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  Fatty Liver Disease

Merck NASH
  EASL: Serum Cholesterol Changes Associated with NGM282 Treatment in Obese Insulin Resistant Cynomolgus Monkeys and NASH Patients are Reversed with Lipid Lowering Agents - (04/24/17)
EASL: NGM282, a Novel Variant of FGF19, Significantly Reduces Hepatic Steatosis and Key Biomarkers of NASH: Results of a Phase 2, Multicenter, Randomized, Double-Blinded, Placebo Controlled Trial in Biopsy-Confirmed NASH Patients - (04/24/17)
Merck-backed NGM Bio hits its marks in midstage NASH trial

by Ben Adams |
Apr 24, 2017
Fierce 15 company NGM Bio says it met its primary endpoint of reducing liver fat in NASH patients, with hints of antifibrotic activity, as the small biotech looks to get into the mix with its big biopharma rivals for a blockbuster market.
The Bay Area biotech presented its data at this year's International Liver Congress (ILC) in Amsterdam alongside the likes of Bristol-Myers Squibb and Gilead, which among a host of other companies are looking to reduce liver fat and scarring in the livers of patients, who are typically overweight or medically obese, and often have Type 2 diabetes.
In some patients, liver fat can lead to liver damage, scarring, and potentially cirrhosis and eventually liver failure (and sometimes liver cancer); it's predicted by some to become the number one medical reason for liver transplants by 2050, replacing hep C and alcoholism, and could affect as many as 400 million people around the world. There are no marketed meds for the condition, and analysts have said a future market could be worth tens of billions of dollars to those who get it right; NGM Bio is hoping to be one of these winners.
The biotech says its lead product candidate, the injectable NGM282, met its primary endpoint of reducing liver fat, as evidenced by the use of magnetic resonance imaging-estimated proton density fat fraction, with the 3-mg and 6-mg dose groups lowering absolute liver fat content by 9.7% and 11.9%, respectively, against a dummy treatment over 12 weeks.
Of the small batch of 53 patients (across both doses) treated with NGM282, 34% reached a normal liver fat content, with the greatest effect seen in those with the highest baseline liver fat content and most active disease. In all, 79% of patients in the study met its primary endpoint of a reduction of at least 5% in liver fat.
NGM282, a nontumorigenic, engineered variant of the human hormone FGF19, also showed a hint of ability to improve scarring, although it also came with a spike in cholesterol levels, something also seen in some other NASH studies. This will remain a concern given that many patients with NASH will also be at high risk of CV disease.
Jeff Jonker, the biotech's president, told FierceBiotech that although the study was not powered to see an improvement in fibrosis, "biomarkers of fibrosis were examined as exploratory endpoints in the study and we see statistically significant results from several."
Fibrosis will likely prove to be a major factor in NASH when it comes to the market, alongside reducing liver fat (which will not always lead to scarring and inflammation), as liver fat can also be reduced in some patients in its early stages with diet and exercise. Jonker said that the biotech did however see "statistically significant changes in two key markers of liver fibrosis (PIIINP and TIMP-1) in our phase 2 study at both doses. Decreases in both of these markers are associated with fibrolytic activity. Additionally, decreases in the overall Enhance Liver Fibrosis (ELF) Score were seen at both doses, with statistical significance achieved with the 3-mg dose." But, as yet, both PIIINP and TIMP-1 are not widely accepted as being surrogates for NASH scarring.
But Jonker explained that, because excess fat in the liver is "the precipitating event or insult that drives inflammation and cellular damage in the liver, which in turn drives fibrosis and ultimately cirrhosis, NGM282 works to arrest this entire cascade of NASH activity."
He says this study "confirms that NGM282 reverses steatosis and improves markers of inflammation and fibrosis, thereby warranting further development in NASH."
It is however behind front-runners Genfit, a French biotech, and Intercept, with other drugs from BMS, Gilead, Novartis and Allergan also in the mix.
NGM designed the molecule to maintain the biological activity of FGF19, which modulates two receptors: FGFR4, a primary regulator of bile acid synthesis in the liver, and FGFR1c, a signaling receptor in metabolic processes in adipose tissue (peripheral fat) that regulates de novo lipogenesis, glucose homeostasis and body weight.
The biotech hopes NGM282's activity on those receptors make it a powerful and direct modulator of multiple pathways that are key to the development and progression of NASH. Jonker explains, however, that the industry largely stopped work on FGF19 in the early 2000s, when animal studies of FGF19 identified the hormone drives tumor formation in rodents.
