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标题: AASLD2016 [1869年]罗氏的TLR7 [打印本页]

作者: StephenW    时间: 2016-10-7 17:10     标题: AASLD2016 [1869年]罗氏的TLR7

1869
Optimization of a Phase 2 Study Design in Chronic
Hepatitis B (CHB) Patients Based on Safety, Pharmacokinetics
(PK) and Pharmacodynamics (PD) from Phase
1 Studies Using Two Prodrugs of a Toll-like Receptor 7
(TLR7) Agonist
Joseph Grippo2, Ilia Folitar1, Jeroen van de Wetering de Rooij3,
Sharon Passe4, David R. Blue4, Ignacio Rodriguez4, Scott H.
Fettner4, Elizabeth Calleja4; 1Roche Innovation Center Basel,
Basel, Switzerland; 2Clinical Pharmacology, Roche Innovation
Center New York, New York, NY; 3PRA Health Sciences, Groningen,
Netherlands; 4Roche Innovation Center New York, New
York, NY
Background: Given orally, RO6870868 (single prodrug) or
RO6864018 (double prodrug) rapidly convert to the TLR7
agonist RO6871765 (1765), which is being evaluated as an
immunomodulator to treat CHB. Clinical and non-clinical data
indicate that in general, safety and tolerability of TLR7 agonists
are associated with their PD effects. The relationship between
1765 exposures, PD biomarkers and safety from these Phase
1 studies were analyzed in order to optimize design of a
Phase 2 study in CHB patients. Methods: Safety, tolerability
and PK/PD after RO6870868 dosing were evaluated from a
single ascending dose study in 60 healthy volunteers (HVs).
Clinical data with RO6864018 dosing was collected from a
study including 41 HVs and 34 Hepatitis C (HCV) patients
who received single and/or multiple doses. Both studies were
double-blind, placebo-controlled and evaluated ascending
doses ranging from 200 to 2000 mg. TLR7 response markers
including neopterin, interferon (IFN)-α, IP-10, ISG-15, OAS1
and TLR7 were measured. Results: The 1765 PK profile was
comparable following oral administration of either prodrug
yielding similar dose-dependent effects. A minimal threshold
of 25 ug*hr/mL 1765 was required to initiate PD responses.
A temporal pattern of PK/PD response was found with 1765
exposures peaking at 1-2 hrs, TLR7 mRNA and IFN-α within
6 hours, OAS1, ISG-15 at ~12 hours and neopterin at 36 to
48 hours post dose. PK/PD correlations were found for neopterin,
IFN-α, IP-10, ISG-15, OAS1, MX1 and TLR7. Little or
no response was observed for TNF-α, IL-6, IL-10 or IL-12p40.
Doses up to 800 mg were well tolerated. Higher doses had
significant variability in tolerability and PD responses and were
associated with some reports of reversible flu-like symptoms.
The number of subjects with measureable systemic IFN, mean
IFN levels and the intensity of flu-like symptoms increased with
higher 1765 exposure. A multinomial logistic regression analysis
was conducted to relate outcomes defined by the presence
of systemic IFN and adverse events associated with flu-like
symptoms to 1765 exposure in subjects receiving RO6864018
every other day. This analysis enabled dose selection to exhibit
TLR7 responses and minimize flu-like symptoms. Conclusion:
Evaluation of clinical safety, PK and PD using two prodrugs of
a TLR7 agonist revealed similar responses and allowed better
design of a Phase 2 study in CHB patients evaluating different
doses and schedules to optimize TLR7 responses while minimizing
potential safety and tolerability liabilities.
Disclosures:
Joseph Grippo - Employment: Roche, Roche, Roche, Roche
Sharon Passe - Employment: Hoffmann-La Roche
David R. Blue - Employment: Hoffmann - La Roche
Ignacio Rodriguez - Employment: Hoffmann - La Roche
Scott H. Fettner - Employment: Hoffmann-LaRoche
Elizabeth Calleja - Employment: Roche
The following people have nothing to disclose: Ilia Folitar, Jeroen van de Wetering
de Rooij

