The Science of Hope

Mechanism of Action

Aramchol targets stearoyl-CoA desaturase 1 (SCD1), the rate-limiting step in the synthesis of monounsaturated fatty acids (MUFAs), the major fatty acid of triglycerides, cholesteryl esters, and membrane phospholipids. Aramchol also increases metabolite flux through the trans-sulfuration pathway, leading to a rise in glutathione (GSH) and the GSH/glutathione disulfide (GSSG) ratio, which preserve cellular antioxidant levels and intracellular redox status.

Potential Indication

NASH and Fibrosis

Program Overview

Aramchol (arachidyl amido cholanoic acid) is a first-in-class, novel synthetic small molecule, a conjugate of cholic acid and arachidic acid, liver targeted SCD1 modulator, developed as an oral therapy for the treatment of NASH (nonalcoholic steatohepatitis) and fibrosis.

Aramchol’s ability to modulate hepatic lipid metabolism was discovered and validated in animal models, demonstrating downregulation of the three key pathologies of NASH: steatosis, inflammation, and fibrosis. The effect of Aramchol on fibrosis is mediated by downregulation of steatosis and directly on human collagen producing cells.

In a 52-week phase 2b study, Aramchol improved NASH resolution and fibrosis, in a dose-dependent manner with excellent safety and tolerability profile.

A 53% higher exposure is achieved when dividing 600mg QD Aramchol to 300mg twice daily (BID). Since this higher exposure is expected to improve efficacy, Aramchol 300mg BID was selected for a phase 3 study in patients with NASH and fibrosis.

Aramchol is currently being evaluated in a phase 3 clinical trial for patients with NASH and advance fibrosis. An Open-Label Part is ongoing that is designed to explore the kinetics of histological outcome measures and non-invasive tests as a function of treatment duration. (ClinicalTrials.gov Identifier: NCT04104321).

Mechanism of Action

Amilo-5MER has a unique mode of action up stream to all pro inflammatory cytokine production which are currently being used and in clinical trials.

Amilo-5MER binds to three pro-inflammatory amyloid proteins, Serum Amyloid A, or SAA, Transthyretin and Apolipoprotein B with high affinity. The first two are known to be active only in their aggregated forms. SAA constitutes acute phase reactants, whose concentration in serum rise rapidly in response to acute stimuli such as infection and trauma. By binding to SAA, Amilo-5MER interferes with SAA aggregation and therefor inhibits the destructive autocrine, self-amplifying cytokine loop that causes additional inflammatory reaction.

Potential Indication

We are currently developing Amilo-5MER as an oral treatment for mild to moderate Ulcerative Colitis. However, as its MoA is relevant to other chronic inflammatory diseases, we are also looking at additional multiple indications and develop formulations accordingly.

Program Overview

Amilo-5MER is a novel, 5 amino acid peptide that target the fibrillation of Serum Amyloid A to form aggregates. Aggregation of SAA is an essential step in macrophages activation that leads to chronic inflammation. The switch from an acute immune response to chronic inflammation raise the potential for tissue destruction and chronic inflammatory disease.

In LPS induced inflammation in mice, the animal model for systemic inflammation, Amilo-5MER reduced IL-6, TNF α, IFN γ and IL-1β levels in the serum. Elevated levels of these pro inflammatory cytokine is the hallmark of acute and chronic inflammatory conditions

Amilo-5MER is being developed through a research collaboration between Galmed and the Hebrew University of Jerusalem. The molecule originated in the laboratory of Prof. David Naor, from the Lautenberg Center for Immunology and Cancer Research, Faculty of Medicine, The Hebrew University.

First in-human Phase 1 trial of Amilo-5MER assessing Amilo-5MER safety, tolerability, and pharmacokinetics in healthy volunteers is ongoing.

Mechanism of Action

Gut microbiome

Potential Indication

NASH and fibrosis