olorinab (APD371) / Pfizer - LARVOL DELTA

A combination of peripherally restricted CB1 and CB2 cannabinoid receptor agonists reduces bladder afferent sensitisation in cystitis. (PubMed, Eur J Pharmacol) - "Peripherally restricted CB1R preferential agonists, ACEA and PrNMI and peripherally restricted CB2R selective agonists, 4Q3C and olorinab all reduced the mechanosensitivity of mucosal bladder afferents...Our data indicated that peripherally restricted CB1R and CB2R agonists effectively reduce the sensitisation of probable nociceptive afferents in the bladder in cystitis. The findings also suggest a potential benefit of simultaneously targeting both the CB1Rs and CB2Rs to ameliorate LUTS in cystitis."

Journal • Interstitial Cystitis • Musculoskeletal Pain • Pain

Drugs of the future for diarrhea-predominant irritable bowel syndrome: an overview of current investigational drugs. (PubMed, Expert Opin Investig Drugs) - "Clinical trial evidence has shown that loperamide, eluxadoline, alosetron, ramosetron, bile acid sequestrants, and rifaximin can modulate GI alterations and benefit patients with IBS-D. Among the potential therapies, ibodutant, ibudilast, blautix, BOS-589, solabegron, vibegron, olorinab, ebastine, and ORP-101 have demonstrated possible effects but remain confirmed...Therefore, we should focus on developing new, efficient, and affordable medications for IBS-D. The government, insurers, and society must recognize this need and collaborate to ensure its fulfillment."

Journal • Review • Gastrointestinal Disorder • Inflammation

Cannabinoids and the GI Tract. (PubMed, Clin Gastroenterol Hepatol) - "The CB agonist, olorinab, reduced abdominal pain in inflammatory bowel disease in an open-label trial and in constipation-predominant irritable bowel syndrome in a placebo-controlled trial. Cannabinoid mechanisms alter inflammation in pancreatic and liver diseases. In conclusion, cannabinoids, particularly agents affecting CB mechanisms, have potential for inflammatory, gastroparesis, and pain disorders; however, the trials require replication and further understanding of risk-benefit to enhance use of cannabinoids in gastrointestinal diseases."

Journal • Review • CNS Disorders • Constipation • Dyspepsia • Gastroenterology • Gastrointestinal Disorder • Hepatology • Immunology • Inflammation • Inflammatory Bowel Disease • Pain • Rare Diseases

Kinetic context to improve CB2R agonist efficacy (ACS-Fall 2023) - "MethodsCryo-electron microscopy (cryo-EM) structures were made of CB2R in complex with the Gi protein for the non-selective agonist CP55,940 and three structurally diverse CB2R-selective agonists HU308, APD371 (Olorinab) and LEI-102 (a novel compound)...ConclusionsStructural biology studies combined with site-directed mutagenesis and extensive molecular pharmacology research have revealed the molecular basis of target engagement of CB2R agonists. This provides a framework for the rational design and understanding of experimental drugs targeting the CB2R."

Clinical • Oncology • Pain

Structural basis of selective cannabinoid CB receptor activation. (PubMed, Nat Commun) - "Here, we report the discovery of LEI-102, a CBR agonist, used in conjunction with three other CBR ligands (APD371, HU308, and CP55,940) to investigate the selective CBR activation by binding kinetics, site-directed mutagenesis, and cryo-EM studies...This study delineates the molecular mechanism of CBR activation by selective agonists and highlights the role of lipophilicity in CBR engagement. This may have implications for GPCR drug design and sheds light on their activation by endogenous ligands."

Journal • Renal Disease

Efficacy and safety of olorinab, a full agonist of the cannabinoid receptor 2, for the treatment of abdominal pain in patients with irritable bowel syndrome: Results from a phase 2b randomized placebo-controlled trial (CAPTIVATE). (PubMed, Neurogastroenterol Motil) - P2 | "Although olorinab was well-tolerated and improved weekly AAPS, the primary endpoint was not met. However, in participants with moderate-to-severe pain at baseline (AAPS ≥6.5), olorinab 50 mg significantly improved weekly AAPS compared with placebo."

