Pharmacokinetics, Pharmacodynamics and Safety of Mocravimod After Single and Multiple Oral Dosing in Healthy Japanese Participants

Technical Summary: Pharmacokinetics, Pharmacodynamics, and Safety of Mocravimod in Healthy Japanese Participants

Problem and Rationale
Mocravimod is a synthetic immunomodulatory agent that functions as a selective sphingosine-1-phosphate receptor-1 (S1P₁) modulator. Upon administration, it is rapidly phosphorylated in vivo to mocravimod-phosphate, the active metabolite responsible for functional antagonism of the S1P₁ receptor. This mechanism leads to the internalization of the receptor and the sequestration of lymphocytes within secondary lymphoid organs, thereby reducing circulating lymphocyte counts and suppressing immune cell trafficking. While previous clinical studies in predominantly Caucasian and mixed populations have established the dose-dependent immunomodulatory activity, pharmacokinetics (PK), and safety profile of mocravimod, there was a need to characterize these parameters specifically in a Japanese population. This was necessary to address potential inter-ethnic differences in drug disposition and to support global clinical development, despite the expectation that CYP3A4-mediated metabolism (the primary route of biotransformation) would be comparable between East Asian and European populations.

Methodology
The study was a single-centre, randomized, double-blind, placebo-controlled, parallel-group, ascending-dose Phase I trial conducted at Shinanozaka Clinic in Tokyo, Japan. It involved 64 healthy Japanese male participants aged 20–55 years with a BMI between 18.5 and 25.0 kg/m². The trial consisted of two sequential parts:

1. Single-Dose Part: Evaluated oral doses of 0.3, 1.0, 2.0, and 3.0 mg.
2. Multiple-Dose Part: Evaluated once-daily (QD) oral doses of 1.2 mg and 2.0 mg for 28 days.

Pharmacokinetic assessments involved validated liquid chromatography–tandem mass spectrometry (LC–MS/MS) methods to quantify mocravimod and mocravimod-phosphate in whole blood. Non-compartmental analysis was used to derive PK parameters (e.g., $T_{max}$, $C_{max}$, $AUC$, $t_{1/2}$). Pharmacodynamic (PD) assessments focused on peripheral blood lymphocyte counts (absolute lymphocyte count, ALC), heart rate via Holter electrocardiography, and white blood cell subsets (T-cells, B-cells, monocytes, NK cells). Safety was monitored through adverse events, clinical laboratory tests, vital signs, and electrocardiography.

Key Contributions
This manuscript provides the first comprehensive characterization of the PK, PD, and safety profiles of mocravimod specifically in healthy Japanese participants. It establishes the dose-exposure relationship and the reversibility of pharmacodynamic effects in this demographic, facilitating the comparison of Japanese data with previously published non-Japanese data.

Results

• Pharmacokinetics:

  • Systemic exposure to both mocravimod and mocravimod-phosphate increased with dose following both single and multiple dosing.
  • Single Dose: The median time to maximum concentration ($T_{max}$) ranged from 6 to 10 hours. The apparent terminal half-life ($t_{1/2}$) was approximately 104–139 hours for mocravimod and 109–136 hours for mocravimod-phosphate.
  • Multiple Dose: Steady state was achieved by Day 28. Both $C_{max,ss}$ and $AUC_{\tau}$ increased with dose. Accumulation ratios indicated moderate accumulation with limited fluctuation. The half-life values remained comparable to single-dose observations.
  • The PK profile was predictable and consistent with first-order elimination.

• Pharmacodynamics:

  • Lymphopenia: Mocravimod induced dose-dependent, reversible reductions in peripheral lymphocyte counts.
    • In the single-dose study, maximal decreases occurred approximately 10–12 hours post-dose. At doses of 1.0 mg and above, statistically significant reductions in $E_{max}$ and $AUC_{0-24}$ were observed compared to placebo.
    • In the multiple-dose study, sustained reductions were observed, with maximal decreases occurring between Day 5 and Day 28. The maximal decrease from baseline was 79% (1.2 mg) and 84% (2.0 mg) versus 19% for placebo.
  • Heart Rate: Transient, dose-dependent decreases in heart rate were observed. In the multiple-dose study, reductions were most apparent on Days 2–3 (approximately 4–7 bpm placebo-adjusted) and were no longer evident by Day 5. No serious cardiac adverse events occurred.
  • White Blood Cell Subsets: Multiple dosing led to reversible reductions in circulating T-cell and B-cell subsets, with relative increases in monocytes and natural killer cells, consistent with S1P₁-mediated redistribution.

• Safety:

  • All adverse events were mild in severity. No serious adverse events (SAEs) or study discontinuations due to adverse events occurred.
  • Common adverse events included transient increases in liver enzymes (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase) and blood triglycerides, as well as nasopharyngitis.
  • No clinically significant laboratory abnormalities or electrocardiographic findings were observed.

Significance and Claims
The authors conclude that mocravimod demonstrates predictable pharmacokinetics, expected pharmacodynamic effects, and good tolerability in healthy Japanese participants. The findings are consistent with prior observations in non-Japanese populations, supporting the ethnic generalizability of mocravimod's exposure–response relationships. The study confirms that the PK parameters are comparable between Japanese and non-Japanese populations, with minor differences likely attributable to body weight variations rather than metabolic enzyme differences. The reversible nature of the lymphopenia and transient heart rate effects aligns with the known mechanism of S1P₁ modulation and supports the further clinical development of mocravimod for immune-mediated diseases. The authors note limitations regarding the small sample size, the exclusive inclusion of male participants, and the primarily descriptive nature of the analyses, suggesting that future studies in patient populations are required to fully characterize the clinical relevance of these findings.