Tolerability and Bioavailability of the P144 Peptide Inhibitor of TGF-β1 After Topical Administration in Healthy Volunteers
Condition: Healthy
Study type: Interventional
Phase: Phase 1

Summary: 
      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 assess
      the tolerability and safety of topical application of P144 in healthy volunteers.
    

Detailed description: 
      Three different formulations of DIGNA P144 cream (containing 100 μg/mL, 200 μg/mL and 300
      μg/mL) will be tested in healthy volunteers. Tolerability evaluation is performed through the
      specific cutaneous tolerability visual scale of Frosch and Kligman. Safety assessment is
      carried out by studying vital signs, physical examination, by performing laboratory tests,
      electrocardiogram and reporting any adverse events experienced. This is the first time that
      P144 will be administered in humans. The topical route has been chosen since the indication
      for which P144 is going to be clinically developed will be cutaneous sclerosis associated to
      scleroderma.

      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.
    

Intervention name(s): P144 cream; P144 cream; P144 cream; Placebo
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): P144 cream will be given at a dose of 100 μg/mL; P144 cream will be given at a dose of 200 μg/mL; P144 cream will be given at a dose of 300 μg/mL; Placebo will be randomly given to 4 subjects in each panel
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Keywords: P144; TGF-β1; Healthy volunteers; Cutaneous tolerability; Skin fibrosis; systemic scleroderma; systemic sclerosis; Safety