MRT-6160

2024年10月29日，渤健和Neomorph宣布一项总价14.5亿美元的最新合作，渤建新闻稿称通过此次合作双方将利用双方优势，共同开发用于治疗阿尔茨海默病、罕见神经系统疾病和免疫疾病的多个分子胶降解剂。 这是MNC自进入10月以来，在分子胶降解剂领域的第三笔合作，此前（2024年10月28日）诺华曾宣布就一款处于临床阶段的分子胶产品MRT-6160跟Monte Rosa Therapeutics达成，交易总价超过22亿美元的总价值。另外，2024年10月15日，辉瑞与TRIANA同样就分子胶降解剂达成合作，交易最高金额超过15亿美元。 事实上，自2023年起，就有包括BMS、罗氏、诺和诺德、默沙东等MNC与biotech达成分子胶技术平台/项目相关合作，潜在交易金额总值已远超过百亿美元。 在这个领域频繁发生的交易向我们阐述一个不容忽视的事实，即以分子胶和PROTAC为代表的靶向蛋白降解（Targeted Protein Degraders，TPD）技术时代正在靠近。 01 从分子胶到靶向蛋白降解剂 分子胶算是较早被发现的靶向蛋白降解剂，其背后的故事最早可追溯至1971年。 1971年，山德士公司的一名微生物学家Jean Borel和其妻子意外分离出了一种真菌代谢物，即环孢霉素A（CsA）。在后续的研究中，Borel发现CsA具有很强的免疫抑制功能。在后续实验中，CsA被证实是一种新的，选择性强的，高效免疫抑制剂，并于1983年获FDA批准上市，用作肾、肝和心脏移植的免疫抑制剂。 CsA获FDA批准的同年，Fujisawa也正在试图通过筛选生物活性微生物产品来寻找新的免疫抑制剂。1987年时，他们发现了一种与CsA具有相似活性的FK506（tacrolimus）。 CsA和FK506的出现促进了分子胶作用机制的发现。1991年，彼时的刘军教授在哈佛大学斯图尔特·施雷伯实验室做博士后，他使用亲和层析技术发现环孢菌素A可以像胶水一样将两种蛋白（亲环素和钙调节神经磷酸酶）粘在一起，即分子胶功能。（刘军教授还发现FK506可同时结合FK506结合蛋白-12（FKBP12）和钙调节神经磷酸酶，也具有分子胶功能。） 这一发现为新药研发提供了新的解题思路，并打破了蛋白磷酸酶“不可成药”靶点的传说。 所谓“不可成药”靶点，通常指的是一类通过传统方法难以/尚未靶向、但极具临床意义的治疗靶点。这些靶点因表面相对平滑、缺乏明显的结合口袋或者因其独特的结构特征或生物学特性，使得传统的小分子药物难以与其有效结合，一直是新药研发中试图攻克的难题。据统计，与人体疾病相关的致病蛋白中，超过 80% 的蛋白质不能被目前常规方式所靶向。 亨廷顿舞蹈症的致病蛋白变异HTT（mHTT）就是备受关注的“不可成药”靶点之一。日前，在瑞孚迪（Revvity）和药时代就“难成药靶点蛋白降解研究进展和技术交流”为话题举行了一场直播活动中，复旦大学生命科学学院鲁伯埙教授以“难成药靶点的靶向干预：亨廷顿病研究带来的启示”为题进行了精彩分享。鲁教授以详细的研究案例，向大家讲解了ATTEC技术在疾病治疗中关键作用，并指出ATTEC技术极有可能成为一个新的技术平台为更多其它疾病的治疗带去希望，比如可通过降解肝脏内脂滴达到治疗代谢性疾病/老年黄斑变性等疾病的目的，通过清除破损线粒体去治疗唐氏综合症、帕金森病等。另外，鲁教授还提到了他们团队正在尝试通过小分子胶水稳定特定蛋白（如p53）来治疗疾病，并分享了相关研究细节和当前得到的一些初步结果。 活动还邀请到了上海佰君生物王希玲博士。分享过程中王博士先向大家简单介绍了TPD技术的一些研究概况，指出目前业内聚焦的不可成药靶点主要包括： Small GTPases：比如RAS家族蛋白（KRAS、HRAS和NRAS）。 Phosphatases：包括酪氨酸磷酸酶（PTPs）和丝/苏氨酸磷酸酶（PSTPs）。 Transcription factors (TFs)：包括p53、Myc、雌激素受体(ER)和雄激素受体（AR）。 Epigenetic targets Other proteins：包括蛋白质-蛋白质相互作用(PPIs)及其网络。 以上这些靶点涉及众多生命学过程，与多种疾病的发生息息相关。 之后王博士还向大家介绍了目前TPD技术领域的一些入局企业和重要管线，并以KRASG12C为例进行具体分享。 作为最后一位出场的嘉宾，瑞孚迪高通量药物筛选资深应用科学家刘欣毅博士则基于目前企业在开发靶向蛋白降解剂中的实际解决方案出发，系统介绍了瑞孚迪现已建立的TPD技术全流程平台，并指出目前瑞孚迪已建立从基因靶点发现、linker分子优化和结合验证、分子胶筛选、三元复合物活性验证、PROTAC活性验证、HTT蛋白均相检测、细胞活性验证、活体验证等在内的全方位服务，可助力药企更快更高效完成产品的开发。尤其是活体验证部分，瑞孚迪在此方面有多年行业积累，已构建起成熟的检测体系。 结语 现如今距离首次发现分子胶已经过去了三十余年，分子胶已从最初的理论成为了一种创新的靶向蛋白质降解的新药开发技术，并已有不少产品进入临床阶段。目前进度较快的大多为分子胶/ PROTAC，知名的沙利度胺及其类似物也被发现具有分子胶功能。其余的，比如gene-based strategies、bioPROTAC、oligoTAC、LYTAC、ATTEC、AUTAC和abTAC等均还处在临床前研究中。但就向文章开头所讲，这一领域正在受到MNC广泛关注。 欢迎扫描下图二维码，观看直播回放，了解TPD技术从基础研究到具体开发中的更多知识点！ 长按扫码，查看直播回放  关于我们   ABOUT 在瑞孚迪（Revvity），我们将“ 不可能 ” 视为灵感，将“ 做不到 ” 视为原动力。瑞孚迪提供健康科学解决方案、前沿技术和专业服务，业务涵盖科研探索、开发、诊断、治疗的端到端全流程。依托在转化多组学技术、生物标志物鉴定、成像、疾病的预测、筛查、检测与诊断、信息学等领域的多年深耕，瑞孚迪正以科技之能，突破人类潜能的边界。 2023年瑞孚迪的营业额超过27亿美元，全球拥有11,000多名员工，为制药和生物技术企业、诊断实验室、科研机构和政府机构等客户提供多样化服务。公司是标准普尔500指数的成员，客户遍及全球190多个国家和地区。  欢迎朋友们走进“药时代直播间”！秉持“聚焦新药研发，荟萃行业精华，分享交流合作，共筑健康天下！”这一宗旨和目标，药时代将推出一系列优质的直播课程，邀请行业专家就新药研发相关的焦点话题做精彩的解读和分享，帮助朋友们学习新知识，掌握新技能，结交新朋友。衷心感谢朋友们长期以来的支持、惠助！我们将竭尽全力，持续不断地为朋友们带来优质、有价值、高品质的内容！ 点击这里，观看直播

Executed global exclusive development and commercialization license agreement with Novartis to advance VAV1-directed molecular glue degraders including MRT-6160 for immune-related conditions; $150M upfront payment, eligible for up to $2.1B milestones and U.S. P&L share MRT-6160 Phase 1 SAD/MAD study ongoing with initial clinical data expected by Q1 2025 Phase 1/2 study of MRT-2359, in development for MYC-driven solid tumors, ongoing with updated clinical results anticipated by year-end MRT-8102, a NEK7-directed molecular glue degrader targeting diseases driven by IL-1β and the NLRP3 inflammasome, on track for IND filing in H1 2025 Strengthened cash position, including anticipated $150 million upfront from Novartis, expected to fund operations into 2028 through multiple anticipated proof-of-concept clinical readouts BOSTON, Nov. 07, 2024 (GLOBE NEWSWIRE) -- Monte Rosa Therapeutics, Inc. (Nasdaq: GLUE), a clinical-stage biotechnology company developing novel molecular glue degrader (MGD)-based medicines, today