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Novel Thyroid Beta Receptor Agonist Cut LDL-C in NAFLD Patients

<ѻý class="mpt-content-deck">— Small phase II study also found reductions in liver fat vs placebo
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SAN FRANCISCO -- Patients with non-alcoholic fatty liver disease and hypercholesterolemia who were treated with a novel, liver-directed thyroid beta receptor agonist had significant declines in low-density lipoprotein (LDL) cholesterol compared with a placebo group, according to a small phase II study presented here.

All patients randomized to receive the treatment -- called VK2809 -- either once daily or every other day were linked with about a -22% placebo-adjusted change in LDL cholesterol at week 12, reported Rohit Loomba, MD, of the University of California, San Diego.

At a late-breaking trial presented at The Liver Meeting, the annual meeting of the American Association of the Study for Liver Diseases (AASLD), he explained that beta receptors play a key role in lipid metabolism, but that the receptor is localized to the liver, with in-vivo evidence suggesting that beta activation provides anti-fibrotic effects.

"An agent that reduces liver fat, improves systemic lipids, and antagonizes fibrotic signaling could provide multi-pronged benefits in non-alcoholic steatohepatitis [NASH]," Loomba said.

Moreover, this novel prodrug "has good liver selectivity," he added -- with preclinical models showing an accumulation of the drug primarily in the liver, not the heart or brain.

"Selected activation and differentiation chemistry provides this agent liver-targeted sensitivity and potentially reduces the risk of systemic effects," he noted.

In a separate video interview commenting about various drugs in development to treat non-alcoholic fatty liver disease, Scott Friedman, MD, of the Icahn School of Medicine at Mount Sinai in New York City, told ѻý that drugs that reduce liver fat by activating the thyroid hormone receptor beta "look extremely promising because they both reduce liver fat and they also improve serum lipids."

"As most clinicians know, patients with NASH have a systemic disease of metabolic syndrome with hyperlipidemia, and in fact the leading cause of death in patients is cardiovascular disease, so drugs that can improve the lipid profile at the same time as they can improve the fat content in the liver are especially appealing," Friedman said.

The study by Loomba's team assessed the safety and efficacy of the drug in reducing LDL cholesterol and as a secondary endpoint, magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) reduction images. Patients were randomized to receive either 10 mg orally of the drug daily, every other day, or placebo. MRI-PDFF was performed after 12 weeks of treatment. There were 32 patients -- 16 in each treatment group -- randomized to treatment at baseline, with 15 randomized to placebo.

Patients were eligible for inclusion if they had LDL cholesterol ≥110 mg/dL, liver fat content ≥8% by MRI-PDFF, and triglycerides ≥120 mg/dL, with a body mass index of 18.5 to 40, free triiodothyronine, free thyroxine, and thyroid-stimulating hormone within normal range.

Overall, patients were a mean age of about 50, about 60% were men, and a large majority were white. Liver fat was slightly lower in the placebo arm (MRI-PDFF 13% in placebo versus around 18% in treatment groups), Loomba noted.

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

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

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

Other secondary outcomes included significant reductions in lipoprotein(a), which may be a marker for the risk of developing heart disease, and apolipoprotein B (the primary protein in LDL cholesterol) at 12 weeks for the treatment group versus placebo. Loomba said this potentially suggested some cardiovascular benefit to the treatment if it was continued.

Examining safety, there was no significant difference between the treatment arms, no serious adverse events in any arm, and "excellent GI tolerability," Loomba noted.

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

A study in biopsy-confirmed NASH patients is underway, Loomba said. He added that a second MRI-PDFF was performed 4 weeks after completion of the study, and the team is analyzing that data to gauge durability of response, and plan to submit this to the next European Association for the Study of the Liver International Congress.

Developer Viking Therapeutics said it's also pursuing studies of VK2809 in glycogen storage diseases.

Disclosures

Loomba disclosed support from Gilead, Merck, Intercept, NuSirt, Genfit, Promedior, 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, Glympse bio, Cymabay, Ionis, CohBar, Bird Rock Bio, Cirius Consulting. and Viking Therapeutics.

Friedman disclosed 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.

Primary Source

American Association for the Study of Liver Diseases

Loomba R, et al “VK2809, a Novel Liver-Directed Thyroid Receptor Beta Agonist, Significantly Reduces Liver Fat in Patients with Non-Alcoholic Fatty Liver Disease: A Phase 2 Randomized, Placebo-Controlled Trial” AASLD 2018; Abstract LB-4.