OATP1B1

2024年2月，国外Biotech公司公布活性分子1. NivasorexantNivasorexant（ACT-539313）是 Actelion 公司生产的一种口服选择性 OX1 受体拮抗剂，是首个进入临床开发阶段的产品，最近完成了针对暴食症的概念验证 II 期临床试验。图片来源：February 2024 (drughunter.com)Jodi T. Williams等人报告了从双重奥曲肽受体拮抗剂开始的发现工作，并描述了一个偶然的发现引发的药物化学计划，最终确定了强效的 SO1RA ACT-539313。该化合物在大鼠日程表诱发的多尿症模型中的疗效支持了将其作为临床前候选药物的决定。对 DORA 系列进行先导化合物优化的过程中，研究者发现了一种结构修饰，这种修饰导致了从双重拮抗作用到 OX1 选择性拮抗作用的转变，原始吡咯烷系列的主要缺点，即在人类肝脏微粒体中的稳定性和 CYP3A4 抑制作用，也可以通过将中心环改为吗啉来解决。对 OX1 的效力、选择性和溶解性进行微调后，一些化合物被优先用于评估其在中枢神经系统中的分布。化合物 20（ACT-539313）成为最有希望进行体内研究的候选化合物。4-Acyl-3-triazolobenzylmorpholines 的 hOX1/OX2 IC50、选择性和人体微粒体稳定性在吗啉核心（20）的合成中，首先使用市售的 N-叔丁氧羰基-3-碘-二苯基丙氨酸，对其进行叔丁氧羰基脱保护，然后还原成相应的氨基醇。先用氯乙酰氯酰化，然后环化，得到吗啉酮 I-3。随后用 1,2,3-三唑进行芳基化、酰胺还原，再与所需的羧酸进行酰胺偶联，就得到了目标化合物。合成 4-酰基-3-苄基吗啉（20）基于可溶性和易于合成的考虑，化合物 20（ACT-539313）被优先用于药物开发。化合物 20（ACT-539313，nivasorexant）已经完成了 I 期临床试验，最近又完成了针对暴食症的 II 期临床试验，但未达到主要终点。2. ACT-1016-0707Cyrille Lescop等人发现新型、口服活性和选择性 LPA1 受体拮抗剂 ACT-1016-0707，可作为治疗纤维化疾病的临床前候选药物。图片来源：February 2024 (drughunter.com)ACT-1016-0707是来自 Idorsia 的一种强效口服活性 LPAR1 拮抗剂，在小鼠血管渗漏靶点接合模型中显示出疗效，被选定用于治疗纤维化疾病的临床前开发。值得注意的是，ACT-1016-0707 在结构上有别于之前公开的 LPAR1 拮抗剂，这可能有助于将其与其他因肝胆毒性问题而受阻的临床候选药物区分开来。哌啶 3 是一种强效、选择性溶血磷脂酸受体亚型 1 受体（LPAR1）拮抗剂，在小鼠皮肤血管渗漏靶点参与模型中显示出疗效。然而，化合物 3 与人体血浆蛋白结合率很高，在大鼠体内的清除率也很高，这可能会严重阻碍其临床开发。经过不断的先导优化，最终开发出了药效强、蛋白结合率低、代谢稳定、口服活性高的氮杂环丁烷 17。大鼠药代动力学（PK）研究显示，17 在肝脏中蓄积。体外研究表明，17 是有机阴离子共转运多肽 1B1 （OATP1B1）的底物。虽然类似物 24 不再是 OATP1B1 的底物，但 PK 研究表明该化合物会进行肠肝再循环。将羧酸侧链替换为非酸性的硫酰胺分子并进一步微调支架后，产生了强效、口服活性的 LPAR1 拮抗剂 49，并将其用于治疗纤维化疾病的临床前开发。从 Boc 保护的氮杂环丁烷-3-羧酸 73（方案 3）开始制备磺酰胺 48。在吡啶中用 POCl3 活化酸 73，然后与 6-氯-4-甲氧基吡啶-3-胺偶联，得到酰胺 96，产率中等。将溴吡啶分子与异丙烯基硼酸频哪醇酯进行铃木偶联，可以得到产率较高的烯烃 97。在 Pt2O 催化下，右侧吡啶上的异丙基被氢化，而左侧的 2-氯吡啶基没有被还原（98）。通过 Boc 脱保护，得到氮杂环丁烷 99，在碱存在下用硫酰胺处理 99，将其转化为所需的硫酰胺 48。同样，氮杂环丁烷 63与磺酰胺反应也可得到磺酰胺 49。制备氨基磺酸 48 和 49a体外数据表明，化合物 49 是一种强效、选择性 LPAR1 拮抗剂，在 LPA 诱导的皮肤血管渗漏小鼠模型中具有口服活性。基于上述特性，硫酰胺 49 被选为治疗纤维化疾病的临床前开发候选药物，目前正在进行首次人体试验研究。3. CT1812CT1812是Cognition Therapeutics 公司生产的一种具有口服活性和脑渗透性的 sigma-2 受体拮抗剂，目前正处于治疗阿尔茨海默病的 II 期临床7研究阶段。图片来源：February 2024 (drughunter.com)Gilbert M. Rishton等人开发了一种无偏见的表型神经元测定法来测量可溶性 Aβ 寡聚体的突触毒性效应。筛选了一系列通过条件提取法制备的中枢神经系统类药物小分子。发现了能防止和逆转神经元中 Aβ 寡聚体的突触毒性效应的化合物，首款口服小分子研究药物 7（CT1812）正在进行治疗阿尔茨海默病的研究。异吲哚啉抗 AβO 化合物的一般合成方法已经开发出来。通过钯介导的芳基碘化物 14 和 15与 2-甲基-3-丁炔-2-胺的偶联，得到了 gem-二甲基取代的丙炔胺 16 和 17（17 的收率为 74%），从而可以直接获得 gem-二甲基取代的异吲哚啉。这些化合物随后被氢化为中间胺 19 和 20（20 的产率为 100%）。现有的手性 α-甲基胺 12 和 18以及 gem-二甲基取代胺 19 和 20 与相应的双苄基溴 21-23 缩合，得到异吲哚啉抗 AβO 化合物 4-7（7 的收率为 63%）。制备异吲哚啉化合物 4-7化合物 7（CT1812）是口服治疗阿尔茨海默病的第一类小分子候选药物。与安慰剂相比，CT1812 能显著提高 AD 患者 CSF 中 Aβ 寡聚体的浓度，降低突触蛋白和磷酸化 tau 片段的浓度，并逆转 CSF 中许多表达失调的 AD 相关蛋白。4. AZD1390AZD1390 是AstraZeneca公司生产的一种强效、选择性共济失调毛细血管扩张症突变激酶（ATM）抑制剂，具有良好的临床前 PK 和 NHP PET 研究中显著的脑暴露，被选中用于临床开发，以探索 ATM 对颅内恶性肿瘤的放射增敏作用。图片来源：February 2024 (drughunter.com)从临床候选药物 AZD0156 （4 ）开始，Kurt G. Pike等人对咪唑喹啉-2-酮支架进行了研究，目的是改善其在人体中的中枢神经系统暴露。除了调节亲脂性，他们还探索了旨在减少氢键、碱性和分子灵活性的策略。这些研究发现化合物 24（AZD1390）是一种非常有效的 ATM 选择性抑制剂，具有良好的临床前药代动力学特征。化合物 24 作为临床候选药物被开发，以探索 ATM 对颅内恶性肿瘤的放射增敏作用。通过对咪唑并[4,5-c]喹啉-2-酮系列进行优化，在提高 BBB 穿透性的同时，保持了 4 所固有的出色药效、选择性和特性，最终确定了首个据报道适合临床开发的脑穿透性 ATM 抑制剂 24（AZD1390）。目前，AZD1390（24）正处于与放疗联合治疗颅内恶性肿瘤的 1 期临床研究中   探索无环碱性取代基。碱性中心和芳香核心之间的四原子连接物（丙氧基）似乎是提高药效的最佳选择，在 24 号喹啉上引入一个氟后，化合物的各种性质达到了令人满意的平衡，符合我们的进展标准。 无环碱性取代基的 SARa从6-溴-4-氯-7-氟喹啉-3-羧酸乙酯 37 开始，制备了一系列 7-氟喹啉类似物。溴化物 38 与 6-氟吡啶-3-基)硼酸反应生成中间体 39，中间体 39 随后与一系列环胺发生 SNAr 反应，生成化合物 12 和 16。O 键类似物（21 和 24）是39 与适当的醇（用氢化钠预处理以形成烷氧化物）进行处理而制备的。在这些情况下，对反应条件和亲核剂化学计量的控制足以防止喹啉的 C-7 氟发生位移。含碱性侧链的 7-氟-1,3-二氢-2H-咪唑并[4,5-c]喹啉-2-酮的合成5. TYA-108TYA-018 是 Tenaya Therapeutics 公司的一种临床前小分子 HDAC6 抑制剂，在射血分数保留型心力衰竭（HFpEF）雄性小鼠模型中显示出临床前疗效。值得注意的是，TYA-018 在与 SGLT2 抑制剂联用时显示出更强的疗效，治疗 HFpEF 的一个有前途的靶点。此外，TYA-018 还能抑制人心脏成纤维细胞的活化，增强心肌细胞的线粒体呼吸能力。图片来源：February 2024 (drughunter.com)中间体化合物3的合成目标化合物TYA-108的合成参考文献https://doi.org/10.1021/acs.jmedchem.3c01894https://doi.org/10.1021/acs.jmedchem.3c01827https://doi.org/10.1021/acsmedchemlett.1c00048https://doi.org/10.1021/acs.jmedchem.3c02277声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号   粉丝群/投稿/授权/广告等请联系公众号助手 觉得本文好看，请点这里↓

Clinical and real-world evidence data support treatment with ERLEADA® (apalutamide) and niraparib plus abiraterone acetate given with prednisone in patients with prostate cancer Additional updates will be presented on innovative targeted releasing systems TAR-200 and TAR-210 in bladder cancer RARITAN, N.J., Jan. 24, 2024 /PRNewswire/ -- Johnson & Johnson announced today new clinical and real-world evidence data will be featured in 18 abstracts at this year's ASCO GU Symposium (San Francisco, January 25-27), highlighting the Company's commitment to transform the science of genitourinary (GU) cancers. Key presentations will include new real-world evidence data adding to the strong and differentiated clinical profile of ERLEADA® (apalutamide) in the treatment of various stages of prostate cancer, patient-reported outcomes data from the Phase 3 MAGNITUDE study of niraparib plus abiraterone acetate given with prednisone, and updates on targeted releasing systems TAR-200 and TAR-210. "We are applying our GU expertise to advance the science of prostate cancer and bladder cancer," said Kiran Patel, M.D., Vice President, Clinical Development, Solid Tumors, Johnson & Johnson Innovative Medicine. "A recent FDA approval of new labelling for ERLEADA reinforces the impact of this standard-of-care treatment on reducing PSA to undetectable levels when added to