reported business highlights and financial results for the third quarter that ended September 30, 2024. “We continue to make significant progress towards pioneering the discovery and development of highly selective molecular glue degraders against paradigm-shifting targets. The recently announced global license agreement with Novartis to advance VAV1-directed MGDs for immune-related conditions marks a transformative milestone towards that goal,” said Markus Warmuth, M.D., Chief Executive Officer of Monte Rosa Therapeutics. “We believe this agreement will accelerate and broaden the scope of clinical development of MRT-6160 across a spectrum of immune-mediated conditions while retaining substantial value for Monte Rosa. Moreover, the resources provided by this agreement are expected to meaningfully extend our cash runway and enable us to advance our pipeline to potential value-creating milestones and to further leverage our industry-leading QuEEN™ discovery engine to design and develop novel MGDs for previously undruggable targets across a variety of disease areas, including immunology and inflammation (I&I), cardiovascular, and metabolic diseases. We look forward to sharing initial clinical data from the ongoing Phase 1 study of MRT-6160 by Q1 2025.” Dr. Warmuth continued, “We have made significant progress advancing our second I&I program, MRT-8102, toward an expected IND application in the first half of 2025. Turning towards our oncology pipeline, we look forward to sharing updated clinical results from the Phase 1 dose escalation portion of the MRT-2359 study by year-end, and we’re pleased with the progress of our cell cycle portfolio, including the CDK2 and cyclin E1 programs, with both advancing towards development candidate nominations.” RECENT HIGHLIGHTS MRT-2359, GSPT1-directed MGD for MYC-driven solid tumors Monte Rosa continues to evaluate MRT-2359 in a Phase 1/2 clinical trial in MYC-driven solid tumors (NCT05546268). In June 2024, the Company announced that it had obtained encouraging initial safety and pharmacodynamic data from the 0.5 mg dose using the 21 days on, 7 days off regimen. Monte Rosa continues to evaluate a higher 0.75 mg, 21 days on, 7 days off dose cohort. MRT-6160, VAV1-directed MGD for immune-mediated conditions In October, the Company announced a global exclusive development and commercialization license agreement with Novartis to advance VAV1 MGDs including MRT-6160, currently in Phase 1 clinical development for various immune-related conditions. Under the terms of the agreement, Novartis will obtain exclusive worldwide rights to develop, manufacture and commercialize MRT-6160 and other VAV1 MGDs and will be responsible for all clinical development and commercialization, starting with Phase 2 clinical studies. Monte Rosa remains responsible for completion of the ongoing Phase 1 clinical study of MRT-6160. Novartis has agreed to pay Monte Rosa $150 million upfront. Monte Rosa is eligible to receive up to $2.1 billion in development, regulatory, and sales milestones, beginning upon initiation of Phase 2 studies, as well as tiered royalties on ex-U.S. net sales. Monte Rosa will co-fund any Phase 3 clinical development and will share any profits and losses associated with the manufacturing and commercialization of MRT-6160 in the U.S. The agreement is subject to customary closing conditions including regulatory clearance.In August, Monte Rosa announced that the first participants had been dosed in an MRT-6160 Phase 1 single ascending dose/multiple ascending dose (SAD/MAD) study. MRT-8102, NEK7-directed MGD for inflammatory diseases driven by IL-1β and the NLRP3 inflammasome In September, Monte Rosa presented preclinical data at the Inflammasome Summit demonstrating that its development candidate MRT-8102, a first-in-class NEK7-directed MGD for the treatment