Pompe disease is caused by a deficiency of acid-alpha-glucosidase (GAA) that degrades glycogen to glucose in the lysosome. Cipaglucosidase alfa is intended to replace the absent or impaired endogenous enzyme.
Cipaglucosidase alfa is stabilised by miglustat minimising the loss of enzyme activity in the blood during infusion of this hydrolytic glycogen-specific enzyme enriched with bis-M6P N-glycans for high affinity cation-independent mannose-6-phosphate receptor (CI-MPR) binding. After binding, it is internalised in the lysosome where it undergoes proteolytic cleavage and N-glycan trimming which are both required to yield the most mature and active form of the GAA enzyme. Cipaglucosidase alfa then exerts enzymatic activity in cleaving glycogen and reducing intramuscular glycogen, and ameliorating tissue damage.
Cipaglucosidase alfa was evaluated with and without miglustat in 11 ambulatory ERT-experienced subjects with LOPD, reached peak concentrations at approximately the end of the 4-hour duration of IV infusion, and declined in a biphasic manner to 24 hours from the start of infusion.
Pharmacokinetic summary at clinical dose:
| PK Parameter | Cipaglucosidase alfa 20 mg/kg in combination with miglustat 260 mg | Cipaglucosidase alfa 20 mg/kg |
|---|---|---|
| Cmax (mcg/mL) | 345 (18.5) | 325 (13.5) |
| AUC0-∞ (mcg*h/mL) | 1812 (20.8) | 1410 (15.9) |
AUC0-∞ = area under the curve from time 0 to infinity; Cmax = maximum observed plasma concentration
Cipaglucosidase alfa is not expected to bind to plasma proteins. The mean volume of distribution of cipaglucosidase alfa ranged from 2.0 to 4.7 L. The distribution half-life was increased by 48% following usage of both cipaglucosidase alfa and miglustat. Correspondingly, plasma clearance decreased by 27%.
Following the administration of a single dose of miglustat 260 mg in combination with cipaglucosidase alfa 20 mg/kg in fasting adults with Pompe disease in a phase ½ trial, total GAA protein partial AUCtmax-24h (time of maximum concentration at the end of infusion to 24 hours post-start of infusion) increased by 44% relative to cipaglucosidase alfa 20 mg/kg alone.
Cipaglucosidase alfa does not cross the blood-brain barrier.
Cipaglucosidase alfa is eliminated primarily in the liver by proteolytic hydrolysis. The mean terminal elimination half-life for cipaglucosidase alfa ranged from 1.6 to 2.6 hours.
Based on pooled population pharmacokinetic analysis, gender, age (18 to 74 years old), and race/ethnicity did not have clinically meaningful effect on the exposure to cipaglucosidase alfa in combination with miglustat. Of the total number of patients treated with cipaglucosidase alfa in combination with miglustat in clinical trials for LOPD, 17 (11%) were 65 to 74 years of age, and none were 75 years of age and older.
The pharmacokinetics of cipaglucosidase alfa in combination with miglustat therapy have not been evaluated in patients with hepatic impairment.
No studies with cipaglucosidase alfa in combination with miglustat therapy have been carried out in subjects with impaired renal function. The disposition of cipaglucosidase alfa is not expected to be impacted by renal impairment.
Nonclinical data for cipaglucosidase alfa revealed no special hazard for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity, genotoxicity, carcinogenicity, and mutagenicity.
There was no effect of cipaglucosidase alfa in combination with miglustat therapy on spermatogenesis in rats.
In a segment II embryo-fetal development study, no adverse findings were observed in pregnant rats or their offspring up to an exposure margin of 15.5-fold and 3.4-fold, respectively, for cipaglucosidase alfa and miglustat based on plasma AUC exposure. However, in rabbits for both miglustat and the combination group (cipaglucosidase alfa with miglustat), maternal effects including decreased food consumption and body weight gains were evident. Cardiovascular malformations and variations were not elevated in the cipaglucosidase alfa groups without miglustat when compared to the control groups. These results indicate that the combination of cipaglucosidase alfa with miglustat resulted in increased cardiovascular malformations (atretic pulmonary trunk, ventricular septum defect, and dilated aortic arch) in rabbits at doses of 8.8-fold and 4.8-fold, respectively, the MRHD (based on mg/kg basis) or 12.1-fold and 2.6-fold, respectively, based on plasma AUC after a single exposure, or 84 and 18.5 based on cumulative exposure for matching human and animal dosing regimens.
In a segment III pre-and post-natal development study in rats, cipaglucosidase alfa alone or in combination with miglustat was administered to pregnant females. Maternal and pup mortality were observed with the combination cipaglucosidase alfa and miglustat, and pup mortality was also increased with cipaglucosidase alfa alone. There was no NOAEL for the combination at exposure margins up to 15.5-fold and 3.4-fold, respectively, for cipaglucosidase alfa and miglustat based on plasma AUC exposure. Evaluation of milk in rats from the combination treatment group showed excretion of miglustat and cipaglucosidase alfa in rat milk. At 3 hours post dose, the ratio of cipaglucosidase alfa exposure in rat milk to plasma was 0.038.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
