Prostate specific membrane antigen tumour activated T-cell engager therapy (Janux Therapeutics/Merck & Co)

SAN DIEGO--( BUSINESS WIRE )-- Janux Therapeutics, Inc. (Nasdaq: JANX) (Janux), a clinical-stage biopharmaceutical company developing a broad pipeline of novel immunotherapies by applying its proprietary technology to its Tumor Activated T Cell Engager (TRACTr) and Tumor Activated Immunomodulator (TRACIr) platforms, today reported financial results for the second quarter ended June 30, 2024, and provided a business update. “ We are pleased with the progress we have made this quarter, particularly with the ongoing enrollment of our PSMA-TRACTr (JANX007) and EGFR-TRACTr (JANX008) clinical trials. These advancements, along with the $7.5 million milestone payment from Merck, underscore the potential of our TRACTr and TRACIr platforms to develop transformative cancer therapies,” said David Campbell, Ph.D., President and CEO of Janux Therapeutics. “ We are also excited to welcome Eric Dobmeier and Natasha Hernday to our Board of Directors. Their extensive experience and proven leadership in the biopharmaceutical industry will be invaluable as we continue to advance our pipeline and strategic goals.” RECENT BUSINESS HIGHLIGHTS AND FUTURE MILESTONES: The company continues to enroll patients in the first-in-human Phase 1 clinical trial of JANX007 in mCRPC (NCT05519449) and JANX008 in advanced or metastatic solid tumors (NCT05783622). Janux anticipates providing an update on JANX007 data and doses selected for expansion cohorts in the second half of 2024. An update on JANX008 data is expected in 2025. Board strengthened with key appointments. Eric Dobmeier, J.D., has more than 20 years of experience in the biotechnology industry as both an executive and board member. Most recently, he was the President and CEO of Chinook Therapeutics, where he led the company through multiple strategic growth initiatives ultimately leading to its acquisition by Novartis in 2023 for $3.5 billion. Prior to Chinook, Mr. Dobmeier spent 16 years in a series of positions of increasing responsibility at Seattle Genetics, including Chief Operating Officer, during the company’s growth from 60 to 1,200 employees, from a market cap of $150 million to over $8 billion and through its transition to a commercial company with FDA approval and launch of Adcetris, a novel lymphoma drug. During his career, Mr. Dobmeier has been directly involved in raising more than $2 billion in equity capital and led negotiation of many corporate alliances with leading biotechnology and pharmaceutical companies. He is currently a venture partner at Samsara Biocapital and serves on the boards of directors of Structure Therapeutics and Abdera Therapeutics. Natasha Hernday previously served as Chief Business Officer and a member of the Executive Committee at Seagen Inc. (formerly Seattle Genetics) and was pivotal in driving business development, including alliance management, strategic partnerships, mergers, and acquisitions. Ms. Hernday led the acquisition of Cascadian Therapeutics in 2018 for approximately $614 million and a global strategic oncology collaboration with Merck in 2020 for over $1.5 billion in upfront cash and equity. Ms. Hernday’s strategic insight and successful track record in transactions culminated in Seagen's acquisition by Pfizer in 2023 for $43 billion. Prior to her role at Seagen, Ms. Hernday spent 16 years at Amgen, where she began her career in discovery research, then held various leadership positions in corporate development and corporate