A Phase 3 Study to Evaluate the Safety and Pharmacokinetics of Berotralstat Prophylaxis in Children With Hereditary Angioedema Who Are 2 to < 12 Years of Age

The purpose of this study is to evaluate the pharmacokinetics (PK) and safety of berotralstat to determine the appropriate weight-based dose for pediatric participants 2 to < 12 years old for prophylactic treatment to prevent attacks of hereditary angioedema (HAE).

开始日期2022-10-25

申办/合作机构

BioCryst Pharmaceuticals, Inc.

NCT04933721

/ Active, not recruiting临床3期

An Open-label Study to Provide Berotralstat Access to Subjects With Type 1 and 2 Hereditary Angioedema Who Were Previously Enrolled in Berotralstat Studies

This is a phase 3b open-label study providing access to berotralstat for HAE patients who were previously enrolled in berotralstat studies.

开始日期2021-07-23

申办/合作机构

BioCryst Pharmaceuticals, Inc.

NCT03873116

/ Completed临床3期

A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group Study to Evaluate the Efficacy and Safety of Two Dose Levels of BCX7353 as an Oral Treatment for the Prevention of Attacks in Subjects With Hereditary Angioedema

This is a phase 3, multi-center, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of oral BCX7353 in preventing acute angioedema attacks in patients with Type I and Type II HAE who live in Japan.

开始日期2018-12-27

申办/合作机构

BioCryst Pharmaceuticals, Inc.

100 项与 Berotralstat Hydrochloride 相关的临床结果

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100 项与 Berotralstat Hydrochloride 相关的转化医学

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100 项与 Berotralstat Hydrochloride 相关的专利（医药）

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项与 Berotralstat Hydrochloride 相关的文献（医药）

2025-04-01·Journal of Comparative Effectiveness Research

Comparison of real-world healthcare resource utilization and costs among patients with hereditary angioedema on lanadelumab or berotralstat long-term prophylaxis

Article

作者: Shah, Chintal H ; Schultz, Bob G ; Evans, Kristin A ; Juethner, Salomé ; Sing, Krystal ; Princic, Nicole

Aim: Hereditary angioedema (HAE) is a rare and chronic genetic condition. Lanadelumab and berotralstat, two plasma kallikrein inhibitors, have both been approved for long-term prophylaxis in patients with HAE; however, real-world data comparing costs and healthcare resource utilization (HCRU) are lacking. Materials & methods: This retrospective study used administrative healthcare insurance claims data (Merative™ MarketScan ® Commercial, Medicare and Early View Research Databases; 1 July 2017–31 July 2023) to identify patients with HAE who initiated lanadelumab or berotralstat and were persistent for ≥18 months or 6 months, respectively. Sex, baseline healthcare costs and baseline number of on-demand treatment/short-term prophylaxis medication claims were used to calculate covariate balancing propensity scores for inverse probability of treatment weighting. Following weighting, outcomes during the 6-month follow-up period in patients receiving berotralstat were compared with those during months 0–6, 7–12 and 13–18 in lanadelumab-treated patients. Results: Fifty-seven lanadelumab- and 32 berotralstat-treated patients were included. After weighting, more berotralstat-treated patients had an all-cause inpatient admission (berotralstat, 9.4%; lanadelumab, months 0–6, 4.0%, 7–12, 1.8%, months 13–18, 2.0%) and emergency room visit (berotralstat, 21.9%; lanadelumab, months 0–6, 14.0%, 7–12, 8.0%, months 13–18, 17.9%). Total HAE treatment costs were similar during months 0–6 (lanadelumab, $377,326 vs berotralstat, $373,010), but decreased in months 7–12 ($319,967) and 13–18 ($283,241) of lanadelumab. On-demand treatment/short-term prophylaxis costs were lower for lanadelumab across the three follow-up periods than for berotralstat during months 0–6 (berotralstat, $60,451; lanadelumab, months 0–6, $46,336, months 7–12, $37,578, months 13–18, $23,968). The proportion of lanadelumab-treated patients who reduced dosing frequency was 24.8% during months 7–12 and 21.6% during months 13–18. Conclusion: Patients with HAE initiating lanadelumab versus berotralstat may require less on-demand and supportive HAE treatments and incur lower treatment-related and total healthcare costs. The ability to reduce lanadelumab dosing frequency after an attack-free period may be key in treatment selection, given the combination of cost savings and lower healthcare resource utilization.

