033: Clinical Assessment of Mocravimod as a Victim of Drug-Drug Interactions via CYP3A Metabolism & Transporters

Statement of Purpose, Innovation or Hypothesis: Mocravimod (MOC), a novel sphingosine-1-phosphate receptor (S1PR) modulator in phase 3 development in patients with acute myeloid leukemia (AML) undergoing allogeneic hematopoietic cell transplantation (allo-HCT), is predominantly metabolized via the CYP3A4 pathway based upon in vitro data. The potential therapeutic effects are prevention of peripheral lymphocyte recirculation. MOC and its active metabolite mocravimod-phosphate (MOC-P) is a victim of BCRP but not of OAPT1B1 or OATP1B3 transporters. Preliminary pharmacokinetic (PK) modeling of phase 1b data suggested that CYP3A4 inhibitors and cyclosporin (CsA) could increase exposure to MOC significantly. Given the  co-administration of MOC with CYP3A4 inhibitors (e.g. azoles and CsA) in allo-HCT patients, two phase 1 studies were conducted to evaluate the drug-drug interactions (DDI) of MOC in combination with itraconazole (ITZ) or CsA.

Description of Methods & Materials: Two open-label fixed sequence studies were conducted in healthy volunteers to assess the effects of multiple dosing of a strong cytochrome P450 (CYP) 3A4 and PgP inhibitor ITZ and multiple dosing of a strong CYP3A4, PgP and BCRP inhibitor CsA on the single-dose pharmacokinetics of MOC. Blood samples were collected to determine MOC and MOC-P. MOC and MOC-P have long half-lives and therefore AUC_0-inf was determined using non-linear mixed effect modeling¹. Ratios of geometric least square (LS) means and 90% CIs were constructed for AUC_0-inf and C_max. Additionally, safety and tolerability of mocravimod were monitored.

Data & Results: ITZ co-administration with MOC did not affect the MOC and MOC-P C_max; geometric mean ratio (GMR) of 0.92 [0.85-1.01] and 0.99 [0.92-1.08] fold, respectively. AUC_0-inf was similar and independent of ITZ co-administration; GMR of 1.04 [0.97-1.11] and 1.11 [1.04-1.18] for MOC and MOC-P, respectively. CsA co-administration with MOC had a minor effect on MOC and a moderate effect MOC-P C_max; geometric mean ratio (GMR) of 1.15 [1.10-1.20] and 1.87 [1.66-2.11] fold, respectively. A minor effect was observed on AUC_0-inf ; GMR of 1.31 [1.24-1.38] and 1.46 [1.35-1.59] for MOC and MOC-P, respectively. PK modeling showed no effect of ITZ or CsA on the clearance of MOC or MOC-P, indicating limited CYP3A4 inhibition. Modeling indicated a potential small effect of BCRP inhibition by CsA on the absorption phase of MOC and MOC-P.  Based on the pharmacological mechanism of action of S1PR modulators bradycardia is a potential adverse event (AE) class effect as well as lymphopenia. In these studies, bradycardia, 88%/84% of HV in ITZ study (with/without ITZ) and 100%/100% in CsA study (with/without CsA) and lymphocyte count decreases 76%/68% in ITZ study and 43%/53% in CsA study were the most common AEs. AEs were generally mild, and treatment emergent AEs were similar with or without co-administration of ITZ or CsA.

Interpretation, Conclusion or Significance: MOC, ITZ and CsA were generally well tolerated when administered alone or in combination. The PK of MOC and MOC-P are bioequivalent with or without co-administration of multiple doses of the strong CYP3A4 inhibitor ITZ and a minor interaction is observed when co-administered with CsA. Taken together, MOC can be co-administered with CYP3A4 inhibitors such as azoles or CsA without dosage adjustments in allo-HCT patients.

Disclosures: All authors are employees of Priothera SAS.

Citations/References: ¹Svensson EM, C Acharya, B Clauson, KE Dooley, and MO Karlsson, 2016, Pharmacokinetic Interactions for Drugs With a Long Half-Life — Evidence for the Need of Model-Based Analysis, AAPS J, 18(1):171-179.

Additional Information/Authors: N.A.