Novel Beta Receptor Agyist Thyroid Cutting LDL-C in NAFLD Patients


SAN FRANCISCO – Patients with non-alcoholic fatty liver disease and novel hypercholesterolemia, beta-directed beta thyroid receptors in the liver experienced a significant decrease in low-density lipoprotein (LDL) cholesterol compared to the placebo group, according to the phase II study presented here .

All patients randomized to receive treatment – called VK2809 – either daily or every day were associated with about -22% placebo-adjusted changes in LDL cholesterol at 12 weeks, according to Rohit Loomba, MD, of the University of California. , San Diego.

In a solitary trial presented at The Liver Meeting, the annual meeting of the American Association of Study for Liver Diseases (AASLD), he explained that beta receptors play a key role in lipid metabolism, but these receptors are localized to the liver, with in-vivo evidence showing that Beta activation provides anti-fibrotic effects.

"Agents that reduce liver fat, increase systemic lipids, and antagonize fibrotic signaling can provide multi-branch benefits in non-alcoholic steatohepatitis [NASH], "Loomba said.

In addition, the new prodrug "has good heart selectivity," he added – with preclinical models that show drug accumulation, especially in the liver, not the heart or brain.

"Selected activation and differentiation chemistry provides sensitivity targeted at the liver and has the potential to reduce the risk of systemic effects," he said.

In a separate video interview commenting on various drugs in development to treat non-alcoholic fatty liver disease, Scott Friedman, MD, of the Icahn Medical School on Mount Sinai in New York City, said MedPage Today that drugs that reduce liver fat by activating beta thyroid hormone receptors "look very promising because they reduce liver fat and they also improve serum lipids."

"As most doctors know, patients with NASH have systemic metabolic syndrome with hyperlipidemia, and actually the main cause of death in patients is cardiovascular disease, so drugs that can increase lipid profiles at the same time because they can increase fat content in the liver is very interesting, "Friedman said.

Research by the Loomba team assessed the safety and efficacy of the drug in reducing LDL cholesterol and as a secondary endpoint, images of weight reduction in magnetic proton fat fraction (MRI-PDFF). Patients were randomly assigned to receive 10 mg of oral medication every day, every day, or placebo. MRI-PDFF is done after 12 weeks of treatment. There were 32 patients – 16 in each treatment group – randomized to treatment at baseline, with 15 randomly assigned to placebo.

Patients were eligible to be included if they had LDL cholesterol 10110 mg / dL, liver fat levels ≥8% by MRI-PDFF, and triglycerides 20120 mg / dL, with a body mass index of 18.5 to 40, free triiodothyronine, free thyroxine and thyroid stimulating hormone in the normal range.

Overall, the patients were an average age of around 50, about 60% were male, and most were white. Liver fat was slightly lower in the placebo arm (MRI-PDFF 13% in placebo versus about 18% in the treatment group), Loomba noted.

LDL cholesterol was significantly lower in the treatment group after 12 weeks (around -24% in the group every day and around -20% in the daily group).

Patients in both treatment groups were associated with a significant 58% relative change in liver fat by MRI-PDFF at 12 weeks compared with placebo, with Loomba characterizing the decline as "one of the most significant reductions we noticed in the 12-week trial with oral therapy. "

In addition, he noted that up to 91% of patients (in the treatment group every day) had a response (defined as a reduction of ≥30% liver fat at 12 weeks) compared with 18% of the placebo group.

Other secondary results included a significant reduction in lipoprotein (a), which could be a marker for the risk of developing heart disease, and apolipoprotein B (the main protein in LDL cholesterol) at 12 weeks for the treatment group compared to placebo. Loomba said this could potentially suggest some cardiovascular benefits in treatment if continued.

Checking safety, there were no significant differences between the treatment groups, no serious side effects on any arm, and "excellent GI tolerability," Loomba said.

In addition, the mean levels of alanine aminotransferase and aspartate transaminase in patients treated with VK2809 decreased compared with placebo at week 12, and no other liver function tests were significantly different, the authors said. There are also no changes in cardiovascular safety markers, or changes in body weight, pulse, or blood pressure observed between groups.

A study in NASH patients was confirmed by a biopsy being carried out, Loomba said. He added that the second PDFF MRI was carried out 4 weeks after the completion of the study, and the team analyzed the data to measure the durability of the response, and planned to submit this to the next European Association for the International Heart Congress Study.

Viking developer Therapeutics said it was also pursuing the VK2809 study in glycogen storage disease.

Loomba revealed support from Gilead, Merck, Intercept, NuSirt, Genfit, Promoter, Kinemed, Adheron, Allergan, Immuron, Galmed, Intercept, Arisaph, Shire, BMS, Galectin, Immuron, NGM, Siemens, Eli Lilly, GE, Octeta, Gemphire , Arrowhead Research, Second Genome, Median Technologies, Conatus, Novo Nordisk, Pfizer, Celgene, Boehringer Ingelheim, Metacrine, CohBar, GNI, GRI, Bio Olympics, Cymabay, Ionis, CohBar, Bio Bird Rock, Cirius Consulting. and Viking Therapeutics.

Friedman revealed support from Contravir, Gemphire, Cisbio, Nitto, Forbion, RiverVest, Scholar Rock, Northern Biologics, XTuit Pharmaceuticals, Takeda, Allergan, Symic Bio, Galmed, Bristol Myers Squibb, Metacrine, Genfit, Metagenix, Viking Therapeutics, Boehringer Ingelheim, Cirius Therapeutics, Blade Therapeutics, Surrozen, Enanta, Angion Biomedica, Madrigal, Affimune, DeuteRx, Vivace Therapeutics, Jecure Therapeutics, Kallyope, AbbVie, Lexicon, Zafgen, 3V Bio, Axcella Health, North Sea Therapeutics, Glycotest, Salix, Escient Therapeutics, Arbutus, Lifemax Laboratories, Galectin Therapeutics, Arrowhead, CymaBay, Perspectum, Avaliv Therapeutics, VL45 Biotech, Morphic Rock Therapeutics, Exalenz Biosciences, Novartis, Revive Therapeutics, NGM, Inception Biosciences, Glympse Bio, Five Prime Therapeutics, Novo Nordisk, Seal Rock Therapeutics , Janssen, Can-Fite Biopharma, Second Genome, Pfizer, and Fortress Biosciences.

2018-11-13T15: 15: 00-0500


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