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Interim Results of a Multicentre, Open-Label Phase 2 Clinical Trial (MYR203) to Assess Safety and Efficacy of Myrcludex B in Combination with Peg-Interferon Alpha 2a in
Patients with Chronic HBV/Hdv Co-Infection
Heiner Wedemeyer1, Katrin Schöneweis2, Pavel O Bogomolov3, Natalia V Voronkova4, Vladimir Chulanov5,
Tatyana Stepanova6, Birgit Bremer7, Patrick Lehmann7, Regina Raupach7, Lena Alleiss8,9, Maura Dandri8,9, Sandra Ciesek10,
Ulf Dittmer10, Walter E. Haefeli11,12, Alexander Alexandrov2 and Stephan Urban12,13, (1)Department of Gastroenterology and Hepatology, Essen University Hospital,
(2)Myr Gmbh,
(3)Hepatology, State Budgetary Institution of Healthcare,
(4)Hepatology, Moniki,
(5)Central Research Institute ofEpidemiology,
(6)Modern Medicine Clinic, Moscow, Russian Federation,
(7)Department of Gastroenterology, Hepatology
and Endocrinology, Hannover Medical School,
(8)Department of Internal Medicine, University Medical Center Hamburg-Eppendorf,
(9)Lübeck-Borstel Partner Site, German Center for Infection Research (DZIF), (10)Institute of Virology, University Hospital Essen,
(11)Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital,
(12)Heidelberg Partner Site, German Center for Infection Research (DZIF),
(13)Department of Infectious Diseases, Molecular Virology, Heidelberg University Hospital
Background: Myrcludex B (MyrB) is an NTCP-receptor
specific first-in-class entry inhibitor developed to treat HBV and HDV infected patients. MyrB monotherapy for 24w induced continuing serum and intrahepatic HDV RNA decline in a forgoing phase 2 trial (MYR202), without affecting HBsAg. We now present interim results of a phase 2 study on HBV/HDV co-infected patients receiving 2mg MyrB alone or two doses of MyrB daily plus peg-interferon α 2a (PEG-IFNα) compared to PEG-IFNα alone for 48w. Methods: 60 HBeAgnegative
patients with chronic HBV/HDV co-infection were
randomized in 4 arms. Patients received 180 μg PEG-IFNα once weekly (A) or MyrB s.c. at 2mg (B) or 5mg (C) once daily plus PEG-IFNα, or MyrB alone (D) for 48w. Treatment-free follow-up was 24w. Primary endpoint was serum HDV RNA negativation at w72; secondary endpoints included HDV RNA negativation at w48, ALT normalization, and >1log HBsAg reduction. Results: Safety: MyrB was well tolerated with 123 drug-related AEs at w48 (mild n=101, moderate n=20, severe n=2) mainly caused by total bile acid increase. The majority
of reported AEs (n=425) were related to PEG-IFNα. No SAE was reported during the 48w treatment period. Efficacy: At w48, serum HDV RNA levels declined in all MyrB treatment arms (median reductions from baseline: 4.59 log10 IU/ml in B (n=15), 5.33 log10 IU/ml in C (n= 14), and 2.47 log10 IU/ml in D (n=14)). PEG-IFNα alone reduced HDV RNA by 1.95 log10 IU/ml. HDV RNA was undetectable in 2/15 (A), 10/15 (B), 8/14 (C) and 2/14 (D) patients at w48. ALT normalization at w48 was pronounced in arm D (10/14) compared to 4/14 in arm A, 4/15 in arm B and 6/15 in arm C. Remarkably, HBsAg levels declined by >1log10 in 7/15 (B) and in 3/14 (C) patients treated with MyrB/PEG-IFNα combination (HBsAg negativation in 2/15 in B). No HBsAg change was observed under monotherapy. Eight paired biopsies available from patients in arm D showed intrahepatic HDV RNA decline of median 1.80log10 and reduction in necroinflammation (6/8) and in liver fibrosis (4/8) at w48. A median 2.4log10 HDV RNA reduction was observed in the combination groups (arms B+C n=5). All arms showed strong reduction of HDAg-positive cells. Conclusion: Administration of MyrB for 48w alone and in combination with PEG-IFNα was safe. Combination therapy showed a strong synergism on HDV RNA decline and induced profound HBsAg declines in a substantial number of patients. This study provides first evidence that entry inhibition by Myrcludex B in combination with PEG-IFNα bears curative potential for chronic HDV and HBV infection. |
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发表于 2018-10-4 21:44
