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Nerve Growth Factors as new inroads in chronic and neuropathic pain

Stakeholder Opinions: Targeting Nerve Growth Factor for Pain Therapy - Groundbreaking class to breathe new life into saturated market - this is the somewhat pompous and overdone title a new market research report from companiesandmarkets.com, published in 2010, on a new potential class of analgesics for neuropathic pain.

More and more modern research shows how important the role is of NGF in neuropathic pain. ^[1]^[2]^[3]^[4] That is the reason that different compenies focussed on this new target in the treatement of neuropathic pain. Especially since this is a real domain with a hugh unmet need.

Research and development of new NGF antagonists in chronic pain

For 2407 UK Pounds you can obtain the report on NGF antagonists, and the report is dated: 05 Mar 2010. A little teaser from the table of content we can find in the internet:

Therapies targeting nerve growth factor (NGF) in pain
NGF antagonists
TrkA inhibitors
NGF trap molecules that compete with TrkA receptors
Pipeline overview
Strong presence of Big Pharma in NGF pipeline
Key Nerve growth factor projects in development
Overview of NGF antagonists and Overview of TrkA inhibitors
Tanezumab (RN624; Pfizer)
First Phase III studies to yield results in 2011
Promising Phase II data
Peripheral neuropathy and paresthesia documented in Phase II studies
Pfizer will obtain arthritis approval first
Tanezumab will be priced equivalent to existing biologics
REGN475 (SAR-164877, Sanofi-Aventis/Regeneron)
JNJ-42160443 (formerly AMG403, Ortho-McNeil-Janssen Pharmaceuticals/Amgen)
PG110 (hu-alphaD11, Abbott)
Overview of TrkA inhibitors
BXL1H5 (huMNAC-13; BioXell/Cosmo Pharmaceutical SpA)

Clearly there are some similarities to other biologicals, and the report states some important questions and statements:

Will anti-NGFs mirror the impact of anti-TNFs?

Similar to anti-TNFs, anti-NGFs will become the first biological drugs in chronic pain but unlike anti-TNF, anti-NGFs will remain the last-line therapeutic choice if cost remains high.

In the introduction the report states some intersting facts. They state that clinical studies have shown inhibition of nerve growth factor (NGF) has a strong analgesic effect. According to the report three methods block or sequester the NGF signal transduction pathway:

NGF antagonists,
tropomyosin-related kinase A inhibitors and
NGF trap molecules.

Now the NGF pathway is quite interesting, and even old, off patent compounds such as acetyl-l-carnitine seem to influence the NGF and part of the analgesic effects might be contributed to this mechanism of action. ^[5]

Pfizer: tanezumab most advanced

The most advanced pipeline candidate is Pfizer's tanezumab with currently in phase III. Pfizer has gathered Phase I and II clinical trial data on osteoarthritic pain and chronic lower back pain and in these trials demonstrated efficacy, as well as a acceptable safety and tolerability. ^[6]^[7] However, trials have not yet been published.

Tanezumab is undergoing clinical trials for the treatment of different pain indications, including chronic low back pain, .knee and hip pain due to osteoarthritis , bone cancer pain, as well as interstitial cystitis and painful bladdersyndrome as well as Pain Associated With Endometriosis and Pain Associated With Chronic Abacterial Prostatitis. The highest dose tested is tanezumab 10 mg IV. No studies in diabetic neuropathy so far.

As with other new principles of treatment, the safety of the NGF targeting therapies is still unanswered.

Adverse effects shown in tanezumab trials indicate peripheral neuropathy, dysesthesia and paresthesia were the most frequent, however, no patient has taken tanezumab for longer than 6 months.

NGF antagonists in neuropathic pain

For the time being nerve growth factors remain a promise, but we really need to await full and completed phase III programmes in order to be able to find the efficacy and tolerability profiles of these drugs.

From the Centre for the study and treatment of Neuropathic Pain and Neuropathy in Soest, the Netherlands
This site helps patients and treating physicians, neurologists, anesthesiologists and other pain specialists to find the best and most up to date research findings related to neuropathy and neuropathic pain and the treatment thereof.
In our centre we are specialised in treating patients suffering from neuropathic pain and neuropathy following an Integrated Medicine concept. Part of our activities are within the field of consultation. We assist pharmaceutical companies in R&D strategies related to finding new drugs to treat neuropathic pain and neuropathy.

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

Referenties

[1]: Rukwied R, Mayer A, Kluschina O, Obreja O, Schley M, Schmelz M. | NGF induces non-inflammatory localized and lasting mechanical and thermal hypersensitivity in human skin. | Pain. | 2010 Mar;148(3):407-13. Epub 2009 Dec 22.

[2]: Golden JM, Tarleton RL. | Trypanosoma cruzi: cytokine effects on macrophage trypanocidal activity. | Exp Parasitol. | 1991 May;72(4):391-402.

[3]: Watson JJ, Allen SJ, Dawbarn D. | Targeting nerve growth factor in pain: what is the therapeutic potential? | BioDrugs. | 2008;22(6):349-59. doi: 10.2165/0063030-200822060-00002.

[4]: Sabsovich I, Wei T, Guo TZ, Zhao R, Shi X, Li X, Yeomans DC, Klyukinov M, Kingery WS, Clark JD. | Effect of anti-NGF antibodies in a rat tibia fracture model of complex regional pain syndrome type I. | Pain. | 2008 Aug 15;138(1):47-60. Epub 2008 Feb 20.

[5]: Vivoli E, Di Cesare Mannelli L, Salvicchi A, Bartolini A, Koverech A, Nicolai R, Benatti P, Ghelardini C. | Acetyl-L-carnitine increases artemin level and prevents neurotrophic factor alterations during neuropathy. | Neuroscience. | 2010 Jun 2;167(4):1168-74. Epub 2010 Mar 16.

[6]: Cattaneo A. | Tanezumab, a recombinant humanized mAb against nerve growth factor for the treatment of acute and chronic pain. | Curr Opin Mol Ther. | 2010 Feb;12(1):94-106.

[7]: Abdiche YN, Malashock DS, Pons J. | Probing the binding mechanism and affinity of tanezumab, a recombinant humanized anti-NGF monoclonal antibody, using a repertoire of biosensors. | Protein Sci. | 2008 Aug;17(8):1326-35. Epub 2008 May 27.