Lyell Immunopharma, Inc.

Archon Biosciences came about as most startups do, the result of happenstance and good timing. Unlike many, the biotechnology company also had a Nobel Prize winner to help it along.In 2019, James Lazarovits was researching nanotechnology at a University of Toronto lab when he fell upon computational protein design, a fast-evolving field preoccupied by decades-old problems of how to predict the shapes of life's building blocks.He moved to Seattle to pursue it, joining one of the field's preeminent hubs, the University of Washington's Institute for Protein Design. At a dinner party there, he met George Ueda, who was also working at the institute in the lab of David Baker, a protein design pioneer who this year won the Nobel Prize in chemistry for his work.Baker happened to be leaving his old office at the university's health sciences building and asked Lazarovits and Ueda whether they wanted to take it over. Together, the three co-invented the technology that would become the foundation of Archon, which launched publicly Wednesday with $20 million in seed funding and another $7 million in grants.Founded last year, Archon remains secretive about which diseases it plans to target and how exactly its technology works. But broadly, it aims to build better biologic drugs via what it calls “antibody cages.“Antibodies are fantastic molecules,“ said Lazarovits, who is Archons CEO. “They didn't evolve to be drugs, but we've co-opted them to do pretty incredible, extraordinary things inside of the body.“Archon is using antibody cages to tune the proteins into specific configurations that are well-suited to reach drug targets.Permission granted by Archon BiosciencesArchons approach is to use computationally designed proteins to coerce an antibody into a precise nanostructure, giving it different distribution and binding properties without tinkering with its underlying amino acid sequence.According to Lazarovits, this simplifies the process of designing and manufacturing antibody drugs. Often when we make changes to antibodies, what made them a really good drug in the first place can sometimes be lost, he said. We view this as a bolt-on solution. How can we improve the properties of an antibody while minimizing the amount of change?Archon has hired 17 full-time employees to develop its technology, he said. With its financial runway stretching into 2026, Archon plans to select a lead program and, eventually, raise another round of private investment to fund the start of a clinical trial.The seed financing was led by Madrona Ventures and included six other investors, among them Alexandria Venture Investments.For Baker, Archon adds to a list of more than 20 companies he has helped found, including Sana Biotechnology, Lyell Immunopharmaand Xaira Therapeutics. '

Strengthens Lyell’s clinical pipeline with the addition of IMPT-314, a dual-targeting CD19/CD20 CAR T-cell product candidate Data from ImmPACT’s multi-center Phase 1-2 clinical trial of IMPT-314 in patients with large B-cell lymphoma treated in the 3rd line CAR-naïve setting to be presented at a major medical conference later this year; initiation of a pivotal trial for IMPT-314 expected in 2025 Lyell has prioritized its pipeline to focus on next-generation CAR T-cell therapies, including IMPT-314 and LYL119, and is discontinuing development of LYL797, LYL845 and earlier-stage TIL programs Cash runway following the close of the transaction is expected to fund operations into 2027, through important clinical milestones for each pipeline program Lyell will host an investor webcast at 4:30 PM ET today Oct. 24, 2024 -- Lyell