Mini-COMET: Safety and Efficacy of ≥97 Weeks’ Avalglucosidase Alfa in Infantile-Onset Pompe Disease Participants Previously Treated With Alglucosidase Alfa

Author Type(s)

Faculty

Document Type

Abstract

Publication Date

2022

DOI

10.1016/j.gim.2022.01.566

Journal Title

Genetics in Medicine

Department

Pediatrics

Abstract

Introduction: Pompe disease is a rare, progressive neuromuscular disorder caused by lysosomal acid α-glucosidase (GAA) deficiency and glycogen accumulation, leading to cellular dysfunction, progressive muscle damage, and functional disabilities. Patients with infantile-onset Pompe disease (IOPD) experience life-threatening cardiac, respiratory, and motor pathology from GAA deficiency. While treatment with alglucosidase alfa has improved the survival, cardiac function, and motor development of patients with IOPD, a significant unmet clinical need remains. Avalglucosidase alfa has been designed with an ∼15-fold increase in mannose-6-phosphate (M6P) content versus alglucosidase alfa, to improve cation-independent M6P receptor-mediated uptake, glycogen clearance, and hence clinical efficacy. Avalglucosidase alfa is approved in the United States for patients with late-onset Pompe disease aged ≥1 year and in Japan for all patients with Pompe disease. Methods: Mini-COMET (NCT03019406), a phase 2, open-label, ascending-dose, 3-cohort study, enrolled 22 participants aged 1–12 years with IOPD who had previously received a stable dose of alglucosidase alfa for ≥6 months and demonstrated clinical decline or sub-optimal response (per-protocol). In the 25-week primary analysis period (PAP), participants received the following: Cohort 1 – avalglucosidase alfa 20 mg/kg every 2 weeks (qow [n=6]); Cohort 2 – avalglucosidase alfa 40 mg/kg qow (n=5); Cohort 3 avalglucosidase alfa arm – avalglucosidase alfa 40 mg/kg qow (n=5); and Cohort 3 alglucosidase alfa arm – pre-enrollment stable dose of alglucosidase alfa (n=6; 20 mg/kg qow [n=1], 40 mg/kg qow [n=2], 20 mg/kg weekly [qw; n=1], 30 mg/kg qw [n=1], and 40 mg/kg qw [n=1]). All 22 participants entered the open-label extended treatment period (ETP) to receive avalglucosidase alfa 20 mg/kg or 40 mg/kg qow or their maximum tolerated avalglucosidase alfa dose. Per-protocol, Cohort 1 participants were to continue on avalglucosidase alfa 20 mg/kg qow in the ETP, unless they had further clinical decline, in which case their dose could be increased to 40 mg/kg qow. Cohort 2 and Cohort 3 – avalglucosidase alfa-arm participants were to continue on their 40 mg/kg qow avalglucosidase dose. Cohort 3 – alglucosidase alfa-arm participants were to switch to avalglucosidase alfa 40 mg/kg qow. Results: The first participant enrolled in Mini-COMET on October 12, 2017 and at data cut-off (March 19, 2021) participants had been on-study for ≥97 weeks. Of the 22 participants, 20 are receiving avalglucosidase alfa at 40 mg/kg qow and 2 participants from Cohort 1 remain on avalglucosidase alfa 20 mg/kg qow. Median treatment compliance was 100%. Safety profiles in the PAP and ETP were similar. There were no treatment-related serious or severe treatment-emergent adverse events (TEAEs) or deaths. All 22 participants had TEAEs, with 11 having events considered possibly related to treatment. Most common TEAEs in the ETP were rash (8 participants); fall, pneumonia, and pyrexia (7 participants each); headache and upper respiratory tract infection (6 participants each); and vomiting (5 participants). Most common TEAEs considered possibly related to treatment in the ETP were rash (4 participants), urticaria and nausea (3 participants each). The higher avalglucosidase alfa dose (40 mg/kg qow) was well-tolerated, with no increased safety risk seen in participants who switched from alglucosidase alfa to avalglucosidase alfa. Immune response in patients switched from alglucosidase alfa to avalglucosidase alfa was modest, with immunoglobulin (Ig)G antidrug antibody (ADA) peak titers and ADA persistence to avalglucosidase alfa no greater than the experience with alglucosidase alfa. Three participants receiving avalglucosidase alfa 40 mg/kg qow had peak or last avalglucosidase alfa ADA titer of 6400. Anti-alglucosidase alfa ADA were low in all participants at Baseline (Week 0); 3 participants showed increase in alglucosidase alfa ADA after switching to avalglucosidase alfa, with concurrent less immuno eactivity to avalglucosidase alfa. Most participants had motor decline prior to enrollment. On avalglucosidase alfa, participants’ motor function, measured by Gross Motor Function Measure-88 (GMFM-88), Quick Motor Function Test (QMFT), and Pompe specific Pediatric Evaluation of Disability Inventory (Pompe-PEDI) Functional Skills Scale: Mobility Domain was stable or showed improvements (Table). At Baseline, 1 participant in Cohort 2 had an abnormal left-ventricular mass (LVM) Z-score (2.8 [normal range −2 to 2]), which improved during the PAP to within normal range. At Week 97, all participants had LVM Z-scores within normal range. Biomarkers levels for muscle damage (creatine kinase) and glycogen burden (hexose tetrasaccharide) were increased at Baseline in all cohorts and continuously trended towards the upper limits of normal over time (Table). Conclusion: These data support the positive clinical impact on motor and cardiac function with use of avalglucosidase alfa in patients with IOPD, even the patients who were on the highest alglucosidase alfa doses improved when switching to a lower dose of avalglucosidase alfa (40 mg/kg qow). Avalglucosidase alfa was well-tolerated, with no increased safety risk seen in participants switching from alglucosidase alfa to avalglucosidase alfa. [Formula presented]

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