Final results of a multicenter, open-label phase 2b clinical trial to assess safety and efficacy of Myrcludex B in combination with Tenofovir in patients with chronic HBV/HDV co-infection

Wedemeyer, Heiner; Богомолов, П. О.; Blank, Antje; Allweiss, Lena; Dandri-Petersen, M.; Bremer, Birgit; Воронкова, Н. В.; Schöneweis, Katrin; Pathil, Anita; Burhenne, Jürgen; Haag, Mathias; Schwab, Matthias; Haefeli, Walter-Emil; Wiesch, J.S. zur; Alexandrov, Alexander I.; Urban, Stephan

doi:10.1016/s0168-8278(18)30224-1

Cited by 117 publications

(111 citation statements)

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“…(16,26) Prolonged use of myrcludex B and tenofovir in HBV/HDV coinfected patients in a phase IIb trial resulted in a decrease of ALT levels compared to tenofovir alone. (27) This study supports further investigation of NTCP-inhibition in cholestasis with defined etiologies. For example, in PBC/primary sclerosing cholangitis (PSC) plasma bile salt concentrations are moderately elevated in early stages of disease, (28) allowing for an innocuous further increase in bile salt levels after myrcludex B treatment.…”

Section: Discussionsupporting

confidence: 82%

“…Notably, long‐term myrcludex B treatment in humans does not lead to pruritus or diarrhea, despite increased plasma bile salt levels to ∼200 μm . Prolonged use of myrcludex B and tenofovir in HBV/HDV coinfected patients in a phase IIb trial resulted in a decrease of ALT levels compared to tenofovir alone . This study supports further investigation of NTCP‐inhibition in cholestasis with defined etiologies.…”

Section: Discussionmentioning

confidence: 86%

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Na+‐taurocholate cotransporting polypeptide inhibition has hepatoprotective effects in cholestasis in mice

Slijepćević¹,

Abbing²,

Fuchs

et al. 2018

Hepatology

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Accumulation of bile salts (BSs) during cholestasis leads to hepatic and biliary injury, driving inflammatory and fibrotic processes. The Na+‐Taurocholate Cotransporting Polypeptide (NTCP) is the major hepatic uptake transporter of BSs, and can be specifically inhibited by myrcludex B. We hypothesized that inhibition of NTCP dampens cholestatic liver injury. Acute cholestasis was induced in mice by a 3.5‐diethoxycarbonyl‐1.4‐dihydrocollidine (DDC) diet or by bile duct ligation (BDL). Chronic cholestasis was investigated in Atp8b1‐G308V and Abcb4/Mdr2 deficient mice. Mice were injected daily with myrcludex B or vehicle. Myrcludex B reduced plasma alkaline phosphatase (ALP) levels in DDC‐fed, Atp8b1‐G308V and BDL mice by 39%, 27% and 48% respectively. Expression of genes involved in fibrosis, proliferation and inflammation was reduced by myrcludex B treatment in DDC‐fed and Atp8b1‐G308V mice. NTCP‐inhibition increased plasma BS levels from 604±277 to 1746±719 μm in DDC‐fed mice, 432±280 to 762±288 μm in Atp8b1‐G308V mice and from 522±130 to 3625±378 μm in BDL mice. NTCP‐inhibition strongly aggravated weight loss in BDL mice, but not in other cholestatic models studied. NTCP‐inhibition reduced biliary BS output in DDC‐fed and Atp8b1‐G308V mice by ∼50% while phospholipid (PL) output was maintained, resulting in a higher PL/BS ratio. Conversely, liver injury in Abcb4 deficient mice, lacking biliary phospholipid output, was aggravated after myrcludex B treatment. Conclusion: NTCP‐inhibition by myrcludex B has hepatoprotective effects, by reducing BS load in hepatocytes and increasing the biliary PL/BS ratio. High micromolar plasma BS levels after NTCP‐inhibition were well tolerated. NTCP‐inhibition may be beneficial in selected forms of cholestasis. (Hepatology 2018).

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 86%

Na+‐taurocholate cotransporting polypeptide inhibition has hepatoprotective effects in cholestasis in mice

Slijepćević¹,

Abbing²,

Fuchs

et al. 2018

Hepatology

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“…1,2 Interferon therapy is currently the only option for the treatment of HDV infection. However, there are several new and investigational therapeutics on the horizon targeting both HBV and/or HDV, including entry inhibitors, such as Myrcludex B in combination with tenofovir, 39 prenylation inhibitors, RNA-interfering molecules and nucleic acid polymers.…”

Section: Hepatitis D Virus In Australiamentioning

confidence: 99%

Epidemiology and phylogenetic analysis of hepatitis D virus infection in Australia

Jackson

MacLachlan

Cowie

et al. 2018

Internal Medicine Journal

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“…The primary endpoint (HDV RNA reduction by 2log or negative) was achieved by 46.4%, 46.8%, 76.6%, and 3.3% of patients in arms A (2 mg), B (5 mg), C (10 mg), and D (tenofovir disoproxil fumarate [TDF]), indicating a dose-dependent antiviral efficacy of MyrB. The mean liver stiffness values were also significantly declined in all MyrB groups but not the control TDF group, 122 demonstrating superiority by targeting NTCP (Figure 12).…”

Section: Sodium Taurocholate Cotransporting Polypeptidementioning

confidence: 99%

Medicinal chemistry strategies toward host targeting antiviral agents

2020

Medicinal Research Reviews

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Direct-acting antiviral agents (DAAs) represent a class of drugs targeting viral proteins and have been demonstrated to be very successful in combating viral infections in clinic. However, DAAs suffer from several inherent limitations, including narrow-spectrum antiviral profiles and liability to drug resistance, and hence there are still unmet needs in the treatment of viral infections. In comparison, host targeting antivirals (HTAs) target host factors for antiviral treatment. Since host proteins are probably broadly required for various viral infections, HTAs are not only perceived, but also demonstrated to exhibit broad-spectrum antiviral activities. In addition, host proteins are not under the genetic control of viral genome, and hence HTAs possess much higher genetic barrier to drug resistance as compared with DAAs. In recent years, much progress has been made to the development of HTAs with the approval of chemokine receptor type 5 antagonist maraviroc for human immunodeficiency virus treatment and more in the pipeline for other viral infections. In this review, we summarize various host proteins as antiviral targets from a medicinal chemistry prospective. Challenges and issues associated with HTAs are also discussed. K E Y W O R D S broad-spectrum antivirals, direct-acting antiviral agents, drug resistance, host targeting antiviral agents

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Final results of a multicenter, open-label phase 2b clinical trial to assess safety and efficacy of Myrcludex B in combination with Tenofovir in patients with chronic HBV/HDV co-infection

Cited by 117 publications

References 0 publications

Na+‐taurocholate cotransporting polypeptide inhibition has hepatoprotective effects in cholestasis in mice

Na+‐taurocholate cotransporting polypeptide inhibition has hepatoprotective effects in cholestasis in mice

Epidemiology and phylogenetic analysis of hepatitis D virus infection in Australia

Medicinal chemistry strategies toward host targeting antiviral agents

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