Trametinib dimethyl sulfoxide

Potentially best-in-class RAS-targeting franchise advancing with both ERAS-0015 and ERAS-4001 expected to enter the clinic in 2025 Ongoing Phase 3 SEACRAFT-2 registrational trial progressing well with Stage 1 randomized data expected in H2 2025 Robust balance sheet with cash, cash equivalents, and marketable securities of $440 million as of December 31, 2024 is expected to fund operations into H2 2027 SAN DIEGO, March 20, 2025 (GLOBE NEWSWIRE) -- Erasca, Inc. (Nasdaq: ERAS), a clinical-stage precision oncology company singularly focused on discovering, developing, and commercializing therapies for patients with RAS/MAPK pathway-driven cancers, today provided business updates and reported financial results for the fiscal quarter and full year ended December 31, 2024. “In 2024, we prepared our RAS-targeting franchise to enter the clinic and further advanced our registrational program for naporafenib. The high enthusiasm for our RAS-targeting franchise is encouraging, particularly as our potential best-in-class pan-RAS molecular glue ERAS-0015 and our potential first-in-class pan-KRAS inhibitor ERAS-4001 approach the clinic. The high prevalence of KRAS alterations and the significant unmet need among these patients offer substantial opportunities for both candidates in key indications, namely colorectal, lung, pancreatic, and other solid tumor cancers,” said Jonathan E. Lim, M.D., Erasca’s chairman, CEO, and co-founder. “The SEACRAFT-2 trial is progressing well, and with FDA Fast Track Designation (FTD) granted in NRASm melanoma, this combination has the potential to be first-to-market in this area of high unmet need with no approved targeted therapies.” Dr. Lim added, “We have an exciting year ahead focused on shutting down RAS and expect multiple value drivers in 2025 and beyond. In the second half of 2025, we expect Stage 1 randomized data from SEACRAFT-2 in patients with NRASm melanoma. For our RAS-targeting franchise, we expect investigational new drug (IND) submissions for ERAS-0015 in mid-second quarter and for ERAS-4001 in the second quarter of 2025. We continue to be well capitalized and capital efficient and have revised our cash runway guidance from the first half of 2027 to the second half of 2027.” Research and Development (R&D) Highlights RAS-Targeting Franchise Announced Progress Across RAS-Targeting Franchise: In October 2024, Erasca presented a program update for the pan-RAS molecular glue ERAS-0015 and pan-KRAS inhibitor ERAS-4001 as part of a virtual investor event. The updates highlighted the rapid progress observed across both programs including in-house confirmation of potential best-in-class profiles for both agents and completion of many key activities to support IND submissions. In-Licensed Potential Best-in-Class and First-in-Class RAS-Targeting Franchise: In May 2024, Erasca announced exclusive license agreements for two preclinical RAS programs—a potential best-in-class pan-RAS molecular glue (ERAS-0015) and a potential first-in-class pan-KRAS inhibitor (ERAS-4001). ERAS-0015 and ERAS-4001 are potent, orally bioavailable molecules with complementary RAS inhibitory mechanisms. ERAS-0015 has the potential to address unmet medical needs in approximately 2.7 million patients who are diagnosed annually worldwide with RAS-mutant tumors, including the more than 2.2 million patients with KRAS-mutant tumors whom ERAS-4001 could also address. Naporafenib Program Presented Promising SEACRAFT-1 Phase 1b Data: In October 2024, Erasca announced promising initial Phase 1b data for naporafenib plus trametinib (MEKINIST®) in the melanoma cohort of SEACRAFT-1 at the 36th EORTC-NCI-AACR (ENA) Symposium on Molecular Targets and Cancer Therapeutics. Efficacy and tolerability data supported the rationale for pursuing an NRASm melanoma tissue-specific indication and reinforced the potential of the ongoing Phase 3 SEACRAFT-2 registrational trial, which was initiated in the second quarter of 2024. Analysis of Median Overall Survival (mOS) Data for Naporafenib and Trametinib: In March 2024, a pooled analysis of