Tirzepatide

多肽化学合成的常见路线包括经典溶液合成、固相多肽合成（SPPS），以及可溶性载体或标签辅助的液相多肽合成。不同文献对液相合成（LPPS）的命名范围存在差异，本文采用2022年综述讨论标签辅助液相路线的用语范围。经典溶液法的工艺开发通常需要针对中间体设计分离步骤；SPPS则借助树脂载体和过滤洗涤，简化了迭代操作。两者各有适用场景，不能以单一路线概括所有产品的成本和放大表现。 SPPS的设备与物料需求受树脂类型、溶胀性、目标序列及工艺条件影响。树脂溶胀、过滤洗涤，以及部分步骤所需的过量氨基酸和偶联试剂，可能增加反应体积、溶剂用量及废物处理负担。 标签辅助液相路线使肽链在溶液中延伸，并利用标签的溶解性、分配或分离特征完成后处理。部分案例显示了减少过量试剂与溶剂用量的潜力，但其效果仍依赖标签、序列、分离方式和工艺边界，需要逐项验证。 TAPS技术概述和现状 2022年综述按载体或分离策略讨论了多分散聚乙二醇（PEG）、膜增强多肽合成（MEPS）、氟相技术、离子液体、PolyCarbon、疏水聚合物及基团辅助纯化（GAP）等方向。 TAPS通常指标签辅助多肽合成（tag-assisted peptide synthesis），涵盖不同标签及后处理路线。Molecular Hiving™ 是 Jitsubo 开发的标签辅助液相多肽合成技术。2020 年，Jitsubo 与 Bachem 公布了该技术的许可协议。，九洲多肽技术团队利用自研Tag标签，完成平台技术开发，成功应用于定制肽交付，PMI/cEF指标明显下降。 以常见C端负载、向N端延伸的Fmoc路线为例，通常先将首个氨基酸连接至可溶性标签，再按顺序进行脱保护、偶联及必要的后处理。部分工艺通过反溶剂沉淀回收带标签肽，另一些工艺采用液液萃取，在两相之间分离带标签肽和小分子杂质；完成肽链组装后，再按路线脱除标签及保护基并纯化。 技术局限及后续研究方向 标签辅助逐步延伸面临序列相关的溶解性与分离挑战。链长增加后，肽链与保护基对物性的影响可能削弱标签对相行为的控制，对于较长或复杂的目标肽，可以评估片段合成与连接的收敛路线。 Egelund等在2026年JACS论文中将TAPS与芳基硒酯氨解连接（ASAL）结合，通过片段连接制备了特立帕肽、TTI及替尔泊肽等目标分子，展示了降低差向异构化及减少试剂、溶剂消耗的研究潜力。这一结果说明，片段连接可扩展标签辅助策略的适用范围，但该平台涉及含硒试剂，工业化道路依然面对不少挑战，未来还需评价残留、清除、安全及废物处理。 虽然Fmoc体系已有研究基础，但不能代替对每条产品路线的适用性验证。当前值得持续关注的问题包括：标签制备及回收的经济性、不同保护基与特殊氨基酸的兼容性、标签脱除及残留控制、片段连接的差向异构化、相分离效率和全流程杂质谱。 后续研究可围绕标签设计与回收、绿色溶剂筛选、过程分析、连续反应及分离衔接、自动化和片段连接等方向展开。可评估溶剂和试剂的替代方案，减少高危害物质的使用，并跟踪欧盟对相关物质的分类与限制进展。总之，TAPS为多肽制造提供了更多可评估的技术选项。  · 参考资料 ·  Takahashi, D.; Yano, T.; Fukui, T. Novel diphenylmethyl-Derived Amide Protecting Group for Efficient Liquid-Phase Peptide Synthesis: AJIPHASE. Org. Lett. 2012, 14, 4514–4517. doi:10.1021/ol302002g. Okada, Y.; Suzuki, H.; Nakae, T.; Fujita, S.; Abe, H.; Nagano, K.; Yamada, T.; Ebata, N.; Kim, S.; Chiba, K. Tag Assisted Liquid Phase Peptide Synthesis Using Hydrophobic Benzyl Alcohols as Supports. J. Org. Chem. 2013, 78, 320–327. Takahashi, D.; Inomata, T.; Fukui, T. AJIPHASE®: A Highly Efficient Synthetic Method for One Pot Peptide Elongation in the Solution Phase by an Fmoc Strategy. Angew. Chem., Int. Ed. 2017, 56, 7803–7807. Sharma, A.; Kumar, A.; de la Torre, B. G.; Albericio, F. LiquidPhase Peptide Synthesis (LPPS): A Third Wave for the Preparation of Peptides. Chem. Rev. 2022, 122, 13516–13546. Egelund, P. H. G.; Rachid, A.; Ayoub, A.; et al. Towards Sustainable Synthesis of Peptide Therapeutics via Tag-Assisted Peptide Synthesis and Aryl Selenoester Aminolysis Ligation. J. Am. Chem. Soc. 2026, 148(24), 25050–25061. doi:10.1021/jacs.6c05882. Bachem. Introduction to Peptide Synthesis Methods. https://www.bachem.com/knowledge-center/introduction-to-peptide-synthesis-methods/ ACS Green Chemistry Institute Pharmaceutical Roundtable. More Efficient LPPS. https://reagents.acsgcipr.org/reagent-guides/greener-peptide-synthesis/list-of-reagents/more-efficient-lpps/  · 免责声明 ·  本公众号注明原创的内容权利均属九洲药业所有，未经授权，不得擅自使用或许可他人使用。如需获得授权，请和九洲药业提前联系。已获得授权的，应在授权范围内使用，并注明来源且不得再全部或部分转授权他人。 本公众号对转载、分享的内容、陈述、观点判断保持中立，不对所包含内容的合法性、准确性、可靠性或完善性提供任何明示或暗示的保证，该等内容版权归原作者所有，仅供学习参考之用，若对转载、分享的内容有任何权利疑问，烦请联系九洲药业。

INLIGHT Phase 1 data continue to support WVE-007’s novel mechanism of action to improve body composition by inducing fat loss without muscle loss, and support a once- or twice-yearly dosing regimen Six-month data from ongoing Phase 2a monotherapy trial in individuals with high BMI, high adiposity, and comorbidities anticipated in 2027 WVE-007/tirzepatide combination trial ongoing; Wave announces plan to integrate its maintenance clinical trial with this ongoing combination trial CAMBRIDGE, Mass., Nov. 13, 2026 (GLOBE NEWSWIRE) -- Wave Life Sciences, Inc. (Nasdaq: WVE), a clinical-stage biotechnology company focused on unlocking the broad