2025-01-01·Allergy and Asthma Proceedings

Idiopathic non-mast cell angioedema: Treatment insights from global experts

Article

作者: Christiansen, Sandra C. ; Zuraw, Bruce L. ; for the 2023 International HAEA/HAEi Symposiu

Background: Idiopathic non‐mast cell angioedema (INMA) is a rare disease typified by recurrent attacks of cutaneous and subcutaneous swelling. Every attack carries the potential for severe morbidity and, in the case of laryngeal involvement, mortality. Whereas therapies approved for hereditary angioedema (HAE) have been used in the care of patients with INMA, little is known with regard to their efficacy for the treatment of this disease. Objective: The objective was to gather evidence from global experts, ranking their assessment of on-demand therapy (ODT) and long-term prophylactic (LTP) treatment efficacy for INMA. Methods: A survey was developed and distributed to international experts invited to attend a 2023 symposium. INMA was diagnosed by standardized criteria. Linkert scales were used to rate the efficacy for ODT and LTP therapy. Enrollment was closed after 1 month and the data were analyzed. Results: Surveys were distributed to 31 experts from 16 countries with a 77% response rate (n = 24) reporting on 300 patients with INMA. Efficacy rankings of ODT were the following: icatibant (14 experts with 93 treated patients), 46.2% high and 38.7% moderate; and plasma-derived C1 inhibitor (C1INH) (13 experts with 31 treated patients), 32.3% moderate and 45.2% mild. Efficacy rankings of LTP were the following: antifibrinolytics (11 experts with 52 treated patients), 23.1% high and 38.5% moderate; lanadelumab (5 experts with 19 treated patients), 21% high and 79% moderate; and subcutaneous C1INH (3 experts with 19 treated patients), 21.1% moderate and 79.0% mild. LTP efficacy was also recorded for berotralstat and progestin. Conclusion: Icatibant (ODT) and either antifibrinolytics or lanadelumab (LTP) were ranked as the most efficacious treatments for the patients with INMA (among medications with at least five treated patients) by the expert physicians. Progestins, berotralstat, and plasma derived C1INH each demonstrated a favorable prophylactic effect; however, broader experience will be required to formulate overall recommendations.

2025-01-01·Journal of Investigative Dermatology

Identifying Potential Drug Targets for Keloid: A Mendelian Randomization Study

Article

作者: Luo, Xusong ; Wang, Yinmin ; Yuan, Zhaoqi ; Liu, Fei ; Wang, Xiuxia ; Yang, Jun

Keloids are a skin fibrosis disease characterized by troublesome symptoms, a varying degree of recurrence and inevitable side effects from treatments. Thus, identifying their drug targets is necessary. A 2-sample Mendelian randomization analysis was conducted using proteins from the intersection of the deCODE database and "The Druggable Genome and Support for Target Identification and Validation in Drug Development" as the exposure variable. The outcome variable was based on recently published GWAS of keloids. Summary data-based Mendelian randomization and colocalization analysis was employed to distinguish pleiotropy from linkage. Candidate targets underwent drug target analysis. The primary findings were validated through single-cell RNA-sequencing data, Western Blot and immunofluorescence staining on keloids. Seven proteins were identified as potential drug targets for keloids. Among these proteins, Hedgehog-interacting protein, neurotrimin [NTM], KLKB1, and CRIPTO showed positive correlations with keloids, while PLXNC1, SCG3 and PDGFD exhibited negative correlations. Combined with the single-cell RNA-sequencing data, NTM, PLXNC1, and PDGFD were found highly expressed in the fibroblasts. NTM showed a significant increase in keloids as compared to normal scars. In accordance with the analysis, higher levels of protein expression of NTM in keloids compared to normal skin was observed. The identified proteins may be appealing drug targets for keloids treatment with a special emphasis on NTM.

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项与 Berotralstat Hydrochloride 相关的新闻（医药）

