Spotlight – Nash in 2023 and beyond

The first half of this year saw some major ructions in the non-alcoholic steatohepatitis (Nash) space, most notably mid-stage trial successes for 89Bio and Viking Therapeutics. The second half of 2023 will also see some important phase 2 readouts, with Boehringer Ingelheim and Akero aiming to build on somewhat equivocal earlier showings. 

Looking beyond that, 2024 could play host to some even more intriguing data. Lilly hopes to show that Mounjaro, already gilded with clinical success in diabetes and obesity, can win out in Nash too. Big pharma is also represented by Pfizer and Astrazeneca, both of which are trialling mechanisms unproven in this disease. 

Metabolic hormones

Incretins are a major research area in Nash. Next up to yield mid-stage data could be survodutide, a GLP-1/glucagon co-agonist being developed by Boehringer Ingelheim and Zealand Pharma.

The project hit a snag in June when phase 2 data showed it to be effective in obesity, but with alarmingly high rates of discontinuations. Its phase 2 Nash trial ought to generate data at the end of this year, and investors will be watching closely for any signs of similar toxicity. 

Another GLP-1 combo, this time with a GIP agonist rather than a glucagon agonist, will report mid-stage data a few months later, and side-effects seem to be less of a worry with this one. The asset in question is Lilly’s Mounjaro, already forecast to be a blockbuster in both diabetes and obesity. 

The results seen so far on incretins are mixed, and phase 3 remains a big test. Novo Nordisk’s GLP-1 semaglutide, which succeeded cleanly in diabetes and obesity, hit on Nash resolution in its mid-stage trial but missed on fibrosis improvement. Sema’s pivotal Nash study could report top-line data in 2024, probably after the phase 2 trials of both survodutide and Mounjaro read out.

Known unknowns

Novo is hedging its bets by combining sema with another mechanism which has much more evidence of effectiveness behind it: FGF21 agonism. This has worked for 89Bio and slightly less convincingly for Akero. A trial looking at Akero’s FGF21 efruxifermin in Nash with cirrhosis will report next quarter, and bearing in mind the findings with efruxifermin in Nash without scarring, the statistical analyses will be of great interest.

Also following an established mechanism is Ascletis Pharma, whose thyroid hormone receptor agonist ASC41 is pharmacologically similar to Madrigal’s resmetirom. Resmetirom kicked off a resurgence of the Nash space with a pivotal hit 18 months ago; hopes for this mechanism were also raised by Viking’s hit with its thyroid hormone receptor agonist, VK2809. ASC41 is in a phase 2 study run by Ascletis’s subsidiary Gannex, which should report towards the end of 2024. 

Astrazeneca and Pfizer, meanwhile, are ploughing different furrows. Astra’s mitiperstat is a myeloperoxidase inhibitor, a mechanism better known for being pursued by Biohaven in amyotrophic lateral sclerosis. The theory in Nash is that myeloperoxidase activates pathways relevant for inflammation and cell death, but it is notable that Pfizer canned a phase 1 myeloperoxidase inhibitor five years ago. 

Pfizer is instead pursuing a combination approach in Nash. Ervogastat, an ACC inhibitor, is being tested both as monotherapy and on top of the DGAT2 inhibitor clesacostat in the Mirna trial. The former blocks intrahepatic triglyceride synthesis and the latter de novo lipogenesis. Ionis is also looking at DGAT2 inhibition with ION224; the company says antisense inhibition of DGAT2 improved liver steatosis and lowered lipid levels in animal studies.

Madrigal’s resmetirom is odds-on to be the first drug ever approved in Nash, probably in the spring or summer of next year. It may not have the market to itself for long.