potential of RNA medicines to transform human health, today highlights WVE-007 progress at ObesityWeek ® , the annual congress of The Obesity Society, taking place in Washington, D.C. from November 14-17, 2026. WVE-007 is an investigational GalNac-siRNA developed with Wave’s proprietary chemistry to target fat metabolism through silencing INHBE mRNA. “At this year’s ObesityWeek annual meeting, we will be connecting with the healthcare providers and broader community driving the future of obesity care, and we are eager to share how a body composition–focused approach could address the treatment gaps that exist today for individuals living with obesity,” said Christopher Wright, MD, PhD, Chief Medical Officer at Wave Life Sciences. “The Phase 1 single-dose portion of our INLIGHT clinical trial continues to demonstrate that WVE-007 impacts the desired biology with potent, durable Activin E reductions leading to body composition improvements and a favorable safety profile. We continue to advance our ongoing higher BMI Phase 2a monotherapy trial, which is evaluating WVE-007’s potential to expand the treatment landscape for obesity, particularly for individuals who need an alternative to incretins. We expect six-month follow-up data in 2027, which will include body composition measurements as well as liver fat changes that could accelerate development in MASH. In parallel, we are also investigating WVE-007 as a complementary approach to enhance fat loss with incretins, and as a post-incretin weight maintenance strategy. We look forward to engaging with the community and highlighting the progress of our INLIGHT™ clinical trial.” ObesityWeek ® presentations Oral presentation: Silencing Inhbe With a GalNAc-SpiNA siRNA Drives Tissue Remodeling and a Healthy Metabolic Profile (Saturday, November 14 – 4:30-4:45 p.m., Potomac D456, Ballroom Level) Presenter: Ginnie (Hsiu-Chiung) Yang, PhD, SVP, Translational Medicine, Wave Life Sciences Poster presentation: Interim Data from INLIGHT: A Phase 1 Study of WVE-007 In Adults Living With Overweight and Obesity ​ (Sunday, November 15 - 2:30-3:30 p.m., Poster # 435, Exhibit Hall BCD​) Presenter: Cynthia Caracta, MD, Executive Director of Development, Wave Life Sciences Corporate symposium: Rethinking success in the treatment of overweight and obesity through body composition: What are we made of? (Saturday, November 14 – 11:45am-1:15 p.m., Riverview Ballroom A) Presenters: Angela Fitch, MD, FACP, MFOMA, Dipl ABOM Board Trustee, Obesity Action Coalition; Past President, Obesity Medicine Association; Chief Medical Officer and Co-Founder, knownwell, Boston, MA Mehmet Furkan Burak, MD, Co-Chair, Obesity Group, Endocrine Society, Assistant Professor of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA Christopher Wright, MD, PhD, Chief Medical Officer, Wave Life Sciences Erik Ingelsson, MD, PhD, Chief Scientific Officer, Wave Life Sciences This presentation will feature discussion on the current obesity treatment landscape and the potential for new therapeutic approaches to address key limitations of chronic weight management. The session includes discussion from leading clinicians on why improving body composition, including reducing harmful visceral fat while preserving lean mass, may serve as an important measure of meaningful change. Wave will also present an overview of the WVE-007 clinical program. WVE-007 clinical program updates The ongoing Phase 1 portion of the INLIGHT™ clinical trial is evaluating single doses of WVE-007 in otherwise healthy individuals living with