androgen deprivation therapy. With the addition of new analyses presented at ASCO GU, we are progressing in our ambition to address unmet patient needs through earlier treatment intervention with the goal of improving and extending patients' lives." "Our data across six different mechanisms of action underscore the breadth and depth of J&J's GU portfolio and our commitment to redefine treatment paradigms and pioneer new therapeutic advances for people with prostate and bladder cancers," said Luca Dezzani, M.D., U.S. Vice President, Medical Affairs, Solid Tumors, Johnson & Johnson Innovative Medicine. "In addition to traditional endpoints like overall survival, we are committed to assessing patients' well-being and investing in studies and real-world analyses based on patient populations that reflect everyday clinical practice." Delivering patient-centric innovation in prostate cancer With a deep legacy in the treatment of prostate cancer, J&J is committed to improve outcomes in metastatic disease, while defining new standards of care for patients at all stages of disease. New data at ASCO GU build on the strong clinical profile of ERLEADA® with real-world evidence supporting its impact on survival and PSA responses. Additional presentations highlight the company's commitment to advance equity in clinical trials. Key presentations include: Real-world survival rates as presented in the ROME (Abstract #57) and ROMA (Abstract #58) studies, which reviewed patients in an oncology database with metastatic castration-sensitive prostate cancer (mCSPC) who were treated with ERLEADA® or enzalutamide (ROME) or ERLEADA® or abiraterone acetate (ROMA). U.S. real-world evidence comparing PSA90 response in patients with mCSPC six months after initiating ERLEADA® or enzalutamide (Abstract #51). A first look at the design of the LIBERTAS study, the first Phase 3 trial evaluating ERLEADA® plus intermittent vs continuous androgen deprivation therapy (ADT) in patients with mCSPC, inclusive of all gender identities (Abstract #TPS236). Patient-reported outcomes from the Phase 3 MAGNITUDE study evaluating niraparib with abiraterone acetate plus prednisone in patients with BRCA-positive metastatic castration-resistant prostate cancer (mCRPC) (Abstract #105). Data from the ongoing Phase 3 PRIMORDIUM study, including baseline characteristics of PSMA-PET positive and negative high-risk patients with biochemical recurrence after radical prostatectomy (Abstract #119). Working to transform bladder cancer treatment with novel drug delivery technology and precision therapies Data in bladder cancer underscore J&J's vision to advance the treatment paradigm and address unmet patient needs through bladder-sparing and Bacillus Calmette-Guérin (BCG)-free therapies in earlier-stage disease, and precision medicine for patients with specific genetic mutations. ASCO GU presentations showcase innovative targeted releasing systems TAR-200 and TAR-210, and new real-world evidence data on the proportion and prognosis of fibroblast growth factor receptors (FGFR) alterations in Japan. Highlights include: Insights on the reasons for refusal or ineligibility for radical cystectomy from an analysis of the SunRISe-1 study evaluating TAR-200, a gemcitabine-containing targeted releasing system being studied in patients with BCG-unresponsive high-risk non-muscle-invasive bladder cancer (HR-NMIBC) (Abstract #701). Preliminary results evaluating a novel urine-based screening assay to detect FGFR alterations and select patients who may respond to TAR-210, an erdafitinib-containing targeted releasing system being studied in patients with NMIBC with select FGFR alterations (Abstract #676). Data describing the proportion and prognosis of Japanese patients with fibroblast growth factor receptor 2 or 3 (FGFR2 or 3) altered advanced or metastatic urothelial cancer (Abstract #647). The complete list of Company-sponsored abstracts follows: About ERLEADA® ERLEADA ® (apalutamide) is an androgen receptor signaling inhibitor indicated for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and for the treatment of patients with metastatic castration-sensitive prostate cancer (mCSPC). ERLEADA® received U.S. FDA approval for nmCRPC in February 2018, and received U.S. FDA approval for mCSPC in September 2019. To date, more than 150,000 patients worldwide have been treated with ERLEADA®. Additional ongoing Phase 3 studies include ATLAS, evaluating ERLEADA® for patients with localized prostate cancer with radiation therapy, and PROTEUS, evaluating ERLEADA® for patients with localized prostate cancer treatment after radical prostatectomy. For more information, visit . About AKEEGA® AKEEGA® is a combination, in the form of a dual-action tablet (DAT), of niraparib, a highly selective poly (ADP-ribose) polymerase (PARP) inhibitor, and abiraterone acetate, a CYP17 inhibitor. AKEEGA® together with prednisone or prednisolone was approved in April 2023 by the European Medicines Agency, and in August 2023 by the U.S. FDA, for the treatment of patients with BRCA-mutated metastatic castration-resistant prostate cancer (mCRPC). Additional marketing authorization applications are under review across a number of countries globally. Additional ongoing studies include the Phase 3 AMPLITUDE study, evaluating