patients with NRASm melanoma dosed with the combination of naporafenib and trametinib at two different doses across two different trials (Phase 1b and Phase 2) showed an mOS of 13.0 and 14.1 months, respectively. The pooled dataset compared favorably relative to historical benchmarks. Corporate Highlights Extended Cash Runway into H2 2027: In 2024, Erasca raised $251 million in equity financings, including a $45 million oversubscribed private placement financing and a $184 million oversubscribed underwritten offering, both of which were led by high-quality new and existing healthcare-focused investors and both of which helped extend our anticipated cash runway into the second half of 2027. Strengthened Leadership Team and RDCAB: Erasca strengthened its leadership team and Research, Development, and Commercial Advisory Board (RDCAB) with three key appointments. Michael Humphries, Ph.D., was appointed as vice president of medical affairs, bringing to Erasca over 15 years of medical affairs, clinical development, and drug discovery experience at Array Biopharma, Bayer Oncology, ARIAD Pharmaceuticals, Takeda, AnHeart Therapeutics, and Nuvation Bio. His leadership includes three U.S. launches of next-generation tyrosine kinase inhibitors in three variants of oncogene-addicted non-small cell lung cancer (NSCLC). In his most recent role at Nuvation Bio, Dr. Humphries served as vice president head of medical affairs where he built out the medical affairs strategy, infrastructure, culture, and personnel. He earned his Ph.D. in cell and developmental biology from the University of Colorado at Denver. Yifah Yaron, M.D., Ph.D., was appointed as vice president of clinical development, bringing over 18 years of experience in clinical drug development focusing on oncology. She most recently led clinical teams at Harpoon Therapeutics (acquired by Merck), and served in clinical development roles at Cytomx Therapeutics, Exelixis, and Genentech. During her time at Exelixis, Dr. Yaron held increasing leadership responsibilities on the cabozantinib program, including serving as a member of the clinical filing team for the first indication in medullary thyroid cancer. Dr. Yaron completed an oncology fellowship at UCSF and an internal medicine residency at University of Rochester Strong Memorial Hospital. She earned her M.D. and Ph.D. degrees (Ph.D. in biological chemistry) as well as her B.S. in biology from the University of California, Los Angeles. Jean-Michel Vernier, Ph.D., was appointed as senior chemistry advisor with 25+ years of drug discovery and development experience. He currently serves as senior vice president of chemistry at Radionetics Oncology and previously served as Erasca’s vice president of chemistry. He held positions of increasing responsibilities at several companies, including Ignyta, Ardea Biosciences, Merck Research Laboratories, and SIBIA Neurosciences. Throughout his career, Dr. Vernier has led departments engaged in early-stage drug discovery programs and drug substance GMP production. He has co-authored more than 30 peer-reviewed publications and is an inventor on more than 50 U.S. patents. Dr. Vernier earned his Ph.D. in synthetic organic chemistry from the University Louis Pasteur, Strasbourg, France, and was a postdoctoral fellow at Colorado State University. Michael Humphries, Ph.D., was appointed as vice president of medical affairs, bringing to Erasca over 15 years of medical affairs, clinical development, and drug discovery experience at Array Biopharma, Bayer Oncology, ARIAD Pharmaceuticals, Takeda, AnHeart Therapeutics, and Nuvation Bio. His leadership includes three U.S. launches of next-generation tyrosine kinase inhibitors in three variants of oncogene-addicted non-small cell lung cancer (NSCLC). In his most recent role at Nuvation Bio, Dr. Humphries served as vice president head of medical affairs where he built out the medical affairs strategy, infrastructure, culture, and personnel. He earned his Ph.D. in cell and developmental biology from the University of Colorado at Denver. Yifah Yaron, M.D., Ph.D., was appointed as