Immunopharma, Inc. (Nasdaq: LYEL) announced today that it has entered into a definitive agreement to acquire ImmPACT Bio USA Inc. (“ImmPACT”), a privately-owned clinical-stage biotechnology company. ImmPACT’s lead program, IMPT-314, is a CD19/20-targeting chimeric antigen receptor (CAR) T-cell product candidate that Lyell will continue to develop for hematologic malignancies, including large B-cell lymphoma. IMPT-314 was designed to outperform the efficacy of approved CD19 CAR T-cell therapies via a dual-targeting CAR T-cell design and to improve CAR T-cell persistence by enriching for naïve and central memory T cells during manufacturing. The acquisition of ImmPACT is expected to significantly strengthen Lyell’s clinical-stage pipeline of next- generation CAR T-cell therapies and complement its suite of proprietary technologies designed to generate longer-lasting, functional T cells to achieve more durable outcomes for patients with solid tumors and hematologic malignancies. “Lyell’s vision is to bring meaningful and durable clinical benefit to patients suffering from cancer with our next-generation cell therapies,” stated Lynn Seely, M.D., Lyell’s President and Chief Executive Officer. “The emerging data from ImmPACT’s ongoing Phase 1-2 trial and the Phase 1 clinical data from a published UCLA-sponsored trial suggest the potential of IMPT-314 to have improved complete response rates and duration of response compared to the approved CD19 CAR T-cell therapies in CAR-naïve patients with aggressive B-cell lymphoma. Since licensing this product candidate from UCLA, the team at ImmPACT has made impressive progress in the multi-center IMPT-314 Phase 1-2 clinical program. We look forward to presenting initial data from this program at a major medical conference later this year and initiating a pivotal trial for IMPT-314 in 2025.” “I am incredibly proud of the ImmPACT team and all of their accomplishments in developing next-generation CAR T-cell therapies,” stated Sumant Ramachandra, M.D., Ph.D., Chief Executive Officer of ImmPACT. “This transaction validates our novel science and enhances the potential for this therapy to make a meaningful impact on patients' lives. I am confident that in Lyell, we have found a team that shares our passion for advancing novel science to benefit patients.” ImmPACT licensed its dual-targeting CD19/CD20 CAR T-cell product candidate from the University of California, Los Angeles (UCLA). Phase 1 data in 13 patients with relapsed/refractory (R/R) aggressive non-Hodgkin lymphoma treated in a UCLA-sponsored clinical trial were presented at the 2024 AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy. CAR T-cell naïve patients with R/R diffuse large B-cell lymphoma or primary mediastinal B-cell lymphoma after at least two lines of therapy or mantle cell lymphoma, follicular lymphoma or chronic lymphocytic leukemia/small lymphocytic lymphoma after at least three lines of therapy were evaluated. Autologous T cells were obtained and enriched for CD14-/CD25-/CD62L+ naïve or memory T cells. Twelve out of 13 patients achieved a complete or partial response (92% objective response rate), with ten achieving a confirmed complete response (CR) (77% CR rate). The median progression-free survival was 50.1 months, and median overall survival was not reached with a median follow up of 32 months (range: 5.7 – not estimable). A favorable safety profile was observed. The ongoing Phase 1-2 clinical trial initiated by ImmPACT is a multi-center, open-label clinical trial designed to evaluate the tolerability and clinical benefit of IMPT-314 in patients with R/R aggressive B-cell