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Emerging Paradigms in the treatment of NASH (Non-Alcoholic Steatohepatitis)

18 Sep Emerging Paradigms in the treatment of NASH (Non-Alcoholic Steatohepatitis)

Nonalcoholic Steatohepatitis (NASH) is a form of Non-Alcoholic Fatty Liver Disease (NAFLD) and is characterized by the buildup of FAT in the liver. This condition is marked by hepatitis, inflammation, cell damage and fat deposits in the liver. These fat deposits can cause fibrosis of the liver, in turn leading to liver cancer or cirrhosis.

According to an estimate only 20 percent of the people suffering from NAFLD have NASH, while the rest only have a simple fatty liver. While nearly 40 percent in the U.S are afflicted with NAFLD, around 3 to 4 percent have NASH. The American Liver foundation estimates that over 100 million people suffer from NAFLD in the U.S alone.

Though the exact cause of the disease is still unknown, NASH often develops from underlying conditions such as obesity and type 2 diabetes, and can affect people of any age. Individuals who have insulin resistance, high triglyceride levels or abnormal cholesterol levels, hypertension and uncontrolled blood glucose are at an increased risk of developing this condition. NASH also increases the chances of developing cardio vascular anomalies and can lead to death from liver-related causes.

The diagnosis usually involves blood tests, use of imaging techniques such as ultrasound, CT scans and MRI, and a liver biopsy. Losing weight through a healthy diet and exercise can help reduce the fat in the liver and is usually the recommended course of action. Currently there are no approved therapies for this condition, with treatment limited to alleviating the symptoms of the condition.

According to a report by Reports and Data, the Global NASH market will be worth over USD 13.38 Billion by 2026. The healthcare costs associated with this disease are likely to reach USD 18 billion by 2030 from USD 5 billion now, if the disease is left untreated.

Akero Therapeutics (NASDAQ: AKRO)

Market Cap: $563.68M; Current Share Price: 19.74 USDChart
Data by YCharts

AKR-1, the company’s lead candidate for the treatment of NASH, is an engineered analog of the naturally-occurring hormone FGF21, a human polypeptide sequence combined with Fc domain of human immunoglobulin (IgG1). Its novel design allows for sustained signaling through FGF21 receptors, which helps in lowering liver fat, reducing inflammation and fibrosis of the liver. Moreover it is an amalgamation of the metabolic and anti-fibrotic approaches to treating NASH.

The candidate can restore lipid metabolism in the liver and prevent hepatocyte stress and death. It also helps inhibit downstream inflammation and fibrosis.

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The company has designed the hormone in such a way that its half-life has been extended from a mere two hours to over 3 days for once-weekly subcutaneous administration. It also targets different sources of fatty liver such as dietary fat, de novo lipogenesis in liver and adipose tissue lipolysis. AKR-001 improves insulin sensitivity, redirects calories away from the liver to other tissues and muscles in the body thereby reducing lipotoxicity, oxidative stress, inflammatory response, and inhibits fibrosis. Unlike others AKR-001 does not lead to weight gain and can reduce cardiovascular diseases.

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In June 2019, the company initiated the dosing of patients in a Phase 2a BALANCED study, which is a multicenter, randomized, double-blind, placebo-controlled, dose-ranging trial in biopsy-confirmed patients with NASH. The primary clinical endpoint of the study measures absolute change from baseline in hepatic fat fraction measured by Magnetic Resonance Imaging – Proton Density Fat Fraction (MRI-PDFF) Week 12.

The company raised over $98.4 million in net proceeds through an Initial Public Offering of Stocks in June 2019. The IPO was priced at $16.00 per share for a total of 6,612,500 shares. Akero closed the second quarter with cash and cash equivalents of $162.7 million as of June 30, 2019.


Market Cap: $145.29M; Current Share Price: 0.3856 USDChart
Data by YCharts

Its lead candidate for the treatment of HIV is Leronlimab (PRO 140), a fully humanized IgG4 monoclonal antibody directed against CCR5, otherwise known as viral-entry inhibitors. This acts by blocking the HIV (R5) subtype entry into T-cells, used by HIV as a molecular portal, and masking the CCR5 co-receptor, but leaving its ability to provide an immune response intact. Though it does not exhibit agonist activity towards CCR5, it has demonstrated antagonist activity to CCL5, a central mediator in inflammatory diseases.

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So far the company has conducted over 7 clinical trials for Leronlimab (PRO 140) that have proven its ability to reduce HIV viral load in patients, offering minimal side-effects and lower dosages as compared to conventional medicine.

In April 2019, CytoDyn announced the topline results from its Phase 2b monotherapy trial. In addition, it filed an application for an investigational new drug application (IND) with a Phase 3 protocol for a monotherapy trial with the FDA. The study will be conducted by Amarex Clinical Research, its principal CRO. It is currently engaged in a crucial Phase 3 trial for Leronlimab (PRO 140), as an adjunct therapy to HAART (Highly Active Anti-Retroviral Therapy). Additionally, it has also initiated a Phase 2 trial for treatment of Graft versus Host Disease (GvHD), in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), who are undergoing bone marrow stem cell transplantation. CytoDyn also plans to file for an Orphan Drug Designation for Colon Cancer.

