Correction to “Comments on: Increasing Enzyme Mannose-6-Phosphate Levels but Not Miglustat Coadministration Enhances the Efficacy of Enzyme Replacement Therapy in Pompe Mice”

doi:10.1124/jpet.123.002014err

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Comments on: Increasing Enzyme Mannose-6-Phosphate Levels but Not Miglustat Coadministration Enhances the Efficacy of Enzyme Replacement Therapy in Pompe Mice - June 01, 2024

The above article [Brudvig JJ, Tuske S, Castelli J, Weimer JM (2024) J Pharmacol Exp Ther, 389:310–312; DOI: https://doi.org/10.1124/jpet.123.002014], contained errors in Fig. 1B. The human AUC value should be 1410 (μg x h/ml) for 0 mg/kg miglustat and should be 1812 (μg x h/ml) for miglustat 260 mg (∼10 mg/kg). The human T_1/2 (h) should be 2.2 (↑47.7%) for miglustat 260 mg (∼10 mg/kg). The human AUC units should be μg (=microgram) rather than ng (=nanogram).

Fig. 1.

Miglustat coadministration increases cipaglucosidase alfa exposure in mice and humans and enhances glycogen clearance and musculoskeletal function in Pompe mice. (A) The stability of alglucosidase alfa and cipaglucosidase alfa were measured with a fluorescence-based thermal denaturation assay as previously described (Center for Drug Evaluation and Research, 2023). The two enzymes display similar thermal stability profiles, with lower stability at pH 7.4 versus pH 5.2. Melting temperatures (T_m) for each condition are shown in the key to the right of the graph. (B) Pompe (Gaa KO) mice on 129/SVE genetic background at 20 weeks of age (n = 5 5/group) were administered cipaglucosidase alfa with or without miglustat, and ERT exposure area under the curve (AUC) was measured with an enzyme activity assay and reported as units of hydrolyzed 4-MU-Glc. Individuals with Pompe disease (ERT-switch ambulatory patients, n = 11) were administered cipaglucosidase alfa with or without miglustat, and ERT exposure AUC was measured with a liquid chromatography tandem mass spectrometry (LC-MS/MS) rhGAA signature peptide assay and reported as mass of protein (Johnson et al., 2022). Miglustat increased exposure (AUC) by 6.8% in mice and 28.5% in humans and increased half-life by 27.4% in mice and 60.0% in humans. (C–E) Gaa KO mice (n = 5–8 male mice/group) were treated at 12–16 weeks of age with biweekly intravenous injections of vehicle, 20 mg/kg alglucosidase alfa, 20 mg/kg cipaglucosidase alfa, or 20 mg/kg cipaglucosidase alfa plus 10 mg/kg miglustat (oral gavage 30 minutes prior). (C and D) After four administrations (8 weeks), mice treated with cipaglucosidase alfa plus miglustat have reduced glycogen storage substrate levels (amyloglucosidase digestion method) that are statistically indistinguishable from wild type in the quadriceps and near–wild type in the triceps. (E) After eight biweekly administrations (16 weeks), mice treated with the cipaglucosidase alfa plus miglustat combination have increased grip strength. Bars are mean ± S.D. One-way ANOVA with Sídák’s multiple comparisons test comparing each group to wild type and vehicle. #P ≤ 0.05 versus vehicle; *P ≤ 0.05 versus wild type. n.s., not significant.

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