Long-term effects of avalglucosidase alfa in late-onset Pompe disease

Patients with late-onset Pompe disease treated with avalglucosidase alfa (AVAL) for 97 weeks maintained improvement from baseline in respiratory function, motor function, muscle strength, and health-related quality-of-life in the extended treatment period of the COMET trial. Participants who switched to AVAL after 49 weeks of treatment with alglucosidase alfa (ALGLU) showed stabilisation of treatment effect.

AVAL is a recombinant human GAA enzyme replacement therapy enriched with mannose-6-phosphate to increase cellular uptake compared with ALGLU. In the primary analysis period of the phase 3 COMET trial (NCT02782741), AVAL resulted in greater improvements in forced vital capacity (FVC), which was the primary endpoint, as well as in other outcomes, and a more favourable safety profile compared with ALGLU in 100 treatment-naïve patients with late-onset Pompe disease [1].

The open-label, extended-treatment period of the COMET trial investigated the efficacy and safety of AVAL in late-onset Pompe disease participants after 97 weeks of treatment and safety was measured up to the last follow-up (≥97 weeks) [2]. All 51 participants receiving AVAL (20 mg/kg every 2 weeks) in the primary analysis period continued this treatment in the extended treatment period (AVAL arm). From the remaining 49 participants receiving ALGLU (20 mg/kg every 2 weeks) in the primary analysis period, 44 entered the extended treatment period and received AVAL (switch arm, 20 mg/kg every 2 weeks). Prof. Benedikt Schoser (Friedrich Baur Institute, Germany) presented the results.

At week 97, participants in the AVAL arm had a least-squares mean sustained change of +2.65 (SE 1.05) on FVC% and +18.60 (SE 12.1) for the 6-minute walk test distance. Improvements in secondary efficacy outcomes of max. inspiratory pressure and max. expiratory pressure % predicted also continued. In the switch-arm, the change in FVC% predicted stabilised to +0.36 (SE 1.12) and this was +4.56 (SE 12.44) for the 6-minute walk test distance. Improvements in hand-held dynamometry (HHD) and quick motor function test (QMFT) continued in both arms. Moreover, biomarkers of Pompe disease burden (urinary Hex4 and serum creatine kinase) also improved from baseline to week 97, decreasing to or near the normal range by week 97.

In both treatment groups, no new safety concerns were observed during treatment for a minimum of 97 weeks and participants who switched from ALGLU to AVAL presented no safety- or immunogenicity-related problems. Treatment-emergent serious adverse events were detected in 17 AVAL-arm and 10 switch-arm participants; 4 and 2 of these, respectively, were related to treatment.

Overall, these results support long-term maintenance of clinically meaningful outcomes with AVAL.

1. Diaz-Manera J, et al. Lancet Neurol. 2021;20(12):1012–1026.
2. Schoser B, et al. COMET: Efficacy and safety of avalglucosidase alfa in late-onset Pompe disease participants after 97 weeks of treatment. OPR-019, EAN 2022, 25–28 April, Vienna, Austria.

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Posted on 22 August 2022