lymphoma and determine a recommended Phase 2 dose. Initial Phase 1-2 clinical data evaluating IMPT-314 primarily in patients who have received at least two prior lines of therapy for large B-cell lymphoma will be presented at a major medical conference this year. IMPT-314 has received Fast Track Designation from the U.S. Food and Drug Administration for the treatment of R/R aggressive B-cell lymphoma. Lyell expects to initiate a pivotal trial in 2025 for IMPT-314 in patients in the 3rd line setting who have not yet been exposed to CAR T-cell therapy. In connection with the acquisition, Lyell has prioritized its pipeline to focus resources on its most differentiated CAR T-cell clinical programs, including IMPT-314 following the close of the acquisition and LYL119. The enhanced anti-exhaustion technology incorporated into LYL119, including c-Jun overexpression, NR4A3 knockout, Epi-R and Stim R, has the potential to achieve improved efficacy at lower cell doses with an acceptable safety profile. In a validated in vivo preclinical model of non-small cell lung cancer, LYL119 achieved tumor control at a 10-fold lower cell dose than LYL797 with more gradual cell expansion to peak, and a substantial increase in the duration of cell killing demonstrated by a repetitive tumor cell killing assay in vitro. Lyell is discontinuing development of LYL797, its ROR1-targeted CAR T-cell product candidate to focus on the Phase 1 clinical trial of its next-generation ROR1-targeted CAR T-cell product candidate LYL119, which is expected to initiate enrollment of patients with platinum-resistant ovarian cancer or relapsed/refractory endometrial cancer this year or early next year. The LYL845 tumor-infiltrating lymphocyte (TIL) program is also being discontinued as the clinical data in patients with advanced melanoma did not meet our rigorous pre-determined criteria for continued development. Its next-generation TIL and rejuvenation programs that are in preclinical development will also be discontinued. Following the close of the transaction, Lyell expects its cash balance will fund operations into 2027, through important clinical milestones for each pipeline program, including initiation of a pivotal trial for IMPT-314, which is expected to start in 2025. Upon closing, Lyell will acquire worldwide rights to ImmPACT’s pipeline, including the next- generation bispecific CD19/CD20 autologous CAR T-cell therapy, currently in clinical development for B-cell lymphoma and autoimmune diseases, and an activating TGF-beta Claudin 18.2 CAR T-cell candidate, which is in preclinical development. Lyell will prioritize the development of IMPT-314 for patients with B-cell lymphoma. Deal terms include upfront consideration payable upon closing the potential transaction of $30 million in cash, subject to certain adjustments, and 37.5 million shares of Lyell common stock. ImmPACT shareholders will also be eligible to receive contingent consideration consisting of 12.5 million shares of Lyell common stock that may be earned upon the achievement of a value-enhancing clinical milestone and a low single-digit royalty on future net sales of the dual-targeting CD19/20 CAR T-cell product in the United States. The proposed transaction, which has been unanimously approved by the Boards of Directors of both companies, is expected to close in the fourth quarter of 2024. The closing of the proposed transaction is subject to expiration of the Hart-Scott-Rodino antitrust waiting period and the satisfaction of other customary closing conditions. Goldman Sachs & Co LLC is acting as sole financial advisor to Lyell in this transaction and