Vofatamab

成纤维细胞生长因子 (FGF) 信号通过 FGF 受体 (FGFR1-4) 协调胎儿发育，有助于组织和全身稳态，但也可以促进肿瘤发生。各种药物已被开发出来，包括泛 FGFR 抑制剂（erdafitinib 和 futibatinib）、FGFR1/2/3 抑制剂（infigratinib 和 pemigatinib）以及一系列更具特异性的药物，其中一些已进入临床使用。Erdafitinib 被批准用于患有FGFR2/3改变的尿路上皮癌患者，futibatinib 和 pemigatinib 被批准用于患有FGFR2融合和/或重排的胆管癌患者。这些药物的临床益处部分受到高磷酸盐血症的限制，这是由于 FGFR1 的脱靶抑制以及 FGFR 基因中耐药突变的出现、旁路信号通路的激活、同时发生的TP53改变以及可能的上皮-间质转化相关的亚型转换。下一代小分子抑制剂，如lirafugratinib和LOXO-435，以及FGFR2特异性抗体bemarituzumab，预计将降低高磷酸血症的风险，并能够克服某些耐药突变。近日，日本国立癌症中心的Masaru Katoh研究团队概述了 FGFR 抑制剂的发展和当前的临床作用(图1），并提供了对未来研究方向的展望。Nature Reviews Clinical Oncology ( IF 78.8 )01FGFR的结构与异常信号FGFs由具有球状或非典型β三叶结构的保守核心结构域组成，可分为典型FGFs（FGF1-10、FGF16-18、FGF20和FGF22）、内分泌型FGF（FGF19/FGF15、FGF21和FGF23）以及FGF同源因子（FGF11-14）。全长FGF受体（FGFR1-4）是I型跨膜蛋白，具有三个细胞外免疫球蛋白样结构域和一个胞内酪氨酸激酶结构域。典型的FGF与硫酸乙酰肝素辅因子一起通过FGFR传递信号，而内分泌型FGF与klotho共受体（KLA和KLB）和硫酸乙酰肝素辅助因子一起通过FGFR传递信号。FGF–FGFR信号传导参与细胞存活、增殖、代谢、迁移和分化，包括生理作用，如协调胎儿发育和维持组织和/或全身稳态。这些受体也可以驱动肿瘤的发展。图1.FGFR信号传导和致癌激活机制概述癌症患者的FGFR改变通过异常的FGFR信号传导促进肿瘤发生：FGFR扩增导致FGFR过度表达和下游信号通路过度激活；FGFR融合或重排导致融合伴侣介导的FGFR二聚化、磷酸化改变和异常的下游信号传导；细胞外区或跨膜结构域中的FGFR突变通过改变对FGF配体的特异性或亲和力，以及配体非依赖性二聚化来激活FGFR；酪氨酸激酶结构域中的FGFR突变由于自身抑制机制的破坏而结构性性地激活FGFR（图1）。02小分子FGFR抑制剂一些小分子FGFR抑制剂已被开发用于治疗含有FGFR改变的癌症患者，如尿路上皮癌、脑癌、乳腺癌、CCA、胃癌、肝癌、肺癌、卵巢癌和宫颈癌。能够结合酪氨酸激酶结构域ATP结合位点的FGFR抑制剂通常分为多激酶FGFR抑制剂或选择性FGFR抑制剂。Derazatinib、dovitinib、tasurgratinib、lenvatinib、lucitanib、nintedanib和ponatinib都是多激酶FGFR抑制剂，对除FGFR外的多种RTK具有活性。然而，由于其广泛的活性，与选择性FGFR抑制剂相比，多激酶FGFR抑制剂的作用机制和不良反应都很复杂（图2）。图2.FGFR抑制剂和药物结合03FGFR靶向治疗的临床活性目前，根据在II期试验中观察到的疗效和耐受性，美国食品药品监督管理局（FDA）在这些适应症的二线或更后线的治疗中加速批准erdafitinib、futibatinib、infigratinib和pemiginib。在erdafitinib的临床研究（BLC2001）中，根据FGFR3或FGFR2/FGFR3融合物中至少一种突变的存在，选择局部晚期和/或不可切除的尿路上皮癌患者。整体队列的ORR为40%，中位无进展生存期（mPFS）和中位总生存期（mOS）分别为5.5个月和13.8个月。46%的患者出现≥3级不良事件，在初步分析中包括低钠血症（11%）、口腔炎（10%）和乏力（7%），以及长期随访的指甲（15%）、口炎（14%）和皮肤事件（8%）。任何级别的高磷血症都发生在大多数接受泛FGFR抑制剂或FGFR1/2/3抑制剂的患者中。这种不良反应很可能反映了泛FGFR或FGFR1/2/3抑制剂对FGF23信号传导的抑制，因为这种分泌蛋白依赖于与近端小管上皮细胞膜上的FGFR1和klotho的结合。该复合物通过抑制磷酸钠协同转运蛋白（NPT2a/c）调节肾脏中的磷酸盐吸收。FGFR1在这一过程中的作用得到证实，因此，开发FGFR2特异性和FGFR3特异性抑制剂有望避免或降低这种不良反应的发生率。04FGFR抑制剂的耐药机制对FGFR抑制剂的耐药可以反映额外的体细胞FGFR突变的存在，包括一些原发性肿瘤中的先天突变和治疗后肿瘤中的获得性耐药突变。一项系统分析了12项研究的数据，这些研究涉及82例FGFR2改变的肝内CCA患者，这些患者使用FGFR抑制剂治疗后疾病进展，报告称60%(49/82)的患者发生FGFR2激酶结构域的继发性突变。新生发生的FGFR改变通常会促进肿瘤发生，而在某些选择压力下，可以获得额外的突变，从而使生存和进化成为可能。05靶向fgfr新疗法进展异功能蛋白降解物(HPDs）、嵌合抗原受体（CAR）T细胞、抗体偶联药物（ADC）、放射免疫偶联物（RICs）和可溶性受体是能够靶向FGF–FGFR信号级联的潜在新治疗模式，其中一些已经或正在临床试验中进行测试。5.1异功能蛋白降解物(HPDs）HPDs具有双片段，使其能够与靶蛋白和E3泛素连接酶相互作用，从而诱导靶蛋白的泛素化介导的蛋白酶体降解。LC-MB12是一种基于infigratinib的CRBN型HPD，能够优先降解FGFR2，并抑制表达TEL–FGFR2融合的Ba/F3细胞和FGFR2扩增的SNU16胃癌细胞的增殖。相比之下，DGY-09-192是另一种基于 infigratinib的HPD，旨在募集VHL，从而优先降解FGFR1和FGFR2。这些药物目前仍处于临床前开发阶段。5.2 CAR-T细胞疗法由于PAX3–FOXO1的下游作用，FGFR4在儿科横纹肌肉瘤中普遍过表达。然而，N535K和V550L等耐药性突变通常在治疗前出现，这可能会限制小分子抑制剂的有效性。