AKEEGA® with prednisone or prednisolone in a biomarker-selected patient population with metastatic castration-sensitive prostate cancer (mCSPC). For more information, visit . About BALVERSA® BALVERSA® (erdafitinib) is a once-daily, oral FGFR kinase inhibitor indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (mUC) with susceptible fibroblast growth factor receptor 3 (FGFR3) genetic alterations whose disease progressed on or after at least one line of prior systemic therapy. BALVERSA ® is not recommended for the treatment of patients who are eligible for and have not received prior PD-1 or PD-(L)1 inhibitor therapy.1 Patients are selected for therapy based on an FDA-approved companion diagnostic for BALVERSA®. Information on FDA-approved tests for the detection of FGFR genetic alterations in urothelial cancer is available at: . BALVERSA® received Breakthrough Therapy Designation from the U.S. FDA in 2018 and received accelerated approval in 2019 for the treatment of adults with locally advanced or mUC which has susceptible FGFR3 or FGFR2 genetic alterations and who have progressed during or following at least one line of prior platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.2 The Company submitted a marketing authorization application to the European Medicines Agency in September 2023 for BALVERSA® as a treatment for adult patients with FGFR3-altered, locally advanced unresectable or metastatic urothelial carcinoma that has progressed following therapy with a PD-(L)1 inhibitor. In 2008, Janssen Pharmaceuticals entered into an exclusive worldwide license and collaboration agreement with Astex Pharmaceuticals to develop and commercialize BALVERSA®. For more information, visit . About TAR-200 TAR-200 is an investigational targeted releasing system designed to provide controlled release of gemcitabine into the bladder, sustaining local drug exposure for weeks at a time. The safety and efficacy of TAR-200 are being evaluated in Phase 2 and Phase 3 studies in patients with muscle-invasive bladder cancer (MIBC) in SunRISe-2 and SunRISe-4 and non-muscle-invasive bladder cancer (NMIBC) in SunRISe-1 and SunRISe-3. About TAR-210 TAR-210 is an investigational targeted releasing system designed to provide controlled release of erdafitinib into the bladder. The safety and efficacy of TAR-210 is being evaluated in a Phase 1 study in patients with MIBC and NMIBC (NCT05316155). About Cetrelimab Cetrelimab is an investigational anti-programmed cell death receptor-1 (PD-1) monoclonal antibody being studied to treat bladder cancer, prostate cancer, melanoma, and multiple myeloma as part of a combination treatment. Cetrelimab is also being evaluated in multiple other combination regimens across the Johnson & Johnson portfolio. AKEEGA® IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS The safety population described in the WARNINGS and PRECAUTIONS reflect exposure to AKEEGA® in combination with prednisone in BRCAm patients in Cohort 1 (N=113) of MAGNITUDE. Myelodysplastic Syndrome/Acute Myeloid Leukemia AKEEGA® may cause myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). MDS/AML, including cases with fatal outcome, has been observed in patients treated with niraparib, a component of AKEEGA®. All patients treated with niraparib who developed secondary MDS/cancer-therapy-related AML had received previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy. For suspected MDS/AML or prolonged hematological toxicities, refer the patient to a hematologist for further evaluation. Discontinue AKEEGA® if MDS/AML is confirmed. Myelosuppression AKEEGA® may cause myelosuppression (anemia, thrombocytopenia, or neutropenia). In MAGNITUDE Cohort 1, Grade 3-4 anemia, thrombocytopenia, and neutropenia were reported, respectively in 28%, 8%, and 7% of patients receiving AKEEGA®. Overall, 27% of patients required a red blood cell transfusion, including 11% who required multiple transfusions. Discontinuation due to anemia occurred in 3% of patients. Monitor complete blood counts weekly during the first month of AKEEGA® treatment, every two weeks for the next two months, monthly for the remainder of the first year and then every other month, and as clinically indicated. Do not start AKEEGA® until patients have adequately recovered from hematologic toxicity caused by previous therapy. If hematologic toxicities do not resolve within 28 days following interruption, discontinue AKEEGA® and refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions AKEEGA® may cause hypokalemia and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. In post-marketing experience, QT prolongation and Torsades de Pointes have been observed in patients who develop hypokalemia while taking abiraterone acetate, a component of AKEEGA®. Hypertension and hypertensive crisis have also been reported in patients treated with niraparib, a component of AKEEGA®. In MAGNITUDE Cohort 1, which used prednisone 10 mg daily in combination with AKEEGA®, Grades 3-4 hypokalemia was detected in 2.7% of patients on the AKEEGA® arm and Grades 3-4 hypertension were observed in 14% of patients on the AKEEGA® arm. The safety of AKEEGA® in patients with New York Heart Association (NYHA) Class II to IV heart failure has not been established because these patients were excluded from MAGNITUDE. Monitor