VK2809 A PHASE 2B, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER STUDY TO ASSESS THE EFFICACY, SAFETY, AND TOLERABILITY OF VK2809 ADMINISTERED FOR 52 WEEKS FOLLOWED BY A 4-WEEK OFF-DRUG PHASE IN SUBJECTS WITH BIOPSY PROVEN NON-ALCOHOLIC STEATOHEPATITIS WITH FIBROSIS - VOYAGE

Start Date16 Feb 2021

Sponsor / Collaborator

Viking Therapeutics, Inc.

NCT04173065 / CompletedPhase 2

VK2809 A Phase 2B, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Assess the Efficacy, Safety, and Tolerability of VK2809 Administered for 52 Weeks Followed by a 4-Week Off-Drug Phase in Subjects With Biopsy Proven Non-Alcoholic Steatohepatitis With Fibrosis

The study includes 52 weeks, double-blind treatment period. Clinic visits will occur at Randomization and every four weeks from Week 4 through Week 52 and through End of Study period. The study includes a post-dosing study visit that will occur 4 weeks after the last dose of study drug. This visit represents the End-of-Study Visit (Week 56 Visit). Three hundred thirty-seven subjects will be enrolled into five treatment arms and there will be an equal distribution of males and females in each treatment arm. Subjects will be stratified by gender, fibrosis stage, and diabetes status.

Start Date15 Nov 2019

Sponsor / Collaborator

Viking Therapeutics, Inc.

NCT02927184 / CompletedPhase 2

A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Assess The Efficacy, Safety, and Tolerability of VK2809 Administered for 12 Weeks Followed by a 4-Week Off-Drug Phase in Patients With Primary Hypercholesterolemia and Non-Alcoholic Fatty Liver Disease

This study will investigate the efficacy, safety, and tolerability of VK2809 in lowering LDL-C and liver fat content in patients with primary hypercholesterolemia and fatty liver disease. The primary efficacy endpoint is percent change from baseline LDL-C at the end of the treatment period (Week 12). Secondary endpoints include effects on liver fat content and other liver and lipid markers, as well as effects on safety and tolerability, and pharmacokinetic (PK) measurements.

Start Date28 Sep 2016

Sponsor / Collaborator

Viking Therapeutics, Inc.

100 Clinical Results associated with MB-07811

100 Translational Medicine associated with MB-07811

100 Patents (Medical) associated with MB-07811

Literatures (Medical) associated with MB-07811

01 Sep 2023·Journal of pharmaceutical and biomedical analysis

Development and validation for bioanalysis of VK2809, its active metabolite VK2809A and glutathione-conjugated metabolite MB06588 in rat liver using LC-MS/MS

Article

Author: Wang, Jiankun ; Jin, Hao-Wen ; Zhang, Yu ; Xie, Tao ; Zhen, Le ; Jin, Xin ; Xu, Bi-Xin ; Wang, Guangji ; Xu, Si-Tao

VK2809 is a promising drug candidate in Phase II clinical trials for the treatment of non-alcoholic steatohepatitis (NASH). It is a prodrug with a HepDirect strategy, which can achieve selective hepatic metabolic activation, generating an active metabolite VK2809A as a potent and selective agonist for thyroid hormone receptor beta (TRβ), a concomitant reactive metabolite VK2809B, and a glutathione (GSH) conjugate MB06588. Currently, there is no convenient and sensitive bioanalytical method for the simultaneous determination of the above three metabolites. Herein, we established an LC-MS/MS method to separate VK2809 and its metabolites on the XSelect HSS T3 column and quantified them in negative electrospray ionization mode. Subsequently, several factors were investigated such as the use of 60% acetonitrile for homogenization to stabilize the analytes, the addition of 20 mM glutathione for the derivation of VK2809B, and the protein precipitation with methanol containing Sobetirome as the internal standard (IS). The method exhibited good linearity for all compounds (19.4-388.4 nM for VK2809; 27.4-2744.4 nM for VK2809A and 10.6-211.0 nM for MB06588) with great correlation coefficients (r > 0.996). The method validation also demonstrated acceptable precision (RSD < 13.0% for VK2809, RSD < 7.9% for VK2809A, RSD < 14.4% for MB06588) and accuracy (92.7%-103% for VK2809, 91.2%-107.3% for VK2809A, 96%-106.7% for MB06588). The matrix effect, recovery, and stability were also suitable to determine all the analytes. This method is suitable for the bioanalysis of VK2809 and its metabolites and has been successfully applied to the study of intrahepatic exposure in rats. It is expected to be further practiced in drug design, optimization, and metabolism study in the following research.

