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.

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