patients for hypertension, hypokalemia, and fluid retention at least weekly for the first two months, then once a month. Closely monitor patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia, or fluid retention, such as those with heart failure, recent myocardial infarction, cardiovascular disease, or ventricular arrhythmia. Control hypertension and correct hypokalemia before and during treatment with AKEEGA®. Discontinue AKEEGA® in patients who develop hypertensive crisis or other severe cardiovascular adverse reactions. Hepatotoxicity AKEEGA® may cause hepatotoxicity. Hepatotoxicity in patients receiving abiraterone acetate, a component of AKEEGA®, has been reported in clinical trials. In post-marketing experience, there have been abiraterone acetate-associated severe hepatic toxicity, including fulminant hepatitis, acute liver failure, and deaths. In MAGNITUDE Cohort 1, Grade 3-4 ALT or AST increases (at least 5 x ULN) were reported in 1.8% of patients. The safety of AKEEGA® in patients with moderate or severe hepatic impairment has not been established as these patients were excluded from MAGNITUDE. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with AKEEGA®, every two weeks for the first three months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient's baseline should prompt more frequent monitoring and may require dosage modifications. Permanently discontinue AKEEGA® for patients who develop a concurrent elevation of ALT greater than 3 x ULN and total bilirubin greater than 2 x ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation, or in patients who develop ALT or AST ≥20 x ULN at any time after receiving AKEEGA®. Adrenocortical Insufficiency AKEEGA® may cause adrenal insufficiency. Adrenocortical insufficiency has been reported in clinical trials in patients receiving abiraterone acetate, a component of AKEEGA®, in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Monitor patients for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with abiraterone acetate. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased doses of corticosteroids may be indicated before, during, and after stressful situations. Hypoglycemia AKEEGA® may cause hypoglycemia in patients being treated with other medications for diabetes. Severe hypoglycemia has been reported when abiraterone acetate, a component of AKEEGA®, was administered to patients receiving medications containing thiazolidinediones (including pioglitazone) or repaglinide. Monitor blood glucose in patients with diabetes during and after discontinuation of treatment with AKEEGA®. Assess if antidiabetic drug dosage needs to be adjusted to minimize the risk of hypoglycemia. Increased Fractures and Mortality in Combination with Radium 223 Dichloride AKEEGA® with prednisone is not recommended for use in combination with Ra-223 dichloride outside of clinical trials. The clinical efficacy and safety of concurrent initiation of abiraterone acetate plus prednisone/prednisolone and radium Ra 223 dichloride was assessed in a randomized, placebo-controlled multicenter study (ERA-223 trial) in 806 patients with asymptomatic or mildly symptomatic castration-resistant prostate cancer with bone metastases. The study was unblinded early based on an Independent Data Monitoring Committee recommendation. At the primary analysis, increased incidences of fractures (29% vs 11%) and deaths (39% vs 36%) have been observed in patients who received abiraterone acetate plus prednisone/prednisolone in combination with radium Ra 223 dichloride compared to patients who received placebo in combination with abiraterone acetate plus prednisone. It is recommended that subsequent treatment with Ra-223 not be initiated for at least five days after the last administration of AKEEGA®, in combination with prednisone. Posterior Reversible Encephalopathy Syndrome AKEEGA® may cause Posterior Reversible Encephalopathy Syndrome (PRES). PRES has been observed in patients treated with niraparib as a single agent at higher than the recommended dose of niraparib included in AKEEGA®. Monitor all patients treated with AKEEGA® for signs and symptoms of PRES. If PRES is suspected, promptly discontinue AKEEGA® and administer appropriate treatment. The safety of reinitiating AKEEGA® in patients previously experiencing PRES is not known. Embryo-Fetal Toxicity The safety and efficacy of AKEEGA® have not been established in females. Based on animal reproductive studies and mechanism of action, AKEEGA® can cause fetal harm and loss of pregnancy when administered to a pregnant female. Niraparib has the potential to cause teratogenicity and/or embryo-fetal death since niraparib is genotoxic and targets actively dividing cells in animals and patients (e.g., bone marrow). In animal reproduction studies, oral administration of abiraterone acetate to pregnant rats during organogenesis caused adverse developmental effects at maternal exposures approximately ≥0.03 times the human exposure (AUC) at the recommended dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of AKEEGA®. Females who are or may become pregnant should handle AKEEGA® with protection, e.g., gloves. Based on animal studies, AKEEGA® may impair fertility in males of reproductive potential. ADVERSE REACTIONS The safety of AKEEGA® in patients