Oral Migalastat HCl Leads to Greater Systemic Exposure and Tissue Levels of Active α-Galactosidase A in Fabry Patients when Co-Administered with Infused Agalsidase.

UnlabelledMigalastat HCl (AT1001, 1-Deoxygalactonojirimycin) is an investigational pharmacological chaperone for the treatment of α-galactosidase A (α-Gal A) deficiency, which leads to Fabry disease, an X-linked, lysosomal storage disorder. The currently approved, biologics-based therapy for Fabry disease is enzyme replacement therapy (ERT) with either agalsidase alfa (Replagal) or agalsidase beta (Fabrazyme). Based on preclinical data, migalastat HCl in combination with agalsidase is expected to result in the pharmacokinetic (PK) enhancement of agalsidase in plasma by increasing the systemic exposure of active agalsidase, thereby leading to increased cellular levels in disease-relevant tissues. This Phase 2a study design consisted of an open-label, fixed-treatment sequence that evaluated the effects of single oral doses of 150 mg or 450 mg migalastat HCl on the PK and tissue levels of intravenously infused agalsidase (0.2, 0.5, or 1.0 mg/kg) in male Fabry patients. As expected, intravenous administration of agalsidase alone resulted in increased α-Gal A activity in plasma, skin, and peripheral blood mononuclear cells (PBMCs) compared to baseline. Following co-administration of migalastat HCl and agalsidase, α-Gal A activity in plasma was further significantly increased 1.2- to 5.1-fold compared to agalsidase administration alone, in 22 of 23 patients (95.6%). Importantly, similar increases in skin and PBMC α-Gal A activity were seen following co-administration of migalastat HCl and agalsidase. The effects were not related to the administered migalastat HCl dose, as the 150 mg dose of migalastat HCl increased α-Gal A activity to the same extent as the 450 mg dose. Conversely, agalsidase had no effect on the plasma PK of migalastat. No migalastat HCl-related adverse events or drug-related tolerability issues were identified.Trial registrationClinicalTrials.gov NCT01196871

Gaboxadol in angelman syndrome:A double-blind, parallel-group, randomized placebo-controlled phase 3 study

Purpose: To evaluate efficacy and safety of gaboxadol for treatment of children with Angelman syndrome (AS). Method: In this international, double-blind, phase 3 trial, we randomized children 4–12 years old with a molecular diagnosis of AS and a Clinical Global Impression (CGI)-severity score ≥3 to either daily administration of weight-based gaboxadol or matching placebo for 12 weeks. The primary endpoint was the CGI-Improvement-AS (CGI-I-AS) score at week 12. Secondary endpoints included the proportion of participants with CGI-I-AS response of ≤3 (i.e., at least “minimal improvement”) and ≤2 (i.e., at least “much improvement”) at week 12. Safety and tolerability were monitored throughout the study. Weight based dosing of study drug ranged from 0.125 mg/kg to 0.24 mg/kg depending on weight range. Results: Between August 2019 and November 2020, 104 participants were enrolled: participants 4–12 years old were randomly (1:1) assigned to gaboxadol (n = 47) or placebo (n = 50), and 7 other participants 2─3 years old who received gaboxadol and were assessed for safety only. All gaboxadol-treated participants and 48 of 50 placebo-treated participants completed treatment. There was no significant difference in CGI-I-AS between groups: at week 12, mean CGI-I-AS score was 3.3 (SD, 1.00) and 3.2 (SD, 1.05) in the gaboxadol and placebo groups, respectively, yielding a least squares mean difference of zero (p = 0.83). There were no between-group significant differences with respect to CGI-I-AS responses. Gaboxadol was well tolerated in all age groups of this study. Conclusions: There was no significant difference in CGI-I-AS between gaboxadol and placebo after 12 weeks of study treatment in pediatric AS participants. Clinicaltrials.gov: NCT04106557.</p

Two-by-two panel of total plasma α-Gal A activity AUC stick plots for agalsidase alone and co-administered with migalastat HCl.

<p>Upper left and right plots show individual patient changes between agalsidase beta alone and when co-administered with 150 mg migalastat HCl (upper left) or 450 mg migalastat (upper right) for plasma α-Gal activity AUC_0-∞. Lower left and right plots show individual patient changes between agalsidase alfa alone and when co-administered with 150 mg migalastat HCl (lower left) or 450 mg migalastat HCl (lower right) for plasma α-Gal activity AUC_0-∞. Patients’ actual ID number is blinded with the following code: Treatment and Dose (AB = agalsidase beta, 0.5 = 0.5 mg/kg dose or 1.0 = 1.0 mg/kg dose; AA = agalsidase alfa, 0.2 = 0.2 mg/kg dose)–migalastat HCl dose (150 = 150 mg, 450 = 450 mg)–arbitrary sequential number (1 through 23). Increases in plasma α-Gal activity AUC_0-∞ are observed for all patients with the exception of AB1.0-450-14 shown in the upper left plot.</p

Mean (SD) total plasma α-Gal A activity-time profile panel for all treatments.

<p>Mean α-Gal A activity increased at all post-dose time points for all treatments after co-administration with migalastat HCl. Increases after co-administration do not appear to be related to migalastat dose.</p

Patient Disposition.

<p>Patient Disposition.</p

Mean (SD) plasma migalastat concentration-time profiles following co-administration of agalsidase with 450 mg or 150 mg migalastat HCl, and 150 mg migalastat HCl alone.

<p>Whether co-administered with agalsidase (Stage 1/Period 2) or administered alone (Stage 1/Period 3), plasma migalastat concentrations were similar at all post-dose time points. Mean concentration-time profiles following administration of 450 mg migalastat HCl (Stage 2/Period 2) were approximately dose proportional to 150 mg (Stage 1).</p

Plasma Migalastat PK Summary.

<p>^a Geometric mean (CV%)</p><p>^b Median (range)</p><p>^c Arithmetic mean (CV%)</p><p>Plasma Migalastat PK Summary.</p