2025-05-01

·GlobeNewswire-Health Care

BioCryst Appoints Steve Frank to Board of Directors

RESEARCH TRIANGLE PARK, N.C., May 01, 2025 (GLOBE NEWSWIRE) -- BioCryst Pharmaceuticals, Inc. (Nasdaq:BCRX) today announced that the company has appointed healthcare investment banking leader Steve Frank to its board of directors. Mr. Frank serves as chairman of global healthcare investment banking at J.P. Morgan. He was previously global group head of worldwide healthcare investment banking at Bear Stearns before it was acquired by J.P. Morgan in 2008. Mr. Frank is a trusted corporate advisor, supporting countless transactions including pharmaceutical, biotechnology, medical device and healthcare services firms. A standout institutional investor before becoming a banker, Mr. Frank directed and built State Farm’s multi-billion-dollar life science equity portfolio in the 1980s and early 1990s. He maintains the accreditation as a Chartered Financial Analyst today. “Steve is one of the most accomplished and respected healthcare investment bankers in the industry and we look forward to adding his expertise to the board. His experience with innovative business development transactions and value-creating capital allocation are a perfect fit as BioCryst builds on its commercial success, accelerates towards profitability and advances its pipeline,” said Dr. Nancy Hutson, chair of the BioCryst board of directors. “BioCryst is uniquely positioned in the biopharma space with the rare combination of a commercial product growing closer to $1 billion in peak sales, a strong cash position that makes the company independent of the capital markets, and a next wave of potential best-in-class medicines in the clinic. I am excited to join this world-class board at such an important time for the company,” Mr. Frank said. Mr. Frank currently serves on the board of Precigen. He holds a B.S. from Illinois State University and an M.B.A. from the University of Chicago. About BioCryst Pharmaceuticals BioCryst Pharmaceuticals is a global biotechnology company with a deep commitment to improving the lives of people living with complement-mediated and other rare diseases. BioCryst leverages its expertise in structure-guided drug design to develop first-in-class or best-in-class oral small-molecule and protein therapeutics to target difficult-to-treat diseases. BioCryst has commercialized ORLADEYO® (berotralstat), the first oral, once-daily plasma kallikrein inhibitor, and is advancing a pipeline of small-molecule and protein therapies. For more information, please visit www.biocryst.com or follow us on LinkedIn. Forward-Looking StatementsThis press release contains forward-looking statements, including statements regarding future results, performance or achievements. These statements involve known and unknown risks, uncertainties and other factors which may cause BioCryst’s actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. These statements reflect our current views with respect to future events and are based on assumptions and are subject to risks and uncertainties. Given these uncertainties, you should not place undue reliance on these forward-looking statements. Some of the factors that could affect the forward-looking statements contained herein include: BioCryst’s ability to successfully implement or maintain its commercialization plans for ORLADEYO; BioCryst’s ability to successfully progress its pipeline development plans; the results of BioCryst’s partnerships with third parties may not meet BioCryst’s current expectations; risks related to government actions, including that decisions and other actions, including as they relate to pricing, may not be taken when expected or at all, or that the outcomes of such decisions and other actions may not be in line with BioCryst’s current expectations; the commercial viability of ORLADEYO, including its ability to achieve sustained market acceptance and demand; ongoing and future preclinical and clinical development of product candidates may take longer than expected and may not have positive results; the outcome of preclinical testing and early clinical trials may not be predictive of the success of later clinical trials, and interim results of a clinical trial do not necessarily predict final results; BioCryst may not be able to enroll the required number of subjects in planned clinical trials of product candidates; BioCryst may not advance human clinical trials with product candidates as expected; the FDA or other applicable regulatory agency may require additional studies beyond the studies planned for products and product candidates, may not provide regulatory clearances which may result in delay of planned clinical trials, may impose certain restrictions, warnings, or other requirements on products and product candidates, may impose a clinical hold with respect to product candidates, or may withhold, delay or withdraw market approval for products and product candidates; product candidates, if approved, may not achieve market acceptance; BioCryst’s ability to successfully commercialize its products and product candidates; BioCryst’s ability to successfully manage its growth and compete effectively; risks related to the international expansion of BioCryst’s business; timing for achieving and sustainability of profitability and positive cash flow may not meet management’s expectations; statements and projections regarding financial guidance and goals and the attainment of such goals may differ from actual results based on market factors and BioCryst’s ability to execute its operational and budget plans; and actual financial results may not be consistent with expectations, including that revenue, operating expenses and cash usage may not be within management’s expected ranges. Please refer to the documents BioCryst files periodically with the Securities and Exchange Commission, specifically BioCryst’s most recent Annual Report on Form 10-K, Quarterly Reports on Form 10-Q, and Current Reports on Form 8-K, which identify important factors that could cause actual results to differ materially from those contained in BioCryst’s projections and forward-looking statements. BCRXW Contact:John Bluth+1 919 859 7910jbluth@biocryst.com

