BioTheryX, Inc.

SAN DIEGO, CA, USA I July 17, 2024 I Biotheryx, Inc., a biopharmaceutical company discovering and developing a portfolio of first-in-class protein degraders with a focus on validated targets in cancer and inflammatory diseases, today announced that the first patient has been dosed in its Phase 1 clinical trial evaluating BTX-9341, an investigational oral and bifunctional degrader of cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6), as a monotherapy and in combination with fulvestrant for patients with advanced and/or metastatic hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer who have previously received CDK4/6 inhibitor therapy either in the adjuvant or metastatic setting. “BTX-9341 is a potent and selective CDK4/6 degrader that has shown significant anti-tumor activity in both CDK4/6 inhibitor naïve and resistant preclinical models. We are optimistic that it will meet a critical unmet medical need for patients with HR+/HER2- breast cancer who have received prior CDK4/6 inhibitor therapy,” said Leah Fung, Ph.D., CEO of Biotheryx. “Dosing the first patient in this trial represents a significant milestone for Biotheryx, the patients we aim to serve and the scientists who have made this possible.” The Phase 1 clinical trial will begin with dose escalation of BTX-9341 as a monotherapy, followed by a combination with fulvestrant and will conclude with dose expansion of BTX-9341 in combination with fulvestrant. The trial will assess safety, tolerability, pharmacokinetic and pharmacodynamic activity of BTX-9341 as a monotherapy and in combination with fulvestrant. Once the recommended Phase 2 dose of the combination has been determined, there will be a formal evaluation of efficacy in an expansion cohort. “We are thrilled to have dosed the first patient with BTX-9341 at The START Center for Cancer Research,” stated START Co-Founder and Co-Director of Clinical Research, Dr. Amita Patnaik, MD, FRCPC. “BTX-9341 is a highly novel, first-in-class, potent and selective degrader of CDK4/6, representing an innovative therapeutic approach. It has the potential to transform the care of patients with advanced and/or metastatic HR+/HER2- breast cancer, particularly those who have received prior CDK4/6 inhibitor therapies. This milestone is perfectly aligned with START’s mission to accelerate drug development and provide early access to cutting-edge anticancer therapies, bringing hope to patients and their families.” In preclinical studies, orally administered BTX-9341 demonstrated in vivo CDK4/6 degradation and improved anti-tumor activity as a monotherapy compared to current standard of care treatment regimens. BTX-9341 also demonstrated synergies with selective estrogen receptor degraders including fulvestrant, elacestrant and camizestrant in CDK4/6 naïve and resistant models. About BTX-9341 BTX-9341 is a first-in-class, oral degrader of CDK4/6, important targets for a range of cancers and clinically validated in HR+/HER2- breast cancer. In preclinical breast cancer models, BTX-9341 demonstrated superiority to CDK4/6 inhibitors through potent and highly selective catalytic degradation of CDK4 and CDK6, robust inhibition of Cyclin E and CDK2 transcription, cell cycle arrest and ultimately superior in vivo efficacy in breast cancer xenografts. Beyond this increased efficacy potential, BTX-9341 is differentiated from CDK4/6 inhibitor approaches through the ability to overcome key resistance mechanisms that limit the impact of inhibitors in second line HR+/HER2- breast cancer. About Biotheryx, Inc. Biotheryx is a clinical-stage biopharmaceutical company discovering and developing a portfolio of first-in-class protein degraders, including bifunctional degraders and molecular glues. Our focus is on deploying the differentiated potential of degraders towards validated targets in cancer and inflammatory disease. Members of our founding and scientific teams previously developed the IMiDs, the first U.S. Food and Drug Administration (FDA) approved modulators of Cereblon, the most widely validated E3 ligase involved in protein degradation, and we have applied our expertise in Cereblon binding to build our proprietary PRODEGY platform. Biotheryx’s clinical program, BTX-9341, a bifunctional degrader of CDK4 and CDK6, began a Phase 1 clinical trial in the third quarter of 2024. Biotheryx’s pipeline also includes BTX-10908, a first-in-class degrader of SOS1 for pan-KRAS mutant cancers and PDE4 degraders for inflammatory diseases. For more information, please visit biotheryx.com and engage with us on LinkedIn . SOURCE: Biotheryx