作者: StephenW    时间: 2016-10-7 17:11

1869年
AASLD2016 [1869年]罗氏的TLR7
慢性阶段2试验设计的优化
乙肝基于安全(CHB)患者,药代动力学
从第一阶段(PK)和药效学(PD)
1研究使用Toll样受体7的两个前药
(TLR7)激动剂
约瑟夫Grippo2,伊利亚Folitar1,吉荣范·德·Wetering德Rooij3,
沙龙Passe4,大卫R. Blue4,伊格纳西奥Rodriguez4,斯科特H.
Fettner4,伊丽莎白Calleja4; 1Roche创新中心巴塞尔,
瑞士巴塞尔; 2Clinical药,罗氏创新
中心纽约,纽约,纽约州; 3PRA健康科学,格罗宁根,
荷兰; 4Roche创新中心,纽约,
纽约,NY
背景:口服,RO6870868(单药)或
RO6864018(双前体药物)迅速转换为TLR7
激动剂RO6871765(1765),其被评估为
免疫调节剂治疗慢性乙型肝炎。临床和非临床数据
表明,在TLR7激动剂的一般情况下,安全性和耐受
与它们的PD效应有关。之间的关系
1765暴露,PD生物标志物和安全从这些阶段
1研究以优化的设计进行分析
2期研究慢性乙型肝炎患者。方法:安全性,耐受性
和RO6870868给药后的PK / PD是从一个评估
在60名健康志愿者(HVS)单剂量递增的研究。
与RO6864018给药的临床数据是从收集的
研究包括41 HVS和34丙型肝炎(HCV)的患者
谁接收的单和/或多个剂量。这两项研究分别为
双盲,安慰剂对照,评价升序
剂量范围从200至2000毫克。 TLR7响应标记
包括新喋呤,干扰素(IFN)-α,IP-10,ISG 15,OAS1
和TLR7进行测定。结果:1765的PK分布为
或者前药可比口服给药后
产生相似的剂量依赖效应。一个最小的阈值
25微克*小时/ mL的1765被要求以引发PD响应。
PK / PD响应的时间模式被发现与1765
暴露在1-2小时,TLR7 mRNA和内IFN-α高峰
6小时后,OAS1,ISG在15〜12小时,在新蝶呤36
后48小时的剂量。 PK /被发现的蝶呤PD的相关性,
IFN-α,IP-10,ISG 15,OAS1,MX1和TLR7。很少或
观察到TNF-α,IL-6,IL-10或IL-12p40的没有反应。
剂量高达800mg的耐受性良好。高剂量的有
在耐受性和PD响应显著变化和人
与可逆流感样症状,一些报道有关。
与可测量全身IFN科目的数量,平均
干扰素水平和流感样症状具有增加的强度
高1765曝光。多项式logistic回归分析
被传导到相关的存在界定的成果
与流感样相关系统性IFN和不良事件
症状曝光1765接收RO6864018科目
每个另一天。这种分析使剂量选择展出
TLR7反应和减少流感样症状。结论:
使用两种前体药物临床安全性,PK和PD评价
一个TLR7激动剂透露类似的反应,并允许更好
在CHB患者2期研究评估不同的设计
剂量和方案优化TLR7反应,同时减少
潜在的安全性和耐受责任。
披露:
约瑟夫格里波 - 就业:罗氏公司,罗氏公司,罗氏公司,罗氏
沙龙过时了 - 就业:霍夫曼罗氏公司
大卫R.蓝 - 就业:霍夫曼 - 罗氏
伊格纳西奥·罗德里格斯 - 就业:霍夫曼 - 罗氏
斯科特H. Fettner - 就业:霍夫曼 - 罗氏公司
伊丽莎白CALLEJA - 就业:罗氏
下面的人都没有透露:伊利亚Folitar,吉荣范·德Wetering
德Rooij




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