Credit: Elena Merkulova/iStock/Getty Images Plus

The non-alcoholic steatohepatitis (NASH) drug development landscape has long been a graveyard of failed programmes. The FDA’s approval of Madrigal’s resmetirom (Rezdiffra), an oral thyroid hormone receptor-beta (THRβ) agonist, now changes things for this potentially fatal liver disease.

“It's fantastic to be able to tell your patients, yes, there is a drug that potentially can be used and is approved,” says Arun Sanyal, a hepatologist at Virginia Commonwealth University, who was involved in the development of resmetirom. “It’s a big ‘hurrah moment’ for the field.”

NASH, also known as metabolic dysfunction-associated steatohepatitis (MASH), arises when the accumulation of fat and inflammation in the liver leads to scarring and possibly liver failure. An estimated 10–15 million people are affected in the United States. But even with an approved drug in the medicine box, the path ahead for these patients remains challenging, says Sanyal. “Does this mean we have cured the problem? No,” he says. In phase III testing, resmetirom improved key readouts of liver pathology in just 25–30% of patients. “There's continuous need for better and better drugs,” he says.

These could already be moving through the clinic. The NASH pipeline includes several late-stage candidates that act through a diverse set of mechanisms (Table 1).

Table 1 | Selected drugs in development for NASH

Drug

Company

Properties

Status

Resmetirom

Madrigal

THRβ agonist

Approved

VK2809

Viking

THRβ agonist

Phase II

Efruxifermin

Akero

FGF21 analogue

Phase III

Pegozafermin

89bio/Teva

FGF21 analogue

Phase III

Lanifibranor

Inventiva

Pan-PPAR activator

Phase III

AZD-2693

AstraZeneca

PNPLA3 ASO

Phase II

Rapirosiran

Regeneron/Alnylam

HSD17B13 siRNA

Phase II

ION224

Ionis

DGAT2 ASO

Phase II

Incretin mimetics

Semaglutide

Novo Nordisk

GLP1 agonist

Phase III

Tirzepatide

Lilly

GLP1/GIP co-agonist

Phase II

Survodutide

Boehringer Ingelheim/Zealand Pharma

GLP1/glucagon co-agonist

Phase II

“It is a rising tide that lifts all ships,” says Stephen Harrison, a hepatologist at Pinnacle Clinical Research, who was also involved in resmetirom’s development. “This will be a renaissance.”

Interest is building especially in the potential of incretin mimetics, because of the growing appreciation of the role of metabolic drivers in the disease course. These drugs are already reshaping the type 2 diabetes and obesity markets.

Because of the heterogeneous nature of the disease and its high prevalence, there is likely a need for multiple treatment options, adds Kitty Yale, Chief Development Officer at NASH-focused biotechnology company Akero Therapeutics. “There’s definitely room for more than one medication,” she says.

Complex disease

NASH drugs have been hard to develop in part because of the complexity of the disease. Two key pathophysiological processes characterize the disorder. First, under conditions of metabolic dysfunction, fat builds up in the liver — a stage known as non-alcoholic fatty liver disease (NAFLD). This causes hepatocytes to become stressed and inflamed. “It’s like a refugee crisis as the liver cells try to figure out what to do with all this extra stuff that has just arrived,” says Sanyal.

Mitochondria in hepatocytes seem to be particularly susceptible to damage.

Second, as the inflammatory state becomes chronic, specialized cells in the liver start producing scar tissue, laying down the liver fibrosis that progresses from mild (stage F1) to cirrhosis (stage F4). Fibrotic remodelling of the liver and hepatocyte death can culminate in liver failure, forcing the need for liver transplant.

An ideal drug tackles the build-up of fat, the inflammation and the fibrosis. As NASH drugs will likely be used long-term in many patients, the bar for safety is also high. Until now, no therapeutics have been up to the task.

Last year, the FDA rejected Intercept’s application for marketing authorization for obeticholic acid (OCA) to treat NASH. The drug activates the farnesoid X receptor, a transcriptional regulator of various pathways related to NASH, and is approved for primary biliary cholangitis, an autoimmune disease of the bile duct. OCA produced modest efficacy against NASH and fibrosis but, crucially, had side effects including pruritis, dyslipidemia and gallstones — prompting the FDA’s independent advisory panel to vote 15-to-1 against its approval for NASH last year.

Earlier flops include Conatus Pharmaceuticals’s emricasan, a caspase inhibitor that aimed to block cell death pathways in hepatocytes but was found to worsen fibrosis in phase II; and Gilead’s antifibrotic drug selonsertib, which the company shelved after it failed to show efficacy in phase III.