vice president of clinical development, bringing over 18 years of experience in clinical drug development focusing on oncology. She most recently led clinical teams at Harpoon Therapeutics (acquired by Merck), and served in clinical development roles at Cytomx Therapeutics, Exelixis, and Genentech. During her time at Exelixis, Dr. Yaron held increasing leadership responsibilities on the cabozantinib program, including serving as a member of the clinical filing team for the first indication in medullary thyroid cancer. Dr. Yaron completed an oncology fellowship at UCSF and an internal medicine residency at University of Rochester Strong Memorial Hospital. She earned her M.D. and Ph.D. degrees (Ph.D. in biological chemistry) as well as her B.S. in biology from the University of California, Los Angeles. Jean-Michel Vernier, Ph.D., was appointed as senior chemistry advisor with 25+ years of drug discovery and development experience. He currently serves as senior vice president of chemistry at Radionetics Oncology and previously served as Erasca’s vice president of chemistry. He held positions of increasing responsibilities at several companies, including Ignyta, Ardea Biosciences, Merck Research Laboratories, and SIBIA Neurosciences. Throughout his career, Dr. Vernier has led departments engaged in early-stage drug discovery programs and drug substance GMP production. He has co-authored more than 30 peer-reviewed publications and is an inventor on more than 50 U.S. patents. Dr. Vernier earned his Ph.D. in synthetic organic chemistry from the University Louis Pasteur, Strasbourg, France, and was a postdoctoral fellow at Colorado State University. Key Upcoming Milestones SEACRAFT-2: Randomized pivotal Phase 3 trial for naporafenib plus trametinib in patients with NRASm melanoma Phase 3 Stage 1 randomized dose optimization data expected in H2 2025 AURORAS-1: Phase 1 trial for ERAS-0015 (pan-RAS molecular glue) in patients with RASm solid tumors IND filing expected in mid-Q2 2025 Initial Phase 1 monotherapy data in relevant tumor types expected in 2026 BOREALIS-1: Phase 1 trial for ERAS-4001 (pan-KRAS inhibitor) in patients with KRASm solid tumors IND filing expected in Q2 2025 Initial Phase 1 monotherapy data in relevant tumor types expected in 2026 Phase 3 Stage 1 randomized dose optimization data expected in H2 2025 IND filing expected in mid-Q2 2025 Initial Phase 1 monotherapy data in relevant tumor types expected in 2026 IND filing expected in Q2 2025 Initial Phase 1 monotherapy data in relevant tumor types expected in 2026 Fourth Quarter and Full Year 2024 Financial Results Cash Position: Cash, cash equivalents, and marketable securities were $440.5 million as of December 31, 2024, compared to $322.0 million as of December 31, 2023. Research and Development (R&D) Expenses: R&D expenses were $26.1 million for the quarter ended December 31, 2024, compared to $24.8 million for the quarter ended December 31, 2023. The increase was primarily driven by increases in expenses incurred in connection with clinical trials, preclinical studies, discovery activities, and outsourced services and consulting fees. R&D expenses were $115.4 million for the full year ended December 31, 2024, compared to $103.8 million for the full year ended December 31, 2023. Erasca also recorded $22.5 million of in-process R&D expense during the year ended December 31, 2024 for upfront payments under Erasca’s ERAS-0015 and ERAS-4001 license agreements. General and Administrative (G&A) Expenses: G&A expenses were $9.6 million for the quarter ended December 31, 2024, compared to $9.1 million for the quarter ended December 31, 2023. The increase was primarily driven by an increase in personnel costs, including stock-based compensation expense. G&A expenses were $41.7 million for the full year ended December 31, 2024, compared to $37.7 million for the full year ended December 31, 2023. Net Loss: Net loss was $32.2 million for the quarter ended December 31, 2024, compared to $29.7 million for the quarter ended December 31, 2023. For the full year ended December 31, 2024, Erasca reported