APHEXDA MOTIXAFORTIDE 62 mg/1.7mL Injection, Powder, Lyophilized, For Solution, 1 vial — NDC 73441-062-01 (Billing 73441-0062-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action 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.

12.2Pharmacodynamics In vitro studies showed that the concentration for half-maximal inhibition (IC 50 ) of motixafortide towards CXCR4 ranges from 0.42 – 4.5 nM, the binding affinity (K D ) is 7.9 pM and the dissociation rate (Kd) from the CXCR4 receptor is 3.38e-5 s-1 with receptor occupancy maintained over >72 hours. The pharmacodynamics of motixafortide was evaluated in clinical studies conducted in healthy volunteers, healthy donors paired with recipients with advanced hematological malignancies, and multiple myeloma patients.

Across all clinical studies, mobilization of CD34+ to peripheral blood was observed. In healthy volunteers after administration of motixafortide as monotherapy, CD34+ cell counts increased with time, reaching maximal levels at 16 hours postdose. Thereafter, CD34+ cell counts declined slightly but remained elevated well above baseline at the last observation timepoint 24 hours postdose.

Data on the fold increase in peripheral blood CD34+ cell count (cells/mcL) by apheresis day were evaluated in the placebo-controlled part of the GENESIS study. The fold increase in CD34+ cell count over the 24-hour period, from the day prior to the first apheresis (before filgrastim administration) to the next morning before filgrastim administration (12 hours after APHEXDA administration) is summarized in Table 2. During this 24-hour period, a single dose of motixafortide or placebo was administered 10 to 14 hours prior to apheresis.

Table 2: Fold Increase in Peripheral Blood CD34+ Cell Count following Pre-treatment with Filgrastim and Administration of APHEXDA in GENESIS APHEXDA and Filgrastim Placebo and Filgrastim Median Mean (SD) Median Mean (SD) 6.7 7.7 (7.5) 1.5 1.6 (0.7) Cardiac Electrophysiology A thorough QT study in 38 healthy volunteers showed APHEXDA prolongs the QTcI interval in a concentration-dependent fashion. At 1.7-fold the C max of the maximum approved recommended dose (1.25 mg/kg), the mean placebo-corrected QTcI change from baseline was 11 (90% CI: 8 to 14) msec.

12.3Pharmacokinetics The pharmacokinetics of motixafortide were evaluated using both noncompartmental and population PK approaches in various populations, including healthy volunteers, patients with acute myeloid leukemia, and patients with multiple myeloma. Subjects received single or multiple doses ranging between 0.24 mg/kg to 2 mg/kg of APHEXDA administered by subcutaneous injections using a weight-based (mg/kg) dosing strategy as monotherapy or in combination with filgrastim with or without chemotherapy. The PK characteristics of motixafortide following subcutaneous administration were similar across all study populations.

A population pharmacokinetic analysis was conducted using 2240 plasma motixafortide concentrations from 223 individuals, including 81 healthy subjects, 37 patients with acute myeloid leukemia, and 105 patients with multiple myeloma. Motixafortide pharmacokinetics following subcutaneous administration were adequately described by a 3-compartment model with first-order absorption, dose-dependent relative bioavailability, and linear elimination kinetics. Minimal to… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action 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.

12.3Pharmacokinetics The pharmacokinetics of motixafortide were evaluated using both noncompartmental and population PK approaches in various populations, including healthy volunteers, patients with acute myeloid leukemia, and patients with multiple myeloma. Subjects received single or multiple doses ranging between 0.24 mg/kg to 2 mg/kg of APHEXDA administered by subcutaneous injections using a weight-based (mg/kg) dosing strategy as monotherapy or in combination with filgrastim with or without chemotherapy. The PK characteristics of motixafortide following subcutaneous administration were similar across all study populations.

A population pharmacokinetic analysis was conducted using 2240 plasma motixafortide concentrations from 223 individuals, including 81 healthy subjects, 37 patients with acute myeloid leukemia, and 105 patients with multiple myeloma. Motixafortide pharmacokinetics following subcutaneous administration were adequately described by a 3-compartment model with first-order absorption, dose-dependent relative bioavailability, and linear elimination kinetics. Minimal to no drug accumulation was observed following once daily dose administration and, as such, the single dose PK profile is considered representative of a steady state profile.

Absorption After subcutaneous injection as either a single or repeated dose at 0.24 to 2 mg/kg, motixafortide appeared in plasma with time to maximum concentration occurring at approximately 0.25 to 1.17 hours. Distribution Motixafortide is highly bound to human plasma proteins (>99%). The estimated volume of distribution of the central compartment in a typical subject is 27 L.