高管变更

2025-03-22

·精准药物

【J. Med.Chem.】从弱到强：基于片段药物设计（FBBD）的40年突破之路

基于片段的药物设计（FBDD）已成为药物发现的重要策略，与传统高通量筛选（HTS）形成互补。历经近50年发展，推动多款药物成功上市。结构与计算工具的整合，显著提升FBDD效率，助力理性药物设计。随着药物靶点向“不可成药”领域及新治疗模式延伸，FBDD在靶向复杂生物分子中展现关键潜力。持续融合前沿计算与筛选技术（如虚拟筛选、机器学习），突破药物化学瓶颈，加速创新疗法开发。小片段撬动大突破自1981年提出以来，基于片段的药物设计（FBDD）已成为药物发现的核心策略之一。其核心逻辑是筛选低分子量化合物（约150–300 Da），这些片段虽与靶蛋白结合较弱，但通过化学修饰可优化为强效药物。1990年代，“核磁共振（SAR by NMR）”技术首次实现片段筛选，随后X射线晶体学、表面等离子体共振（SPR）等方法进一步推动技术普及，使FBDD融入主流药物研发流程。成果斐然：从“不可成药”到临床突破 FBDD已催生8款FDA批准药物及超50个临床候选化合物。首款成功案例是2011年获批的黑色素瘤药物Zelboraf，其研发仅用6年。随后，多款里程碑药物涌现： Pexidartinib（2015年）：一种CSF-1R抑制剂； Venetoclax（ABT-199，2016年）：一种Bcl-2抑制剂，能够破坏蛋白–蛋白相互作用； Erdafitinib（2019年）：一种用于治疗尿路上皮癌的FGFR抑制剂； Berotralstat（BCX7353，2020年）：一种用于治疗遗传性血管水肿的丝氨酸蛋白酶抑制剂； Sotorasib（AMG 510，2021年）：一种KRAS-G12C抑制剂，针对一个被认为难以治疗的“不可药化”蛋白； Asciminib（ABL001，2021年）：一种新型的BCR-ABL1别构抑制剂； Capivasertib（AZD5363，2023年）：一种AKT激酶抑制剂。超半数药物为激酶抑制剂，但Venetoclax和Sotorasib的成功证明FBDD在难治靶点中的潜力。此外，FBDD在苗头化合物优化、靶点可药性评估中展现高效性，甚至延伸至PROTAC等新兴疗法，成为药物创新的“多面手”。图1. 过去四十年基于片段的药物设计里程碑。3D分子结构由Schrödinger 2022.3（Maestro 13.3）中的LigPrep模块生成。图2. 从基于片段的药物设计（FBDD）衍生的FDA批准药物。展示了从FBDD衍生的FDA批准药物的化学结构。基于片段的药物设计（FBDD）：优势与挑战并存（1）优势： FBDD能筛选来自广泛化学空间的小分子片段，适用于各种靶点，包括蛋白质和RNA，具有较强的靶点适应性。片段库由低分子量化合物组成，通常遵循“三原则”，这使得它们在优化时具有更大潜力。 FBDD还可以通过敏感的筛选方法检测弱结合物，这些物质通常在高通量筛选中被忽略。片段筛选的时间较短，能够显著降低成本和时间。此外，FBDD能初步评估靶点的可药物性，帮助风险评估，无需参考化合物，易于实施。片段扩展有助于探索结构-活性关系（SAR），推动新型先导化合物开发。FBDD已应用于新型治疗模式，如PROTACs，利用片段连接原理，具有低分子量和弱结合亲和力，表明其在优化新药模式中的潜力。（2）挑战：片段库质量：需平衡多样性、合成可行性与理化性质，构建高质量库难度高；筛选灵敏度：弱结合检测依赖先进技术（如NMR、X射线），设备与经验门槛较高；苗头物选择：高命中率下需结合配体效率（LE）、结合模式分析（NMR/冷冻电镜）筛选优质片段；规模压力：百万级片段库涌现，传统实验筛选难以负荷，需虚拟筛选预筛以降低成本；人工优化局限：片段扩展依赖药物化学经验，面对海量数据与复杂相互作用，效率受限。表1. 片段筛选方法筛选方法样品要求灵敏度（亲和力）优势缺点配体观察NMR（STD-NMR, Water-LOGSY, CMPG, T1rho）低（<50 μM样品） mM–nM 不需要同位素标记。无法检测紧密结合物。对靶标大小没有限制。不适用于所有靶标。灵敏度高，能检测弱结合物。无法检测紧密结合物。可在筛选中使用片段混合物。 19F-NMR 低（<50 μM样品） mM–μM 灵敏的筛选方法。片段需要用氟标记。高通量筛选方法。只能检测弱结合物。适用于蛋白质和RNA靶标。不需要靶标标记，对靶标没有大小限制。蛋白质观察NMR（HSQC, 19F-NMR）高（>10 μM, 10–100 mg） mM–nM 可检测紧密结合物和弱结合物。需要标记蛋白质。提供结构信息。筛选时间较长。确定结合位点。 X射线晶体学高（10–50 mg） mM–nM 提供结构信息。无法检测结合亲和力和特异性。检测结合模式。需要高质量的晶体进行浸泡。表面等离子共振（SPR）低（<1 mg） μM–nM 高通量筛选方法。需要将靶标固定。提供筛选中的结合动力学数据。需要参考化合物设置实验。不适用于所有靶标。不适用于检测弱结合物。等温滴定量热法（ITC）高（>10 μM样品） μM–nM 提供结合曲线来测量结合亲和力。低通量实验。确定焓变或熵驱动的结合。需要较高浓度的样品。不适用于每个靶标。需要参考化合物设置实验。不适用于检测弱结合物。热变性实验（TSA）/差示扫描荧光法（DSF）低（∼μM–nM） μM–nM 高通量筛选实验假阳性率较高。不适用于每个靶标。需要参考化合物设置实验。本征质谱法低（nM, μg–1 mg） μM–nM 高通量筛选实验需要仔细优化实验条件。只需要微克级样品。不适用于弱结合物。微尺度热泳动法（MST）低（<μM） μM–nM 能测量结合亲和力。低通量筛选方法。不适用于弱结合物。生物层干涉法（BLI）低（∼μM） μM–nM 高通量方法不适用于弱结合物。适用于确认苗头化合物。荧光偏振法（FP）低（<μM） μM–nM 高通量筛选方法不适用于弱结合物。不适用于每个靶标。需要参考化合物设置实验。表型筛选无要求 μM–nM 筛选具有良好细胞渗透性的化合物。命中率低，需要确认靶标-苗头化合物的相互作用。适用于筛选共价片段仅适用于紧密结合物。不需要纯化靶标。需要确认靶标。生化实验低（<μM） μM–nM 高通量筛选实验靶标需要具有酶活性或已被充分表征。可以直接测量片段对靶标的影响。不适用于弱结合物，导致命中率低。筛选过程中需要较高浓度的片段。虚拟筛选无要求无要求高通量方法假阳性率高。筛选过程中不需要化合物和样品。需要通过实验筛选确认苗头化合物。适合筛选百万至十亿个化合物。能够考虑多个结合口袋。展望基于片段的药物设计（FBDD）有望成为药物发现的关键驱动力。随着分子生物学和生物信息学的进展，靶标空间已扩展到RNA及RNA结合蛋白（RBPs），为治疗提供了超越传统蛋白靶标的新机遇。例如，FDA批准的RNA剪接调节剂Risdiplam，通过调节SMN2前mRNA的剪接，成功治疗了相关疾病。然而，RNA及RBPs的极性和灵活性使得传统方法难以靶向，而FBDD凭借识别小分子和弱结合片段的优势，提供了有效的探索途径。高分辨率的冷冻电子显微镜（cryo-EM）揭示了复杂的蛋白质/RNA结构，帮助发现潜在的结合位点。同时，人工智能和分子建模技术加强了对RNA和蛋白质复合物的理解，提供了更精确的药物设计线索。多样化的片段库扩展了化学空间，结合实验和计算筛选提高了命中率和靶点识别能力。 FBDD与新兴计算技术的结合，使得药物设计更加强大和多功能。未来，FBDD有望攻克难以靶向的复杂靶标，如蛋白质-蛋白质相互作用和RNA靶点。将机器学习和人工智能整合到FBDD中，将加速药物发现过程，解决未满足的医学需求。参考文献： https://pubs.acs.org/doi/10.1021/acs.jmedchem.5c00424

