Ruxolitinib Phosphate

吴妮 | 撰文 又一 | 编辑 半个月前，一则中国药企挑战跨国药企重磅药物的头对头试验成功的消息发布。 3月9日，同源康医药发布公告，宣布其自主研发的TY-959在对比奥希替尼作为一线治疗EGFR突变肺癌脑转移的关键II期临床试验中，主要研究终点即颅内客观缓解率(iORR)达到了预期目的。 据此，同源康宣布TY-959头对头击败奥希替尼。 奥希替尼2024全球销售额达到65.80亿美元，是阿斯利康第二大畅销药。“头对头击败大药”意味着动摇大药的主导地位，侵占其市场份额。本来，对这种王者量级药物的“头对头挑战”成功，算是全世界制药界的重磅新闻。但“被击败”的阿斯利康向媒体回应称，无法就现有信息给予反馈。这则新闻并未在业界激起多少浪花，反倒引起不少质疑。 上一次有头对头成功的消息，还是康方生物PD/VEGFA双抗在一项三期临床中头对头击败K药，相较于K药显著延长了患者PFS。消息发布当天，业界震动，康方生物的股价大幅上涨，盘中最高涨幅达到87.5%。 比起康方生物的广受赞同，同源康的操作饱受质疑，目前同源康宣布“头对头击败奥希替尼”的依据，只有EGFR肺癌脑转移亚组颅内客观缓解率(iORR)，没有OS数据，病人数据量也不够——缺少的数据需要通过大III期进行验证。而且氘代技术自带争议，被认为是一种规避研发失败风险、节省研发时间的“微创新”。 同源康发布这一消息，被认为有多种动机。没有悬念，二级市场股价拉升。公告发布前一个交易日，股价提前拉升3.55%。公告发布第二天，正好是港股通标的正式调整，宜明昂科、来凯医药、科济药业、科笛、艾美疫苗、康宁杰瑞制药6家创新药公司被踢出港股通，唯一新调入港股通的创新药企正是同源康，当天同源康股价上涨16.18%。 其次，试图以II期数据申请附条件上市。同源康在公告里提到，公司计划近期向国家药品监督管理局药品审评中心提交NDA（新药申请）上市申请，进一步推动TY-9591的商业化进程。 公告里特别强调了针对EGFR突变肺癌脑转移适应症的优效性，同源康很有可能会申报肺癌脑转移亚组的附条件获批。 此前，迪哲药业的舒沃替尼凭借“悟空6”II期注册临床试验，在国内获批用于EGFR ex20ins突变亚型。强生EGFR/cMet双抗凭借I期81例病人的单臂试验获得FDA加速批准上市。 港股也给出了态度，短暂的大涨之后是4天连跌，截至3月14日同源康股价回归了公告发布前的水平。比起几天内大涨大跌的股价，同源康走进了港股通的舒适区——港股通半年调整一次，至少此后半年，同源康都会稳稳躺在港股通名单里。 -01- “氘”出一条捷径 同源康此路有迹可循。 2023年，梯瓦制药的“氘丁苯那嗪”刷新全球销售额，晋升为10亿美元品种。而“被氘”的丁苯那嗪早在2019年就被“氘丁苯那嗪”抢占了市场，后者占据超过70%的市场份额，成为亨廷顿症的主流用药。 氘丁苯那嗪在2017年获FDA批准上市，是首个氘代药物。氘代修饰就是将药物分子中特定氢原子(H)替换成氘原子(D)。氢-氘交换不会改变药物的任何其他生物学特性，如其形状、大小或与靶点结合的能力。但理论上可以改善药物分子在体内吸收、分布、代谢的效果，降低给药剂量或频率，提高安全性并获得更佳疗效。 梯瓦制药的氘丁苯那嗪确实显著减缓代谢过程，其半衰期接近非氘代的2倍，给药次数降低为一天两次，而且副作用更小。 氘代修饰不仅是成药性优化的重要策略，也是突破化合物专利、规避新药研发风险的手段，所以被视为一种创新的捷径。梯瓦成功之后，更多药企尝试氘代技术，包括辉瑞、诺华、默克等大型跨国药企巨头。目前已经上市的还有泽璟医药研发的氘代药物多纳非尼，以及BMS的 TYK2 抑制剂氘可来昔替尼。 也一些有希望的氘代药物候选者被放弃。GSK曾引进过一款治疗HIV的氘代药物，因为担心患者对它们产生耐药性而放弃。到目前为止，氘化药物的成功案例还都属于个例。 氘代药物的支持者承认存在这种技术路线许多陷阱。氘化药物制造商Auspex的原科学创始人托马斯·甘特（Thomas Gant）说，大多数合成化学家都不太了解氘化试剂或底物存在时的化学反应。 他说：“令人相当惊讶的是，许多大多数化学家认为不会对氢的位置产生影响的反应，实际上会导致相当多的氢自由基随机化并四处游离。所以你进行这些反应时，预期它对你的氘代药物没有影响，但实际上，在某些情况下你会看到相当显著的影响。这会使氘在分子中分散开来”，这样你就不再拥有原始化合物了。 氘代修饰的方法也不一定完全规避专利风险。甘特是一家专门从事制药和氘代（技术）的咨询公司Recondite Falls Discovery的高管。他表示，氘代化合物被视为新的化学实体，可以申请专利。但他解释说，要获得专利，“你必须实际进行化学操作，制备出氘代化合物，展示光谱，展示氘掺入率，并展示生物学特性以证明可感知到的益处。” 江苏瑞途律所合伙人王玉姣等人在评论“氘代鲁索替尼美国专利无效案”时说到，“在现有技术未公开代谢位点的情况下，氘代药物存在基于改善的药物动力学性质而具备创造性的可能性；而在现有技术公开了代谢位点的情况下，针对代谢位点进行氘代改进的氘代药物，如何发现并证明氘代药物“预料不到的技术效果”以使氘代药物具有可专利性，应成为专利申请中关注的重点。” 如果真的把氘代当成捷径，这条路便不是看起来那么好走的。 -02- 同源康的“头对头挑战”成色如何 同源康的定位是专注于开发用于癌症治疗的小分子靶向疗法的公司。但创始人吴豫生过往经历里，关于肿瘤药物研发的信息比较少。 吴豫生从2011年-2017年担任泰基鸿诺医药（一家过去主要从事提供定制化医药中间体合成服务的公司）的董事长兼首席执行官，更早之前在先灵葆雅担任高级主任研究员，负责用于治疗血栓、肥胖症及阿尔兹海默病的新药研发。 公司管线除了TY-9591，其他几款在研药物尚处在较早阶段。这张保险牌成为支撑同源康市值的主要支柱。在招股书中，就强调TY-9591是通过对奥希替尼改良而来，强调相比于后者的优势。 同源康的融资之路一直很顺利，2018年起5年内累计融资达到9.487亿元。但连年亏损加上对赌协议的压力，让同源康迫切寻求上市。 2024年8月20日，在创新药仍旧面临资本寒冬的情况下，同源康医药在港交所顺利挂牌上市。如今不到一年，同源康已经迫不及待兑现TY-9591的价值。 