Analysts quickly weighed in on abstracts from the International Liver Congress (ILC) 2018, set for next month in Paris, disclosed early Wednesday by the European Association for the Study of the Liver (EASL).

The early take on findings in the important nonalcoholic steatohepatitis (NASH) category suggested that privately held NGM Biopharmaceuticals Inc. continued to impress with NGM-282, its engineered variant of recombinant human fibroblast growth factor 19 (rhFGF19) and cytochrome P450 (CYP) 7A1 that reduces liver fat content, while Madrigal Pharmaceuticals Inc. did not disappoint with iterative data on MGL-3196, its oral thyroid hormone receptor (THR) beta agonist.

NGM's open-label NASH biopsy data looked "almost too good to be true" for a small 12-week study, Evercore ISI analyst Josh Schimmer wrote in an email, appearing "highly encouraging with what we think is a reasonably positive read-through to MDGL's 36-week biopsy data."

In an industry note, Jefferies Group LLC analyst Michael Yee called the data from NGM, a competitor of Intercept Pharmaceuticals Inc., "compelling," with "robust fibrosis improvement."

NGM-282 previously produced impressive effects in reducing liver fat and enzymes. Reporting last year at the ILC in Amsterdam, NGM officials homed in on the asset's liver de-fatting feats while reporting that NGM-282 met the primary and key secondary endpoints in a phase II trial in 82 individuals with NASH. (See BioWorld Today, April 25, 2017.)

Data reported in the new abstract (GS-014) came from a subset of patients treated with 3 mg of NGM-282 once daily through subcutaneous injection. With fibrosis measured by biopsy, eight participants (50 percent) improved by greater than one stage, and three improved by two stages.

"These results are largely in line with results from ICPT's OCA [obeticholic acid, or Ocaliva] and GILD's [selonsertib], which showed ~40 percent of patients demonstrating a greater than one stage improvement in fibrosis vs. 10-20 percent for placebo-treated patients in each study," Yee wrote. The Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score, or NAS, decreased by 2 points (at least 1 point on inflammation or ballooning) in 10 (63 percent) subjects. "Notably," Yee pointed out, "NGM reported that eight (50 percent) subjects met histological endpoints currently being used in phase III NASH studies."

As reported previously, NGM-282 was safe, with increase in LDL and gastrointestinal side effects as the most frequent adverse events (AEs).

Yee saw a read-through to Intercept in the NGM data, writing, "in our view, we believe these results further validate ICPT's drug, as OCA acts by indirectly increasing the production of FGF19 in addition to its direct effect on hepatocytes."

"Overall, we view the NGM data as very intriguing for a 12-week study but still speculative with a small number of patients and no control arm," Schimmer added. "In ICPT's phase II FLINT trial, 19 percent of patients had an improvement of fibrosis in the placebo arm; while NGM's results appear improved vs. this, the error bars are still wide. In addition, we think the approach validates MDGL's, which has benefits in convenience (oral vs. subcu once daily) and safety."

'One of the most compelling approaches to treating NASH'

Turning to Madrigal, Schimmer pronounced MGL-3196 "one of the most compelling approaches to treating NASH in development," observing that the drug also has meaningful effect on LDL and triglycerides.

"Expectations into the NASH study biopsy data in May are very high; whether the drug can have a dramatic improvement in histology over 36 weeks is what investors are currently focused on," he wrote. "We're simply looking for evidence that the clinical signals are translating into histology benefit and that, over an extended period of time, we believe MGL-3196 can indeed become an important new therapy for NASH."

Top-line phase II data from Madrigal prompted the company's shares (NASDAQ:MDGL) to soar 88.3 percent, or $40.88, to close at $87.18 on Dec. 6, 2017. (See BioWorld, Dec. 7, 2017.)

The new EASL abstract showed that MGL-3196 prompted triglyceride reductions of 30.1 percent, LDL-C reductions of 12.9 percent and lipoprotein a, or Lp(a), reductions of 37.5 percent, all compared to placebo. Madrigal also reported liver enzyme reductions from baseline of 16.1 percent in ALT and 16.2 percent in AST. Even those scant updates were enough to give the company's shares a bit of lift, closing Wednesday at $109.28 for a gain of $4.73, or 4.5 percent.

Analysts were a bit flummoxed about data on the Gilead Sciences Inc. combination of farnesoid X receptor (FXR) agonist GS-9674 with acetyl-CoA carboxylase, or ACC, inhibitor GS-0976 (firsocostat) and internally developed apoptosis signal-regulating kinase, or ASK-1, inhibitor selonsertib.

"This was a highly anticipated data point given the potential read-through to GILD's ongoing phase III studies in [selonsertib], which are set to report data next year, and initial data in GS-9674," Schimmer wrote.

GS-9674 was picked up in 2015 from privately held Phenex Pharmaceuticals AG in a deal valued at up to $470 million, while GS-0976 was gained in the 2016 acquisition of Nimbus Apollo Inc., a wholly owned subsidiary of Nimbus Therapeutics, for $400 million up front and $800 million in development-related milestone payments. (See BioWorld Today, Jan. 7, 2015, and April 5, 2016.)

Seventy patients were treated with either monotherapy or different combinations of the three drugs during a 12-week study. The abstract showed that MRI-based proton density fat fraction (PDFF) reductions were significant, compared to baseline, for the '0976, '9674 and selonsertib+'0976 arms. However, none of the arms saw a significant reduction in magnetic resonance elastrography (MRE), which quantifies liver fibrosis, and ALT was decreased only in the selonsertib+GS-0976 arm.

"In addition, the combo studies with SEL generally seem less efficacious than the monotherapy results for GS-0976 or GS-9674," Schimmer wrote, though he acknowledged that patient numbers were small. RBC Capital Markets analyst Brian Abrahams had a more positive take on the findings, writing in a first glance that "overall, the abstract for phase II combo data from GILD's three NASH assets, selonsertib (ASK1), GS-0976 (ACC), and GS-9674 (FXR), supports possible activity of each of the components, demonstrates their potential combinability, and importantly shows no safety issues – in aggregate reaffirming the viability of their program, though not necessarily providing any definitive conclusions on how its overall efficacy will stack up long term."

The first clinical data on GS-9674 suggested the compound – previously written off by the Street, in the view of Abrahams – could be viable, with statistically significant 16 percent MRI-PDFF improvements, in a "generally comparable range to what OCA has shown," he observed. "However, this is hard to fully interpret without placebo, with positive signals on MRE and [liver function tests] offset by the fibrosis marker PIII-NP moving in the wrong direction both as monotherapy and when combined with selonsertib. Key will also be longer-term data and potential for safety differentiation," he added, since the abstract reported limited AE data.

The combo of selonsertib+0976 "generally looked more impressive than the selonsertib+9674 activity on imaging/biomarkers [but] we need more data to determine which dual (or triple) combos might be best," Schimmer added.

In other abstracts of interest, Jefferies' Yee pointed to data from Assembly Biosciences Inc. on ABI-H0731, a protein allosteric modulator, from an ongoing phase Ib study in healthy volunteers and noncirrhotic viremic participants with chronic hepatitis B virus (HBV). Safety has been clean, to date, and the drug showed up to 4-logs viral reduction DNA in a subset of HBV patients in the second and most recent cohort, results that topped those of competing phase I candidates, Yee said, such as Johnson & Johnson's JNJ-6379, a selective HBV replication inhibitor designed to inhibit both early and late stages of the viral life cycle.

Still to come at EASL are late-breakers from companies such as Cymabay Therapeutics Inc., Johnson & Johnson, Novartis AG and Roche Holding AG. The ILC begins April 11.