Daclatasvir和Asunaprevir双重治疗表现出很高的治愈率在HCV基因型1

StephenW

www.natap.org

Data Presented at APASL from First Completed Phase 3 Trial of All-oral Chronic Hepatitis C Regimen in Chinese Patient Population Shows Daclatasvir and Asunaprevir DUAL Therapy Demonstrated High Cure Rates Among HCV Genotype 1b Patients

Monday, February 22, 2016 6:59 am EST

"These results signal that the daclatasvir and asunaprevir regimen could provide a highly effective all-oral, interferon- and ribavirin-free treatment for many Chinese HCV patients with genotype 1b infection”

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) today announced data from the first completed all-oral chronic hepatitis C (HCV) regimen Phase 3 trial that includes a Chinese patient population. The results of the registrational trial, which studied daclatasvir in combination with asunaprevir for 24 weeks in Asian (non-Japanese) patients with genotype 1b HCV, were presented today at the Asian Pacific Association for the Study of the Liver Conference (APASL) in Tokyo. Genotype 1b is particularly prevalent in China, where interferon/ribavirin combination regimens are still the current standard of care.

The primary endpoint of the study was sustained virologic response at post-treatment week 24 (SVR24). In the study, 91% of patients from China achieved SVR24, which rose to 98% of patients without NS5A resistance-associated variants (RAVs) at baseline. SVR24 results were similarly high across all subgroups with genotype 1b HCV, including those with cirrhosis (90%), and patients from Korea (94%) and Taiwan (87%).

SVR24 rates were also higher in all patients without baseline NS5A RAVs (n=137/139 [99%]), regardless of the presence (98%) or absence (99%) of cirrhosis, and lower in patients with baseline NS5A RAVs (n=8/19 [42%]). Baseline NS5A RAVs were present in 12% of patients. HCV NS5A RAVs exist naturally (albeit in lower prevalence vs wildtype) and can emerge after virologic response failure. Screening for the presence of specific NS5A mutations can help physicians determine the best patients for treatment by identifying those most likely to achieve cure with an NS5A-containing regimen.

In the trial presented today, across all patient cohorts, all serious adverse events (SAEs) (n=5/159 [3%]), grade 4 laboratory abnormalities (n=3/159 [1.9%]) and deaths (n=1/159 [1%]) that occurred on treatment were unrelated to the study drugs. Two patients discontinued due to adverse events (AEs). The most common AEs (> 5% of patients) were decrease in platelets (9%), upper respiratory tract infection (8%), ALT increase (7%), ANC decrease (7%), monocyte decrease (6%), white blood cell decrease (6%), thrombocytopenia (6%), and pruritus (6%).

“These results signal that the daclatasvir and asunaprevir regimen could provide a highly effective all-oral, interferon- and ribavirin-free treatment for many Chinese HCV patients with genotype 1b infection,” said Dr. Lai Wei, Professor of Hepatology & Medicine and Director, Peking University Hepatology Institute, Chief, Department of Hepatology, Peking University People’s Hospital. “This is an important finding because the burden of HCV in China is extremely high, and newer direct-acting antivirals have yet to be introduced for any patients.”

The daclatasvir and asunaprevir regimen already is approved by regulatory authorities in several countries across the Asia Pacific region, including Japan, Korea and Taiwan, as well as in some countries in Latin America and Eastern Europe. At APASL, Bristol-Myers Squibb is also presenting other data for the daclatasvir and asunaprevir regimen in Asian populations, including integrated safety, pooled resistance and pooled exposure data.

“So much progress has been made globally in the fight against chronic hepatitis C, but the battle against the disease is not over,” said Douglas Manion, M.D., head of Specialty Development, Bristol-Myers Squibb. “At Bristol-Myers Squibb, we continue to seek out areas and patient populations that remain in need of new treatment solutions, such as China, where at last count 13 million people are estimated to be living with the disease.”