Clinical • Journal • P2b data • Constipation • Gastroenterology • Gastrointestinal Disorder • Immunology • Pain

Interventions for the management of abdominal pain in Crohn's disease and inflammatory bowel disease. (PubMed, Cochrane Database Syst Rev) - "We found low certainty evidence that transcranial direct current stimulation may improve pain intensity compared to sham stimulation. We could not reach any conclusions on the efficacy of any other interventions on pain intensity, pain frequency, and treatment success. The certainty of the evidence was very low due to the low numbers of studies and participants in each comparison and clinical heterogeneity amongst the studies. While no serious or total adverse events were elicited explicitly with any of the treatments studied, the reported events were very low. The certainty of the evidence for all comparisons was very low, so no conclusions can be drawn."

Journal • Review • CNS Disorders • Crohn's disease • Depression • Fatigue • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Mood Disorders • Pain • Psychiatry • Ulcerative Colitis

[VIRTUAL] EFFICACY AND SAFETY OF OLORINAB, A PERIPHERALLY ACTING, HIGHLY SELECTIVE, FULL AGONIST OF CANNABINOID RECEPTOR 2, FOR THE TREATMENT OF ABDOMINAL PAIN IN PATIENTS WITH IRRITABLE BOWEL SYNDROME: RESULTS FROM A PHASE 2B RANDOMIZED STUDY: Discussion (UEGW 2021) - No abstract available

Clinical • P2b data • Gastrointestinal Disorder • Immunology • Pain

[VIRTUAL] EFFICACY AND SAFETY OF OLORINAB, A PERIPHERALLY ACTING, HIGHLY SELECTIVE, FULL AGONIST OF CANNABINOID RECEPTOR 2, FOR THE TREATMENT OF ABDOMINAL PAIN IN PATIENTS WITH IRRITABLE BOWEL SYNDROME: RESULTS FROM A PHASE 2B RANDOMIZED STUDY (UEGW 2021) - "Although olorinab improved AAPS from BL and appeared to induce a dose-dependent response, overall primary and secondary endpoints were not met. However, there was a clinically meaningful and statistically significant improvement in AAPS with 50 mg olorinab vs PBO in a subset of participants with a greater severity of abdominal pain at BL. There was a trend for larger treatment effect relative to placebo in participants with IBS-C."

Clinical • P2b data • Constipation • Crohn's disease • Gastrointestinal Disorder • Immunology • Infectious Disease • Inflammatory Bowel Disease • Pain

[VIRTUAL] Olorinab, a Peripherally Acting, Highly Selective, Full Agonist of the Cannabinoid Receptor 2 (CB2), Reduces Calcium Influx Following TRPV1 Activation in Human Visceral Nociceptors (IASP 2021) - "Examination of sensory neurons in patients with chronic pain conditions often display neuronal hyperexcitability in response to various stimuli. This may be, in part, due to sensitization of sensory nerves. Our findings showed that olorinab reduced capsaicin responses in human primary visceral nociceptors, confirming that activation of CB2 is a relevant antinociceptive pathway in human tissue."

Gastroenterology • Gastrointestinal Disorder • Immunology • Pain

CAPTIVATE: Olorinab in IBS-C and IBS-D (clinicaltrials.gov) - P2; N=273; Terminated; Sponsor: Arena Pharmaceuticals; Trial completion date: Feb 2022 ➔ Apr 2021; Active, not recruiting ➔ Terminated; Trial primary completion date: Jan 2021 ➔ Apr 2021; Business Decision

Clinical • Trial completion date • Trial primary completion date • Trial termination • Gastrointestinal Disorder • Immunology • Pain

