Apitegromab

Apitegromab is a fully human monoclonal IgG4 antibody that binds to promyostatin and latent myostatin and inhibits the activation of myostatin, blocking myostatin signaling.

The PK of apitegromab were characterized in healthy adult subjects and in patients with SMA using population pharmacokinetic modeling.

Pharmacokinetics of apitegromab were linear and dose-proportional in the range of 10 mg/kg to 20 mg/kg (twice the recommended dosage) in patients with SMA.

Following administration of apitegromab once every 4 weeks in patients with SMA, approximately 2-fold accumulation of apitegromab exposures were observed, and exposures reached steady state by approximately 16-20 weeks.

Distribution

The apitegromab mean (coefficient of variation % [CV%]) steady state volume of distribution in patients with SMA (2 to 21 years of age) was estimated to be 2.16 L (48%).

Elimination

Apitegromab is expected to be degraded into small peptides and amino acids via catabolism in the same manner as endogenous IgGs.

The mean value (CV%) of clearance of apitegromab in patients with SMA (2 to 21 years of age) was estimated to be 0.055 L/day (50%). The mean value (CV%) of the terminal elimination half-life of apitegromab was estimated to be 31.2 days (32%).

Specific Populations

Pediatric Patients

The PK of apitegromab was characterized in pediatric patients 2 years of age and older using a population pharmacokinetic model. Following weight-based dosing of apitegromab 10 mg/kg, model-predicted steady state exposures (Cmax, Ctrough and AUC) of apitegromab was comparable between patients 2 to 12 years of age and 13 to 21 years of age.

Male and Female Patients and Racial or Ethnic Groups

Based on the population PK analysis, sex, race, and ethnicity had no effect on apitegromab PK in patients with SMA.

Patients with Renal or Hepatic Impairment

No clinical studies were conducted to evaluate the PK of apitegromab in patients with renal or hepatic impairment. Apitegromab is degraded by proteolytic enzymes and is not expected to undergo renal elimination or metabolism by hepatic enzymes.

Drug Interaction Studies

An effect of apitegromab on the PK of co-administered medications is not expected. Based on the population PK analysis, SMN-modulating therapies (nusinersen and risdiplam) had no effect on apitegromab PK in patients with SMA.

Adverse effects on bone were observed in toxicology studies conducted in rats. In a study in which apitegromab (0, 10, 30, 100, or 300 mg/kg) was administered weekly by intravenous injection for 12 weeks, fissure at the femoral head physis was observed at all doses at the end of the dosing and recovery periods. The fissure was associated with partial or complete absence of the epiphysis and with degenerative (resorption) and reactive (fibrosis, woven bone, hyperplastic osteoclasts) changes at the femoral neck and proximal metaphysis. Qualitative findings of partial or complete missing femoral head epiphysis were observed in computed tomography images of apitegromab-exposed animals. Weekly intravenous administration of apitegromab (0, 30, 100, or 300 mg/kg) to rats for 26 weeks resulted in a dose-related increase in the incidence and severity of adverse changes in the femoral head/neck (femoral head loss, thinning, fracture, fragmentation of the femoral neck) observed by in vivo radiography at the end of the dosing and recovery periods.

A no-effect dose for bone effects was not identified. The lowest effect doses for adverse effects on bone in 12- and 26-week studies in rats (10 and 30 mg/kg, respectively) were associated with apitegromab exposures (AUC) lower than that in humans at the MRHD.