Treatment of chronic hepatitis D with the entry inhibitor myrcludex B: First results of a phase Ib/IIa study

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• 作者：Pavel Bogomolov¹ ; ² ; Alexander Alexandrov³ ; Natalia Voronkova¹ ; ² ; Maria Macievich¹ ; ² ; Ksenia Kokina¹ ; ² ; Maria Petrachenkova¹ ; ² ; Thorsten Lehr⁴ ; Florian A. Lempp⁵ ; ⁶ ; Heiner Wedemeyer⁷ ; Mathias Haag⁸ ; ⁹ ; ¹⁰ ; Matthias Schwab⁸ ; ⁹ ; ¹⁰ ; ¹¹ ; ¹² ; Walter E. Haefeli⁵ ; ¹³ ; Antje Blank⁵ ; ¹³ ; ^&dagger ; ; ^{antje.blank@med.uni-heidelberg.de" class="auth_mail" title="E-mail the corresponding author} ; Stephan Urban⁵ ; ⁶ ; ^&dagger ;
• 关键词：ALT ; alanine aminotransferase ; AST ; aspartate aminotransferase ; BSA ; bovine serum albumin ; blq ; below limit of quantification ; cccDNA ; covalently closed circular deoxyribonucleic acid ; CHB ; chronic hepatitis B ; CHD ; chronic hepatitis D ; d ; hepatocyte death rate ; DNA ; deoxyribonucleic acid ; HBeAg ; HBe antigen ; HBsAg ; HBs antigen ; HBV ; hepatitis B virus ; HDV ; hepatitis D virus ; IFN ; interferon ; lod ; limit of detection ; loq ; limit of quantification ; NOEL ; no observed effect level ; NLME ; non-linear
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：65
• 期：3
• 页码：490-498
• 全文大小：930 K

文摘

The therapeutic option for patients with chronic hepatitis delta virus infection (CHD) is limited to interferon alpha with rare curative outcome. Myrcludex B is a first-in-class entry inhibitor inactivating the hepatitis B virus (HBV) and hepatitis D virus (HDV) receptor sodium taurocholate co-transporting polypeptide. We report the interim results of a pilot trial on chronically infected HDV patients treated with myrcludex B, or pegylated interferon alpha (PegIFNα-2a) or their combination.

Methods

Twenty-four patients with CHD infection were equally randomized (1:1:1) to receive myrcludex B, or PegIFNα-2a or their combination. Patients were evaluated for virological and biochemical response and tolerability of the study drugs at weeks 12 and 24.

Results

Myrcludex B was well tolerated and no serious adverse event occurred. Although hepatitis B surface antigen levels remained unchanged, HDV RNA significantly declined at week 24 in all cohorts. HDV RNA became negative in two patients each in the Myrcludex B and PegIFNα-2a cohorts, and in five patients of the Myrcludex B + PegIFNα-2a cohort. ALT decreased significantly in the Myrcludex B cohort (six of eight patients), and HBV DNA was significantly reduced at week 24 in the Myrcludex B + PegIFNα-2a cohort. Virus kinetic modeling suggested a strong synergistic effect of myrcludex B and PegIFNα-2a on both HDV and HBV.

Conclusions

Myrcludex B showed a strong effect on HDV RNA serum levels and induced ALT normalization under monotherapy. Synergistic antiviral effects on HDV RNA and HBV DNA in the Myr-IFN cohort indicated a benefit of the combination of entry inhibition with PegIFNα-2a to treat CHD patients.

Lay summary

Myrcludex B is a new drug to treat hepatitis B and D infection. After 24 weeks of treatment with myrcludex B and/or pegylated interferon α-2a, HDV R NA, a relevant marker for hepatitis D infection, decreased in all patients with chronic hepatitis B and D. Two of eight patients which received either myrcludex B or pegylated interferon α-2a, became negative for HDV RNA, and five of seven patients who received both drugs at the same time became negative. The drug was well tolerated.