蛋白降解靶向嵌合体上市批准临床结果

2025-02-28

·化学经纬

基于片段的药物设计，从过去到现在及未来展望

基于片段药物设计（FBDD）作为一种强大的药物发现策略，与传统的高通量筛选（HTS）药物发现方法相辅相成。在过去的近半个世纪里，FBDD经历了显著的演变，已有多款经其发现的药物获得市场批准。近日（Feb. 24)，J. Med. Chem刊载了一篇社论，评述了SBDD的过去、当前、和未来。结构和计算工具的整合显著提高了FBDD的效率，促进了合理药物设计的发展。随着药物发现领域不断拓展，超越传统可成药靶点并探索新模式，FBDD有望在针对广泛生物分子（包括具有挑战性、和难以成药的靶点，如蛋白质和RNA）方面发挥关键作用。 FBDD的持续进步，特别是通过引入尖端计算和筛选方法，将为未来药物化学的成功铺平道路。 01 SBDD的昨天自1981年首次引入以来，基于片段药物设计已被证明是一种在药物发现初期识别活性分子的有前景的方法。SBDD涉及筛选低分子量化合物，这些化合物最初与靶蛋白弱结合，但通过药物化学的努力有潜力进一步改造成强效药物。后来，20世纪90年代发展了“通过NMR的SAR”方法，突显了NMR光谱学在识别小分子片段结合物中的应用。这一策略为FBDD作为药物发现策略奠定了基础。此后，包括X射线晶体学、表面等离子共振（SPR）和热移分析在内的新方法在片段筛选中得到了开发，使片段筛选更容易融入药物发现工作流程。如今，FBDD已成为制药、生物技术公司和学术机构广泛使用的主流筛选方法。历史上，FBDD在药物开发中取得了几个里程碑式的成功，已有八款FDA批准的药物源自该方法，超过50种化合物进入临床阶段。首款由FBDD衍生的FDA批准药物是Zelboraf（Vemurafenib，PLX4032），由Plexxikon开发的BRAF抑制剂，用于治疗黑色素瘤。 Zelboraf于2005年启动，2011年获批，展示了FBDD在加速药物发现时间线方面的效率。随后，受益于FBDD的FDA批准药物包括： Pexidartinib（2015年），CSF1R抑制剂； Venetoclax（ABT-199，2016年），Bcl-2抑制剂，破坏蛋白质-蛋白质相互作用； Erdafitinib（2019年），用于尿路上皮癌的FGFR抑制剂； Berotralstat（BCX7353，2020年），用于遗传性血管性水肿的丝氨酸蛋白酶抑制剂； Sotorasib（AMG 510，2021年），针对“难以成药”KRAS-G12C蛋白的抑制剂； Asciminib（ABL001，2021年），新型BCR-ABL1变构抑制剂； Capivasertib（AZD5363，2023年），AKT激酶抑制剂。值得注意的是，大多数药物属于激酶抑制剂。然而，Venetoclax和Sotorasib的成功，突显了FBDD在药物开发中针对广泛难治靶点的潜力。除了获批药物外，FBDD还取得了大量从活性到先导化合物的成功，突显了其在不同靶点家族中的广泛应用。 02 FBDD的优势与挑战 2.1、FBDD的优势在不同的活性化合物发现筛选方法中，FBDD具有几个优势：（1）、它需要从多样化的化学空间中筛选的化合物数量较少，适合包括蛋白质和RNA在内的多样化靶点，提供跨靶点的多功能性。（2）、片段库由低分子量化合物（约150-300 Da）组成，通常遵循“三规则”，具有更大的优化潜力。（3）、FBDD使用筛选方法，能够灵敏地检测弱结合物，这些弱结合物通常会被高通量筛选遗漏。（4）、FBDD的筛选通常可以在几天内完成，显著减少了活性识别的时间和成本。（5）、此外，片段筛选还提供了靶点可药物性的初步指示，作为项目战略规划的风险评估。用户友好的检测设置和无需参考化合物的特点使这种方法更容易应用于基于靶点的药物发现项目。在验证活性骨架后，片段扩展可以系统地探索结构-活性关系（SAR），促进新型先导化合物的开发。