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Although no drug has been approved to treat non-alcoholic steatohepatitis (NASH), the clinical drug development landscape around the disease is maturing rapidly. Gilead Sciences Inc.and Intercept Pharmaceuticals Inc. are awaiting further readouts from Phase III NASH trials in the first half of 2019. Compounds in mid-stage trials have now demonstrated an ability to impact the disease in a short amount of time, and regulators have provided clarity around acceptable surrogate endpoints for early trials, which helps make trial design more efficient. As a result, companies are expanding their portfolios, contemplating combination drug strategies and eying new targets.

The field became more crowded in January, when Merck & Co. Inc.teed up its first clinical candidate, a compound acquired from NGM Biopharmaceuticals Inc.that targets fibroblast growth factor (FGF) receptor 1c. Two months after NGM’s November 2018 presentation of proof-of-concept clinical data for NGM313, Merck exercised its option to license the compound as part of a broad 2015 collaborative R&D agreement with NGMaround biologics that target pathways of metabolic regulation.[See Deal]“We made this first step into NASH, having been closely monitoring the field for the last several years,” said Eirum Chaudhri, global director of scientific affairs for hepatitis at Merck Research Laboratories.

“When we evaluated NGM313 a number of things stood out as very favorable,” Chaudhri said. “It does not appear to have an impact on FGF receptors 2c, 3c or 4, versus some of the other drugs similar in class to this drug,” she noted. The receptor specificity, the proportion of trial participants that had a liver fat reduction of 30% or more while on the drug, and the time to achieve that level of fat reduction with a single dose, as well as benefits in lipid profile, were the features that drove Merck to move forward with a licensing agreement, Chaudhri highlighted.

NGM also showed data from a Phase II trial of a more advanced FGF-targeting compound, NGM282, in November. Those results were striking in that the compound could move the needle on fibrosis in a matter of three months or so. “We never imagined that fibrosis had so much plasticity that you could have an impact in so short an interval,” said Scott Friedman, dean for therapeutic discovery and chief of the division of liver diseases, at the Icahn School of Medicine at Mount Sinai. But the dosing schedule is aggressive and the drug elevates LDL cholesterol, suggesting its best use may be as an induction therapy to be followed by maintenance with oral compounds that do not have the same lipid liability. Aiming for a more favorable lipid profile, Merck placed its bet on NGM313, now renamed MK-3655, and plans to take it into Phase IIb trials by year-end to assess the effect of the drug on liver histology and glucose control in NASH patients with or without diabetes. As is the case with many large pharmas focused on NASH drug development, it synergizes with Merck’s existing portfolio in diabetes – specifically GLP-1 agonists and SGLT2 inhibitors.

MK-3655 targets the metabolic component of NASH, which sets off the spectrum of non-alcoholic fatty liver disease (NAFLD) and NASH, Chaudhri said. Preventing that initial metabolic insult, which flows into programmed cell death, oxidative stress, inflammation and then fibrosis, is “the best opportunity currently in the NASH field to prevent the secondary downstream sequellae of the disease,” she commented. Plus, while NASH has an end-organ effect in the liver, it is really a systemic disorder. “It ties very much to metabolic dysregulation within the body,” she said. Two-thirds of diabetics, for example, will have some sort of underlying NAFLD or NASH. “The data shared in November showed at day 36 beneficial effects on the fat within the liver, but also that some of the glucose parameters [were] turning in a favorable direction.”

Other companies with a long-term history in obesity and diabetes that are leveraging assets in those disease areas into NASH include Novo Nordisk AS,Eli Lilly & Co.,Sanofi,Bristol-Myers Squibb Co.and the Janssen Pharmaceuticals Inc.unit of  Johnson & Johnson. Add to that large companies like Novartis AGand Pfizer Inc., which are working together on combination strategies in NASH and, along with Gilead, some with long-term programs for liver disease.[See Deal]“There is a lot of activity from companies coming in from different angles,” said Rohit Loomba, professor of medicine at theUniversity of California, San Diego, and founding director of the UCSD NAFLD translational research unit.

