Apitegromab

There are no adequate data on the developmental risk associated with the use of apitegromab in pregnant women. Monoclonal antibodies, such as apitegromab, are known to cross the placental barrier with a higher likelihood of fetal exposure with administration during the third trimester; therefore, apitegromab may be transported from the mother to the fetus across the placenta during the pregnancy. When apitegromab was administered by IV infusion to rats throughout pregnancy and lactation, adverse effects on offspring reproductive and neurobehavioral function were observed at clinically-relevant maternal apitegromab exposures.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

There are no data on the presence of apitegromab in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Maternal IgG is known to be present in human milk, and the potential for absorption of apitegromab to lead to inhibition of myostatin activation in the breastfed infant is unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for apitegromab, and any potential adverse effects on the breastfed infant from apitegromab, or from the underlying maternal condition.

Carcinogenesis

Carcinogenicity studies have not been conducted with apitegromab.

Mutagenesis

Genetic toxicology studies have not been conducted with apitegromab.

Impairment of Fertility

Once-weekly intravenous injection of apitegromab (0, 30, 100, or 300 mg/kg) to rats prior to and during mating and continuing in females to gestation day 6 resulted in decreased sperm concentrations, estrous cycle disruption, decreased male and/or female mating and fertility indices, and increased postimplantation loss at all doses. A no-effect dose for adverse effects on fertility and early embryonic development was not identified. The lowest dose tested (30 mg/kg) was associated with apitegromab exposures (AUC) lower than that in humans at the MRHD.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of apitegromab for SMA was evaluated in a randomized, double-blind, and placebo-controlled study (Study 1). In Study 1, apitegromab was evaluated in 128 patients with SMA (2 to 21 years at the start of the study), which included 53 patients 2 to 12 years of age [mean 7 years of age] who received the recommended dosage of apitegromab (10 mg/kg once every 4 weeks) for a mean exposure of 49 weeks. Of those 53 patients, 43% were female, 66% were White, 11% were of Hispanic or Latino ethnicity, 4% were Asian, and 2% were Black or African-American. The adverse reaction information presented below is from the patients who received the recommended dosage of apitegromab, unless otherwise noted.

The most common adverse reactions (reported in at least 20% of patients treated with apitegromab and more frequently than in placebo) were upper respiratory tract infections, vomiting, cough, other viral infections, headache, gastroenteritis, pharyngitis, and hypersensitivity. The following table lists the common adverse reactions that occurred in at least 5% of patients treated with apitegromab and at least 5% more frequently than placebo.

Adverse Reactions Reported in ≥5% of Patients with SMA Treated with Apitegromab 10 mg/kg and ≥5% More Frequently than in Placebo (Study 1):

¹ Includes nasopharyngitis, rhinovirus infection, sinusitis, viral upper respiratory tract infection, upper respiratory tract infection, nasal congestion, rhinorrhea, rhinitis.
² Includes metapneumovirus infection, parvovirus B19 infection, COVID-19, respiratory syncytial virus infection, respiratory syncytial virus bronchiolitis, influenza, parainfluenzae, adenovirus, respiratory tract infection viral, and viral infection.
³ Includes other similar terms.
⁴ Includes pharyngitis, pharyngitis streptococcal, oropharyngeal pain.
⁵ Includes dermatitis acneiform, dermatitis atopic, eczema, flushing, rash, rash maculo-papular, urticaria
⁶ Includes application site reaction, catheter site pain, infusion related reaction, infusion site bruising, infusion site pain, injection site bruising, injection site pain.
⁷ Includes other similar terms.
⁸ Includes foot fracture, clavicle fracture, femur fracture, tibia fracture, torus fracture.
⁹ Includes fatigue, lethargy.

Acute Respiratory Failure

In Study 1, serious events of acute respiratory failure in the setting of lower respiratory tract infections occurred in two patients treated with apitegromab at a dose of 10 mg/kg and in one patient that received placebo.

Pneumonia

In Study 1, serious adverse events of pneumonia occurred in three patients treated with apitegromab at a dose of 10 mg/kg and in no patients that received placebo.

Laboratory Findings

Creatine Phosphokinase

In Study 1, CPK increases were seen more frequently in patients treated with apitegromab 10 mg/kg (n=53) compared to placebo (n=50). By month 12, mean CPK levels increased by 91 U/L in patients treated with apitegromab compared to 3 U/L in placebo. Increases in CPK were seen in 28% of patients treated with apitegromab, compared to 12% in placebo; among these, 3 patients (6%) treated with apitegromab had CPK elevations of greater than 2.5 times the upper limit of normal (ULN), compared to none in placebo. Similar patterns of elevations were seen in patients receiving apitegromab who were over 12 years of age compared to those 2 to 12 years of age. One patient with elevated CPK at baseline who received apitegromab 20 mg/kg (twice the recommended dosage) in the 13 to 21 age group had further CPK increases to greater than 10 times the ULN. Patients with CPK elevations in Study 1 have generally been asymptomatic.