超越传统的“五规则”领域，FBDD在新的治疗模态中也开始显示出其应用前景，如蛋白降解靶向嵌合体（PROTACs）。这些分子通常由两个功能部分组成：一个与感兴趣的靶蛋白结合，另一个与E3泛素连接酶结合，通过化学连接子连接。PROTACs的设计策略遵循片段连接原理，这是FBDD中的一个关键概念。有趣的是，最近的研究表明，PROTACs的结合部分通常具有片段的特征，包括低分子量、和对感兴趣蛋白、或E3连接酶的弱固有结合亲和力。这种相似性表明，FBDD可能在优化和扩展新兴药物模态的化学空间方面发挥重要作用，进一步增强其对未来药物发现的影响。 2.2、SBDD面临的挑战虽然过去已经取得了几个成功案例，但FBDD仍面临一些挑战。首先，选择高质量的片段库因需平衡考虑多种因素而变得复杂，包括库的多样性、化学空间的覆盖范围、物理化学性质和合成可行性。其次，筛选方法的灵敏度在FBDD中至关重要，因为片段通常与靶点弱结合。目前有近十几种筛选方法可用，其中NMR是片段筛选和活性确认的强大工具。配体和蛋白质观察的NMR方法能够对多样化靶点进行高灵敏度的片段筛选，并获得令人满意的活性率。第三，片段扩展的活性选择在FBDD中至关重要。片段筛选通常会在多样化靶点中产生高活性率。配体效率（LE）通常是在活性选择过程中的一种“经验法则”，以反映片段-靶点相互作用是特异性的而非随机的。此外，理解活性化合物的结合模式也是优先级选择的重要标准。因此，NMR、X射线晶体学和冷冻电镜等结构生物学工具在确定二元或三元复合物的结构中发挥着关键作用，从分子水平上确认靶点参与。第四，片段库的迅速扩展对筛选工作量提出了巨大压力。如今，已有包含数百万片段的库存库，如果没有大量时间和成本投入，很难筛选出高质量的活性化合物。为了克服这一障碍，虚拟筛选等计算方法提供了一种互补解决方案，在湿实验室验证之前筛选超大型片段库。另一方面，从片段筛选中获得的活性化合物可以为进一步的虚拟活性优先级提供信息，允许一个迭代的“计算-实验”循环，提高活性识别的成功率。最后，片段扩展和连接子设计需要药物化学专业知识，以确保新合成的化合物有效地占据蛋白质结合位点。然而，人工驱动的过程本质上受到活性化合物数量增加和预测其与靶蛋白相互作用复杂性的限制。因此，可以考虑利用人工智能分析大型数据集，预测蛋白质-配体相互作用，并通过自动片段连接和扩展设计化合物。 03 展望未来展望未来，片段药物设计有潜力成为未来药物发现的关键驱动力。分子生物学和生物信息学的最新进展将靶点空间扩展到RNA和RNA结合蛋白（RBPs），为超越传统蛋白质靶点的治疗干预提供了未开发的潜力。例如，FDA批准的RNA剪接调节剂Risdiplam通过改变SMN2前mRNA的剪接，促进外显子7的包含，从而作为U1小核核糖核蛋白有效剪接其RNA靶点的增强剂。然而，RNA和RBPs通常具有高度极性和灵活的结合位点，难以用传统方法靶向。FBDD凭借其识别小而弱结合片段的能力以及对潜在结合位点的广泛覆盖，为探索这些复杂靶点提供了一种高效方法。此外，高分辨率的冷冻电镜结构正在阐明复杂的蛋白质/RNA结构，揭示用于合理药物设计的潜在结合位点。基于人工智能的结构预测工具正在补充实验方法，以了解RNA的三级结构以及RNA和蛋白质之间的复杂结构。先进的分子建模技术提供了关于构象灵活性和配体诱导的结构变化的见解，以及可能为片段扩展或连接提供机会的潜在隐秘口袋。多样化的片段库，包括共价弹头和特殊基团，正在扩展用于筛选的化学空间。实验和计算筛选方法的结合通过揭示新的可药物位点和提高活性率来增强活性识别。最终，FBDD与新兴计算技术的协同作用使我们能够更深入地了解作用机制，使片段方法越来越强大和多功能。随着该领域的不断发展，FBDD有望解决历史上难以处理的靶点，如变构调节位点、蛋白质-蛋白质相互作用、RNA和RNA结合蛋白。将机器学习和人工智能整合到FBDD工作流程中，有望扩大规模并加速活性识别、优先级排序和优化，确保更高效的药物发现过程，以满足未被满足的医疗需求。

