Spotlight – What's next in Nash

The future of an early stage yet closely watched non-alcoholic steatohepatitis project was thrown in doubt last month, when Johnson & Johnson returned rights to ARO-PNPLA3 to Arrowhead. The small biotech must now decide whether to push into mid-stage trials alone, a difficult decision considering how tough to target Nash has proven.

Full phase 1 data on the RNAi asset are now awaited and if it does progress, it will join a long list of candidates already in phase 2. Much attention here is focused on Viking’s VK2809, mechanistically similar to Madrigal’s resmetirom, which triumphed in its pivotal trial late last year. Viking’s Voyage trial will read out in the spring, but before that several other projects are due to yield data.

As with the late-stage Nash pipeline, the heterogeneity of the pharmacological approaches is striking. In the analysis below, which covers only those compounds whose phase 2 trials are likely to report in the first half of the year, no fewer than nine mechanisms are employed.

One of the first phase 2 studies to read out will be the Enliven trial of 89bio’s pegozafermin. “We are hoping to demonstrate that pegozafermin can improve liver fibrosis and show Nash resolution,” 89Bio’s chief medical officer, Hank Mansbach, tells Evaluate Vantage. He declines to state the exact delta over placebo the company expects to see, but SVB analysts write that a 15% placebo-adjusted rate of fibrosis would be meaningful.

Akero’s efruxifermin, also a subcutaneous FGF21 analogue, posted a somewhat questionable hit in phase 2 in September. A second mid-stage trial of efruxifermin is set to read out in the back half of this year, so does not appear in the table below.

Mansbach believes that the efruxifermin data bode well for 89Bio’s project. “If we have a successful study ... the FGF21 analogue category becomes the most promising approach to Nash.”

Enliven is a larger trial that Akero’s Harmony – 216 patients versus 128 – so maybe it will be able to demonstrate a more robust effect. If the trial fails, 89Bio will be in trouble: pegozafermin is its only asset, and while it can fall back on the project’s use in severe hypertriglyceridemia it would lose the much larger Nash opportunity. 

Reading the runes

Elsewhere, Northsea Therapeutics reported interim data from its Icona trial of icosabutate in early 2021, with the PPAR agonist demonstrating decreases in Nash and fibrosis biomarkers and an absence of serious toxicity signals in the first 90 patients in the trial. Topline data from the full 280 patients are expected by the end of March.

The omens for PPAR agonists are mixed. In 2019 Cymabay’s seladelpar was beaten by placebo in its phase 2 trial, leading to its shelving in Nash; it is still in trials for primary biliary cholangitis. The following year Genfit’s elafibranor failed in phase 3. But Inventiva’s lanifibranor hit in its phase 2 trial, and phase 3 data ought to emerge next year. 

Sagimet Biosciences is in a similar situation to Northsea, having reported interim data on its Nash project denifanstat, with full results expected in the coming weeks. As a fatty acid synthase inhibitor, denifanstat directly targets the drivers of Nash by reducing excess liver fat and decreasing inflammation, Sagimet says, and in fairness that is exactly what it did at the interim look, cutting liver fat by 33% over placebo.

Full data from Fascinate-2 ought to cover the trial’s primary efficacy endpoints of improvement in non-alcoholic fatty liver disease activity score without worsening of fibrosis and steatohepatitis resolution without worsening of fibrosis – harder metrics to hit. 

The sole big pharma pursuing a phase 2 Nash trial appears to be Novartis, which is conducting the Elivate trial of tropifexor plus licogliflozin. These compounds, however, do not appear in the pipeline on the company’s website, so its development plans here are unclear. 

Fantastic Voyage? 

Viking has said that the Phase 2b Voyage trial of its thyroid hormone receptor agonist VK2809 will generate data next quarter. Investors will hope for signs of similar efficacy to resmetirom; Madrigal’s project improved Nash and fibrosis in phase 3.

But Voyage is looking at a very different primary endpoint – liver fat – with Nash resolution relegated to a secondary. The direct effect of VK2809 on fibrosis is not listed as an outcome measure. 

Another thyroid hormone receptor agonist is in phase 2. Terns Pharmaceuticals’ TERN-501 is being tested both as monotherapy and in combination with a bile acid receptor agonist, TERN-101, in the Duet trial. While there is a highly promising pharmacological precedent for the former, the latter has a less distinguished forerunner. 

Intercept’s bile acid receptor agonist Ocaliva yielded mixed results when data from the phase 3 Regenerate trial in Nash with fibrosis were reanalysed last July, and the Reverse trial in compensated cirrhosis due to Nash was disclosed as a straight-up failure two months later. Perhaps this means that TERN-501 has a better chance of succeeding when it is administered alone.

Followers of Terns, and of all the groups in the below table, will find out very soon whether further development in Nash is justified.