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LBO-004
Safety, pharmakokinetics and antiviral activity of novel capsid
assembly modulator (CAM) JNJ-56136379 (JNJ-6379) in treatmentnaive
chronic hepatitis B (CHB) patients without cirrhosis
F. Zoulim1,2, J.Z. Yogaratnam3, J.J. Vandenbossche4, O. Lenz4,
W. Talloen4, C. Vistuer4, I. Moscalu5, A. Streinu-Cercel6, S. Bourgeois7,
M. Buti8, J. Crespo9, J.M. Pascasio10, C. Sarrazin11,
T. Vanwolleghem12,13, L. Blatt3, J. Fry3. 1Croix Rousse Hospital, Hospices
Civils de Lyon, Department of Hepatology, Lyon, France; 2INSERM U1052-
Cancer Research Institute of Lyon, Lyon, France; 3Alios Biopharma (a
Janssen Pharmaceutical Company of Johnson & Johnson), South San
Francisco, United States; 4Janssen Pharmaceuticals BV, Beerse, Belgium;
5Spitalul Clinic Republican, Chisinau, Moldova; 6National Institute for
Infectious Diseases “Prof. Dr. Matei Balş, Carol Davila University of
Medicine and Pharmacy, Bucharest, Romania; 7ZNA Jan Palfijn, Clinical
Pharmacology Unit, Merksem, Belgium; 8Hospital Universitario Vall
d'Hebrón, Unidad de Heptologia, Barcelona, Spain; 9Hospital
Universitario Marques de Valdecilla, Servicio Aparato Digestivo, IDIVAL,
Santander, Spain; 10Hospital Universitario Virgen del Rocio, UGC
Enfermedades Digestivas, Sevilla, Spain; 11Medizinische Klinik II, St.
Josefs-Hospital, Wiesbaden, Germany; 12Erasmus MC, University
Medical Center, Department of Gastroenterology and Hepatology,
Rotterdam, Netherlands; 13University Hospital, Department of
Gastroenterology and Hepatology, Antwerp, Belgium
Email: [email protected]
Background and Aims: JNJ-6379 is a potent and selective HBV
replication inhibitor with a dual mode of action, inhibiting both early
and late steps of the viral life cycle. This study aims to evaluate safety,
pharmacokinetics and antiviral activity of multiple ascending doses
of JNJ-6379 in CHB patients.
Method: Treatment-naïve, HBeAg-positive or -negative CHB patients,
with plasma HBV DNA >2000 IU/mL, METAVIR <F3 and ALT/AST <2.5
the upper limit of normal, were enrolled into this ongoing,
randomized, double-blind, placebo-controlled Phase 1b study.
Patients were randomized in a 3:1 ratio to receive JNJ-6379 or
placebo for 28 days with 8 weeks follow-up. To date, 3 groups have
been evaluated (25 mg QD [after 100 mg loading dose], 75 mg QD
and 150 mg QD). Evaluation of a fourth group (250 mg QD) is
ongoing.
Results: Across all groups (n = 36), median agewas 42.5 years (range:
21–58), 83% males, 78% Caucasian, 11% Asian, 6% Black/African
American, 6% other/not reported. 25% of patients were HBeAgpositive.
At Day 29, substantial reductions from baseline in HBV DNA (Table)
and HBV RNA were observed in all 3 treatment groups. No notable
changes in HBsAg were observed.
Adverse events (AEs) or laboratory abnormalities ≥Grade 3 were
infrequent (≤3 patients/dose); 64% (23/36) experienced ≥1 AE on
treatment (25 mg, n = 9/12; 75 mg, n = 6/12; 150 mg, n = 8/12). There
was one serious AE (right frontal lobe mass, unrelated to study drug),
one discontinuation due to AEs (isolated ALT/AST flare with no
bilirubin elevation, likely related to study drug), and no dose-limiting
toxicities. After repeated administration, drug exposure increased in a
dose-dependent manner. Apparent drug clearance was low, and
similar across groups and ethnicities.
Conclusion: JNJ-6379 administered for 28 days was generally well
tolerated and resulted in potent antiviral activity at all doses
evaluated, and the data from this study warrants additional
evaluation of the compound in phase 2a. |
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发表于 2018-3-31 08:17
