Romidepsin

近日，迪哲医药发布公告称，其2款全球首创新药JAK1抑制剂戈利昔替尼和LYN/BTK双靶点抑制剂DZD8586在淋巴瘤领域的4项最新研究成果，在第65届美国血液学会（ASH）年会上得以公布。迪哲医药2款新药最新研究成果发布情况图片来源：迪哲医药公告2021年12月在A股科创板上市的迪哲医药，业绩一直处于亏损状态，据2023年Q3季报显示，前三季营收4010.24万元，净利润亏损高达8.29亿元，而2022年的净利润亏损为7.36亿元，亏损的扩大，加上营收额与亏损额的巨大悬差，不免让人担忧迪哲医药能否扭亏摘U。收入格局已变首款产品火爆迪哲医药此前虽无产品上市，但在2018年至2021年期间一直都有收入，分别为3941.92万元、4101.75万元、2776.08万元和1028.54万元，不过，这些收入均来自向阿斯利康收取的技术支持服务费。迪哲医药2018年以来收入情况图片来源：迪哲医药招股书/2021年报2023年8月，迪哲医药迎来大转折，首款产品舒沃替尼获国家药监局批准上市，用于治疗含铂化疗进展或不耐受的EGFR Exon20ins突变型晚期NSCLC成人患者。舒沃替尼的获批上市，不仅让在创新药研发上拼搏数年的迪哲医药终于有了上市产品，且收入结构发生了根本性的转变，据其2022年报和2023Q3季报显示，2022年以来，之前技术支持服务再无任何收入，而舒沃替尼却有4010万元的销售额，彻底由过去靠卖服务转变为卖产品。值得一提的是，舒沃替尼是中国自研的首款针对Exon20ins突变型晚期NSCLC的靶向药，也是肺癌领域首个且唯一获得中美双“突破性疗法认定”的国创新药，在国内获批是基于WU-KONG6临床试验，据研究结果显示，客观缓解率（cORR）达60.8%，整体安全性与传统EGFR-TKI相似，疗效性和安全性均为同类潜在最佳，从获批上市到9月底，仅一个月时间，就创下了4010万元的销售额，显示出强大的市场竞争力。而迪哲医药还在挖掘舒沃替尼用于一线治疗Exon20ins突变型晚期NSCLC的潜力，目前已经进展至3期临床，据在2023年欧洲肿瘤内科学会（ESMO）大会上公布的最新数据显示，100%患者靶病灶出现肿瘤缩小，一线单药治疗EGFR Exon20ins突变型晚期NSCLC的客观缓解率（ORR）达78.6%，其中300mg组中位无进展生存期（mPFS）为12.4个月。舒沃替尼开发路径图片来源：迪哲医药2023半年报从2015年到2019年，全球EGFR Exon20ins非小细胞肺癌新发患者从5.7万增至6.4万，预计2030年新发患者人数将达8.6万人，随着一线治疗的国际临床试验进展，向全球市场进军是早晚的事。全球2015-2030年EGFR Exon20ins非小细胞肺癌新发病人数量图片来源：迪哲医药招股书此外，舒沃替尼与另一款核心产品，也就是戈利昔替尼联合治疗耐药NSCLC的临床试验也已进展至2期临床试验，意味着舒沃替尼成为爆款产品的潜力更大。迪哲出品款款精品好日子还在后面说回文章开头提到的戈利昔替尼和DZD8586，来头不比舒沃替尼小。戈利昔替尼是全球首个且唯一针对外周T细胞淋巴瘤（PTCL）的高选择性JAK1抑制剂，用于治疗既往至少接受过一次标准治疗复发或难治外周T细胞淋巴瘤（r/r PTCL）成人患者的上市申请已在2023年9月获国家药监局受理并纳入优先审评，值得一提的是，2022年2月还获美国FDA快速通道认定，用于治疗r/r PTCL。据国际多中心临床试验JACKPOT8研究结果显示，纳入疗效评估的88名r/r PTCL受试者中，39例（44.3%）受试者达到肿瘤缓解，其中21例完全缓解（CR，23.9%），18例部分缓解（PR，20.5%），安全性分析纳入的112例患者，中位相对剂量强度为100%，不良事件（TRAEs）大多可恢复或临床可管理，且耐受性良好，安全性优势明显。诺华的芦可替尼是全球首款获批上市的JAK1抑制剂，也是国内获批的首款且用于治疗肿瘤的JAK1抑制剂，据药渡数据显示，芦可替尼上市以来市场规模持续增长，诺华和因塞特2022年合计销售额已达40.99亿美元。芦可替尼全球销售情况图片来源：药渡数据芦可替尼在国内获批以来，市场销售额也是持续增长，据药渡数据显示，2023年上半年销售额已达2.90亿元，是2022年销售额的62.63%，预计2023年全年销售额仍然处于上涨通道。芦可替尼国内销售情况图片来源：药渡数据芦可替尼的市场表现，足以证明JAK1抑制剂在肿瘤领域的前景一片光明，据统计，2019年全球约有3.65万例外周T细胞淋巴瘤（PTCL）新发患者，预计2030年将增长至4.68万例。2015年-2030年全球PTCL发病人数图片来源：迪哲医药招股书戈利昔替尼一“出道”就自带“光环”，其是PTCL领域全球首个且截至上市申请获受理时唯一的NDA申报阶段JAK1抑制剂，临床试验研究也已证实其与已获批用于治疗r/r PTCL的普拉曲沙、罗米地辛、贝林司他和西达本胺等药物，在疗效性和安全性上均具有明显优势。戈利昔替尼与其他药物疗效和安全对比图片来源：迪哲医药招股书另一款药物DZD8586是针对B细胞非霍奇金淋巴瘤（B-NHL）的非共价LYN/BTK双靶点抑制剂，虽然临床进展没有戈利昔替尼快速，目前仅处于2期临床试验阶段，但DZD8586或能解决BTK抑制剂治疗B-NHL的耐药问题。据临床试验数据显示，整体客观缓解率（ORR）达64.7%，50mg剂量ORR高达71.4%，针对不同B-NHL亚型，包括 DLBCL、CNSL、CLL，均显示抗肿瘤疗效，尤其在DLBCL患者中，ORR高达83.3%，特别是在BTK抑制剂耐药患者中，ORR达50%。前有舒沃替尼的开道，后有戈利昔替尼的即将获批，加上管线产品中DZD8586的后续“集结”，迪哲医药在肿瘤领域的好日子就快来到了。肿瘤只是“开胃菜”自免领域也有看点迪哲医药从成立之初，就立志于在肿瘤及自身免疫性疾病领域闯出一番天地，其IPO招股书显示，戈利昔替尼（DZD4205）的适应症临床研究管线中也有免疫性疾病的布局。舒沃替尼适应症开发策略图片来源：迪哲医药招股书其实JAK1抑制剂最扎堆的适应症并不是肿瘤领域，而是自免领域，在迪哲医药筹划IPO上市之时（截至2021年8月），全球已获批上市的7款JAK1抑制剂中，只有诺华的芦可替尼获批了骨髓纤维化/真性红细胞增多症肿瘤相关适应症，而在研的JAK1抑制剂中，自免适应症也多过于肿瘤。据统计，2019年全球JAK1抑制剂市场规模约为55亿美元，预计到2030年将达305亿美元，可以说自免领域对JAK1抑制剂市场规模的贡献要大于肿瘤领域，或许是出于抢占市场的考虑，迪哲医药在开发舒沃替尼的策略上，选择了先肿瘤，后自免的思路。2018-2030年全球JAK1抑制剂市场规模图片来源：迪哲医药随着舒沃替尼在肿瘤领域站住脚后，迪哲医药自然也不会放弃舒沃替尼作为JAK1抑制剂，也能在自免领域分得一杯羹的机会。结语虽说响鼓不用重锤，但重锤肯定比轻锤敲击的响声更加振聋发聩，迪哲医药业绩亏损的主要原因，在于其研发上的巨大投入，2022年的研发投入为6.65亿元，2023年依然保持增长状态，上半年为3.43亿元，同比增长4.20%，随着部分产品及开发策略中部分适应症的先行获批，迪哲医药已处于收获期，摘U的日子也就不远了。参考来源迪哲医药公告、年报及招股书