“Early programmes were thinking of NASH in different buckets, hoping if you just treat the fibrosis in the liver without treating the NASH, that that will work,” says Rebecca Taub, Chief Medical Officer at Madrigal.

Moderate progress

Resmetirom provides a two-for-one alternative, even if questions remain over how it exerts its effect.

The drug activates THRβ, a nuclear hormone receptor that is predominantly expressed in the liver and that acts as a key regulator of metabolic pathways in this organ. This target has attracted NASH drug developers ever since experimental THRβ agonists were shown to improve liver metabolic profiles in mice. Genetic studies have found that people with downregulation of THRβ have an increased risk of NASH.

The full mechanisms by which THRβ activation improves NASH remain unclear, but these agonists promote the generation of new mitochondria and boost the ability of hepatocytes to burn lipids. Resmetirom also reduces fibrosis, but the biology of this is less understood.

“There is quite a bit known about the pathways, but I would not call it 100%,” says Taub. Whatever the mechanism of the drug’s anti-fibrotic effect, she adds, it appears safe. “There is a normal wound healing process that you don’t want to interrupt.”

The FDA approved the drug based in part on results of a pivotal phase III study. 966 patients with mild-to-moderate NASH (up to stage F3), received once daily oral treatment with 80 mg or 100 mg resmetirom or placebo for 52 weeks. NASH resolution, defined by histological analysis of biopsy samples, with no worsening of fibrosis was observed in 25–30% of resmetirom recipients, compared with 10% of placebo recipients. Treatment was associated with fibrosis improvement by at least one stage with no worsening in NAFLD activity score (an 8-point scale of NAFLD features) in 25% of resmetirom recipients, versus just under 15% in the placebo group.

“The effect size is moderate,” says Sanyal. “But it’s the first drug that looks like it has a shot at goal here.”

The drug also reduced circulating low-density lipoprotein levels by about 15%, compared with no change in the placebo arm.

The most frequent adverse events associated with resmetirom were diarrhoea and nausea.

These findings were supported by a phase III safety study in patients with NAFLD and by earlier phase II data.

“The safety profile is very solid,” says Harrison.

Annual sales of resmetirom could generate over US$3.5 billion by 2028, show analyst predictions collected by Cortellis. This would be a boon for Madrigal, which has no other approved drugs. The compound was originally discovered by Roche and out-licensed to VIA Pharmaceuticals in 2008, a company that later merged with Madrigal.

For Sanyal, resmetirom’s clinical success attests to the field’s growing maturity. “The pharmaceutical industry is getting more sophisticated. They know exactly what target profile they are looking for, while previously they were guessing a little bit,” he says.

Next up

In some cases, drug developers are focusing on key targets in liver health, including fibroblast growth factor 21 (FGF21) and peroxisome proliferator-activated receptors (PPARs). Both camps have experienced bumps in the clinic, but their candidates hold promise in terms of the breadth of the biology they can impact.

FGF21 is a central regulator of protective pathways in the liver, shielding hepatocytes when sugar levels are high. It acts by both dialling up antioxidant pathways, and by shunting metabolites from the liver into adipose tissue for storage.

Such pleiotropic effects could translate into a broad clinical profile.

Last year, 89bio and Teva reported that their pegozafermin, an FGF21 analogue, improved NASH and fibrosis over 24 weeks in a phase II study in patients with stage F2 or F3 NASH. The sponsors are planning phase III trials.

Akero’s rival FGF21 contender, efruxifermin, also reduced NASH and improved fibrosis after 24 weeks of treatment in patients with stage F2 or stage F3 fibrosis. These findings were supported by recent 96-week follow-up data.

Akero is also trialling efruxifermin in advanced NASH (stage F4), hoping to differentiate from resmetirom and other candidates that are under investigation in pre-cirrhotic NASH. Although efruxifermin reduced NASH in this population, it failed to hit the fibrosis endpoint in a 36-week interim analysis of the phase II study. Patients at this stage of disease might require longer treatment times to show evidence of fibrosis reversal, says Yale. “We probably were a little aggressive in our powering calculations,” she says.

Akero expects 96-week data from this trial early next year.

Previous attempts to develop FGF21 analogues by companies including Pfizer were scuppered by the rapid clearance of these agents from the circulation. The latest candidates have extended half-lives, thanks to pegylation and other modifications at key residues, enabling subcutaneous dosing once weekly or potentially once every two weeks.