of inflammatory diseases driven by interleukin-1β (IL-1β) and the NLRP3 inflammasome, is a potent, selective, and durable molecular glue degrader of NEK7. The data provide preclinical proof of concept that a NEK7 MGD leads to inhibition of the NLRP3 inflammasome and IL-1 release to reduce the effects of inflammation, supporting the potential to address central and peripheral inflammatory disorders.Monte Rosa expects to submit an IND application for MRT-8102 in H1 2025. CDK2 and Cyclin E1-directed MGD programs In October, Monte Rosa presented preclinical data at the 36th EORTC-NCI-AACR Symposium on the potential of its cyclin E1 (CCNE1)-directed MGDs for the treatment of CCNE1-amplified solid tumors. The data demonstrated that Monte Rosa’s MGD degrades cyclin E1 with a high level of selectivity, sparing other closely related proteins, including other cyclins, and cyclin-dependent kinases (CDKs). The data also showed that a cyclin E1-directed MGD led to downstream pathway inhibition and induced tumor growth suppression and regression preferentially in CCNE1-amplified and over-expressing tumor cell lines and xenograft models. Cyclin E1 MGDs may represent a potential novel therapeutic approach by directly and selectively targeting a frequently amplified non-enzymatic driver oncogene relevant in multiple solid tumors.Monte Rosa is progressing both its CDK2 and cyclin E1-directed MGD programs to development candidate nominations. QuEEN™ (Quantitative and Engineered Elimination of Neosubstrates) discovery engine In October, Monte Rosa made a preprint available in BioRxiv entitled, “Mining the Cereblon Target Space Redefines Rules for Molecular Glue-induced Neosubstrate Recognition,” which demonstrates a vast expansion of what had been considered druggable within the cereblon target space. Monte Rosa has identified more than 1,600 proteins predicted to be compatible with cereblon across diverse target classes that can potentially be targeted with molecular glue degraders. ANTICIPATED MILESTONES Announce the recommended Phase 2 dose and data from the Phase 1 dose escalation portion of the MRT-2359 Phase 1/2 study including safety, biomarker data, and clinical activity before the end of 2024. The Company also expects to provide guidance on Phase 2 expansion cohorts before year-end.Report initial data from the Phase 1 SAD/MAD study of MRT-6160 in healthy volunteers by Q1 2025. The Phase 1 study of MRT-6160 is designed to provide early insights into safety, pharmacokinetics, VAV1 protein degradation, and key downstream pharmacodynamic markers including CD69, IL-2, IL-6, and IL-17.Submit an IND application for MRT-8102 in H1 2025.Nominate a CDK2 program development candidate before year-end 2024. UPCOMING INVESTOR CONFERENCES Monte Rosa management will participate in the following investor conferences: Guggenheim Securities Healthcare Innovation Conference (Boston, Mass.) – Markus Warmuth, M.D., Chief Executive Officer, to participate in a fireside chat, November 11, 2024, at 3:30 p.m. EST.Jefferies London Healthcare Conference (London, UK) – November 19, 2024. A webcast of the fireside chat will be accessible via the “Events & Presentations” section of Monte Rosa’s website at ir.monterosatx.com, and an archived version will be made available for 30 days following the presentation. THIRD QUARTER 2024 FINANCIAL RESULTS Collaboration revenue: Collaboration revenue for the third quarter of 2024 was $9.2 million. Collaboration revenue represents revenue recorded under the Roche license and collaboration agreement. No collaboration revenue was recognized during the same period in 2023. Research and Development (R&D) expenses: R&D expenses for the third quarter of 2024 were $27.6 million, compared to $28.3 million during the same period in 2023. R&D expenses were driven by the successful achievement