It is pursuing 8 cancer indications besides NASH and intends to launch preclinical studies in Melanoma, Pancreatic Cancer, Breast, Prostate, Colon, Lung, Liver and Stomach Cancer.

Galectin Therapeutics (NASDAQ: GALT)

Market Cap: $201.61M; Current Share Price: 3.56 USDChart
Data by YCharts

The company’s lead candidate GR-MD-02 has shown a marked effect on liver fibrosis in animal models, thereby leading to further research in liver diseases such as fibrotic liver disease, lung fibrosis, in addition to kidney fibrosis and cardiovascular fibrosis as potential therapeutic areas for the future. Galectin is pursuing the therapeutic application of GR-MD-02 in patients with NASH (fatty liver disease) with advanced fibrosis and cirrhosis. The FDA accepted the IND application for this drug and approved its phase I trial in January 2013; it has also been awarded a Fast Track designation.

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The company initiated a phase 2b NASH-CX trial in December 2017, the results of which demonstrated a “breakthrough for patients with NASH cirrhosis”. The NASH-CX trial is a randomized, double-blind, placebo-controlled trial with nearly 162 patients with NASH Cirrhosis, the final stage in the progression of non-alcoholic steatohepatitis (NASH), who received 2 mg/kg or 8 mg/kg of GR-MD-02 or placebo every other week for 52 weeks, for a total of 26 doses. The results from the study show that GR-MD-02 has met its primary clinical endpoint of reduction in HVPG (hepatic venous pressure gradient) and the secondary endpoint of reduction in the development of new esophageal varices in patients without varices at baseline.

Encouraged by these results, the company announced the initiation of a Phase 3 clinical trial program In May 2018, with its galectin-3 inhibitor GR-MD-02 in NASH cirrhosis under guidance from FDA.

Furthermore the company’s pipeline also consists of the study of its galectin inhibitors for combination immunotherapy clinical trials, with its initial focus being Melanoma, which is currently undergoing a phase 1b clinical trial and an exploratory Phase 2a clinical trial of GR-MD-02 in patients with moderate to severe plaque psoriasis

GR-MD-02 is backed by a strong intellectual property right portfolio extending through 2031 and covering its composition of matter, various methods of use, and methods of production.


Market Cap: $65.65M; Current Share Price: 6.10 USDChart
Data by YCharts

NeuLiv, the company’s third development program using its proprietary DN-TNF Platform, is being developed for the treatment of nonalcoholic steatohepatitis (NASH) by harnessing the body’s innate immune system to mount an offense on the disease. INmune bio believes that NeuLiv, a TNF inhibitor that neutralizes soluble TNF (sTNF) without affecting trans-membrane TNF (tmTNF) or TNF receptors, has the potential to treat the underlying cause of NASH thereby stopping its progression and helping the liver heal.

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The company is developing two proprietary delivery systems namely INKmune, which allows for relaying priming signals to resting Natural Killer (NK) cells through a simple IV infusion and DN-TNF Platform that targets TNF otherwise known as the “master” cytokine.

The drug candidate can directly target soluble TNF, the cytokine which is primarily responsible for causing chronic inflammation. Unlike a more generic approach taken by other drugs, NeuLiv focuses on the peripheral, regional and local causes of chronic inflammation in patients with NASH, which helps slow down the progression of the disease and promotes hepatic repair mechanism.

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In addition, the company’s pipeline consists of candidates for Alzheimer’s disease (XPro1595) and Oncology. INmune is planning to initiate a phase I clinical trials in patients with mild-to-moderate Alzheimer’s disease, targeting the reduction of neuroinflammation using soluble TNF. The company candidate for oncology, INB03, has completed a phase I open label dose escalation trial in patients with advanced cancer, with plans to initiate a phase II in the Q1 of 2020.

Hepion Pharmaceuticals (NASDAQ: HEPA)

Market Cap: $10.38M; Current Share Price: 3.005 USDChart
Data by YCharts

A clinical stage biotechnology company, Hepion is developing targeted therapies for liver diseases, such as non-alcoholic steatohepatitis (NASH) and chronic hepatitis virus infection (HBV, HCV, HDV). CRV-431, the company’s lead drug candidate, is a pleiotropic liver disease drug that binds to cyclophilin isomerase enzymes and inhibits cyclophilin function, far greater than any other cyclophilin inhibitor.

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The company’s therapeutic strategy involves developing drugs that target multiple molecular pathways, have an excellent safety profile with minimal side-effects and offer targeted action thereby minimizing the risk of adverse effects.

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The drug candidate has shown an excellent safety profile in animal models and preclinical studies, in addition to having diverse mechanisms of action, 5-times higher accumulation in the liver and antiviral properties. The candidate has also shown to possess antiviral, anti-steatotic, anti-inflammatory, anti-fibrotic, and anti-cancer properties, besides protection from cellular stress and death, which differentiates it from other drug candidates.

The company is currently engaged in a single dose study to assess the safety, tolerability and pharmacokinetics of CRV431, as standalone and in combination with Tenofovir Disoproxil Fumarate in patients with HBV. Hepion’s other areas of therapeutic focus include Hepatocellular Carcinoma and Viral Hepatitis.

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