Gilead’s hopes that its lead NASH asset, selonsertib, could succeed as a stand-alone therapy were thwarted on February 11, when it disclosed that a Phase III trial in patients with compensated cirrhosis due to NASH failed to meet its primary endpoint: only 14.4% of patients treated at one dose of selonsertib and 12.5% percent of patients treated at another met the specified study goal, compared with 12.8% of patients who received placebo. (Also see "In NASH, Gilead Swung For The Fences And Struck Out Again" - Scrip, 12 Feb, 2019.) Gilead expects a readout from a second Phase III trial of selonsertib, an inhibitor of apoptosis signal-regulating kinase 1 (ASK1), in patients with bridging fibrosis (an earlier stage of disease) by mid-year. But even a successful outcome there would leave it with just a single positive pivotal trial to show regulators for approval.

Nonetheless, the company remains focused on patients with advanced fibrosis, who have the highest risk of clinical complications, and therefore on therapies that can regress fibrosis and combinations that can have a bigger depth or breadth of effect on fibrosis. “In this population, fibrosis is the greatest predictor of outcomes in clinical events,” noted Gilead’s executive director of fibrosis biology, David Breckenridge. That suggests a role both for direct anti-fibrotics and also for targets that are part of the underlying cause of the disease. “That is a lot of the rationale for our current combinations strategy going forward,” he said.

In addition to the Phase III selonsertib studies, Gilead has completed enrollment for a large Phase II trial (ATLAS) that is exploring the possible combinations of its three oral agents: selonsertib, GS-0976 (an acetyl-CoA carboxylase inhibitor) and GS-9674 (a farnesoid X receptor agonist). Selonsertib is home grown, while GS-0976 and GS-9674 were acquired from other companies.[See Deal][See Deal] ATLAS data are expected by year-end and will show the extent to which an ACC- or FXR-targeting drug can be used in combination with selonsertib.

FXR is the target for many compounds in trials for NASH including Intercept’s obeticholic acid (OCA). Intercept expects to announce top-line data from an interim analysis of its Regenerate pivotal trial of OCA by the end of March.

Gilead’s ATLAS study is a “comprehensive assessment of combination therapy and monotherapy approaches on biopsy and other plasma-based biomarkers in an international setting,” said Loomba, who is the study’s principal investigator.

“We believe that in this disease combinations will be necessary to increase the proportion of patients who will respond and to increase the magnitude of response in those patients,” added Gilead’s VP of clinical research, Rob Myers. “Our approach now is to wait until ATLAS study data become available end of this year. Then let the data guide us as to what regimen we take into Phase III.”

Parallels exist between NASH and idiopathic pulmonary fibrosis (IPF) drug development, in which two drugs with modest efficacy were approved in 2014, and none since. In both situations, a variety of phenotypes leads to fibrosis.

“We see a role for [drugs] that directly target that myofibroblast activation and the regulation of collagen turnover,” Breckenridge said. “Some of those are being tested in IPF and we see parallels to advanced fibrosis in NASH.” Also, to diabetic kidney disease, which shares core pathways with NASH and IPF. To that end, Gilead recently announced a collaboration with Scholar Rock Holding Corp. around compounds that target TGFβ complexes. It also recently announced a deal with Yuhan Corp. under which Gilead gained rights to additional undisclosed targets it believes are relevant to advanced fibrosis; to test that hypothesis further. [See Deal]

Metabolic targets like the TGFβ pathways may be relevant to earlier-stage disease because of the potential to improve lipids or glycemic control. They are also attractive from a development perspective because of the ability to get a quick readout of efficacy by measuring liver fat with MRI PDFF imaging, Myers noted. “In addition to targeting fibrosis directly, it makes sense to consider pathways important in driving disease progression,” he added. FGF21 is another metabolic target of interest to NASH drug developers. Akero Therapeutics Inc., which raised $135 million in two financings in 2018, licensed its lead FGF21 analog from Amgen Inc.last June. In October, 89Bio launched with a portfolio of small molecules licensed from Teva Pharmaceutical Industries Ltd., including an FGF21 analog, simultaneously raising $60 million in a series A round.[See Deal] FGF21 is predominantly produced by the hepatocytes in the liver and leads to improvement in liver homeostasis and also, in animal models, appears to improve metabolic activity. 

