重磅！我国原创抗癌新药西达本胺获准全球上市 2015/01/28 来源：生物探索1月27日，深圳微芯生物科技公司在市政府新闻发布厅举行原创新药、国家863及"重大新药创制"专项成果西达本胺新闻发布会。西达本胺是全球首个获准上市的亚型选择性组蛋白去乙酰化酶口服抑制剂，也是中国首个授权美国等发达国家专利使用的原创新药，首个适应症为复发及难治性外周T细胞淋巴瘤。 1月27日，深圳微芯生物科技公司在市政府新闻发布厅举行原创新药、国家863及"重大新药创制"专项成果西达本胺新闻发布会。西达本胺是全球首个获准上市的亚型选择性组蛋白去乙酰化酶口服抑制剂，也是中国首个授权美国等发达国家专利使用的原创新药。此举将填补我国T细胞淋巴瘤治疗药物的空白，也标志着我国基于结构的分子设计、靶点研究、安全评价、临床开发到实现产业化全过程的整合核心技术与能力得以显着提升，是我国医药行业的历史性突破。
中国首个授权美国等发达国家专利使用的原创新药 西达本胺（Chidamide，商品名爱谱沙/epidaza）属于全新作用机制的综合靶向抗肿瘤靶向药物，其首个适应症为复发及难治性外周T细胞淋巴瘤，前期临床结果显示，患者临床获益率近50%，生存期明显延长。据微芯生物总裁兼首席科学官鲁先平介绍，西达本胺的新机制专门针对转移复发和免疫逃逸，将会用于多种类型的肿瘤，目前乳腺癌和肺癌研究都已进入三期临床。未来西达本胺将会是有效帮助患者克服耐药性、复发和转移的重要手段。西达本胺针对首个适应症复发及难治性外周T细胞淋巴瘤的新药申请已获得国家食品药品监督管理总局（CFDA）批准，并完成药品生产质量管理规范认证，首批产品最快今年三月初上市。此外，微芯生物已授权美国、日本、台湾等国家和地区同步开展单药及联合其他抗肿瘤药物针对其他血液肿瘤、非小细胞肺癌及乳腺癌等实体瘤的临床研究。鲁先平在接受采访时说："该领域，近几年才出现两三个新药，治疗费用分别相当于每月28万人民币和14万人民币。西达本胺在临床有效性、安全性以及使用方便性上均优于其它产品，并且在价格上只有相关产品的十分之一。"
西达本胺作用机制 外周T细胞淋巴瘤（PTCL）是一组异质性很强的淋巴细胞异常增殖性疾病，包括约18种病理亚型。PTCL在中国的年发病人数约为6万人，年患病率约90/百万，可归属于罕见病范畴。组蛋白去乙酰化酶（HDAC）为表观遗传调控重要酶家族，通过开发HDAC抑制剂，可在染色质结构水平上对肿瘤起到治疗效果。西达本胺是一个中国原创的新型口服亚型选择性HDAC抑制剂，对HDAC1、2、3、10亚型具有选择性抑制作用。西达本胺通过对特定HDAC亚型的抑制及由此产生的染色质重构与基因转录调控作用（即表观遗传调控作用），抑制淋巴及血液肿瘤的细胞周期并诱导肿瘤细胞凋亡；诱导和增强自然杀伤细胞（NK）和抗原特异性细胞毒T细胞（CTL）介导的肿瘤杀伤作用及抑制肿瘤病理组织的炎症反应，不仅能直接贡献于对T淋巴瘤中循环肿瘤细胞及局部病灶产生疗效作用，同时也可能应用于诱导和增强针对其他类型肿瘤的抗肿瘤细胞免疫的整体调节活性。
FDA批准3种药物 FDA于2009年和2011年分别批准了两个以PTCL为适应证的新药上市，普拉曲沙（pralatrexate）和罗米地辛（Istodax），虽然具有一定疗效，但安全耐受性仍然较差。此外，在2014年7 月 3 日，美国 FDA 批准 Beleodaq (belinostat) 用于PTCL 患者治疗。Beleodaq 通过阻止有助于 T 细胞发生癌变的酶起作用。这款药物适用于治疗后（复发性）疾病又卷土重来或对以前治疗无效（难治性）的患者。Beleodaq 的安全性及有效性在一项由 129 名复发或难治性 PTCL 受试者参与的临床研究中得到评价。所有受试者均以 Beleodaq 治疗，直到他们的疾病发生恶化或副作用变得不可接受。结果显示，25.8% 受试者的癌症在治疗后消失（完全缓解）或缩小（部分缓解）。Beleodaq 与普拉曲沙由 Spectrum 制药上市销售。Istodax 由塞尔基因上市销售。不过这三款产品都是静脉注射，西达本胺为口服用药，具有更方便的临床服药方式和更好依从性。
我国原创药发展的新希望国家"重大新药创制"科技专项技术副总师陈凯先 尽管我国是全球第一大制剂药和第二大原料药产国，但是98%的产品属于发达国家专利过期的仿制药。而真正具有自主知识产权的创新药绝无仅有。而我国老百姓要使用专利未过期的创新药，基本依赖进口，但是价格昂贵非一般人能够承受。国家"重大新药创制"科技专项技术副总师陈凯先表示，深圳是我国生物医药的发展中非常重要的城市，从过去跟随国外研发的防治者、跟跑者逐渐向并跑者的方向发展，并在某些方面走到国际引领的位置。
关于深圳微芯 深圳微芯生物由留美归国博士团队创立于2001年，专长于原创小分子药物研发。在肿瘤、糖尿病/代谢疾病、免疫性疾病领域建立了多个从实验室到临床及产业化阶段的原创新药产品线。目前，微芯生物已申请67项化合物全球发明专利，其中36项已获授权。