03 Sep 2022·Expert review of endocrinology & metabolism

Thyroid hormones as a disease modifier and therapeutic target in nonalcoholic steatohepatitis

Review

Author: Puengel, Tobias ; Tacke, Frank ; Spranger, Joachim ; Wirth, Eva K.

INTRODUCTION:

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide and closely interconnected to the metabolic syndrome. Liver-specific and systemic signaling pathways orchestrating glucose and fatty acid metabolism contribute to intrahepatic accumulation of lipids and inflammatory processes eventually causing disease progression to nonalcoholic steatohepatitis (NASH), liver fibrosis, and cirrhosis. Since a high number of key regulatory genes regarding liver homeostasis are directly mediated via thyroid hormone (TH) signaling, targeting TH receptors (TRs) represent a promising therapeutic potential for the treatment of NAFLD.

AREAS COVERED:

In this review, we elucidate the effects of TH on metabolic regulations in the liver via local availability and actions. We discuss recent advances and the potential impact of thyromimetics in basic research and clinical trials including liver-targeted and TRβ-specific agents for the treatment of NAFLD.

EXPERT OPINION:

Unselective TR targeting can be accompanied by negative side effects due to high TRβ expression in other organs and TRα-mediated effects. Recent advances in drug development and the introduction of liver-targeted thyromimetics selectively activating TRβ such as Resmetirom (MGL-3196) and VK2809 bring new hope of translating the knowledge on local TH effects into effective hepatic lipid-clearing therapies against NASH.

01 Aug 2020·Thyroid : official journal of the American Thyroid AssociationQ1 · MEDICINE

Thyroid Hormone Analogues: An Update

Q1 · MEDICINE

Review

Author: Zucchi, Riccardo

The development of thyroid hormone (TH) analogues was prompted by the attempt to exploit the effects of TH on lipid metabolism, avoiding cardiac thyrotoxicosis. Analysis of the relative distribution of the α and β subtypes of nuclear TH receptors (TRα and TRβ) showed that TRα and TRβ are responsible for cardiac and metabolic responses, respectively. Therefore, analogues with TRβ selectivity were developed, and four different compounds have been used in clinical trials: GC-1 (sobetirome), KB-2115 (eprotirome), MB07344/VK2809, and MGL-3196 (resmetirom). Each of these compounds was able to reduce low-density lipoprotein cholesterol, but a phase 3 trial with eprotirome was interrupted because of a significant increase in liver enzymes and the contemporary report of cartilage side effects in animals. As a consequence, the other projects were terminated as well. However, in recent years, TRβ agonists have raised new interest for the treatment of nonalcoholic fatty liver disease (NAFLD). After obtaining excellent results in experimental models, clinical trials have been started with MGL-3196 and VK2809, and the initial reports are encouraging. Sobetirome turned out to be effective also in experimental models of demyelinating disease. Aside TRβ agonists, TH analogues include some TH metabolites that are biologically active on their own, and their synthetic analogues. 3,5,3'-triiodothyroacetic acid has already found clinical use in the treatment of some cases of TH resistance due to TRβ mutations, and interesting results have recently been reported in patients with the Allan-Herndon-Dudley syndrome, a rare disease caused by mutations in the TH transporter MCT8. 3,5-diiodothyronine (T2) has been used with success in rat models of dyslipidemia and NAFLD, but the outcome of a clinical trial with a synthetic T2 analogue was disappointing. 3-iodothyronamine (T1AM) is the last entry in the group of active TH metabolites. Promising results have been obtained in animal models of neurological injury induced by β-amyloid or by convulsive agents, but no clinical data are available so far.