SAN DIEGO, July 17, 2024 /PRNewswire/ -- Biotheryx, Inc., a biopharmaceutical company discovering and developing a portfolio of first-in-class protein degraders with a focus on validated targets in cancer and inflammatory diseases, today announced that the first patient has been dosed in its Phase 1 clinical trial evaluating BTX-9341, an investigational oral and bifunctional degrader of cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6), as a monotherapy and in combination with fulvestrant for patients with advanced and/or metastatic hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer who have previously received CDK4/6 inhibitor therapy either in the adjuvant or metastatic setting. "BTX-9341 is a potent and selective CDK4/6 degrader that has shown significant anti-tumor activity in both CDK4/6 inhibitor naïve and resistant preclinical models. We are optimistic that it will meet a critical unmet medical need for patients with HR+/HER2- breast cancer who have received prior CDK4/6 inhibitor therapy," said Leah Fung, Ph.D., CEO of Biotheryx. "Dosing the first patient in this trial represents a significant milestone for Biotheryx, the patients we aim to serve and the scientists who have made this possible." The Phase 1 clinical trial will begin with dose escalation of BTX-9341 as a monotherapy, followed by a combination with fulvestrant and will conclude with dose expansion of BTX-9341 in combination with fulvestrant. The trial will assess safety, tolerability, pharmacokinetic and pharmacodynamic activity of BTX-9341 as a monotherapy and in combination with fulvestrant. Once the recommended Phase 2 dose of the combination has been determined, there will be a formal evaluation of efficacy in an expansion cohort. "We are thrilled to have dosed the first patient with BTX-9341 at The START Center for Cancer Research," stated START Co-Founder and Co-Director of Clinical Research, Dr. Amita Patnaik, MD, FRCPC. "BTX-9341 is a highly novel, first-in-class, potent and selective degrader of CDK4/6, representing an innovative therapeutic approach. It has the potential to transform the care of patients with advanced and/or metastatic HR+/HER2- breast cancer, particularly those who have received prior CDK4/6 inhibitor therapies. This milestone is perfectly aligned with START's mission to accelerate drug development and provide early access to cutting-edge anticancer therapies, bringing hope to patients and their families." In preclinical studies, orally administered BTX-9341 demonstrated in vivo CDK4/6 degradation and improved anti-tumor activity as a monotherapy compared to current standard of care treatment regimens. BTX-9341 also demonstrated synergies with selective estrogen receptor degraders including fulvestrant, elacestrant and camizestrant in CDK4/6 naïve and resistant models. About BTX-9341 BTX-9341 is a first-in-class, oral degrader of CDK4/6, important targets for a range of cancers and clinically validated in HR+/HER2- breast cancer. In preclinical breast cancer models, BTX-9341 demonstrated superiority to CDK4/6 inhibitors through potent and highly selective catalytic degradation of CDK4 and CDK6, robust inhibition of Cyclin E and CDK2 transcription, cell cycle arrest and ultimately superior in vivo efficacy in breast cancer xenografts. Beyond this increased efficacy potential, BTX-9341 is differentiated from CDK4/6 inhibitor approaches through the ability to overcome key resistance mechanisms that limit the impact of inhibitors in second line HR+/HER2- breast cancer. About Biotheryx, Inc. Biotheryx is a clinical-stage biopharmaceutical company discovering and developing a portfolio of first-in-class protein degraders, including bifunctional degraders and molecular glues. Our focus is on deploying the differentiated potential of degraders towards validated targets in cancer and inflammatory disease. Members of our founding and scientific teams previously developed the IMiDs, the first U.S. Food and Drug Administration (FDA) approved modulators of Cereblon, the most widely validated E3 ligase involved in protein degradation, and we have applied our expertise in Cereblon binding to build our proprietary PRODEGY platform. Biotheryx's clinical program, BTX-9341, a bifunctional degrader of CDK4 and CDK6, began a Phase 1 clinical trial in the third quarter of 2024. Biotheryx's pipeline also includes BTX-10908, a first-in-class degrader of SOS1 for pan-KRAS mutant cancers and PDE4 degraders for inflammatory diseases. For more information, please visit biotheryx.com and engage with us on LinkedIn. SOURCE Biotheryx, Inc.

