Summary of research progress in the field of liver diseases (03.02)

Summary of research progress in the field of liver diseases (03.02)

March 02, 2018 Source: WuXi PharmaTech

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1. New drug targeting AMPK can significantly improve the symptoms of NAFLD core diseases

Recently, Poxel SA unveiled a proof-of-concept experimental data at the 2018 International NASH Congress in London, which is a diet-induced, tissue-biopsy-recognized nonalcoholic steatohepatitis (NASH). The effect of the PXL770 was evaluated in a mouse model. The data show that PXL770 as a new type of non-alcoholic fatty liver disease (NAFLD) treatment can improve the symptoms of core diseases.

NASH is characterized by the accumulation of fat in the liver and induces inflammation and fibrosis. The prevalence of NASH in some parts of China can be as high as 27%. The number of NASH patients in the United States is also as high as 16 million. In the absence of effective treatment, NASH may induce severe liver problems including liver cancer.

Poxel's PXL770 is a direct activator of the best-in-class adenosine monophosphate-activated protein kinase (AMPK). AMPK is involved in many aspects such as lipid metabolism, glucose balance and inflammation. Due to its regulation in various metabolic pathways, targeting AMPK provides a good entry point for the treatment of many chronic metabolic diseases including NASH.

In this study, the investigators evaluated the efficacy of PXL770 in diet-induced obese NASH mice at baseline and at the end of treatment. At 8 weeks, mice were orally administered PXL770 (n=12) or placebo twice daily at a dose of 35 mg/kg or 75 mg/kg. The results showed that both doses of PXL770 significantly reduced the NAFLD activity score (NAS) and reduced steatosis, inflammation, and hepatocellular ballooning. The reduction in hepatic triglycerides in the treatment group confirmed the benefit of the drug for hepatic steatosis. In addition, PXL770 significantly reduced a group of key gene expressions involved in fibrosis, including type I and type III collagen genes, with gene expression downregulation of more than 60% at both drug doses.

â–² Dr. Thomas Kuhn, CEO of Poxel SA (Source: Poxel SA)

“These preclinical data are very convincing, consistent with our expected effect on activating AMPK. These results validate the unique potential of PXL770 in NAFLD, and there is a significant and unmet medical need in the NAFLD field,” said Poxel SA Executive Director Dr. Thomas Kuhn said: "When our Phase 1b clinical trial is about to come to a successful conclusion, we plan to launch a Phase 2a clinical study of patients with NAFLD. This study is expected to begin in the second half of 2018. And, we The potential to treat other metabolic diseases with PXL770 is also being explored."

2. Children's hepatitis B drugs are eligible for orphan drugs

ContraVir has announced that the US FDA has granted orphan drug status to its main drug, tenofovir exalidex (TXLTM), which is used to treat chronic hepatitis B infection in patients aged 0-11 years. Orphan drug qualifications enable developers of the drug to receive incentives. TXL's qualification means that the company has a seven-year patent period in the United States after the drug is approved, and enjoys financial assistance in clinical research and development, as well as an accelerated review by the FDA.

Hepatitis B is a liver disease that affects a wide range. 400 million people worldwide suffer from chronic hepatitis B, and more than 780,000 people die each year from hepatitis B complications. Currently available antiviral treatments can control chronic hepatitis B, but not cure the disease. Even under long-term treatment, patients are still likely to develop cirrhosis and liver cancer.

TXL is a very effective tenofovir prodrug. Tenofovir is the active ingredient of Vemlid® (tenoflavone levamide) and Viread® (tenofovir disoproxil fumarate). TXL's novel liver-targeting structure reduces the systemic circulation of tenofovir, thereby reducing the side effects of the drug on kidneys and bones, which is especially important in children who are still developing. ContraVir has completed Phase 2 clinical trials of TXL and is currently optimizing formulations to further enhance drug delivery. To date, TXL has provided clinical evidence for antiviral activity and demonstrated excellent safety, tolerability and pharmacokinetic characteristics.

â–² Mr. James Sapirstein, CEO of ContraVir (Source: ContraVir)

“We are very pleased to report that TXL is currently the only research or approved therapy for the availability of orphan drugs for hepatitis B drugs in pediatric patients,” said ContraVir CEO James Sapirstein: “This title stands out A major medical need that has not been met in this extremely vulnerable patient population and provides a key development path for the new drug TXL for this patient population."