Results from a multicenter, open-label, pivotal phase II study of chidamide in relapsed or refractory peripheral T-cell lymphoma (Annals of Oncology) Accepted May 11, 2015. Background Chidamide is a novel benzamide type of subtype-selective histone deacetylase (HDAC) inhibitor with unique mechanisms of action compared with marketed HDAC inhibitors. This phase II study was to evaluate the efficacy and safety of chidamide in relapsed or refractory peripheral T-cell lymphoma (PTCL) in Chinese population. Patients and methods Patients with relapsed or refractory PTCL of different subtypes received chidamide of 30 mg orally twice per week. The primary end point was overall response rate (ORR). Responding patients should be confirmed at least 4 weeks after the criteria of the response were first met, and were reviewed by an independent review committee. Results Eighty-three patients were enrolled and 79 patients with eligible PTCL histology were for efficacy assessments. Patients enrolled over 10% were with subtypes of PTCL not otherwise specified (34%), anaplastic large-cell lymphoma (22%), extranodal natural killer (NK)/T-cell lymphoma, nasal type (20%), or angioimmunoblastic T-cell lymphoma (AITL, 13%). The ORR was 28% (22 of 79) including 14% (11 of 79) with complete response/unconfirmed complete response (CR/CRu). Median progression-free survival and overall survival were 2.1 and 21.4 months, respectively. AITL patients tended to have higher ORR (50%) and CR/CRu rate (40%), as well as more durable responses, to chidamide treatment. Most adverse events (AEs) were grade 1 or 2, and AEs ≥grade 3 that occurred in ≥10% patients were thrombocytopenia (22%), leucopenia (13%) and neutropenia (11%), respectively. Conclusion Chidamide represents a novel oral benzamide class of HDAC inhibitor with significant single-agent activity and manageable toxicity in relapsed or refractory PTCL, and provides a much needed treatment option in this indication in China. Results led to China Food and Drug Administration approval of chidamide in this indication.
