Lead Indication

Millions of American adults suffer from obesity, metabolic syndrome, diabetes and cardiovascular disease associated with hyperlipidemia. About 110 million adults in the US are obese; about 88 million, or 34.5% of American adults, are prediabetic; and about 34.2 million Americans suffer from type-2 diabetes. Among this huge patient population, Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD) is very common. In fact, about 80 million, or 30% of the US adult population, suffer from MASLD. Globally, between 20 to 30 percent of the populations in Western developed countries are affected by MASLD. While MASLD can often be benign and reversible with improvements in diet and lifestyle, about 20% of all MASLD patients are at increased risk for developing MASH, a more dangerous inflammatory liver disease that can progress toward liver cirrhosis and liver cancer. Currently, MASH affects an estimated 15 million American adults and this number is expected to rise exponentially in the coming years, driven by the increasing prevalence of obesity, diabetes and metabolic syndrome. The global MASH market size is projected to reach $31 billion by 2027, from $2 billion in 2020, at a CAGR of 46.7% during 2021-2027. In 2017, the direct lifetime costs associated with MASLD/MASH were $222.6 billion; $95.4 billion of this was for patients with MASH.

It is estimated that by 2030, complications resulting from MASH will be the leading cause for liver transplantation procedures in the US. Currently, there is one FDA approved therapy for MASH, but is only effective in less than 30% of MASH patient population, and only indicated for those with non-cirrhotic MASH. Changes in diet and lifestyle and the use of some off-label drugs (e.g., statins) can help support MASH patients, depending on the stage of the disease.

Over the last decades, the development of therapies for MASH has become a high priority of the pharmaceutical industry and a diverse pipeline of innovative drug candidates has been progressing toward the clinic in recent years. However, due to the complex nature of the disease and pipeline attrition, drug failures during late-stage clinical trials have been even more common than in other therapeutic areas, such as cancer, for example. The causes for MASH are multifactorial and incompletely understood, and it seems likely that combination therapies do not result in better clinical outcomes than monotherapies, adding additional layers of complication to clinical trial design.

Through our drug discovery platform Oxysterol Therapeutics® technology, we have identified Oxy210, a proprietary oxysterol drug candidate, for targeting MASH. Oxy210 displays a unique combination of anti-inflammatory and antifibrotic properties driven in part by inhibiting three major drivers of MASH: 1) transforming growth factor-beta (TGF-β) signaling in hepatic stellate cells (HSC; cells that are responsible for fibrosis in the liver), 2) Hedgehog (Hh) signaling in HSC that causes their activation, and 3) Toll-Like Receptor (TLR) signaling in Kupffer cells and macrophages that are responsible for inflammation in the liver. In a preclinical humanized hyperlipidemic mouse model of MASH, Oxy210 significantly inhibited liver inflammation and fibrosis and showed promising disease modifying effects, in addition to favorable drug safety and pharmacokinetic (PK) profiles. Importantly, given that the majority of patients with MASH die of cardiovascular complications, Oxy210 also inhibited atherosclerosis that develops in parallel with MASH through its cholesterol lowering and anti-inflammatory effects.

Also significant is our recent finding that Oxy210, in addition to its antifibrotic and anti-inflammatory effects, also inhibits cellular aging (senescence) in vitro and in vivo in preclinical models of fibrotic diseases, including MASH and idiopathic pulmonary fibrosis (IPF).  With the greater emphasis being placed by the medical and scientific community on longevity and aging research, this has further brought importance to Oxy210 as a potential drug candidate.