S1PR1 agonist a promising treatment for rheumatoid arthritis

The selective agonist of sphingosine-1-phosphate receptor-1 (S1PR1), proximod, appears to be well tolerated and helps reduce blood lymphocyte count in patients with rheumatoid arthritis (RA), according to a phase I study.

The trial was conducted in two parts. Part 1 included 124 healthy volunteers (mean age 34.3 years, 50 percent women, 94 percent Han Chinese) who were randomly assigned to one of 10 cohorts receiving a single oral dose of proximod (0.125, 0.25, 0.5, 1, 1.5, 2, 3, 5, 10, or 15 mg) or placebo. In part 2, 10 healthy volunteers (mean age 39.9 years, 50 percent women, 100 percent Han Chinese) were randomly assigned to receive once-daily doses of proximod 5 mg or placebo, while 24 patients with RA (mean age 52.7 years, 92 percent women, 92 percent Han Chinese) were randomly assigned to receive once-daily doses of proximod 5 mg, proximod 10 mg, or placebo.

The primary outcomes of safety, tolerability, and pharmacokinetic profile of proximod were assessed for 72 days in healthy volunteers and for 48 days in patients with RA.

In part 1, all doses of proximod were well tolerated. None of the healthy volunteers experienced dose-related adverse reactions or serious adverse events. In part 2, 74 adverse reactions were documented in eight (80 percent) healthy volunteers and 22 (92 percent) RA patients. Adverse events related to treatment were mostly mild or moderate.

As for the pharmacokinetic profile, the concentration levels of proximod and its active metabolite, proximod-phosphate, gradually increased in part 2. The half maximal effective concentration of the S1PR1 agonist for proximod-phosphate (6.1 ng/mL) was reached on day 14 in the two 5-mg groups and on day 7 in the 10-mg group. The mean C_trough values for proximod-phosphate on day 28 were 7.7 and 10.2 ng/mL in healthy volunteers and RA patients, respectively, who received the 5-mg dose, and 15.3 ng/mL in RA patients who received the 10-mg dose.

In the RA cohort, a reduction in lymphocyte count occurred after treatment, with nadir levels reached at approximately day 28. The corresponding percentage decline from baseline in lymphocyte count was 65.25 percent in the 5-mg group, 71.64 percent in the 10-mg group, and 20.57 percent in the placebo group.