overweight or obesity. WVE-007 continues to be generally safe and well tolerated, with no discontinuations, and no drug-related serious adverse events. There were no clinically meaningful changes in clinical laboratory measurements, including lipid profiles or liver function tests. Individuals in the top three dose cohorts (240 mg, 400 mg, 600 mg) are being followed through the final 12-month assessment timepoint. To date, single-dose Activin E reductions are durable, dose-dependent, and consistently above therapeutic threshold, with mean maximums of 82%, 84%, and 88%, respectively. In the 240 mg cohort, for which all subjects have reached one year follow-up, single-dose placebo-adjusted mean Activin E reductions from baseline remained significant. While Activin E reductions were consistent and deep across cohorts, both preclinical and Phase 1 clinical data continue to indicate baseline body composition (higher BMI, higher adiposity) is associated with greater therapeutic effects. The average baseline BMI in the Phase 1 study is 31.7 kg/m 2 and continues to be lower than Phase 2 and 3 obesity trials. In the 240 mg cohort, which had the highest baseline BMI, placebo-adjusted reductions in visceral fat, total fat, and waist circumference, with preservation of lean mass continued to be observed one year following a single dose. The 400 mg and 600 mg cohorts had lower baseline BMI. Data from the 600 mg cohort at six months was similar to previously-reported 400 mg data, with placebo-adjusted reductions in visceral fat and waist circumference and preservation of lean mass, while total fat remained relatively unchanged. Across the three cohorts, individuals with higher BMI and higher baseline adiposity continued to have a more pronounced treatment effect. The Phase 2a portion of the INLIGHT™ trial in individuals with higher BMI (35-50 kg/m²) and higher baseline adiposity, with and without type 2 diabetes, is ongoing, evaluating multiple doses of the 240 mg and 400 mg dose levels of WVE-007. To date, baseline adiposity in this trial is substantially higher than in the Phase 1 portion and in line with Phase 2 and 3 trials in individuals living with obesity. The trial includes multiple assessments over a 12-month period, including body weight, waist circumference, body composition (MRI and DEXA), liver fat (MRI-PDFF), HbA1c, and lipid levels. These data will inform further development of WVE-007 in obesity, as well as in MASH, type 2 diabetes, and other cardiometabolic diseases. Wave expects to deliver six-month data from its Phase 2a trial in 2027. Wave has also initiated a Phase 2a combination trial evaluating WVE-007 with weekly tirzepatide compared to tirzepatide alone in individuals living with obesity (BMI 35-50 kg/m²) and type 2 diabetes. Today, Wave is announcing its plan to integrate its maintenance clinical trial with this ongoing combination trial, which is expected to enhance operational efficiencies and accelerate time to data. Visit Wave at ObesityWeek ® Attendees are invited to visit Wave at Booth #428 to learn more about WVE-007 and Wave’s differentiated approach to addressing obesity with its SpiNA design siRNA. About Wave Life Sciences Wave Life Sciences (Nasdaq: WVE) is a biotechnology company focused on unlocking the broad potential of RNA medicines to transform human health. Wave’s PRISM ® platform combines multiple RNA medicine modalities, chemistry innovation, and deep insights in human genetics to deliver scientific breakthroughs that treat both rare and common disorders. Its toolkit of RNA-targeting