因此，研究人员开发了靶向FGFR4的CAR-T细胞，如RJ154-HL和3A11，具有不同的靶向FGFR4的scFv。目前，靶向FGFR的CAR-T细胞也仍处于临床前开发阶段。5.3 基于抗体的药物Aprutumab是一种全人源抗FGFR2抗体，它识别FGFR2b和FGFR2c亚型共同N末端区域P23、L27和E29周围的表位，并已被证明能诱导这些变体的内化和运输至溶酶体降解。 Aprutumab和bemarituzumab在I期临床试验中均显示出良好的安全性和耐受性。目前，bemarituzumab已作为联合疗法进行II期和III期临床试验，而Aprutumab用于开发ADCs和RICs。5.3.1基于Aprutumab开发的ADCsAprutumab ixadotin（前身为BAY-1187982）是具有不可裂解连接子的抗FGFR2 ADC，LY3076226是具有可裂解连接子的抗FGFR3 ADC。然而，测试这两种药物的第一阶段试验(nct22368951)由于耐受性差和活性有限而终止。5.3.2基于Aprutumab开发的RICs此外，Aprutumab和抗FGFR3抗体vofatamab分别用于FGFR2靶向的RIC（227Th-Aprutumab，BAY 2304058）和FGFR3靶向的RIC，225Ac-vofatamab（FPI-1966）和111In vofatamab（FPI-1967）。BAY 2304058仍处于临床前开发阶段，而FPI-1966（用于放射免疫疗法）和FPI-1967（用于放射成像）目前正在I/II期试验(NCT05363605)中进行测试，用于表达FGFR3的晚期实体瘤患者。5.4可溶性FGFR受体可溶性FGFR受体，如衍生自FGFR1c的细胞外结构域的FP-1039和衍生自FGFR 3c的细胞外区域的Recifecept，是另一类通过充当诱饵受体来捕获FGFR配体的重组蛋白药物。FP-1039已显示对促有丝分裂FGF配体具有高亲和力，并且在FGFR1扩增的肺癌和FGFR2突变的子宫内膜癌的小鼠异种移植模型中具有抗肿瘤作用。FP-1039在一期试验中具有可接受的耐受性。测试FP-1039与各种化疗联合用药的Ib期试验（NCT01868022)）显示同时接受紫杉醇和卡铂治疗的鳞状非小细胞肺癌患者的ORR为47%，同时接受培美曲塞和顺铂治疗的恶性胸膜间皮瘤患者的ORR为39%。06全文总结当前阶段，小分子FGFR抑制剂和靶向FGFR的生物制剂已经开发出来并在后期试验中进行了测试，其中几种小分子FGFR抑制剂已被批准用于含有FGFR改变的癌症患者。然而，某些不良事件，如FGFR1脱靶抑制导致的高磷酸盐血症和获得性耐药，继续限制了这些药物的临床益处。选择性第三代抑制剂，如那些特异性靶向FGFR2或FGFR3的抑制剂，正在临床开发中，这些药物可能避免或大大降低高磷血症的风险，并可能克服其他突变介导的耐药性。针对FGFR2扩增或过表达的GEA患者测试抗FGFR2b单克隆抗体bemarituzumab的III期临床试验--正在进行中。参考文献FGFR-targeted therapeutics: clinical activity, mechanisms of resistance and new directions作者：YWH声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号   粉丝群/投稿/授权/广告等请联系公众号助手 觉得本文好看，请点这里↓

Company recently acquired IND for ongoing Phase 2 clinical trial evaluating 225Ac-PSMA I&T, a small molecule radiopharmaceutical targeting PSMA positive mCRPC FPI-1434 preliminary Phase 1 data expected in Q2 2023 FPI-1966 and FPI-2059 Phase 1 trials open and recruiting patients Strong balance sheet with runway into Q1 2025 supports ongoing execution of multiple clinical programs HAMILTON, ON and BOSTON, March 16, 2023 /PRNewswire/ -- Fusion Pharmaceuticals Inc. (Nasdaq: FUSN), a clinical-stage oncology company focused on developing next-generation radiopharmaceuticals as precision medicines, today announced financial results for the fourth quarter ended December 31, 2022 and provided an update on clinical and corporate developments. Chief Executive Officer John Valliant, Ph.D. commented, "We have made significant progress towards our goal of bringing the power of targeted alpha therapies (TATs) to patients with cancers of high unmet need, while continuing to build on our radiopharmaceutical capabilities, including actinium supply. We have an exciting and diversified pipeline that includes one Phase 2 and three Phase 1 clinical programs, and our first program under the collaboration with AstraZeneca