Another long-standing NASH focus is the PPARs, nuclear receptors that recruit transcriptional coregulators to control gene expression. There are three PPAR isoforms, and each of these has effects with possible NASH benefits: PPARα boosts mitochondrial fat-burning in hepatocytes, PPARδ in liver-resident macrophages dampens inflammation, and PPARγ reduces fibrosis. PPARγ activation also has known insulin-sensitizing effects beyond the liver, exemplified by the thiazolidinedione class of drugs for type 2 diabetes.

Inventiva’s pan-PPAR agonist lanifibranor takes on all three of the PPARs. The company expects that its bonus metabolic effects on insulin activity could be key to its function.

“If you don’t act on the metabolism upstream of the liver manifestations, you have not done a good job,” says Pierre Broqua, CSO at Inventiva. “You really need to improve the metabolic features.”

Previous PPAR-activating programmes, such as Genfit’s elafibranor, targeted only the α/δ isoforms of the nuclear receptor, and failed in NASH due to lack of efficacy. PPARγ activators, meanwhile, carry known risks including congestive heart failure and bladder cancer. By designing lanifibranor to hit all three PPAR isoforms equally and only to a moderate extent, Inventiva hopes to find a sweet spot that offers both efficacy and safety.

Clinical data remains key. In 2021, Inventiva reported that high-dose lanifibranor seemed safe and effective in a phase II trial. In February, however, the company paused enrolment of an ongoing phase III study of the drug after liver enzyme levels spiked in one patient receiving the drug.

Concerns also linger over weight gain that can be caused by PPARγ activation, as was seen in lanifibranor’s phase II study.

The genetics of liver disease is also providing a rich seam of gene variants that are associated with NASH. Candidates aimed at targets such as PNPLA3 and HSD17B13 are in mid-stage clinical testing. Boehringer Ingelheim recently partnered with the siRNA biotech RiboCure in a deal worth up to US$2 billion to develop therapies aimed at disease-causing genes in NASH.

Incretin expansion

With the rise of GLP1 mimetics for metabolic diseases, large pharmaceutical firms believe that these therapies might also yield dividends in NASH. Not only is NASH a common comorbidity of type 2 diabetes, obesity and cardiovascular disease, but it also shares key pathobiological drivers of these diseases, including the accumulation of excess fatty metabolites and associated inflammation.

So far, the data suggest that these drugs can trigger NASH resolution. In a phase II trial of Novo Nordisk’s GLP1 mimetic semaglutide, the most advanced incretin mimetic in development for NASH, 72 weeks of treatment led to NASH resolution in 59% patients receiving the highest dose versus 17% patients in the placebo group.

But semaglutide failed to improve fibrosis in the study, casting doubt over whether it can tackle fibrosis. Longer treatment might be needed for the improvement in liver fat and metabolic features to filter through into improved fibrosis via slowing disease progression, thinks Bei Zhang, head of research in obesity, diabetes and NASH at Novo Nordisk. Top-line data from Novo’s ongoing phase III trial of this incretin mimetic in NASH are due in the second half of 2024.

“If semaglutide can improve fibrosis as well as the NASH, that’s almost like a home run,” says Sanyal, who is involved in the trials.

In February, Boehringer Ingelheim and Zealand Pharma announced top-line results from a phase II trial of survodutide, its glucagon/GLP1 receptor dual agonist, in NASH. The drug met its primary endpoint of histological improvement in NASH at 48 weeks, achieved in 83% of survodutide-treated patients versus 18% of placebo-treated patients. The drug was also associated with a statistically significant improvement in fibrosis, a secondary endpoint. These results have buoyed expectations that next-generation incretins may offer even better efficacy profiles.

From biopsy to biomarkers

Beyond the therapeutics, there has also been progress on the biomarker side. A long-standing challenge for the NASH field is the need to diagnose and track the disease in clinical trials by liver biopsy, an invasive procedure that hampers trial recruitment. Biopsy analysis also varies between observers, creating ‘noise’ in trial readouts and necessitating large, long studies to detect efficacy signals.

But most drug development programmes now incorporate non-invasive tests to diagnose the disease and to monitor the effects of treatment, says Sanyal. Researchers are trialling MRI-based measures of hepatic fat content, for example, as well as ultrasound detection of liver stiffness as a proxy for fibrosis. Consortia in the EU and the USA are working with regulators to qualify such biomarkers for use in drug development.

Notably, the FDA's accelerated approval of resmetirom did not include a requirement for biopsy diagnosis in the prescribing information.

“We have drugs coming, and biomarkers are being developed,” says Sanyal. “Everybody gets that it's not one or the other — both have to happen together.”

With a first NASH approval in place, hopes are high that more drugs and better biomarkers are around the corner.

“We've been going in circles for 20 years, but now finally I think we have broken this,” says Sanyal.