Developing a Potential Solution for the NASH Epidemic

For years, the biopharmaceutical industry has been working diligently to bring new treatments to patients with nonalcoholic steatohepatitis (NASH), a chronic, progressive type of fatty liver disease. In NASH, excessive amounts of fat build up in the liver, causing inflammation, liver cell injury and fibrosis (scarring). Although NASH is primarily a liver disease, at the core, these patients have metabolic issues that result in multiple co-morbidities, such as obesity, high triglycerides and cholesterol, and diabetes. Most patients with NASH experience few or no symptoms until the disease has progressed and, therefore, remain undiagnosed until a very late stage. That means the disease progresses undetected, damaging the liver over years or even decades and increasing the risk of severe liver-related complications, including cirrhosis, liver failure, hepatocellular cancer (HCC) and cardiovascular complications, which often leads to death in these patients. In the United States, NASH is now a leading cause of liver transplantation. 

NASH represents a large and rapidly growing problem both in the US and worldwide. An estimated 8% of the US population suffers from the disease, and the prevalence is increasing, largely due to the obesity epidemic and the rise in prevalence of Type 2 diabetes and metabolic syndrome. By 2030, an estimated 27 million Americans are projected to be affected. The growing NASH epidemic places a significant financial burden on the US health care system. The lifetime costs for all NASH cases were estimated to be nearly $318 billion in 2017, and that number will only grow if the projections for increased prevalence prove true. 

New Treatments for NASH Are Urgently Needed

Despite the significant individual, societal and economic impact of NASH, no treatments are approved for this disease by the US Food and Drug Administration (FDA). Currently, management of NASH is limited to treatment of co-morbidities, such as with medications to induce weight loss and improve glycemic control, and lifestyle changes, including diet and exercise, which are difficult to maintain over time. 

Several treatments are in development, but many of them have considerable limitations. Most investigational compounds target only limited facets of NASH even though it is a complex, multi-faceted disease. For example, some therapies address the liver manifestations of the disease but do not tackle the underlying core issue of metabolic dysregulation. Other compounds have a less than ideal tolerability profile and are associated with high rates of gastrointestinal (GI) side effects, pruritis (severe itching) or other adverse events that could affect patients’ quality of life, adherence to treatment, and clinical outcomes.  

Another challenge in developing a therapeutic for NASH is that patients must consider it convenient. Because NASH is a chronic disease, those affected will need to stay on treatment for many years, and, because those affected often have no symptoms, it should be easy to take and incorporate into patients’ lives to ensure compliance. 

Pursuing a Novel Solution for NASH

At 89bio, we are working to address these challenges by developing a novel solution—BIO89-100—a specifically engineered glycoPEGylated analog of FGF21, an endogenous metabolic hormone that regulates glucose, lipid metabolism and energy expenditure.  

We believe FG21 analogs represent the most promising class of drugs to treat NASH and could become a mainstay of therapy. FGF21 not only addresses the liver manifestations of NASH, but also the multiple metabolic co-morbidities that affect most patients. Clinical studies have shown that FGF21 has a direct impact on NASH by reducing liver fat, liver inflammation and the resultant fibrosis. Furthermore, FGF21 has been shown to reduce triglyceride and cholesterol levels and improve insulin sensitivity, abnormalities often seen in patients with NASH. 

BIO89-100 has the potential to be an ideal therapeutic for NASH because it combines strong efficacy and a favorable tolerability profile with potential best-in-class weekly or every-two-week dosing convenience. In our Phase 1b/2a proof-of-concept study, BIO89-100 was shown to significantly reduce fat in the liver, improve key markers of liver injury (ALT), and improve lipid levels and glycemic markers that are indicative of the multiple co-morbidities that worsen the disease. Specifically, in this trial of 81 patients, patients treated with BIO89-100 showed relative reductions in liver fat of up to 70% versus placebo, with greater than 85% of patients experiencing liver fat reduction greater than 30%. Importantly, we observed few tolerability issues – a key finding for a disease that requires chronic treatment.

As part of our comprehensive clinical development program for BIO89-100 in NASH, we recently initiated the Phase 2b ENLIVEN trial. This multi-center, randomized, double-blind, placebo-controlled study is designed to evaluate the safety and efficacy of BIO89-100 in approximately 220 patients with fibrosis stage 2 or 3 NASH. Patients will be treated for 24 weeks with an extension period of 24 weeks and will receive either weekly or every-two-week subcutaneous injections of BIO89-100 using a new liquid formulation. 

Committed to Finding Innovative Treatments to Benefit Patients

As highlighted by the many setbacks and failures in NASH in recent years, developing a new treatment for this complex, multifactorial disease is challenging. The expected significant increase in the number of cases and the lack of an FDA-approved treatment underscores the dire medical need in this patient population. Based on the uniquely engineered structure of BIO89-100 and the encouraging clinical trial data to date, we believe this novel compound has the best clinical profile in the FGF21 class and could be the treatment of choice for NASH. We are hopeful it could serve as the backbone of treatment for the disease.  

At 89bio, our team is committed to finding innovative treatments to benefit patients with this serious disease. We remain steadfast in our dedication to finding an innovative solution to combat the epidemic of NASH and provide much needed hope to people who have been waiting far too long for an effective and well-tolerated FDA-approved therapy.

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