Madrigal Cements Case For Hepatic Fat Reduction, Other NASH Benefits With MGL-3196

Madrigal’s selective THR beta agonist continues to demonstrate hepatic fat-lowering abilities in 36-week data, along with lipid-lowering characteristics. The company hopes to initiate a Phase III study in early 2019.

Madrigal Pharmaceuticals Inc.’s updated 36-week biopsy data for its THR beta agonist MGL-3196 in non-alcoholic steatohepatitis (NASH) shows a statistically significant ability to reduce hepatic fat across multiple measures, likely positioning the compound to enter Phase III development in early 2019.

Seen for nearly two years as a trailing star in NASH, where four other companies already have advanced candidates into Phase III, MGL-3196 lost a bit of its luster in September when Viking Therapeutics Inc.’s Phase II candidate from the same class showed even greater fat-reduction capability (mean reduction of 58%) – albeit in a small, 12-week study in non-alcoholic fatty liver disease (NAFLD), a precursor to NASH. (Also see "Viking’s Liver Fat Reduction Data Portend A New Competitor In NASH" - Scrip, 18 Sep, 2018.) Both MGL-3196 and VK2809 are selective thyroid receptor beta agonists being positioned as NASH drugs offering hepatic fat reduction along with cardiovascular benefits. (Also see "Madrigal's Early Phase IIb NASH Data Show Clinically Meaningful Fat Reduction" - Scrip, 6 Dec, 2017.)

Viking presented data from its 35-patient, Phase II study of VK2809 in NAFLD patients with elevated levels of low-density lipoprotein cholesterol (LDL-C) Nov. 12 at the American Association for the Study of Liver Diseases (AASLD) annual meeting showing that the drug produced a 21.8% placebo-adjusted reduction in LDL-C levels in 24 patients given the study drug for 12 weeks. It also reiterated data from September showing 58.1% median relative change in liver fat from baseline.

In 36-week data derived from liver biopsies, Madrigal reported Nov. 12 its candidate yielded a 49% mean relative liver fat reduction compared to baseline in a high-exposure cohort of its Phase IIb study and a mean 37% reduction in all patients, compared to an 8% reduction in the placebo arm.

On the measure of absolute fat reduction from baseline, the high-exposure cohort saw a mean 9.4% reduction and the overall group receiving ‘3196 saw an 8.5% reduction, while the reduction was 2.3% for the placebo group.

The percentage of patients who achieved 30% or greater reduction in liver fat – considered clinically beneficial for resolving NASH – was 77% in the high-exposure cohort, 68% in all patients receiving study drug and 30% in the placebo arm. All of the fat-reduction metrics for patients receiving ‘3196 achieved statistical significance.

Last December, Madrigal reported that MGL-3196 demonstrated a mean 36% reduction in hepatic fat from baseline after 12 weeks in the same study, based on findings from MRI-estimated proton density fat fraction (MRI-PDFF). The Philadelphia-area firm then revealed top-line 36-week data in May showing that the 12-week data were predictive of histologic response at 36 weeks. (Also see "Madrigal May Shake Up NASH Race With Phase II Resolution Data" - Scrip, 31 May, 2018.)

Those data suggested better NASH resolution than three of the agents already in Phase III – Intercept Pharmaceuticals Inc.’s obeticholic acid (OCA), Genfit SA’s elafibranor and Allergan PLC’s cenicriviroc. (Also see "Genfit May Be Gaining An Edge In NASH Race" - Scrip, 26 Oct, 2017.)

Share Price Declines Despite Positive Data

Investors responded enthusiastically to Madrigal’s initial 36-week data look in May, with the company’s share price rising 145% May 31 to close at $265.61. This time around, even though the latest data are positive and MGL-3196 is poised to move into Phase III in 2019, Madrigal shares fell 21.6% Nov. 13 to $146.21, in a down market for biotech stocks. The stock closed at $186.51 on Nov. 12, with Madrigal’s AASLD presentation scheduled for after the trading day ended.

JMP Securities analyst Liisa Bayko called Madrigal’s Phase IIb readout “meaty” in a Nov. 12 note that reiterated a “market outperform” rating for the stock. She indicated that the data looked promising not only for approval in NASH, but possibly as a therapy for dyslipidemia patients as well. That the drug led to NASH resolution in a majority of patients without a worsening of fibrosis was a good sign given that demonstrating such an ability likely would be ‘3196’s primary Phase III endpoint, Bayko added.

