Delving into the Latest Updates on Olorinab with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Olorinab (USAN), APD-371

Target

CB2

Mechanism

CB2 agonists(Cannabinoid CB2 receptor agonists)

Therapeutic Areas

Nervous System DiseasesDigestive System Disorders

Active Indication-

Inactive Indication

Abdominal PainCrohn DiseaseIrritable bowel syndrome with diarrhea

Originator Organization

Arena Pharmaceuticals, Inc.

Active Organization-

Inactive Organization

Arena Pharmaceuticals, Inc.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

Structure

Molecular FormulaC18H23N5O2

InChIKeyTVCYLBQVKJBKGA-GMXVVIOVSA-N

CAS Registry1268881-17-9

The synthesis and degradation of endocannabinoids, location of cannabinoid (CB) receptors, and cannabinoid mechanisms of action on immune/inflammatory, neuromuscular, and sensory functions in digestive organs are well documented. CB₂ mechanisms are particularly relevant in immune and sensory functions. Increasing use of cannabinoids in the United States is impacted by social determinants of health including racial discrimination, which is associated with tobacco and cannabis co-use, and combined use disorders. Several conditions associated with emesis are related to cannabinoid use, including cannabinoid hyperemesis or withdrawal, cyclic vomiting syndrome, and nausea and vomiting of pregnancy. Cannabinoids generally inhibit gastrointestinal motor function; yet they relieve symptoms in patients with gastroparesis and diverse nausea syndromes. Cannabinoid effects on inflammatory mechanisms have shown promise in relatively small placebo-controlled studies in reducing disease activity and abdominal pain in patients with inflammatory bowel disease. Cannabinoids have been studied in disorders of motility, pain, and disorders of gut-brain interaction. The CB₂-receptor agonist, cannabidiol, reduced the total Gastroparesis Cardinal Symptom Index and increases the ability to tolerate a meal in patients with gastroparesis appraised over 4 weeks of treatment. In contrast, predominant-pain end points in functional dyspepsia with normal gastric emptying were not improved significantly with cannabidiol. The CB₂ 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 CB₂ 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.

01 May 2023·Neurogastroenterology and motility

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)

Article

Author: Cash, Brooks D. ; Cataldi, Fabio ; English, Brett A. ; Lipkis, Donald ; Turner, Stewart ; Tack, Jan ; Lembo, Anthony ; Chang, Lin ; Lindstrom, Beatriz ; Skare, Sharon ; Kunkel, David C. ; Gu, Guibao ; Gilder, Kye

Abstract:

Background:

Olorinab is a highly selective, peripherally acting, full agonist of cannabinoid receptor 2. This study assessed the efficacy and safety of olorinab to treat abdominal pain in patients with irritable bowel syndrome with diarrhea (IBS‐D) and constipation (IBS‐C).

Methods:

CAPTIVATE was a phase 2b, randomized, double‐blind, placebo‐controlled, parallel‐group trial. Eligible participants aged 18–70 years with IBS‐C and IBS‐D diagnosed per Rome IV received olorinab 10 mg, 25 mg, or 50 mg three times daily (TID) or placebo TID for 12 weeks. The primary endpoint was the change in patient‐reported average abdominal pain score (AAPS) from baseline to Week 12.

Key Results:

A total of 273 participants were randomized to receive olorinab 10 mg (n = 67), olorinab 25 mg (n = 67), olorinab 50 mg (n = 69), or placebo (n = 70). Although a treatment response was observed across all groups, the weekly change in average AAPS from baseline to Week 12 was not significantly different between placebo and any olorinab dose. In a prespecified subgroup analysis of participants with a baseline AAPS ≥6.5, olorinab 50 mg (n = 35) significantly improved AAPS compared with placebo (n = 30) (p = 0.014). Adverse event rates were comparable between olorinab and placebo and there were no reported serious adverse events or deaths.

