Drug Rescue and Repurposing: Benjamin Alman

Drug Rescue and Repurposing: Benjamin Alman

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By: Benjamin Alman

What drug are you investigating for its repurposing potential?

Nefopam was developed in the 1960s and is widely used in Europe for its analgesic properties. Part of the benzoxazocine chemical class, it is an alternative to opioids for relief of moderate to severe pain, with effects stronger than aspirin.1

For what new purpose is the drug being studied?

Our lab has investigated the use of Nefopam in fibroproliferative processes to inhibit cell proliferation and reduce tumor growth and scar size. As a key mediator of canonical Wnt signaling, β-catenin levels have been shown to regulate the number of mesenchymal cells that contribute to wound repair and scar size. Its stabilization has also been shown to cause aggressive fibromatosis, a locally invasive soft tissue tumor consisting of mesenchymal cells with cytologic similarity to hypertrophic scars.2 Because there are limited pharmacologics to treat these β-catenin-induced disorders, we undertook a screen to identify potential therapeutics from a library of over 2,000 compounds which are naturally occurring or have been used in humans.3 From this screen, Nefopam was found to inhibit cell viability in cultures of hypertrophic wound samples and aggressive fibromatosis samples, but not in normal fibroblasts.4

What are the research findings?

In a series of follow-up experiments, Nefopam was found to inhibit cell proliferation in cultures of aggressive fibromatosis tumors and hypertrophic skin wounds. It demonstrated the ability to target canonical Wnt signaling and reduce β-catenin protein levels. In a mouse model of aggressive fibromatosis, Nefopam treatment reduced the number of tumors that developed. In skin wounding experiments, mice treated with Nefopam had scar diameters half that of control mice.4

What do you hope is the future of the drug in this field?

Because it is already used in patients and has a strong safety record, Nefopam can be quickly brought to the clinic for new uses. Applied daily as a cream over the course of 3 weeks, Nefopam can reduce scar formation following surgery or injury. Development and commercialization are underway in collaboration with MaRS Innovation and Novotek Therapeutics Co. Ltd., in China. Clinical trials of the compound as ‘ScarX’ are anticipated to begin this year, in Toronto.5 If this drug is approved for use as a topical agent to mitigate the common occurrence of scarring, it is more likely to be approved in an oral form to treat the rare patient with aggressive fibromatosis.

What do you think is the future of drug rescue and repurposing?

In biomedical research where efficient translation can make the difference between success or failure of a product, drug repurposing offers the advantage of expediting the move from bench to bedside. Drugs that are already in use come with safety reports, pharmacokinetic profiles, efficacy records, and other such data which eliminate the need for extensive resource-demanding clinical trials. Drug libraries like the one we tested (MicroSource Spectrum collection) are particularly valuable for interrogating known drugs for novel applications, especially for diseases with limited therapeutic options.3 On the other hand, because these drugs are repurposed, issues around intellectual property arise and can cause concern for pharmaceutical, biotechnology, and venture capital companies.

Benjamin Alman
A.J. Latner Professor and Chair of Orthopaedics
Vice Chair Research, Department of Surgery, University of Toronto
Head, Division of Orthopaedics and Senior Scientist, Program in Developmental & Stem Cell Biology
Hospital for Sick Children

References
1. Wang, R. I. and E. M. Waite (1979). “The clinical analgesic efficacy of oral nefopam hydrochloride.” J Clin Pharmacol 19(7): 395-402.
2. Bowley, E., D. B. O’Gorman, et al. (2007). “Beta-catenin signaling in fibroproliferative disease.” J Surg Res 138(1): 141-150.
3. Peacock, C. D., Q. Wang, et al. (2007). “Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma.” Proc Natl Acad Sci U S A 104(10): 4048-4053.
4. Poon, R., H. Hong, et al. (2012). “A high throughput screen identifies Nefopam as targeting cell proliferation in beta-catenin driven neoplastic and reactive fibroproliferative disorders.” PLoS One 7(5): e37940.
5. Priest, L. (2012). “Canadian discovers method to radically minimize scars.” The Globe and Mail: 1, 8.