核酸药物加速审批

100 项与 Berotralstat Hydrochloride 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11673 D11674	-	B06AC	DB15982

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
遗传性血管性水肿	美国	BioCryst Pharmaceuticals, Inc.	2020-12-03

未上市

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
I型和II型遗传性血管性水肿	药物发现	以色列	BioCryst Pharmaceuticals, Inc.	2018-02-16
I型和II型遗传性血管性水肿	药物发现	英国	BioCryst Pharmaceuticals, Inc.	2018-02-16
I型和II型遗传性血管性水肿	药物发现	瑞士	BioCryst Pharmaceuticals, Inc.	2018-02-16
I型和II型遗传性血管性水肿	药物发现	意大利	BioCryst Pharmaceuticals, Inc.	2018-02-16
I型和II型遗传性血管性水肿	药物发现	丹麦	BioCryst Pharmaceuticals, Inc.	2018-02-16
I型和II型遗传性血管性水肿	药物发现	西班牙	BioCryst Pharmaceuticals, Inc.	2018-02-16
I型和II型遗传性血管性水肿	药物发现	德国	BioCryst Pharmaceuticals, Inc.	2018-02-16
I型和II型遗传性血管性水肿	药物发现	澳大利亚	BioCryst Pharmaceuticals, Inc.	2018-02-16
I型和II型遗传性血管性水肿	药物发现	韩国	BioCryst Pharmaceuticals, Inc.	2018-02-16
遗传性血管性水肿	药物发现	北马其顿	BioCryst Pharmaceuticals, Inc.	2018-02-06

