Transforming the Treatment of NASH
Madrigal’s most advanced clinical candidate, resmetirom, is a once daily, oral, thyroid hormone receptor (THR) β-selective agonist designed specifically to treat the underlying causes of NASH in the liver, while improving multiple atherogenic lipid profiles.
Mechanism of Action
Thyroid hormone, through activation of its β-receptor in hepatocytes, plays a central role in liver function impacting a range of health parameters from levels of serum cholesterol and triglycerides to the pathological buildup of fat in the liver. THR-β action is key to proper liver function, including regulation of mitochondrial activity such as breakdown of liver fat and control of the level of normal, healthy mitochondria. Patients with NASH have reduced levels of THR-β receptor activity in the liver.
To optimize effectiveness of the THR-β pathway for therapeutic purposes in liver diseases, it is important to avoid activity at the THR-α receptor, the predominant systemic receptor for thyroid hormone responsible for activity outside the liver including in the heart and bone.
Madrigal recognized that greater selectivity for THR-β and liver targeting would be needed to deliver the full therapeutic potential of THR-β agonism. Resmetirom has been shown to be highly selective based on:
- Both in vitro and in vivo THR-β receptor functional assays.
- Specific uptake into the liver, virtually avoiding any uptake into tissues outside the liver.
To date, in short and long-term human and animal studies, resmetirom (1) has been shown to be generally safe and well-tolerated, (2) lacks clinical activity at the THR-α receptor and does not impact bone or cardiac parameters, and (3) does not impact thyroid axis hormones.
Resmetirom is the only orally administered, small-molecule, liver-directed, truly β-selective THR agonist in Phase 3 development.
Clinical Data Support the Potential of Resmetirom
Phase 3 and Phase 2 clinical data support Madrigal’s belief that resmetirom has the potential to become the first therapy approved for NASH patients with liver fibrosis:
- In MAESTRO-NASH, a 52-week serial liver biopsy Phase 3 study in more than 950 patients, resmetirom achieved both primary endpoints and potentially clinically meaningful effects with both daily oral doses, 80 mg and 100 mg, relative to placebo:
- NASH resolution (ballooning of 0, inflammation of 0-1) and ≥2-point NAS reduction with no worsening of fibrosis (p<0.0001 at both doses); and
- Fibrosis improvement by at least one stage with no worsening of NAS (p=0.0002 and <0.0001 at 80 and 100 mg, respectively).
- Results from the Phase 3 MAESTRO-NAFLD-1 safety study demonstrated resmetirom was safe, well-tolerated and provided statistically significant improvements in key measures of liver and cardiovascular health.
- Data from the Phase 2 study published in The Lancet, demonstrated that liver fat reduction of ≥30% with resmetirom was associated with NASH resolution and liver fibrosis reduction as measured by liver biopsy. Liver fat was measured by MRI-derived Proton Density Fat Fraction (MRI‐PDFF).
- Phase 2 results also demonstrated treatment with resmetirom lowered multiple atherogenic lipids and lipoproteins, including LDL-cholesterol, apolipoprotein B, triglycerides and lipoprotein (a) ― a key potential benefit as NASH patients have elevated cardiovascular risk.
- To date, resmetirom has demonstrated a generally favorable safety and tolerability profile including in Phase 3 studies in which over 2,000 patients have enrolled, with many treated for more than one year.
Madrigal is currently conducting four Phase 3 clinical trials to demonstrate the safety and efficacy of resmetirom for the treatment of NASH: MAESTRO-NASH, MAESTRO-NAFLD-1, MAESTRO-NAFLD-OLE, and MAESTRO-NASH Outcomes. Data from the MAESTRO program will form the basis for a potential subpart H submission to FDA for accelerated approval for the treatment of NASH in the U.S.