ViewPoints: A Viking raid on Madrigal solidifies THR as the hottest new thing in NASH

Viking Therapeutics looks to have the next best thing in non-alcoholic steatohepatitis (NASH)- or it might, once it gets around to testing its candidate in NASH patients. But in the meantime, Viking's Phase II data point towards a big shakeup in liver disease that could mean lots of dollar signs in the near future.

What happened

Viking got a shot in the arm- and its market cap- on September 18 after announcing top-line Phase II data from its non-alcoholic fatty liver disease (NAFLD) programme. In the 45-patient study, both tested doses of VK2809 significantly lowered LDL cholesterol and lipid fat fraction as measured by MRI at 12 weeks; strikingly, 91 percent of patients on a daily dose of the oral therapy had a liver fat reduction of at least 30 percent, which the company described as a "responder" benchmark for patients likely to show improvement in liver histology. In the placebo arm, 18 percent of patients achieved the same level of liver fat reduction.

Combining both dosing arms, the company said that two thirds of all patients had at least a 50-percent reduction in liver fat.

CEO Brian Lian emphasised that the strong efficacy profile gives the company ample flexibility in choosing a final dose for further development, with "a lot of room to dose down-" despite a clean safety profile that saw little in the way of adverse events for the thyroid hormone receptor (THR) agonist. The company also teased additional protective effects on atherosclerotic markers, but said it was saving much of the data for a future conference, likely at the American Association for the Study of Liver Diseases (AASLD) meeting in November.

The backstory

Viking isn't the first company to stumble on modulating thyroid activity as a means of lowering lipids; the vital role of thyroid signalling in regulating energy expenditure makes it an intriguing target for metabolic diseases. However, cardiac side effects also tend to follow in the path of THR modulation, which has slowed development for the drug class.

Researchers at Karo Bio had hoped to avoid this complication back in 2012 by honing in on a specific receptor subtype, THR beta, which has limited cardiac involvement. However, the researchers instead found cartilage damage in a dog model, paired with liver enzyme elevations that led the company to discontinue the programme.

Viking argues that its target, THR beta1, can get around those historic problems by being ultra-specific to the liver, allowing it to simultaneously lower liver and systemic lipid levels without cartilage or cardiac side effects. That idea looked to be validated by data from Madrigal Pharmaceuticals, which is advancing its own THR beta agonist, MGL-3196. Earlier this year, the company said the candidate improved fibrosis scores in biopsies from NASH patients, corroborating non-invasive biomarker data collected earlier that had shown a reduction in liver fat. (See ViewPoints: Proof is in the histological pudding for Madrigal’s MGL-3196)

Competitor impact

On a conference call to discuss the results, Lian didn't mince words, saying that "this magnitude of liver fat reduction exceeds that reported for any other oral agent currently in development for NASH." That, paired with a clean safety profile that saw more adverse events in placebo-treated patients, will make for a significant shakeup in NASH if borne out in larger studies.

And while Viking had received a boost in its share price when Madrigal released its data- interpreted by investors as a validation of the proof of concept for the THR beta mechanism- Madrigal shares fell 10 percent on September 18 as the competition got tighter. (See ViewPoints: Can Viking Therapeutics invade NASH?)

Of course, caveats of cross-trial comparisons apply; Madrigal studied patients with NASH, in contrast to Viking's more mild NAFLD population, and had a longer study endpoint of 36 weeks. It's also worth noting that Viking's primary endpoint was LDL-lowering, rather than liver fat reduction, and the company has yet to obtain biopsy data that could validate its early biomarker results. Plus, the known potential for cardiac and liver effects means that long-term safety studies are likely to be paramount for the drug class.

Final thoughts

Although Viking didn't discuss the possibility of a new partnership with its data release, the idea seemed to be at the top of investors' mind as they speculated on the ramifications of a potential best-in-class NASH therapy. Rumours had circulated after Madrigal's promising data that the company was courting bidders for a potential buy-out. However, any parties kicking those tires will certainly need to evaluate the options at Viking, whose market cap was still only a third of Madrigal's by the time markets closed on September 18.

To read more ViewPoints articles, click here.