strategy, including as Director, Mergers & Acquisitions and as Director, Out-Partnering, playing a key role in numerous high-value transactions. Additionally, Ms. Hernday served on the Board of Alpine Immune Sciences, which was acquired by Vertex Pharmaceuticals in 2024 for $4.9 billion. Janux received a $7.5 million payment from Merck triggered by the achievement of an undisclosed development milestone for the first collaboration target under the companies’ 2020 Research Collaboration and Exclusive License Agreement. SECOND QUARTER 2024 FINANCIAL RESULTS: Cash and cash equivalents and short-term investments: As of June 30, 2024, Janux reported cash and cash equivalents and short-term investments of $646.3 million compared to $344.0 million at December 31, 2023. Research and development expenses: Research and development expenses for the quarter ended June 30, 2024, were $14.9 million compared to $14.9 million for the comparable period in 2023. General and administrative expenses: General and administrative expenses for the quarter ended June 30, 2024, were $7.8 million compared to $6.9 million for the comparable period in 2023. Net loss: For the quarter ended June 30, 2024, Janux reported a net loss of $6.0 million compared to a net loss of $17.5 million for the comparable period in 2023. Janux’s TRACTr and TRACIr Pipeline Janux’s first clinical candidate, JANX007, is a TRACTr that targets PSMA and is being investigated in a Phase 1 clinical trial in adult subjects with metastatic castration-resistant prostate cancer (mCRPC). Janux’s second clinical candidate, JANX008, is a TRACTr that targets EGFR and is being studied in a Phase 1 clinical trial for the treatment of multiple solid cancers including colorectal cancer, squamous cell carcinoma of the head and neck, non-small cell lung cancer, and renal cell carcinoma. We are also generating a number of additional TRACTr and TRACIr programs for potential future development, some of which are at development candidate stage or later. We are currently assessing priorities in our preclinical pipeline. About Janux Therapeutics Janux is a clinical-stage biopharmaceutical company developing tumor-activated immunotherapies for cancer. Janux’s proprietary technology enabled the development of two distinct bispecific platforms: Tumor Activated T Cell Engagers (TRACTr) and Tumor Activated Immunomodulators (TRACIr). The goal of both platforms is to provide cancer patients with safe and effective therapeutics that direct and guide their immune system to eradicate tumors while minimizing safety concerns. Janux is currently developing a broad pipeline of TRACTr and TRACIr therapeutics directed at several targets to treat solid tumors. Janux has two TRACTr therapeutic candidates in clinical trials, the first targeting PSMA is in development for prostate cancer, and the second targeting EGFR is being developed for colorectal, lung, head and neck, and renal cancers. For more information, please visit www.januxrx.com and follow us on LinkedIn . Forward-Looking Statements This news release contains certain forward-looking statements that involve risks and uncertainties that could cause actual results to be materially different from historical results or from any future results expressed or implied by such forward-looking statements. Such forward-looking statements include statements regarding, among other things, Janux’s ability to bring new treatments to cancer patients in need, expectations regarding the timing, scope and results of Janux’s development activities, including its ongoing and planned