Dizal is running three different confirmatory trial options by the FDA, hoping to file its lymphoma candidate golidocitinib for an accelerated approval in the near future. Just as the FDA revisits two accelerated approvals in peripheral T cell lymphoma (PTCL), AstraZeneca spinout Dizal Pharmaceutical is charting its own path for a potential conditional nod in the blood cancer. The Chinese biotech has phase 2 tumor response data for its JAK1 inhibitor golidocitinib that, as CEO Xiaolin Zhang, Ph.D., pointed out, look better than readouts from existing therapies in previously treated PTCL. Specifically, 44.3% of 88 PTCL patients who had received median two lines of prior therapies responded to golidocitinib, according to updated data from part B of the JACKPOT8 trial presented at the American Society of Hematology annual meeting. These include 21 patients (23.9%) who achieved a complete response. The responses were durable, lasting more than 20 months at median as more than half of patients were still responding after a median follow-up of 12.5 months. Besides, 46 patients (52.3%) were still alive at the data cutoff, with a median overall survival of 19.4 months. In contrast, current standard treatments can only give this type of patient about six to eight months of survival benefit, Zhang noted during an interview with Fierce Biotech. Armed with the phase 2 data, Dizal is discussing with the FDA about filing for an accelerated approval, although Zhang declined to offer a timeline. But before a potential application, the company still needs to jump through a couple more hoops. Dizal is advancing golidocitinib at a volatile time for the PTCL space. In fall 2021, Bristol Myers Squibb pulled its PTCL treatment Istodax off the market after the HDAC inhibitor failed to outdo the traditional CHOP regimen in a confirmatory phase 3 trial in newly diagnosed patients. During an advisory committee meeting last month, the FDA questioned two PTCL drugs that have significant delays in producing confirmatory evidence for their accelerated approvals. The two meds are Acrotech Biopharma’s folate analog inhibitor Folotyn and HDAC inhibitor Beleodaq. In their single-arm trials in pretreated patients, both agents showed an overall response rate below 30% and a median duration of response shorter than 10 months.   RELATED: FDA's oncology office uses advisory committee to spotlight timely accelerated approval confirmation   After some major delays, Acrotech has finally formed a confirmatory trial agreement with the FDA to test the two drugs in a phase 3 trial in the front-line setting. The phase 2/3 study, which includes an initial optimal dose-finding part, kicked off in October, and the final readout is expected in 2030. Dizal was AstraZeneca’s China R&D center until a spinoff in 2017. The company had originally planned to immediately file golidocitinib for approval based on tumor response data but now has to face an FDA reality. To prevent delays in completing postmarketing studies, the agency recently started to require that a confirmatory trial be underway at the time of a cancer drug’s accelerated approval. Now Dizal is left thinking what that phase 3 program should look like. The company is running three different options by the FDA, Zhang said. It could conduct a front-line study following Acrotech’s example. But such a trial will take a long time, given the current median survival of first-line patients is close to five years. And recruitment for a rare disease like PTCL will be slow, Zhang said.  