3. Organ chip lays the foundation for hepatitis B drug development

Hepatitis B virus (HBV) infection is currently incurable and affects hundreds of millions of people worldwide. The therapeutic field is slow to develop due to the lack of models that can be used to test potential therapies. Recently, scientists at Imperial College London have tested viral infections in artificial organ models, and this success is expected to accelerate research in this area. Related papers have been published in Nature Communications.

The artifact function mimics the cellular composition and physiology of the entire organ and can be used as an alternative to animal models in drug safety testing, but so far they have not been used to test the interaction of infectious diseases with organs. Imperial College researchers used artificial liver-organized chips (Organs-on-chips) to test their response to hepatitis B virus infection to determine the interaction between pathogens and artificial organs.

The organ chip places the living cells of the human body on scaffolds that are similar in physical, mechanical, and structural structure to the target organ. A catheter is placed around the cell to simulate the flow of blood through the body, and the drug or virus flows through the catheter through the cell. Compared to conventional methods, live cells used for testing last longer on the chip and require lower doses of infection than traditional model systems. The results indicate that liver cells on the organ chip can infect physiological levels of HBV and produce a similar biological response to the virus as the human liver, including immune cell activation and other infection markers. Moreover, this platform reveals a complex means by which the HBV virus evades the intrinsic immune response, a finding that could be used for future drug development. Although the technology is still in its early stages, researchers say it will eventually allow patients to acquire new, personalized medicines. In the future, doctors are expected to use cells from actual patients instead of universal cell lines to test their response to certain drugs, making treatment more targeted and effective.

â–² The main author of the paper, Dr. Marcus Dorner (Source: Imperial College London)

The main author of the paper, Dr. Marcus Dorner, said: "This is the first time that organ chip technology has been used to test for viral infections. Our work represents the next application frontier of this technology, and we hope it will ultimately reduce the costs associated with clinical trials. Time will benefit the patient in the long run."

4. New clinical trials seek to improve liver fibrosis and cirrhosis in patients

Intercept has announced that it will launch a Phase 3 clinical trial called REVERSE. The study was a randomized, double-blind, placebo-controlled, multicenter study evaluating oxalicholic acid in approximately 540 patients with cirrhosis who were diagnosed with nonalcoholic steatohepatitis (NASH) by biopsy. Efficacy and safety of (oceticholic acid, OCA).

Nonalcoholic steatohepatitis (NASH) is a liver disease in which fat accumulates in the liver and can cause liver fibrosis and cirrhosis. It is estimated that NASH will soon become the most common cause of advanced liver disease, and these patients usually require a liver transplant. There are currently no approved treatment options for NASH, and there is still a huge medical need to be met in this area.

The REVERSE trial will be conducted in North America, Europe, Australia and New Zealand. The primary endpoint was the percentage of subjects with at least one stage of histological improvement in liver fibrosis with a NASH Clinical Research Network (CRN) system score after 12 months of treatment. Patients will be randomly assigned to one of three groups in a 1:1:1 ratio, receiving 10 mg of OCA once daily, 10 mg of OCA once daily, but titrated to 25 mg at three months, or placebo. Patients who successfully complete the REVERSE double-blind phase will be eligible to participate in the open-label extension phase trial for up to 12 months.

â–² Dr. Mark Pruzanski, President and CEO of Intercept (Source: Intercept)

"NASH will soon surpass hepatitis C and become the leading cause of liver transplantation in the United States and Europe, so there is an urgent need for effective treatments to reverse liver fibrosis and cirrhosis in patients," Dr. Mark Pruzanski, President and CEO of Intercept, commented: "OCA is currently the only NASH drug approved by the US FDA for breakthrough therapy. With the progress of our phase 3 clinical studies REGENERATE and REVERSE, we are expected to bring the first approved therapy to patients with liver fibrosis and cirrhosis. Patients with NASH have a higher risk of developing liver failure."

Reference materials:

[1] Poxel Presents Preclinical Proof-of-Concept Data for PXL770 in Non-Alcoholic Steatohepatitis (NASH) at Global NASH Congress 2018

[2] ContraVir Pharmaceuticals Announces TXLTM Has Been Granted Orphan Drug Designation for the Treatment of HBV in a Pediatric Population

[3] Organ-on-chip technology enters next stage as experts test hepatitis B virus

[4] Intercept Announces Phase III REVERSE Trial Evaluating OCA for the Treatment of NASH Patients With Compensated Cirrhosis

Original Title: Summary of Research Progress in the Field of Liver Diseases (No. 34)

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