with BRCAm mCRPC was evaluated in Cohort 1 of MAGNITUDE. The most common adverse reactions (≥10%), including laboratory abnormalities, are decreased hemoglobin, decreased lymphocytes, decreased white blood cells, musculoskeletal pain, fatigue, decreased platelets, increased alkaline phosphatase, constipation, hypertension, nausea, decreased neutrophils, increased creatinine, increased potassium, decreased potassium, increased AST, increased ALT, edema, dyspnea, decreased appetite, vomiting, dizziness, COVID-19, headache, abdominal pain, hemorrhage, urinary tract infection, cough, insomnia, increased bilirubin, weight decreased, arrhythmia, fall, and pyrexia. Serious adverse reactions reported in >2% of patients included COVID-19 (7%), anemia (4.4%), pneumonia (3.5%), and hemorrhage (3.5%). Fatal adverse reactions occurred in 9% of patients who received AKEEGA®, including COVID-19 (5%), cardiopulmonary arrest (1%), dyspnea (1%), pneumonia (1%), and septic shock (1%). DRUG INTERACTIONS Effect of Other Drugs on AKEEGA® Avoid coadministration with strong CYP3A4 inducers. Abiraterone is a substrate of CYP3A4. Strong CYP3A4 inducers may decrease abiraterone concentrations, which may reduce the effectiveness of abiraterone. Effects of AKEEGA® on Other Drugs Avoid coadministration unless otherwise recommended in the Prescribing Information for CYP2D6 substrates for which minimal changes in concentration may lead to serious toxicities. If alternative treatments cannot be used, consider a dose reduction of the concomitant CYP2D6 substrate drug. Abiraterone is a CYP2D6 moderate inhibitor. AKEEGA® increases the concentration of CYP2D6 substrates, which may increase the risk of adverse reactions related to these substrates. Monitor patients for signs of toxicity related to a CYP2C8 substrate for which a minimal change in plasma concentration may lead to serious or life-threatening adverse reactions. Abiraterone is a CYP2C8 inhibitor. AKEEGA® increases the concentration of CYP2C8 substrates, which may increase the risk of adverse reactions related to these substrates. Please see the full Prescribing Information for AKEEGA®. ERLEADA® IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Cerebrovascular and Ischemic Cardiovascular Events — In a randomized study (SPARTAN) of patients with nmCRPC, ischemic cardiovascular events occurred in 3.7% of patients treated with ERLEADA® and 2% of patients treated with placebo. In a randomized study (TITAN) in patients with mCSPC, ischemic cardiovascular events occurred in 4.4% of patients treated with ERLEADA® and 1.5% of patients treated with placebo. Across the SPARTAN and TITAN studies, 4 patients (0.3%) treated with ERLEADA® and 2 patients (0.2%) treated with placebo died from an ischemic cardiovascular event. Patients with history of unstable angina, myocardial infarction, congestive heart failure, stroke, or transient ischemic attack within 6 months of randomization were excluded from the SPARTAN and TITAN studies.   In the SPARTAN study, cerebrovascular events occurred in 2.5% of patients treated with ERLEADA® and 1% of patients treated with placebo. In the TITAN study, cerebrovascular events occurred in 1.9% of patients treated with ERLEADA® and 2.1% of patients treated with placebo. Across the SPARTAN and TITAN studies, 3 patients (0.2%) treated with ERLEADA®, and 2 patients (0.2%) treated with placebo died from a cerebrovascular event.  Cerebrovascular and ischemic cardiovascular events, including events leading to death, occurred in patients receiving ERLEADA®. Monitor for signs and symptoms of ischemic heart disease and cerebrovascular disorders. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Consider discontinuation of ERLEADA® for Grade 3 and 4 events.  Fractures — In a randomized study (SPARTAN) of patients with nmCRPC, fractures occurred in 12% of patients treated with ERLEADA® and in 7% of patients treated with placebo. In a randomized study (TITAN) of patients with mCSPC, fractures occurred in 9% of patients treated with ERLEADA® and in 6% of patients treated with placebo. Evaluate patients for fracture risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents.   Falls — In a randomized study (SPARTAN), falls occurred in 16% of patients treated with ERLEADA® compared with 9% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Falls occurred in patients receiving ERLEADA® with increased frequency in the elderly. Evaluate patients for fall risk.  Seizure — In two randomized studies (SPARTAN and TITAN), 5 patients (0.4%) treated with ERLEADA® and 1 patient treated with placebo (0.1%) experienced a seizure. Permanently discontinue ERLEADA® in patients who develop a seizure during treatment. It is unknown whether anti-epileptic medications will prevent seizures with ERLEADA®. Advise patients of the risk of developing a seizure while receiving ERLEADA® and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others.  Severe Cutaneous Adverse Reactions — Fatal and life-threatening cases of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) occurred in patients receiving ERLEADA®.  