Lixumistat (IM156) in Fibrosis

Lixumistat (IM156) in Fibrosis

Fibrosis is a prevalent medical condition associated with a variety of both rare and common diseases.  The annualized incidence of major fibrosis-related conditions is approximately 1 in 20.  The standard of care for fibrotic conditions is limited, with newly approved drugs demonstrating moderate effectiveness, with narrow indications, and generally not well-tolerated. As such, the medical need in fibrosis remains high and there is an urgent need for safe and effective medications

ImmunoMet has recently completed a Phase 1 study in healthy volunteers that demonstrated target engagement at clinically relevant doses, providing strong rationale for clinical characterization of the anti-fibrotic effects of lixumistat (IM156) in a Phase 2 proof-of-concept study in patients with idiopathic pulmonary fibrosis (IPF).

How It Works

Lixumistat (IM156), a novel Protein Complex 1 inhibitor, has anti-fibrotic activity as demonstrated in preclinical in vitro assays and in vivo models. In human fibroblasts lixumistat (IM156) inhibition of OxPhox activity, as measured by reduced oxygen consumption rate (OCR), abolishes the TGFβ-dependent activation of fibroblasts to myofibroblasts. Lixumistat (IM156)-dependent inhibition of the activation to and/or activity of myofibroblasts is manifest in vitro as reduced expression of alpha-smooth muscle actin (a-SMA) and collagen deposition following cytokine treatment. Evidence suggests that this anti-fibrotic activity is mediated predominantly by the AMPK activation that results from decreased ATP generation following treatment with lixumistat (IM156). Lixumistat (IM156) demonstrated statistically significant dose-dependent anti-fibrotic effects in the standard mouse bleomycin model with either prophylactic or therapeutic dosing schedules. Lixumistat (IM156) has also demonstrated anti-fibrotic activity in a variety of preclinical animal models of fibrosis, including, peritoneal, hepatic, and renal fibrosis models (Ju et al., 2016, Lam et al., 2018, Tsogbadrakh et al., 2018). The unique mechanism of action of lixumistat (IM156) is a novel therapeutic approach to address the unmet medical needs in patients with fibrotic diseases and may be an important complement to the current standard of care.

TGFβ is active in converting fibroblasts to myofibroblasts, leading to fibrotic episodes.  Lixumistat (IM156) mitigates this conversion by affecting the mitochondrial activity of AMPK and TGFβ. TGFβ greatly increases metabolic activity in test cells, as measured by Oxygen Consumption Rate (OCR).  The addition of lixumistat (IM156) inhibits this activation, without affecting the viability of non-targeted cells.