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Preclinical&clinical development of peptide inhibitor of tgf-beta formulated as novel treatment for lung fibrosis

Peptide administration for lung fibrosis treatment using formulation based on medusa technology.
develop a sustained release formulation os p144 or p17, loquid or freeze-dried form, for subcutaneous administration route and carry on preclinical and clinical trials.

Systemic sclerosis (SSc, or scleroderma) is a rare multisystemic disorder characterized by the excess synthesis of extracellular matrix proteins, resulting in fibrosis of the skin and visceral organs (including gastrointestinal tract, lungs, heart and kidneys). While the pathogenesis of SSc is complex and poorly understood, the major pathways involved in the development of the condition are microvascular and immunological abnormalities, coupled to deregulation of fibroblast activity. SSc can be classified according to the degree of skin thickening and organ involvement: diffuse cutaneous (with a higher risk of heart and kidney damage) and limited cutaneous. While skin fibrosis has the greatest impact on quality of life, pulmonary fibrosis has the greatest impact on mortality. Lung fibrosis is characterised by progressive interstitial fibrosis, which leads to decreasing lung volume and progressive pulmonary insufficiency. Scleroderma has a prevalence of 31 per million in Europe, with 40% of these patients suffering lung manifestations Interstitial lung disease associated to SSc (ILD-SSc) represents a plethora of clinical disorders that can result in widespread tissue transformation and structural damage to the lung parenchyma, impairing respiratory function. ILD is classified as a restrictive lung disease, with decreased lung compliance and vital capacity. Histologically, it is characterized by the activation of lung fibroblasts coupled with the production of excess extracellular matrix proteins, and inflammatory and fibrotic mediators, provoking elevated levels of immune cells. ILD-SSc involves significant inflammation followed by dysfunctional repair and exuberant fibrosis. Of 10 patients with SSc, 4 are estimated to have ILD, with a forced vital capacity (FVC) less than 75% the predicted, and homeostatic deviation of both the circulatory and immune system. These biological aberrations often result in microvascular damage due to fibrosis, as well as an enhanced inflammatory response due to immunologic disturbances, which may lead to collagen deposition and lung fibrosis, impairing gas exchange. The exact pathophysiological and chronological events underlying ILD in SSc remain poorly understood The unfavourable clinical outcome associated with pulmonary complications of this disease has fuelled an intense search for new therapeutic strategies with particular emphasis on early and accurate diagnosis. TGFβ-1 is a pleiotropic cytokine with strong immunomodulatory and profibrogenic effects, and it is one of the main mediators of fibrosis due to its capacity to induce collagen synthesis and contribute to the pathological fibrotic processes. Thus, TGFβ-1 represents a molecular therapeutic target in this disease and inhibiting this cytokine with agents that block its activity in vivo may be a promising approach to develop therapies to treat the fibrosis associated with pathologies that involve chronic inflammation To date, no pharmacologic therapies for ILD have received regulatory approval, and all therapies are administered 'off-label', including corticosteroids. Pharmacological management of ILD in SSc usually involves a two-pronged approach: controlling the tissue fibrosis using anti-fibrotic drugs and curtailing excessive tissue injury with immunosuppressant drugs. Although controlled data is lacking, corticosteroids are usually used in conjunction with other immunosuppressors to treat ILD secondary to connective tissue disease. In pulmonary fibrosis associated with scleroderma, alveolitis and pulmonary function may be improved with steroid therapy P144 and P17 are TGF-β1 inhibitors. P144 has recently been tested clinically for the treatment of the skin fibrosis of patients with SSc. The regulatory agencies of Spain, United Kingdom, Germany, Italy, Poland and Hungary have approved the IMPD describing the CMC and preclinical packages of P144 (Disitertide) formulated as a cream, and a Phase II clinical trial has also been completed in those countries. The preclinical package, as well as the results of the Phase II and the design of a Phase IIb/Phase III trial, have been discussed with the EMA’s COMP in different meetings. However, despite the promising effects observed in a Phase II clinical trial, the lack of a systemic formulation for this compound has precluded its development for the treatment of systemic manifestations of scleroderma, such as ILD. Moreover, the hydrophobic nature of these peptides considerably limits its dissolution for administration by conventional methods. Both perptides will be tested in preliminary studies to decide the best candidate to this project. In this project, we aim to circumvent the issue related to the systemic administration of one of these peptides by combining the expertise of Flamel Technologies and its Medusa drug delivery platform and the experience gathered by DIGNA and the network of experts in SSc that have participated in the clinical development of P144 and P17.
Acronym: 
NEO-DPEP
Project ID: 
7 625
Start date: 
31-08-2012
Project Duration: 
28months
Project costs: 
5 000 000.00€
Technological Area: 
Clinical Research, Trials
Market Area: 
Pharmaceuticals/fine chemicals

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