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本帖最后由 StephenW 于 2019-11-2 20:22 编辑
692
SAFETY, PHARMACOKINETIC, PHARMACODYNAMIC AND
VIRAL DATA AFTER 6-WEEKS OF DOSING WITH TLR7
AGONIST RO7020531 IN CHRONIC HEPATITIS B PATIENTS
Man-Fung Yuen1, Rozalina Ivanova Balabanska2, Kosh
Agarwal3, Yonghong Zhu4, Joseph Grippo5, Yuyan Jin4,
Qiudi Jiang4, Miriam Triyatni6, Ruchi Upmanyu7, Katerina
Glavini8, Tomas Racek8 and Edward J. Gane9, (1)University
of Hong Kong, Queen Mary Hospital, (2)Acibadem City Clinic,
Tokuda Hospital Sofia, (3)Institute of Liver Studies, King’s
College Hospital, (4)Roche Innovation Center Shanghai, (5)
Roche Innovation Centre New York, (6)Roche Innovation
Centre Basel, (7)Roche Innovation Center Welwyn, (8)
Roche Innovation Center Basel, (9)Auckland Clinical Studies,
Auckland, New Zealand
Background: RO7020531 is a double prodrug of the
active toll-like receptor 7 (TLR7) agonist RO7011785 in
clinical development for a curative regimen against chronic
hepatitis B (CHB). We present the interim data from 3 CHB
patient cohorts on safety, tolerability, pharmacokinetics (PK),
pharmacodynamics (PD) and HBsAg dynamics Methods:
Each cohort comprised 10 virologically suppressed CHB
patients (2 on placebo: 8 on active drug); 2 cohorts received
150 mg and 1 cohort received 170 mg RO7020531/placebo
orally every other day (QOD) for 6 weeks and patients
were followed up for further 6 weeks after the last dose
PD activity was investigated by changes in protein and
metabolite markers as well as in markers of transcriptional
responses Although 6 weeks of RO7020531 dosing is not
aimed to demonstrate efficacy, quantitative HBsAg levels
were measured at baseline, end of 6-week treatment (EOT)
and at end of 6-week follow up Results: Throughout 6
weeks of dosing, RO7020531 was safe and acceptably
tolerated A total of 87 adverse events (AEs) were reported
in 19/30 patients, most of which mild, except of 7 moderate
AEs reported in 4 patients and one severe AE (related flulike
symptoms after one dose) There were 2 study drug
discontinuations No pattern of AEs was observed, apart from
transient flu-like symptoms in 7 patients. PK parameters of the
active metabolite, RO7011785, in CHB patients are consistent
between Day 1 to Day 41 and comparable to those in healthy
volunteers PD activity consistent with TLR7 activation was
demonstrated and maintained following multiple doses at 150
mg, where more than 70% of the patients had a response in all
evaluated biomarkers Analysis of the PD data following 170
mg dose is ongoing There was high variability in the HBsAg
levels at baseline (1 01-25,010 IU/mL) The Mean (Standard
Deviation) HBsAg log10 decline at EOT was placebo: 0.0102
(0.0642); 150mg: 0.0243 (0.0845); 170mg: -0.0410 (0.1611)
and after 6 weeks of follow-up was placebo: -0.0457
(0.0644); 150mg: -0.0728 (0.1124); 170mg: -0.1392 (0.1508).
Conclusion: RO7020531 was safe and acceptably tolerated
in 6-week QOD dosing in CHB patients, with predictable PK
and solid evidence of immune activation across all patients
Conclusions on HBsAg dynamics could not be made due to
the short treatment duration RO7020531 is currently being
tested in not-treated CHB patients. Its clinical benefit in
promoting functional cure will be evaluated in combination
studies of longer duration. |
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发表于 2019-11-2 20:21