of key milestones in our R&D organization, including the continuation of the MRT-2359 clinical study, the progression and growth of our preclinical pipeline, the advancement of MRT-6160 to enter the clinic, and the continued development of the Company’s QuEEN™ discovery engine. Non-cash stock-based compensation constituted $2.6 million of R&D expenses for Q3 2024, compared to $2.3 million in the same period in 2023. General and Administrative (G&A) expenses: G&A expenses for the third quarter of 2024 were $8.1 million compared to $8.7 million during the same period in 2023. G&A expenses included non-cash stock-based compensation of $1.6 million for the third quarter of 2024, compared to $2.2 million for the same period in 2023. Net loss: Net loss for the third quarter of 2024 was $23.9 million, compared to $30.3 million for the second quarter of 2024. Cash position and financial guidance: Cash, cash equivalents, restricted cash, and marketable securities as of September 30, 2024, were $247.1 million, compared to cash, cash equivalents, restricted cash, and marketable securities of $267.1 million as of June 30, 2024. The end of Q3 cash position does not include the recently announced $150 million upfront payment due from Novartis, subject to customary closing conditions including regulatory clearance. Based on current cash, cash equivalents, restricted cash, marketable securities, and the anticipated $150 million upfront payment due from Novartis, the Company expects its cash and cash equivalents to be sufficient to fund planned operations and capital expenditures into 2028. About MRT-2359MRT-2359 is a potent, highly selective, and orally bioavailable investigational molecular glue degrader (MGD) that induces the interaction between the E3 ubiquitin ligase component cereblon and the translation termination factor GSPT1, leading to the targeted degradation of GSPT1 protein. The MYC transcription factors (c-MYC, L-MYC and N-MYC) are well-established drivers of human cancers that maintain high levels of protein translation, which is critical for uncontrolled cell proliferation and tumor growth. Preclinical studies have shown this addiction to MYC-induced protein translation creates a dependency on GSPT1. By inducing degradation of GSPT1, MRT-2359 is designed to exploit this vulnerability, disrupting the protein synthesis machinery, leading to anti-tumor activity in MYC-driven tumors. About MRT-6160MRT-6160 is a potent, highly selective, and orally bioavailable investigational molecular glue degrader of VAV1, which in preclinical studies has shown deep degradation of its target with no detectable effects on other proteins. VAV1, a Rho-family guanine nucleotide exchange factor, is a key signaling protein downstream of both the T- and B-cell receptors. VAV1 expression is restricted to blood and immune cells, including T and B cells. Preclinical studies have shown that targeted degradation of VAV1 protein via an MGD modulates both T- and B-cell receptor-mediated activity. This modulation is evident both in vitro and in vivo, demonstrated by a significant decrease in cytokine secretion, proteins vital for maintaining autoimmune diseases. MRT-6160 has shown promising activity in preclinical models of multiple immune-mediated conditions. Under the terms of an agreement announced in October 2024, Novartis will obtain exclusive worldwide rights to develop, manufacture and commercialize MRT-6160 and other VAV1 MGDs, subject to customary closing conditions including regulatory clearance. About MRT-8102MRT-8102 is a potent, highly selective, and orally bioavailable investigational molecular glue degrader (MGD) that targets NEK7 for the treatment of inflammatory diseases driven by IL-1β and the NLRP3 inflammasome. NEK7 has been shown to be required for NLRP3 inflammasome assembly, activation and