春季银行宣布推出使用Inarigivir 400mg强化免疫激活研究的有希

StephenW

Spring Bank Announces Presentation of Promising Results from Study Highlighting Immune-Activation with Inarigivir 400mg
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June 06, 2019 08:00 ET | Source: Spring Bank Pharmaceuticals, Inc.

HOPKINTON, Mass., June 06, 2019 (GLOBE NEWSWIRE) -- Spring Bank Pharmaceuticals, Inc. (Nasdaq: SBPH), a clinical-stage biopharmaceutical company developing novel therapeutics for the treatment of viral infections, inflammatory diseases and certain cancers, today announced it would present promising results from a healthy volunteer study highlighting the activation of the immune system with inarigivir soproxil 400mg, an orally administered hepato-selective immunomodulator, at The Science of HBV Cure 2019 meeting in Singapore on Saturday, June 8, 2019. The results from this study further demonstrate that inarigivir could become a backbone immune-activator in a combinatorial treatment for chronic hepatitis B virus (HBV) that accelerates and substantially increases functional cure rates for chronic HBV patients.

The results from this study demonstrate that, across all patients, inarigivir rapidly increased activation markers of innate immunity on circulating peripheral monocytes and dendritic cells, which was sustained over a ten-day period of dosing without evidence of tolerance. “Key opinion leaders in the field of hepatitis B treatment believe that re-activation of the chronic HBV patient’s immune system will be required to achieve a significant elevation in HBV functional cure rates,” said Kris Iyer, Ph.D., Spring Bank’s Chief Scientific Officer and Co-Founder. “The results from this study indicate that inarigivir could be a backbone immunomodulator in a combinatorial treatment for chronic HBV without the tolerability issues of interferon therapy as we strive to significantly enhance the functional cure rates for HBV patients.”

Professor Antonio Bertoletti, the Principal Investigator of the study at Duke–NUS Medical School in Singapore, added, “This new immune activation data for inarigivir combined with its effects on HBV DNA, HBV RNA and HBsAg presented in the recently-completed ACHIEVE trial serves as further confirmation of the mechanism of action of inarigivir as a selective immunomodulator for potential HBV cure. In this study, we evaluated immune activation in PBMCs and serum cytokines from healthy volunteers treated with inarigivir 400mg daily.  We conducted extensive flow cytometric analysis of selected immune cells using markers for T, NK and myeloid cell activation, and also performed NanoString® RNA analysis of PBMCs. We observed an associated activation of CD8+ T-cells and down-regulation of NK cells resulting in a potentially favorable adaptive immune profile of inarigivir for antiviral response. The results from this study also demonstrated a lack of systemic cytokine activation that is consistent with the selective intra-hepatic targeting of inarigivir, resulting in a favorable tolerability profile.”

Spring Bank will also present further data from the ACHIEVE trial on baseline biomarkers for inarigivir response, including baseline viral burden as determined by HBsAg levels, and the role of serum IP-10 and hepatitis B genotypes, at The Science of HBV Cure 2019 meeting. “The compelling data generated from the responder population in our ACHIEVE trial was instrumental in the design of our recently launched inarigivir CATALYST clinical program that could potentially elevate the clinical responses to inarigivir,” said Dr. Iyer. “We now have a much clearer understanding of the heterogeneity of response to inarigivir with respect to both host and viral factors in HBV patients, and we believe this knowledge will increase the likelihood of success with our inarigivir clinical program.”

Inarigivir Clinical Development
Spring Bank has recently launched two global Phase 2 trials (CATALYST 1 and CATALYST 2) examining the administration of inarigivir 400mg as monotherapy and co-administration with a NUC in naïve and virally-suppressed chronic HBV patients. The CATALYST trials include multiple patient cohorts with dosing periods to include 12 weeks, 24 weeks, and 48 weeks. These trials are designed to demonstrate functional cure in chronic HBV patients and Spring Bank could potentially be in a position to reveal functional cure data from one or more of these trials in 2020.

In addition, Gilead Sciences, Inc. is conducting a Phase 2 trial examining the co-administration of inarigivir  50mg and tenofovir alafenamide 25mg (marketed by Gilead as Vemlidy®) and the co-administration of inarigivir 200mg and Vemlidy® in naïve chronic HBV patients, as well as, the administration of inarigivir 100mg in virally-suppressed patients who currently are and continue to be treated with a NUC. Preliminary data from this trial is anticipated to be presented at a scientific conference later this year.