a net loss of $161.7 million, or $(0.69) per basic and diluted share, compared to a net loss of $125.0 million, or $(0.83) per basic and diluted share, for the full year ended December 31, 2023. About Erasca At Erasca, our name is our mission: To erase cancer. We are a clinical-stage precision oncology company singularly focused on discovering, developing, and commercializing therapies for patients with RAS/MAPK pathway-driven cancers. Our company was co-founded by leading pioneers in precision oncology and RAS targeting to create novel therapies and combination regimens designed to comprehensively shut down the RAS/MAPK pathway for the treatment of patients with cancer. We have assembled one of the deepest RAS/MAPK pathway-focused pipeline in the industry. We believe our team’s capabilities and experience, further guided by our scientific advisory board which includes the world’s leading experts in the RAS/MAPK pathway, uniquely position us to achieve our bold mission of erasing cancer. Cautionary Note Regarding Forward-Looking Statements Erasca cautions you that statements contained in this press release regarding matters that are not historical facts are forward-looking statements. The forward-looking statements are based on our current beliefs and expectations and include, but are not limited to: our expectations regarding the potential therapeutic benefits and potential patient population for each of our product candidates, including naporafenib, ERAS-0015, and ERAS-4001; the planned advancement of our development pipeline, including the anticipated timing of data readouts for the SEACRAFT-2, AURORAS-1, and BOREALIS-1 trials; the anticipated timing of the IND submissions for the AURORAS-1 and BOREALIS-1 trials; and the sufficiency of our cash, cash equivalents, and marketable securities to fund operations into the second half of 2027. Actual results may differ from those set forth in this press release due to the risks and uncertainties inherent in our business, including, without limitation: our approach to the discovery and development of product candidates based on our singular focus on shutting down the RAS/MAPK pathway, a novel and unproven approach; preliminary results of clinical trials are not necessarily indicative of final results and one or more of the clinical outcomes may materially change as patient enrollment continues, following more comprehensive reviews of the data and more patient data become available; the analysis of pooled Phase 1 and Phase 2 naporafenib plus trametinib data covers two clinical trials with different designs and inclusion criteria, which cannot be directly compared, and therefore may not be a reliable indicator of survival data; due to differences between trial designs and subject characteristics, comparing clinical data across different trials may not be a reliable indicator of such data; results from preclinical studies or early clinical trials not necessarily being predictive of future results; we only have one product candidate in clinical development and all of our other development efforts are in the preclinical or development stage; our SEACRAFT trials may not support the registration of naporafenib; our assumptions around which programs may have a higher probability of success may not be accurate, and we may expend our limited resources to pursue a particular product candidate and/or indication and fail to capitalize on product candidates or indications with greater development or commercial potential; potential delays in the commencement, enrollment, data readout, and completion of clinical trials and preclinical studies; our dependence on third parties in connection with manufacturing, research, and preclinical and clinical testing; unexpected adverse side effects or inadequate efficacy of our product candidates that may limit their development, regulatory approval, and/or commercialization, or may result in recalls or product liability claims; unfavorable results from preclinical studies or clinical trials; the inability to realize any benefits from our current licenses, acquisitions, and