preclinical studies and clinical trials, the timing of and plans for regulatory filings, the potential benefits of Janux’s product candidates and platform technologies, expectations regarding the use of Janux’s platform technologies to generate novel product candidates and the strength of Janux’s balance sheet and the adequacy of cash on hand. Factors that may cause actual results to differ materially include the risk that compounds that appear promising in early research do not demonstrate safety and/or efficacy in later preclinical studies or clinical trials, the risk that Janux may not obtain approval to market its product candidates, uncertainties associated with performing clinical trials, regulatory filings and applications, risks associated with reliance on third parties to successfully conduct clinical trials, the risks associated with reliance on outside financing to meet capital requirements, and other risks associated with the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such drugs. You are urged to consider statements that include the words “may,” “will,” “would,” “could,” “should,” “believes,” “estimates,” “projects,” “promise,” “potential,” “expects,” “plans,” “anticipates,” “intends,” “continues,” “designed,” “goal,” or the negative of those words or other comparable words to be uncertain and forward-looking. For a further list and description of the risks and uncertainties Janux faces, please refer to Janux’s periodic and other filings with the Securities and Exchange Commission, which are available at www.sec.gov . Such forward-looking statements are current only as of the date they are made, and Janux assumes no obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise. Janux Therapeutics, Inc. Condensed Balance Sheets (in thousands) June 30, 2024 December 31, 2023 Assets (unaudited) Current assets: Cash and cash equivalents $ 14,662 $ 19,205 Accounts receivable 7,500 — Short-term investments 631,631 324,823 Prepaid expenses and other current assets 8,146 5,213 Total current assets 661,939 349,241 Restricted cash 816 816 Property and equipment, net 5,940 7,003 Operating lease right-of-use assets 20,077 20,838 Other long-term assets 2,640 2,509 Total assets $ 691,412 $ 380,407 Liabilities and Stockholders’ Equity Current liabilities: Accounts payable $ 1,253 $ 2,424 Accrued expenses 8,568 7,387 Current portion of deferred revenue 94 1,705 Current portion of operating lease liabilities 1,630 1,517 Total current liabilities 11,545 13,033 Operating lease liabilities, net of current portion 22,190 23,025 Total liabilities 33,735 36,058 Total stockholders’ equity 657,677 344,349 Total liabilities and stockholders’ equity $ 691,412 $ 380,407 Janux Therapeutics, Inc. Unaudited Condensed Statements of Operations and Comprehensive Loss (in thousands, except share and per share data) Three Months Ended June 30, Six Months Ended June 30, 2024 2023 2024 2023 Collaboration revenue $ 8,897 $ 1,057 $ 10,149 $ 3,105 Operating expenses: Research and development 14,898 14,924 28,968 30,789 General and administrative 7,821 6,881 15,164 13,345 Total operating expenses 22,719 21,805 44,132 44,134 Loss from operations (13,822 ) (20,748 ) (33,983 ) (41,029 ) Total other income 7,863 3,240 13,264 6,062 Net loss $ (5,959 ) $ (17,508 ) $ (20,719 ) $ (34,967 ) Other comprehensive gain (loss): Unrealized gain (loss) on available-for-sale securities, net (1,092 ) (321 ) (2,281 ) 475 Comprehensive loss $ (7,051 ) $ (17,829 ) $ (23,000 ) $ (34,492 ) Net loss per common share, basic and diluted $ (0.11 ) $ (0.42 ) $ (0.40 ) $ (0.84 ) Weighted-average shares of common stock outstanding, basic and diluted 54,451,666 41,836,238 51,750,690 41,800,304