同源康的情况，可以和国内另一家氘代药物的制造商泽璟制药进行对比。泽璟研发的多纳非尼算是经典肝癌靶向药索拉非尼的氘代版本，也曾做出头对头击败索拉非尼的结果，取得了总生存期（OS）等临床数据优效。 作为首个国产氘代药物，且是肝癌一线靶向药，多纳非尼当时受到的监管标准比较高。在这种情况下，多纳非尼凭借II期数据在2021年6月实现了附条件上市。 从市场格局来看，多纳非尼上市的时候，索拉非尼正好在走下坡路。 2020年索拉非尼在国内被宣告专利销售额无效，2021年索拉非尼被列入集采，拜耳选择弃标，一步步让出市场份额。泽璟是吃到红利的药企之一，多纳非尼销售额慢慢爬升，2023年接近4亿元，对泽璟这样一家刚商业化的公司来说算是比较大的贡献。 而TY-9591不管临床设计，还是市场格局都不及多纳非尼乐观。目前TY-9591的II期试验入组数太少，仅有iORR还不足以令人信服，“头对头击败奥希替尼”的自宣文案还有待商榷。 而且奥希替尼（阿斯利康）、翰森（阿美替尼）、艾力斯（伏美替尼）、贝达（贝福替尼）等三代EGFR TKI正处于当打之年，销售逐年攀升。2024年，奥希替尼全球销售额高达65.80亿美元。 氘代药物的理想情况是best in class，但如果最终没有实现临床优效，只能成为fast follow。 期待TY-959III期数据维持头对头击败奥希替尼的结论。如若不然，一个biotech的fast follow很难挤进这场巨头之战。这也是为什么很多公司都具备氘代的技术手段，但是考虑到III期要头对头试验，就放弃了这种产品思路。 TY-959的未来十分值得关注。因为如果“头对头击败巨头”仅仅成为一种宣传标语，没有经得住科学考证的内核支撑，“头对头挑战成功”终将成为一种讽刺。 参考文献： 药物分子氘代修饰方法研究进展.中国医药工业杂志2024, 55(11) .李嘉怡等 Deuterium switcheroo breathes life into old drugs .Bethany Halford.July 4, 2016 浅析氘代鲁索替尼美国专利无效案——Case IPR2017-01256  喜欢我们文章的朋友点个“在看”和“赞”吧，不然微信推送规则改变，有可能每天都会错过我们哦~ 免责声明 “汇聚南药”公众号所转载文章来源于其他公众号平台，主要目的在于分享行业相关知识，传递当前最新资讯。图片、文章版权均属于原作者所有，如有侵权，请在留言栏及时告知，我们会在24小时内删除相关信息。 信息来源：深蓝观 往期推荐 本平台不对转载文章的观点负责，文章所包含内容的准确性、可靠性或完整性提供任何明示暗示的保证。

The Independent Data Safety and Monitoring Board (DSMB) confirmed the remarkable efficacy results and a positive benefit/risk profile of MaaT013 in this patient population The Company plans for submission with the European Medicines Agency in June 2025, targeting a potential approval in mid-2026 Lyon, France, March 18th, 2025 – 6:00pm CET – MaaT Pharma (EURONEXT: MAAT – the “Company”), a clinical-stage biotechnology company and a leader in the development of Microbiome Ecosystem TherapiesTM (MET) dedicated to enhancing survival for patients with cancer through immune modulation, announced, after recently receiving the approval of its Pediatric Investigation Plan (PIP) by the EMA Pediatric Committee, that the DSMB completed its final safety assessment of the pivotal Phase 3 trial ARES, a single-arm, open-label, multicenter European study evaluating the efficacy and safety of MaaT013 in acute Graft-versus-Host Disease patients with gastrointestinal involvement (GI-aGvHD) in third-line treatment, refractory to steroids and refractory or intolerant to ruxolitinib. “This DSMB’s positive review is another key milestone for MaaT Pharma, further validating MaaT013’s consistently favorable clinical profile, demonstrated over the years in clinical development in a highly fragile patient population,” stated Gianfranco Pittari, MD, PhD, Chief Medical Officer of MaaT Pharma. “It underscores our determination to enhance outcomes in patients with aGvHD through innovative therapies.” The Phase 3 study met its primary endpoint, and