TREM-1 inhibitor for the treatment of scleroderma - Project Summary/Abstract
Scleroderma that includes localized scleroderma (LS) and systemic sclerosis (SSc) is a rare but
devastating autoimmune disorder. Current therapies all have side effects, are limited and associate with 10
year survival of 55%, showing the need for novel approaches. The long-term goal of this project is to
develop a new mechanism-based, efficient and well tolerable scleroderma therapy.
Triggering receptor expressed on myeloid cells 1 (TREM-1), an inflammation amplifier, contributes to
the development of fibrosis in SSc. In patients, number of activated macrophages in the fibrotic areas is
increased and associates with fibrosis severity. Activation of TREM-1 leads to overproduction of MCP-
1/CCL2 and M-CSF/CSF-1, resulting in macrophage recruitment to an injured area and the sclerotic lesion
formation in rats with scleroderma. In animal models, TREM-1 blockade inhibits inflammation and
ameliorates a variety of autoimmune diseases. The hypothesis of the "proof-of-concept" Phase I is that
TREM-1 blockade can prevent and treat scleroderma.
Current TREM-1 inhibitors all attempt to block binding of TREM-1 to its still uncertain ligand(s). To
minimize risk of failure in clinical development, we developed a first-in-class ligand-independent TREM-1
inhibitory peptide GF9 that is well-tolerated and can be formulated into SignaBlok's long half-life
macrophage-specific lipopeptide complexes (LPC) to improve its half-life and targeting to the inflammation
areas. The major goal of the Phase I study is to show that TREM-1 blockade by GF9-LPC alleviates the
disease in a bleomycin (BLM)-induced mouse model of scleroderma.
Phase I specific aims are to: 1) optimize TREM-1 inhibitory compositions for their functionality in vitro
and pharmacokinetics in vivo and select the lead, 2) test two doses of the lead selected in a BLM-induced
mouse model of scleroderma. We will generate, optimize and select the lead based upon its functionality in
vitro and its PK profile in vivo. We will test two doses of the lead for its ability to prevent and treat lung,
heart, muscle and skin fibrosis in a mouse model of multiorgan fibrosis in vivo. Histology/IHC studies will be
performed. Serum and tissue MCP-1, CSF-1, VEGF, TGFβ, TNFα, IL-6, and IL-1β will be analyzed.
It is anticipated that the Phase I study will identify a novel, first-in-class, well tolerable agent as a
powerful platform for development of an effective and well-tolerable systemic scleroderma therapy, thereby
improving treatment and survival of patients. Its anticipated safety is supported by good tolerability of
SignaBlok's GF9-based formulations by long term-treated mice. Prototypes of SignaBlok's LPC are well
tolerated in humans. TREM-1 blockade by SignaBlok competitor's inhibitory peptide LR12 (Inotrem,
France) was safe in healthy and septic subjects. If successful, Phase I will be followed in Phase II by
toxicology, ADME, pharmacology and CMC studies, filing an IND and subsequent evaluation in humans.
