defined infusion-associated reactionsd 21 (41) 21 (48)
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Data cut-off: March 11, 2022. Numbers reported are the number (%) of participants with at least 1 TEAE in each category

aParticipants in the avalglucosidase alfa arm received avalglucosidase alfa for 145 weeks. Participants in the switch arm switched from alglucosidase alfa to avalglucosidase alfa after week 49, and thus received avalglucosidase alfa for 97 weeks

b5 participants discontinued treatment during the extension period by week 145 for 6 adverse events (treatment-related: ocular hyperemia and erythema (experienced by the same participant), urticaria, respiratory distress; non-treatment related: acute myocardial infarction, pancreatic adenocarcinoma

cPancreatic adenocarcinoma considered not related to treatment

dDefined as an adverse event that occurred during either the infusion or observation period following the infusion, related or possibly related to the investigational treatment

Five participants discontinued during the extension phase due to six adverse events: four treatment-related events (ocular hyperemia and erythema experienced by the same participant, urticaria in one participant, and respiratory distress in one participant) and two non-treatment-related events (acute myocardial infarction in one participant and fatal pancreatic adenocarcinoma in one participant). During the extension period, 13 (25%) participants in the avalglucosidase alfa arm and 12 (27%) in the switch arm experienced serious adverse events; these were deemed treatment related in three avalglucosidase alfa participants (pruritus in one participant, nausea in one participant and headache, skin discoloration, chills, blood pressure increased, body temperature increased, heart rate increased, and oxygen increased in one participant) and two switch participants (urticaria in one participant and respiratory distress and tongue edema in one participant).

Immunogenicity

In the avalglucosidase alfa arm, 12/51 (23.5%) participants had titers ≥ 12,800 at any time point. The proportion of these participants with high ADA titers (≥ 12,800) decreased from baseline to week 97 and week 145, and a majority of participants had ADA titers in the low range at week 145 (Fig. 4a). At week 145, 46 avalglucosidase alfa participants had available titers: 33 were positive, of which 3 had high titers (12,800, 25,600 and 51,200).

Fig. 4.

Fig. 4

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Anti-avalglucosidase alfa antibody titers at weeks 49, 97 and 145. A Participants in the avalglucosidase alfa arm. B Participants who switched from alglucosidase alfa to avalglucosidase alfa at week 49. Percentages are based on the number of participants at week 49. At some timepoints, the total number of participants across titer categories is less than 100% due to the number of participants with available data and participant discontinuations

Previous exposure to alglucosidase alfa appeared to provide a degree of immune tolerance in participants who switched to avalglucosidase alfa. A majority of these participants (86%) were anti-avalglucosidase alfa ADA-positive at the time of switch due to cross-reactivity. In patients with existing ADA at switch, titers boosted by no more than 2 titer levels. Six participants developed an attenuated ADA response after the switch (five tolerized and one had a transient response). In the switch arm, the proportion of participants with high ADA titers (≥ 12,800) increased from baseline to week 97 and decreased from week 97 to week 145 (Fig. 4b). Among switch participants, 8/44 (18.2%) had titers < 12,800 before switch (i.e., up to Week 49) and titers > 12,800 after switch, and 17/44 (38.6%) had titers ≥ 12,800 before switch, of which 3 (6.8%) had titers < 12,800 after switch, 11 (22.7%) had stable titers ≥ 12,800 before and after switch, and 3 (6.8%) had increased titers after switch.

Discussion

This analysis from the COMET trial adds to the evidence base supporting long-term avalglucosidase alfa treatment for LOPD. During the double-blind treatment period (baseline to week 49), avalglucosidase alfa had a trend toward more favorable effects than alglucosidase alfa on respiratory, motor, and patient-reported outcomes in treatment-naïve participants with LOPD [22]. The first 48 weeks of the open-label extension period (week 49 to week 97) demonstrated stabilization and maintenance of early improvements for participants treated with avalglucosidase alfa over 97 weeks (avalglucosidase alfa arm), as well as stabilization of these parameters during the first 48 weeks of avalglucosidase alfa treatment among switch participants [23].

