Motixafortide

Risk Summary

Based on its mechanism of action, motixafortide can cause fetal harm when administered to a pregnant woman. There are no available data with motixafortide use in pregnant women informing the risk of embryo-fetal toxicity. Animal models link dysfunction in CXCR4/SDF-1 signaling to adverse outcomes in mammalian embryo-fetal development and suggest risk to normal placental development (see Data). No animal studies have been conducted to evaluate the effect of motixafortide on reproduction and fetal development. Advise pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriages for the indicated population is unknown. 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.

Data

Animal Data

Animal reproduction studies have not been conducted with motixafortide to evaluate its effect on reproduction and embryo-fetal development. Disruption of CXCR4/SDF-1 signaling in mice and other models caused increased embryo-fetal lethality, and impairment of vascularization, cardiac anomalies, reduced hematopoiesis, impaired bone marrow myelopoiesis, disorganized neural layers in cerebellum, and reduced neural innervation of limbs. CXCR4/SDF-1 levels have been shown to play a key role in stimulating trophoblast proliferation and differentiation necessary for appropriate placental growth and function in humans.

There are no data on the presence of motixafortide in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential serious adverse reactions in the breastfed child, advise females that breastfeeding is not recommended during the motixafortide treatment and for 8 days after the final dose.

Carcinogenicity studies with motixafortide have not been conducted. Motixafortide was not genotoxic in an in vitro bacterial mutation assay (Ames test), in an in vitro chromosomal aberration test using V79 Chinese hamster cells, or in an in vivo bone marrow micronucleus test in mice after intravenous injected at doses up to 4 mg/kg (12 mg/m²).

Fertility studies have not been conducted with motixafortide. No histopathological evidence of toxicity to male or female reproductive organs was observed in 28-day repeat-dose toxicity studies in rats and dogs.

• Anaphylactic Shock and Hypersensitivity Reactions
• Injection Site Reactions
• Potential for Tumor Cell Mobilization in Patients in Leukemia
• Leukocytosis
• Potential for Tumor Cell Mobilization

Clinical Trials Experience

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 motixafortide was evaluated in the GENESIS study based on data from 92 patients with multiple myeloma who received at least one dose of motixafortide 1.25 mg/kg subcutaneously and filgrastim and 42 patients who received placebo and filgrastim for mobilization of hematopoietic stem cells for collection and apheresis. The premedication regimen changed during the conduct of the trial as evidence of hypersensitivity reactions was noted. Of the 92 patients who received at least one dose of motixafortide, 14 patients received the triple-drug premedication regimen and 78 did not receive the triple-drug premedication regimen (either received no premedication or another premedication regimen).

Serious adverse reactions occurred in 5.4% of patients receiving motixafortide in combination with filgrastim. Serious adverse reactions included vomiting, injection site reaction, hypersensitivity reaction, injection site cellulitis, hypokalemia and hypoxia.

One patient did not receive the 5th dose of filgrastim due to an elevated white blood cell count following administration of motixafortide. The most common adverse reactions occurring in GENESIS (>20% and at least 2% higher than the filgrastim + placebo arm) were injection site reactions (pain, erythema and pruritus), pruritus, flushing, and back pain. Table 1 summarizes the common adverse reactions in GENESIS.

Table 1. Common Adverse Reactions in Patients with Multiple Myeloma During Hematopoietic Stem Cell Mobilization and Apheresis in GENESIS^a:

^a Adverse reactions that occurred in ≥10% in motixafortide-treated patients and ≥2% more than placebo-treated patients.
^b All reactions were grade 3.
^c Injection site reactions includes: injection site bruising, injection site discomfort, injection site erythema, injection site induration, injection site mass, injection site nodule, injection site pain, injection site pruritus, injection site rash, injection site swelling, injection site urticaria, injection site cellulitis and injection related reaction.
^d Flushing includes hot flush.
^e Rash includes: rash erythematous, rash maculo-papular, rash papular and rash pruritic.
^f Back pain includes spinal pain and sacral pain.
^g Paresthesia includes: paresthesia oral, hypoesthesia, hypoesthesia oral and burning sensation.

Clinically relevant adverse reactions that occurred in the motixafortide arm only in <10% of patients include dermatitis exfoliative generalized, ear swelling, pyrexia, chills, dizziness, tremor and hypertension.