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本帖最后由 StephenW 于 2018-4-6 08:59 编辑
EASL 2018 FRI-327
Dose response and safety of the daily, oral RIG-I agonist Inarigivir
(SB 9200) in treatment naïve patients with chronic hepatitis B:
results from the 25mg and 50mg cohorts in the ACHIEVE trial
M.-F. Yuen1, M. Elkashab2, C.-Y. Chen3, C. Coffin4, S. Fung5,
S. Greenbloom6, J.W. Jang7, R.W.-J. Jeng8, D.J. Kim9, Y.J. Kim10,W. Kim11,
K.S. Lee12, Y.-S. Lim13, A. Ramji14, R. Iyer15, C. Macfarlane15,
K. Jackson16, S. Locarnini16, N. Afdhal15, H. Chan17. 1University of Hong
Kong; 2Toronto Liver Centre; 3Chia-Yi Christian Hospital; 4University of
Calgary; 5University of Toronto; 6Toronto Disgestive Disease Associates
Inc; 7The Catholic University of Korea; 8Chang-Gung University; 9Hallym
University College of Medicine; 10Seoul National University Hospital;
11Borame Medical Center; 12Yonsei University; 13Asan Medical Center;
14University of BC; 15Spring Bank Pharmaceuticals; 16VIDRL; 17Chinese
University of Hong Kong
Email: [email protected]
Background and Aims: Inarigivir (previously SB 9200) is an oral HBV
antiviral with both direct acting activity and immune-modulation
through activation of the pattern recognition receptor retinoic acidinducible
gene 1 (RIG-I). The ACHIEVE trial is a placebo controlled
trial of ascending doses of inarigivir daily or placebo for 12 weeks,
followed by a switch to 300mg tenofovir for 12weeks.We report here
the dose response at 25 mg (cohort 1) and 50 mg (cohort 2) daily of
Inarigivir on HBV DNA, HBsAg and HBV RNA.
Method: All patients were treatment naïve, non-cirrhotic with
elevated ALT. 20 patients per cohortwere randomized 4:1 to inarigivir
or placebo. Two patients in cohort 2 dropped out secondary to patient
preference at day 1 and week 2 and are not in the analysis. 38 of 40
patients were Asian and genotypes B/C predominated.
Results: No clinical or biochemical > grade 3 AE’s, no SAE’s and no
interferon like side effects reported. Overall 5 ALT flares > 200 IU/ml
were seen, 2 on placebo and three on Inarigivir. One inarigivir 50 mg
patient had an ALT of 487 IU/ml at week 4 and was switched to
tenofovir. Week 12 anti-viral response is shown in the Table.
Compared to placebo both HBV DNA (t-test, p < 0.001) and HBV
RNA (t-test, p = 0.008) declined in combined inarigivir 25 and 50 mg
cohorts. Overall HBeAg -ve patients had a greater anti-viral response
than HBeAg + ve patients. HBV DNA response was superior in those
with baseline HBV DNA < 6log10 and HBsAg < 4log10 irrespective of
HBeAg status indicating effect of viral burden on response. HBV RNA
was undetectable at week 12 in 2 of 7 patients with HBeAg –ve
disease in cohort 1 and all 4 patients in cohort 2. Overall 4 of 30
inarigivir treated patients had a > 0.5 log reduction in HBsAg.
Placebo
Inarigivir
25mgHBeAg
+ ve
Inarigivir
25 mgHBeAg
−ve
Inarigivir
50 mgHBeAg
+ ve
Inarigivir
50 mgHBeAg
−ve
Number 8 9 7 11 5
Age 38 37 43 36 47
Gender M:F 6 : 2 5 : 4 3 : 4 9 : 2 5
Baseline ALT 74 82 75 75 65
Baseline HBV
DNA log10
6.36 7.86 5.69 7.79 4.55
Change in DNA
(BL toweek 12)
log10
+0.33 −0.37 −0.86 −0.61 −1.05
Baseline HBsAg
log10
3.75 4.31 3.17 4.12 2.96
Change in HBsAg
(BL toweek 12)
log10
−0.18 −0.08 −0.34 −0.07 0
Baseline HBV
RNA log10
4.23 6.36 4.20 6.58 3.15
Change in HBV
RNA (BL to
week 12) log10
+0.99 −0.32 −1.84 −0.46 −3.15
Conclusion: Low dose Inarigivir is well tolerated and associated with
reduction in HBV DNA and HBV RNA. This effect is seen without a fully
activated immune response and consistent with a direct anti-viral
effect which may reflect targeting HBV RNA encapsidation.
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发表于 2018-4-6 08:47