IL-1β release both in vitro and in vivo. Aberrant NLRP3 inflammasome activation and the subsequent release of active IL-1β and interleukin-18 (IL-18) has been implicated in multiple inflammatory disorders, including gout, cardiovascular disease, neurologic disorders including Parkinson’s disease and Alzheimer’s disease, ocular disease, diabetes, obesity, and liver disease. In a non-human primate model, MRT-8102 was shown to potently, selectively, and durably degrade NEK7, and resulted in near-complete reductions of IL-1β models following ex vivo stimulation of whole blood. MRT-8102 has shown a favorable profile in non-GLP toxicology studies. About Monte RosaMonte Rosa Therapeutics is a clinical-stage biotechnology company developing highly selective molecular glue degrader (MGD) medicines for patients living with serious diseases in the areas of oncology, autoimmune and inflammatory diseases, and more. MGDs are small molecule protein degraders that have the potential to treat many diseases that other modalities, including other degraders, cannot. Monte Rosa’s QuEEN™ (Quantitative and Engineered Elimination of Neosubstrates) discovery engine combines AI-guided chemistry, diverse chemical libraries, structural biology, and proteomics to identify degradable protein targets and rationally design MGDs with unprecedented selectivity. The QuEEN discovery engine enables access to a wide-ranging and differentiated target space of well-validated biology across multiple therapeutic areas. Monte Rosa has developed the industry’s leading pipeline of MGDs, which spans oncology, autoimmune and inflammatory disease and beyond. Monte Rosa has a global license agreement with Novartis to advance VAV1-directed molecular glue degraders and a strategic collaboration with Roche to discover and develop MGDs against targets in cancer and neurological diseases previously considered impossible to drug. For more information, visit www.monterosatx.com. Forward-Looking Statements This communication includes express and implied “forward-looking statements,” including forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements include all statements that are not historical facts and in some cases, can be identified by terms such as “may,” “might,” “will,” “could,” “would,” “should,” “expect,” “intend,” “plan,” “objective,” “anticipate,” “believe,” “estimate,” “predict,” “potential,” “continue,” “ongoing,” or the negative of these terms, or other comparable terminology intended to identify statements about the future. Forward-looking statements contained herein include, but are not limited to, statements about our ability to grow our product pipeline and to accelerate and broaden the scope of clinical development of MRT-6160 across a spectrum of immune-mediated conditions, statements around the Company’s QuEENTM discovery engine and the Company’s view of its potential to identify degradable protein targets and rationally design MGDs with unprecedented selectivity, statements related to the Company’s strategic agreements, goals of such agreements and any related milestone, royalty or other payments related thereto, statements related to the ability of the Company to advance its pipeline to potential value-creating milestones, statements around the productivity of the QuEEN discovery engine and the potential of the Company’s MGDs against a broad spectrum of targets, including undruggable targets across a variety of disease areas, such as I&I, cardiovascular, and metabolic diseases, statements about the advancement and timeline of our preclinical and clinical programs, pipeline and the various products therein, including (i) our ongoing clinical development of our GSPT1 degrader referred to as MRT-2359, including its ability to be selective, our expectations for the nature, significance, and timing for our disclosure