Olipudase alfa

Olipudase alfa is a recombinant human acid sphingomyelinase that reduces sphingomyelin (SM) accumulation in organs of patients with Acid Sphingomyelinase Deficiency (ASMD).

The pharmacokinetics (PK) of olipudase alfa were assessed in 49 adult ASMD patients from all clinical studies, receiving single or multiple administrations. At the dose of 3 mg/kg administered once every 2 weeks, the mean (percent coefficient of variation, CV%) maximum concentration (C_max) and area under the concentration-time curve over a dosing interval (AUC_0-τ) at steady state were 30.2 µg/mL (17%) and 607 µg.h/mL (20%), respectively.

Absorption

There is no absorption since olipudase alfa is administered intravenously.

Distribution

The estimated mean (CV%) volume of distribution of olipudase alfa is 13.1 L (18%).

Biotransformation

Olipudase alfa is a recombinant human enzyme and is expected to be eliminated via proteolytic degradation into small peptides and amino acids.

Elimination

The mean (CV%) clearance of olipudase alfa is 0.331 L/h (22%). The mean terminal half-life (t_1/2) ranged from 31.9 to 37.6 hours.

Linearity/non-linearity

Olipudase alfa exhibited linear pharmacokinetics over the dose range of 0.03 to 3 mg/kg. Following a dose escalation regimen from 0.1 to the maintenance dose of 3 mg/kg administered once every 2 weeks, there was minimal accumulation in plasma levels of olipudase alfa.

Special populations

There were no clinically relevant differences in olipudase alfa pharmacokinetics based on gender.

Population pharmacokinetic analysis indicated that the exposure in Asian (n=2) and other race patients (n=2) were within the exposure ranges observed for Caucasian patients.

Elderly (≥65 years old)

Population pharmacokinetic analysis did not indicate a difference in exposure in elderly (only 2 patients between 65 and 75 years of age were included in clinical studies with olipudase alfa).

Paediatric

The PK of olipudase alfa were assessed in 20 paediatric patients including 4 adolescent patients, 9 child patients and 7 child/infant patients (Table 11). Olipudase alfa exposures were lower in paediatric patients compared to those in adult patients. However, these differences were not considered to be clinically relevant.

Table 11. Mean (CV%) of olipudase alfa PK parameters following administration of 3 mg/kg every 2 weeks in adolescent, child and child/infant patients with ASMD:

Descriptive statistics represent the post hoc estimates of steady-state exposures using population PK analysis.
AUC_0-τ: area under the plasma concentration versus time curve over a dosing interval; C_max: maximum plasma concentration; n: total number of patients.

Hepatic impairment

Olipudase alfa is a recombinant protein and is expected to be eliminated by proteolytic degradation. Therefore, impaired liver function is not expected to affect the pharmacokinetics of olipudase alfa.

Renal impairment

Four patients (11.1%) with mild renal impairment (60 mL/min ≤ creatinine clearance <90 mL/min) were included in the ASCEND study. There were no clinically relevant differences in olipudase alfa pharmacokinetics in patients with mild renal impairment. The impact of moderate to severe renal impairment on the pharmacokinetics of olipudase alfa is not known. Olipudase alfa is not expected to be eliminated through renal excretion. Therefore, renal impairment is not expected to affect the pharmacokinetics of olipudase alfa.

Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, single dose toxicity and repeated dose toxicity conducted in wild type animals (mice, rats, rabbits, dogs and monkeys) at dose levels 10 times above the Maximum recommended human dose (MRHD). Studies to evaluate the mutagenic and carcinogenic potential of olipudase alfa have not been performed.

In acid sphingomyelinase knockout (ASMKO) mice (a disease model for ASMD), mortality was observed following an administration of single doses of olipudase alfa ≥3.3 times higher than MRHD as an intravenous bolus injection. However, repeat dose studies show that administration of olipudase alfa via a dose escalation regimen did not result in compound-related mortality and reduced the severity of other toxicity findings up to the highest tested dose of 10 times the MRHD.

An increased incidence of exencephaly was observed when pregnant mice were treated daily with olipudase alfa at exposure levels comparable to the human exposure at the recommended maintenance therapeutic dose and frequency. This incidence was slightly higher than historical control data. The relevance of this observation for humans is unknown. The daily intravenous administration of olipudase alfa to pregnant rabbits did not result in fetal malformations or variations at exposures significantly exceeding the human exposure at the recommended maintenance therapeutic dose and frequency.