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FXR Biology and Our Approach

The farnesoid X receptor (FXR) is a nuclear hormone receptor expressed selectively in various tissues, including the liver and GI tract, and implicated in multiple cellular processes that regulate bile acids, lipid metabolism and inflammation. FXR activation in the GI tract leads to release of fibroblast growth factor 19, or FGF19, which signals through receptors in the liver. Preclinical and clinical studies have shown that targeting FXR directly in the liver has advantages beyond FGF19 signaling alone.

We have invested in building a foundation of chemistry and biology expertise to driveinnovative drug discovery and development. We believe these internal capabilities allow us to gain insights into disease targets and mechanisms and more quickly and purposefully design drugs with characteristics that we view as key to safety and efficacy. With this systematic approach, we have designed our lead product candidate MET409 as a novel FXR agonist and have identified a potential role for it in the treatment of NASH, IBS-D and IBD. MET409, was purposefully designed to be a non-bile acid, sustained engagement FXR agonist with high potency that could be dosed orally once-daily. With this profile, we believe MET409 has the potential to be a best-in-class drug with a key differentiated safety and efficacy profile from other FXR agonists in development.

FXR in NASH

We are currently conducting a Phase 1 clinical trial of MET409 in healthy volunteers. In addition to monitoring safety and pharmacokinetics, we are assessing FXR target engagement in this trial via blood-based biomarkers.

Following completion of the Phase 1 clinical trial, we plan to evaluate MET409 as a treatment for three liver and GI diseases in parallel, beginning with NASH. We plan to submit an investigational new drug application, or IND, and following acceptance, initiate a Phase 1b clinical trial in NASH before the end of 2018 and Phase 2 clinical trials in NASH, IBS-D and UC in the first half of 2019.

Beyond our FXR program, we are building a pipeline of novel drug candidates against other drug targets by taking advantage of our drug discovery and development capabilities.

Non-alcoholic Steatohepatitis (NASH)

NASH is a liver disease that exists along a continuum of progressive liver deterioration and is characterized by fatty deposits, inflammation and cellular damage. Globally, an estimated 6% of the population has NASH with approximately 16 million patients in the United States as of 2015. Over time, individuals with NASH may develop scarring or fibrosis of the liver which can progress to loss of liver cells and irreversible scarring, or cirrhosis, and ultimately require liver transplant. There is an increased risk of liver cancer in NASH patients as well as a higher risk of death from cardiovascular disease.

Today, there are no approved therapies for NASH, and the disease, therefore, represents a significant unmet medical need. While numerous drug targets are being explored to treat NASH, it has been challenging to demonstrate significant clinical benefit across the key disease characteristics of inflammation, ballooning and fibrosis.

Targeting FXR has been shown clinically to improve each of these three characteristics of NASH. The FXR agonist class for the treatment of NASH has evolved over time as drug developers have sought to harness its potential; however, each iteration to date has had limitations. The first generation of FXR agonists are derived from a bile acid chemical structure which has demonstrated dose-limiting side effects, including pruritus. However, a first generation FXR agonist with sustained FXR engagement has been shown to improve NASH in clinical trials.

The second generation of FXR agonists are based on non-bile acid chemical structures, but have shown transient engagement with FXR with once-daily dosing, which may limit efficacy. MET409 was purposefully designed to be an optimized next-generation FXR agonist with features of a non-bile acid chemical structure and sustained FXR engagement. With this profile, we believe MET409 has the potential to be a best-in-class NASH drug with a key differentiated safety and efficacy profile from other FXR agonists in development.

FXR in GI Diseases

Irritable Bowel Syndrome with Diarrhea (IBS-D)

We also plan to develop MET409 as a potential first-in-class FXR agonist for GI diseases affecting large patient populations with high unmet needs. IBS-D is a functional GI disease whereby patients experience diarrhea and abdominal discomfort or pain.

IBS-D affects up to an estimated 4% of the adult population in major markets, with an estimated nine million patients in the United States as of 2013.

Prior clinical studies have shown that up to 30% of IBS-D patients have evidence of bile acid malabsorption (BAM), which could account for their symptoms. As one key role of FXR is bile acid regulation, drugs that target FXR could reduce the bile acid pool and, in turn, reduce diarrheal symptoms in IBS-D patients with BAM. As there are several modalities to diagnose BAM, we believe it will be possible to use a precision medicine approach to identify and treat this subset of IBS-D patients.

Inflammatory Bowel Disease (IBD)

We also intend to develop MET409 for the treatment of IBD, including ulcerative colitis (UC) and Crohn’s disease, as we believe FXR plays a key role in the disease process.

Patients with IBD can suffer from abdominal pain and bloody diarrhea and have increased risk of colorectal cancer. The global incidence of IBD is increasing and as of 2015, it was estimated that there were 3.1 million people in the United States with IBD. Global drug sales for IBD are approximately $9.0 billion annually, with injectable biologics commonly used to treat patients with moderate-to-severe IBD. While these biologic agents can be effective initially, they increase the risk of opportunistic infections and can be cumbersome to administer.

In preclinical studies of our FXR agonists, we have observed improvement in colon inflammation on a level similar to that of biologics. We believe an oral once-daily drug, such as our FXR agonists, could be an attractive treatment option for IBD patients.

Inflammation and Fibrosis

In addition to our FXR program, Metacrine has continued to invest in drug discovery on other drug targets, particularly in NASH. We have sought to identify drug targets that have effects on inflammation and/or fibrosis for which we believe we could develop proprietary small molecule drugs.