For the treatment-naive participants who received avalglucosidase alfa for all 145 weeks, substantial early gains in most respiratory and motor function parameters were either maintained or further improved up to 145 weeks of treatment. This trend is consistent with the findings of the phase 1 NEO1 trial of avalglucosidase alfa [35] and 6 years of follow-up in the phase 2 NEO-EXT extension study [36]. Furthermore, concurrent decreases in urinary HEX4 and serum creatine kinase were also maintained, reflecting long-term control of glycogen burden and muscle damage, respectively. These findings support avalglucosidase alfa as a first-line treatment for LOPD.

For participants who received alglucosidase alfa for the first 49 weeks, early gains in respiratory function, motor function and biomarkers were smaller than gains in the avalglucosidase alfa arm. After they switched to avalglucosidase alfa, respiratory function parameters (FVC, MIP and MEP percent predicted), two physical function parameters (HHD lower extremity composite score and SF-12 PCS score) and Pompe disease biomarkers further improved from week 49 to week 145, such that changes from baseline at week 145 were comparable to those in the avalglucosidase alfa arm. Switch arm participants remained stable but did not improve as much as the avalglucosidase alfa arm on 6MWT distance, 6MWT percent predicted, and the QMFT, GMFM-88 and GCSC total scores. Because alglucosidase alfa is known to yield lower cellular enzyme uptake compared with avalglucosidase alfa, incomplete degradation of glycogen during the 49 weeks of alglucosidase alfa treatment may have allowed some continued disease progression at the cellular level [18–20, 37]. The stability after switching and apparent catch-up effect on some parameters support avalglucosidase alfa for second-line treatment of LOPD and suggest that earlier initiation of avalglucosidase alfa may be beneficial.

The fact that switch participants did not have an increase in adverse events or immunogenicity after switching demonstrates that patients with LOPD can safely switch from alglucosidase alfa to avalglucosidase alfa in a clinical setting [23]. Participants who received avalglucosidase alfa for 145 weeks had decreasing ADA titers over time irrespective of starting or peak ADA titers. The proportion of participants with titers ≥ 12,800 decreased and the proportion who tolerized during the extension period increased over time (Fig. 4). Most participants who remained ADA-positive at week 145 had titers in the low range (100–800).

For patients with LOPD and their physicians, maintaining respiratory function, ambulation and functional endurance over time are clinically meaningful outcomes, given the progressive decline that occurs in untreated Pompe disease [4, 38–40] and in some patients during long-term treatment with alglucosidase alfa [17, 41, 42]. Thus, even small gains or maintenance of function observed in the COMET trial show that avalglucosidase alfa can offset the progressive course of LOPD more effectively than alglucosidase alfa. Collectively, the three respiratory function parameters (FVC, MIP and MEP percent predicted), two physical function parameters (HHD lower extremity composite score and SF-12 PCS score) and Pompe disease biomarkers improved with avalglucosidase alfa treatment, whether started at baseline (avalglucosidase alfa arm) or week 49 (switch arm).

Certain limitations of this long-term analysis from a double-blind trial with treatment crossover must be considered. Since the comparator group switched treatment to avalglucosidase alfa during the extension period, direct comparisons to long-term alglucosidase alfa treatment cannot be made within the context of this study. While participants in both treatment arms would be expected to receive the same or similar multidisciplinary care in a large-scale, randomized, multinational study of this kind, we did not evaluate the impact of any variances in multidisciplinary and supportive care. Stability in both study groups over 3 years, whether they started treatment on avalglucosidase alfa or switched treatment to avalglucosidase alfa, may be compared to real-world studies that have shown a decline starting at 2–3 years of treatment with alglucosidase alfa [10–16]. Data from ongoing real-world experience with avalglucosidase alfa treatment will be important for evaluating its effectiveness and safety long term.