[VIRTUAL] CANNABINOID RECEPTOR 2 (CB2) LOCALIZATION IN COLONIC TISSUE AND PRIMARY SENSORY DORSAL ROOT GANGLIA (DRG) NEURONS ISOLATED FROM RODENTS WITH COLITIS AND CHRONIC VISCERAL HYPERSENSITIVITY (DDW 2021) - "Dual staining of colonic tissues with CB2 receptor probes and a broad marker of immune cells (CD45) reveal that CB2 receptors are predominantly located in non-immune cells regardless of disease state. Additional studies are needed to identify the non-immune cells that predominantly express CB2 receptors and determine whether olorinab has a direct functional impact on these cellular targets."

Preclinical • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Pain • PTPRC

Effect of Olorinab on Gastrointestinal Transit in Patients With Irritable Bowel Syndrome (clinicaltrials.gov) - P1; N=1; Terminated; Sponsor: Arena Pharmaceuticals; N=24 ➔ 1; Trial completion date: Oct 2021 ➔ Apr 2021; Recruiting ➔ Terminated; Trial primary completion date: Aug 2021 ➔ Apr 2021; Strategic business decision

Clinical • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Gastrointestinal Disorder • Immunology

Olorinab (APD371), a peripherally acting, highly selective, full agonist of the cannabinoid receptor 2, reduces colitis-induced acute and chronic visceral hypersensitivity in rodents. (PubMed, Pain) - "CB2 mRNA was detected in colonic tissue, particularly within epithelial cells, and dorsal root ganglia, with no significant differences between healthy, colitis, and CVH states. These results demonstrate olorinab reduces visceral hypersensitivity via CB2 agonism in animal models, suggesting that olorinab may provide a novel therapy for IBD- and IBS-associated abdominal pain."

Journal • Preclinical • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Pain

Arena Pharmaceuticals Reports Topline Results from Phase 2b CAPTIVATE Clinical Trial (Arena Press Release) - P2, N=273; CAPTIVATE (NCT04043455); Sponsor: Arena Pharmaceuticals; "Arena Pharmaceuticals...announced topline results from...CAPTIVATE clinical trial evaluating three doses of olorinab...in participants with abdominal pain due to Irritable Bowel Syndrome (IBS)....A pre-specified analysis assessed participants with baseline AAPS ≥ 6.5 (median), representing those with moderate to severe pain. This subgroup accounted for 50% of the overall study population. Within this subgroup, the 50 mg treatment group showed a clinically meaningful and statistically significant (p=0.01) reduction in AAPS of 1.64 points compared to placebo and 3.93 points from baseline at week 12....'Look forward to sharing the full data from this well-executed trial at an upcoming medical meeting.'"

P2b data • CNS Disorders • Immunology • Inflammatory Bowel Disease • Pain

"Second bump in the road for Arena’s reboot (Via @JacobPlieth) https://t.co/ARmvaw9mWT #olorinab #etrasimod $ARNA" (@evaluatevantage)

APD371: Expiry of patents related to compositions-of-matter and methods of treatment utilizing olorinab and related compounds in US, China, Japan, Canada, India, Russia, South Korea and Australia, EU, Venezuela and Brazil in 2030 (Arena) - Annual Report 2020

Patent • Crohn's disease • Inflammatory Bowel Disease

Effect of Olorinab on Gastrointestinal Transit in Patients With Irritable Bowel Syndrome (clinicaltrials.gov) - P1; N=24; Recruiting; Sponsor: Arena Pharmaceuticals

Clinical • New P1 trial • Gastrointestinal Disorder • Immunology

Olorinab: Data from P2 CAPTIVATE trial (NCT04043455) for abdominal pain associated with irritable bowel syndrome in mid-Q1 2021 (Arena) - Q3 2020 Results

P2 data • Pain

CAPTIVATE: Olorinab in IBS-C and IBS-D (clinicaltrials.gov) - P2; N=273; Active, not recruiting; Sponsor: Arena Pharmaceuticals; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Gastrointestinal Disorder • Immunology • Pain