StephenW

春季银行宣布推出使用Inarigivir 400mg强化免疫激活研究的有希望的结果
电邮打印友好分享
2019年6月6日08:00 ET |资料来源：Spring Bank Pharmaceuticals，Inc。

马萨诸塞州霍普金顿，2019年6月6日（GLOBE NEWSWIRE） -  Spring Bank Pharmaceuticals，Inc。（纳斯达克股票代码：SBPH），一家临床阶段的生物制药公司，开发用于治疗病毒感染，炎症性疾病和某些癌症的新疗法，宣布它将在2019年6月8日星期六在新加坡举行的HBV Cure 2019年科学会议上用健康的志愿者研究提出有希望的结果，该研究强调免疫系统的激活，使用口服肝脏选择性免疫调节剂inarigivir soproxil 400mg。本研究进一步证明，inarigivir可成为慢性乙型肝炎病毒（HBV）组合治疗的骨干免疫激活剂，可加速并大幅提高慢性HBV患者的功能治愈率。

该研究的结果表明，在所有患者中，inarigivir迅速增加对循环外周单核细胞和树突细胞的先天免疫的活化标记，其持续超过10天的给药期而没有耐受性证据。乙型肝炎治疗领域认为，需要重新激活慢性HBV患者的免疫系统，以实现HBV功能治愈率的显着提升，“春天银行首席科学官兼联合创始人Kris Iyer博士说。 “这项研究的结果表明，在没有干扰素治疗的耐受性问题的情况下，inarigivir可能是慢性HBV组合治疗中的骨架免疫调节剂，因为我们努力显着提高HBV患者的功能治愈率。”

新加坡杜克新加坡国立大学医学院研究的首席研究员Antonio Bertoletti教授补充说：“这项针对inarigivir的新免疫激活数据结合其最近完成的ACHIEVE试验中对HBV DNA，HBV RNA和HBsAg的影响服务作为进一步确认inarigivir作为潜在HBV治愈的选择性免疫调节剂的作用机制。在这项研究中，我们研究了每天400mg inarigivir治疗的健康志愿者的PBMC和血清细胞因子的免疫激活。我们使用T，NK和骨髓细胞激活标记对选定的免疫细胞进行了广泛的流式细胞术分析，并对PBMC进行了NanoString®RNA分析。我们观察到CD8 + T细胞的相关活化和NK细胞的下调，导致抗病毒应答的inarigivir的潜在有利的适应性免疫谱。该研究的结果还表明缺乏全身细胞因子激活，与肝内注射选择性肝内靶向无关，导致良好的耐受性特征。

Spring Bank还将在ACVIEVE试验中提供关于inarigivir反应基线生物标志物的进一步数据，包括HBsAg水平确定的基线病毒负荷，以及血清IP-10和乙型肝炎基因型的作用，参见HBV治愈2019年会议。 “我们的ACHIEVE试验中响应者群体产生的令人信服的数据有助于我们最近推出的inarigivir CATALYST临床计划的设计，该计划可能会提高对inarigivir的临床反应，”Iyer博士说。 “我们现在对HBV患者宿主和病毒因子对inarigivir反应的异质性有了更清晰的认识，我们相信这些知识将增加我们的inarigivir临床计划成功的可能性。”

Inarigivir临床开发
Spring Bank最近推出了两项全球第二阶段试验（CATALYST 1和CATALYST 2），检测了inarigivir 400mg作为单药治疗和与幼稚和病毒抑制慢性HBV患者的NUC共同给药。 CATALYST试验包括多个患者队列，其给药期包括12周，24周和48周。这些试验旨在证明慢性HBV患者的功能性治愈，Spring Bank可能有可能在2020年从一项或多项试验中揭示功能性治愈数据。

此外，Gilead Sciences，Inc。正在进行一项2期试验，研究共同给予inarigivir 50mg和tenofovir alafenamide 25mg（由Gilead作为Vemlidy®销售）以及inarigivir 200mg和Vemlidy®在初治慢性HBV患者中的共同给药以及在目前并且继续用NUC治疗的病毒抑制患者中给予inarigivir 100mg的剂量。该试验的初步数据预计将在今年晚些时候的科学会议上公布。

