MASH UP? Liver disease could be the next big market
People with obesity and diabetes are at higher risk of developing fatty liver disease. The 2024 approval of a first drug to treat serious forms of this condition unlocks another multi-billion-dollar treatment category.
It took decades to uncover a safe, effective obesity medicine. The path to a successful drug for severe fatty liver disease been similarly long and failure strewn.
So it was a big deal when, in March 2024, Madrigal’s Rezdiffra (resmetirom) became the first FDA-approved treatment for the liver scarring – fibrosis – that characterises moderate to severe fatty liver disease. Sales of the drug are expected to top $3 billion by 2030, according to Evaluate forecasts.
By then, the overall therapy market for this condition – now known as metabolic dysfunction-associated steatohepatitis (MASH), and, as the name suggests, strongly linked to obesity and diabetes - could be worth more than three times that. Evaluate forecasts top $9.5 billion by the end of the decade. (The term ‘MASH’ replaced non-alcoholic steatohepatitis – NASH - in 2023.)
On its own, fatty liver is difficult to diagnose as it can’t be seen or felt. Diagnosis typically requires blood tests and/or a liver biopsy.
The revolution in obesity treatment is dragging MASH into the spotlight, however. Three quarters of people with overweight and more than 90% of those with obesity suffer from fatty liver (which, un-treated, can result in liver failure.) Some of those are now being treated with obesity medicines like Wegovy (semaglutide). Weight loss may reduce the chance of patients’ progression to MASH; Novo Nordisk’s semaglutide and Eli Lilly’s tirzepatide (sold for obesity as Zepbound) are both in testing for MASH.
Semaglutide hasn’t yet hit the mark on reducing fibrosis, but Lilly’s drug showed a significant improvement in MASH-related fibrosis in a Phase 2 read-out at the EASL Liver Congress in June 2024.
Several other dual GLP-1/glucagon receptor agonists are in the mix: Boehringer Ingelheim in 2024 reported positive Phase 2 fibrosis results from survodutide (not yet approved for MASH or obesity) and top-line Phase 2b data from Altimmune’s pemvidutide is expected in the first quarter of 2025.
The MASH pipeline includes over half a dozen Phase 3 or Phase 2 candidates covering several different mechanisms of action beyond incretins. (See Table 1)
Product
Company
Mechanism of Action
Estimated WW Launch
WW Sales 2030
PHASE III
Lanifibranor
Inventiva
Peroxisome proliferator-activated receptor (PPAR) agonist
31/12/2026
909
Belapectin
Galectin Therapeutics
Galectin-3 inhibitor
31/12/2025
840
Semaglutide (Ozempic)
Novo Nordisk
GLP-1 receptor agonist
751
Efruxifermin
Akero Therapeutics
Fibroblast growth factor 21 (FGF21) stimulant
721
Pegozafermin
89bio
31/12/2027
659
Survodutide*
Boehringer Ingelheim
Glucagon receptor (GCGR) agonist; Glucagon-like peptide 1 (GLP-1) receptor agonist
Azemiglitazone*
Cirius Therapeutics
Mitochondrial target of thiazolidinediones (mTOT) regulator (second generation insulin sensitiser)
PHASE II
Denifanstat
Sagimet Biosciences
Fatty acid synthase inhibitor
12/2028
401
Pemvidutide
Altimmune
GCGR/GLP-1 agonist
12/2027
281
Tirzepatide
Eli Lilly
GIP/GLP-1 agonist
131
Tesamorelin
Theratechnologies
Growth hormone releasing hormone receptor agonist
12/2033
169
*Sales forecasts unavailable for private company candidates
The MASH pipeline includes over half a dozen Phase 3 or Phase 2 candidates covering several different mechanisms of action beyond incretins.
If Rezdiffra and its followers prove even partly as effective at resolving MASH as incretins are at dropping weight, medicines for fatty liver disease and fibrosis could soon follow obesity’s extraordinary growth trajectory.
