Motixafortide

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 on 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.

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 motixafortide administration) is summarized in Table 1. During this 24-hour period, a single dose of motixafortide or placebo was administered 10 to 14 hours prior to apheresis.

Table 1: Fold Increase in Peripheral Blood CD34+ Cell Count following Pre-treatment with Filgrastim and Administration of motixafortide in GENESIS

Cardiac Electrophysiology

A thorough QT study in 38 healthy volunteers showed motixafortide 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.

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 motixafortide 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 46.5 L/h.

No mass balance studies were conducted in humans.

In studies conducted in rats and dogs, the total amount of ¹⁴C-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 a weight-based dose and therefore is not considered clinically meaningful.

Age

In the population PK analysis, age as a covariate was not found to be a statistically significant predictor of motixafortide PK.

Drug Interaction Studies

In vitro studies showed a lack of significant (>25%) cytochrome P450 (CYP) inhibition in human hepatocytes, a lack of CYP induction potential in human hepatocytes, and a low potential for transporter-mediated interactions. As such, motixafortide has a low potential for both metabolism- and transporter-mediated drug interactions.