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它将在2019年6月8日星期六在新加坡举行的HBV Cure 2019年科学会议上用健康的志愿者研究提出有希望的结果

平凡之路123

好消息！

mingbai

今天8号了，有新消息吗？

StephenW

mingbai 发表于 2019-6-8 21:05
今天8号了，有新消息吗？

https://ir.springbankpharm.com/s ... 3-bc5b-380fc32799a8

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The Science of HBV Cure Meeting – June 8, 2019
Update on Inarigivir: a novel RIG-I agonist to stimulate
Innate Immunity and promote functional cure in
chronic HBV
Nezam Afdhal MD, DSc
Chief of Gastroenterology, Hepatology and Nutrition, BIDMC
Charlotte and Irving Rabb Professor of Medicine,
Harvard Medical School
1
Forward Looking Statements
This presentation includes forward-looking statements within the meaning of the
Private Securities Litigation Reform Act of 1995. Forward-looking statements
include, among other things, statements, other than historical facts, regarding: the
progress, scope, duration or results of clinical trials and preclinical studies of
inarigivir soproxil (“inarigivir”), SB 9225 or any of our other product candidates or
programs, such as the size, design, population, conduct, cost, objective or
endpoints of any clinical trial, or the timing for initiation or completion of or
availability of results from any clinical trial (including our Phase 2 clinical trials of
inarigivir in patients with chronic Hepatitis B virus); the potential benefits that may
be derived from any of our product candidates; our future operations, financial
position, revenues, costs, expenses, uses of cash, capital requirements or our need
for additional financing; or our strategies, goals, milestones, prospects, beliefs,
intentions, plans, expectations, forecasts or objectives. Words such as
“anticipates,” “believes,” “plans,” “expects,” “projects,” “future,” “intends,” “may,”
“will,” “should,” “could,” “estimates,” “predicts,” “potential,” “continue,”
“guidance,” and similar expressions sometimes identify forward-looking
statements. Any forward-looking statement involves known and unknown risks,
uncertainties and other factors that may cause our actual results, levels of activity,
performance or achievements to differ materially from those expressed or implied
by such forward-looking statement, and, therefore, you are cautioned not to place
undue reliance on any forward-looking statement. These factors include, but are
not limited to: whether our cash resources will be sufficient to fund our continuing
operations for the period anticipated; the components, timing, costs and results of
our clinical trials, preclinical studies and other development activities involving our
product candidates; whether certain top-line results from our clinical trials
materially change as more information becomes available; whether results
obtained in preclinical studies and clinical trials will be indicative of results
obtained in future clinical trials; whether inarigivir, SB 9225 or any of our other
product candidates will advance through the clinical trial process on a timely basis
and receive approval from the United States Food and Drug Administration or
equivalent foreign regulatory agencies; and whether, if inarigivir or any of our
other product candidates obtain regulatory approval, it will be successfully
distributed and marketed. These and other risks and uncertainties that we face are
described in our most recent Annual Report on Form 10-K, filed with the Securities
and Exchange Commission (SEC) on March 11, 2019, and in other filings that we
make with the SEC from time to time.
All forward-looking statements speak only as of June 8, 2019 and should not be
relied upon as representing our views as of any other date. We specifically disclaim
