5 WARNINGS AND PRECAUTIONS

5.1 Anaphylactic Shock and Hypersensitivity Reactions

Anaphylactic shock occurred in 0.7% of APHEXDA-treated patients in clinical studies (n=407). The time to anaphylactic shock was between 5 minutes and 30 minutes after drug administration. Hypersensitivity reactions occurred in 7.6% of APHEXDA-treated patients in the GENESIS study. In addition, pruritus, flushing, urticaria, rash, erythema, vomiting, nausea and chills have been reported.

Premedicate all patients prior to each dose of APHEXDA 30-60 minutes prior to administration with a triple-drug premedication regimen that includes an H1-antihistamine, an H2 blocker, and a leukotriene inhibitor [see Dosage and Administration (2.1)]. Patients receiving concomitant negative chronotropic drugs (e.g., beta blockers) may be more at risk for hypotension in case of hypersensitivity reaction. When appropriate, beta blockers should be replaced with non-chronotropic drugs.

Administer APHEXDA only in a setting where personnel and therapies are immediately available for the treatment of anaphylaxis and other systemic reactions. Monitor patients for signs or symptoms of hypersensitivity reactions for one hour following administration of APHEXDA and manage reactions promptly.

5.2 Injection Site Reactions

Injection site reactions were reported in 73% of patients receiving APHEXDA in the GENESIS trial. Symptoms of injection site reactions included pain, erythema, pruritus, bruising, discomfort, induration, mass, nodule, rash, swelling, and urticaria. Among 92 patients treated with APHEXDA, the highest severity of the reactions was severe in 9%.

Premedicate with an analgesic medication (e.g., acetaminophen) prior to each APHEXDA dose. Use analgesic medication and local treatments postdose, as needed.

5.3 Tumor Cell Mobilization in Patients with Leukemia

For the purpose of hematopoietic stem cell (HSC) mobilization, APHEXDA may cause mobilization of leukemic cells and subsequent contamination of the apheresis product. Therefore, APHEXDA is not intended for HSC mobilization and harvest in patients with leukemia.

5.4 Leukocytosis

Administration of APHEXDA in conjunction with filgrastim increases circulating leukocytes as well as HSC populations. Monitor white blood cell counts during APHEXDA use.

5.5 Potential for Tumor Cell Mobilization

When APHEXDA is used in combination with filgrastim for HSC mobilization, tumor cells may be released from the marrow and subsequently collected in the leukapheresis product. The effect of potential reinfusion of tumor cells has not been well-studied.

5.6 Embryo-fetal Toxicity

Based on its mechanism of action, APHEXDA can cause fetal harm when administered to a pregnant woman. Animal models link dysfunction in CXCR4/SDF-1 signaling to adverse outcomes in mammalian embryo-fetal development and suggest risks to normal placental development.

Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with APHEXDA and for 8 days after the final dose [ see Use in Specific Populations (8.1, 8.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on its mechanism of action, APHEXDA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data with APHEXDA 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.

8.2 Lactation

Risk Summary

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 APHEXDA treatment and for 8 days after the final dose.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating APHEXDA.

Contraception

Females

APHEXDA can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with APHEXDA and for 8 days after the final dose [see Use in Specific Populations (8.1)].

8.4 Pediatric Use

The safety and effectiveness of APHEXDA have not been established in pediatric patients.

8.5 Geriatric Use

Of the total number of patients in the GENESIS study, 33.8% were ≥65 years old, while 1.25% were ≥75 years old in the APHEXDA arm. No overall differences in safety or effectiveness were observed between these patients and younger patients.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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/m 2).

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.

14 CLINICAL STUDIES

The efficacy of APHEXDA in combination with filgrastim was evaluated in the GENESIS study (NCT 03246529). In this randomized, double-blind, placebo- controlled study, 122 patients with multiple myeloma were randomized in a 2:1 ratio to receive APHEXDA 1.25 mg/kg subcutaneously (N=80) or placebo (N=42). Prior to receiving APHEXDA or placebo, patients received daily morning doses of filgrastim 10-15 mcg/kg for 4 days. On the evening of Day 4, patients received APHEXDA or placebo. On Day 5, patients received a fifth morning dose of filgrastim within 1 hour prior to their first apheresis (12 hours ± 2 hours from the APHEXDA/placebo administration). The apheresis cell collection goal for the study was ≥ 6 × 10 6 CD34+ cells/kg. The assessment of CD34+ cells was performed by central and local laboratories. Central laboratory assessments were used for the efficacy results. Local laboratory results were used for clinical treatment decisions.

In the event that the cell collection goal was not achieved with the first apheresis on Day 5, patients received another morning dose of filgrastim on Day 6 within 1 hour prior to their second apheresis. In the event that the cell collection goal was still not achieved, patients received a second administration of APHEXDA or placebo on the evening of Day 6 and a seventh dose of filgrastim in the morning of Day 7 within 1 hour prior to a third apheresis. If the collection goal was not achieved, patients received an eighth dose of filgrastim in the morning of Day 8 within 1 hour prior to a fourth apheresis.

The median age of the study population was 63 years (range 34-75); 65% were males, 86% Caucasian, 8% African American, 2% Asian and 10% were of Hispanic or Latino ethnicity. Seventy percent of patients were previously treated with lenalidomide.

The efficacy of APHEXDA was based upon the proportion of patients who achieved a cell collection goal of ≥ 6 × 10 6 CD34+ cells/kg in up to 2 aphereses after administration of filgrastim and a single administration of APHEXDA or placebo.

Efficacy results showed that 67.5% of patients in the APHEXDA treatment arm versus 9.5% in the placebo arm achieved the cell collection goal of ≥ 6 × 10 6 CD34+ cells/kg in up to 2 aphereses after a single administration of APHEXDA or placebo, resulting in an adjusted difference between treatment arms of 56.8% (p < 0.0001) (Table 3).

Table 3: Proportion of Patients Who Achieved CD34+ Cell Collection Goal Following Single Administration of APHEXDA or Placebo (GENESIS)

*The reported p values are two sided based on the Cochran-Mantel-Haenszel common proportion difference method stratifying for response status (CR or PR) at baseline and to baseline platelet count (<200 × 10 9/L or ≥ 200 × 10 9/L).

Multiple factors can influence time to engraftment and graft durability following stem cell transplantation. In the GENESIS study, time to neutrophil and platelet engraftment and graft durability following transplantation were similar across treatment groups.