Background/Purpose: Melanocortin (MC) type 1 and type 3 receptor stimulation is associated with anti-inflammation and promotion of inflammatory resolution. AP1189 is a biased MC type 1 and 3 receptor agonist aimed for oral administration currently in clinical development for treatment of active Rheumatoid Arthritis.

Methods: The pharmacokinetic profile of the compound has been evaluated in healthy male volunteers at three dose levels (N=27). Following once daily dosing with oral suspension for 14 days, PK analyses showed rapid absorption with tmax observed 1.5-2.5 hours post dosing. Elimination half-time between 19 (lowest dose) and 23 (highest dose) hrs (CV%: 13 and 21%). Approximately 10% of the compound was excreted unchanged in the urine. No drug accumulation was observed after steady state had been reached at day 7. Expose (based on AUC) was supra-proportional with a moderate increase of 2.25 when the dose was doubled. The most common side effects observed were nausea and headache with low to moderate intensity and observed in the time matched placebo controls too. Specifically, no sign of immunosuppression was observed. No, treatment related effect on vital signs were observed and telemetric CV safety evaluation did not reveal any QTcF prolongation nor other cardiac safety concerns.

The compound is currently tested in a double-blind placebo-controlled Phase 2a clinical trial in Europe with once daily dosing for four weeks as add on to Methotrexate (MTX) in previous MTX naïve patients with clinical disease activity (CDAI) above 22. The primary aim of the study is to evaluate safety and tolerability and potential treatment effects of the compound relative to placebo. The primary efficacy readout is defined as fraction of patients where disease activity goes for high (ie CDAI >22) to mediate or lower disease activity. The aim is to include a minimum of 105 subjects treated with either 50 mg AP1189, 100 mg AP1189 or placebo.

Results: An interim analysis of the first 26 patients showed the following:

16 women, 10 men, median age 57 (high/low: 79/27), median CDAI: 34 (high/low: 49/24) were treated with MTX according to the investigator’s discretion (10-15 mg po once weekly increasing to 15-25 mg during the 4 weeks study period). 9 were treated with placebo, 9 with 50 mg AP1189 and 8 with 100 mg AP1189 as add on to the MTX treatment. There were no dropouts, and no serious adverse events were observed. The most common reported adverse events were nausea (9 cases disturbed equally between the three treatment groups) and 3 cases of headache. No signs of immunosuppression were observed. Median CDAI at end of treatment between groups were 18.5 (high/low: 46/4). 7 patients had low disease activity (CDAI 2.9-10); 9 had moderate disease activity (CDAI 10,1-22), 10 pts had high disease activity (CDAI >22). CDAI at end of treatment distributed between the three treatment groups: Placebo: 4 out of 9 (44%); 50 mg AP1189: 6 out of 9 (67%), 100 mg: 6 out of 8 (75%). To secure blinding of investigators and sponsor no further evaluation of group specific effects was made. Completion of the study is planned for third quarter 2021.

Conclusion: AP1189 is novel oral available compound with anti-inflammatory and pro-resolving effect with the potential to treat active RA

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/ap1189-a-novel-oral-biased-melanocortin-agonist-with-anti-inflammatory-and-pro-resolving-effect-for-the-treatment-of-rheumatoid-arthritis/