News (Medical) associated with MB-07811

07 Jun 2024

·www.biospace.com

MASH Clash Between Lilly and Boehringer-Zealand Takes Center Stage at EASL24

Pictured: A fatty liver over a cell/Taylor Tieden for BioSpace You would be forgiven if, with all the cancer news from ASCO24 in Chicago this week, you missed the hepatology data dump at the 2024 Congress of the European Association for the Study of the Liver in Milan, Italy. However, there’s a battle brewing between Eli Lilly and the partnered companies Boehringer Ingelheim and Zealand Pharma in metabolic dysfunction-associated steatohepatitis (MASH), previously referred to as nonalcoholic steatohepatitis (NASH). The drugs being tested in MASH belong to the now-blockbuster class of therapies known as glucagon-like peptide-1 receptor agonists (GLP-1s). Lilly’s tirzepatide is already approved for type 2 diabetes (marketed as Mounjaro) and weight loss (marketed as Zepbound), spaces it shares with Novo Nordisk’s semaglutide products Ozempic and Wegovy—a duopoly that has led to skyrocketing revenue for both companies, which continue to seek additional indications. Meanwhile, Boehringer and Zealand are looking to leap into the space with its own GLP-1 agonist, survodutide, which is under investigation for obesity and other indications. What was interesting this week at EASL24 was the GLP-1 clash between Lilly and Boehringer/Zealand in the MASH space, with both sides providing readouts on their latest Phase II data and each declaring victory. MASH is a potentially deadly fatty liver disease that affects more than 115 million people globally and is expected to increase to 357 million by 2030. In March, the FDA approved Madrigal Pharmaceuticals’ Rezdiffra, a liver-directed thyroid hormone receptor (THR)-β agonist, as the first-ever treatment for the disease. On Wednesday, Lilly’s Phase II data was presented at the European Association for the Study of the Liver (EASL24), showing that 54.9% of MASH patients treated with a 5-mg dose of tirzepatide saw at least a one-stage improvement in fibrosis. In the study of MASH patients with F2 and F3 fibrosis, tirzepatide treatment was found to be more effective than placebo in achieving MASH resolution without worsening of fibrosis. Just two days later, following a data leak snafu at EASL24 on Thursday, Boehringer and Zealand announced that survodutide demonstrated “breakthrough improvement” in liver fibrosis with no worsening of MASH in 64.5% of patients with F2 and F3 fibrosis. The companies said the new data also revealed up to 52.3% of adults with fibrosis stages F1, F2 and F3 had improvement in fibrosis without worsening of MASH. Survodutide, which is licensed to Boehringer from Zealand, is moving into a Phase III study. While GLP-1 drugs may have beneficial effects on MASH by improving insulin sensitivity, reducing liver fat accumulation and reversing fibrosis, Jefferies analysts said in a note to investors this week that they “don’t think GLP-1s will eliminate the market opportunity” for Madrigal in MASH. Likewise, Evercore ISI analysts opined, “there is room for different treatment options for patients with different needs, including daily oral pills and injectable products.” Evercore estimated a potential U.S. market opportunity for Madrigal’s Rezdiffra of $4 billion, while Jefferies’ estimate was considerably lower, pegging peak U.S. sales for Rezdiffra at $2.3 billion. Of course, there are a host of other promising MASH candidates, including Akero Therapeutics. Also at EASL24 this week, Viking Therapeutics announced its candidate VK2809—a thyroid hormone beta receptor agonist—significantly improved secondary histologic endpoints at 52 weeks with no worsening of fibrosis, as assessed by hepatic biopsy. And tomorrow, 89bio will be presenting Phase IIb data for pegozafermin, a specifically engineered glycoPEGylated analog of fibroblast growth factor 21. Meanwhile, new data from Altimmune and a preclinical poster presentation from Aligos Therapeutics also hint at promise in the treatment of MASH. Still, MASH is a complex and confounding disease that has caused many once-promising programs to be discontinued. However, with a projected $25.7 billion total market by 2032 in the U.S., France, Germany, Italy, Spain, the U.K. and Japan, competitors will continue to be in hot pursuit of Madrigal, which has set the standard. Let the clash of the MASH titans begin! Greg Slabodkin is the news editor at BioSpace. You can reach him at greg.slabodkin@biospace.com. Follow him on LinkedIn.