Belinostat for Peripheral T-Cell Lymphoma The majority of patients with peripheral T-cell lymphoma (PTCL) will either be refractory or relapse to the currently available frontline therapies with a subsequent median overall survival <6 months. Histone deacetylase (HDAC) inhibitors have demonstrated significant activity in T-cell neoplasms, and recently the BELIEF trial of belinostat (Be-leodaq), a pan-HDAC inhibitor with high affinity for class I and II HDACs, was completed in relapsed/refractory PTCL. This study demonstrated a complete response rate of 11%, with an overall response rate of 26%. These results have been confirmed in a smaller trial that also included patients with cutaneous T-cell lymphomas. Given the similar response rates achieved by pralatrexate (Folotyn) and romidepsin (Istodax), belinostat has become the third agent approved by the US Food and Drug Administration for use in relapsed/refractory PTCL, thus providing another option for patients with these aggressive malignancies. The peripheral T-cell lymphomas (PTCLs) are a diverse group of mature T-cell neoplasms that typically display aggressive clinical features with inferior response rates and survival outcomes to conventional chemotherapy when compared with their B-cell counterparts. In the largest population registry to date in which 84% of patients receiving chemotherapy received either CHOP or CHOEP as initial therapy, 25% of patients were primary refractory, with a median overall survival (OS) of 2.5 months. Of those who managed a response to induction chemotherapy, 53% relapsed with a median OS of 6 months. Given the dismal prognosis of relapsed/refractory PTCL, the major challenges that are faced today include improving frontline therapies to induce more durable remissions, and also identifying effective salvage regimens. In July 2014, belinostat (Beleodaq) became the third agent behind the antifolate pralatrexate (Folotyn) and fellow his-tone deacetylase (HDAC) inhibitor romidepsin (Istodax) to be approved by the US Food and Drug Administration (FDA) for the treatment of patients with relapsed/refractory PTCL. Histone deacetylases are a group of enzymes along with histone acetyltransferases (HATs) that regulate the acetylation of histone and nonhistone proteins. The acetylation status of these proteins greatly influences the degree of binding between histones and DNA within the nucleus, and the subsequent accessibility of DNA for transcription, thereby affecting protein expression in a manner that could promote malignant behavior. Although lymphomagenesis is complex, dysregulation of HDACs has been well established as a significant step in this process, and this provides the rationale towards utilizing HDAC inhibitors in these neoplasms. Eighteen different HDACs are described, belonging to four different classes that can be further differentiated by their zinc dependency. Zinc-dependent HDACs encompass class I (HDACs 1, 2, 3, and 8), IIa (HDACs 4, 5, 7, and 9), IIb (HDACs 6 and 10), and IV (HDAC 11), while class III HDACs, otherwise known as sirtuins (SIRT1-7), are dependent on nico-tinamide adenine dinucleotide (NAD). HDAC inhibitors have demonstrated efficacy in PTCLs and cutaneous T-cell lymphomas (CTCLs),as well as other hematological and solid-organ malignancies.7-10 Through epigenetic modification, HDAC inhibitors primarily exert their effects by lowering the apoptotic threshold of malignant cells by the down-regulation of antiapoptotic proteins, upregulation of proapoptotic proteins, inhibition of DNA repair, and induction of DNA damage. HDAC inhibitors are pleiotropic agents, and beyond the histone-DNA complex they affect the acetylation status of many nonhistone proteins such as chaperones, oncogenes, signaling molecules and transcription factors, contributing to their effectiveness as antineoplastic agents.5
Belinostat is a hydroxamic acid-derived, pan-HDAC inhibitor that demonstrates high affinity for the class I and II HDACs.11-12 In comparison, romidepsin is a cyclic tetrapeptide-derived pan-HDAC inhibitor that primarily functions through class I HDACs, with only weak effects on the class IIb HDAC6.