Study Design

The Phase 3, open-label study evaluated daclatasvir and asunaprevir in interferon- ineligible and/or intolerant non-Japanese Asian patients with chronic HCV genotype 1b infection. Patients received daclatasvir 60 mg (tablet) once daily plus asunaprevir 100 mg (soft capsule) twice daily for 24 weeks. The primary endpoint was sustained virologic response at post-treatment week 24 (SVR24). The study treated 159 patients overall, 80% from mainland China, 11% from Korea and 9% from Taiwan, including patients with cirrhosis (33%), IL28B nonCC genotypes (40%), and aged ≥70 years (4%).

About Hepatitis in China

HCV represents a significant public health burden in China and is now the fourth most commonly reported infectious disease countrywide. An estimated 13 million Chinese are currently living with HCV, and genotype 1b, one of seven major genotypes of the virus, is the most common, representing 57% of the total infected population in China.

About Daclatasvir

In many countries, daclatasvir, marketed as Daklinza, is approved as part of a regimen with sofosbuvir. Daklinza is approved by the U.S. Food and Drug Administration (FDA) for use with sofosbuvir, with or without ribavirin, for the treatment of patients with HCV genotype 1 or genotype 3 infection. SVR rates are reduced in HCV genotype 3-infected patients with cirrhosis receiving Daklinza in combination with sofosbuvir for 12 weeks. When Daklinza is used in combination with other agents, the contraindications applicable to those agents are applicable to the combination regimen. Daklinza is contraindicated in combination with drugs that strongly induce CYP3A and P-glycoprotein transporter, and, thus, may lead to lower exposure and loss of efficacy of Daklinza. Please see full Important Safety Information below for more details.

About Bristol-Myers Squibb in HCV

Bristol-Myers Squibb is focused on helping to eradicate hepatitis C around the world, with a primary emphasis on difficult-to-treat patients, including those millions in countries where population-based HCV solutions remain a high unmet need.

In July 2014, Japan became the first country in the world to approve the use of a daclatasvir-based regimen for the treatment of chronic hepatitis C. Since then, daclatasvir-based regimens have been approved in more than 50 countries across Europe, Central and South America, the Middle East and the Asia-Pacific region.

U.S. Indication and Important Safety Information - DAKLINZA™ (daclatasvir)

INDICATIONS

Daklinza™ (daclatasvir) is indicated for use with sofosbuvir, with or without ribavirin, for the treatment of patients with chronic hepatitis C virus (HCV) genotype 1 or genotype 3 infection.

Limitations of Use:

    Sustained virologic response (SVR12) rates are reduced in HCV genotype 3-infected patients with cirrhosis receiving Daklinza in combination with sofosbuvir for 12 weeks.

CONTRAINDICATIONS

    When used in combination with other agents, the contraindications applicable to those agents are applicable to the combination regimen; refer to the respective prescribing information.
    Drugs contraindicated with Daklinza: strong inducers of CYP3A that may lead to loss of efficacy of Daklinza include, but are not limited to:
    -Phenytoin, carbamazepine, rifampin, St. John’s wort (Hypericum perforatum).

WARNINGS AND PRECAUTIONS

    Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: Coadministration of Daklinza and other drugs may result in known or potentially significant drug interactions. Interactions may include the loss of therapeutic effect of Daklinza and possible development of resistance, dosage adjustments for other agents or Daklinza, possible clinically significant adverse events from greater exposure for the other agents or Daklinza.
    Serious Symptomatic Bradycardia When Coadministered with Sofosbuvir and Amiodarone: Post-marketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is coadministered with sofosbuvir in combination with another direct-acting antiviral, including Daklinza. A fatal cardiac arrest was reported with ledipasvir/sofosbuvir.
    -Coadministration of amiodarone with Daklinza in combination with sofosbuvir is not recommended. For patients taking amiodarone who have no alternative treatment options, patients should undergo cardiac monitoring, as outlined in Section 5.2 of the prescribing information.
    -Patients also taking beta blockers or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with coadministration of amiodarone.
    -Bradycardia generally resolved after discontinuation of HCV treatment.

    Risks Associated with Ribavirin Combination Treatment: If ribavirin is used as part of the regimen, the warnings and precautions for ribavirin, particularly the pregnancy avoidance warning, apply. See the ribavirin full prescribing information for complete information.

ADVERSE REACTIONS

    In clinical trials (Ally 2, 3) with the Daklinza and sofosbuvir regimen, the most common adverse reactions (≥ 5%) were, respectively: headache (8%, 14%), fatigue (15%, 14%), nausea (9%, 8%), diarrhea (7%, 5%).