来源：医药速览 DAC抗体偶联蛋白降解剂PROTAC药物由三部分构成，包括目标蛋白结合物、泛素连接酶配体和连接子。但PROTAC通常面临细胞摄取差和生物利用度低的问题，在健康细胞和癌细胞之间缺乏区分可能会引发脱靶毒性，而DAC（Degrader-antibody conjugates） 模式的出现为PROTAC药物提供了新的思路。 图1 ADC和DAC区别   01   DAC具有PROTAC的优势 通过催化发挥作用，所需的药物剂量低：传统的小分子药物主要是通过与靶标蛋白结合占据蛋白上的活性位点，从而抑制靶标蛋白的作用。而PROTAC是将靶标蛋白与E3泛素连接酶拉近并进行泛素化最终导致靶标蛋白的降解，该过程属于“事件驱动”性反应。研究表明很低剂量的泛素化就可以诱导靶标蛋白的降解。 靶向以往不可成药靶点：小分子药物发挥作用需要与靶标蛋白长时间高强度结合，而PROTAC只要有配体能够结合即可发挥作用，因此可以作用于一些小分子无法结合的靶点。 克服耐药性：小分子抑制剂和抗体耐药性的产生多数是因为靶标蛋白的突变使得药物无法作用于原来的表位，而PROTAC是直接将靶标蛋白进行降解，因此在一定程度上能够避免由于点突变产生的耐药性。 应用范围广：PROTAC理论上可以降解细胞内所有种类的蛋白，针对肿瘤以外的疾病领域（如神经、免疫、感染等），也具有较大的开发潜力。 DAC克服PROTAC的局限性 PROTAC 具有高分子量并且在药代动力学和成药性研究中表现较差，透膜性较差。DAC 通过单抗与膜抗原结合后内化将 PROTAC 递送至细胞质，PROTAC 本身较差的透膜性可以避免旁观者效应引起正常细胞内蛋白被降解。    PROTAC 产生的脱靶效应。通过抗体的靶向性，将 PROTAC 递送进特定的细胞中，双重特异性极大降低 PROTAC 的脱靶效应。   02   DAC机制 DAC与ADC机制相似，DAC在血液循环中尽可能保持稳定，随后抗体特异性识别肿瘤相关抗原，DAC被内化至内含体和溶酶体，在蛋白水解酶或者酸性环境中，DAC被降解，释放有效载荷（PROTAC），随后发挥作用。 图2 DAC机制图 DAC的开发相比于ADC更为复杂： （1）与ADC payload的广泛细胞毒性不同的是，DAC的降解剂需要对特定肿瘤细胞有靶向生物活性。因此DAC的抗原必须同时满足ADC内化与运输标准，以及在降解剂靶向的敏感细胞上高度表达。 （2）降解剂一般效力要弱于细胞毒性payload，所以需要高载药量（DAR一般大于4），这种高载药量势必也会引起聚集的问题，并对药物的代谢动力学产生负面影响。 （3）DAC PROTAC通常比ADC的有效载荷更大或更具亲脂性。因此，需要开发新的接头设计和偶联方法来克服这一问题。 （4）一些降解剂缺乏可供偶联的共价连接基团，便需要考虑将必要的化学基团加入降解剂结构中去。这就需要开发可裂解的PROTAC与Linker之间的接头，或溶酶体酶切后留在降解剂上的接头片段不干扰其生物学功能。这一点也是DAC结构设计中最重要的一环。 （5）此外还需要考虑：DAC的降解剂载荷在溶酶体系统中的稳定性、降解剂载荷有效逃离溶酶体隔室的能力、以及有效载荷的旁观者效应倾向。   03   DAC药物 DAC对外公布的药物并不多，但DAC领域布局的玩家不少。基因泰克、默克,乐高化工，Silverback、biotheryx、财团法人生物技术开发中心、Angiex，嘉兴优博生物，宜联生物均有DAC专利。 图3 部分在研DAC药物 ORM-5029是Orum在TPD2平台上利用GSPT1降解剂开发的一款HER2/HER3特异性双靶向的AnDC，目前作为一种潜在的FIC靶向蛋白质降解剂拟开发用于HER2 表达的乳腺癌治疗。 图4 ORM-5029使用的linkerpayload ORM-5029与Smol006、T-DM1和/或T-dxd相比， ORM-5029在HER2+细胞系中显示出10-1000倍的效力优势。 在BT474异种移植模型中给予单剂量治疗后，ORM-5029的活性优于T-DM1，与T-dxd相当。 在体外活性测试中，ORM-5029在不同表达水平的HER2细胞中也显示出强大的杀伤活性，表现出优于CC-885和T-Dxd的活性。 ORM-6151与ORM-5029使用相同的linkerpayload, 靶向CD33靶点，用于治疗急性髓性白血病（AML），分别在CD33positive和negative的细胞系上进行体外火星验证，发现其相较于CC-90009和Mylotary具有较好的选择性和细胞活性。 ORM-6151在体内实验中，表现出与CC-90009和Mylotary明显的优势。3mg/kg单次给药就能完全消退肿瘤。 Ref. 文献来源：Drugs and technology微信公众号