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LB-33
TLR7 Agonist RO7020531 Triggers Immune
Activation after Multiple Doses in Chronic
Hepatitis B Patients
Dr. Edward J. Gane1, Dr. Kosh Agarwal2, Dr. Rozalina
Balabanska3, Dr. Yonghong Zhu4, Dr. Lu Gao4, Dr. Joseph
Grippo5, Dr. Yuyan Jin4, Dr. Miriam Triyatni6, Dr. Ilia Folitar6,
Ms. Ruchi Upmanyu7, Dr. Katerina Glavini6, Dr. Eoin Coakley5,
Dr. Tomas Racek6 and Prof. Man-Fung Yuen8, (1)Auckland
Clinical Studies, (2)Institute of Liver Studies, King’s College
Hospital NHS Trust, (3)Acibadem City Clinic, Tokuda Hospital
Sofia, (4)Roche Innovation Center Shanghai, (5)Roche
Innovation Center New York, (6)Roche Innovation Center
Basel, (7)Roche Products Ltd, (8)Department of Medicine,
University of Hong Kong, Queen Mary Hospital
Background: RO7020531 is a double prodrug of the active
toll-like receptor 7 (TLR7) agonist RO7011785 and is in
clinical development as a component of a curative treatment
regimen against chronic hepatitis B (CHB). RO7020531
previously demonstrated activation of TLR7 signaling in
healthy volunteers when given as single ascending doses
(SAD) and multiple ascending doses (MAD). These new
data from this study demonstrate the safety, tolerability,
pharmacokinetics (PK) and pharmacodynamics (PD) in
virologically suppressed CHB patients. Methods: This first
cohort of 10 virologically suppressed CHB patients received
150 mg RO7020531/placebo every other day (QOD) for 6
weeks and were followed up for 6 weeks after the last dose.
Safety, tolerability and PK were assessed. PD activity was
investigated by changes in protein and metabolite markers
(neopterin, IFN-α, IP-10, TNF-α, IL-6, IL-10, IL-12p40) as well
as in markers of transcriptional responses (ISG15, OAS-1,
MX1 and TLR7). Further cohorts of CHB patients are ongoing.
Results: Throughout 6 weeks of dosing, RO7020531 was
observed to be safe and with acceptable tolerability. A total
of 23 adverse events (AEs) were reported in 7/10 patients,
all of which were mild, with the exception of one AE of flu
like symptoms of moderate intensity. While no pattern of AEs
was observed, transient flu-like symptoms in 2 patients were
likely associated with PD effects. The PK characteristics
of active TLR7 agonist, RO7011785, in CHB patients were
similar to those observed in healthy subjects with no exposure
accumulation with the QOD dosing regimen. PD response,
consistent with TLR7 activation, was demonstrated across
all CHB patients. They exhibited various ranges of maximum
fold increase from baseline for the protein, metabolite and
transcriptional response markers (1.2- 36.4 fold for IP-10, 1.4-
6.1 fold for neopterin, 5.3 – 270.3 fold for ISG15, 2.5 – 41.5
fold for OAS-1, 5.6 – 87.4 fold for MX1 and 1.62- 6.84 fold
for TLR7). A clear positive correlation between exposure and
response in most of the PD markers was seen in both healthy
subjects and CHB patients. Conclusion: RO7020531 was
safe and had acceptable tolerability in 6-week QOD dosing
in CHB patients, with evidence of immune activation across
all patients. Based on these encouraging data, further CHB
patient cohorts are being enrolled to define the optimal dose,
which can be used in future studies in combination with other
HBV therapies towards a CHB cure regimen. |
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发表于 2018-12-8 18:42