Clinical ResultPhase 2Phase 3Drug Approval

05 Jun 2024

·www.fiercepharma.com

Lilly touts fibrosis win as it pads case for tirzepatide in MASH

As more metabolic dysfunction-associated steatohepatitis contenders come to the fore, analysts at Evercore ISI posit that the disease “is not a ‘one-drug-suits-all’ marketplace.” Back in February, Eli Lilly teased “clinically meaningful” results around the ability of its dual GLP-1/GIP med tirzepatide to curb fibrosis in patients with fatty liver disease. Now, the company is laying out the fine details. In Lilly’s phase 2 SYNERGY-NASH trial, 54.9% of patients on tirzepatide 5 mg, 51.3% of patients on tirzepatide 10 mg and 51% of patients on tirzepatide 15 mg saw their fibrosis decrease by at least one stage without their metabolic dysfunction-associated steatohepatitis (MASH) worsening. That compared with just 29.7% of MASH patients in the placebo group who saw their fibrosis improve, according to a late-breaking abstract published ahead of the EASL International Liver Congress. Analysts at Evercore ISI called tirzepatide’s fibrosis results “solid” and said they “may be slightly better” than those for Madigral Pharmaceuticals' approved MASH drug Rezdiffra. Still, the analysts cautioned that the Lilly readout is “not quite as strong” as data from clinical-stage MASH competitors Akero Therapeutics and 89bio. In March, Madrigal ended a decades-long wait for an effective MASH treatment when its candidate resmetirom was approved as the first drug for the fatty liver disease under the brand name Rezdiffra. Following Lilly’s tirzepatide data drop, Madrigal’s stock plunged nearly 9% in early Wednesday trading, Investor’s Business Daily reported. Still, Madrigal and other MASH players shouldn’t be too intimidated, with the Evercore team positing that the disease “is not a ‘one-drug-suits-all’ marketplace.” “With large markets of this magnitude, we think there is room for different treatment options for patients with different needs including daily oral pills and injectable products,” the analysts explained in a Wednesday note to clients. All told, the Evercore team figures Rezdiffra still has a shot at a roughly $4 billion market opportunity in the U.S. Lilly’s fibrosis data come after the company unveiled positive midstage results in MASH in early February. At the time, Lilly said tirzepatide helped 74% of overweight or obese adults with MASH clear the disease with no worsening of liver scarring after 52 weeks. The 74% figure came from tirzepatide’s 15-mg dose. For the 10-mg and 5-mg doses, clearance rates clocked in at 63.1% and 51.8%, respectively. In the placebo group, just 12.6% of patients experienced MASH clearance. Despite the apparent MASH win, it remains unclear what Lilly’s plans are for a potential tirzepatide label expansion, the Evercore ISI team pointed out. Tirzepatide is currently approved in Type 2 diabetes and obesity as Mounjaro and Zepbound, respectively. Meanwhile, Lilly is testing its drug in a suite of other indications, too, such as sleep apnea in obese patients and heart failure with preserved ejection fraction. Demand remains an ongoing concern for the compound, so much so that Lilly is slotting $9 billion to establish a record-breaking production facility in Indiana. As for Madigral, the company early last month said it had enough cash on hand to “fully resource” the launch of Rezdiffra, with CEO Bill Sibold citing “remarkable interest” for the med among doctors. At the time, Madrigal noted it had reached more than 80% of its top physician targets, which primarily include about 6,000 high-volume MASH-treating physicians. All told, Madrigal is targeting 315,000 MASH patients actively being treated by doctors in the U.S. Elsewhere, Viking Therapeutics this week unveiled secondary endpoints results on its own MASH hopeful after previously reporting that its phase 2b study VOYAGE had met its primary endpoint. Specifically, up to 75% of patients who received Viking’s investigational drug, known as VK2809, achieved MASH resolution with no worsening of fibrosis versus 29% of patients in the trial’s control arm. Up to 57% of patients experienced a one-stage or greater improvement in fibrosis with no worsening of MASH compared with 34% for placebo.