Metabolism Motixafortide undergoes non-specific degradation into small peptides and individual amino acids and their derivatives by catabolic pathways. Catabolism can occur in both blood and liver microsomes. In in vitro studies using human and animal biomaterials, no prominent unique human metabolites were identified.

Elimination Motixafortide has an effective half-life in human plasma of approximately 2 hours. The elimination kinetics were similar in healthy subjects and patients with multiple myeloma. Apparent total clearance of motixafortide for a typical subject is

46.5L/h. No mass balance studies were conducted in humans. In studies conducted in rats and dogs, the total amount of 14 C-labeled motixafortide-related material excreted in urine was approximately 80% and 82%, respectively, of the dose administered and no parent drug was detected in urine.

In both species, no metabolite exceeded 30% of total clearance. Specific Populations Renal Impairment Based on the population PK analysis, in patients with mildly to moderately decreased renal function, the pharmacokinetic profile of motixafortide was not significantly affected. While the effect of severe renal impairment on the clearance of motixafortide has not been evaluated, a significant effect is not anticipated.

Hepatic Impairment Motixafortide is catabolized in both the liver and blood, and animal data suggest that the main excretion pathway of its metabolites is via the kidneys and biliary excretion is minimal. Based on the population PK analysis, mildly impaired liver function did not significantly affect the pharmacokinetic profile of motixafortide. The effect of moderate to severe hepatic impairment has not been evaluated, but the risk for adverse reactions due to increased exposure is low because motixafortide is administered as a single dose.

Race/Ethnicity In the population PK analysis, ethnicity as a covariate was not found to be a statistically significant predictor of motixafortide PK. Gender In the population analysis, minimal effect of gender was seen on the overall pharmacokinetic profile of motixafortide. Despite higher relative bioavailability in females compared to males, the mg/kg dosing strategy and generally lower body weights in females result in only 10% higher exposures (AUC 0-24h and C max ) in females versus males for… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics In vitro studies showed that the concentration for half-maximal inhibition (IC 50 ) of motixafortide towards CXCR4 ranges from 0.42 – 4.5 nM, the binding affinity (K D ) is 7.9 pM and the dissociation rate (Kd) from the CXCR4 receptor is 3.38e-5 s-1 with receptor occupancy maintained over >72 hours. The pharmacodynamics of motixafortide was evaluated in clinical studies conducted in healthy volunteers, healthy donors paired with recipients with advanced hematological malignancies, and multiple myeloma patients.

Across all clinical studies, mobilization of CD34+ to peripheral blood was observed. In healthy volunteers after administration of motixafortide as monotherapy, CD34+ cell counts increased with time, reaching maximal levels at 16 hours postdose. Thereafter, CD34+ cell counts declined slightly but remained elevated well above baseline at the last observation timepoint 24 hours postdose.

Data on the fold increase in peripheral blood CD34+ cell count (cells/mcL) by apheresis day were evaluated in the placebo-controlled part of the GENESIS study. The fold increase in CD34+ cell count over the 24-hour period, from the day prior to the first apheresis (before filgrastim administration) to the next morning before filgrastim administration (12 hours after APHEXDA administration) is summarized in Table 2. During this 24-hour period, a single dose of motixafortide or placebo was administered 10 to 14 hours prior to apheresis.

Table 2: Fold Increase in Peripheral Blood CD34+ Cell Count following Pre-treatment with Filgrastim and Administration of APHEXDA in GENESIS APHEXDA and Filgrastim Placebo and Filgrastim Median Mean (SD) Median Mean (SD) 6.7 7.7 (7.5) 1.5 1.6 (0.7) Cardiac Electrophysiology A thorough QT study in 38 healthy volunteers showed APHEXDA prolongs the QTcI interval in a concentration-dependent fashion. At 1.7-fold the C max of the maximum approved recommended dose (1.25 mg/kg), the mean placebo-corrected QTcI change from baseline was 11 (90% CI: 8 to 14) msec.

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) Cell Collection Goal APHEXDA and Filgrastim (N = 80) Placebo and Filgrastim (N = 42) p-value 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).

Proportion of patients with ≥ 6 × 10 6 CD34+ cells/kg in up to 2 aphereses – Central laboratory 67.5% 9.5% <0.0001 Proportion of patients with ≥ 6 × 10 6 CD34+ cells/kg in 1 apheresis – Central laboratory 63.8% 2.4% <0.0001 Proportion of patients with ≥ 2 × 10 6 CD34+ cells/kg in 1 apheresis – Central laboratory 87.5% 38.1% <0.0001 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.

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, 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 injection 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.