    In clinical trials (Ally 1) with Daklinza, in combination with sofosbuvir and ribavirin, the most common adverse reactions (≥ 5%) were, in the cirrhosis cohort and the post-liver transplantation cohort, respectively: headache (12%, 30%), anemia (20%, 19%), fatigue (15%, 17%), nausea (15%, 6%), rash (8%, 2%), diarrhea (3%, 6%), insomnia (3%, 6%), dizziness (0, 6%), somnolence (5%, 0).

DRUG INTERACTIONS

    CYP3A: Daklinza is a substrate. Moderate or strong inducers may decrease plasma levels and effect of Daklinza. Strong inhibitors (e.g., clarithromycin, itraconazole, ketoconazole, ritonavir) may increase plasma levels of Daklinza.
    P-gp, OATP 1B1 and 1B3, and BCRP: Daklinza is an inhibitor, and may increase exposure to substrates, potentially increasing or prolonging their adverse effect.
    See Sections 4, 7, and 12.3 of the Daklinza Full Prescribing Information for additional established and other potentially significant drug interactions and related dose modification recommendations. Refer to the prescribing information for other agents in the regimen for drug interaction information.

DAKLINZA IN PREGNANCY:

    No adequate human data are available to determine whether or not DAKLINZA poses a risk to pregnancy outcomes. Animal studies of Daklinza at exposure above the recommended human dose have shown maternal and embryofetal toxicity.
    If Daklinza and sofosbuvir are administered with ribavirin, the information for ribavirin with regard to pregnancy testing, contraception, and infertility also applies to this combination regimen. Refer to the ribavirin prescribing information.

NURSING MOTHERS:

    It is not known whether DAKLINZA is present in human milk, affects human milk production, or has effects on the breastfed infant. Daklinza was present in the milk of lactating rats. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for DAKLINZA and any potential adverse effects on the breastfed child from DAKLINZA or from the underlying condition.
    When Daklinza is administered with ribavirin, the nursing mothers’ information for ribavirin also applies to this combination regimen. Refer to the nursing mothers’ information in the ribavirin prescribing information.

Please click here for the Daklinza full prescribing information.

StephenW

www.natap.org

在APASL从中国患者群体全口腔慢性丙型肝炎养生先完成3期临床试验提供的数据显示Daclatasvir和Asunaprevir双重治疗表现出很高的治愈率在HCV基因型1b的患者

周一，2016年2月22日6:59 EST

“这些结果预示着该daclatasvir和asunaprevir方案可以为许多中国丙肝患者的基因1b型感染提供了一个高效的全口服，干扰素和利巴韦林免费治疗”

普林斯顿，N.J .--（BUSINESS WIRE） - 施贵宝公司（NYSE：BMY）今天宣布，从第一个完成全口慢性丙型肝炎（HCV）方案3期临床试验，其中包括一个中国病人人群数据。在registrational审判，这在亚洲（非日本）的患者与基因1b型HCV研究daclatasvir结合asunaprevir 24周的结果，今天被提出了在亚太协会肝脏会议在东京研究（APASL）为。基因型1b是在中国，干扰素/利巴韦林联合治疗方案仍然是当前注意标准尤为普遍。

该研究的主要终点是持续在治疗后的第24周（SVR24）病毒学应答。在这项研究中，来自中国的患者91％达到SVR24，这在基线上升至98％的患者没有NS5A耐药相关变体（RAVS）。 SVR24结果在所有亚组基因1b型HCV同样高，包括肝硬化（90％），和患者来自韩国（94％）和台湾（87％）。

SVR24率在所有患者也高于无基线NS5A RAVS（N =一百三十九分之一百三十七[99％]），无论存在（98％）或肝硬化的存在（99％），和较低的患者基线NS5A RAVS的（ N = 8/19 [42％]）。基线NS5A RAVS存在于12％的患者。 HCV NS5A RAVS（低流行尽管VS野生型）自然存在，后病毒学应答故障可能出现。筛选特定NS5A突变的存在可以帮助医生确定最佳的患者进行治疗通过识别那些最有可能与含NS5A-方案达到治愈。