any obligation to update any forward-looking statement, except as required by
applicable law. All trademarks, service marks, trade names, logos and brand names
identified in this presentation are the properties of their respective owners.
This presentation also contains estimates and other statistical data generated by
independent parties and by us relating to market size and statistics. These
estimates involve a number of assumptions and limitations, and you are cautioned
not to give undue weight to such estimates.
2
Inarigivir – Hepatic-Selective Immunomodulator with a Dual Mechanism
of Action
RIG-I
RIG-I
TYPE III
IFNs
OATP1
DAA EFFECT
TARGETING
REPLICATION
COMPLEX
HBV pgRNA
5’ 3’
HBV pgRNA
5’ 3’
HBV polymerase
Reverse
transcription
Viral
replication
ε ε
INARIGIVIR
Hepatocyte
RIG-I ACTIVATION
AND BINDING TO
HBV PGRNA
NNRTI
Dual antiviral effect against HBV
Inarigivir is a RIG–I Agonist designed to:
• Restore hepatic-selective innate and
adaptive immune response1
stimulating the production of type I and
III IFNs without systemic toxicity
• Inhibit the HBV replication complex via
a direct acting antiviral effect as a nonnucleoside
reverse transcript inhibitor
(NNRTI)
• Target cccDNA and is only oral agent
to demonstrate reduction in HBV DNA,
HBV RNA and HBsAg
• Potential backbone immunomodulator
for combinatorial treatments of HBV
1 Sato et al. Immunity. 2015;42:123-132.
3
14 healthy volunteers
Inarigivir 400 mg /Daily
0 4h 12h
Day 1 Day 12
11 Days 400 mg
Samples 0 2h 6h 24h
Cytokines in sera (IFN-a, IP-10, TNF-a, IFN-g, IL-6, IL-12p70)
PBMC for flow cytometry analysis (T, NK, myeloid cells activation)
PBMC for Nanostring analysis
HEALTHY VOLUNTEERS TRIAL DESIGN
4
Results summary
• Serum cytokine levels of IFN-a, IFN-g, TNF-a, IL-6 and IL-12p70 were
undetectable while IP-10 levels declined after inarigivir treatment.
• As early as 2h post treatment, phenotypic analysis showed uniform up- regulation of activation markers on monocytes (CCR2, CD16, CD86) and
dendritic cells (CD86).
• The frequency of peripheral NK and CD8+ T cells declined and was
associated with reduction of activating receptor NKG2D (NK cells) and
increase of activation markers CD39 and HLA-DR (T cells).
• Measurements of immune cell activation before and after the first and
final dose demonstrated a similar response with no evidence of
tolerance.
5
Conclusion
• Inarigivir transiently modifies expression of activation markers on
circulating immune cells in a uniform and non-tolerance inducing
manner, without an associated increase of serum cytokines.
• These findings validate inarigivir’s ability to activate intracellular
innate immune pathways with a safety profile that demonstrates
minimal serum cytokine activation and toxicity.
6
PRIMARY
ENDPOINT
SECONDARY
ENDPOINTS
Safety and HBV
DNA reduction at
12 weeks
PK, change in serum HBV DNA, HBsAg,
HBV RNA, HBcrAg and HBeAg from
baseline to weeks 12 and 24
Up to 80
non-cirrhotic
HBV subjects,
randomized 4:1
between inarigivir and
placebo Inarigivir - 200 mg
Placebo
Inarigivir - 100 mg
Inarigivir - 50 mg
Inarigivir - 25 mg
Tenofovir 300 mg daily
All patients switch to tenofovir 300
mg monotherapy
12 weeks (inarigivir monotherapy QD)
12 weeks
Inarigivir monotherapy 12 weeks followed by switch to Tenofovir 300 mg for 12 weeks
Cohort 1
Cohort 2
Cohort 3
Cohort 4
ACHIEVE Phase 2 Dose Escalation Study
Pbo
Epos
Pbo
Eneg
E+ve
25mg
E-ve
25mg
E+ve
50mg
E-ve
50mg
E+ve
100 mg
E-ve
100 mg
E+ve
200 mg
E-ve
200 mg
n 8 8 9 7 11 5 13 4 8 7
Age 35 48 37 43 36 47 34 46 42 52
M:F 7:1 5:3 5:5 3:3 9:2 5:0 7:6 3:1 4:4 2:5
ALT 85 53 82 75 75 65 75 90 54 73
