Miricorilant

Miricorilant is Corcept Therapeutics' Phase 2b selective glucocorticoid receptor modulator for NASH/MASH, running the 175-patient MONARCH trial (NCT06108219) with a liver-fat MRI-PDFF endpoint [1]. The bet builds on a 2023 Phase 1b readout that showed approximately 30% liver fat reduction in NASH patients on 100 mg twice-weekly dosing [10], now being tested placebo-controlled at scale. Topline is expected in H2 2026. The competitive bar has moved materially in the last 18 months: resmetirom launched in 2024 and semaglutide's ESSENCE Phase 3 (published NEJM 2025) hit both MASH resolution and fibrosis improvement [2][9].

Novel compound, first-in-indication mechanism for NASH. MONARCH is active-not-recruiting per ClinicalTrials.gov, meaning dosing is underway and enrollment is closed [1]. Corcept is running four supporting Phase 1 programs in parallel: a mechanistic hepatic de novo lipogenesis study in MASLD patients (NCT06947304) [3], a Phase 1b single-dose PK study in MASH patients (NCT07553663, ~15 patients, 60 mg single dose, started April 2026) [4], a bioavailability plus optional food-effect study in healthy adults comparing Kinetisol vs. spray-dried dispersion tablet formulations (NCT07240116, completed April 2026), and a hepatic impairment PK study (NCT05553470). Nonclinical and Phase 1 disposition data supporting once-daily dosing were published in J Clin Pharmacol in 2026 [5]. Prior Phase 1b NASH data (NCT05117489) reported by Corcept in July 2023 showed ~30% MRI-PDFF liver fat reduction after 12 weeks of 100 mg twice-weekly dosing, along with HOMA-IR, LDL, and triglyceride improvements [10]. Important safety history: an earlier Phase 2 study in 2021 was suspended after transient ALT/AST elevations appeared in 4 of 5 patients on daily dosing. Elevations resolved on withdrawal and did not recur on rechallenge at revised dosing, which is the basis for the intermittent/lower-exposure regimen carried into MONARCH. No FDA breakthrough, fast track, orphan, or accelerated approval designation has been disclosed for miricorilant in NASH. Corcept's 2025 10-K (filed February 2026) frames miricorilant as pipeline expansion beyond its Cushing's syndrome franchise, alongside relacorilant [6].

Cortisol is the body's main stress hormone. It tells the liver to make glucose, store fat, and dial up inflammatory signaling. It works by binding the glucocorticoid receptor (GR), a protein inside cells that travels to the nucleus and switches gene programs on and off. In NASH, patients have too much liver fat and chronic low-grade hepatic inflammation, and GR signaling drives both lipogenesis (fat-making) and gluconeogenesis (sugar-making). Cushing's syndrome patients, who have pathologically high cortisol, develop hepatic steatosis at high rates, which is the indirect genetic case for GR as a NASH target. Miricorilant is a selective glucocorticoid receptor modulator (SGRM). Modulator, not pure antagonist, has a specific meaning here: it blocks the metabolically damaging GR effects (lipogenesis, gluconeogenesis, inflammatory transcription) while avoiding progesterone-receptor cross-binding, which is the promiscuity problem in Corcept's older drug Korlym (mifepristone) that drives its pregnancy-termination and endometrial-thickening warnings and restricts its use to Cushing's. Miricorilant is also reported to act as a mineralocorticoid receptor antagonist, which may contribute to metabolic effects but also raises electrolyte-monitoring considerations. Liver-specific human proof-of-concept came in the 2023 Phase 1b NASH study (NCT05117489): a ~30% MRI-PDFF liver fat reduction over 12 weeks in patients dosed 100 mg twice weekly, with concurrent HOMA-IR, LDL, and triglyceride improvements [10]. An earlier 2021 human proof-of-concept study also showed miricorilant blunted olanzapine-induced weight gain and metabolic dysregulation in healthy volunteers [7]. The evidence base is therefore: (1) direct NASH-patient liver-fat data at Phase 1b, (2) a metabolic-rescue study in olanzapine users, (3) the Cushing's-hepatic-steatosis analogy, and (4) preclinical GR-knockout data. Suggestive and increasingly specific to liver, but not yet decisive without placebo control and a histology-eligible cohort.