Rezdiffra is a once-daily pill which acts on a type of thyroid hormone receptor involved in fatty acid breakdown; Phase 3 data showed improvement or stabilisation of fibrosis in 80% of patients. Viking’s VK2809, another liver-selective thyroid hormone receptor beta agonist, showed promising Phase 2b results in June 2024; Aligos Therapeutics’ Phase 2a THR-b agonist followed suit in mid-September.
There are multiple potential targets but finding and hitting a disease-specific one has not been easy.
But it’s early days. Fibrosis - a pathological version of wound repair that features across many other diseases – involves a complex nest of cell types and signalling pathways, many of which underpin healthy processes, too. There are multiple potential targets but finding and hitting a disease-specific one has not been easy. Intercept’s Ocaliva (obeticholic acid), sold since 2016 for a rare bile duct condition, is a recent MASH casualty: it received a second FDA rebuttal in June 2023.
Over half a dozen MASH hopefuls are analogues of human fibroblast growth factor 21 (FGF-21), a metabolism-related hormone secreted by the liver. FGF-21 has several beneficial effects, including increasing insulin sensitivity, reducing inflammation and generally protecting liver cells from stressors including over- and under-eating.
89Bio’s pegozafermin, a long-acting FGF-21 analog, is the subject of two global Phase 3 MASH trials. Phase 2b data was promising, hitting two primary endpoints: an at least 1-stage improvement in fibrosis, and an improvement in NASH measures with no worsening of fibrosis.
Evaluate consensus forecasts first-year pegozafermin sales in 2027, reaching over $650m by 2030. Sales figures for Akero Therapeutics’ Phase 3 efruxifermin (licensed from Amgen) are similar; some analysts suggest that Akero and 89Bio’s fibrosis data is stronger that that from Rezdiffra and tirzepatide.
An FGF-21-based drug isn’t a done deal, though: candidates at Eli Lilly – the first to get an FGF-21 analog into the clinic, Bristol Myers Squibb and Pfizer were all dropped. (Novo Nordisk has a once-weekly FGF-21 analog in Phase 2.)
Others are chasing different fibrosis targets. Inventiva’s Phase 3 lanifibranor activates three isoforms of PPAR (peroxisome proliferator-activated receptor), potentially providing anti-fibrotic, anti-inflammatory and beneficial metabolic effects. (PPAR-alpha and PPAR-gamma agonists are already sold for diabetes and cholesterol-related disorders.) Top-line results from the France-based company’s candidate are expected in late 2025; Evaluate forecasts point to 2030 sales over $900m.
Galectin Therapeutics’s belapectin inhibits galectin-3, a protein implicated in liver fibrosis and liver cell damage; it’s in a Phase 2b/3 trial to prevent esophageal varices (unwanted bleeding) in MASH-associated liver cirrhosis. (Denmark-headquartered Galecto completed a Phase 1/2b trial of a similar compound in 2023 before running out of cash and re-structuring.)
Sagimet Biosciences’ oral denifanstat is the only inhibitor of fatty acid synthase (FASN) in the clinical MASH pipeline. After positive Phase 2b data in June 2024, the molecule – whose mechanism targets fat accumulation, inflammation and fibrosis – was granted FDA Breakthrough Designation in October and will begin Phase 3 this year.
Private Rivus Pharmaceuticals’ HU6 is different again; This once-daily pill works by increasing resting metabolism and revving up fat burn; it’s in Phase 2a testing for obesity-related heart failure as well as in a Phase 2 MASH trial. Phase 2a MASH data showed significant reductions in liver fat, body weight (for the two higher doses) and inflammatory and metabolic markers.
Improving liver fibrosis is the most compelling predictor of clinical outcomes in MASH (and is therefore what regulators want to see). But inflammation, fat accumulation and insulin sensitivity are important too. Hence GLP-1s are being tested alongside more liver-specific compounds like resmetirom and FGF-21 agonists (Lilly and Akero). Twinning an FGF-21 agonist with a thyroid receptor agonist could also be promising.
The most effective solutions for complex, multi-factorial conditions like MASH and obesity are likely to combine multiple mechanisms.