"But our research revealed the mechanism by which endogenous FGF19 induces hepatocellular carcinoma in those animal models," he says. "The insights gained from substantial in-house research led us to design NGM282 to eliminate the FGF19 signaling activity behind the tumorigenic properties seen in mice while retaining the biologic activity of the human hormone on bile acid synthesis and metabolic regulation."
Other companies are taking a different approach: Intercept's obeticholic acid (OCA) is an agonist of the farnesoid X receptor (FXR), which is a nuclear receptor. FXRs like OCA (there are many in development in the industry, including at Gilead, Novartis and Allergan) turn on as many as 100 different genes, "though their mechanism of action in NASH appears to be primarily through the upregulation of FGF19," Jonker says.
"As such, FXRs are activating the same mechanisms (FGFR4 and FGFR1c) as NGM282, but at a much lower level of FGF19 upregulation."
Genfit's elafibranor, meanwhile, is a dual PPAR receptor agonist that aims to modulate targets that play a role in various aspects of metabolic syndrome.
Over the last few days, both Gilead and BMS posted data from their candidates in NASH at ILC, with broadly similar results. Gilead's GS-0976, which the Big Biotech acquired from Nimbus Therapeutics in a $1.2 billion deal signed last year, showed in a small and open-label test-involving just 10 patients-that GS-0976 was able to block the formation of new fat in the liver (de novo lipogenesis) by 29% over the 12-week study period.
The drug also achieved a sizable 43% reduction in liver fat by the end of the trial, although the data on liver fibrosis (scarring) was marginal. Using a biomarker for fibrosis (liver stiffness), patients on GS-0976 showed a decline from 3.4 to 3.1 kPa at week 12, but this was just barely statistically significant.
BMS, meanwhile, posted data for its 16-week, 74-patient trial for the subcutaneously injected pegylated analogue of human fibroblast growth factor 21 BMS-986036, at two dosing regimens versus placebo.
Both the 10-mg dose given daily and a high 20-mg once-a-week injection hit its marks of significantly reducing liver fat: by 6.8% with the daily injections and 5.2% for the weekly dose, compared with 1.3% for a placebo.
Its candidate, licensed from Ambrx, also reduced biomarkers for fibrosis, as well as measures of liver stiffness and enzymes indicative of liver injury.
While not having the financial thrust of these rivals, NGM Bio is set up nicely for future trials, given its substantial backing from a five-year deal with Merck, as well as a host of VCs, and a phase 2b study with NGM282 is already planned.
Jonker says: "Given both the magnitude of effect seen in the phase 2 trial and the relatively short 12 weeks needed to achieve that improvement in liver fat, we're consulting hepatology community leaders and regulators to design the next trial to assess the full impact of NGM282 after an appropriate duration of treatment.
"The next trial will be a phase 2b with histology endpoints to measure change from baseline in nonalcoholic fatty liver disease activity score, improvement in fibrosis without worsening of NASH and/or NASH resolution without worsening of fibrosis." Jonker said he has not, however, committed to "a specific timeline" on the study. As with Genfit and more recently Intercept, Jonker says that NGM's plan is also "to use the standard for 'NASH resolution' that has been endorsed by both the FDA and the Liver Forum" in future tests.
Jonker says that NGM is "fortunate to have the capital and capabilities to rapidly progress NGM282 in NASH, and that is exactly what we are doing."
He added, however, that "we are aware that bringing NGM282 to market will require substantial late-stage development and commercialization expertise and infrastructure. We're considering a full range of options for NGM282 to optimize the value of this compound. Above all, we want to ensure this drug candidate is given every opportunity to deliver its full potential benefit for patients with NASH."
Questions abound, however, over the future of NASH treatments in general at this early stage, and ahead of last weekend's congress, analysts at Bernstein put out a primer on the condition, saying: "We see commercialization [of NASH drugs] as highly challenging. Diagnosis is currently tied to liver biopsy; there are no 'easy' measures of treatment effectiveness (like HbA1c, total cholesterol or blood pressure). Broad acceptance of less invasive disease markers is still years' away.
It added that "treatment benefit for most patients is questionable," and that the "disease will remain asymptomatic in the vast majority of patients." It sees the "success case" for the market as being around $7 billion in global sales by 2025.
Better administration will also likely be needed, given that NGM's candidate is injected; oral meds or ones requiring fewer injections will probably become more attractive to patients, especially in the Type 2 diabetes population who are already injecting drugs such as GLP1s or insulin.