MONARCH (NCT06108219) is a Phase 2b placebo-controlled study, n=175, in adults with NASH/MASH [1]. Primary endpoint is percent relative change in liver fat by MRI-PDFF (magnetic resonance imaging proton density fat fraction, a non-invasive quantitative liver-fat measurement) from baseline in Cohort A and Cohort B, indicating a dose-ranging design. MRI-PDFF is the standard NASH Phase 2 proof-of-concept endpoint: a relative reduction of 30% or more is the threshold generally associated with downstream histological improvement, and it is how resmetirom, semaglutide, efruxifermin, and pegozafermin all showed early liver-fat signals before their histology trials [2][9]. Enrollment is complete based on the ACTIVE_NOT_RECRUITING status. Design concerns are real. At n=175, the trial is powered to detect a placebo-adjusted MRI-PDFF signal but is too small to say much about NASH resolution or fibrosis improvement, which is what the FDA requires for approval. There is no biomarker enrichment beyond standard NASH inclusion criteria, so the trial will not tell investors which patient subgroups respond best. There is also no combination arm. If Phase 3 needs to test miricorilant on top of GLP-1 or resmetirom (increasingly likely given ESSENCE and MAESTRO-NASH), MONARCH will not answer the combination question, and Phase 3 design decisions get pushed into a separate readout window. A positive Phase 2b buys Corcept the right to run a much larger, biopsy-based Phase 3, likely with a combination arm.

Our model estimates a 5% chance this drug is eventually approved. It starts from the historical base rate for Phase 2 drugs in this area (about 23%), then adjusts using ten facts about the trial and sponsor. What moves the number most: it is helped by more secondary endpoints than usual; it is held back by heavier-than-usual blinding, the sponsor's thin or weak approval record, and weak or limited earlier-phase results. The other facts land near average for this stage, so they leave the estimate roughly where the base rate put it.

Efficacy risk is real but the class has finally started to work. NASH has burned Genfit (elafibranor Phase 3 miss) and Intercept (obeticholic acid rejected twice), and Akero missed fibrosis in Phase 2b SYMMETRY in F4 cirrhotic patients. The counterweight: resmetirom is approved, and semaglutide's ESSENCE Phase 3 showed statistically significant improvement in both MASH resolution (62.9% vs. 34.1% placebo) and fibrosis stage (36.8% vs. 22.4% placebo), with 32.7% of semaglutide patients achieving both endpoints vs. 16.1% on placebo [9]. Novo Nordisk filed for approval in H1 2025. The class works; the question for miricorilant is differentiation on top of that. Safety risk is mechanism-specific: blocking the glucocorticoid receptor risks HPA-axis rebound (the hypothalamic-pituitary-adrenal axis is the hormonal feedback loop that regulates cortisol; block the receptor chronically and the body ramps up cortisol production to compensate, which can cause adrenal insufficiency symptoms on discontinuation), plus off-target progesterone, androgen, or mineralocorticoid effects if selectivity slips under chronic dosing. Miricorilant has a specific liver-safety history: the 2021 Phase 2 study was suspended after transient ALT/AST elevations in 4 of 5 patients on daily dosing. Elevations resolved on withdrawal and did not recur on rechallenge at the revised twice-weekly regimen used in the 2023 Phase 1b [10], but MONARCH is the first placebo-controlled test of whether the safer regimen holds at scale. Mifepristone (Corcept's older non-selective compound) carries warnings for pregnancy termination, endometrial thickening, and hypokalemia; miricorilant's selectivity should reduce but not eliminate these liabilities. Execution risk is moderate. Corcept is a small endocrinology company by history, and a NASH Phase 3 (typically 1,000+ patients with paired biopsies, plausibly a combination-arm design) is a different operational category. Commercial risk if approved: resmetirom (Rezdiffra) launched in 2024 at $47,400 per year and is establishing standard of care in F2/F3 fibrosis, and semaglutide is likely to become a second approved MASH drug with a large existing prescriber base and formulary footprint. Any new NASH entrant now needs either better fibrosis reversal, add-on benefit over GLP-1 or resmetirom, better tolerability, or a defined responder subgroup where GR modulation wins.

Watch, don't chase. The signal to look for is the MONARCH MRI-PDFF readout in H2 2026: a placebo-adjusted relative reduction of 30% or more, replicating the Phase 1b liver fat signal against placebo, with no adrenal insufficiency or transaminase flare, is a genuine Phase 3 trigger. Anything below 20%, or with HPA-axis or ALT/AST safety signals reminiscent of the 2021 suspension, collapses the program. Corcept can afford to run this. The 2025 10-K reports full-year revenue of $761.4M (driven by Korlym), net income of $99.7M, and $532.4M in cash and investments at year-end 2025, against 2026 revenue guidance of $900M to $1B [6][11]. A NASH Phase 3 of ~$250 to 350M spread over 5+ years is affordable but would be a materially larger operational and financial commitment than anything Corcept has run. Relacorilant's Phase 3 GRACE program in Cushing's syndrome remains the nearer-term stock catalyst. Miricorilant in NASH is optionality, not the core thesis. The Q1 2026 earnings call has already passed. The next checkpoints are the Q2 2026 earnings call (expected late July or early August 2026), the Q3 2026 call (expected late October or November 2026), and the MONARCH topline itself. If MONARCH prints a clean signal, the more interesting commercial question is whether Corcept partners the NASH program (it has no metabolic-disease sales infrastructure) or tries to run Phase 3 alone, and whether that Phase 3 must include an add-on-to-semaglutide or add-on-to-resmetirom arm to be approvable in a two-drug market.