Project: Psoriasis Anti-inflammatory Treatment
The PAT project aims at developing an effective and safe treatment for psoriasis taking advantage of the anti-inflammatory properties of TMX-302 (see Annex). TMX-302 (Background IPR of Telormedix) binds with high specificity a pivotal receptor (Toll-like Receptor 7) of the immune cells (plasmacytoid dendritic cells) that are responsible for triggering the disease. The project will produce TMX-302 innovative formulations for oral as well as topical treatment of psoriasis. Efficacy and safety of the formulated compound will be studied and compared to currently used therapies in a suite of proof-of-concept preclinical experiments by using unique but validated animal models that closely mimic development of psoriasis in humans._x000D__x000D_Psoriasis is a T cell-mediated (auto-) immune disease affecting around 2% of the population worldwide. The treatment of psoriasis is aimed at the reduction of inflammation by the use, traditionally, of immunosuppressive agents. For mild psoriasis, use of local corticosteroids, vitamin D preparations, calcineurin inhibitors and phototherapy might be sufficient for achieving control of skin lesions. However, about a third of psoriasis patients suffer from moderate to severe disease, necessitating the administration of systemic agents with anti-inflammatory and immunosuppressive capacities. Earlier drugs used for moderate to severe psoriasis, such as corticosteroids, methotrexate and cyclosporine, induced broad immune suppressive activities leading to an increased susceptibility towards infections and a heightened risk of cancer development, along with a host of other adverse side effects._x000D__x000D_Recently, more selective therapeutics (also termed biologicals) became available, including monoclonal antibodies (mAb) targeting pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and the two p40-containing cytokines interleukin-12 (IL-12) and IL-23. Although these biologicals have shown potent anti-inflammatory actions in psoriasis, these drugs, which have to be administered by injection, suffer from a series of shortcomings, including the generation of antibodies by the host against these agents rendering them inefficient, as well as suppression of immunity against intracellular pathogens such as viruses, mycobacteria and listeria (with anti-TNF-alpha agents)._x000D__x000D_Hence, the goal of future drug development for chronic inflammatory pathologies such as psoriasis is the generation of agents that are anti-inflammatory without being immunosuppressive._x000D__x000D_Telormedix has developed a novel class of small molecules acting as Toll-like receptor 7 (TLR7) “partial agonists” to potently dampen the inflammatory response without inducing immunosuppression, thus potentially fulfilling the above requirements. In in vivo studies, these compounds have been shown to be well tolerated upon systemic administration and to exert a potent anti-inflammatory activity without inducing a state of immunosuppression. These TLR7 partial agonists hold the promise of generating improved anti-inflammatory responses in the treatment of psoriasis._x000D_In this project, we propose to extensively test a TLR7 partial agonist, TMX-302, in well-established animal models of psoriasis and skin inflammation provided by the Department of Dermatology of the University Hospital Zurich (USZ). _x000D__x000D_The CO objective of the PAT project is to acquire the knowledge base needed to proceed on both pre-clinical studies and clinical trials for a new highly effective and safe treatment of psoriasis. _x000D__x000D_The project will develop appropriate oral and topical formulations for TMX-302, as both route of administration are viewed as practicable for the treatment of psoriasis and we want to ensure the achievement of the best and most efficacious formulation for the Telormedix’ compound. These formulations developed by the consortium Ps Midatech Biogune and Molecular Profiles are required to obtain a proof of concept for the targeted skin disease using the selected animal models. Standard formulations appear not well suited for oral bioavailability of TMX-302 as well as for highly efficient skin penetration. The use of Midatech’s nanoparticles formulated by using Molecular Profiles’ technology promise to ensure the required formulations. The in vitro assays with human tissues to be performed by Biopta will trigger the selection of the best formulation for gut epithelium and/or skin penetration and drug delivery._x000D__x000D_ _x000D__x000D_ _x000D_
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Acronym
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PAT
(Reference Number: 7783)
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Duration
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01/09/2013 - 31/08/2016
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Project Topic
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The project will extensively test a TLR7–specific anti-inflammatory compound, TMX-302, in established animal models of psoriasis. The objective being to acquire the knowledge base needed to proceed on pre-clinical studies and clinical trials for a new effective and safe treatment of psoriasis.
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Network
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Eurostars
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Call
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Eurostars Cut-Off 9
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Project partner
