Biotech tries everything it can in Nash

The Nash pipeline is pharmacologically diverse, and some projects look like very long shots.

Non-alcoholic steatohepatitis is back. Years in which nothing much seemed to work in the metabolic disorder were swept aside this week by the clear success of Madrigal’s resmetirom in its pivotal trial, with the company’s value more than trebling as a result. 

Simultaneously investors piled into Viking, which has a Nash candidate with the same mechanism as resmetirom. But this is in mid-stage trials, and there are several more advanced Nash projects that might – if their developers are lucky – have a more immediate chance of contesting this sizeable market. 

Interestingly none of the other phase 3 Nash agents share resmetirom’s pharmacology, thyroid hormone receptor-β agonism. More than that, no two agents in this cohort have the same mechanism at all – an indication of how willing biotechs are to throw anything they have at this disease. 

Novo Nordisk is one of the major contenders here, via its metabolic blockbuster semaglutide. In phase 2 the subcutaneous form of the GLP-1 agonist hit the primary endpoint, with a significantly higher percentage of treated patients seeing Nash resolution versus those given placebo. But it missed the confirmatory secondary endpoint, fibrosis improvement.

Dosage might have played a part in the misfire. In the phase 2 trial semaglutide was dosed up to 0.4mg daily, a very different schedule to those used in the drug’s approved indications – 1mg weekly as Ozempic in diabetes and 2.4mg weekly as Wegovy in obesity. 

The ongoing phase 3, Essence, is dosing the agent at 2.4mg weekly. Should the trial fail on either Nash resolution or fibrosis it might not be the end of the project in Nash, as the FDA only requires one endpoint hit; however, that outcome would raise the question of how Novo might compete against Madrigal.

Interim data are due in 2024, and Novo hopes that these will form the basis of regulatory filings; the sellside is confident, with 2028 Nash forecasts exceeding $1bn. 

Sprinting and stalling

In a similar timreframe to the Essence readout, data on a project from tiny Galectin could arrive. Belapectin’s phase 2/3 Navigate trial is looking specifically at preventing oesophageal varices, the enlarged veins in the oesophagus that can occur in people with serious liver diseases, in patients with liver scarring due to Nash.

Even if the study succeeds Galectin’s nanocap status makes marketing the project all but impossible. Navigate would have to hit the bar set by Madrigal’s Maestro-Nash study if Galectin is to hook a partner. 

Perhaps a likelier candidate is lanifibranor, a PPAR regulator being developed by Inventiva. Results from part 1 of the Nativ3 trial, assessing lanifibranor’s effect on endpoints including Nash resolution and improvement of fibrosis, are expected in 2024, and will determine whether the trial proceeds to stage 2. If positive, the part 1 data will also allow Inventiva to request accelerated approval.

In terms of heft, the only group likely to put up a fight against Novo or indeed Madrigal is Astrazeneca. The UK company is testing cotadutide, a GLP-1/glucagon agonist, in non-cirrhotic Nash with fibrosis. Data from the phase 2/3 Proxymo-Advance trial could emerge next year, the company said in an update last month. 

Two of the projects in the phase 3 pipeline have stalled. Intercept’s Ocaliva got a CRL in 2020 and has since posted lacklustre trial results – and reanalyses of those results – but the company still plans to refile in the US by the end of the year.

And Galmed has paused its Armor trial while it reformulates Aramchol from its free acid form to a compound called Aramchol meglumine, which has longer patent protection. It is not clear when the study might resume, and in the meantime Galmed’s share price of 32 cents puts the group at risk of being delisted from Nasdaq.

Mid-stage threats

Still, those interested in this segment might well take the view that phase 2-stage assets, most obviously Viking’s VK2809, are in fact the best bets. VK2809’s mechanistic similarity to Madrigal’s resmetirom is the main factor here, and with phase 2b data due at the start of the new year investors are a state of agitation. 

The trial has an unusual endpoint, however – reduction in liver fat at three months, rather than the usual Nash resolution/fibrosis improvement over the longer term. The more rigorous outcomes will not come for another year or two.

89Bio also has phase 2 data on its FGF21 analogue, pegozafermin, due in the coming quarter. But again, this has a completely different pharmacological action to anything in the late-stage queue.

Biotech’s everything-but-the-kitchen-sink approach, in terms of mechanisms of action, seems unlikely to generate widespread success in Nash. Few of these projects, if any, look likely to be able to match Madrigal’s triumph.

The late-stage Nash pipeline
Product Company Mechanism Status 2028e Nash sales ($m)
Resmetirom/
MGL-3196
Madrigal/
Roche
Thyroid hormone receptor β agonist Ph3 Maestro-Nash trial hit Dec 2022 1,718*
Semaglutide (Ozempic/
Wegovy)
Novo Nordisk GLP-1 receptor agonist Ph3 Essence trial to report interim data in 2024 1,274
Ocaliva Intercept  Bile acid receptor agonist Ph3 Regenerate reanalysis in Nash with fibrosis reported mixed data Jul 2022
Ph3 Reverse trial in compensated cirrhosis due to Nash failed Sep 2022
663
Lanifibranor Inventiva/
Sino 
PPAR regulator Ph3 Nativ3 trial to report interim data 2024 836
Belapectin Galectin  Galectin-3 inhibitor Ph2/3 Navigate trial in prevention of oesophageal varices in Nash cirrhosis to report 2024 572
Aramchol Galmed Stearoyl-CoA desaturase 1 regulator Ph3 Armor trial suspended while Galmed reformulates agent as Aramchol meglumine  492
Cotadutide Astrazeneca Glucagon & GLP-1 receptor agonist Ph2b/3 Proximo-Advance trial in non-cirrhotic Nash with fibrosis to report interim data 2023 -
MSDC-0602K Cirius Mitochondrial target of thiazolidinediones regulator Ph3 trial in pre-diabetes or type 2 diabetes with Nash or NAFLD to report 2024 -
*Post Maestro-Nash readout consensus forecast of SVB, Raymond James and B Riley. Source: Evaluate Pharma, clinicaltrials.gov, analyst notes.

Note: article updated on December 23rd to clarify reporting date of Galectin's Navigate trial and remove an academic trial of Novo's semaglutide. 

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