Conclusions

In the COMET trial extension, participants treated with avalglucosidase alfa for 145 weeks maintained improvements from baseline in respiratory function, motor function, muscle strength, and biomarkers of Pompe disease. Participants who switched from alglucosidase alfa to avalglucosidase alfa improved or maintained stability on these parameters and experienced no new safety- or immunogenicity-related concerns after switching. These data support the long-term maintenance of clinically meaningful outcomes with avalglucosidase alfa in patients with LOPD.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 964 KB) (964.3KB, docx)

Acknowledgements

The COMET trial was sponsored by Sanofi. The authors acknowledge the trial investigators and team members at the study sites listed in the Online Resource to this manuscript; Yi Wang, PhD, of Sanofi for statistical support; Jane M. Gilbert, BSc, CMPP and Kim Coleman Healy, PhD, CMPP of Elevate Scientific Solutions for publication support services (contracted by Sanofi); and Laurie LaRusso, MS, ELS, of Chestnut Medical Communications for medical writing and editing (contracted by Sanofi). The contents of this manuscript do not reflect the views of the Department of Veterans Affairs or the U.S. government.

Declarations

Conflicts of interest

P.S. Kishnani—Consultant/Advisory Board: Amicus Therapeutics, Asklepios Biopharmaceutical, Inc.), JCR Pharmaceuticals, Maze Therapeutics, and Sanofi. Grant/Research Support: Amicus Therapeutics and Sanofi. Other Financial or Material Support: Amicus Therapeutics, Baebies, and Sanofi (Pompe and Gaucher Disease Registry); Asklepios Biopharmaceutical, Inc. (equity options); and Maze Therapeutics (equity which is developing a small molecule therapy for Pompe disease); J. Díaz-Manera—Consultant/Advisory Board: Amicus, Audentes, Lupin, Sanofi, Sarepta, and Spark Therapeutics. Grant/Research Support: Audentes, Boehringer Ingelheim, Sanofi, and Spark Therapeutics. Other Financial or Material Support: Boehringer Ingelheim (receipt of intellectual property rights/patent holder); S. Illarioshkin—Speakers Bureau/Honoraria for non-CME: Ever Pharma, Merz Pharma, and Servier; A.T. van der Ploeg—Consultant/Advisory Board: Amicus, BioMarin, Sanofi, and Spark Therapeutics. Grant/Research Support: Amicus, BioMarin, Sanofi, and Spark Therapeutics; P.R. Clemens—Consultant/Advisory Board: Epirium Bio, Pompe Registry North American Advisory Board, TRiNDS Catalyst Education and Med Learning Group. Grant/Research Support: Amicus, NS Pharma, ReveraGen BioPharma, Sanofi, and Spark Therapeutics; J.W. Day—Consultant/Advisory Board: Affinia Therapeutics, AMO Pharma, Avidity Biosciences, Biogen, Cytokinetics, Epirium Bio, Ionis Pharmaceuticals, Kate Therapeutics, Novartis Gene Therapies, Roche/Genentech Pharmaceuticals, Sarepta Therapeutics, Scholar Rock, Shift Therapeutics, Vertex Pharmaceuticals. Grant/Research Support: AMO Pharma, Audentes, Astellas Gene Therapies, Avidity Biosciences, Biogen, Cure SMA, Cytokinetics, Genentech, Ionis Pharmaceuticals, Muscular Dystrophy Association, Novartis Gene Therapies, Roche Pharmaceuticals, Sanofi, Sarepta Therapeutics, Scholar Rock, SMA Foundation. Patent holder/Royalties: Athena Diagnostics for Genetic Testing; A. Toscano—Member of the European Reference Network for Neuromuscular Disorders (ERN-NMD)—Project ID No 739543; H. Kushlaf—Consultant/Advisory Board: Argenx, Immunovant, Sanofi, Takeda, and UCB. Speakers Bureau/Honoraria for non-CME: Akcea Therapeutics; S. Ladha—Consultant/Advisory Board: Sanofi. Grant/Research Support: Sanofi. Speakers Bureau/Honoraria for non-CME: Sanofi; S. Attarian—Nothing to disclose; G. Carvalho—Nothing to disclose; A. Kostera-Pruszczyk—Consultant/Advisory Board: Argenx, Biogen, Roche, and PTC Therapeutics. Grant/Research Support: Biogen, Kedrion Biopharma, Sanofi, and Takeda. Speakers Bureau/Honoraria for non-CME: Biogen, CSL Behring, Kedrion Biopharma, Novartis, PTC Therapeutics, Roche, Sanofi, and Takeda; S. Erdem-Özdamar—Speakers Bureau/Honoraria for non-CME: Sanofi; O. Goker-Alpan—Consultant/Advisory Board: AVROBIO, Chiesi, Prevail Therapeutics, Sanofi, and Takeda. Grant/Research Support: 4D Molecular Therapeutics, Homology Medicines, and Spark Therapeutics; T. Mozaffar—Consultant/Advisory Board: Alexion Pharmaceuticals, Argenx, Astellas Gene Therapies, Avro Bio, Sanofi, Spark Therapeutics, and Maze Therapeutics; V. Straub—Consultant/Advisory Board: Sanofi. Grant/Research Support: Astellas Gene Therapies and Sanofi. Speakers Bureau/Honoraria for non-CME: Sanofi; M. Roberts—Consultant/Advisory Board: Amicus and Sanofi; K. An Haack—Employee: Sanofi. Stock Ownership/Stock Option: Sanofi; O. Huynh-Ba—Employee: Sanofi. Stock Ownership/Stock Option: Sanofi; S. Tammireddy—Employee: Sanofi. Stock Ownership/Stock Option: Sanofi; M. Periquet—Former Employee: Sanofi (Sanofi employee at the time of manuscript preparation). Stock Ownership/Stock Option: Sanofi; N. Thibault—Employee: Sanofi. Stock Ownership/Stock Option: Sanofi; T. Zhou—Employee: Sanofi. Stock Ownership/Stock Option: Sanofi; M.M. Dimachkie—Consultant/Advisory Board: Abata/Third Rock, Abcuro, Amazentis, Argenx, Catalyst Pharmaceuticals, Cello, Covance/Labcorp, CSL-Behring, EcoR1, Janssen Pharmaceuticals, Kezar Life Sciences, MDA, Momenta, NuFactor, Octapharma, Priovant, Ra Pharma/UCB, Roivant Sciences Inc, Sanofi, Shire Takeda, Scholar Rock, Spark Therapeutics, UCB Biopharma. Grant/Research Support: Alexion, Alnylam Pharmaceuticals, Amicus, BioMarin, Bristol-Myers Squibb, Catalyst Pharmaceuticals, Corbus Grifols, CSL Behring, FDA/OOPD, GlaxoSmithKline, Genentech, Grifols, Kezar Life Sciences, Mitsubishi Tanabe Pharma, MDA, NIH, Novartis, Octapharma, Orphazyme, Ra Pharma/UCB, Sanofi, Sarepta Therapeutics, Shire Takeda, Spark Therapeutics, The Myositis Association, UCB Biopharma/Ra Pharma, Viromed/Helixmith, and TMA. Patent Holder/Royalties: Medlink and UpToDate; B. Schoser—Consultant/Advisory Board: Amicus, Argenx, Astellas, Maze, Sanofi, Pepgen, and Taysha; Grant/Research Support: Amicus and Astellas.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary file1 (DOCX 964 KB) (964.3KB, docx)

Data Availability Statement

Qualified researchers may request access to patient-level data and related study documents. Patient-level data will be anonymized, and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi’s data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org/.

The study protocol and statistical analysis plan were published and are freely available as open access [23].

Articles from Journal of Neurology are provided here courtesy of Springer

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