Safety, Pharmacokinetics, and Efficacy of Olorinab, a Peripherally Acting, Highly Selective, Full Agonist of the Cannabinoid Receptor 2, in a Phase 2a Study of Patients With Chronic Abdominal Pain Associated With Crohn's Disease

Abstract

Background: This randomized, open-label phase 2a study investigated the safety/tolerability, pharmacokinetics, and efficacy of olorinab-a highly selective, peripherally acting, full agonist of the cannabinoid receptor 2-in patients with Crohn's disease (CD) experiencing abdominal pain.

Methods: Eligible subjects 18-80 years of age with quiescent to mildly active CD were randomized to receive olorinab 25 or 100 mg three times daily for 8 weeks. The primary objective was to assess safety/tolerability.

Results: Fourteen subjects received olorinab 25 mg (N = 6) or 100 mg (N = 8). Ten subjects [4 (67%) in the 25-mg group and 6 (75%) in the 100-mg group] reported a total of 34 treatment-emergent adverse events (TEAEs; 32 grade 1/2, not serious events; 2 grade 3, serious, not treatment-related events). No dose reductions or discontinuations due to TEAEs or deaths were reported. Dose-proportional increases in olorinab exposure from 25 to 100 mg were observed, with minimal accumulation at both doses. At week 8, the mean (SD) change from baseline in average abdominal pain score at peak olorinab plasma concentrations was -4.61 (1.77) in the 25-mg group (P = 0.0043) and -4.57 (2.17) in the 100-mg group (P = 0.0036). The change from baseline at week 8 in the mean (SD) number of pain-free days per week was +1.60 (2.61) in the 25-mg group and +2.33 (3.62) in the 100-mg group. No subject required pain medication on study.

Conclusions: Patients with quiescent to mildly active CD receiving olorinab experienced mild-to-moderate adverse events and an improvement in abdominal pain scores in this study.

Keywords: CB2 agonist; Crohn’s disease; cannabinoid; olorinab; pain.

Figure 1.

Change in weekly AAPS at trough, peak, and evening trough olorinab plasma concentrations. Mean change over time in weekly AAPS measured at trough (predose), peak (1.5 hours postdose), and evening trough (predose) olorinab plasma concentrations in the 25-mg (A) and 100-mg (B) TID dose groups. Summary of mean change from baseline in AAPS at weeks 4 and 8 in the olorinab 25- and 100-mg TID dose groups (C). ^aFor evening trough at week 2, n = 7 for mean weekly AAPS. *P < 0.05; **P < 0.01 vs baseline. BL, baseline.

Figure 2.

Pain relief response with olorinab. Proportion of patients who had ≥30% reduction from baseline in weekly peak AAPS (A), trough AAPS (B), evening trough AAPS (C), and daily AAPS (averaged over peak, trough, and evening trough diary entries; D) with olorinab 25 or 100 mg TID and in all subjects at weeks 4 and 8, and were considered pain relief responders. Pain relief response was assessed using observed data (ie, in subjects with evaluable data at weeks 4 and 8).

Figure 3.

Daily AAPS in the first week of treatment with olorinab. Mean (SD) daily AAPS during the first week of treatment with olorinab 25 mg TID and olorinab 100 mg TID (A), and in all subjects (B). BL, baseline.

Figure 4.

Change in the number of pain-free days per week with olorinab. Change from baseline in the mean (SD) number of pain-free days per week with olorinab 25 mg TID and olorinab 100 mg TID (A) and in all subjects (B). No subjects experienced a pain-free day at baseline. EOT analysis used the last available value for subjects who withdrew early or did not have week 8 data.

Figure 5.

Percent change in mean CD-PRO domain scores with olorinab. Absolute percent change in mean CD-PRO scores with olorinab 25 mg TID (A) and olorinab 100 mg TID (B) across domains. Percent change was calculated separately for each domain by subtracting the mean week 8 score as a percentage of the maximum possible domain score from the baseline mean score as a percentage of the maximum possible domain score, for patients with both baseline and week 8 data.