Programs

pipeline image

Our Approach

Since our founding in 2014, we have invested in building a foundation of chemistry and biology expertise to drive innovative 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 therapies with characteristics that we view as key to safety and efficacy.

Our most advanced program targets the farnesoid X receptor, or FXR, which is central to modulating liver and GI diseases. FXR agonism has been investigated in large-scale clinical trials and has shown clinically relevant improvements in non-alcoholic steatohepatitis, or NASH, a liver disease characterized by excess liver fat, inflammation and fibrosis. We believe that potency, sustained exposure and continuous target engagement are key to optimizing therapeutic benefit with an FXR targeted therapy. Leveraging our extensive chemistry and biology expertise, we have built a proprietary library of over 2,500 FXR compounds, and have selected two novel, oral FXR candidates from a unique chemical scaffold, MET409 and MET642, that have the potential to deliver improved tolerability and therapeutic outcomes. MET409 and MET642 were purposefully designed to be differentiated treatments for NASH as potent, sustained FXR agonists, with the ability to be dosed orally once daily. With our program, we believe we can be the leader in developing differentiated FXR agonist therapies for NASH and other GI diseases.

Step 1 of 4

The FXR drug (agonist) is taken orally and travels through the stomach to the intestine. In the intestine the FXR agonist binds to and activates the FXR receptor.

Step 2 of 4

FXR receptor activation causes cells in the intestine to release a protein called FGF19 which travels to the liver

Step 3 of 4

Once in the liver FGF19, binds to its receptor and causes a decrease in the synthesis of bile acids.

Step 4 of 4

In addition to the intestine, the FXR agonist also activates FXR receptors in the liver which can provide additional regulation of bile acid synthesis and maintenance of the bile acid pool.

Metacrine FXR Legend

 

MET409 has been investigated in a Phase 1b proof-of-concept clinical trial in NASH patients, in which it demonstrated notable improvements in NASH biomarkers after 12 weeks of treatment. To evaluate the potential of our FXR program as the backbone of combination therapy in NASH, we are evaluating MET409 in a Phase 2a combination trial with empagliflozin (Jardiance®), a sodium-glucose cotransport-2 (SGLT2) inhibitor, in patients with both type 2 diabetes mellitus (T2DM) and NASH. Type 2 diabetes and NASH co-exist in many patients, with abnormal liver fat content being present in up to 70%, and biopsy-proven NASH detected in 20%, of type 2 diabetic patients. We are continuing to evaluate other potential combination clinical trials with MET409 in NASH, as well as developing MET409 as a monotherapy.

In addition to MET409, we are evaluating a second FXR candidate, MET642, which originates from the same base chemotype as MET409, and has shown comparable FXR target engagement and pharmacology in preclinical studies, as well as increased potency and differentiated pharmaceutical properties. We completed a Phase 1 clinical trial of MET642 in healthy volunteers, in which treatment with MET642 was safe and generally well-tolerated and demonstrated a sustained pharmacokinetic (PK) profile and robust FXR target engagement after 14 days of daily oral dosing in healthy participants. With the completion of the Phase 1 trial, we are now evaluating MET642 in a Phase 2a, 16-week, randomized, placebo-controlled trial in patients with NASH.  We anticipate selecting a candidate of MET409 or MET642 for a Phase 2b monotherapy biopsy trial in NASH as early as in the second half of 2021 and beginning that trial as early as the end of 2021 if the candidate is MET409 or the first half of 2022 if the candidate is MET642.

We also plan to develop our FXR product candidates as potential treatments for GI diseases affecting large patient populations with high unmet need and to opportunistically explore other disease areas. We intend to pursue development of our FXR agonist product candidates for the treatment of Inflammatory Bowel Disease, or IBD, including Ulcerative Colitis, or UC, and Crohn’s disease, as we believe FXR plays a key role in the disease process of IBD. We believe an oral, once-daily therapy with FXR agonists could be an attractive treatment option for UC patients that may prefer oral administration instead of injectable biologics that are cumbersome to administer chronically. In preclinical studies of our FXR agonists, we have observed improvement in colon inflammation on a level similar to that of injectable biologics currently used for treatment. We intend to submit an investigational new drug application, or IND, in the first half of 2022 and initiate a Phase 2a proof-of concept clinical trial of either MET409 or MET642 for the treatment of UC in the first half 2022. We plan to use the Phase 1 clinical trial data in healthy volunteers and clinical data in NASH  to help inform our IBD development program.