[VIRTUAL] EXPRESSION AND LOCALIZATION OF CANNABINOID RECEPTORS AND THE EFFECT OF OLORINAB, A PERIPHERALLY ACTING, HIGHLY SELECTIVE, FULL AGONIST OF THE CANNABINOID RECEPTOR 2, ON VISCERAL HYPERSENSITIVITY IN RODENT MODELS OF IRRITABLE BOWEL SYNDROME AND INFLAMMATORY BOWEL DISEASE (UEGW 2020) - "Olorinab reduced visceral hypersensitivity in colitis and CVH rodents; these results suggest that CB2 activation causes antinociceptive actions in visceral sensory pathways. The presence of CB2 in colonic tissue and in primary sensory DRG neurons was validated through qRT-PCR and ISH studies, implying that both sites may contribute to the antinociceptive activity of olorinab. The colocalization of CB2 receptors in specific cell types are under investigation to identify the mechanisms involved in olorinab-mediated responses."

Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Pain

Arena Pharmaceuticals’ Presence at United European Gastroenterology Week Strengthens Ongoing Commitment to the Gastrointestinal Disease Community (PRNewswire) - "Arena Pharmaceuticals, Inc. (Nasdaq: ARNA) will present new data from the Phase 2 OASIS trial and its open-label extension for its investigative drug candidate etrasimod, a next-generation, once-daily, oral, highly selective sphingosine 1-phosphate (S1P) receptor modulator, in patients with moderately to severely active ulcerative colitis (UC) at the 26th Annual United European Gastroenterology (UEG) Week. Arena will also present preclinical data for olorinab, a peripherally acting, highly selective, full agonist of the cannabinoid receptor 2 (CB2), in development for the treatment of visceral pain in gastrointestinal (GI) diseases. UEG Week is taking place virtually October 11-13, 2020....Arena Sponsored Symposium Details....Speakers: William Sandborn, MD..."

P2 data • Preclinical • Inflammatory Bowel Disease • Ulcerative Colitis

Arena Pharmaceuticals Completes Full Enrollment of Olorinab Phase 2 CAPTIVATE Trial for Abdominal Pain in Irritable Bowel Syndrome (PRNewswire) - "Arena Pharmaceuticals...today announced that it has completed full enrollment of the Phase 2b CAPTIVATE trial evaluating olorinab...for the potential treatment of abdominal pain in irritable bowel syndrome (IBS)....We look forward to seeing topline Phase 2 data in early 2021."

Enrollment closed • P2b data

Ironwood GERDs its loins for Linzess press after phase III bomb (Bioworld) - "Arena Pharmaceuticals Inc., with the olorinab in a phase IIb study called Captivate, testing the cannabinoid CB2 receptor agonist for abdominal pain associated with IBS-C as well as IBS-D. Top-line results are expected in the first quarter of 2021."

P2b data • Pain

Arena completes full enrollment of etrasimod phase 2 ADVISE trial for atopic dermatitis, provides program updates (Arena Press Release) - "Etrasimod ELEVATE UC 52 Phase 3 trial in ulcerative colitis (UC) ongoing and on track; ELEVATE UC 12 Phase 3 trial expected to initiate in H2 2020; topline data for both trials expected by year end 2021...Etrasimod CULTIVATE Phase 2b dose-ranging trial in Crohn's disease (CD) initiated and ongoing; considering options to help facilitate availability of topline data in 2021; withdrawing previously announced overall program guidance based on expected COVID-19 impact on trial execution including site activation and enrollment...Olorinab CAPTIVATE Phase 2b trial in abdominal pain associated with irritable bowel syndrome (IBS-C, IBS-D) ongoing; experiencing some COVID-19 related impact on trial enrollment; topline data expected between Q4 2020 and Q1 2021..."

New P3 trial • P2b data • P3 data: top line • Trial status • Crohn's disease • Inflammatory Bowel Disease • Ulcerative Colitis