Skadden, Arps, Slate, Meagher & Flom LLP is acting as its legal advisor. Cooley LLP is acting as ImmPACT’s legal advisor. Lyell’s management will host an investor conference call and Webcast beginning at 4:30 pm ET today. The Webcast can be accessed here. A replay of the event and presentation materials will be archived on the Investor page of the Lyell Website following the end of the event. Lyell is a clinical-stage company advancing a pipeline of next-generation CAR T-cell therapies for patients with solid tumors or hematologic malignancies. Lyell’s product candidates are enhanced with novel technology designed to generate T cells that resist exhaustion and have qualities of durable stemness in order to drive durable tumor cytotoxicity and achieve consistent and long-lasting clinical response. Lyell is based in South San Francisco, California with facilities in Seattle and Bothell, Washington. To learn more, please visit www.lyell.com. The content above comes from the network. if any infringement, please contact us to modify.

ROR1 CAR-T细胞疗法LYL797，在报告了临床死亡事件后，研发公司Lyell Immunopharma努力挣扎了4个月后，最终还是宣布停止对其的开发。 又一领先的ROR1 CAR-T管线停止，预示着ROR1靶点的不详。 患者死亡事件 2024年6月，Lyell报告了LYL797在三阴乳腺癌（TNBC）的I期临床中发生了一例死亡事件。 延伸阅读：实体瘤CAR-T患者死亡，股价跌去36% LYL797是一款基于Lyell公司专有的Gen-R技术平台开发的ROR1靶向CAR-T细胞，经过体外重编程使T细胞过表达蛋白质c-JUN，从而实现延缓衰竭并保持抗肿瘤功能。 在一项针对三阴乳腺癌的I期临床中，一名患者在第41天出现5级呼吸衰竭后死亡。此外，22%的患者中出现肺炎相关的剂量限制毒性，最常见的严重程度为3级或更高。 出现死亡事件的可能原因是ROR1靶点。 虽然ROR1在正常的肺部细胞中几乎不表达，但是在一些肺癌中呈现出异常高表达，而考虑到乳腺癌的特殊位置，一些患者实际上已经出现了乳腺癌的肺转移情况，这也使得一些患者出现肺部受累的情况。 LYL797挣扎无效 实际上，LYL797的这例死亡事件并没有引起美国FDA的警惕，临床并未暂停。Lyell公司仅是对临床进行了调整。 Lyell公司在2024年8月发布的第二季度财报中，还报告了LYL797的临床开发计划，包括针对三阴性乳腺癌（TNBC）或非小细胞肺癌（NSCLC）的临床继续进行，扩大标签至卵巢癌和子宫内膜癌，以及下半年提交针对多发性骨髓瘤和慢性淋巴细胞白血病的第二个IND。 很明显，死亡事件一开始并未打击到Lyell公司对于LYL797的信心。同时，该公司以TNBC研究的最高剂量队列中，40%的客观缓解率和60%的临床获益率，作为宣传的主要数据。 然后，期间不知道发生了什么，在距第二季度财报发布2个月多后，Lyell公司突然宣布要停止对LYL797的开发工作。 Lyell公司的首席执行官Lynn Seely在电话会议上，表明LYL797遇到了安全问题，并且没有“足够广泛的治疗窗口”。 另外，同时被放弃的还包括LYL845在内的TIL项目，停止LYL845的原因很明确，因为临床数据不符合持续开发的预期标准，导致其他TIL项目也一同被放弃了。 仍然死磕ROR1 小编猜测，LYL797的安全问题主要还是归因于，ROR1靶点比较难把控。 无独有偶，另一家ROR1开发公司Oncternal也报告了ROR1 CAR-T（ONCT-808）临床发生了死亡案例，同时预期ONCT-808治疗会发生不良事件。ONCT-808的临床已经停止，同时该公司现在正在考虑战略代替方案....... 延伸阅读： 2个核心管线同时暴雷，首席医疗官出走 ROR1 CAR-T：临床数据出炉 但是，ROR1开发难度高也不好使。在LYL797失败后，Lyell公司仍然在死磕ROR1 CAR-T。 因为Lyell公司在管线重组以后，新的核心管线赫然是以LYL797为基础开发的下一代的ROR1 CAR-T疗法LYL119。Lyell公司表示，LYL119能够在更低剂量下产生更好的疗效，并具有更广泛的治疗窗口。 ROR1 CAR-T的下一代产品LYL119在c-JUN过表达的基础上还增添了多项技术，例如敲除NR4A3基因进一步减少T细胞凋亡和衰竭，采用Stim-R™技术来强化信号转导，采用该公司的Epi-R™技术生产具有持久干细胞特性的T细胞。 最后在本身的技术之外，还结合了来自哈佛大学Wyss研究所的T细胞增强支架技术来强化临床获益，这种技术提供了一种能够模拟人体淋巴系统的支架材料，这种支架材料可以携带激活CAR-T需要的IL-2以及CAR-T上的CD3受体和CD28受体。 目前，该公司已经完成了LYL119的IND提交，预计将于今年或明年初启动针对铂类耐药卵巢癌或复发/难治性子宫内膜癌的1期临床。 CD19/CD20 CAR-T也挺香 另一个好消息是，Lyell公司也没有头铁到眼里只有ROR1。 在自身管线或是因为安全性、或是因为疗效被放弃，只剩下一根独苗LYL119后，Lyell公司将目光放到了外部，瞄准了一家小型CAR-T研发公司ImmPACT Bio，并以3000万美元现金和3750万股Lyell普通股对ImmPACT Bio进行收购。 被Lyell公司看中的是ImmPACT管线内一款CD19/CD20 CAR-T细胞候选产品IMPT-314。ImmPACT的其他管线（包括Claudin 18.2 CAR-T）优先级并不高。 IMPT-314是一款自体的、CD19/CD20双特异性CAR-T细胞，被开发用于治疗B细胞淋巴瘤和自身免疫性疾病。Lyell公司将优先开发IMPT-314的B细胞淋巴瘤适应症。 IMPT-314目前正在进行临床研究，预计将于今年晚些时候发布IMPT-314针对大B细胞淋巴瘤的临床数据。IMPT-314的关键试验预计将于2025年启动。 根据Lyell公司第二季度财报，截止2024年6月30日，拥有现金、现金等价物和有价证券4.911亿美元。 尽管收购ImmPACT需要花费一定现金，但是Lyell公司删减了管线的开发工作，仅剩2条临床管线，这使得Lyell公司的现金流支持公司运营至2027年。 小结 虽然但是，Lyell公司一口气停了好几个内部管线的开发，包括LYL797和全部的TIL项目，还是令人对其的研发实力产生质疑。 这一点也反应到了股市上，Lyell公司的股票持续下跌，截止本文发布前，已经跌至1美元以下，报9.27美分/股。 参考资料： 1.https://ir.lyell.com/news-releases/news-release-details/lyell-immunopharma-acquire-immpact-bio-and-prioritizes-its 2.https://ir.lyell.com/news-releases/news-release-details/lyell-immunopharma-reports-business-highlights-and-financial-5 本周好文推荐 如需转载请联系佰傲谷并在醒目位置注明出处 · · · · · · · ·