MRT-2359

近年来，靶向蛋白质降解剂（TPD）逐渐走进人们的视野，以PROTAC、分子胶为代表的靶向蛋白降解技术已发展为小分子药物的重要模式。 从2019年首个PROTAC分子（ARV-110）进入临床开始，层出不穷的蛋白降解剂相继进入临床研究阶段。受益于独特的作用机制，蛋白降解剂不仅能靶向以往难成药的靶点，还为耐药患者提供了可选治疗方案。 图1. 蛋白降解剂发展时间线[1] 根据医药魔方NextPharma®数据库，蛋白降解剂早期研发主要围绕AR、ER、BTK等靶点。如今，蛋白降解领域迎来了新的发展阶段，研究人员正将目光投向更多新颖的靶标领域。 越来越多的蛋白降解剂管线显示，传统上难以成药的靶标（如IKZF1/3、GSPT1、VAV1、WIZ、BCL6等）正变得越来越容易实现（表1）。这一转变标志着靶向蛋白质降解技术的应用范围正在不断扩大，为药物研发带来了新的机遇和挑战。 表1. 靶向蛋白降解领域的靶点[2] 分子胶的新发现 科学家通过对来那度胺（FDA批准的多发性骨髓瘤药物）及其相关免疫调节药物（IMiDs）的作用机制进行深入研究，发现了这些药物能够结合并重塑E3泛素连接酶CRBN，进而促进转录因子IKZF1和IKZF3（IKAROS家族锌指转录因子1/3）的泛素化。研究人员进一步认识到，其他分子胶可能也具备重塑CRBN的潜力，从而能够靶向更多蛋白质。 尽管如此，早期进入临床的项目仍然集中在来那度胺所降解的靶点上。例如，Celgene（2019年被BMS收购）基于来那度胺类似物发现了CC-92480（又名mezigdomide），并对其进行优化，以降解IKZF1和IKZF3。目前，该药物正处于多发性骨髓瘤的III期临床开发阶段。此外，激酶CK1α作为来那度胺的另一个降解靶点，也成为了早期开发的重点。 GSPT1（G1 to S phase transition 1）是一种翻译终止因子，通过与eRF1结合识别终止密码子，迫使蛋白质在翻译后与核糖体分离。GSPT1的下调可导致多种肿瘤细胞中关键蛋白的异常表达，抑制肿瘤细胞增殖或诱导其凋亡。BMS在2016年首次将GSPT1降解剂CC-90009推进到临床阶段，但后来由于未公开的原因终止了该项目。 GSPT1的降解可能会关闭整体蛋白质翻译，并可能引发许多不良事件。为了提高GSPT1降解的有效性和耐受性，BMS转向了抗体-分子胶偶联物策略。BMS-986497分子将GSPT1降解分子胶和CD33靶向抗体结合，这样能更有效地将降解剂递送到癌细胞。 今年7月，诺华在Science杂志发表论文，他们发现了一种基于CRBN的、能够靶向转录因子WIZ的分子胶降解剂。该分子胶可以提高小鼠和灵长类动物体内的胎儿血红蛋白（fetal hemoglobin，HbF）水平。这一发现表明，分子胶有望为开发治疗镰状细胞病（SCD）的新药铺平道路。 新靶点，新征程 Monte Rosa是开发靶向GSPT1分子胶的先驱之一，他们研发的MRT-2359临床表现出色，在MYC驱动的实体瘤患者中具有良好的治疗指数和可耐受的安全性。随着其降解平台的建立，Monte Rosa发现了更多的靶点，VAV1就是其中之一。Monte Rosa首席执行官Markus Warmuth表示：“我确信，在过去10-20年里，大型制药公司的每个免疫学团队都曾关注过VAV1这一靶点。” VAV1是一种鸟嘌呤核苷酸交换因子（GEF），与B细胞和T细胞的信号传导密切相关。Monte Rosa研发的VAV1降解剂MRT-6160在自身免疫性疾病动物模型中显示出临床前疗效，效果与标准治疗（JAK抑制剂和S1P调节剂）相当。目前，这种降解剂已进入临床I期试验，并将在自身免疫性疾病中进一步的试验。 此外，转录因子IKZF1和IKZF3是经典的CRBN的新底物。研究人员指出，数百种转录因子含有G-loop的C2H2锌指结构（包括IKZF2和WIZ），这为分子胶降解剂提供了更多潜在靶点。然而，像GSPT1和CK1α这样的非转录因子蛋白中的CRBN新底物，也携带G-loop降解结构域，使它们也处于IMiDs的作用范围内。 目前，大多数分子胶是偶然发现的。