New drug treatment in development for patients living with liver disease

Caption: Cincera Board of Directors and Management Team (L to R). Top row: Dr Michael Bettess (Chair), Dr Melissa McBurnie (Director), Dr Katherine Nielsen (Director), A/Prof. Bernard Flynn (CEO); Bottom row: Prof. Stuart Pitson (CSO), Dr Giang Le (Head of Medicinal Chemistry), Dr Melissa Pitman (Senior Scientist), Dr Cassandra Yong (Operations Manager). Credit: Supplied by Cincera

Bolstered by MTPConnect's BTB program, biotech company Cincera is developing a drug to treat severe and life-threatening liver diseases.

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) account for a significant proportion of liver disease burden globally, affecting 34 percent and 12 percent of the US and Australian populations respectively. These diseases are characterised by fibrosis, or accumulation of scar tissue in the liver following an injury or inflammatory insult, such as in obesity and other metabolic disorders. NAFLD can progress irreversibly to NASH, which in turn can lead to serious liver damage, including cirrhosis, liver failure, hepatocellular carcinoma, and ultimately death. Currently, there are no treatments for NASH; it remains a major unmet medical need in our society and a leading trigger for liver transplant surgery and liver cancer.

Aiming to bridge this gap, biotech company Cincera Therapeutics Pty Ltd (Cincera) is developing a new NASH treatment that, if successful, would significantly improve quality of life for millions of patients; it could also potentially save the lives of many NASH patients and reduce the economic liability of these diseases.

Cincera, which has operations in Melbourne and Adelaide, was incorporated in January 2018 with the purpose of developing new small molecule medicines for difficult-to-treat inflammatory and fibrotic conditions associated with obesity and metabolic disorders, with potential applications in many other disease areas, including cancer.

In September 2020, Cincera was awarded $1 million in matched funding through Round 2 of MTPConnect's Biomedical Translation Bridge (BTB) program; the company was also paired with BTB venture partner BioCurate for mentoring and commercialisation support. At the initiation of the BTB funding period, Cincera was in the early stages of lead optimisation, having only completed cell-based experiments to show that its compounds were suppressing identified targets in the molecular pathways of fibrosis. Promising lead compounds were discovered; however, their properties required refinement and optimisation before the compounds could be considered candidates for clinical studies.

Discovering and developing a first-in-class drug has always been the most difficult task in the drug discovery process, with teams inevitably navigating uncharted waters. A novel approach to treating a complex and challenging disease state like fibrosis requires careful analysis of the biological effects of the drug, both in terms of therapeutic benefit and adverse effects. For this reason, Cincera pulled together a world-class team of drug discovery professionals, scientific advisors and key opinion leaders. This team includes professionals with biotech and big pharma experience, clinician researchers in fibrotic and metabolic disease, and other scientists with a track record in fibrosis drug discovery.

Benefitting from a consortium of Australian and international collaborators – including Monash University, University of South Australia and the Baker Heart and Diabetes Institute – more than 400 novel compounds were evaluated, with thousands of data points acquired in various in vitro and in vivo studies. It took three years of intensive medicinal chemistry and drug-lead optimisation to allow Cincera to emerge from the lead optimisation process to the nomination of a drug candidate that is safe and shows promising anti-fibrotic efficacy (liver, lung and kidney), as well as high selectivity against a large range of safety pharmacology targets.

This result represents a completely novel and unique anti-fibrotic mechanism of action; to date, no other competitors have reported similar anti-fibrotic activities to inhibit the target of interest. This new, first-in-class drug candidate for fibrotic and metabolic disease is a landmark Australian invention.

Data supporting the therapeutic benefits and safety of this molecule has enabled Cincera to access an additional $2 million in funding from Brandon Capital's Medical Research Commercialisation Fund (MRCF) under a Series A option. This funding will enable Cincera to continue to refine its mechanism of action and initiate its preclinical development, while undertaking further fundraising to bring it to the clinic.

Arriving at a safe and efficacious drug candidate for the treatment of fibrotic disease is a triumph of Australian drug discovery ingenuity. Approximately 46 percent of disease-related deaths and the majority of disease-related hospitalisations are attributable to fibrosis, underscoring the importance and potential impact of this innovation. Metabolic disease can induce fibrosis in multiple organs, particularly the liver, heart and kidney. End-stage organ failure brought about by these diseases claims many lives each year, and is a major economic burden.

While it will be some years before this drug candidate has suitably progressed through clinical trials to see its therapeutic benefits in patients, preclinical studies in animal models demonstrate clear benefits over other anti-fibrotic drugs under evaluation, both in terms of safety and efficacy.

According to Associate Professor Bernard Flynn, Cincera's Co-founder, CEO and Research Director, the journey to create a first-in-class drug treatment for chronic diseases like liver and heart failure has been an enormously challenging, but deeply satisfying effort.

"While we still have some way to go to demonstrating therapeutic benefit in humans, it all starts with having the right molecule to bring into the clinic and I am confident that our drug candidate is that molecule," he said.

"It is well-positioned to address the major unmet medical needs of patients living with NAFLD/NASH, heart failure, diabetic nephropathy and/or pulmonary fibrosis."

To learn more, visit Cincera.