NGM and Merck Announce Broad Strategic Collaboration to Discover, Develop and Commercialize Novel Biologic Therapeutics
Partnership Combines NGM's Unique Biology-focused Research Platform with Merck's Late-stage Clinical and Commercialization Strengths to Discover Medicines for Serious Diseases

SOUTH SAN FRANCISCO, Calif. & KENILWORTH, N.J., February 23, 2015--(BUSINESS WIRE)-- NGM Biopharmaceuticals, Inc., a privately-held biotechnology company and Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced they have entered into a multi-year collaboration to research, discover, develop and commercialize novel biologic therapies across a wide range of therapeutic areas. This agreement will become effective upon the expiration of the waiting period under the Hart-Scott-Rodino Antitrust
Improvements Act.
"We are very pleased to establish this alliance with Merck, which will be transformational for NGM, providing us with the resources and flexibility to pursue our ambitious research and development goals while preserving our unique drug discovery culture," said William J. Rieflin, Chief Executive Officer of NGM. "We look forward to working with Merck to generate a robust pipeline of therapies with the potential to make a significant difference in the lives of patients."
"NGM has developed a uniquely powerful research program that has permitted identification of novel, and quite consequential, pathways for metabolic regulation," said Dr. Roger M. Perlmutter, President of Merck Research Laboratories. "Through this new collaboration, we hope to apply Merck's well-established translational capabilities to advance innovative biologics that address the needs of patients suffering from diabetes, metabolic dysregulation, and malignancy."
The collaboration includes multiple drug candidates currently in preclinical development at NGM, including NP201, which is being evaluated for the treatment of diabetes, obesity and nonalcoholic steatohepatitis (NASH). NGM will lead the research and development of the existing preclinical candidates and have the autonomy to identify and pursue other discovery stage programs at its discretion. Merck will have the option to license all resulting NGM programs following human proof of concept trials. If Merck exercises this option, Merck will lead global product development and commercialization for the resulting products, if approved.
Under the terms of the agreement, Merck will make an upfront payment to NGM of $94 million and will purchase a 15 percent equity stake in NGM for $106 million at a price per share that represents a 20 percent premium to NGM's most recent financing. Merck will commit up to $250 million to fund all of NGM's efforts under the initial five-year term of the collaboration, with the potential for additional funding if certain conditions are met.
Prior to Merck initiating a Phase 3 study for a licensed program, NGM may elect to either receive milestone and royalty payments or, in certain cases, to co-fund development and participate in a global cost and revenue share arrangement of up to 50 percent. The agreement also provides NGM with the option to participate in the co-promotion of any co-funded program in the United States. Merck will have the option to extend the research agreement for two additional two-year terms.
"This collaboration brings together our biology-driven research and development product platform with Merck's late-stage development and commercialization expertise, while also enabling NGM to explore exciting new drug targets," commented Dr. Jin-Long Chen, Founder and Chief Scientific Officer of NGM. "Both companies' commitment to scientific excellence and willingness to creatively combine our strengths was key to establishing this relationship."
NGM's lead program, NGM282, currently in clinical development for primary biliary cirrhosis (PBC) and NASH, as well as programs that are the focus of NGM's pre-existing collaboration agreements, are not subject to the option under the Merck collaboration.
NGM Conference Call Information
NGM will host a conference call and live audio webcast today at 9:30 a.m. ET. To participate in the conference call, please dial 1-877-930-8423 (domestic) or 1-253-642-1003 (international) and refer to conference ID 89756919. The live webcast can be accessed via http://edge.media-server.com/m/p/x7uj3857.
The archived webcast will be available on the Company's website, www.ngmbio.com, beginning approximately two hours after the event.
About NGM Biopharmaceuticals
NGM Biopharmaceuticals is a private biopharmaceutical company using a biology-centric approach to create novel biologics for the treatment of a broad spectrum of life-threatening diseases. NGM's lead compound, NGM282, is in a Phase 2b study for the treatment of PBC. NGM282 has received Orphan Drug Designations in the U.S. and EU, and has been granted Fast Track Designation for PBC by the U.S. Food and Drug Administration. NGM has established collaborations with Merck, MedImmune, Daiichi Sankyo and JDRF. NGM is financed by The Column Group, Prospect Ventures, Rho Ventures, Tichenor Ventures, Topspin Ventures and other leading investors around the world. For more information, please visit www.ngmbio.com.
About Merck
Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube.
Merck Forward-Looking Statement
This news release includes "forward-looking statements" within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of Merck's management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline products that the products will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.
Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; Merck's ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of Merck's patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck's 2013 Annual Report on Form 10-K and the company's other filings with the Securities and Exchange Commission (SEC) available at the SEC's Internet site (www.sec.gov).