Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Amicus Therapeutics Europe Limited, Block 1, Blanchardstown Corporate Park, Ballycoolin Road, Blanchardstown, Dublin, D15 AKK1, Ireland e-mail: info@amicusrx.co.uk
Pharmacotherapeutic group: Other alimentary tract and metabolism products, enzymes
ATC Code: A16Ab23
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.
A 52-week phase 3 randomised, double-blind, active-controlled, international, multi-centre clinical trial was conducted in adult subjects (≥ 18 years) diagnosed with Pompe disease. Subjects were randomised 2:1 to receive 20 mg/kg cipaglucosidase alfa in combination with 195 mg or 260 mg miglustat based on the subject’s weight, or 20 mg/kg alglucosidase alfa in combination with placebo every other week for 52 weeks. The efficacy population included a total of 122 subjects of which 95 subjects had received prior ERT with alglucosidase alfa (ERT-experienced) and 27 subjects had never received ERT (ERT-naïve).
Demographics, baseline 6-Minute Walk Distance (6MWD), and sitting percent predicted Forced Vital Capacity (FVC) were generally similar in the 2 treatment arms, see Table 2. More than two thirds (67%) of ERT-experienced subjects had been on ERT treatment for more than 5 years prior to entering the phase 3 trial (mean of 7.4 years).
Table 2. Subject demographics and baseline characteristics:
| Baseline characteristics | Cipaglucosidase alfa in combination with miglustat n=85 | Alglucosidase alfa in combination with placebo n=37 |
|---|---|---|
| Age at informed consent (years), mean (SD) | 47.6 (13.3) | 45.4 (13.4) |
| Male gender, n % | 36 (42.4) | 19 (51.4) |
| Weight (kg), mean (SD) | 72.8 (14.7) | 79.4 (25.0) |
| ERT-experienced, n (%) | 65 (76.5) | 30 (81.1) |
| Age at first ERT dose (years), mean (SD) | 40.8 (12.7) | 38.7 (15.1) |
| 6MWD (m), mean (SD) | 357.9 (111.8) | 351.0 (121.3) |
| Sitting % FVC, mean (SD) | 70.7 (19.6) | 69.7 (21.5) |
6MWD: 6-minute walk distance; ERT: enzyme replacement therapy; FVC: sitting percent predicted forced vital capacity;
SD: standard deviation
Key efficacy endpoints included assessment of 6MWD (primary endpoint), and the sitting percent predicted FVC. Key pharmacodynamic endpoints included serum creatine kinase (CK) and urinary glucose tetrasaccharides (Hex-4).
All subjects (ERT-experienced and ERT-naïve) treated with cipaglucosidase alfa in combination with miglustat therapy had a mean improvement in walk distance from baseline of 20.0 meters as compared to those treated with alglucosidase alfa-placebo with a mean of 8.3 meters, indicating a cipaglucosidase alfa in combination with miglustat treatment effect of 11.7 meters (95% CI [-1.0, 24.4]; p=0.07) (Table 3).
The ERT-experienced subjects treated with cipaglucosidase alfa in combination with miglustat therapy (n = 65) had a mean improvement in walk distance from baseline of 15.9 meters as compared to a mean of 1.0 meter for alglucosidase alfa in combination with placebo (n=30), indicating a cipaglucosidase alfa/miglustat treatment effect of 14.9 meters (95% CI [1.2, 28.6]).
The ERT-naïve subjects treated with cipaglucosidase alfa in combination with miglustat therapy (n=20) had a mean improvement in walk distance from baseline of 28.5 meters as compared to 52.7 meters for alglucosidase alfa in combination with placebo (n=7), indicating a cipaglucosidase alfa/miglustat treatment effect of -24.2 meters (95% CI [-60.0, 11.7]).
Table 3. Summary of 6MWD in all subjects at 52 weeks:
| 6MWD (meters) | Cipaglucosidase alfa in combination with miglustat | Alglucosidase alfa in combination with placebo |
|---|---|---|
| Baseline | ||
| n Mean (SD) Median | n=85 357.9 (111.8) 359.5 | n=37 351.0 (121.3) 365.5 |
| Change from baseline at week 52 | ||
| n Mean (SD) (95% CI) | n=85 20.0 (3.5) (13.1, 26.9) | n=37 8.3 (5.3) (-2.2, 18.8) |
| Change to week 52 | ||
| Diff. of means (SE) (95% CI) 2-sided p value | 11.7 (6.4) (-1.0, 24.4) p = 0.07* | |
CI: confidence interval; Diff.: difference; SD: standard deviation; SE: standard error
Reported data based on mixed model for repeated measures (MMRM) analysis with actual time point of assessments (ITT-OBS population) excluding outlier in the ITT population.
* Primary endpoint did not achieve superiority.
All subjects (ERT-experienced and ERT-naïve) treated with cipaglucosidase alfa in combination with miglustat therapy showed a mean change in FVC from baseline of -1.4% as compared with subjects treated with alglucosidase alfa-placebo of -3.7%, indicating a cipaglucosidase alfa-miglustat treatment effect of 2.3% (95% CI [0.2, 4.4]) (Table 4).
The ERT-experienced subjects treated with cipaglucosidase alfa in combination with miglustat therapy (n=65) showed a mean change in FVC from baseline of -0.2% as compared with subjects treated with alglucosidase alfa in combination with placebo (n=30) of -3.8%, indicating a cipaglucosidase alfa-miglustat treatment effect of 3.6% (95% CI [1.3, 5.9]).
The ERT-naïve subjects treated with cipaglucosidase alfa in combination with miglustat therapy (n=20) showed a mean change in FVC from baseline of -5.2% as compared with subjects treated with alglucosidase alfa-placebo (n=7) of -2.4%, indicating similar rates of decline of -2.8% difference with a 95% CI (-7.8, 2.3).
Table 4. Summary of percent predicted FVC in all subjects at 52 weeks:
| Sitting percent predicted FVC | Cipaglucosidase alfa in combination with miglustat | Alglucosidase alfa in combination with placebo |
|---|---|---|
| Baseline | ||
| n Mean (SD) Median | n=85 70.7 (19.6) 70.0 | n=37 69.7 (21.5) 71.0 |
| Change from baseline at week 52 | ||
| n Mean (SD) (95% CI) | n=85 -1.4 (0.6) (-2.5, -0.3) | n=37 -3.7 (0.9) (-5.4, -2.0) |
| Change to week 52 | ||
| Diff. of means (SE) (95% CI) | 2.3 (1.1) (0.2, 4.4) | |
CI: confidence interval; Diff.: difference; SD: standard deviation; SE: standard error
Reported data based on mixed model for repeated measures (MMRM) analysis with actual time point of assessments (ITT-OBS population) excluding outlier in the ITT population.
The observed effects for the secondary endpoints supported the conclusions drawn from the 6MWD and sitting % predicted FVC.
Subjects who were treated with 20 mg/kg cipaglucosidase alfa in combination with the enzyme stabiliser miglustat every other week showed a mean reduction of -22.4% in CK compared to a mean increase of +15.6% in the alglucosidase alfa and placebo treated subjects, and a mean reduction of -31.5% in Hex-4 compared to a mean increase of +11.0% in subjects who were treated with alglucosidase alfa and placebo after 52 weeks.
The European Medicines Agency has deferred the obligation to submit the results of studies with cipaglucosidase alfa in one or more subsets of the paediatric population in the treatment of glycogen storage disease Type II (Pompe disease) (see section 4.2 for information on paediatric use).
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.
Table 5. 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.
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