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by Multiple Authorship | December 15th, 2018

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Multiple Drugs Advance for Fatty Liver Disease

Laird Harrison

November 13, 2018

SAN FRANCISCO — Although numerous drugs for nonalcoholic steatohepatitis (NASH) have shown positive results in phase 2 clinical trials, the cure might lie in combinations of drugs with different mechanisms, experts say.

In fact, curing NASH might turn out to be as challenging as curing type 2 diabetes, said Sidney Barritt IV, MD, from the University of North Carolina at Chapel Hill.

Unlike hepatitis C, which can be treated with the blockbuster antiviral drugs that have recently proven so effective, NASH is more complicated because there are no effective drugs to treat it.

With the obesity epidemic, NASH is increasingly common, and results from phase 2 trials attracted throngs of conference-goers with questions here at The Liver Meeting 2018.

Some of the results look encouraging, Barritt told Medscape Medical News. "I think they're clinically significant."

Phase 2 results have been positive for MGL-3196 (Madrigal Pharmaceuticals), GS-9674 (Gilead Sciences), NGM282 (NGM Bio), arachidyl amido cholanoic acid (Aramchol, Galmed Pharmaceuticals), tropifexor (Novartis), and VK2809 (Viking Therapeutics).

All the drugs reduced liver fat measured with MRI-derived proton density fat fraction (PDFF). The drugs also improved various other measures of the disease, such as NASH Activity Score, fibrosis, and alanine aminotransferase.

These NASH agents add to the four already in phase 3 trials: obeticholic acid (Ocaliva, Intercept Pharmaceuticals), elafibranor (Genfit), selonsertib (Gilead), and cenicriviroc (Tobira Therapeutics).

But no clear winner has emerged from these studies. It's hard to know how well the biomarkers measured in trials will protect patients from sickness and death, Barritt explained. NASH destroys the liver gradually; most of its victims die from the heart disease or cancer that results from this damage, which takes decades.

The real test is going to be real-world efficacy. Are the drugs going to have the impact that we expect them to have based on the clinical trial data?

"The real test is going to be real-world efficacy," he said. "Are the drugs going to have the impact that we expect them to have based on the clinical trial data?"

The development of NASH is mostly related to lifestyle factors, such as overeating and lack of exercise, so there is no obvious target for a drug as there is with a virus. As a result, drug makers have focused on various aspects of inflammation, fat accumulation, and scar formation.

Like obeticholic acid, GS-9674 and tropifexor are farnesoid X receptor (FXR) agonists, which help regulate bile acids, carbohydrate and lipid metabolism, and insulin sensitivity. They also play a role in growth and regeneration after liver injury.

MGL-3196 and VK2809 are thyroid hormone-receptor beta agonists designed to mediate the effects of the thyroid hormone on the liver, on low-density-lipoprotein cholesterol, on triglycerides, on fatty liver, and on insulin sensitivity.

Arachidyl amido cholanoic acid inhibits stearoyl CoA desaturase. It has a "dual mode of action on liver fibrosis, downregulation of steatosis, and a direct effect on hepatic stellate cells, the human collagen-producing cells," according to Galmed Pharmaceuticals.

The potential for all these approaches was evident in the phase 2 results presented. But the most effective treatments might be a combination of drugs that act on different pathways, said Keyur Patel, BM, from Duke University in Durham, North Carolina, who is a GS-9674 investigator.

In a separate phase 2 trial now underway, Gilead is testing the combination of GS-9674 plus selonsertib, a small-molecule inhibitor of apoptosis signal-regulating kinase 1 (ASK1), plus GS-9676, an acetyl-CoA carboxylase inhibitor, Patel told Medscape Medical News.

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Early Transplant in Alcoholic Hepatitis Feasible

  • by Michael Smith, North American Correspondent, MedPage Today October 23, 2017
  • WASHINGTON -- Selected patients with a failing liver owing to alcoholic hepatitis, but who have not been abstinent for several months, can still have "acceptable" short-term survival after transplant, a researcher said here.

In a retrospective analysis of patients in 12 transplant centers, 1-year survival was 94% over a median follow-up of 1.6 years, according to Brian Lee, MD, of the University of California San Francisco.

But the survival rate fell to 84% after 3 years, largely owing to continued alcohol use after the transplant, Lee said at the Liver Meeting, the annual conference of the American Association for the Study of Liver Diseases (AASLD).

"Sustained alcohol was the strongest predictor of post-transplant death," Lee said.

There are no effective therapies for long-term survival in severe alcoholic hepatitis, which has about a 70% mortality rate after 6 months, Lee noted. A transplant can be life saving, he added.

But most U.S. centers won't perform a transplant unless the patient has been abstinent for at least 6 months, although there is recent research suggesting that an early procedure -- ignoring the 6-month rule -- can be beneficial in selected patients.

 

 

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Concierge Medicine:  6-11-2017

The day after my friend sent me a link to this NY Times article: https://www.nytimes.com/2017/06/03/business/economy/high-end-medical-care.html , I met a real life concierge internist at a meeting. Full disclosure, I told him that I ran a website FindADoc.Com and that concierge physicians looking to attract patients could do worse that become Featured Docs on FindADoc. He has a patient base of 200 souls and charges $3000 a year, which I quickly translated to $600k a year. He has minimal overheads. No nurses, NP or PA. Patients have direct access to his cell phone 24/7. When I told him about this article, and the fact that the charge is up to $80,000 a patient or family, I could feel his jaw drop as he made the quick calculation!

In truth, this really is nothing new. At a well-known hospital in the Upper East Side, NY, much larger sums of money change hands, just not quite like that, or so openly. For $700m, you can build a new Pavillion with your name on it. Or for $300 million, change the name of the hospital and medical school to yours! That way, when you call up with an ingrowing toe-nail, guess how long you mind have to wait to have it fixed!!

 

 

The Obesity Epidemic

The obesity epidemic now involves all 50 States and most of the globe. Tme metabolic syndrome is the most common manifestation of this epidemic.

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