Open-Label PROPEL Study Results Highlight Longterm Impact of Cipaglucosidase Alfa and Miglustat in Late-Onset Pompe Disease


The phase 3 PROPEL study demonstrated the long-term effectiveness of cipaglucosidase alfa/miglustat in late-onset Pompe disease, with improved 6-minute walk distance and lung function.

Tahseen Mozaffar, MD, director of the division of neuromuscular diseases in the department of neurology at the School of Medicine at UC Irvine

Tahseen Mozaffar, MD

New data from the phase 3 PROPEL study (NCT04138277) showed that treatment with cipaglucosidase alfa (Pombiliti)/miglustat (Opfolda), a recently approved 2-component agent, was effective in patients with late-onset pompe disease (LOPD) for up to 104 weeks. These data, presented at the 2023 American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) annual meeting, held November 1-4, in Phoenix, Arizona, highlight the longterm sustained impact of this combination approach.1

Led by Tahseen Mozaffar, MD, director of the division of neuromuscular diseases in the department of neurology at the School of Medicine at UC Irvine, 119 patients from the original double-blind trial entered the open-label extension (OLE), 91 of which were enzyme-replacement therapy (ERT)-experienced and 28 who were ERT-naïve. At 104 weeks, the mean change in percentage predicted 6-minute walk distance (6MWD) change was +3.1 (SD, 8.07) for ERT-experienced patients who continued on with cipaglucosidase alfa/miglustat (cipa/mig; n = 82) vs –0.5 (SD, 7.76) for those who switched from alglucosidase alfa/placebo (alg/pbo; n = 37).

Over the same time, investigators observed changes of +8.6 (SD, 8.57) and 8.9 (SD, 11.65) for ERT-naïve patients in the cipa/mig and alg/pbo groups, respectively. Forced vital capacity (FVC), a measure of lung function, was improved through treatment. At the conclusion of the analysis, mean change in percentage predicted FVC was –0.6 (SD, 7.50) for the cipa/mig group and –3.8 (SD, 6.23) for the switch group in ERT-experienced patients, and –4.8 (SD, 6.48) and –3.1 (SD, 6.66) in ERT-naïve patients, respectively.

The 2-component therapy, marketed by Amicus Therapeutics, also improved biomarker levels of creative kinase and hexose tetrasaccharide over the 104-week stretch. During that time, treatment with the combination medication did not result in any new safety signals, with 3 noted patients discontinuing treatment because of infusion-associated reactions of urticaria, urticaria and hypotension, and anaphylaxis.

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The 52-week analysis of the study, published in Neurology in 2022, showed a mean improvement in 6MWD of 14 m with cipa/mig vs approved ERT therapy but did not reach statistical superiority (P = .072). The 2-component therapy achieved a nominally statistically significant and clinically meaningful 3% mean improvement in percentage predicted FVC for superiorirt over approved therapy (P = .023). Outcomes consistently favored cipa/mig in all subgroups for the overall and ERT-experienced populations, regardless of baseline 6MWD and percentage predicted FVC.2

Earlier this year, at the 2023 American Academy of Neurology annual meeting, Mozaffar presented data from an open-label phase 1/2 study (NCT02675465) assessing the combination agent in patients with LOPD. Also known as study ATB200-02, pooled analyses of the ERT-experienced cohorts showed improvements in 6MWD from baseline of 3.1 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, across months 6, 12, 24, and 48 of treatment. 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.3

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 FVC 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.

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1. Mozaffar T, Bratkovic D, Byrne BJ, et al. Long-term efficacy and safety of cipaglucosidase alfa/miglustat in ambulatory patients with Pompe disease: a phase III open-label extension study (ATB200-07). Presented at: AANEM 2023; November 1-4; Phoenix, AZ. POSTER 291
2. Mozaffar T, Bratkovic D, Byrne B, et al. Cipaglucosidase alfa/miglustat versus algucosidas alfa/placebo in late-onset Pompe disease (LOPD): PROPEL study subgroup analyses. Neurology. 2022;98(18 suppl).
3. 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.
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