positive topline results (full details here) were reported in January 2025, demonstrating high efficacy for MaaT013 with a significant gastrointestinal overall response rate at Day 28 of 62%, exceeding the initially expected response rate of 38%. The DSMB, composed of 4 independent experts, had previously reviewed data on 30 patients in October 2023 and had concluded that MaaT013 demonstrated a positive benefit/risk ratio based on a good safety profile and positive preliminary efficacy results. The experts completed their review during the last meeting and reviewed safety data from 66 patients up to the data cut-off of the primary analysis. The DSMB confirmed that “given the remarkable efficacy results, the study results show an acceptable safety profile and a favorable benefit /risk ratio”. The DSMB members will continue to review safety on an ongoing basis until the 1-year follow-up. “With both the Pediatric Investigation Plan approved by the EMA Pediatric Committee and now positive DSMB confirmation, we continue to build a strong momentum toward a potential market approval, with the opportunity to have the first-approved microbiome-based drug in Europe,” concluded Hervé Affagard, co-founder and CEO and of MaaT Pharma. Next Steps for MaaT013 in aGvHD: Submission of a Centralized Marketing Authorization Application (MAA) to the EMA is expected in June 2025. Evaluation of the One-year Overall Survival (secondary endpoint evaluation) is expected in Q4 2025. The Company is actively engaging with investors and potential partners to advance toward the regulatory phase and commercialization. About acute Graft-versus-Host Disease Acute Graft-versus-Host Disease occurs in patients within 100 days of undergoing a stem cell or bone marrow transplant, where the transplanted cells initiate an immune response and attack the transplant recipient’s organs, causing inflammation of the skin, liver and/or gastro-intestinal tract and leading to significant morbidity and mortality. GI involvement is associated with severe complications such as profound diarrhea, abdominal pain, intestinal bleeding, and death. These complications are often life-threatening, with increased mortality risk, due to the challenges of managing severe GI inflammation and the associated risks of infection, malnutrition, and organ failure. The standard first line therapy for treating aGvHD is the use of systemic steroids. If patients do not respond to steroids, they are considered Steroid Resistant (SR) and other agents can be administered. Currently, the second-line treatment for steroid-refractory acute graft-versus-host disease (SR aGvHD) is