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426
Safety and Immunogenicity of Single and
Multiple Injections of the Therapeutic Vaccine
TG1050 in NUC-Suppressed Chronic Hepatitis
B (CHB) Patients: Unblinded Analysis of a
Double-Blind, Placebo-Controlled Phase 1b
Study
Claire Fournier1, François Habersetzer2, Martin Sprinzl3,
Stanislas Pol4, Carla S. Coffin5, Vincent Leroy6, Mang M. Ma7,
Heiner Wedemeyer8, Ansgar W. Lohse9, Robert Thimme10,
Perrine Martin11, Genevieve Inchauspe12, Celine Halluard13,
Benoit Sansas14, Kaidre Bendjama13, Maud Brandely13
and Fabien Zoulim15, (1)CHUM, Service D’hépatologie,
Montreal, Canada, (2)Institut Hospitalo-Universitaire, Pôle
Hépato-Digestif, Hôpitaux Universitaires De Strasbourg,
Strasbourg, France, (3)Medizinische Klinik Und Poliklinik,
Mainz, Germany, (4)Liver Department, Hôpital Cochin and
Université Paris Descartes, France, (5)University of Calgary,
Liver Unit, Division of Gastroenterology and Hepatology,
Calgary, Canada, (6)CHU Grenoble Alpes, Grenoble,
France, (7)University of Alberta, (8)Hannover Medical
School, Hamburg, Germany, (9)1st Department of Medicine,
University Medical Centre Hamburg-Eppendorf, Hamburg,
Germany, (10)University of Freiburg, Freiburg, Germany,
(11)Dept. of Infectious Diseases, Lyon, France, Transgene
SA, (12)Transgene SA, Dept. Maladies Infectieuses, Lyon,
France, (13)Transgene SA, Dept. Affaires Médicales, Illkirch,
France, (14)Smart Data Lab, Illkirch Graffenstaden, France,
Transgene SA, (15)Department of Hepatology, Croix Rousse
Hospital, Hospices Civils De Lyon, France
Background: TG1050 is an adenovirus 5 (Ad5)-based
vaccine encoding HBV polymerase (POL), core and envelope
(ENV) domains aimed at inducing a broad HBV-specific T cell
response, which is a key determinant of disease resolution
in CHB. TG1050.02 is a phase 1b study carried out in NUC
suppressed patients. Methods: 48 patients were enrolled,
randomized 1:1:1 across 3 dose levels (DL) of 109, 1010, 1011
virus particles (vp) and then 3:1 within each DL to placebo.
12 patients were enrolled in the Single Dose (SD) cohort to
receive a single subcutaneous (sc) injection while 36 patients
enrolled in the Multi Dose (MD) cohort received 3 weekly sc
injections. At inclusion, patients had to be HBV DNA negative
after at least 2 years of NUC therapy. Enrollment was restricted
to patients with undetectable levels of neutralizing anti-Ad5
antibodies (NAd5) in the SD cohort and open regardless of
NAd5 titers in the MD cohort. Patients were assessed for
safety, immunogenicity and viral markers (HBsAg). T-cell
responses were monitored by INFγ ELISPOT on PBMCs after
10-day stimulation. ELISPOT results were stratified into low
or high pre-immunity groups according to baseline NAd5 titers
above or below the median of the cohort. Results: TG1050
was well tolerated; main drug-related adverse events (AEs)
were grade 1 or 2 injection site reactions. No ALT flare, no
SAE and no signs of immune-related AEs were observed.
No HBV specific T-cells were detected under placebo in both
SD and MD cohorts and only one sporadic response (1 MD
patient) was observed in the low 109 vp dose. In contrast,
administration of the vaccine was followed by rapid onset of
HBV-specific T cells as early as 2 weeks after vaccination for
POL, Core or ENV. 4 out of 5 patients evaluated receiving
1010 or 1011 vp had response against at least 1 vaccine
antigen, 2 developed multi-antigen responses in the SD
cohort. Similarly, patients in the MD cohort with low NAd5
titers and receiving the 2 highest doses developed responses
against multiple antigens, mainly in the 1010 vp dose. In MD
patients with high NAd5 baseline titers ELISPOT data were
inconclusive. Decline of HBsAg was modest reaching 0.4 log.
Conclusion: The trial reached its safety primary endpoints
and demonstrated immunogenicity of TG1050 as well as its
capacity to break immune tolerance in CHB with improvement
of T cell responses to multiple HBV antigens, including ENV.
Data support future trials including combination studies with
other antiviral agents.
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