Clinical ResultDrug ApprovalPhase 2

05 Jun 2024

·firstwordpharma.com

Lilly’s tirzepatide proves its MASH mettle in mid-stage update at EASL

After securing near-celebrity status for tirzepatide as a diabetes and obesity treatment, Eli Lilly has been exploring the dual GLP-1/GIP agonist’s potential in metabolic dysfunction-associated steatohepatitis (MASH) – and new histological data seem to support that venture. A late-breaker abstract published Wednesday ahead of the European Association for the Study of the Liver (EASL) congress details the magnitude by which tirezpatide improved fibrosis in the Phase II SYNERGY-NASH trial.The pharma’s leadership had previously teased the secondary endpoint results as “clinically meaningful” in February. At the time, Lilly had disclosed 52-week data showing that the 5mg, 10mg, and 15mg doses of tirzepatide all met the primary endpoint of MASH resolution with no worsening of fibrosis, with an improvement rate of 73.9% for participants who received the highest dose compared to 12.6% for those on placebo.The EASL abstract revealed that on the secondary endpoint, tirzepatide led to at least a one-stage reduction in fibrosis with no worsening of MASH in 51% of patients who received the highest dose, 51.3% of those taking the medium dose, and 54.9% for the the lowest dose, a statistically significant improvement over the placebo arm, which had a rate of 29.7%. Tirzepatide’s placebo-adjusted improvement range of 21.3% to 25.2% was in-line with data shared earlier this week by Viking Therapeutics, whose THR-β selective agonist VK2809 achieved a 22.7% benefit versus placebo at a 10mg dose given every other day.In contrast, the sole marketed drug for MASH, Madrigal Pharmaceuticals’ Rezdiffra (resmetirom) – which just won FDA approval in March – saw a roughly 12% placebo-adjusted fibrosis improvement of at least one stage with no worsening of MASH in its pivotal study.Biomarker improvementsThe data also demonstrated that 71.7% to 78.3% of all patients who received tirzepatide achieved a reduction in nonalcoholic fatty liver disease activity score (NAS) by two points or more, compared with 36.7% for placebo. Additionally, Lilly found that patients experienced a decrease in liver enzymes and liver fat, as well as a significant improvement in key imaging biomarkers of liver inflammation and fibrosis. The company noted that those who received tirzepatide had mostly mild-to-moderate adverse events that were mainly gastrointestinal in nature. Plus, patients in the experimental arm had a body weight reduction of up to 17.3%.While the data appear impressive, the development of tirzepatide for MASH may be tricky as Lilly deals with overwhelming demand and limited supply of the GLP-1/GIP agonist. Lilly recently earmarked $9 billion to boost production capacity of the drug at its manufacturing site in Lebanon, Indiana as it deals with bottlenecks linked to the plastic pens used to inject tirzepatide.

Clinical ResultPhase 2Drug Approval

100 Deals associated with MB-07811

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R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Fibrosis	Phase 2	US	Viking Therapeutics, Inc.	15 Nov 2019
Fibrosis	Phase 2	BE	Viking Therapeutics, Inc.	15 Nov 2019
Fibrosis	Phase 2	FR	Viking Therapeutics, Inc.	15 Nov 2019
Fibrosis	Phase 2	MX	Viking Therapeutics, Inc.	15 Nov 2019
Fibrosis	Phase 2	PR	Viking Therapeutics, Inc.	15 Nov 2019
Nonalcoholic Steatohepatitis	Phase 2	US	Viking Therapeutics, Inc.	15 Nov 2019
Nonalcoholic Steatohepatitis	Phase 2	BE	Viking Therapeutics, Inc.	15 Nov 2019
Nonalcoholic Steatohepatitis	Phase 2	FR	Viking Therapeutics, Inc.	15 Nov 2019
Nonalcoholic Steatohepatitis	Phase 2	MX	Viking Therapeutics, Inc.	15 Nov 2019
Nonalcoholic Steatohepatitis	Phase 2	PR	Viking Therapeutics, Inc.	15 Nov 2019

Clinical Result

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Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04173065 (VOYAGE, PRNewswire) Manual	Phase 2	Nonalcoholic Steatohepatitis	-	VK2809 (1 mg QD)	wkiqupvydq(lrkuaklgrf) = jawbrlrrhf piamncmdlo (xudilvpdgj ) View more	Positive	04 Jun 2024
				VK2809 (2.5 mg QD)	wkiqupvydq(lrkuaklgrf) = kwoycxhccd piamncmdlo (xudilvpdgj ) View more
EASL2020	Phase 2	Metabolic dysfunction-associated steatotic liver disease	-	VK2809 5 mg QD	zzqijgeuaj(vpjlvztdty) = VK2809 was well-tolerated in this study; no serious adverse events were reported in any cohort mfqvqpbwkf (nniztgheql )	Positive	27 Aug 2020
				VK2809 10 mg QOD
EASL2019	Phase 2	Metabolic dysfunction-associated steatotic liver disease	-	VK2809 5 mg QD	zbqnruphyr(negukhtssl) = hjtbozchkd qpihpwutna (yqkgweqjqc ) View more	-	11 Apr 2019
				VK2809 10 mg QOD	zbqnruphyr(negukhtssl) = thfhcxvbpv qpihpwutna (yqkgweqjqc ) View more

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