在今天，呈现在所有患者群的试验中，所有严重不良事件（SAE）（N = 5/159 3％]），4级实验室检查异常（N = 3/159 1.9％]）和死亡（N =一百五十九分之一[1％]），它能够处理发生是无关的研究药物。两名患者停药由于不良事件（AES）。最常见的AE（> 5％的患者）为在血小板减少（9％），上呼吸道感染（8％），ALT增加（7％），ANC下降（7％），单核细胞减少（6％），白细胞减少（6％），血小板减少（6％），和瘙痒（6％）。

“这些结果预示着该daclatasvir和asunaprevir方案可以为许多中国丙肝患者的基因1b型感染的一个高效的全口服，干扰素和利巴韦林免费治疗，”赖伟博士，肝病及医学主任教授说， ，北京大学肝病研究所主任，肝病科，北京大学人民医院。 “这是一个重要的发现，因为在中国HCV的负担是非常高的，而新的直接作用抗病毒药物还没有出台任何病人。”

该daclatasvir和asunaprevir方案已经由监管部门在整个亚太地区的一些国家，包括日本，韩国和台湾的批准，以及在一些国家，拉丁美洲和东欧。在APASL，施贵宝公司还将展出其他数据在亚洲人群中，包括集成的安全性，集中性和集中暴露数据的daclatasvir和asunaprevir方案。

“这么多的进展已在全球取得了对慢性丙型肝炎的战斗，但对疾病的战斗还没有结束，”道格拉斯墨宁，医学博士，专业发展，施贵宝公司的负责人说。 “在施贵宝公司，我们将继续寻求仍然存在需要新的治疗方案，如中国，最后算上1300万人，估计与疾病居住地区和患者群体。”

学习规划

在干扰素不合格和/或不能耐受的非日本亚洲患者慢性丙型肝炎病毒基因1b型感染第3阶段，开放标签研究评估daclatasvir和asunaprevir。患者接受daclatasvir 60毫克（片），每天一次加asunaprevir 100毫克（软胶囊），每日24周的两倍。主要终点是持续在治疗后的第24周（SVR24）病毒学应答。该研究整体治疗159例患者，有80％来自中国大陆，韩国11％和9％来自台湾，包括肝硬化患者（33％），IL28B基因型nonCC（40％），和老年≥70岁（4％）。

关于肝炎在中国

HCV代表在中国显著的公共卫生负担，现在是第四个最常见的传染病全国。一个预计有1300万中国人目前生活与HCV和基因型1b，对病毒的七大基因型之一，是最常见的，占中国总人口感染者的57％。

关于Daclatasvir

在许多国家，daclatasvir，销售作为Daklinza，被批准作为与索非布韦一个方案的一部分。 Daklinza由美国食品和药物管理局（FDA），用于与索非布韦批准使用，有或没有利巴韦林，用于治疗患者的HCV基因型1或基因型3感染。 SVR率在HCV基因型3感染者减少肝硬化结合索非布韦接收Daklinza 12周。当Daklinza与其它药剂组合使用时，适用于这些制剂的禁忌症是适用于组合方案。 Daklinza禁忌结合药物强烈诱导CYP3A和P-糖蛋白转运，并且因此，可能会导致较低的曝光和Daklinza的功效的损失。请参见下面的完整的重要安全信息了解更多详情。

关于施贵宝在HCV

施贵宝公司是专注于帮助根除C型肝炎在世界各地，与主要重点放在难以治疗的患者，其中包括数以百万计国家，人口为基础的解决方案，HCV仍较高的未满足的需要。

在2014年7月，日本成为第一个国家在世界上批准慢性丙型肝炎。此后，基于daclatasvir的治疗方案已被批准在欧洲，中亚等50多个国家的治疗使用基于daclatasvir，养生南美，中东和亚太地区。