“Madrigal presented data showing that MRI-PDFF response correlated with improvements in ballooning and inflammation, suggesting that MGL-3196 is not just working via steatotic improvements,” the analyst wrote. “Statistically significant reductions in GGT [gamma-glutamyl transferase] also suggest MGL-3196 could have an effect on oxidative stress, and fibrosis markers continue to show statistically significant reductions over time.”

The 36-week data showed statistically significant and sustained reduction in multiple atherogenic lipids, including a 22.3% reduction from baseline in LDL cholesterol and a 36% reduction in triglycerides. It also showed a 21.9% reduction in apoliprotein-B (Apo B), a 36.5% reduction in apoliprotein-CIII (Apo C3) and a 36% reduction in lipoprotein A.

Both Intercept’s OCA as well as Gilead’s Phase II acetyl CoA carboxylase (ACC) inhibitor GS-9076 have shown increased LDL-C levels in some patients during Phase II studies.

After Madrigal’s data presentation, JPM’s Bayko issued a second note Nov. 13 saying ‘3196 also demonstrated a good safety profile in the 36-week data, with the most frequent adverse event being diarrhea that self-resolved in most instances. In addition, the drug might have shown a safety advantage compared to Viking’s VK2809, she said.

“Management indicated MGL-3196 was not associated with the same pattern of ALT elevations as Viking’s THR-beta agonist, which raised some eyebrows during its late-breaker presentation (although we have not seen the actual data),” Bayko said. Viking stated Nov. 12 that ALT levels for patients receiving VK2809 were lower than those in the placebo group at weeks 12 and 16 of its study, but did not specify if patients receiving study drug had lower ALT levels than at baseline.

Madrigal indicated at AASLD that it plans to study two doses of ‘3196 – 80 mg daily and 100 mg daily – in its Phase III study. Both doses were used in a 36-week extension study to examine liver fat levels by MRI-PDFF.

“The goal is to have two approved doses so patients can dose higher if they want more efficacy – akin to statins,” Bayko said in her Nov. 13 note. “We anticipate there will be two treatment arms and dose will not be assigned by weight, sex or any other criteria.”

Phase III Program Will Incorporate Two Doses

Madrigal is remaining close-mouthed otherwise about its Phase III plans, as dialogue with the US FDA is ongoing. Bayko predicted the Phase III protocol would be revealed during the first quarter of 2019, but also indicated that staffing issues at the Center for Drug Evaluation and Research (CDER) is delaying processes such as finalization of pivotal trial designs.

“This division seems particularly swamped and falling behind PDUFA dates, so we would not be surprised by some delays across the field,” she said.

Madrigal management told Scrip it plans to initiate the Phase III program during the first quarter of 2019. The company reported cash and equivalents of $488.5m on hand at the end of the third quarter, after raising $300m in the prior quarter, and appears to want to take ‘3196 into Phase III on its own. (Also see "Finance Watch: Investors Go Nuts For NASH As Madrigal Raises $300m, Galmed Skyrockets" - Scrip, 15 Jun, 2018.)

“We are moving ahead with our plans to initiate Phase III,” the company said. “We are not actively seeking strategic relationships but, as before, we are open to discussions from potential strategic players.”

In the past Madrigal has indicated that it sees potential for ‘3196 both as monotherapy in NASH because of its range of therapeutic benefits and also as an ideal partner for combination regimens. Combination therapy ultimately is expected to emerge as the standard of care in NASH, but the candidates currently moving toward regulatory filings will be submitted first as monotherapies. (Also see "Combination Strategies A Common Thread In NASH R&D" - Scrip, 21 Nov, 2016.)

“While we believe that ‘3196 as monotherapy will address the NASH phenotype in a significant subset of NASH patients, we are interested in evaluating potential combinations and believe that our drug is well-suited to combine with other mechanisms,” Madrigal told Scrip. Previously, Madrigal CEO Paul Friedman has indicated that an anti-fibrotic agent might be the ideal combination therapy partner for ‘3196.