ruxolitinib. Recently, remestemcel—L-rknd was approved in December 2024 in the US specifically for use in the paediatric population as a second-line treatment. About MaaT013 MaaT Pharma’s Microbiome Ecosystem TherapiesTM (MET) are designed to leverage a full microbiome ecosystem to restore balance and maximize clinical benefits for patients with severe, treatment-induced dysbiosis in acute diseases. MaaT013 is a full-ecosystem, off-the-shelf, standardized, pooled-donor, enema Microbiome Ecosystem TherapyTM for acute, hospital use. It is characterized by a consistently high diversity and richness of microbial species and the presence of ButycoreTM (a group of bacterial species known to produce anti-inflammatory metabolites). MaaT013 aims to restore the symbiotic relationship between the patient’s functional gut microbiome and their immune system to correct the responsiveness and tolerance of immune functions and thus reduce steroid-resistant, gastrointestinal (GI)-aGvHD. MaaT013 has been granted Orphan Drug Designation by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). About MaaT Pharma MaaT Pharma is a leading, late-stage clinical company focused on developing innovative gut microbiome-driven therapies to modulate the immune system and enhance cancer patient survival. Supported by a talented team committed to making a difference for patients worldwide, the Company was founded in 2014 and is based in Lyon, France. As a pioneer, MaaT Pharma is leading the way in bringing the first microbiome-driven immunomodulator in oncology. Using its proprietary pooling and co-cultivation technologies, MaaT Pharma develops high diversity, standardized drug candidates, aiming at extending life of cancer patients. MaaT Pharma has been listed on Euronext Paris (ticker: MAAT) since 2021. Forward-Looking statements All statements other than statements of historical fact included in this press release about future events are subject to (i) change without notice and (ii) factors beyond the Company’s control. These statements may include, without limitation, any statements preceded by, followed by, or including words such as “target,” “believe,” “expect,” “aim”, “intend,” “may,” “anticipate,” “estimate,” “plan,” “project,” “will,” “can have,” “likely,” “should,” “would,” “could” and other words and terms of similar meaning or the negative thereof. Forward-looking statements are subject to inherent risks and uncertainties beyond the Company’s control that could cause the Company’s actual results or performance to be materially different from the expected results or performance expressed or implied by such forward-looking statements.