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The Emerging NASH Crisis

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R&D Points Toward NASH

In late 2018, Bay Area-based Gilead, known for HIV and Hepatitis C drugs, structured a deal worth up to $1.5 billion with Cambridge, MA-based Scholar Rock Holdings Corporation. Gilead would immediately pay $80 million in upfront payments ($50 million cash and $30 million stock). Moreover, Scholar Rock would receive another $25 million based on specific pre-clinical studies and was eligible for up to $1.425 billion in potential payments aggregated across all programs based on achievement of select and targeted clinical development milestones.

Scholar Rock, founded in 2018, was already well endowed compared to many of its Cambridge and Bay Area biotech brethren. For instance, it successfully went public in 2018 at an acceptable valuation for investors. Moreover, prominent institutional investors and an “A” management team bestowed advantage that made some peers envy. And it was earned. Preclinical data was increasingly pointing to a compelling basis for the biotech venture’s pipeline and lead product known as SRK-015 for SMA, as well as preclinical pipeline including TGFβ1 (growth factor beta) for oncology and fibrosis the latter which afflict over 40 million in the United States alone. By making this investment, Gilead seeks to drive innovation in treatments for fibrotic diseases that inhibit the activation of transforming growth factor beta across three programs. Not understood by the public, underlying forces driving this deal include an emerging health epidemic that in many ways mirrors obesity– nonalcoholic steatohepatitis (NASH).  Covered by the Wall Street Journal recently as “Big Pharma’s Big Opportunit,” perhaps now attention on NASH will grow to a wider audience as investors start to internalize a potential $20 billion to $35 billion market potential.

Another Emerging Lifestyle Epidemic?

But how did this happen? What is NASH and why is there such a large potential drug market in the future? Non-alcoholic fatty liver disease (NAFLD) occurs when excess fat builds up in the liver due to causes other than alcohol use. There are two kinds of this disease including 1) non-alcoholic fatty liver (NAFL) and 2) non-alcoholic steatohepatitis (NASH). The former typically doesn’t progress to liver damage or NASH. The latter includes both fatty liver and liver inflammation. The implications are severe as NASH can lead to cirrhosis, liver cancer, liver failure or even cardiovascular disease. Known risk factors include diabetes, obesity, a diet high in fructose, and older age. It is related to insulin resistance and metabolic syndrome. It can be diagnosed by a liver biopsy—a fact that tends to make it more under-diagnosed. Of great concern is that cases in children are dramatically rising. Non-Alcoholic Fatty Liver Disease (NAFLD) is now the most prevalent form of chronic liver disease, impacting 10-20% of the general pediatric population.

There is no cure. Previously, TrialSite News has written on the obesity epidemic, and there is overlap here as the obesity epidemic contributes to NASH.  The overall population with non-alcohol fatty liver disease ranges from 9 to 36.9% depending on which part of the world. Researchers believe that these figures could be underestimated. Figures in the United States range from 20% to 25% by 2022; the Wall Street Journal reported that drug company Allergan noted “nearly a third of adults in the U.S. have fatty liver while as many as 12% have NASH.” At approximately 40 million afflicted with NASH a true crisis is in the making.

NASH is treatable with lifestyle intervention. For example, “weight loss decreases cardiovascular and diabetes risk and can also regress liver disease.” According to one body of research, reductions in weight greater than 10% can induce a near universal NASH resolution and fibrosis improvement by at least one stage. The NIH’s NIDDK recommends weight loss as a treatment. For instance, they suggest that “losing 3 to 5 percent of your body weight can reduce fat in the liver.” Losing up to 10 percent of body weight, NIDDK suggests, can reduce liver inflammation. NIDDK reports that no medicines are currently approved by the FDA (or other agency) for treating NASH. Some research points to some benefits of type 2 diabetes drug pioglitazone (Actos) which has shown to improve NASH in people without diabetes. However, this is not proven. Other studies, including a work by NIDDK’s NASH Clinical Research Network, suggest vitamin E or pioglitazone improved NASH in approximately half of those treated. Based on rapidly growing obesity tends, the unfortunate reality is that millions will face dangerous liver disease.

