We spoke with Andrew Reaume, Ph.D., MBA, President and CEO, and Ramana Kuchibhatla, Ph.D., VP of Clinical Development at Melior Discovery — www.meliordiscovery.com  — about their novel first-in-class insulin sensitizer, tolimidone, which has demonstrated a significant reduction of HbA1c compared to placebo in a recently completed Phase 2B study.

Different Drug Discovery

Melior does drug discovery differently.  They focus on repositioning drugs that have been proven safe but have been discontinued because of low efficacy for their original intended use.  This is a small universe consisting of hundreds of mid-stage compounds, each representing millions of dollars in research investment.

Tolimidone was originally taken to Phase 2 trials by Pfizer for treatment of gastric ulcers. The original ‘Composition of Matter’ patent has expired and Melior has obtained a ‘Method of Use’ patent for diabetes.

Melior’s core expertise is embedded within its theraTRACE® platform, a highly efficient approach to simultaneously test 40 animal models of human disease.  

Each animal model uses genetically modified mice to enable a specific disease to be challenged with a therapeutic agent.

Unlike traditional drug discovery which tests to confirm a hypothesized benefit, Melior uses phenotypic screening, essentially observing results from drug-animal interactions to deduce efficacy in 14 broad therapeutic areas in an unbiased, or non-hypothesis driven manner.

In other words, testing is done without regard to preconceived notions of efficacy and is more comprehensive and efficient compared traditional drug discovery

Tolimidone Study

In the study, patients on metformin therapy with an HbA1c level >7.0% at screening, were randomized to one of three oral doses of tolimidone (25, 50 or 100 mg) or placebo administered once daily for 12 weeks with continued metformin therapy. The study randomized 433 subjects from 61 clinical sites in the U.S. and Korea.

Tolimidone continued to demonstrate an excellent safety profile consistent with previous clinical studies.

This study follows a positive Phase 2A proof-of-concept study that was completed in 2017 in which statistically significant glucose lowering was achieved for both glucose parameters (fasting plasma glucose and area-under-the-curve in a mixed meal tolerance test). In addition, positive trends were seen in lipid parameters and body weight in that 4-week study.

Method of Action

Tolimidone is a small molecule, orally bioavailable drug that works by activating the enzyme lyn kinase, which has several actions that improve metabolic disease.  These actions include:

1. Attenuating insulin resistance
2. Improving dyslipidemia (abnormal amount of lipids (e.g. triglycerides, cholesterol and/or fat phospholipids) in the blood)
3. Reducing obesity

Lyn kinase seems to have a role in the insulin signaling pathway leading to increased glucose utilization within cells.

Tolimidone appears to reduce liver fat and, perhaps most importantly, to enable beta cell regeneration in the pancreas.  An increase in the mass of beta cells is observed. It works in a way that is analogous to thiazolidinediones — sometimes shortened to TZDs or glitazones.

More recent preclinical studies have shown that lyn kinase activation has beneficial effects in the liver including antifibrotic activity and promoting liver repair (hepatocellular regeneration).

“These results firmly establish tolimidone as the first of a new generation of insulin sensitizers. This, coupled with our growing understanding of the additional therapeutic benefits to the liver makes us very enthusiastic about tolimidone’s additional opportunity in Non-alcoholic Steatohepatitis (NASH)”, said Dr. Reaume.

Progress via Partnerships

Melior is using its capabilities embodied within the theraTRACE® platform to build an internal pipeline of development candidates and also partners with pharmaceutical and biopharmaceutical companies to exploit its discoveries.  

Taking tolimidone to a Phase 3 trial will require partner funding.

Many experts, including DeFronzo (ref), believe that it is imperative to treat the disease before substantial beta cell loss has occurred; an event that marks frank T2D.  

If pre-diabetes becomes recognized as a disease state by the FDA, tolimidone may be an ideal first-line therapy for people with pre-diabetes and with newly diagnosed T2D because of its apparent beta cell protection and possibly proliferative benefits. 

The payoff for Melior’s partner would then be high because compared to Metformin, tolimidone appears to reverse the decline in beta cell function while improving insulin sensitivity.  This action profile would significantly slow or stop the progression of Type 2 Diabetes and postpone or avoid costly and painful complications.