人体内有600多种E3连接酶，但目前的分子胶大多是基于CRBN，所以开发可招募除CRBN外的其他E3连接酶的分子胶，成为理性设计的重要策略。 SEED Therapeutics正在研发一种利用DCAF15连接酶降解剪接因子RBM39（一种调节mRNA前体剪接的蛋白质）的分子胶降解剂，该公司的ST-00937分子能够通过重塑DCAF15来泛素化RBM39，目前处于临床前阶段，预计明年进入临床阶段。除ST-00937外，SEED Therapeutics还有近10款在研药物，它们都不依赖于常用的CRBN和VHL（另一种常用的E3泛素连接酶）。 PROTAC的探索之路 异双功能降解剂（heterobifunctional）是一种“哑铃状”分子，具有独特的结构：一端结合目标蛋白（POI），另一端则与E3泛素连接酶相互作用。首批进入临床的蛋白降解剂主要集中在已有上市药物的靶点。 然而，Kymera Therapeutics采取了不同的策略，专注于开发哪些尚未有上市药物的靶点。Kymera Therapeutics的首个进入临床的PROTAC项目靶向IRAK4，这是一个在调节IL-1受体和Toll样受体（TLR）信号通路方面具有重要的作用的蛋白。由于IRAK4的活性既包括酶活性，也包括作为骨架蛋白的功能，因此蛋白降解剂可能比酶活性抑制剂具有更好的效果。Kymera Therapeutics的潜在first-in-class蛋白降解剂KT-474目前处于IIb期试验中，它是首个进入非肿瘤学适应症领域中，进入临床开发阶段的PROTAC分子。 Kymera Therapeutics的下一个临床候选药物KT-621是一种靶向STAT6的PROTAC分子，能够用于特应性皮炎（AD）、哮喘以及慢性阻塞性肺病等疾病。今年10月，Kymera宣布其KT-621的IND已获FDA批准，预计将在不久后在健康志愿者中开展I期试验。 BCL6是一种转录抑制因子，它通过BCL6的BTB结构域招募辅助抑制因子，调节B淋巴细胞的分化，并在生发中心（GCs）的形成中发挥作用。由于BCL6在转录抑制因子复合体中的不受调控的表达和支架作用，使其成为一个理想的PROTAC靶点。 Arvinas公司研发的ARV-393是一种靶向BCL6蛋白的PROTAC药物，目前正在进行临床I期研究。初步研究显示，ARV-393在体内外均能显著降解BCL6，并在多种肿瘤异种移植模型中表现出良好的肿瘤生长抑制（TGI）效果。BMS-986458是由BMS研发的一种BCL6降解剂，目前也处于临床I期，用于治疗非霍奇金淋巴瘤。 结语 从最初偶然发现的沙利度胺，到如今几百条蛋白降解剂管线；从开发已有上市药物的成熟靶点，到探索新一代靶点；从肿瘤领域，到神经退行性疾病、自身免疫性疾病、炎症性疾病等领域……蛋白降解的应用正被不断拓宽，随着更多新靶点的探索和新药物的开发，蛋白降解技术有望在未来实现更多的突破和创新。 参考资料： [1]Brandon Dale et al. Advancing targeted protein degradation for cancer therapy. Nature Reviews Cancer（2021） https://www.nature.com/articles/s41568-021-00365-x [2]Asher Mullard. Protein degraders push into novel target space. Nature Reviews Drug Discovery（2024） https://www.nature.com/articles/d41573-024-00170-9 Copyright © 2024 PHARMCUBE. All Rights Reserved. 欢迎转发分享及合理引用，引用时请在显要位置标明文章来源；如需转载，请给微信公众号后台留言或发送消息，并注明公众号名称及ID。 免责申明：本微信文章中的信息仅供一般参考之用，不可直接作为决策内容，医药魔方不对任何主体因使用本文内容而导致的任何损失承担责任。

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