ISEMBYLD Solution for injection Ref.[116934] Active ingredients: Apitegromab

5.1 Fractures

ISEMBYLD may increase the risk of fractures, including serious fractures [see Adverse Reactions (6.1)]. In Study 1 [see Clinical Studies (14)], 5/53 (9%) of patients treated with ISEMBYLD 10 mg/kg and 3/53 (6%) of patients treated with ISEMBYLD 20 mg/kg (twice the recommended dosage) experienced fractures compared with one patient in the placebo group (2%) who had a fracture. Femur fractures occurred in three patients treated with ISEMBYLD in Study 1. No patients discontinued treatment due to fractures. In an ongoing open-label extension study in which patients received ISEMBYLD 20 mg/kg (twice the recommended dosage), fractures occurred in 22 patients (9%), including 5 serious events of femur fractures. Most patients with fractures had histories of low bone density previous fractures, or contractures. Some fracture events did not have a clear precipitating event (such as a fall).

Animal studies have also demonstrated adverse effects in bone [see Nonclinical Toxicology (13.2)].

Use ISEMBYLD with caution in patients with a history of low bone density or multiple fractures. In patients who experience fractures, weigh the risks and benefits of continuing ISEMBYLD.

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Fractures [see Warnings and Precautions (5.1)]

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 ISEMBYLD for SMA was evaluated in a randomized, double-blind, and placebo-controlled study (Study 1) [see Clinical Studies (14)]. In Study 1, ISEMBYLD 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 ISEMBYLD (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 ISEMBYLD, unless otherwise noted.

The most common adverse reactions (reported in at least 20% of patients treated with ISEMBYLD and more frequently than in placebo) were upper respiratory tract infections, vomiting, cough, other viral infections, headache, gastroenteritis, pharyngitis, and hypersensitivity. Table 1 lists the common adverse reactions that occurred in at least 5% of patients treated with ISEMBYLD and at least 5% more frequently than placebo.

Table 1. Adverse Reactions Reported in ≥5% of Patients with SMA Treated with ISEMBYLD 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 ISEMBYLD 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 ISEMBYLD 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 ISEMBYLD 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 ISEMBYLD compared to 3 U/L in placebo. Increases in CPK were seen in 28% of patients treated with ISEMBYLD, compared to 12% in placebo; among these, 3 patients (6%) treated with ISEMBYLD 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 ISEMBYLD 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 ISEMBYLD 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.

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in the assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of apitegromab-mstn or of other apitegromab products.

In up to 52 weeks of treatment in Study 1, 1/128 (0.8%) of patients treated with ISEMBYLD tested positive for treatment-emergent anti-apitegromab-mstn antibodies at a single time point. No neutralizing antibodies were detected; however, because of the limited data regarding anti-apitegromab-mstn antibodies, the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of apitegromab products is unknown.

Risk Summary

There are no adequate data on the developmental risk associated with the use of ISEMBYLD in pregnant women. Monoclonal antibodies, such as apitegromab-mstn, are known to cross the placental barrier with a higher likelihood of fetal exposure with administration during the third trimester; therefore, apitegromab-mstn may be transported from the mother to the fetus across the placenta during the pregnancy. When apitegromab-mstn 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-mstn exposures [see Animal Data].

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.

Data

Animal Data

In a study in which pregnant rats were administered apitegromab-mstn (0, 30, 100, or 300 mg/kg) by intravenous injection once-weekly throughout organogenesis (gestation days 6 to 17), no adverse effects on embryofetal development were observed. The no-effect dose for adverse effects on embryofetal development (300 mg/kg) was associated with maternal apitegromab-mstn exposures (AUC) approximately 2.5 times that in humans at the maximum recommended human dose (MRHD) of 10 mg/kg.

Once-weekly intravenous administration of apitegromab-mstn (0, 30, 100, or 300 mg/kg) to rats throughout pregnancy and lactation, resulted in delayed sexual maturation and altered neurobehavioral function (increased auditory startle response) in offspring of both sexes at all doses and impaired reproductive function in male offspring at the highest dose. A no-effect dose for adverse effects on pre- and postnatal development was not identified. The lowest dose tested (30 mg/kg) was associated with maternal apitegromab-mstn exposures (AUC) lower than that in humans at the MRHD.

Risk Summary

There are no data on the presence of apitegromab-mstn 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 ISEMBYLD 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 ISEMBYLD, and any potential adverse effects on the breastfed infant from ISEMBYLD, or from the underlying maternal condition.

Animal data suggest adverse effects of apitegromab-mstn on male and/or female reproductive function following exposure during postnatal development or in adulthood [see Use in Specific Populations (8.4) and Nonclinical Toxicology (13.1)].

The safety and effectiveness of ISEMBYLD for the treatment of spinal muscular atrophy have been established in pediatric patients 2 years of age and older. Use of ISEMBYLD for this indication is supported by evidence from an adequate and well-controlled study in pediatric patients 2 to 12 years of age, latent myostatin levels in pediatric patients 2 years of age and older, and pharmacokinetic (PK) modeling comparing pediatric patients 2 to 12 years of age to pediatric patients 13 years of age and older [see Adverse Reactions (6.1), Clinical Pharmacology (12.2, 12.3), and Clinical Studies (14)].

Safety and effectiveness in pediatric patients younger than 2 years of age have not been established.

Juvenile Animal Toxicity Data

Once-weekly intravenous administration of apitegromab-mstn (0, 30, 100, or 300 mg/kg) to juvenile rats from Postnatal Day (PND) 21 through PND 63 resulted in adverse effects on female reproductive function. When female rats exposed to apitegromab-mstn during the postnatal period were mated with naïve males in adulthood, corpora lutea were decreased, preimplantation loss was increased, and numbers of implantation sites and live fetuses were decreased. A no-effect dose was not identified. The lowest effect dose (30 mg/kg) was associated with apitegromab-mstn exposures (AUC) lower than that in humans at the maximum recommended human dose (MRHD) of 10 mg/kg.

Once-weekly subcutaneous administration of apitegromab-mstn (0, 30, 100, or 275 mg/kg) to juvenile rats from PND 7 through PND 28 produced no adverse effects on the developmental endpoints assessed; however, reproductive function was not evaluated. The highest dose tested (275 mg/kg) was associated with apitegromab-mstn exposures (AUC) approximately 7 times that in humans at the MRHD.

Clinical studies of ISEMBYLD did not include patients 65 years of age and older to determine whether they respond differently from younger patients.