Combination of Cipaglucosidase Alfa and Miglustat Shows Sustained Motor and Respiratory Function in Pompe Disease


After 48 months of follow up, cipaglucosidase alfa/miglustat in cohorts of ambulatory patients with Pompe disease had an overall safety profile similar to the approved enzyme replacement therapy.

Tahseen Mozaffar, MD, FAAN, director of the Division of Neuromuscular Diseases, University of California, Irvine

Tahseen Mozaffar, MD, FAAN

Data from the ongoing open-label phase 1/2 study, ATB200-02 (NCT02675465), showed that treatment with cipaglucosidase alfa/miglustat (Amicus Pharma), an investigational two-component therapy for late-onset Pompe disease (LOPD), resulted in sustained, durable mean improvements in motor and respiratory function in both enzyme replacement therapy (ERT)- cohorts and ERT-naïve cohort.1

At 6, 12, 24, 36, and 48 months, pooled analyses of the ERT-experienced cohorts showed improvements in 6-minute walk distance from baseline of 23.1 m (standard deviation [SD], 44.75; n = 16), 33.5 m (SD, 49.62; n = 16), 25.2 m (SD, 63.30; n = 13), and 9.8 m (SD, 85.98; n = 12), 20.7 m (SD, 101.84; n = 9), respectively. Comparatively, the ERT-naïve cohort reported improvements of 36.7 m (SD, 29.08; n = 6) at 6 months, 57.0 m (29.96; n = 6) at 12 months, 54.4 m (SD, 36.18; n = 6) at 24 months, and 43.5 m (45.19; n = 5) at 36 months; and 52.2 m (SD, 46.59; n = 4) at 48 months.

These findings were presented as an abstract presentation in the Therapeutics for Muscle Disease session at the 2023 American Academy of Neurology (AAN) Annual Meeting, April 22-27, in Boston, Massachusetts, by lead author Tahseen Mozaffar, MD, FAAN, director of the Division of Neuromuscular Diseases, University of California, Irvine. The ATB200-02 trial is investigating the long-term efficacy and safety of cipaglucosidase alfa/miglustat, also known as AT-GAA, in adults with Pompe disease. The presentation highlighted biomarker outcomes that were consistent with other efficacy results, as well as an overall safety profile for ambulatory cohorts that was similar to the approved ERT.

The trial enrolled 3 cohorts of adult ambulatory patients based on ERT experience: those with 2 to 6 years (n = 11; aged 18-65 years) or with 7 or more years (n = 6; aged 18-75 years) were both administered 20 mg/kg alglucosidase alfa biweekly, while those who were ERT-naïve (n = 6; aged 18-65 years) were given doses of 20 mg/kg IV cipaglucosidase alfa/260 mg miglustat orally biweekly.

All told, findings showed that percent predicted sitting forced vital capacity (pFVC) was generally stable or improved in the ERT-experienced cohorts, with a mean change from baseline of −0.9% (SD, 8.69; n = 16), −1.2% (SD, 5.95; n = 16), 1.0% (SD, 7.65; n = 13), −0.3% (SD, 6.69; n = 10), and 1.0 (SD, 6.42, n = 6) at 6, 12, 24, 36, and 48 months, respectively. In the ERT-naïve cohort, pFVC improved by 4.2% (SD, 5.04; n = 6), 3.2% (SD, 8.42; n = 6), 4.7% (SD, 5.09; n = 6), 6.2% (SD, 3.35; n = 5), and 8.3% (SD, 4.50, n = 4) at the same respective time points. In ERT-experienced and ERT-naïve cohorts, serum CK and urine Hex4 biomarkers also improved over 48 months.

In October 2022, because of COVID-19-related travel restrictions, the FDA was unable to conduct the required inspection of the WuXi Biologics manufacturing site in China during the review cycle, leading to the deferral on the biologics license application of cipaglucosidase alfa.2 The applications for the combination approach were originally set to be reviewed in mid-2022, with the agency extending the period in May.3

The therapy was also assessed in a phase 3, double-blind, parallel-group PROPEL trial (NCT03729362), the findings of which suggested that AT-GAA improved motor and respiratory functions in Pompe disease compared with an approved ERT, alglucosidase alfa (Lumizyme; Sanofi).4 Those findings were presented at the 2021 Muscular Dystrophy Association’s (MDA) Scientific and Clinical Conference, March 15-18, by Mozaffar.5

In PROPEL, 123 patients who were ERT experienced and naïve were randomly assigned 2:1 to coadministration of AT-GAA (n = 85) or alglucosidase alfa (n = 38) every 2 weeks, at 20-mg/kg doses for each group. They assessed the mean change in 6MWT and percent predicted forced vital capacity (FVC; sitting) from baseline to week 52. Secondarily they evaluated patients with the lower extremities manual muscle test; gait, stairs, Gower, chair test ; and Patient-Reported Outcomes Measurement Information System -physical function and -fatigue.

At week 52, participants in the AT-GAA group showed clinical improvement on 6MWT (mean change, 20.8 m; SD, 7.2) compared with alglucosidase approved therapy (mean change, 7.6 meters; SD, 6.6) but this was not statistically significant (P = .072). A statistically significant improvement in FVC was observed for the AT-GAA group (–0.9 change; SD, 0.7) compared with the alglucosidase group (–4.0 change; SD, 0.8; P = .023).

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1. Mozaffar T, Schoser B, Kishnani P, et al. Long-term Follow-up of Cipaglucosidase Alfa/Miglustat in Ambulatory Patients with Pompe Disease: An Open-label Phase I/II Study (ATB200-02). Presented at: 2023 AAN Annual Meeting; April 22-27, Boston, Massachusetts. Abstract 007. Therapeutics for Muscle Disease session.
2. US FDA defers action on filing for AT-GAA in late-onset Pompe disease. News release. Amicus Therapeutics. October 28, 2022. Accessed May 4, 2023.
3. Amicus Therapeutics Receives Notification of PDUFA Date Extensions for AT-GAA. News release. Amicus. May 10, 2022. Accessed May 4, 2023.
4. Schoser B, Roberts M, Byrne BJ, et al. Safety and efficacy of cipaglucosidase alfa plus miglustat versus alglucosidase alfa plus placebo in late-onset Pompe disease (PROPEL): an international, randomised, double-blind, parallel-group, phase 3 trial. Lancet Neurol. 2021;20(12):1027-1037. doi:10.1016/S1474-4422(21)00331-8
5. Mozaffar T, Bratkovic D, Byrne B, et al. Efficacy and safety of cipaglucosidase alfa/miglustat versus alglucosidase alfa/placebo in late-onset Pompe disease (LOPD): A phase 3 trial (PROPEL). Presented at MDA Clinical and Scientific Conference 2021; March 15–18. Poster 129.
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