CONTROL ID: 1542128
Co-Author Disclosure Status
PRESENTATION TYPE: Late Breaking Oral or Poster
CURRENT CATEGORY: Hepatitis B
CURRENT DESCRIPTORS: I02. Treatment and Clinical Trials
TITLE: Peginterferon Lambda, a New Potential Therapeutic Option for the Treatment of Chronic Hepatitis B: A Phase 2B Comparison with Peginterferon Alfa in Patients with HBeAg-Positive Disease
AUTHORS (FIRST NAME, LAST NAME): Henry Lik-Yuen Chan1, Sang Hoon Ahn2, Ting-Tsung Chang3, Cheng-Yuan Peng4, David K. Wong5, Carla S. Coffin6, Seng Gee Lim7, Pei-Jer Chen8, Harry L. Janssen9, Patrick Marcellin10, Lawrence Serfaty 11, Stefan Zeuzem12, Wenhua Hu13, Linda Critelli13, Juan Carlos Lopez-Talavera13, Elizabeth L. Cooney13
Institutional Author(s): INSTITUTIONS (ALL): 1. Chinese University of Hong Kong, Hong Kong SAR, China.
2. Yonsei University Severance Hospital, Seoul, Korea, Republic of.
3. National Chen Kung University Hospital, Tainan, Taiwan.
4. China Medical University Hospital, Taichung, Taiwan.
5. Toronto Western Hospital University Health Network, Toronto, ON, Canada.
6. Liver Unit, Division of Gastroenterology and Hepatology, University of Calgary, Calgary, AB, Canada.
7. National University Hospital, Singapore, Singapore.
8. National Taiwan University Hospital, Taipei, Taiwan.
9. Erasmus Medical Center, Rotterdam, Netherlands.
10. Hôpital Beaujon, Clichy, France.
11. Hôpital Saint Antoine, Paris, France.
12. Johann Wolfgang Goethe University, Frankfurt, Germany.
13. Bristol-Myers Squibb Research and Development, Wallingford, CT, United States.
ABSTRACT BODY: Background
For patients with chronic hepatitis B (CHB), peginterferon alfa (Alfa) offers benefits of finite treatment, no resistance and higher rates of sustained off-treatment response than HBV nucleos(t)ide analogues; however, frequent adverse events (AE) can compromise efficacy. Peginterferon Lambda-1a (Lambda), a type III interferon, has shown greater early virologic effect and improved tolerability vs Alfa in chronic HCV infection. We report interim Week 24 results from the first comparison of Lambda and Alfa in patients with CHB.
Methods
Adult HBeAg+, interferon-naïve patients with HBV DNA >105 IU/mL and elevated ALT were randomly assigned (1:1) to receive 180µg Lambda or Alfa-2a weekly for 48 weeks. The primary efficacy endpoint is HBeAg seroconversion 24 weeks post-dosing; we present efficacy data through week 24 and cumulative safety data.
Results
The treated population (Lambda, N=80; Alfa, N=83) was of mean age 35.5 years, 76% male, 89% Asian; mean baseline HBV DNA=7.76 log10 IU/mL and mean ALT=139 U/L. Predominant HBV genotypes were B (31%) and C (55%). Through week 24, Lambda recipients had significantly greater reduction in HBsAg levels and more pronounced decline in HBV DNA vs Alfa; HBeAg responses were comparable (Table). Two patients (both Lambda) cleared HBsAg. AEs were common (90% in both groups), but discontinuations were infrequent (4 Lambda, 7 Alfa) and AE spectra differed. Alfa was associated with higher rates of pyrexia (45% vs 10% with Lambda), alopecia (28% vs 9%), headache (29% vs 14%), myalgia (21% vs 3%), grade 1–4 neutropenia (76% vs 8%), and dose reductions (25% vs 8%, mainly due to neutropenia). Total bilirubin elevations were more frequent with Lambda (14% vs 2% with Alfa), but grade 3–4 events were uncommon (2.5% vs 0%). Lambda-treated patients had more frequent grade 3–4 ALT elevations (41% vs 23% with Alfa) and ALT flares (ALT >10x ULN and >2x baseline; 15% vs 7%). 85% of Lambda-associated flares were asymptomatic and preceded by an HBV DNA decline; 25% were followed by HBeAg seroconversion.
