Wednesday, June 17, 2015

Drugs in Clinical Pipeline: Resunab

Resunab [1',1'-dimethylheptyl- Δ8-tetrahydrocannabinol-11-oic acid] is developed to achieve the goal of providing a synthetic Cannabis-derived drug that would show analgesic efficacy and have a low potential for abuse. This idea is proven through various experiments where there is no evidence that Resunab produces psychotropic actions when given at therapeutic doses. In a variety of animal assays, Resunab shows efficacy in models for pain and inflammation. Furthermore, in the rat adjuvant arthritis model, Resunab displayed a remarkable action in preventing the destruction of inflamed joints.

Resunab as a novel synthetic oral drug has the potential to treat chronic inflammation and fibrosis. Pre-clinical and Phase 1 studies have shown Resunab to have a favourable safety, tolerability and pharmacokinetic profile. Resunab is designed to trigger the resolution of chronic inflammation by binding to and activating the CB2 receptor on immune cells (in effect, turning inflammation "off"). Resunab holds the potential to be a safe and potent anti-inflammatory drug with a unique mechanism of action to treat a range of chronic inflammatory diseases.

In June 2015, Corbus Pharma announced that the U.S. Food and Drug Administration (US-FDA) has granted Corbus' lead drug candidate Resunab, Orphan Drug Designation for the treatment of systemic sclerosis. Systemic sclerosis is a chronic, serious, life-threatening inflammatory disease causing fibrosis of skin and internal organs, affecting predominately women in mid-life. Systemic sclerosis is associated with severe morbidity and high mortality. There are currently no FDA-approved drug therapies for systemic sclerosis.

The FDA has already cleared the Corbus' investigational new drug application (IND) for systemic sclerosis and the company is preparing to commence Phase 2 studies.

Common Name: Resunab
Synonyms:  Ajulemic acid; AJA; CT-3; IP-751; AB-III-56; HU-239; CPL 7075
IUPAC Name: (6aR,10aR)-3-(1,1-dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-Dibenzo(b,d)pyran-9-carboxylic acid
CAS Number: 137945-48-3
SMILES: CC(C)(CCCCCC)c2cc1OC(C)(C)[C@@H]3/C=C\C(C[C@H]3c1c(O)c2)C(O)=O
Mechanism of Action: 
Indication: Anti-inflammatory Drugs; Analgesic Drugs; Treatment of Systemic Sclerosis
Development Stage: Phase II
Company: Corbus Pharma

The studies into mechanism of Resunab have produced some contradictory questions.  On the one hand, modest binding to the known cannabinoid receptors, CB1 and CB2 has been reported, and effects by receptor specific antagonists as well as stereospecificity has been observed suggesting a possible role for these receptors in the actions of Resunab. On the other hand, the fact that Resunab does not produce psychoactivity, a process that is believed to require the activation of CB1, appears to be a contradiction. A possible explanation is that Resunab, in addition to activating the receptor, selectively antagonizes a downstream event that is required for psychotropic activity but is not needed for anti-inflammatory actions [1].

1. Burstein, S. Ajulemic acid (IP-751): synthesis, proof of principle, toxicity studies, and clinical trials. AAPS J 2005, 7(1), E143-8.