靶向CD3激活T细胞的TCE双抗可以快速激活T细胞，从而利用T细胞对肿瘤细胞进行杀伤，但是其高强度的激活特性也给治疗带来了一定的负面影响，如CRS，另外也有研究证明，T细胞快速高强度的激活也会导致T细胞的耗竭。为了解决这些问题，有研究筛选了弱化CD3亲合力或者特殊表位的CD3抗体，其中比较知名是Teneobio。 和传统的杂交瘤，噬菌体展示，酵母展示或者单个B细胞筛选技术不同，Teneobio的筛选是通过CD3免疫OmniFlic人源化小鼠（含有特定的轻链，抗体的多样性主要是通过敲入的人V-D-J基因重排）。免疫后的小鼠进行NGS测序，获得超过100种抗体家族，并对这些抗体的CDR3序列分析获得近120种克隆型（序列相似度大于80%）。获得的克隆表达后通过体外评价获得既可以结合CD3同时细胞因子释放低的抗体。 在今年的ASCO会议上，Amgen公开了该技术开发的双抗AMG340的临床数据，AMG340是靶向PSMA/CD3的双抗，该抗体是Amgen收购Teneobio而获得。其实该双抗已经于去年停止临床开发，并被Amgen从管线中抹去，当时并没有披露什么原因，但是大概率也是因为药效不理想，而进行ASCO披露的结果也证实了该推测。 Ⅰ期临床的剂量爬坡探索了1.5-800mg的给药剂量，给药频率为Q3W，其中在剂量高于40mg的队列中采用前剂量给药降低CRS。该临床共42位患者入组，这些患者先前至少接受过2线治疗。安全性方面，给药剂量达到800mg时，副作用在接受范围内，并且没有达到最大耐受剂量。治疗的副作用主要是CRS，但是多数是2级及以下，三级CRS发生率为3.2%。另外的副作用是血小板减少症（14%3级及以上）。疗效方面：41位患者接受了PSA水平评估，在不同的剂量间出现PSA响应（降低），但是没有剂量关系，在27位接受RECIST评估的患者中，14位病情稳定，没有PR。 对比一下下强生的PSMA/CD3双抗JNJ-63898081的临床结果，JNJ-63898081和AMG340结构上类似，都是采用1+1非对称型结构，不同的是JNJ-63898081的CD3采用了强亲合力的抗体。在给药方式方面，JNJ-63898081采用了和血液流类似的给药方案，剂量爬坡最高到60ug/kg。 共出现4例DLTs，其中两例在皮下给药组（3级转氨酶升高）：30 μg/kg 1例和55 μg/kg 1例；另外两例同样在皮下给药组：60 μg/kg（2级弥散性血管内凝血/3级溶血反应）。 治疗相关的副反应方面（TEAEs），有46.2%的患者出现较严重的副反应，最常见的是 CRS(20.5%)、发热(7.7%)、背痛(5.1%)。 CRS主要发生在高剂量队列中，并且基本上都是2级及以下，因此CRS并不算特别严重。 疗效方面：在39位患者中，23位患者接受了评估，所有患者中都没有观察到影像学反应（完全或者部分响应），仅有两位患者治疗后病情稳定，并且在皮下剂量大于30μg/kg的患者中观察到了短暂的PSA降低(降低量>50%)。 对比一下两个双抗，AMG340给到了800mg，而JNJ-63898081的最大爬坡剂量是60 μg/kg，按照一个人80kg，JNJ-63898081最大给药剂量为4.8mg，远低于AMG340，因此从剂量上来看，降低CD3亲合力确实可以提高药物剂量从而可能增加药物在肿瘤组织中的暴露。 而安全性方面，JNJ-63898081虽然没有发生严重的CRS，但是这是建立在相对低的给药剂量前提下，而且JNJ-63898081在30 μg/kg给药剂量下已经出现DLT，因此这也从侧面反映出降低亲合力确实可以降低相关副作用并提高药物的给药剂量。 对比了两个失败的案例，再来看看目前来说相对成功的案例，Janux therapeutics条件激活型双抗JANX007的临床结果。该双抗也是靶向PSMA/CD3，不同的是其采用遮蔽肽对抗体结合表位进行阻挡，当抗体进入肿瘤微环境，在特异性酶的切割下才能激活。 剂量爬坡及给药方案方面，套路基本上都一样，在相对高剂量时进行前期低剂量给药，降低CRS风险。 患者在治疗前平均接受过4线以上的治疗，目前临床爬坡还没有完成，初步的临床数据表明，在剂量≥ 0.2mg (n=6)的患者中，所有患者的PSA都降低了30%的PSA，其中83%的患者PSA降低超过50%，17%的患者PSA降低超过90%，而在低剂量组中≥ 0.1mg (n=18)也观察到PSA的降低，其中6%的患者PSA降低超过90%，而在安全性方面，没有患者发生大于2级的CRS反应。对比分析发现，CRS只是在PSA降低的患者中出现。 JANX007初步的临床结果表明，TCE双抗在PSMA这个靶点上并不是没法成药，而强生和Amgen在这个靶点上的失败也是有多种原因，强生的JNJ-63898081不仅毒性大，而且产生了严重的ADA，从而严重的影响了抗体在肿瘤中的暴露，因此药效也无从谈起。Amgen的AMG340改造后虽然毒性较小，但是高达800mg的给药剂量也没有看到疗效，因此也让我们怀疑，一味的降低细胞因子释放能在体内完全激活T细胞，之前有分析发现，CRS其实是药效的一部分，而且在JANX007的临床中也发现，所有PSA降低的患者在给药后都有CRS副作用。当然JANX007较好的临床效果不仅与其独特的设计有关，而且还有可能其分子量相对较小，在肿瘤中暴露更充分。 AMG340是失败了，但是不能仅仅因为一个分子的失败就全盘否定弱化CD3的设计，下面我们从另外一个角度再次深入分析，你会发现，弱化CD3基本在临床中是符合其理论设计的。 前文介绍了弱化CD3在实体瘤中的疗效，也对比了相同靶点不同双抗在肿瘤中的效果。以下从血液瘤的角度分析一下看看弱化CD3的设计是否达到了其理论目的。在血液瘤中，弱化CD3设计双抗进展最快的是艾伯维的ABBV-383（TNB383B），该抗体也是基于Teneobio人源化小鼠筛选的靶向BCMA的双抗，其中CD3部分的抗体和AMG340的相同，并且其中靶向BCMA为双价设计，目前该双抗已经进入临床Ⅲ期。 其Ⅰ期临床设计如下，在剂量爬坡期，患者接受不同剂量的药物（IV Q3W），不像其它TCE双抗，该双抗没有进行前期的低剂量给药，最高爬坡剂量为120mg，剂量扩增组给药剂量为60mg或者40mg。 疗效方面：在所有接受治疗的患者中，PR为57%，VGPR(very good partial response )为43%,而在目标剂量组（60mg）,PR为60%，VGPR为43%, 在 ≥40 mg剂量组，PR为68%，VGPR为54%，在三药耐药组（PIs、IMiDs和达雷妥尤单抗耐药），PR为54%，VGPR为39%。 安全性方面，ABBV-383虽然没有采用前期低剂量给药策略，但是其整体高级CRS比例并不高，仅2位患者出现 ≥3级CRS 其余都为2级及以下CRS副作用（60mg剂量组）。血液相关毒性主要是嗜中性白血球减少症，贫血，血小板减少，淋巴细胞减少症等。 作为对比，目前已经有两款靶向BCMA/CD3的双抗获批上市，分别是强生的Teclistamab和辉瑞的Elranatamab，这两款双抗都采用了前期低剂量给药，以降低CRS副作用，临床中CRS大部分出现在首次给药后，且基本上都是1-2级，没有出现3级CRS。疗效方面，Teclistamab的CR和VGPR分别为65%和58%；Elranatamab的CR和VGPR分别为61%和51%。因此ABBV-383从疗效来看，总体ORR和上市的两款相当，但是VGPR略低。安全性方面，高剂量直接静脉给药，副作用也在接受范围内，3级及以上的CRS比例并不高。 对比三个BCMA/CD3双抗，ABBV-383在总体疗效和安全性上其实已经达到了原来设计的目的：将T细胞激活和CRS解偶联，从而在具有安全性的同时保持疗效。在PSMA/CD3中的失败和很多因素相关，包括靶点，肿瘤本身，抗体设计等。除了在肿瘤中的应用，该类型的CD3是不是也可以用以自免疾病的治疗，通过增强半衰期，长期持续的对自身的免疫细胞进行杀伤，而且不会因为细胞因子的释放导致副作用。 参考文献： 1、相关新闻报道 2、各公司官网 共建Biomedical创新生态圈！ 如何加入BiG会员？