Race for a Cure

In May of last year, BiopharmaDive produced a helpful NASH clinical pipeline summary. They noted that BioMedTracker (Informa) generated “48 NASH drugs in clinical trials: 14 at Phase 1, 30 at Phase 2 and four at Phase 3.”  Diving into Phase 3 included the following:

  • Gilead: selonsertib, an inhibitor of apoptosis signal-regulating kinase 1
    • Allergan cenicriviroc, a dual diagnostic of C-C chemokine receptor types 2 and 5
    • GenFit’s elafibrinor, a dual diagnostic of the peroxisome proliferator-activated receptors alpha and delta
    • Intercept Pharmaceuticals’ Ocaliv (obethicholic acid), an agonist of farnesold X receptor

Biopharmadive reported that as with hepatitis C, the sponsors will also look to combination therapies. Gilead, for example, presently investigates selonsertib coupled with two other NASH investigational products (GS-0976 and GS-9674). TrialSite News sought to undertake an updated review of posted NASH clinical trials. Presently, there are 66 total commercial NASH active trials including:

                Phase 1                 13

                Phase 2                 48

                Phase 3                 7

Academic, government and nonprofit sponsored trials total 25 and include:

                Phase 1                 8

                Phase 2                 14

                Phase 3                 3

What follows is a breakdown of Phase 3 commercial NASH clinical trials.

Gilead is running two clinical trials. One started in 2017 and is scheduled to end in 2023. The Bay Area-based commercial sponsor seeks to enroll 808 participants. The primary objective of the study is to evaluate whether selonsertib (SEL; GS-4997) can cause fibrosis regression and reduce progression to cirrhosis and associated complications in adults with NASH and bridging (F3) fibrosis. The sponsor has secured 298 research sites across several countries. The other trial will enroll 883 participants and conclude in 2022. A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of Selonsertib in Subjects afflicted with Compensated Cirrhosis Due to (NASH). They have secured 283 participating research sites. The online newsletter NashBiotechs reported that the Gilead Phase 3 is managing to recruit patients in an expedited manner. However, they note some challenges in that “the number of deaths in the arm of the selonsertib (prednisone + selonsertib) was three times higher than that of the placebo (prednisolone alone).” The focused publication posits that these events may cause uncertainty about results in advanced NASH and overall drug safety.

Intercept Pharmaceuticals is running two phase 3 trials. In the first study, the primary objective of is to evaluate whether obeticholic acid (OCA; INT-747) can lead to histological improvement in fibrosis with no worsening of NASH in adults with compensated cirrhosis due to NASH. The sponsor has secured 37 research sites. In the second trial the primary objectives of this study are to evaluate the effect of Obeticholic Acid treatment compared to placebo on 1) histological improvement and 2) liver-related clinical outcomes in patients with non-cirrhotic nonalcoholic steatohepatitis (NASH) with liver fibrosis. The sponsor is recruiting 2,370 participants and the study planned end date is 2022. The FDA has raised concerns that Obeticholic Acid is being incorrectly dosed in some patients with moderate to severe decrease in lived function, resulting in an increased risk of serious liver injury and death. Ocaliva may also be associated with liver injury in some patients with mild disease who are receiving the correct dose. The recommended dosing and monitoring for patients on Ocaliva are described in the current drug label. The FDA is working with the drug manufacturer, Intercept Pharmaceuticals, to address these safety concerns.

In another Phase 3 study, Genfit seeks to evaluate the effect of Elafibranor treatment compared to placebo on 1) histological improvement and 2) all-cause mortality and liver-related outcomes in patients with nonalcoholic steatohepatitis (NASH) and fibrosis. The sponsor plans on concluding the trial in 2021. They report up to 2,000 participants and 312 sites. In Nashbiotechs.com it is posited by the authors that comparing previous efficacy results, safety profile and timing to market clearly favors Genfit’s drug, elafibranor over Intercept’s OCA.

Conclusion

A new batch of NASH drugs is presently in Phase 3 studies—targeted for conclusion within 2 to 4 years. There are some known risk factors with the present batch of drugs, but thus far the benefits appear stronger. Gilead and Intercept Pharmaceuticals are both running two Phase 3 trials. Genfit is also in the running with its own Phase 3 program. In an ideal world, massive amounts of good lifestyle (exercise, healthy diet and considerable weight loss) would help control the growth of NASH in the population. Research shows that this behavior, consistent over time, can help. But evidence suggests that we shouldn’t hold out too much hope for a sudden change in mass behaviors. If the obesity crisis is any indicator, NASH will become a crisis itself. Consequently, like the obesity crisis, the NASH epidemic will worsen and drug makers that can address this disease will earn large rewards within five to ten years.

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