EASL2017 [GS-008] 罗非那泊与利托那韦的2期剂量优化研究 治疗慢

StephenW

GS-008
A phase 2 dose-optimization study of lonafarnib with ritonavir for
the treatment of chronic delta hepatitis—end of treatment results
from the LOWR HDV-2 study
C. Yurdaydin1, R. Idilman1, O. Keskin1, C. Kalkan1, M.F. Karakaya1,
A. Caliskan1, E. Yurdcu1, S.C. Karatayli1,M. Bozdayi1, C. Koh2, T. Heller2,
J. Glenn3. 1Gastroenterology, Ankara University, Ankara, Turkey; 2Liver
Diseases Virology Section, Liver Diseases Branch, NIH/NIDDK, Bethesda;
3Gastroenterology and Hepatology, Stanford University, San Francisco,
United States
E-mail: [email protected]
Background and Aims: Lonafarnib (LNF) is an oral prenylation
inhibitor with demonstrated efficacy in patients infected with
hepatitis delta virus (HDV). This class of agents is known to be
associated with gastrointestinal side effects. Results of the LOnafarnib
With Ritonavir for HDV (LOWR HDV-1) study demonstrated that coadministering
LNF with ritonavir (RTV), an inhibitor of LNF
metabolism, increases the post-absorption levels of LNF, yielding
greater efficacy with lower LNF doses compared to LNF monotherapy.
The aim of LOWR HDV-2 is to identify optimal combination regimens
of LNF and RTV ± PEG-IFNα with efficacy and tolerability for longer
term dosing to induce clinically meaningful reductions in HDV-RNA
and ALT normalization, or enable HDV-RNA clearance.
Methods: 48 patients to date have been enrolled in 3 groups of LNF in
combination with RTV ± PEG-IFNα for 12 or 24 weeks, followed by 24
weeks of treatment-free follow-up (FU). Groups were divided into
high dose LNF (≥75 mg BID) + RTV 100 mg BID (n = 15,12weeks), low
dose LNF (25 or 50 mg BID) + RTV 100 mg BID (n = 20, 24 weeks) and
low dose LNF (25 or 50 mg BID) + RTV 100 mg BID + PEG-IFNα
180 mcg QW (n = 13, 24 weeks). Biochemical parameters and
quantitative serum HDV-RNA viral loads were measured.
Results: Low dose regimens had comparable antiviral efficacy with
less GI side effects than the high dose regimens. On 24-week
treatment, LNF 25 mg BID + RTV resulted in a mean log decline of
−1.74 ( ± 1.20 log10 IU/ml), comparable to the historical response to
PEG-IFNα observed in HIDIT-2. LNF 25 mg BID + RTV + PEG-IFNα,
however, resulted in a mean log decline of −5.57 ( ± 1.99 log10 U/ml),
with 3 of 5 (60%) subjects becoming HDV-RNA PCR-negative and 5 of
5 (100%) of subjects achieving HDV-RNA BLOQ. 2 of 11 (18%) subjects
who completed 12 weeks of LNF 50 mg BID + RTV to date became
HDV-RNA PCR-negative. 9 of 15 (60%) subjects with elevated baseline
ALT have normalized ALT at Week 24. LNF 25 or 50 mg BID based
regimens were associated with mostly grade 1 GI AEs. Results from
EOT and FU visits will be presented.
Conclusions: Low dose LNF (25 or 50 mg BID) with RTV ± PEG-IFNα
including all-oral LNF 50 mg BID + RTV, lead to HDV-RNA PCRnegativity.
LNF 25 mg BID + RTV + PEG-IFNα leads to the highest rate
of HDV-RNA PCR-negativity on 24-week treatment, and suggests that
LNF and PEG-IFNα have synergistic activity. These regimens are
generally well-tolerated, supporting longer duration studies of
greater than 24 weeks, which may lead to HDV cure.

StephenW

EASL2017 [GS-008]

罗非那泊与利托那韦的2期剂量优化研究
治疗慢性三角洲肝炎治疗结果
来自LOWR HDV-2研究
C.Yurdaydin1，R. Idilman1，O.Keskin1，C.Kalkan1，M.F. Karakaya1，
A.Caliskan1，E.Yurdcu1，S.C.Karatayli1，M。 Bozdayi1，C. Koh2，T.Heller2，
格林3。 1安哥拉大学消化内科，土耳其安卡拉; 2肝
疾病病毒科，NIH / NIDDK，贝塞斯达肝病分科;
3G胃肠病学与肝病学，斯坦福大学，旧金山，
美国
电子邮件：[email protected]
背景和目的：Lonafarnib（LNF）是口服异戊烯基化
抑制剂在感染患者中具有疗效
乙型肝炎病毒（HDV）。这类代理人是已知的
与胃肠道副作用有关。 LOnafarnib的结果
利托那韦用于HDV（LOWR HDV-1）的研究表明，联合给药
LNF与利托那韦（RTV）是LNF的抑制剂
代谢增加LNF的吸收后水平，产生
与LNF单一疗法相比，LNF剂量较低的疗效更好。
LOWR HDV-2的目的是确定最佳组合方案
的LNF和RTV±PEG-IFNα，具有疗效和耐受性更长
长期给药以诱导HDV-RNA的临床有意义的降低
和ALT标准化，或启用HDV-RNA清除。
方法：迄今已有48例患者入选3组LNF
与RTV±PEG-IFNα组合12或24周，其次为24
几周免治疗随访（FU）。组分为
高剂量LNF（≥75mg BID）+ RTV 100 mg BID（n = 15,12周），低
剂量LNF（25或50mg BID）+ RTV 100mg BID（n = 20,24周）和
低剂量LNF（25或50mg BID）+ RTV 100mg BID + PEG-IFNα
180 mcg QW（n = 13,24周）。生物化学参数和
测定血清HDV-RNA定量定量病毒载量。
结果：低剂量方案与抗病毒疗效相当
较少的GI副作用比高剂量方案。 24周
治疗，LNF 25 mg BID + RTV导致平均对数下降
-1.74（±1.20 log10 IU / ml），与历史反应相当
在HIDIT-2中观察到PEG-IFNα。 LNF 25mg BID + RTV + PEG-IFNα，
然而，平均对数下降为-5.57（±1.99log10U / ml），
5名（60％）受试者中的3名成为HDV-RNA PCR阴性，5名
5（100％）受试者达到HDV-RNA BLOQ。 11（18％）科目中的2名
谁完成了12周的LNF 50毫克BID + RTV到目前为止
HDV-RNA PCR阴性。 15名（60％）受试者中有9名患有基线升高
ALT在第24周正常化ALT。LNF 25或50 mg BID为主
方案与大多数1级GI AE相关。由于。。。导致的结果
将介绍EOT和FU访问。
结论：低剂量LNF（25或50 mg BID）与RTV±PEG-IFNα
包括全口服LNF 50 mg BID + RTV，导致HDV-RNA PCR阴性。
LNF 25 mg BID + RTV + PEG-IFNα导致率最高
的HDV-RNA PCR阴性24周治疗，并表明
LNF和PEG-IFNα具有协同作用。这些方案是
普遍耐受性好，支持更长时间的研究
大于24周，这可能导致HDV治愈。