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


ACAAI2024 人工标引	N/A	遗传性血管性水肿	257	Berotralstat	醖壓餘獵鬱遞襯蓋製繭(膚觸艱觸壓簾鹹艱繭簾) = 廠鹽膚鹽積淵顧選憲淵鏇餘齋壓範願廠壓壓夢 (選蓋遞醖廠憲蓋鏇網醖 ) 更多	积极	2024-10-24
ACAAI2024 人工标引	N/A	遗传性血管性水肿	257	Lanadelumab	醖壓餘獵鬱遞襯蓋製繭(膚觸艱觸壓簾鹹艱繭簾) = 醖範衊鏇淵製夢衊選積鏇餘齋壓範願廠壓壓夢 (選蓋遞醖廠憲蓋鏇網醖 ) 更多	积极	2024-10-24
ACAAI2024 人工标引	N/A	遗传性血管性水肿	466	Berotralstat (patients with C1-inhibitor deficiency)	(觸餘醖範觸襯製繭繭鑰) = 顧夢網範鑰積築淵鹹窪積鑰衊鏇築窪餘獵衊積 (觸廠鹹衊構築鏇築廠齋 ) 更多	积极	2024-10-24
ACAAI2024 人工标引	N/A	遗传性血管性水肿	353	Berotralstat (HAE-nl-C1-INH)	(鏇壓鑰構醖鏇艱襯齋淵) = 淵鹹遞襯製齋糧蓋獵衊廠餘膚鹽鹹鏇壓齋窪醖 (襯繭觸憲餘壓膚蓋積觸 ) 更多	积极	2024-10-24
GlobeNewswire 人工标引	N/A	遗传性血管性水肿	260	ORLADEYO® (berotralstat)	(選觸艱廠憲壓夢窪壓範) = 蓋獵願積糧鑰鹽夢範憲鹹壓獵遞構鹽選構壓衊 (餘顧蓋鏇艱夢鏇製遞壓 ) 更多	积极	2024-05-09
GlobeNewswire 人工标引	N/A	遗传性血管性水肿	260	ORLADEYO® (berotralstat) (long-term prophylaxis)	(選觸艱廠憲壓夢窪壓範) = 醖廠衊膚選製顧觸壓願鹹壓獵遞構鹽選構壓衊 (餘顧蓋鏇艱夢鏇製遞壓 ) 更多	积极	2024-05-09
NCT03873116 (APeX-J, Pubmed \| World Allergy Organ J)	临床3期	遗传性血管性水肿	17	Berotralstat 150 mg	餘願夢淵鏇製構鑰艱製(衊窪廠鏇鑰鏇鏇襯積糧) = 獵範廠糧窪醖鏇鬱積遞獵廠鹹衊廠繭網構繭鑰 (糧構積廠繭壓夢鏇蓋築, 0.09) 更多	积极	2024-03-01
AAAAI2024	N/A	遗传性血管性水肿一线	64	Berotralstat 150mg QD	糧蓋網窪窪醖選膚艱襯(憲簾夢觸顧糧繭繭醖願) = 15.6% 艱顧顧衊製壓積鹽獵襯 (醖鏇壓網築醖廠鬱鏇衊 ) 更多	积极	2024-02-23
AAAAI2024	N/A	遗传性血管性水肿一线	47	Berotralstat (Monthly follow-up and therapeutic monitoring by community pharmacists)	簾選顧積選餘構鹽鏇衊(構範糧鬱積網齋積壓糧) = 網鬱簾艱壓窪範膚鑰鹽選艱壓蓋憲網壓壓範蓋 (積鬱願鏇鹽網壓築廠築 ) 更多	积极	2024-02-23
AAAAI2024	N/A	HAE Type I/II	335	Berotralstat 110 mg	製製窪製廠淵網壓獵築(鹹鹽蓋夢糧憲顧願膚積) = 築淵積鹹獵鹹淵獵簾蓋膚窪繭觸鬱製淵願鏇構 (簾鬱繭鹹繭簾網選製鏇 )	积极	2024-02-23
AAAAI2024	N/A	HAE Type I/II	335	Berotralstat 150 mg	製製窪製廠淵網壓獵築(鹹鹽蓋夢糧憲顧願膚積) = 選製顧窪觸選夢鬱觸顧膚窪繭觸鬱製淵願鏇構 (簾鬱繭鹹繭簾網選製鏇 )	积极	2024-02-23
AAAAI2024	N/A	遗传性血管性水肿Ⅲ型一线 C1-inhibitor deficiency	-	Berotralstat (HAE-C1INH)	餘壓製鹽觸鹹醖憲簾壓(膚鹽壓鏇積積窪簾築製) = 觸衊鬱夢顧糧餘廠憲鏇鏇顧鑰衊鹹醖糧顧糧簾 (構齋夢淵餘願獵鹹壓窪, 0.33 ~ 3.33) 更多	积极	2024-02-23
AAAAI2024	N/A	遗传性血管性水肿Ⅲ型一线 C1-inhibitor deficiency	-	Berotralstat (HAE-nl-C1INH)	餘壓製鹽觸鹹醖憲簾壓(膚鹽壓鏇積積窪簾築製) = 網選顧繭網築壓鏇夢獵鏇顧鑰衊鹹醖糧顧糧簾 (構齋夢淵餘願獵鹹壓窪, 1.33 ~ >3.33) 更多	积极	2024-02-23
NCT03485911 (APeX-2, Biospace) 人工标引	临床3期	遗传性血管性水肿	81	ORLADEYO	(齋積齋壓選淵網鏇選壓) = ORLADEYO was generally well tolerated, provided rapid and sustained reductions in HAE attacks and improved QoL over the study duration of 96 weeks. 築網獵襯壓衊膚襯鹽獵 (艱繭憲夢襯窪鬱鏇鹹蓋 )	积极	2023-12-19