Spotlight – Nash in 2023 and beyond
The mid-stage Nash pipeline plays host to mechanisms both evidence-backed and unproven, with plenty of data on the horizon.
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.
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.
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.
|The mid-stage Nash pipeline – readouts coming in 2023 and 2024|
|Survodutide (BI 456906)||Boehringer Ingelheim/Zealand||GLP-1/glucagon agonist||Ph2 trial in Nash and fibrosis could report late 2023|
|Efruxifermin||Akero Therapeutics||FGF21 stimulant||Ph2 Harmony trial in non-cirrhotic pts reported Sep 2022; Ph2b Symmetry trial in CC from Nash could report Q4 2023|
|AXA1125||Axcella Health||TGFb inhibitor||Ph2 Emmpact trial in Nash w fibrosis could report late 2023|
|Mounjaro||Lilly||GIP/GLP-1 agonist||Ph2 Synergy-Nash trial could report early 2024|
|Ervogastat +/- clesacostat||Pfizer||ACC inhibitor; DGAT2 inhibitor||Ph2 Mirna trial in Nash w fibrosis could report early 2024|
|ION224||Ionis Pharmaceuticals||DGAT2 inhibitor||Ph2 trial could report early 2024|
|CS0159||Cascade Pharmaceuticals||FXR agonist||Ph2 trial could report mid-2024|
|Mitiperstat (AZD4831)||Astrazeneca||Myeloperoxidase inhibitor||Ph2 Cosmos trial in Nash w fibrosis could report 2024|
|Cilofexor + firsocostat||Gilead Sciences||Bile acid receptor agonist + ACC inhibitor||Ph2 Wayfind trial in combo w semaglutide in CC from Nash could report 2024|
|Novo Nordisk||FGF21 stimulant||Ph2 trial in combo w semaglutide could report 2024|
|ASC41||Ascletis Pharma||Thyroid hormone receptor β agonist||Ph2 trial could report 2024|
|Tipelukast (MN-001)||Medicinova/Kyorin Holdings||5-lipoxygenase inhibitor; leukotriene receptor antagonist; PDE3 and 4 inhibitor||Ph2 trial in NAFLD, type 2 diabetes and hypertriglyceridemia could report 2024|
|CC = compensated cirrhosis. Source: Evaluate Pharma, company websites, clinicaltrials.gov.|