美国指示和重要安全信息 - DAKLINZA™（daclatasvir）

适应症

Daklinza™（daclatasvir）表示用于与索非布韦使用，有或没有利巴韦林，用于治疗慢性丙型肝炎病毒（HCV）基因型1或基因型3感染。

使用限制：

    持续病毒学应答（SVR12）率在HCV基因型3感染患者降低与肝硬化结合索非布韦接收Daklinza 12周。

禁忌症

    当与其它药剂组合使用时，适用于这些制剂的禁忌症是适用于该组合方案;请参见相应的处方信息。
    与Daklinza禁忌药：CYP3A的强诱导剂，可能导致Daklinza功效的损失包括，但不限于：
    -Phenytoin，卡马西平，利福平，圣约翰草（贯叶连翘）。

警告和注意事项

    不良反应或病毒学应答由于药物相互作用损失风险：Daklinza和其他药物合用可能导致已知或潜在的显著药物相互作用。相互作用可能包括Daklinza的治疗效果为其他代理或Daklinza，从其他代理或Daklinza更大的曝光可能临床显著的不良事件的损耗和阻力的可能发展，调整剂量。
    严重症状的心动过缓当索非布韦和胺碘酮合用：当胺碘酮与索非布韦合用与另一种直接作用的抗病毒药物，包括Daklinza症状的心动过缓和心脏起搏器需要干预的情况下上市后病例报告。一个致命的心脏骤停报道与ledipasvir /索非布韦。
    不建议与索非布韦结合Daklinza胺碘酮-Coadministration。对于服用胺碘酮谁没有替代治疗方案的患者，患者应进行心脏监测，如在处方信息第5.2节。
    -Patients同时服用β受体阻滞剂或有潜在心脏合并症和/或晚期肝病可能是在与胺碘酮合用症状的心动过缓的风险增加。
    一般-Bradycardia HCV治疗停药后解决。

    伴有利巴韦林联合治疗的风险：如果利巴韦林作为方案的一部分，利巴韦林的警告和注意事项，尤其是怀孕回避预警，适用。见的完整信息，利巴韦林的完整处方信息。

不良反应

    在临床试验中（同盟2，3）与Daklinza和索非布韦方案中，最常见的不良反应（≥5％），分别为：头痛（8％，14％），疲劳（15％，14％），恶心（ 9％，8％），腹泻（7％，5％）。

    在临床试验中（同盟1）Daklinza，在与索非布韦和利巴韦林组合，最常见的不良反应（≥5％）是，在肝硬化队列和肝脏移植后的队列，分别为：头痛（12％，30％ ），贫血（20％，19％），疲劳（15％，17％），恶心（15％，6％），皮疹（8％，2％），腹泻（3％，6％），失眠（3 ％，6％），头晕（0，6％），嗜睡（5％，0）。

药物相互作用

    CYP3A：Daklinza是一个基片。中度或强诱导剂可降低血浆水平和Daklinza的效果。强抑制剂（例如，克拉霉素，伊曲康唑，酮康唑，利托那韦）可能增加Daklinza的血浆水平。
    P-gp的，OATP 1B1和1B3和BCRP：Daklinza是抑制剂，并可能增加接触基材，无形中增加或延长其不利影响。
    你看，第4节7和Daklinza完整的处方信息的12.3额外的建​​立和其他可能显著药物相互作用及相关剂量的修改建议。指在治疗方案为药物相互作用信息的其它试剂的处方信息。

DAKLINZA在怀孕：

    没有足够的人力数据可用来确定DAKLINZA与否提出到妊娠结局的风险。在曝光的推荐人用剂量以上Daklinza的动物研究显示，孕产妇和胚胎 - 胎仔毒性。
    如果Daklinza和索非布韦与利巴韦林施用，对于怀孕测试，避孕和不孕利巴韦林的信息也适用于这种组合方案。参考利巴韦林处方信息。

哺乳母亲：

    它不知道DAKLINZA是否存在于人乳，影响人的牛奶产量，或对母乳喂养的婴儿的效果。 Daklinza存在于哺乳期大鼠的乳汁。母乳喂养的发展和保健福利应该与母亲的临床需要DAKLINZA和DAKLINZA或从基础条件对母乳喂养儿童的任何潜在的不利影响被视为一起。
    当Daklinza与利巴韦林管理，护理母亲的信息利巴韦林也适用于这种组合方案。请参阅哺乳母亲的信息，利巴韦林处方信息。

请点击这里了解Daklinza完整处方信息。