Phase II Trials in Belinostat The BELIEF study is the largest phase II trial conducted with belinostat in PTCL.14 Eligible patients were adults with relapsed/ refractory PTCL following at least one prior systemic treatment. Belinostat 1000 mg/m2 administered intravenously over 30 min-utes daily on days 1-5 of a 21-day regimen was given to 129 pa-tients across 62 sites in North America, Europe, and Africa. The number of cycles administered was not limited, with patients treated until the development of progressive disease, unaccept-able toxicity, stem cell transplantation, withdrawal of consent, or death. The median age of 64 years (age range, 29-81 years) reflects the epidemiological characteristics of this disease, and 96% of patients had previously progressed on or after CHOP or CHOP-like therapy, reflecting current treatment practices. The median number of lines of previous therapy for this cohort was 2 (range, 1-8), with 19% having undergone a prior autologous stem cell transplant and 2% an allogeneic stem cell transplant. Significantly, of the 120 evaluable patients, 13 achieved a com-plete response (CR; 11%), with a further 18 demonstrating parbelinostat for peripheral t-cell lymphoma response (PR; 15%), for an overall response rate (ORR) of 26%. In responding patients, the median time to response was 5.6 weeks, with the earliest after 4.3 weeks and the latest at 50.4 weeks. The median duration of response (DOR), defined as the date of first response to the date of disease progression or death, was 8.4 months (95% confidence interval [CI], 4.5-29.4). Importantly, 9 patients (7.5%) were able to proceed to a stem cell transplant. Comparison between the three FDA-approved agents in relapsed/ refractory peripheral T-cell lymphoma: belinostat, pralatrexate, and romidepsintial With regard to toxicity, belinostat was well tolerated, with dose reductions of 25% to 50% occurring in 13% of patients and only 7% of all discontinuations due to adverse events. Progressive disease was the most common reason for discontinuation (64%), followed by death (11%), and patient request (8%). Significant myelosuppression was not a factor in this study, with <10% grade 3 or 4 thrombocytopenia or neutropenia. One aspect unique to BeLIEF was that patients were eligible with a platelet count >50,000/µL, unlike studies with pralatrexate (>100,000/µL) and romidepsin (>100,000/µL unless documented bone marrow involvement, upon which 75,000-100,000/µL was permitted). A second smaller study of belinostat in PTCL that also included patients with relapsed/refractory CTCLs has been conducted. Fifty-three patients were enrolled; 20 had relapsed/ refractory PTCL. Similar results to BELIEF were encountered, with a CR of 10% and a PR of 15%, for an ORR of 25% in PTCLs. With respect to CTCLs, 14% of patients responded with a CR of 7%. Grade 3 or 4 hematologic toxicity was seen in <10% of patients. Given the safety prolife of belinostat, a phase I clinical trial combining it with CHOP has been initiated in newly diagnosed PTCL (NCT01839097), with a view to conducting a phase III randomized study in the future comparing it with standard CHOP therapy in these patients. Although all three FDA-approved agents for relapsed/refractory PTCL have never been compared directly in randomized studies, each individual agent produces similar response rates but with differing toxicity profiles. It must be noted that when comparing across the three studies, the patients treated with pralatrexate in the PROPEL trial were the most heavily pretreated and demonstrated the greatest diversity of PTCL subtypes.15 PROPEL (115 patients) demonstrated an ORR of 29%, with the main grade 3/4 toxicities being thrombocytopenia (32%), mucositis (22%), and neutropenia (22%). Meanwhile, an international phase II study of romidepsin (131 patients) demonstrated an ORR of 25%, with the main grade 3/4 toxicities being thrombocytopenia (24%), neutropenia (20%), and infection (19%). Brentuximab vedotin, a chimeric anti-CD30 monoclonal antibody conjugated to the antimitotic agent monomethyl auristatin E, is another option, although its current FDA approval is limited to relapsed/refractory systemic anaplastic large-cell lymphoma (ALCL). In a phase II trial in relapsed/refractory ALCL, brentuximab demonstrated a remarkable 57% CR rate with an ORR of 86%. Until studies comparing these agents directly are completed, firm recommendations as to the optimal therapy in relapsed/ refractory PTCL cannot be made at this time, though good options are now emerging. Therapeutic decisions should be based on individual patient circumstances, histology, and the risk-benefit profiles of each agent. For example, a patient with significant cardiac abnormalities would be at risk of QT prolongation with HDAC inhibitors, and therefore pralatrexate may represent a more logical option, whereas a patient who currently has or is unable to tolerate severe mucositis should be considered for HDAC inhibitors in preference to antifolate therapy. The majority of patients with PTCL will either be refractory or relapse to current frontline therapies. The prognosis of these patients is dismal, with median OS <6 months. Belinostat has recently been approved for use in these malignancies based on the results of the BELIEF trial, which demonstrated an ORR of 25%, with a median DOR of 8.4 months. Though this is not the breakthrough we are looking for, it is a step in the right direction as it adds another option for patients where few exist.
SOURCE(http://www.gotoper.com/publications/ajho/2014/2014sep/belinostat-for-peripheral-t-cell-lymphoma)