Monitor patients for the development of SCARs. Advise patients of the signs and symptoms of SCARs (eg, a prodrome of fever, flu-like symptoms, mucosal lesions, progressive skin rash, or lymphadenopathy). If a SCAR is suspected, interrupt ERLEADA® until the etiology of the reaction has been determined. Consultation with a dermatologist is recommended. If a SCAR is confirmed, or for other Grade 4 skin reactions, permanently discontinue ERLEADA® [see Dosage and Administration (2.2)].  Embryo-Fetal Toxicity — The safety and efficacy of ERLEADA® have not been established in females. Based on findings from animals and its mechanism of action, ERLEADA® can cause fetal harm and loss of pregnancy when administered to a pregnant female. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of ERLEADA® [see Use in Specific Populations (8.1, 8.3)].  ADVERSE REACTIONS   The most common adverse reactions (≥10%) that occurred more frequently in the ERLEADA®-treated patients (≥2% over placebo) from the randomized placebo-controlled clinical trials (TITAN and SPARTAN) were fatigue, arthralgia, rash, decreased appetite, fall, weight decreased, hypertension, hot flush, diarrhea, and fracture.  Laboratory Abnormalities — All Grades (Grade 3-4)  Hematology — In the TITAN study: white blood cell decreased ERLEADA® 27% (0.4%), placebo 19% (0.6%). In the SPARTAN study: anemia ERLEADA® 70% (0.4%), placebo 64% (0.5%); leukopenia ERLEADA® 47% (0.3%), placebo 29% (0%); lymphopenia ERLEADA® 41% (1.8%), placebo 21% (1.6%)   Chemistry — In the TITAN study: hypertriglyceridemia ERLEADA® 17% (2.5%), placebo 12% (2.3%). In the SPARTAN study: hypercholesterolemia ERLEADA® 76% (0.1%), placebo 46% (0%); hyperglycemia ERLEADA® 70% (2%), placebo 59% (1.0%); hypertriglyceridemia ERLEADA® 67% (1.6%), placebo 49% (0.8%); hyperkalemia ERLEADA® 32% (1.9%), placebo 22% (0.5%)  Rash — In 2 randomized studies (SPARTAN and TITAN), rash was most commonly described as macular or maculopapular. Adverse reactions of rash were 26% with ERLEADA® vs 8% with placebo. Grade 3 rashes (defined as covering >30% body surface area [BSA]) were reported with ERLEADA® treatment (6%) vs placebo (0.5%).  The onset of rash occurred at a median of 83 days. Rash resolved in 78% of patients within a median of 78 days from onset of rash. Rash was commonly managed with oral antihistamines, topical corticosteroids, and 19% of patients received systemic corticosteroids. Dose reduction or dose interruption occurred in 14% and 28% of patients, respectively. Of the patients who had dose interruption, 59% experienced recurrence of rash upon reintroduction of ERLEADA®.  Hypothyroidism — In 2 randomized studies (SPARTAN and TITAN), hypothyroidism was reported for 8% of patients treated with ERLEADA® and 1.5% of patients treated with placebo based on assessments of thyroid-stimulating hormone (TSH) every 4 months. Elevated TSH occurred in 25% of patients treated with ERLEADA® and 7% of patients treated with placebo. The median onset was at the first scheduled assessment. There were no Grade 3 or 4 adverse reactions. Thyroid replacement therapy, when clinically indicated, should be initiated or dose adjusted.  DRUG INTERACTIONS  Effect of Other Drugs on ERLEADA® — Co-administration of a strong CYP2C8 or CYP3A4 inhibitor is predicted to increase the steady-state exposure of the active moieties. No initial dose adjustment is necessary; however, reduce the ERLEADA® dose based on tolerability [see Dosage and Administration (2.2)].  Effect of ERLEADA® on Other Drugs   CYP3A4, CYP2C9, CYP2C19, and UGT Substrates — ERLEADA® is a strong inducer of CYP3A4 and CYP2C19, and a weak inducer of CYP2C9 in humans. Concomitant use of ERLEADA® with medications that are primarily metabolized by CYP3A4, CYP2C19, or CYP2C9 can result in lower exposure to these medications. Substitution for these medications is recommended when possible or evaluate for loss of activity if medication is continued. Concomitant administration of ERLEADA® with medications that are substrates of UDP-glucuronosyl transferase (UGT) can result in decreased exposure. Use caution if substrates of UGT must be co-administered with ERLEADA® and evaluate for loss of activity.  P-gp, BCRP, or OATP1B1 Substrates — Apalutamide is a weak inducer of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide 1B1 (OATP1B1) clinically. Concomitant use of ERLEADA® with medications that are substrates of P-gp, BCRP, or OATP1B1 can result in lower exposure of these medications. Use caution if substrates of P-gp, BCRP, or OATP1B1 must be co-administered with ERLEADA® and evaluate for loss of activity if medication is continued.  Please see the full Prescribing Information for ERLEADA®.  