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GRC 15300, a Vanilloid (TRPV)3 antagonist for neuropathic pain

Glenmark Pharmaceuticals Ltd. (GPL) announced in 2009 that its candidate for Neuropathic pain, GRC 15300 has been filed for Phase I trials. GRC 15300 is descibed as a Transient Receptor Potential Vanilloid (TRPV)3 Antagonist.

The TRPV3 physiology might indeed be linked to pain-pathways.^[1] Recent data from Korea University Graduate School of Medicine suggested that endogenous TRPV3 activator exist, that causes nociception. ^[2]

However, more news on TRPV3 modulators is not yet available in the public domain, but we can find novel ligands for the TRPV4 receptor. ^[3]

The TRPV3 receptor seems also to be linked to immunological pathways, which could be of specific importance for neuropathic pain. ^[4]^[5] Certain natural compounds also influence this receptor, menthol for instance activates TRPA1 and TRPV3 in addition to TRPM8. ^[6]

GRC 15300 into development

The molecule has been filed for Phase 1 approval in the United Kingdom in 2009.

GRC 15300 will be one of the first TRPV3 molecules to enter development. In animal models GRC 15300 is as least as efficacious as compared to current Gold standard molecules such as pregabalin and gabapentin, according to the company, but published data are absent.

Since 2009 no news has been released, so there is doubt whether the project is still alive.

Glenmark has allocated its resources in the TRP area and it is said that Glenmark has one of the most in-depth research programs in TRP channels globally. GRC 15300 is said to be highly efficacious in animal models as compared to current Gold standard molecules (pregabalin, gabapentin), and it will not have opiod properties.

In 2009 Mr. Glenn Saldanha, MD & CEO, Glenmark Pharmaceuticals Ltd. said, “We are extremely glad to take GRC 15300 forward into Phase I trials. This is a significant development for our organization as this molecule will be the first TRPV3 antagonist globally to be filed for Phase I trials making it a potential first-in-class. This development is a reaffirmation of Glenmark’s research capabilities and focused approach towards drug discovery and our commitment towards setting new benchmarks in speed, efficiency and continuous progress in the drug discovery space.”

Glenmark commented in a press release about this target in January 2009:

There has been significant scientific interest and commercial attention devoted to the vanilloid receptors as potential pain targets. Several companies have active programs in the TRPV3 space including Pfizer which entered into a collaboration agreement with Hydra Biosciences in 2007 that included potential milestone payment of upto USD 195 million for the first developed product launched, with upside potential for additional approved indications. However so far, no TRPV compounds have reported entry into clinical trials. The Transient Receptor Potential Vanilloid 3 (TRPV3), is a thermosensitive, voltagedependant ligand-gated cation channel. Its tissue expression varies across species. In humans, it is expressed in the superior cervical and trigeminal ganglia and is also expressed in the brain, spinal cord, keratinocytes, tongue and dorsal root ganglion (DRG) of sensory neurons. Across species, TRPV3 subunits are also co-expressed with TRPV1 where they form heteromultimeric structures by interacting with TRPV1 monomers.

TRPV3 receptor mainly acts as a warmth sensor and responds to warm temperatures (33 – 39°C). It is strongly sensitized by various repeated stimuli such as heat, camphor, 2 – aminoethyl diphenylborate (2-APB), carvacrol, thymol and eugenol indicating a potential role in nociception. TRPV3 receptor antagonists are also implicated in the treatment of myasthenic syndrome, NIDDM, breast cancer, and there is limited data available suggesting its putative roles in the neurophysiology of pruritis. Thus, TRPV3 receptor antagonists may be of potential therapeutic benefit in inflammatory and neuropathic pain conditions and a variety of other indications mentioned above with combined market size in excess of 10 Billion worldwide in 2007.

The addressable market: There is a large un-met medical need and the recent concerns around the safety of cox-2 inhibitors should propel sales of safer products. The neuropathic pain market is estimated at around USD 5 billion with over 40 million patients worldwide while the Osteoarthritis market is valued at over USD 5 billion with over 200 million patients worldwide. It is estimated that 9.6% of men and 18.0% of women aged over 60 years have symptomatic osteoarthritis(WHO Report)

May 2010, Jan M. Keppel Hesselink, MD, PhD

Referenties

[1]: Bevan S, Andersson DA. | TRP channel antagonists for pain--opportunities beyond TRPV1. | Curr Opin Investig Drugs. | 2009 Jul;10(7):655-63.

[2]: Bang S, Yoo S, Yang TJ, Cho H, Hwang SW. | Farnesyl pyrophosphate is a novel pain-producing molecule via specific activation of TRPV3. | J Biol Chem. | 2010 Jun 18;285(25):19362-71. Epub 2010 Apr 15.

[3]: Vincent F, Acevedo A, Nguyen MT, Dourado M, DeFalco J, Gustafson A, Spiro P, Emerling DE, Kelly MG, Duncton MA. | Identification and characterization of novel TRPV4 modulators. | Biochem Biophys Res Commun. | 2009 Nov 20;389(3):490-4. Epub 2009 Sep 6.

[4]: Imura K, Yoshioka T, Hirasawa T, Sakata T. | Role of TRPV3 in immune response to development of dermatitis. | J Inflamm (Lond). | 2009 May 25;6:17.

[5]: Steinhoff M, Bíró T. | A TR(I)P to pruritus research: role of TRPV3 in inflammation and itch. | J Invest Dermatol. | 2009 Mar;129(3):531-5.

[6]: Ma S, G G, Ak VE, Jf D, H H. | Menthol derivative WS-12 selectively activates transient receptor potential melastatin-8 (TRPM8) ion channels. | Pak J Pharm Sci. | 2008 Oct;21(4):370-8.