AASLD 2018 – Viking lands blow in early Nash skirmish

Viking’s VK2809 looks at least as good as Madrigal’s MGL-3196 in liver disease – but investors should be careful of making comparisons.

Watch out, Viking is coming. Phase II results with VK2809, presented yesterday at the Liver Meeting in San Francisco, have got investors excited about the project’s chances against a rival thyroid hormone receptor beta agonist, Madrigal's MGL-3196.

Madrigal also presented more mid-stage data with MGL-3196 at the same conference, giving the markets the perfect opportunity to pit the two assets against each other. A cross-trial comparison suggests that Viking’s project has a slight edge – but this conclusion should be taken with a pinch of salt.

Nash or not?

For one, Viking’s phase II study of VK2809 was not designed primarily with Nash in mind. Instead it enrolled patients with primary hypercholesterolaemia and non-alcoholic fatty liver disease, with a primary endpoint of change in LDL cholesterol at 12 weeks.

However, the trial also included a Nash-relevant, but exploratory, secondary endpoint, change in liver fat content at 12 weeks, measured via MRI imaging.

Handily, this was the primary endpoint of Madrigal’s phase II trial of MGL-3196, whose development has so far focused squarely on Nash.

Madrigal has already reported 12 and 36-week data from the trial, and the group’s presentation at the Liver Meeting yesterday concerned longer-term results. But this did not stop comparisons with VK2809 on the 12-week liver fat endpoint – an exercise that made MGL-3196 look ordinary.

Madrigal has highlighted slightly better results with MGL-3196 from an analysis in a group of “high exposure” patients that it said was prespecified.

Viking vs Madrigal: the battle of the thyroid hormone receptor beta agonists
  VK2809 (NCT02927184) MGL-3196 (NCT02912260)
Endpoint 10mg every other day 10mg every day Placebo All MGL-3196 High MGL-3196 Placebo
Placebo-adjusted % change in LDL-C -23.6 -20.2 - - - -
Mean relative % change in liver fat by MRI-PDFF -56.5 -59.7 -8.9 -36.3 -42.0 -9.6
% of patients with liver fat reductions of ≥30% 76.9 90.9 18.2 60.3 75.0 18.4
All at 12 weeks. Source: company presentations.

Viking’s stock opened up 10% this morning, although it soon fell back, and Madrigal fell 4%. But some industry observers questioned the wisdom of comparing trials involving completely different patient populations. The MGL-3196 study evaluated patients with Nash and liver fibrosis, while the VK2809 trial looked at people with NAFLD, a precursor to Nash that involves fat accumulation but not liver damage.

There is also the question of how far VK2809 is behind MGL-3196 in development. Viking will need to carry out a separate Nash trial, and on the group’s third-quarter conference call last week its chief executive, Brian Lian, said the company would file an IND for a study in biopsy-confirmed Nash in the first half of next year.

He would not say whether this would be a phase IIb trial or whether the project might be able to go straight into phase II/III in Nash.

Madrigal, meanwhile, expects to start a phase III/IV Nash trial in the first quarter of 2019. The phase III portion will include around 900 patients, with a primary endpoint of resolution of Nash without worsening of fibrosis at 52 weeks, measured by liver biopsy.

With Nash estimated by some to affect up to 6% of the world’s population, perhaps there is room for both thyroid hormone receptor beta agonists. But the space is becoming ever more crowded, and the recent tie-up between Pfizer and Novartis suggests that smaller companies might find it tough to compete.

Still, if combinations are the way forward in Nash, Madrigal and Viking might attract the interest of bigger players already looking at the disorder.

The next big events in Nash are still the phase III readouts for Intercept’s Ocaliva and Gilead’s selonsertib, due next year (Liver disease is set for its pivotal year, August 10, 2018). But Viking just joined the growing roster of companies to watch out for in this arena.

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