modalities, including RNAi (SpiNA) and RNA editing (AIMers), provides Wave with unmatched capabilities for designing and sustainably delivering candidates that optimally address disease biology. Wave’s lead pipeline programs include obesity (WVE-007), alpha-1 antitrypsin deficiency (WVE-006), and PNPLA3 I148M liver disease (WVE-008), as well as several preclinical programs utilizing the company’s versatile RNA medicines platform. Driven by the calling to “Reimagine Possible,” Wave is leading the charge toward a world in which human potential is no longer hindered by the burden of disease. Wave is headquartered in Cambridge, MA. For more information on Wave’s science, pipeline and people, please visit and follow Wave on X and LinkedIn . Forward-Looking Statements This press release contains forward-looking statements concerning our goals, beliefs, expectations, strategies, objectives and plans, and other statements that are not necessarily based on historical facts, including statements regarding the following, among others: the anticipated initiation, site activation, patient recruitment, patient enrollment, dosing, generation and reporting of data and/or completion of our INLIGHT clinical trial and the timing and announcement of such events; our plans to integrate a maintenance portion into our ongoing Phase 2a combination trial with tirzepatide; the potential of WVE-007’s mechanism as a meaningful and differentiated therapeutic approach for obesity to improve body composition by inducing fat loss without muscle loss, as well as the potential to develop WVE-007 for other indications, including MASH, and cardiovascular disease; the future performance and results of WVE-007 in the Phase 2a portions of our INLIGHT clinical trial, including our expectations that baseline body composition (higher BMI, higher baseline adiposity) is associated with greater therapeutic effects; our understanding that improving body composition, including reducing harmful visceral fat while preserving lean mass, may address treatment gaps and serve as an important measure of meaningful change; our expectations of improved safety and tolerability of WVE-007, particularly relative to existing therapies; the potential benefits of our toolkit of RNA-targeting modalities, including RNAi (SpiNA) and RNA editing (AIMers), compared to others; and the benefits of RNA medicines generally. The words “may,” “will,” “could,” “would,” “should,” “expect,” “plan,” “anticipate,” “intend,” “believe,” “estimate,” “predict,” “project,” “potential,” “continue,” “target” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements in this press release are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual results to differ materially from those indicated by these forward-looking statements as a result of these risks, uncertainties and important factors, including, without limitation, the risks and uncertainties described in the section entitled “Risk Factors” in Wave’s most recent Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC), as amended, and in other filings Wave makes with the SEC from time to time. Wave undertakes no obligation to update the information contained in this press release to reflect subsequently occurring events or circumstances. Contact: Kate Rausch VP, Corporate Affairs and Investor Relations +1 617-949-4827 Investors: James Salierno Director, Investor Relations +1 617-949-4043 InvestorRelations@wavelifesci.com Media : Katie Sullivan Senior Director, Corporate Communications +1 617-949-2936 MediaRelations@wavelifesci.com