Conclusion and Inferences:

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. ClinicalTrials.gov: NCT04043455.

15 Mar 2023·Nature communicationsQ1 · CROSS-FIELD

Structural basis of selective cannabinoid CB₂ receptor activation.

Q1 · CROSS-FIELD

ArticleOA

Author: de Paus, Laura V ; Liu, Zhi-Jie ; Heitman, Laura H ; van den Berg, Richard J B H N ; Li, Xiaoting ; Lichtman, Aron ; Wu, Lijie ; Kumar, Sanjay Sunil ; Hua, Tian ; Yu, Yanan ; van der Stelt, Mario ; Mustafa, Mohammed ; Bouma, Jara ; van der Horst, Cas ; Janssen, Antonius P A ; Chang, Hao ; Pacher, Pal ; Paloczi, Janos ; Mukhopadhyay, Partha

Cannabinoid CB₂ receptor (CB₂R) agonists are investigated as therapeutic agents in the clinic. However, their molecular mode-of-action is not fully understood. Here, we report the discovery of LEI-102, a CB₂R agonist, used in conjunction with three other CBR ligands (APD371, HU308, and CP55,940) to investigate the selective CB₂R activation by binding kinetics, site-directed mutagenesis, and cryo-EM studies. We identify key residues for CB₂R activation. Highly lipophilic HU308 and the endocannabinoids, but not the more polar LEI-102, APD371, and CP55,940, reach the binding pocket through a membrane channel in TM1-TM7. Favorable physico-chemical properties of LEI-102 enable oral efficacy in a chemotherapy-induced nephropathy model. This study delineates the molecular mechanism of CB₂R activation by selective agonists and highlights the role of lipophilicity in CB₂R engagement. This may have implications for GPCR drug design and sheds light on their activation by endogenous ligands.

100 Deals associated with Olorinab

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External Link

KEGG	Wiki	ATC	Drug Bank
D11429	-	-	DB14998

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Irritable bowel syndrome with diarrhea	Phase 2	US	Arena Pharmaceuticals, Inc.	24 Jul 2019
Abdominal Pain	Phase 2	US	Arena Pharmaceuticals, Inc.	19 Jul 2017
Crohn Disease	Phase 2	US	Arena Pharmaceuticals, Inc.	19 Jul 2017

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04043455 (CTgov)	Phase 2	Irritable bowel syndrome with diarrhea \| Abdominal Pain	273	Olorinab (Main Study Period: Olorinab 10 mg)	qwvoxadzeu(ikwkorzglh) = zawfiejnjw bscidwazyu (ujcjjbrpjx, ccpvbkflnu - hxpkovmgwx) View more	-	12 Oct 2022
				Olorinab (Main Study Period: Olorinab 25 mg)	qwvoxadzeu(ikwkorzglh) = igioiqmwdb bscidwazyu (ujcjjbrpjx, dfekwatclm - kdyhpnexyo) View more
NCT03155945 (CTgov)	Phase 2	Crohn Disease \| Abdominal Pain	14	Olorinab (Olorinab 25 mg TID)	mrsuygcwbp(cybcslgfoo) = dpfnrfqhed zpndwuvftk (nngdvcaupu, eyfqlwoprs - pkdrjcvbtg) View more	-	02 Nov 2021
				Olorinab (Olorinab 100 mg TID)	mrsuygcwbp(cybcslgfoo) = tbeylytqmc zpndwuvftk (nngdvcaupu, sbbumwaaaf - obhprnzsvy) View more
NCT04043455 (CAPTIVATE, BusinessWire) Manual	Phase 2	Abdominal Pain	273	Olorinab	mhrjtclyls(tloawbdnvx) = Moderate to severe pain population at 50 mg showed statistically significant, clinically meaningful improvement vs placebo in Average Abdominal Pain Score (AAPS) tvikjocapp (hfdtvembbd ) View more	Positive	02 Mar 2021
				Placebo