Dizal could conduct another randomized study in the relapsed or refractory setting. But that plan isn’t very cost-efficient because golidocitinib would stay in the same indication. Alternatively, Dizal is proposing a novel trial design that evaluates golidocitinib as a first-line maintenance treatment in patients who’ve responded to their initial treatment. Dizal has some initial data to support that approach. An early analysis of the phase 2 JACKPOT26 trial showed that among patients who had achieved complete response after first-line treatment, golidocitinib kept 86.7% in response after a median follow-up of 8.1 months. Among patients who had a partial response after first-line treatment, the drug induced complete response in a third of patients. The data were shared in an abstract, and more updated details will be included in a poster presentation Monday. In addition to the randomized trial design, the current efficacy data from JACKPOT8 only includes five patients enrolled outside of Asia. Two (40%) of these patients responded to golidocitinib. Based on the FDA’s guidance on diversity, Dizal later expanded the trial to include more U.S. and Australian patients. Data from those individuals will be shared with the FDA during future discussions about a new drug application, a Dizal spokesperson told Fierce Biotech. Chinese authorities in September granted priority review to the drug’s PTCL application. Dizal is discussing with many potential partners to commercialize golidocitinib in the U.S., Zhang said. “Probably it’s not going to be realistic to build a commercial [presence] in the States given that drug could be approved in the near future, and you need to have a good organization,” Zhang said. “So for this, a more reasonable plan is to collaborate with someone who has an established salesforce.” But Dizal hasn’t ruled out going solo. The company has another drug, sunvozertinib, which in August got Chinese approval for treating non-small cell lung cancer with EGFR exon20 mutations following chemotherapy. The U.S. regulatory path for sunvozertinib is clearer. Dizal plans to file for an FDA accelerated approval using a single-arm trial that it’s following until the second quarter of 2024, Zhang said. A proposed confirmatory trial testing the EGFR inhibitor as a monotherapy in the first-line setting has already enrolled over 50% of patients. If approved, that drug will compete with Johnson & Johnson’s bispecific antibody Rybrevant, as Takeda has decided to withdraw its small-molecule rival Exkivity from the U.S. market. Dizal is talking to Big Pharmas about partnering up on sunvozertinib as well, Zhang said.