Finding and developing an effective treatment for nonalcoholic steatohepatitis has, so far, been met with as much futility and frustration as developing a treatment for Alzheimer’s disease. Sagimet Biosciences Chief Executive Officer George Kemble believes his company is on the right path, though.
Over the course of the summer and early fall, Sagimet has unveiled impressive data from a mid-stage FASCINATE-1 trial of TVB-2640 in nonalcoholic steatohepatitis (NASH). Data from the study showed that TVB-2640, an oral inhibitor of fatty acid synthase (FASN), significantly decreased liver fat and serum biomarkers of liver injury, fibrosis and inflammation in trial patients. TVB-2640 also significantly decreased alanine aminotransferase (ALT) by up to 20.4% and LDL-cholesterol by up to 7.6%. These decreases indicate improved liver function and metabolic health. Results from the study have been shared at multiple liver conferences and more analysis will be detailed at the November Liver Meeting Digital Experience 2020 of the American Association for the Study of Liver Diseases (AASLD).
In an interview with BioSpace, Kemble said that NASH is a complex disease, which has made it a difficult nut to crack for the pharmaceutical industry. He explained that in some patients, the liver makes extra fat and the body attempts to unsuccessfully remove the fat. The cycle repeats itself in a progressive manner. If untreated, NASH can lead to end-stage liver disease, liver cancer and liver transplantation.
NASH affects more than 16 million people across the United States and the number of patients is expected to increase. Multiple companies have attempted to develop therapeutics for this disease but so far, each one has failed in late-stage clinical trials. Companies like Gilead Sciences, Novo Nordisk and others, have all suffered clinical disappointments in over the past several years and earlier this summer, GENFIT ended its development of elafibranor for NASH following a trial failure. In June, Intercept Pharmaceuticals received a Complete Response Letter from the U.S. Food and Drug Administration for its experimental NASH treatment, obeticholic acid. Currently, there are more than 200 different treatments in development for NASH. There are no approved treatments other than lifestyle changes such as diet, weight loss and exercise. According to iHealthcareAnalyst, the global market for NASH could hit $37.3 billion by 2027.
Kemble said the drug has become a significant healthcare burden and hoped therapies will be approved before it “gets out of hand.” He hopes Sagimet’s asset will play a key role. Sagimet’s TVB-2640 targets the early driver of NASH, which is the build-up of fat. The drug inhibits fat development and removes fat from the liver. In preclinical models, Sagimet showed blocking FASN not only reduces liver fat, but directly reduces inflammation and fibrosis – addressing three major drivers of NASH.
“We want to stop the driver and see what happens,” Kemble said. He added that removing of the fat has an impact on metabolism, inflammation and fibrosis. “It hits all these things simultaneously.”
Even though patients may be in different stages of NASH, Kemble said the drug appears to be able to have an impact on all phases of the disease. He anticipates that as the disease drug is tested in more patients, they will see different levels of efficacy in trial subsets.
Sagimet is planning a Phase IIb study with about300 patients that should begin in 2021. Patients will take an oral dose of TVB-2640 daily for one year. At the end of the year, the company will use MRI technology to determine the liver fat reduction.
Kemble said with each stage of study, Sagimet is not asking one question in hopes of an answer. Instead, the company is taking a more holistic approach to gain as many answers as possible to de-risk the late-stage study.
“We have a good foundation of the disease and how it works and we’re building on top of that with how well our drug works,” he said. “We think we have an important differentiated drug because of all the spots it hits, but, because of the complexity of the disease and the patients, there will be more than one drug that’s important in this field. We expect to be one of them.”