Efficacy and Safety Study of p144 to Treat Skin Fibrosis in Systemic Sclerosis

Phase II, Multicenter, Randomized, Double-blind, Intraindividually Placebo Controlled Clinical Trial, to Evaluate Efficacy and Safety of p144 Topical Administration for Skin Fibrosis in Patients With Systemic Sclerosis

Transforming growth factor-beta 1 (TGF-β1) is consistently over expressed in most fibrotic diseases and displays a variety of profibrotic effects in fibroblasts. Activation of TGF-β receptors induces the activation of several kinase signalling cascades leading to the phosphorylation of SMAD proteins as well as to the activation of SMAD-independent kinases that collectively activate ECM synthesis and fibroblast growth and differentiation into myofibroblasts. TGF-β1 is one of the main mediators in the fibrotic process, associated to both scarring and a long list of pathologies related to chronic inflammation and which affect all type of organs and tissues. An increase in TGF-β1 mRNA and protein levels has been described in these processes. Peptide 144 (P144) is the acetic salt of a 14mer peptide from human TGF-β1 type III receptor (betaglycan). P144 TGF-β1-inhibitor has been specifically designed to block the interaction between TGF-β1 and TGF-β1 type III receptor, thus blocking its biological effects. P144 has shown significant antifibrotic activity in mice receiving repeated subcutaneous injections of bleomycin, a widely accepted animal model of human scleroderma, and could contribute to the development. The purpose of this study is to asses the efficacy and safety of topical application of P144 in the treatment of skin fibrosis in patients with systemic sclerosis.

Systemic sclerosis or scleroderma is a multisystemic disorder characterized by the excessive synthesis and deposition of extracellular matrix proteins that result in the fibrosis of skin and visceral organs (including gastrointestinal tract, lungs, heart and kidneys).

The pathogenesis of scleroderma is complex and still poorly understood, but major pathways involved in the development of the condition are microvascular and immunological abnormalities, as well as dysregulation of fibroblast activity. One of the key molecules involved in the pathogenesis of skin fibrosis is the TGF-β1; TGF-β1 is a cytokine directly responsible for fibroblasts proliferation and collagen and extracellular matrix overproduction.

The affected skin of patients with systemic sclerosis gradually becomes firm, thickened and eventually tightly bound to underlying subcutaneous tissue (indurative phase). It loses hair, oil, and sweat glands becoming dry and coarse. Changes begin distally in the extremities and advance proximally. Lesions develop over a period of time varying from months to a few years. In patients with limited scleroderma, only the skin of fingers, hands, face and lower arms and legs is affected. On the contrary, patients with the diffuse cutaneous disease, skin changes will become generalized, involving initially the extremities and followed by the face and trunk. Rapid progression of these changes over a 2 to 3 year period is usually associated with a greater risk of visceral disease. After several years of disease, the skin may soften and return to normal thickness or become thin and atrophic.

There is currently no approved specific treatment for skin fibrosis in systemic sclerosis neither in the European Union nor the United States of America. P144 belongs to a peptide family that is able to inhibit TGF-β1 in both in vitro and in vivo models characterized by excessive TGF-β1 function. Topical application of P144 exerts a preventive effect precluding the induction of skin fibrosis and the accumulation of collagen in these animals and also has shown its therapeutic properties reducing the skin fibrosis and soluble collagen content in mice with established fibrosis.

The EMEA and FDA have granted P144 the orphan drug status for the treatment of systemic sclerosis. In this study, the percentage of reduction in the soluble collagen content and skin hardness (durometer) will be measured.

Inclusion Criteria:

• Patients male and female >18 < 65 years at time of consent.
• History of Systemic sclerosis (including diffuse scleroderma and limited scleroderma) for less than three years of evolution from the onset of cutaneous manifestations.
• Symmetric lesions in forearms. The extension of the selected symmetric lesions must be at least 15 cm2.
• Stable therapy for at least one month, except in the case of patients under treatment with putative disease modifying agents (immunosuppressants like cyclophosphamide, or azathioprine) that will need at least three months of stable therapy, without the expectation of treatment modifications during the trial period.
• Capable of understanding and willing to provide signed and dated written voluntary informed consent before any protocol specific procedures are performed.
• For female subjects with childbearing potential: use of a known highly effective method of birth control, defined as those which results in a low failure rate: i.e. less 1% per year, (contraceptive pills, intrauterine contraceptive device, implants, vasectomized partner or sexual abstinence), for at least three consecutive months prior to the study, during the study and one month after the end of the study.
• For male subjects with partners of child bearing potential: use of appropriate contraceptive methods (vasectomy, condoms or sexual abstinence), for at least the study period and one month after the end of the study.

Exclusion Criteria:

• Patients diagnosed of:

  • Systemic sclerosis sine scleroderma.
  • Localized scleroderma.
  • Eosinophilic fascitis, eosinophilia myalgia syndrome.

• Any other definable connective tissue disease, such as rheumatoid arthritis, systemic lupus erythematosus, polymyositis, or dermatomyositis.

• Clinically significant overlap condition.

• Significant existing internal organ damage (Kidney, Cardiovascular disease, Pulmonary disease, Gastrointestinal disease) as defined in "Guidelines for clinical trial in systemic sclerosis (scleroderma) " See appendix 1.

• History of skin cancer.

• Other skin diseases affecting the treatment area.

• Patients with substantial history of environmental exposure to tainted rapeseed oil, vinyl chloride, L- tryptophan, bleomycin, trichloroethylene, or silica.

• PUVA therapy within 1 month of study drug initiation.

• Concurrent interventional therapy that might independently influence outcome of trial, such as D-penicillamine, cyclosporine, methotrexate, interferon-α or photopheresis.

• Topical corticosteroids treatment affecting the selected area.

• Cosmetics over the treatment area.

• Pregnant or breast-feeding women.

• Reasonable expectation that the subject will not be able to satisfactorily complete the study:

  • History of or current psychiatric illness that would interfere with the subject's ability to comply with protocol requirements or give informed consent.
  • History of alcohol or drug abuse that would interfere with the subject's ability to comply with protocol requirements.
  • Receipt of any investigational drug within three months of screening visit.
  • Documented noncompliance.