Glenmark Pharmaceuticals SA, the wholly owned Swiss subsidiary of Glenmark Pharmaceuticals Ltd (MUMBAI, India), a research-led, global, fully integrated pharmaceutical company, has applied for phase I clinical trials in Europe for GRC 6211. This drug is the company's leading antagonist of TRPV1 (transient receptor potential vanilloid 1; formerly known as vanilloid receptor 1 or VR1), a ligand-gated ion channel activated by agonists such as capsaicin and other factors such as heat and acidosis. The compound is targeted for a range of pain indications, such as osteoarthritis, dental pain, neuropathic pain, and urinary incontinence. The phase I study will be conducted by Kendle International Inc, a leading global contract research organization (CRO), using single and multiple oral doses with the objective of assessing safety and bioavailability of GRC 6211 in healthy human beings. Glenmark would also be conducting, in parallel, a phase IIa proof-of-concept study. Glenmark hopes to complete phase 1 by June 2007 and the phase IIa pain study by October 2007.
According to the company, preclinical studies have demonstrated GRC 6211 to be highly potent with functional IC50 of 3.8 nM and good bioavailability across species tested. The molecule also exhibited greater than 2600 selectivity over other TRP channels.
Glenmark is in discussions for potential licensing partners for this compound. The company targets launching the molecule in 2011 and aims to be an early launcher in this class. Some of the molecules in the same category currently under development by others include: Merck's lead molecule which is in-licensed from Neurogen and has progressed to phase II; GlaxoSmithKline's molecule presently in phase II; and Pfizer's in-licensed compound from Renovis, which is undergoing preclinical trials.
In addition to GRC 6211, the company has two other candidates for anti-inflammatory pain. GRC 10693, a cannabinoid-2 (CB-2) receptor agonist is being positioned for osteoarthritis, rheumatoid arthritis (RA), and other anti-inflammatory pain. Its preclinical profile indicates a highly potent molecule with functional IC50 of 0.6 nM against a human CB-2, >50% bioavailability across species tested and >1400 fold selectivity over CB-1. GRC 10693 is nonnarcotic, peripherally acting, and has excellent pain-control without the addiction potential associated with opioids. Clinical trials are expected to start in early 2007. GRC 4039 is a selective PDE4 (phosphodiesterase-4) inhibitor and is intended for RA and inflammatory disorders. The compound in preclinical testing has exhibited an IC50 of 2.7 nM, over 3700-fold selectivity to PDE4, bioavailability >90% across species, and a 10-hour half-life, thus indicating potential for a once-daily dosing regimen. Additionally, emesis (vomiting) did not occur in the preclinical models, and there were good results in early toxicology studies and a good safety margin; also, the agent exhibited good action in in-vivo RA and TNF-inhibition models. Clinical trials should be initiated in early 2008.
—A. Techman
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