Motixafortide

APHEXDA is indicated in combination with filgrastim (G-CSF) to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with multiple myeloma. APHEXDA, a hematopoietic stem cell mobilizer, is indicated in combination with filgrastim (G-CSF) to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with multiple myeloma. ( 1 )

For injection: 62 mg as a white to off-white lyophilized powder in a single-dose vial for reconstitution. For Injection: 62 mg as a lyophilized powder in a single-dose vial for reconstitution. ( 3 )

APHEXDA is contraindicated in patients with a history of serious hypersensitivity reactions to motixafortide [see Warnings and Precautions (5.1) ] . History of serious hypersensitivity reaction to APHEXDA. ( 4 )

Anaphylactic Shock and Hypersensitivity Reactions: Premedicate all patients with a combination of an H1-antihistamine, an H2 blocker, and a leukotriene inhibitor prior to each APHEXDA dose. Administer APHEXDA in a setting where personnel and therapies are available for immediate treatment. Observe for signs and symptoms and manage promptly. ( 2.1 , 2.3 , 5.1 ) Injection Site Reactions: The addition of analgesic premedication (e.g., acetaminophen) is recommended. ( 5.2 ) Tumor Cell Mobilization in Patients with Leukemia: APHEXDA may mobilize leukemic cells and should not be used in leukemia patients. ( 5.3 ) Leukocytosis: Increased circulating leukocytes have been observed. Monitor white blood cell counts during APHEXDA use. ( 5.4 ) Potential for Tumor Cell Mobilization: Tumor cells may be released from marrow during HSC mobilization with APHEXDA and filgrastim. Effect of reinfusion of tumor cells is unknown. ( 5.5 ) Embryo-fetal Toxicity: Can cause fetal harm. Advise women of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.6 , 8.1 , 8.3 )

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) ] .

The following clinically significant adverse reactions are discussed in other sections of the labeling: Anaphylactic Shock and Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] Injection Site Reactions [see Warnings and Precautions (5.2) ] Potential for Tumor Cell Mobilization in Patients in Leukemia [see Warnings and Precautions (5.3) ] Leukocytosis [see Warnings and Precautions (5.4) ] Potential for Tumor Cell Mobilization [see Warnings and Precautions (5.5) ] Most common adverse reactions (incidence >20%) are injection site reactions, injection site pain, injection site erythema, injection site pruritus, pruritus, flushing, and back pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Gamida Cell at (844) 477-7478 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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 APHEXDA was evaluated in the GENESIS study based on data from 92 patients with multiple myeloma who received at least one dose of APHEXDA 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 [see Clinical Studies (14) ] . 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 APHEXDA, 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 APHEXDA 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 5 th dose of filgrastim due to an elevated white blood cell count following administration of APHEXDA. 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 Adverse reactions that occurred in ≥10% in APHEXDA-treated patients and ≥2% more than placebo-treated patients. APHEXDA and Filgrastim n=92 % Placebo and Filgrastim n=42 % All Grades Grade ≥3 All reactions were grade 3. All Grades Grade ≥3 Injection site reactions 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. 73 8 5 0 Injection site pain 53 7 5 0 Injection site erythema 27 0 0 0 Injection site pruritus 24 0 0 0 Pruritus 38 11 0 0 Flushing Flushing includes hot flush. 33 7 0 0 Rash Rash includes: rash erythematous, rash maculo-papular, rash papular and rash pruritic. 16 0 5 0 Urticaria 14 1.1 0 0 Erythema 12 0 0 0 Back pain Back pain includes spinal pain and sacral pain. 21 0 17 0 Paresthesia (g) Paresthesia includes: paresthesia oral, hypoesthesia, hypoesthesia oral and burning sensation. 19 0 17 0 Hypokalemia 15 4.3 12 0 Nausea 14 0 12 0 Clinically relevant adverse reactions that occurred in the APHEXDA arm only in <10% of patients include dermatitis exfoliative generalized, ear swelling, pyrexia, chills, dizziness, tremor and hypertension.

6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of APHEXDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: General Disorders and Administration Site Conditions – injection site necrosis, injection site ulcer.

Lactation: Advise not to breastfeed. ( 8.2 )

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 risks 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 treatment with APHEXDA 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.

Motixafortide is an inhibitor of the C-X-C Motif Chemokine Receptor 4 (CXCR4) and blocks the binding of its cognate ligand, stromal-derived factor-1α (SDF-1α)/C-X-C Motif Chemokine Ligand 12 (CXCL12). SDF-1α and CXCR4 play a role in the trafficking and homing of human hematopoietic stem cells to the marrow compartment. Once in the marrow, stem cell CXCR4 can help anchor these cells to the marrow matrix, either directly via SDF-1α or through the induction of other adhesion molecules. Treatment with motixafortide resulted in leukocytosis, and elevations in circulating hematopoietic stem and progenitor cells into the peripheral circulation in mice, rats, dogs, and humans. Stem cells mobilized by motixafortide were capable of engraftment with long-term repopulating capacity in a rodent transplantation model.