of any data from our Phase 1 dose escalation portion of the MRT-2359 Phase 1/2 study, including safety, biomarker data and clinical activity, by the end of 2024, timing for our identification and any disclosure of a recommended Phase 2 dose for MRT-2359 by the end of 2024, and timing of our guidance on initiation of Phase 2 expansion cohorts by the end of 2024, (ii) the ongoing development of our VAV1-directed degrader, referred to as MRT-6160, and the timing of initial data from the Phase 1 SAD/MAD study by the first quarter of 2025 and our expectations regarding the potential clinical benefit for this program, including the contributions by Novartis, (iii) the ongoing development and progress of our NEK7-directed MGD, referred to as MRT-8102, and our expectations around its potential across neurologic indications amongst others, including our expectations to submit an IND to the FDA in the first half of 2025, and our statements around multiple anticipated preclinical and/or clinical readouts and their expected timing, including results from proof-of-concept patient studies, candidates and their applicability to various indications, progressing both our CDK2 and cyclin E1-directed MGD programs, the expected potential clinical benefit of any of our candidates, advancement and application of our pipeline, statements around the advancement and application of our platform, statements concerning our expectations regarding our ability to identify, nominate and the timing of our nominations of additional targets, product candidates, and development candidates, statements around our ability to capitalize on and potential benefits resulting from our research and translational insights, including announcements related to preclinical programs, as well as our the ability to optimize collaborations with industry partners on our development programs, statements about the closing of the transaction with Novartis, obligations under our collaboration agreements, expectations around the receipt of any payments under such agreements and the future development and commercialization of various products, statements regarding regulatory filings for our development programs, including the planned timing of such regulatory filings, such as IND applications, and potential review by regulatory authorities, our use of capital, expenses and other financial results in the future, availability of funding for existing programs, ability to fund operations into 2028, inclusive of the anticipated upfront payment from Novartis, as well as our expectations of success for our programs, strength of collaboration relationships and the strength of our financial position, among others. By their nature, these statements are subject to numerous risks and uncertainties, including those risks and uncertainties set forth in our most recent Annual Report on Form 10-K for the year ended December 31, 2023, filed with the U.S. Securities and Exchange Commission on March 14, 2024, and any subsequent filings, that could cause actual results, performance or achievement to differ materially and adversely from those anticipated or implied in the statements. You should not rely upon forward-looking statements as predictions of future events. Although our management believes that the expectations reflected in our statements are reasonable, we cannot guarantee that the future results, performance, or events and circumstances described in the forward-looking statements will be achieved or occur. Recipients are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date such statements are made and should not be construed as statements of fact. We undertake no obligation to publicly update any forward-looking statements, whether as a result of new information, any future presentations, or otherwise, except as required by applicable