Conclusions
Lambda demonstrated greater early efficacy than Alfa, as defined by HBV DNA and qHBsAg change from baseline; HBeAg responses were comparable. There were fewer hematologic abnormalities and flu-like or musculoskeletal symptoms with Lambda vs Alfa. These favorable results are consistent with findings from Lambda studies in HCV and support ongoing study of Lambda in CHB. | Lambda
Week 12 | Alfa
Week 12 | P value | Lambda
Week 24 | Alfa
Week 24 | P value | HBV DNA change from baseline, log10 IU/mL | -2.58 | -1.78 | 0.0018 | -2.77 | -2.28 | 0.1203 | HBsAg change from baseline, log10 IU/mL | -0.67 | -0.27 | 0.0002 | -0.65 | -0.33 | 0.0075 | HBeAg seroconversion, n/N (%) | 5/80 (6.3) | 5/83 (6.0) | | 5/80 (6.3) | 7/83 (8.4) | | ALT normalization, n/N (%) | 17/80 (21) | 18/83 (22) | | 19/80 (24) | 28/83 (34) | |
译文摘要： 背景：对于慢性乙型肝炎患者来说，对比核苷（酸）类似物，聚乙二醇干扰素α治疗好处更多，无耐药性且治疗后仍能获得较高的持续应答，然而，其常见的不良反应对疗效有所影响。聚乙二醇干扰素λ-1A（λ）为一类III型干扰素，治疗丙型肝炎时，其早期病毒学性表现比α干扰素更强。在治疗慢性乙型肝炎病人方面，我们第一次将聚乙二醇干扰素λ-1A（λ）与聚乙二醇干扰素α作比较，并公布中期24周结果。 方法：
两组干扰素初治患者（数量为1：1），成人， e抗原阳性，DNA >10^5IU/mL，ALT升高，他们被随机分配，接受180µg聚乙二醇干扰素λ-1A（λ）或聚乙二醇干扰素α治疗，治疗期为48周。主要疗效的终点是给药后24周实现e抗原血清学转换，我们在此发布24周疗效数据。 结果： 治疗人群(λ：80例，α：83例)的平均年龄为35.5岁，76%为男性，89%为亚洲人，HBV DNA平均基线为7.76 log10，ALT平均为139U/L。主要的HBV基因类型为B（31%）及C（55%）。24周后，对比接受α治疗的患者，接受λ治疗的表面抗原（HBsAg）及HBV DNA水平都得到更明显的减少或下降（见表）。两例患者（均接受λ治疗）达到表面抗原（HBsAg）清除。两种干扰素的不良反应都较为普遍且形式各异（两组的比例均为90%），但极少停药（λ：4例，α：7例)。α引起发烧的比例更高（45%，而λ是10%），脱发(α：28% ，λ： 9%)，头痛(α：29% ，λ： 14%)，肌痛(α：21% ，λ： 3%)，中性粒细胞减少1-4级(α：76% ，λ： 8%)，剂量减少(α：25% ，λ： 8%，主要由于中性粒细胞减少)。λ导致总胆红素升高概率更高(14%，而α是2%)，但极少发生3-4级升高的情况(α：2.5% ，λ： 0%)。接受λ治疗的病人较常发生ALT 3-4级升高 (41%，而α是23%)，ALT飙升的情况也比较多（ALT 大于10倍ULN以及大于2倍基线，λ： 15%，α：7%）。85%由λ引起的ALT飙升在HBV DNA下降后出现，没有临床症状，25%随后出现E抗原血清学转换。 结论： λ干扰素比α表现出更强的早期疗效，HBV DNA及表面抗原基于基线的变化即可看出，而E抗原应答方面，λ干扰素也更出色。对比α干扰素，λ造成的血液学异常、类流感症状以及肌肉与骨骼症状较少。λ在治疗丙型肝炎的研究以及当前进行的治疗慢性乙型肝炎的研究方面，一致得出此有利结果。 |
| λ
12周
| α 12周 | P 值 | λ
24周 | α24周 | P值 | | HBV DNA 基于基线变化 log10 IU/mL | -2.58 | -1.78 | 0.0018 | -2.77 | -2.28 | 0.1203 | | HBsAg基于基线变化, log10 IU/mL | -0.67 | -0.27 | 0.0002 | -0.65 | -0.33 | 0.0075 | | HBeAg 血清学转换, n/N (%) | 5/80 (6.3) | 5/83 (6.0) |
| 5/80 (6.3) | 7/83 (8.4) |
| | ALT 正常, n/N (%) | 17/80 (21) | 18/83 (22) |
| 19/80 (24) | 28/83 (34) |
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发表于 2012-10-26 17:09