HBV DNA 7.64 4.75 7.86 5.69 7.79 4.55 8.20 5.95 7.88 4.95
HBV RNA 6.44 2.23 6.36 4.2 6.58 1.54 7.23 2.77 6.68 2.86
HBsAg 4.17 2.79 4.32 3.17 4.13 2.96 4.38 2.68 4.15 2.72
GT A 1 1
GT B 2 6 4 3 3 4 4 3 2 5
GT C 6 1 5 1 7 1 8 1 6 2
GT D 2 1 1
Mean Baseline Demographics by IRIG Dosing Cohort and HBeAg status
* 9 HBeAg negative patients had undetectable HBV RNA at baseline 8
IRIG Dose (mg)
Log10
Primary Endpoint: Mean Change from Baseline
in HBV DNA to Week 12 in Placebo (PL) and IRIG cohorts
-0.02
-0.58
-0.73
-0.95
-1.54
9
Week 12 PL or IRIG
Week 24 TDF 300mg
Mean change
(per cohort)
Log10
HBeAg positive patients: Change from Baseline
in HBV DNA at Week 12 and Week 24
P< 0.01: IRIG 50, 100 and
200mg vs PL
PL 25mg 50mg 100mg 200mg PL 25mg 50mg 100mg 200mg
TDF 300mg switch
WEEKS 0 – 12 WEEKS 12 - 24
10
Week 12 PL or IRIG
Week 24 TDF 300mg
Log10
HBeAg negative patients: Change from Baseline
in HBV DNA at Week 12 and Week 24
P< 0.01: IRIG 100mg and
200mg versus PL
PL 25mg 50mg 100mg 200mg PL 25mg 50mg 100mg 200mg
TDF 300mg switch
WEEKS 0 – 12 WEEKS 12 - 24
Week 12 PL or IRIG
Week 24 TDF 300mg
Mean change
(per cohort)
18 of 22 (82%) patients undetectable at week 24 11
Week 12 PL or IRIG
Week 24 TDF 300mg
Log10
HBeAg positive patients: Change from Baseline
in HBV RNA at Week 12 and Week 24
P< 0.01: IRIG 50, 100 and
200mg vs PL
PL 25mg 50mg 100mg 200mg PL 25mg 50mg 100mg 200mg
TDF 300mg switch
WEEKS 0 – 12 WEEKS 12 - 24
Week 12 PL or IRIG
Week 24 TDF 300mg
Mean change
(per cohort)
12
Log10
PL 25mg 50mg 100mg 200mg PL 25mg 50mg 100mg 200mg
TDF 300mg switch
WEEKS 0 – 12 WEEKS 12 - 24
HBeAg negative patients: Change from Baseline
in HBV RNA at Week 12 and Week 24
P =0.05: All cohorts combined
versus PL at week 12
3 placebo and 6 IRIG undetectable
HBV RNA at baseline. 1 placebo became
replicative and detectable at week 12
Week 12 PL or IRIG
Week 24 TDF 300mg
Mean change
(per cohort)
13
Positive Predictors of Response to IRIG
• HBV DNA and HBV RNA
• HBeAg negative – pre-core mutations > core promoter
mutations alone
• Baseline HBsAg < 4log10
• Baseline IP-10 > 310ng/L
• Reduction in IP-10 > 110ng/L between baseline and week
12
• HBsAg
• Genotype B > C
• Good responses genotype A / D but numbers small
14
Baseline HBsAg cutoff of 4log10 Predictor of HBV DNA and
HBV RNA Response to IRIG at Week 12
Change from Baseline
to Week 12 log10
HBV DNA
HBV RNA
Mean change
Baseline HBsAg <4log10 >4log10 <4log10 >4log10
P < 0.001 for both HBV DNA
and HBV RNA
24 HbeAg +ve and 1 HBeAg-ve > 4log10
16 HBeAg +ve and 21 HBeAg -ve < 4log10 15
Genotype A B C D
HBsAg change in log10
Percentage of responders
within each Genotype
GT A 100%
GT B 33%
GT C 10%
GT D 75%
HBsAg Response (> 0.5log10) by Genotype
Genotype response data consistent with
that seen with IFN therapy
16
Week 12
>0.5log10
Week 24
>0.5log10
Total
Responders
Placebo /TDF 1* 2* 2 *ALT flare
> 400 IU/ml
IRIG 25mg/TDF 4# 6 8 # 2 non
sustained of
which 1 dose
reduced
IRIG 50mg/TDF 1$ 2 2 $ 1 non
sustained and
dose reduced
IRIG 100mg/TDF 1 2 2 1 non-sustained
with a flare
IRIG 200mg/TDF 1 3 3 2 GT C patients
Secondary Endpoint: Predefined Responders
with HBsAg Reduction of > 0.5log10
• 16 IRIG patients (26%) met
predefined HBsAg loss criteria
for response at week 12 or 24
• Response in 7 HBeAg negative
(mean 0.7log10) and 9 HBeAg
positive (mean 0.9log10)
• Overall mean responder
reduction of 0.8log10 (range 0.5 –
1.4log10)
17
Mean Change in HbsAg
Week 12: 0.4log10
Range 0.1 – 0.9log10
Week 24: 0.72log10
Range 0.15 - 1.4log10
HBeAg +
HBeAg -
Quantitative HBsAg in Responder Patients > 0.5log10 Reduction
at Week 12 or Week 24 from Baseline
HBsAg
log10
WEEK 0 12 24
Inarigivir Tenofovir