Glucagon receptor co-agonists (GLP-1/glucagon receptor co-agonism) and combinations of GLP-1 analogs and a liver-directed therapy are similarly attracting the interest of many companies – especially those with established franchises in diabetes and obesity. These include GLP-1 agonists such as Novo Nordisk’sVictoza(liraglutide) andOzempic(semaglutide) as well as SGLT2 antagonists. “All of them seem to have not only therapy benefits on the pathways but also elicit a weight loss which by itself is an important therapy in the management of NASH,” said Friedman. That weight loss does not have to be profound – maybe 5-10% of body weight – but it must be sustained.

GLP receptors exist in the gut and changes in conduction – and potentially the microbiome – may drive some of the signals that may be going to the liver from the gut. Co-agonists from Eli Lilly (LY3298176) and Sanofi (SAR438335) are in Phase II and Phase I trials, respectively, in other indications and three dual agents are verging on clinical development in NASH:Hanmi Pharmaceutical Co. Ltd.’s HM51211 is in Phase I whileVelocity Pharmaceutical Development LLC’s SP-1373 and Sanofi’s SAR425899 are preclinical.

For similar reasons, the microbiome will be a rich source of essential therapeutic targets, Friedman said, even if the translational payoff is yet to come. “We are beginning to draw the connection between how different bacteria affect signaling in the gut wall and their communication with the liver.”

Increasing understanding of the genetics in NASH is also guiding development of drugs against current or novel targets. PNPLA3 is one such target: downregulating it to block the accumulation of the protein related to PNPLA3 could improve steatohepatitis. Other siRNA-based inhibitors of metabolic pathways within the hepatocytes may also come in play in NASH drug development. “The field is moving into precision medicine and genomic targets would have a greater play,” Loomba said.Regeneron Pharmaceuticals Inc.discovered one genomic target – an HSD17B13 gene variant, the driver of a March 2018 collaboration withAlnylam Pharmaceuticals Inc.aimed at identifying RNAi therapeutics for NASH and other liver diseases.

Friedman holds hope for “a veritable Achilles heel” functionally, which if manageable with a drug, would stop the disease in its tracks. “It could be [from] the microbiome, it could be nuclear hormone signaling,” he said, but it was not likely to be an anti-fibrotic because fibrosis is a consequence of the chronic inflammation, cell injury and steatosis that characterizes NASH. “You have to look upstream at pathways that lead to damage to hepatocytes,” he noted. Thus far, “we don’t have that hierarchy, so everyone is taking an empiric belts-and-suspenders approach” to treatment.

As noted in a review of the NASH landscape published inIn Vivolast year, the best responses in Phase IIb trials are around 30-40% among treated patients and half as much among placebo – a strong placebo effect that is well documented. (Also see "NASH: Flying The Plane While Building It" - In Vivo, 25 Jul, 2018.) So at best, 65% of the population remains unaffected by drug. “Just as we wouldn’t accept this for essential hypertension or hypercholesterolemia I don’t think that’s anything close to a sufficient therapeutic endpoint but there’s clear evidence that drugs will work, setting the stage for continued improvement in response rates,” Friedman said. “The challenge with combinations is “we don’t have conceptually a clear hierarchy of which pathways drive other pathways.”

“It may be that certain types of patients, depending on their metabolic, inflammatory profile or degree of fibrosis, may benefit from a certain class versus another,” added Chaudhri. An end-state fibrotic patient with cirrhosis and liver decompensation who is close to getting on a transplant list will benefit more from an anti-fibrotic therapy versus a metabolic or an anti-inflammatory. The liver tends to burn out in terms of inflammation over time as that scarring builds and builds and gets to that point of no return. “That heterogeneity in NASH, proceeding from the metabolic to the end-stage disease, may drive what drug to give,” she highlighted. “It’s less about best-in-class and more about what is best for a given patient.”

[Editor's note: An earlier version of this article implied that NGM313/MK-3655 elevates LDL cholesterol. That comment referred to data from NGM282 and has been corrected.]

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