BALVERSA® IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS The safety population described in the Warnings and Precautions reflect a pooled safety population of 479 patients with advanced urothelial cancer and FGFR alterations who received BALVERSA®. Ocular Disorders – BALVERSA® can cause ocular disorders, including central serous retinopathy/retinal pigment epithelial detachment (CSR/RPED) resulting in visual field defect. CSR/RPED occurred in 22% of patients treated with BALVERSA®, with a median time to first onset of 46 days. In 104 patients with CSR, 40% required dose interruptions and 56% required dose reductions; 2.9% of BALVERSA®-treated patients required permanent discontinuation for CSR. Of the 24 patients who restarted BALVERSA® after dose interruption with or without dose reduction, 67% had recurrence and/or worsening of CSR after restarting. CSR was ongoing in 41% of the 104 patients at the time of last evaluation. Dry eye symptoms occurred in 26% of BALVERSA®-treated patients. All patients should receive dry eye prophylaxis with ocular demulcents as needed. Perform monthly ophthalmological examinations during the first 4 months of treatment and every 3 months afterwards, and urgently at any time for visual symptoms. Ophthalmological examination should include assessment of visual acuity, slit lamp examination, fundoscopy, and optical coherence tomography. Withhold or permanently discontinue BALVERSA® based on severity and/or ophthalmology exam findings. Hyperphosphatemia and Soft Tissue Mineralization – BALVERSA® can cause hyperphosphatemia leading to soft tissue mineralization, cutaneous calcinosis, non-uremic calciphylaxis and vascular calcification. Increases in phosphate levels are a pharmacodynamic effect of BALVERSA®. Increased phosphate occurred in 73% of BALVERSA®-treated patients. The median onset time of increased phosphate was 16 days (range: 8–421) after initiating BALVERSA®. Twenty-four percent of patients received phosphate binders during treatment with BALVERSA®. Vascular calcification was observed in 0.2% of patients treated with BALVERSA®. Monitor for hyperphosphatemia throughout treatment. In all patients, restrict phosphate intake to 600-800 mg daily and avoid concomitant use of agents that may increase serum phosphate levels. If serum phosphate is above 7.0 mg/dL, consider adding an oral phosphate binder until serum phosphate level returns to <7.0 mg/dL. Withhold, dose reduce, or permanently discontinue BALVERSA® based on duration and severity of hyperphosphatemia. Embryo-Fetal Toxicity – Based on the mechanism of action and findings in animal reproduction studies, BALVERSA® can cause fetal harm when administered to a pregnant female. In a rat embryo-fetal toxicity study, erdafitinib caused malformations and embryo-fetal death at maternal exposures that were less than the human exposures at the maximum human recommended dose based on AUC. Advise pregnant patients of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment with BALVERSA® and for one month after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with BALVERSA® and for one month after the last dose. ADVERSE REACTIONS In the pooled safety population described in Warnings and Precautions, the median duration of treatment was 4.8 months (range: 0.1 to 43 months). The most common (³20%) adverse reactions were: increased phosphate, nail disorders, stomatitis, diarrhea, increased creatinine, increased alkaline phosphatase, increased alanine aminotransferase, decreased hemoglobin, decreased sodium, increased aspartate aminotransferase, fatigue, dry mouth, dry skin, decreased phosphate, decreased appetite, dysgeusia, constipation, increased calcium, dry eye, palmar-plantar erythrodysesthesia syndrome, increased potassium, alopecia, and central serous retinopathy. In Cohort 1 of the BLC3001 study: Serious adverse reactions occurred in 41% of patients who received BALVERSA®. Serious reactions in >2% of patients included urinary tract infection (4.4%), hematuria (3.7%), hyponatremia (2.2%), and acute kidney injury (2.2%). Fatal adverse reactions occurred in 4.4% of patients who received BALVERSA®, including sudden death (1.5%), pneumonia (1.5%), renal failure (0.7%), and cardiorespiratory arrest (0.7%). Permanent discontinuation of BALVERSA® due to an adverse reaction occurred in 14% of patients. Adverse reactions which resulted in permanent discontinuation of BALVERSA® in >2% of patients included nail disorders (3%) and eye disorders (2.2%). Dosage interruptions of BALVERSA® due to an adverse reaction occurred in 72% of patients. Adverse reactions which required dosage interruption in >4% of patients included nail disorders (22%), stomatitis (19%), eye disorders (16%), palmar-plantar erythrodysesthesia syndrome (15%), diarrhea (10%), hyperphosphatemia (7%), increased aspartate aminotransferase (6%), and increased alanine aminotransferase (5%). Dose reductions of BALVERSA® due to an adverse reaction occurred in 69% of patients. Adverse reactions which required dose reductions in >4% of patients included nail disorders (27%), stomatitis (19%), eye disorders (17%), palmar-plantar erythrodysesthesia syndrome (12%), diarrhea (7%), dry mouth (4.4%), and hyperphosphatemia (4.4%). Clinically relevant adverse reactions in <15% of patients who received BALVERSA® included nausea (15%), pyrexia (15%), epistaxis (13%), vomiting (10%), and arthralgia (10%). DRUG INTERACTIONS Effects of Other Drugs on BALVERSA® Moderate CYP2C9 or Strong CYP3A4 Inhibitors: Consider alternative agents; however, if co-administration is unavoidable monitor closely for adverse reactions. Strong CYP3A4 Inducers: Avoid co-administration with BALVERSA®. Moderate CYP3A4 inducers: If co-administration is required at the start of BALVERSA® treatment, administer BALVERSA® at a dose of 9 mg daily. Serum phosphate level-altering agents: Avoid co-administration use with agents that can alter serum phosphate levels before the initial dose increase period based on serum phosphate levels. Effect of BALVERSA® on Other Drugs P-gp substrates: If co-administration