collaborations, and any future licenses, acquisitions, or collaborations, and our ability to fulfill our obligations under such arrangements; regulatory developments in the United States and foreign countries; later developments with the FDA or EU health authorities may be inconsistent with the feedback received to date regarding our development plans and trial designs; Fast Track Designation may not lead to a faster development or regulatory review or approval process, and does not increase the likelihood that our product candidates will receive marketing approval; our ability to obtain and maintain intellectual property protection for our product candidates and maintain our rights under intellectual property licenses; our ability to fund our operating plans with our current cash, cash equivalents, and marketable securities; and other risks described in our prior filings with the Securities and Exchange Commission (SEC), including under the heading “Risk Factors” in our annual report on Form 10-K for the year ended December 31, 2024, and any subsequent filings with the SEC. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and we undertake no obligation to update such statements to reflect events that occur or circumstances that exist after the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement, which is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. MEKINIST® is a registered trademark owned by or licensed to Novartis AG, its subsidiaries, or affiliates. Contact: Joyce Allaire LifeSci Advisors, LLC jallaire@lifesciadvisors.com Source: Erasca, Inc. Source: Erasca, Inc.

-01- 引言 在细胞的生命活动中，激酶扮演着至关重要的角色，它们如同细胞内的“信号指挥官”，通过催化底物的磷酸化来调控细胞的增殖、分化、迁移和凋亡。然而，一旦激酶的活性失控，就可能引发癌症、自身免疫病等多种疾病。自2001年首个激酶抑制剂伊马替尼（Imatinib）的问世，激酶抑制剂已成为精准医疗领域的一颗璀璨明星，这类药物已彻底改变了多种疾病的治疗格局。 -02- 激酶抑制剂的发展历史 激酶抑制剂的研发始于20世纪80年代，当时科学家们开始认识到激酶在细胞信号传导中的关键作用。然而，由于激酶的ATP结合位点高度保守，且细胞内ATP浓度极高，早期的激酶抑制剂往往缺乏选择性，导致副作用较大。 直到1995年，法舒地尔（Fasudil）在日本获批用于治疗脑血管痉挛，成为首个上市的激酶抑制剂。紧接着，1999年，西罗莫司（Sirolimus）在美国获批，用于器官移植后的免疫抑制，标志着变构激酶抑制剂的诞生。 2001年，伊马替尼（Imatinib）的获批无疑是激酶抑制剂发展史上的里程碑。这款药物通过靶向BCR-ABL融合蛋白，成功治疗了慢性髓性白血病（CML），并将CML患者的10年生存率从不到20%提升至80%以上。伊马替尼的成功不仅证明了激酶作为药物靶点的可行性，也开启了精准医疗的新篇章。 截至2024年，全球已有82种小分子激酶抑制剂获FDA批准，覆盖50种激酶靶点，其中约70%用于癌症治疗。然而，人类激酶组包含约600种成员，目前仅开发了不足10%，大量靶点仍待探索。 -03- 激酶抑制剂的类型 激酶抑制剂根据其作用机制和结合位点，可以分为几大类： 1. ATP竞争性抑制剂 这类抑制剂通过与激酶的ATP结合位点竞争性结合，从而抑制激酶的活性。伊马替尼就是这类抑制剂的代表。ATP竞争性抑制剂的优势在于其广泛的适用性，但由于激酶的ATP结合位点高度保守，这类抑制剂往往缺乏选择性，容易导致副作用。 2. 变构抑制剂 变构抑制剂通过与激酶的变构位点结合，改变激酶的构象，从而抑制其活性。这类抑制剂通常具有更高的选择性，副作用较小。例如，Asciminib就是一款针对ABL激酶的变构抑制剂，其选择性优于伊马替尼。 3. 共价抑制剂 共价抑制剂通过与激酶的活性位点形成共价键，从而实现对激酶的不可逆抑制。这类抑制剂通常具有较高的效力和选择性。例如，奥希替尼（Osimertinib）就是一款针对EGFR突变的共价抑制剂，其疗效显著优于传统的ATP竞争性抑制剂。 4. 双功能分子 双功能分子（如PROTACs）通过同时结合激酶和E3泛素连接酶，诱导激酶的泛素化和降解。这类分子不仅具有抑制激酶活性的作用，还能彻底清除激酶蛋白，从而避免耐药性的产生。PROTACs作为一种新兴的激酶抑制剂类型，具有巨大的潜力。 -04- 激酶抑制剂药物开发现状：从肿瘤到多领域拓展 截至2024年，FDA已批准82种小分子激酶抑制剂（SMKI），其中约70%用于癌症治疗，覆盖50种激酶靶点。典型药物包括针对EGFR突变的奥希替尼（肺癌）、BCR-Abl的泊那替尼（白血病）及FGFR家族的厄达替尼（尿路上皮癌）。其中以拉罗替尼（larotrectinib）为代表的NTRK融合抑制剂，开创了“基于生物标志物而非肿瘤类型”的跨癌种治疗模式。此外，针对脑转移的CNS穿透剂（如劳拉替尼lorlatinib）、多靶点联合疗法（如达拉非尼+曲美替尼）也成主流趋势。 在非肿瘤领域，BTK抑制剂伊布替尼用于多发性硬化症，LRRK2抑制剂探索帕金森病治疗，JAK抑制剂治疗类风湿性关节炎，显示激酶抑制剂在自身免疫病、神经退行性疾病中的潜力。-05- 激酶抑制剂开发的挑战 尽管激酶抑制剂在药物开发中取得了显著进展，但仍面临一些挑战： 1. 耐药性问题：肿瘤细胞通过多种机制产生耐药性，如激酶突变、旁路激活等。这要求科学家们不断开发新的抑制剂和联合治疗方案来克服耐药性。 2. 治疗指数问题：某些激酶抑制剂在抑制肿瘤细胞的同时，也可能对正常细胞产生毒性。提高治疗指数（即药物的有效剂量与毒性剂量之比）是激酶抑制剂开发中的一个重要挑战。 3. 个体化治疗：不同患者的基因型和疾病特征存在差异，需要个性化的治疗方案。如何根据患者的具体情况制定合适的治疗方案是激酶抑制剂开发中的一个重要问题。 4. 成本与可及性：激酶抑制剂的研发和生产成本较高，导致其价格昂贵，影响了患者的可及性。未来AI的辅助设计将可能大大提高激酶抑制剂研发周期。 -06- 结语：迈向未来的激酶疗法 激酶抑制剂的发展印证了“从靶点到临床”的转化医学力量。激酶抑制剂作为精准医疗的重要工具，已经在肿瘤治疗中发挥了重要作用。随着变构抑制剂、PROTAC、多组学整合等技术的成熟，下一代药物将具备更高选择性、更低毒性和抗耐药性。总之，激酶抑制剂具有巨大的发展潜力和广阔的应用前景。我们有理由相信，在不久的将来，激酶抑制剂将为更多患者带来福音，为人类的健康事业做出更大的贡献。 参考文献： 1.Tumour-agnostic kinase inhibitors. Nat Rev Drug Discov.2025 Mar 6 2. Trends in kinase drug discovery: targets, indications and inhibitor design. Nat Rev Drug Discov.2021 Nov;20(11):839-861 3. Kinase drug discovery 20 years after imatinib: progress and future directions. Nat Rev Drug Discov.2021 Jul;20(7):551-569 公众号内回复“ADC”或扫描下方图片中的二维码免费下载《抗体偶联药物：从基础到临床》的PDF格式电子书！ 公众号已建立“小药说药专业交流群”微信行业交流群以及读者交流群，扫描下方小编二维码加入，入行业群请主动告知姓名、工作单位和职务。