law. Certain information contained in these materials and any statements made orally during any presentation of these materials that relate to the materials or are based on studies, publications, surveys and other data obtained from third-party sources and our own internal estimates and research. While we believe these third-party studies, publications, surveys and other data to be reliable as of the date of these materials, we have not independently verified, and make no representations as to the adequacy, fairness, accuracy or completeness of, any information obtained from third-party sources. In addition, no independent source has evaluated the reasonableness or accuracy of our internal estimates or research and no reliance should be made on any information or statements made in these materials relating to or based on such internal estimates and research. Consolidated Balance Sheets(in thousands, except share amounts)(Unaudited) September 30, December 31, 2024 2023 Assets Current assets: Cash and cash equivalents $125,575 $128,101 Marketable securities 116,611 104,312 Other receivables 595 505 Prepaid expenses and other current assets 8,426 3,294 Total current assets 251,207 236,212 Property and equipment, net 31,442 33,803 Operating lease right-of-use assets 27,364 28,808 Restricted cash 4,908 4,580 Other long-term assets 159 352 Total assets $315,080 $303,755 Liabilities and stockholders’ equity Current liabilities: Accounts payable $3,978 $11,152 Accrued expenses and other current liabilities 15,099 14,600 Current deferred revenue 18,918 17,678 Current portion of operating lease liability 3,646 3,162 Total current liabilities 41,641 46,592 Deferred revenue, net of current 25,107 32,323 Defined benefit plan liability 2,823 2,713 Operating lease liability, net of current 40,052 42,877 Total liabilities 109,623 124,505 Commitments and contingencies Stockholders’ equity Common stock, $0.0001 par value; 500,000,000 shares authorized, 61,378,108 shares issued and 61,377,484 shares outstanding as of September 30, 2024; and 50,154,929 shares issued and 50,140,233 shares outstanding as of December 31, 2023 6 5 Additional paid-in capital 659,798 547,857 Accumulated other comprehensive loss (2,322) (2,724)Accumulated deficit (452,025) (365,888)Total stockholders’ equity 205,457 179,250 Total liabilities and stockholders’ equity $315,080 $303,755 Consolidated Statements of Operations and Comprehensive Income (Loss)(In thousands, except share and per share amounts) Three months endedSeptember 30, Nine months endedSeptember 30, 2024 2023 2024 2023 Collaboration revenue $9,216 $— $14,975 $— Operating expenses: Research and development 27,616 28,306 82,697 84,137 General and administrative 8,127 8,662 26,394 24,311 Total operating expenses 35,743 36,968 109,091 108,448 Loss from operations (26,527) (36,968) (94,116) (108,448)Other income (expense): Interest income 2,892 2,227 7,971 6,966 Foreign currency exchange gain (loss), net (153) 27 414 (151)Gain on disposal of fixed assets — — — 24 Loss on sale of marketable securities — — — (131)Total other income 2,739 2,254 8,385 6,708 Net loss before income taxes $(23,788) $(34,714) $(85,731) $(101,740)Provision for income taxes (71) (170) (406) (360)Net loss $(23,859) $(34,884) $(86,137) $(102,100)Net loss per share—basic and diluted $(0.29) $(0.70) $(1.21) $(2.06)Weighted-average number of shares outstanding used in computing net loss per common share—basic and diluted 82,011,670 49,814,903 71,173,647 49,533,143 Comprehensive loss: Net loss $(23,859) $(34,884) $(86,137) $(102,100)Provision for pension benefit obligation 37 14 107 42 Unrealized gain on available-for-sale securities 311 171 295 255 Comprehensive loss $(23,511) $(34,699) $(85,735) $(101,803) InvestorsAndrew Funderburkir@monterosatx.com MediaCory Tromblee, Scient PRmedia@monterosatx.com