Background/Purpose: Melanocortin (MC) type 1 and type 3 receptor stimulation is associated with anti-inflammatory activity and the promotion of inflammatory resolution. AP1189 is novel biased MC1 and MC3 receptor agonist aimed for once daily oral administration in clinical development for treatment of active Rheumatoid Arthritis (RA).

Methods: AP1189 was studied in a four-week double-blind placebo-controlled Phase 2a clinical trial in newly diagnosed and MTX naïve patients presenting with high disease activity (Clinical disease activity index (CDAI) > 22), the BEGIN study. The primary study objectives were to evaluate the safety, tolerability, and potential treatment effects relative to placebo. The primary efficacy endpoint was defined as a reduction in mean CDAI score from baseline to 4-weeks or as the fraction of patients going from severe activity (CDAI >22) to moderate or lower disease activity (CDAI< 22). 105 patients were initiated on MTX therapy at physician’s discretion and randomized to receive either 50 mg AP1189, 100 mg AP1189 or placebo once daily via oral suspension. Patients were treated with AP1189 or placebo once-daily for 4-weeks with a 4-week safety follow-up period. Additional efficacy assessments included ACR scoring, DAS28-CRP and FACIT-Fatigue

Results: Of the 105 randomized patients 102 completed the study dosing. 92 of the 102 patients had CDAI measured after end of the 4-week treatment period without any rescue medication (glucocorticoids) (placebo: n=30; 50 mg: n=29; 100 mg: n=33). Baseline CDAI (mean per group): Placebo: 36.3; 50 mg: 36.1; 100 mg: 39.0. No Serious adverse events were observed. The number of adverse events (AEs) reported were highest in the 50 mg group (total reported AEs: 65) and lowest in the placebo group (total AEs reported: 34). Except for two AEs in the placebo group, all AE were classified as mild or moderate. The most frequent AEs were gastrointestinal disorders with nausea as the dominating event in all three treatment groups. Increases in aminotransferases to levels above upper normal range was observed in the placebo and the 50 mg group, but not in the 100 mg group.

On efficacy, the AP1189 100mg group had a significantly greater decrease in mean CDAI score from baseline and in the ACR20 score as compared to placebo (mean change in CDAI in the above-mentioned population: placebo -9.3, 50 mg -12,0 100 mg -15.5 p=< 0.5 for 100mg vs placebo; ACR20: placebo 33.3%, 50 mg 37.9%, 100 mg 60.6%, p=< 0.5 for 100 mg Vs placebo). Change in disease activity from severe to moderate or lower was numerically higher in AP1189 groups as compared to placebo (CDAI < 22: placebo 40 %, 50 mg 62 %, 100 mg 52 %, NS). Strong trends of efficacy were seen on the DAS28CRP and FACIT-Fatigue indices (to be presented).

Conclusion: AP1189 is novel oral available compound with anti-inflammatory and pro-resolving effects with the potential to treat active RA. Data from the BEGIN study support the further development of AP1189 as a potential safe and efficacious oral therapy for RA and other inflammatory diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-begin-study-a-double-blind-multi-center-two-part-randomized-placebo-controlled-study-of-the-safety-tolerability-and-efficacy-of-4-weeks-of-treatment-with-ap1189-in-early-rheumatoid-arthriti/