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ANALGESIA DRUG DISCOVERY PROGRAMM
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 PL37: a New Therapeutic Class of Small Molecules
Endorphins are produced, inter alia, by painful stimuli, and bind receptors µ and δ, with much higher affinity to the later, thereby inducing a natural analgesia that is extremely short due to the aminopeptidase N (APN)/ neutral endopeptidase (NEP)-mediated degradation as demonstrated as early as 1980 by Professors Bernard Roques and Marie-Claude Fournié-Zaluski.
Indeed, Pharmaleads has been working on this concept since its creation. Pharmaleads conducted a long and careful chemical "lead identification" phase based on the above previously published principles. After several adjustments on the structure of the selected molecules, a relevant sets of models were applied to these molecules. All in all, throughout the various steps chemical analysis was privileged to a mass screening approach.
This work has led to the design and synthesis of PL37 which is the most advanced compound of that new therapeutic class of small molecules that inhibits simultaneously both enzymes NEP and APN.
PL37 characteristics and first pharmacological results led Pharmaleads management to focus its attention on the application of PL37 to neuropathic pain, and, as a temporary/iterative substitute to morphine when patients become tolerant to it. PL37 and its likes have been patented.
In 2007, PL37 has entered the regulatory preclinical Phase, which was completed in 2008. Biodisponibility, toxicity and pharmacology studies have given very positive and encouraging results showing no tolerance, a strong biodisponibility, no detrimental effects.
Neuropathic pain: a strong demand and a rapidly growing market
Neuropathic pain can be defined as a pain, caused by nerve injury, which is often difficult to treat and does not respond to treatments effective in other types of pain. The global prevalence of neuropathic pain is believed to be as high as 6 percent (Bouhassira D et al. Pain, 2008) and greater in those over 55 years of age. Annual incidence of neuropathic pain is estimated to 1% of general population (Dieleman JP et al., Pain, 2008). Diabetic neuropathies are a family of nerve disorders caused by diabetes leading to numbness, weakness and sometimes pain in the hands, arms, feet and legs. About 15 percent of diabetics in the USA (about 3 million people) are thought to experience diabetic nerve pain.
Other causes of neuropathy are anticancer drugs (oxaliplatine, taxol/taxotere), anti-retroviral therapy, herpes zoster infections (shingles).
The market for neuropathic pain treatments is estimated to reach USD 5 billion by 2010 (source: DataMonitor)
Current treatments are far from satisfactory and are led by anti-epileptic agents and tricyclic anti depressants. A new safe, well tolerated and effective drug should take a very significant share of the market (between 10 and 15% in the first years of marketing). That is why numerous drugs are under development. We have identified approximately 150 projects, 75 of them in clinical phases. Most of them are based on old targets (NMDA, CB2 or vanilloid receptors, ion channels, while few are based on a new concept such as PL37. Next steps and a additional family of compounds
In October 1st, 2008, Pharmaleads has received from AFSSAPS (the French Medicine Agency) clearance to run a single ascending dose Phase I study with PL37. This compound is now developped as Debio 0827 by our partner Debiopharm. see News
Additionnal research using the same mechanism of action and the same target have in the meantime allowed Pharmaleads to define a new, although somehow similar, class of potential drugs. Further development are ongoing to validate these molecules on relevant models.
Scientific Advisory Board
Professor Alex Cahana MD, DAAPM, MAS, H.M Hughes Professor and Chief Division of Pain Medicine, Bonica Multidisciplinary Center for Pain Relief and Discovery, Dep. of Anesthesiology, University of Washington, Seattle, WA
Dr Jules Desmeules is a clincial pharmacologist at the Centre multidisciplinaire d'évaluation et de traitement de la douleur Département Anesthésiologie, Pharmacologie et Soins Intensifs, at the same the Hôpital Universitaire Genevois.
Professor Anthony H. Dickenson, is world-known expert in the realm of pain pharmacology, at the University College London.
Dr Rafael Maldonado, M.D., is a clinician and neuropharmacologist. He is Head of the Laboratori de Neurofarmacologia at the Facultat de Ciències de la Salut i de la Vida, Universitat Pompeu Fabra in Barcelona.
Dr Florence Noble is a neuropharmacologist, at the Département de neuropharmacologie des addictions, Faculté de Pharmacie, Paris.
Professor Jean-Claude Willer is Professor of Physiology at Paris School of Medicine (Service Department Physiologie 2, Groupe Hospitalier Pitié-Salpétrière).
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