Viking’s Liver Fat Reduction Data Portend A New Competitor In NASH

In a Phase II study, Viking’s VK2809, with the same mechanism as Madrigal’s MGL-3196, shows significant liver fat reduction in NAFLD patients, along with reduction in LDL cholesterol.

Viking Therapeutics Inc. may have a heavy hitter on its hands if results from a small Phase II study of VK2809 stand up in larger studies – the novel, liver-selective thyroid receptor beta agonist yielded a 58% reduction in liver fat from baseline over 12 weeks, according to top-line data in patients with non-alcoholic fatty liver disease (NAFLD) reported Sept. 18. NAFLD is a precursor condition to non-alcoholic steatohepatitis (NASH).

VK2809 showed a statistically significant reduction in LDL cholesterol levels in the same study, suggesting both cardiovascular and hepatic health benefits.

The San Diego firm’s stock finished the day up 87% at $19.46 per share, as at least one analyst pointed out that the data were numerically superior to widely praised Phase II liver fat reduction data in NASH patients that Madrigal Pharmaceuticals Inc. reported earlier in the year for MGL-3196. Madrigal's selective thyroid hormone receptor beta agonist showed a median 36% reduction in liver fat from baseline after 12 weeks of treatment in Phase II data released in December; Madrigal solidified those findings with 36-week histologic data from liver biopsies in May. (Also see "Madrigal May Shake Up NASH Race With Phase II Resolution Data" - Scrip, 31 May, 2018.)

Viking did not release a full dataset on Sept. 18, because it hopes to present the larger picture at a late-breaker session of the American Association for the Study of Liver Disease conference Nov. 9-13 in San Francisco. However, it noted that NAFLD patients given 10 mg of its drug every other day (n=14) saw a 56.5% median reduction in liver fat from baseline at 12 weeks, while patients who received 10 mg daily (n=15) had a median 59.7% reduction at 12 weeks. That made for a composite median reduction of 58.1% in the 45-patient trial, compared to 8.9% for the trial’s placebo arm (n=16).

“We are encouraged by the magnitude of liver fat reduction observed here, particularly at these low doses,” Viking CEO Brian Lian said during a same-day investor call. “To our knowledge, this magnitude of liver fat reduction exceeds that reported for any other oral agent currently in development for NASH, though obviously no head-to-head studies have been conducted. We believe these results at these relatively modest doses support our view that VK2809’s unique liver-targeting features provide differentiated benefit on this important measure of efficacy in NASH.”

William Blair & Co. analyst Andy Hsieh pointed out that the Viking results appeared numerically superior to Madrigal’s. “While we acknowledge all the caveats associated with cross-trial comparison, owing to the differences in enrollment criteria and patient baseline characteristics, we believe VK2809 achieved numerically better results than Madrigal’s MGL-3196,” he said in a Sept. 18 note, with a 57%-60% range in liver fat reduction in the Viking study compared to a 36%-42% range in the Madrigal trial.

High Proportion Of Patients Met 30% Standard For Fat Reduction

Another potential differentiator between the two candidates, the analyst added, is proportion of patients who achieved a clinically meaningful reduction in liver fat. Multiple studies have linked a liver fat reduction of at least 30% from baseline with greater likelihood of histologic response in NASH patients. Both Madrigal and Viking’s 12-week data were based on a non-invasive measure: magnetic resonance imaging, proton density fat fraction (MRI-PDFF). Madrigal’s 36-week data, however, were derived from liver biopsies, the gold standard for NASH diagnosis.

Viking reported that 76.9% of the patients receiving VK2809 every other day achieved a 30% reduction or greater in liver fat from baseline, while 90.9% in the daily dosing group hit that mark. For the placebo arm, 18.9% achieved at least a 30% reduction of liver fat from baseline.

In Madrigal’s 116-patient Phase II trial, 60.3% of treatment arm patients (n=78) met the 30% or greater liver fat reduction mark, compared to 18.4% of control arm patients (n=38).

Lian also pointed out during the call that 62% dosed every other day and 73% dosed daily with study drug saw at least a 50% reduction in liver fat from baseline, for a composite 67% of treatment-arm patients who Viking termed “super responders.” “While admittedly this is a little bit of our own invention, we nonetheless find it impressive that most patients who received VK2809 saw their liver fat content cut in half,” the exec said.

Blair’s Hsieh called VK2809’s strong safety and tolerability profile, with no serious adverse events reported, an encouraging sign. Meanwhile, the drug actually showed reduced levels of the liver enzyme alanine aminotransferase (ALT) compared to placebo, which alleviated a prior concern for investors, Hsieh said. In a second note issued on Sept. 18, he increased his estimated US peak sales for the drug from $1.25bn to $1.71bn.

Given the its combined safety and efficacy profile in the Phase II study – including a significant reduction in LDL-C reduction, although numbers weren’t given – Lian said VK2809 has a profile that might offer patients a range of health benefits.

“We believe the magnitude of the observed [liver fat reduction] effect suggests promising long-term benefits on histology in patients with NASH,” he said. “In addition, treatment with VK2809 has been shown to improve patients’ overall lipid profiles, with observed reductions in LDL, triglycerides and atherogenic proteins. We believe such results suggest potential benefits in cardiovascular health, an important consideration in the NASH population.”

Biomedtracker concurred with the optimistic takes in its analysis, increasing the drug’s likelihood of approval by seven percentage points to 27%, three percentage points above average for a Phase II NASH candidate. “The results of this study are very positive,” Biomedtracker said, “with both primary and secondary endpoints reaching statistical significance and no serious adverse events reported for the duration of the trial, though the trial was small as it was only a Phase II study.”

Lian said Viking’s next steps are to compile the final dataset from the trial and complete animal toxicity studies of VX2809. The firm anticipates meeting with the US FDA in early 2019, after those tasks are completed, to determine what’s next, which could be a biopsy data trial, the executive said.

“If we could do that in some sort of Phase II/III format, that would be preferable, but we may have to do a Phase IIb standalone,” Lian conceded. “But we won’t know until we have some of those discussions with the agency.”

Along with VK2809, Viking’s pipeline includes Phase II VK5211, a non-steroidal selective androgen receptor modulator (SARM) for treatment and prevention of lean body mass in patients who have undergone hip fracture surgery. (Also see "Viking Flexes Its Muscles Ahead Of Partnering Talks" - Scrip, 23 Feb, 2017.)