Product Pipeline

Overview

CVI Pharmaceuticals is advancing a clinical stage pipeline to address the unmet medical needs in hypercholesterolemia and complex medical challenges of patients in liver and rare metabolic diseases.

Standard of Care lipid-lowering statins are effective at lowering LDL-cholesterol (LDL-C), leading to well- documented CV benefits. However, not all patients can tolerate statins or reach their LDL-C goal on maximally-tolerated statin-dosing. Patients with atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH) who require additional LDL-C lowering on top of maximally-tolerated statin therapy represent a high-risk patient population with an unmet medical need.

Patients with fatty liver disorders, including nonalcoholic steatohepatitis (NASH) and NAFLD, may benefit from reduced liver fat levels. Fatty liver disease is a growing problem globally due to increasing metabolic disorders. Patients with NASHand NAFLD often have associated dyslipidemia. As a result, most NAFLD/NASH patients die from cardiovascular disease.

CVI-LM001 is a novel, first-in-class, safe and oral once daily PCSK9 modulator with distinct mechanisms of action in lowering blood atherogenic LDL-cholesterol and reducing liver fat respectively. Working synergistically with statins, CVI-LM001 has the potential to target patients with hypercholesterolemia and NAFLD/NASH patients with elevated LDL-C. Recently, a 12-week Phase 2 POC trial has successfully completed in China in patients with hypercholesterolemia.

CVI-2742 is a highly potent and liver-targeted second generation thyroid hormone receptor (THR)-β selective agonist with best-in-class potential for treating patients with NASH and NAFLD.

CVI-LM001 Dual Mechanisms of Action to Combat Hyperlipidemia and Fatty Liver Disease

MOA-1: CVI-LM001 upregulates liver LDLR expression and accelerates blood LDL-cholesterol removal via an unique mechanism of inhibition of PCSK9 transcription and prevention of LDLR mRNA degradation; statin activates LDLR transcription via SREBP2 pathway.

LDLR: LDL receptor, SRE-1: sterol-regulatory element, mRNABP: mRNA binding protein, 3’UTR: 3’untranslated region

MOA-2: CVI-LM001 activates hepatic adenosine monophosphate-activated protein kinase (AMPK), a master regulator of cellular energy, which turns on pathways that reduce hepatic fat synthesis and boost fatty acids oxidation.

CVI-LM001 is a novel candidate for cardiometabolic and liver diseases

Preclinical studies:

In a hyperlipidemic hamsters model, treatment with CVI-LM001 (40, 80 and 160 mg/kg, QD) for 4 weeks dose-dependently increased liver LDLR protein levels up to 3.5-fold and decreased circulating PCSK9 levels to 10% of control at the highest dose, this was accompanied by significant reductions in serum LDL-C, TC, and TG. In a diet-induced NASH hamster model, 4 weeks treatment with CVI-LM001 substantially reduced hepatic ballooning and improved NASH score.

Clinical studies:

In a double-blind, randomized Phase 1a study conducted in healthy volunteers, compared to baseline, serum PCSK9 levels was significantly reduced after 10 days of oral treatment with CVI-LM001 (300 mg, QD). Moreover, in a Proof of Mechanism Phase 1b study conducted in subjects with elevated LDL-C, compared with placebo cohort, treatment with CVI-LM001 for 28 days significantly reduced serum LDL-C ,TC , Apo B and PCSK9 levels. CVI-LM001 had a favorable safety profile and was well tolerated in Phase 1 studies conducted in healthy volunteers and hyperlipidemic subjects.

Altogether, these studies demonstrate that CVI-LM001, a novel PCSK9 modulator, has the potential to be a new oral cholesterol-lowering drug and warrant further clinical development. Recently, a 12-week Phase 2 POC trial in China in patients with hypercholesterolemia has successfully completed.

CVI-2742 is a highly potent and liver-targeted second generation THR-β selective agonist with best-in-class potential for treating patients with NASH and hyperlipidemia

MOA studies:

CVI-2742 activates liver THR-β with EC50< 10 nM, with a β-selectivity of > 65 fold and a liver to plasma ratio > 50, representing the best-in-class of the second generation THR-b selective agonist under development.

Preclinical Studies:

In hyperlipidemic mouse model, CVI-2742 one-week treatment substantially reduced serum total cholesterol and LDL-C by > 70% of baseline at 0.5 mg/kg dose and markedly elevated the expression of liver THR-β targeted genes (Ldlr, Dio1 and Me1) without any effects on cardiac THR-α. In a HFD+CCl4 DIO NASH model, CVI-2742 once daily, oral treatment for 4 weeks (0.5 mg/kg) totally eliminated hepatocyte ballooning and steatosis and also greatly improved fibrosis of the animals. In rat and mouse PK models, CVI-2742 demonstrates superior liver enrichment property with a liver to plasma partition ratio > 50, which is the highest among peers.

In preliminary toxicity studies, CVI-2742 displayed a broad safety window (>60-fold of minimal effective dose).

Based on the preclinical POC data set, we believe that CVI-2742 will be a highly effective and safe new drug candidate for treating patients with NASH and hyperlipidemia.

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If you wish to learn more about the research we’re conducting about new lipid-lowering mechanisms or have any questions about the pharmaceutical products we are developing, get in touch with us. Our team is more than happy to address your inquiries. You may contact us via the phone number or email address featured on this website. We hope to hear from you!

Product Pipeline

Overview

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