is unavoidable, separate BALVERSA® administration by at least 6 hours before or after administration of P-gp substrates with narrow therapeutic indices. Please click here to see full BALVERSA® Prescribing Information. About Johnson & Johnson At Johnson & Johnson, we believe health is everything. Our strength in healthcare innovation empowers us to build a world where complex diseases are prevented, treated, and cured, where treatments are smarter and less invasive, and solutions are personal. Through our expertise in Innovative Medicine and MedTech, we are uniquely positioned to innovate across the full spectrum of healthcare solutions today to deliver the breakthroughs of tomorrow, and profoundly impact health for humanity. Learn more at or at . Follow us at @JanssenUS and @JNJInnovMed. Janssen Research & Development, LLC, Janssen Biotech, Inc., and Janssen Scientific Affairs, LLC are Johnson & Johnson companies. Cautions Concerning Forward-Looking Statements This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding product development and the potential benefits and treatment impact of AKEEGA® (niraparib and abiraterone acetate), ERLEADA® (apalutamide), BALVERSA® (erdafitinib), TAR-200, TAR-210, and cetrelimab. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections Janssen Research & Development, LLC, Janssen Biotech, Inc., Janssen Scientific Affairs, LLC, and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product research and development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; manufacturing difficulties and delays; competition, including technological advances, new products and patents attained by competitors; challenges to patents; product efficacy or safety concerns resulting in product recalls or regulatory action; changes in behavior and spending patterns of purchasers of health care products and services; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and descriptions of these risks, uncertainties and other factors can be found in Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended January 1, 2023, including in the sections captioned "Cautionary Note Regarding Forward-Looking Statements" and "Item 1A. Risk Factors," and in Johnson & Johnson's subsequent Quarterly Reports on Form 10-Q and other filings with the Securities and Exchange Commission. Copies of these filings are available online at , or on request from Johnson & Johnson. None of Janssen Research & Development, LLC, Janssen Biotech, Inc., Janssen Scientific Affairs, LLC, nor Johnson & Johnson undertake to update any forward-looking statement as a result of new information or future events or developments. _______________________ 1 BALVERSA Prescribing Information. 2 Clinicaltrials.gov. A Study of Erdafitinib in Participants With Advanced Solid Tumors and Fibroblast Growth Factor Receptor (FGFR) Gene Alterations. . Accessed May 2023. SOURCE Johnson & Johnson

华盖资本是近几年来国内相当活跃的生物制药领域投资机构，许多知名Biotech，CDMO，检测公司如博雅辑因、宜明细胞、华大智造，康泰生物等均为其被投企业。而在去年，该机构就有三项相当成功的投资案例，两项得到国际大厂认可的授权交易和一笔来自上市龙头企业的收购。所投企业均实现了价值方面的增加和实现，在眼光上具有独到之处。本文将对这几项案例背后的技术及其价值进行简单解析和介绍。投资概况在去年，华盖资本投资了国内7家Biotech，技术路线和适应症开发方向各有特色：如舶望制药（siRNA），德睿智药（AI+GLP-1R），传信生物（mRNA），诚益生物（GLP-1R），英诺湖医药（ADC），恩凯赛药（NK细胞），礼邦医药（肾脏药物）。其中舶望制药，传信生物，诚益生物均发生了收购和交易事项。舶望制药在今年1月与诺华达成一项独家许可协议，舶望将多项心血管疗法的管线授权给诺华，并获得1.85亿美元的首付款，并有资格获得最高达41.65亿美元的潜在期权、里程碑付款和商业销售的分级特许使用费。诚益生物在去年11月与阿斯利康达成一项独家许可协议，协议将该公司的小分子GLP-1R激动剂授权给阿斯利康，将获得1.85亿美元的首付款，还将有资格获得高达18.25亿美元的未来临床、注册和商业化里程碑付款以及特许权使用费。传信生物在去年6月时被百克生物收购，收购时溢价12.65倍。可以看出，一方面诺华，阿斯利康等跨国药企以及国内疫苗巨头百克生物确实有丰富自己领域和技术路线的打算，另外一方面这也是对于国内“高卷度”市场的认可。这一定程度上说明上述这些公司在技术上一定有独到之处。前礼来团队缔造的诚益生物：抓住核心痛点如果粗看诚益生物的创始人，可以看出，创始人周敬业，徐剑锋都是前礼来研发方向上的高管，有多个新药研发经验。而开发的管线也非常具有代表性，基本上抓住了适应症方向的痛点和关注焦点：从其专利中可以看到，除了GLP-1R激动剂，该公司管线还可能有甲状腺激素受体激动剂（适应症可能用于一些甲状腺相关疾病），氨基脲敏感性胺氧化酶/血管粘附蛋白-1(SSAO/VAP-1)抑制剂（可能用于非酒精性脂肪肝肝病，骨关节炎，慢性疼痛）而该公司的GLP-1R激动剂也非常切中目前痛点。目前的GLP-1R激动剂，如司美格鲁肽常常需要皮下注射等方式来给药。而该管线本身是一种小分子口服GLP-1R激动剂。只需要口服给药。与已知的小分子GLP-1激动剂相比，该公司的GLP-1R激动剂物显示出更有效的GLP-1激动活性、更有利的药代动力学性质和/或与其他细胞靶(例如，肝细胞转运蛋白诸如OATP1B1)的较少相互作用和相应地改善的安全性(例如，药物-药物相互作用)。小分子GLP-1R激动剂本身就是一种可能改变降糖和肥胖领域现状的药物，因此被大药厂相中也毫不意外。舶望制药：心血管领域备受关注如果从核心成员来看，舶望有不少骨干来自于Arrowhead，CMO James jin以前是诺华中国临床开发负责人，还领导了siRNA药物inclisiran在亚洲地区的项目。在诺华推进inclisiran的临床方面功不可没，可能也和今年的此次交易有关系。业内需求什么，就交易什么，而此次的交易可能比较直接反映了这一情况，心血管市场一直都是诺华的重点对象，毕竟目前诺华的营收重点也是治疗心衰的Entresto，只是即将面临专利悬崖，自然需要更多相关管线。虽然诺华自己有一款用于降血脂的PCSK9靶向siRNA药物inclisiran，但业内对于其他靶点的布局也不在少数。例如AGT，LPA，ANGPTL3等心血管靶点都在其中之列。特别是AGT，AGT可能就是下一个PCSK9。比如，信达去年年末就买了圣因生物靶向AGT的siRNA药物SGB-3908的优先选择权。而业内Alnylam制药的ALN-AGT更是行业领头羊，此前就证明了潜力巨大，早期临床不仅成功验证了不同剂量ALN-AGT在长期能够降低AGT水平，血压也同时得到下降。而从专利中来看，舶望制药对上述如AGT，LPA，ANGPTL3这些靶点均有布局。另外，给药递送问题和延长药物给药频率是小核酸药物的重点关注对象。在递送上，舶望采用的应当是多价GalNAc配体簇，相对于GalNAc单配体，配体簇对于肝脏的递送效率更高，结合亲和力更高，而给药频率延长上，虽然不知道具体原理，但该公司RADS技术平台能够将时间延长到1年。横向对比inclisiran的话，inclisiran的给药间隔是6个月一次。传信生物：后疫情时代下的选择当其他mRNA Biotech陷入低谷，而这家mRNA Biotech实现了被溢价收购时，某种程度上这就是这家企业的胜利。去年的国内外的mRNA药企都不是过得很好，Moderna和辉瑞可能就是典型例子。虽然技术层面mRNA确实是拿了诺奖，但可能也只有今年还能拿诺奖了。一方面，来自新冠病毒方面的需求急剧衰退，另外一方面，早期融资时期的急速扩张和厂房建设为后新冠时期的价值缩水埋下了伏笔，2023年经济环境又因为美联储加息等因素空前紧张，融资不再像以前那么顺利。因此，这个阶段的mRNA Biotech如果真的往Moderna和BioNTech的个性化癌症疫苗这个方向发展可能就面临大量的研发成本和专利技术壁垒，而已经投入的厂房建设和产能扩张就立刻成为了弃子。这种进退两难的情况下，被大厂收购或许是这种情况下的最佳选择。而从技术上来看，本身传信生物就拥有比较完备的mRNA-LNP生产技术路线。因此收购后即使不去开发进入临床的药物，也能够实现一定的战略发展价值。总结自从去年年末以来，大量的国内Biotech企业都获得了大药厂们的橄榄枝，这是对国内药企创新盈利逻辑的认可，同时也在鼓励更多药企和资本涌入这一领域。参考来源：各公司官网及专利