11 of 16 patients had
evidence of HBsAg
reduction in
weeks 0 – 12 on IRIG
18
19 year old Asian male, GT B,
HBeAg positive, IL28b CC
IRIG 200mg Responder – Transcription Inhibition
Continued on TDF Switch
log10
WEEK
• Responder at week 12 all parameters 0.5 – 1 log10
mini ALT flare to 150 IU/ml on switch to TDF with further
reduction
19
Two distinct populations of HBeAg-ve patients for HBsAg response
• 7 responders (HbsAg >0.5log reduction) and 12 non-responders (< 0.1 log
reduction) to IRIG
• Non-responders are a clear subset of non-transcriptionally active patients
(low / undetectable HBV RNA and HBcrAg) despite elevated ALT and HBV
DNA
• Non-replicative subset less likely to have early HBsAg response and should
be accounted for in novel treatment trials
• Rapid cessation of viral production in all IRIG patients – Will duration have
an impact for HBsAg loss?
• Non-replicative subset represents a target population for prolonged HBV
DNA suppression after stopping treatment
20
CATALYST 1 - Global Inarigivir HBV Phase 2b Trial
21
Inarigivir 400mg monotherapy & co-administration with Vemlidy® (tenofovir alafenamide)
25mg HBeAg –ve and +ve non-cirrhotic treatment naïve HBV patients
Response-Guided Trial Design
IRIG 400mg
monotherapy
once daily
12 weeks 12 weeks
IRIG 400mg
monotherapy
3x weekly
IRIG 400mg once
daily + Vemlidy®
25mg once daily
IRIG 400mg 3x
weekly + Vemlidy®
25mg once daily
Vemlidy® 25mg
once daily
Responders
Non-responders
IRIG 400mg +
Vemlidy® 25mg
once daily
IRIG 400mg once daily co-administered
with Vemlidy® 25mg once daily
Capability to observe functional cure
Key endpoints:
HBV DNA & RNA reductions,
HBeAg loss & HBsAg decline/loss
Response at 24
weeks:
HBsAg
>0.5log₁₀
decline &
undetectable
HBV DNA
Together with data from Gilead’s trial of inarigivir + Vemlidy®, will inform Phase 3
treatment-naïve strategy for SB 9225 (IRIG + tenofovir disoproxil fumarate) fixed-dose combination
n=20
n=20
n=20
24 weeks
No treatment – follow to
observe
sustained HBsAg loss
IRIG 400mg monotherapy
once daily
CATALYST 2 - Global Inarigivir HBV Phase 2b Trial
22
24 weeks
Up to week 96
n=40
n=20
Capability to observe functional cure
Cohort 1 – “Stop & Shock”
Stop NUC
therapy
“Shock” with inarigivir
Cohort 2 – “Suppress & Shock”
Key endpoints:
ALT Flare
HBsAg loss
fine needle
aspirase (FNA)
Key endpoint:
HBsAg
loss/reduction
+
Intra-hepatic
virology &
Immunology with
Liver FNA
Inarigivir 400mg in virally suppressed –ve, non-cirrhotic chronic
HBV patients
Will inform Phase 3 program in virally-suppressed patients in 2020
IRIG 400mg monotherapy once
daily added to NUC therapy
Continue
NUC
therapy
24 – 48 weeks Up to week 96
No treatment – follow to
observe
sustained HBsAg loss
Conclusion
• IRIG continuing to be developed as a backbone immunomodulator in
combination studies with agents having different MOAs
• IRIG + NUC studies for up to 1 year in progress with focus on
biomarkers for patient heterogeneity and anti-viral response
• CATALYST trials will evaluate sustained response in naive and
suppressed patients
• Triple therapy combinations under development
23
Acknowledgements
Spring Bank Pharmaceuticals, Inc. would like to thank the ACHIEVE
Investigators and their coordinating staff for their participation and the
patients and their families
Locarnini Laboratory at VIDRL for Central Virology
Dr. Michael Beard, University of Adelaide for cytokine analysis
Dr. Danny Wong, University of Hong Kong, HBcrAg analysis
Gilead Sciences for clinical trial collaboration and providing tenofovir
2

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不错

yyjj777

inarigivir 200mg +taf25 mg 也许就可以治愈一部分。 强生的 三联用药估计太昂贵了。