is progressing towards Phase 1 as planned. "We believe Fusion is well positioned for further progress in 2023 with preliminary data from the FPI-1434 Phase 1 trial expected in the second quarter of 2023. We are also advancing our newest clinical program, FPI-2265, a small molecule TAT targeting prostate specific membrane antigen (PSMA) for the treatment of metastatic castration-resistant prostate cancer (mCRPC), and are driving towards the opportunity to be first-to-market with an actinium-based PSMA agent to meet a significant and growing need for patients. Our deep pipeline of cancer therapeutic candidates continues to be underpinned by our R&D expertise, and our investments in actinium supply and manufacturing which is a critical element of success in the radiopharmaceutical space. We look forward to providing meaningful updates on our diverse pipeline of TATs in the months ahead." Portfolio Update FPI-2265 In February 2023, Fusion acquired an investigational new drug application (IND) for an ongoing Phase 2 clinical trial (the "TATCIST" trial) evaluating 225Ac-PSMA I&T, a small molecule targeting PSMA expressed on prostate cancers. The alpha-emitting radiopharmaceutical being evaluated in the TATCIST trial is now known as FPI-2265. The TATCIST trial is designed to evaluate patients with mCRPC with progressive disease, including patients who are naïve to PSMA targeted radiopharmaceuticals and those who have been pre-treated with 177Lu-based PSMA radiopharmaceuticals such as PLUVICTO™. Fusion plans to expand the Phase 2 program to additional sites and expects to report data on approximately 20 to 30 patients in the first quarter of 2024. FPI-1434 In the Phase 1 trial, Fusion is exploring various dose levels of FPI-1434 as well as two dosing regimens: one with FPI-1434 alone, and another in which a small dose of cold antibody (naked IGF-1R antibody without the isotope) is administered prior to each dose of FPI-1434. The Company anticipates reporting safety, pharmacokinetics, and imaging data, including any evidence of anti-tumor activity, from the Phase 1 trial in the second quarter of 2023. Fusion continues to anticipate the initiation of a Phase 1 combination trial with FPI-1434 and KEYTRUDA® (pembrolizumab) to occur six to nine months following determination of the recommended Phase 2 dose of FPI-1434 monotherapy. FPI-1966 The Phase 1, non-randomized, open-label clinical trial of FPI-1966 in patients with solid tumors expressing FGFR3 is intended to investigate safety, tolerability and pharmacokinetics and to establish the recommended Phase 2 dose. Patient enrollment and dosing is ongoing. The first cohort of the Phase 1 portion of this trial is designed to evaluate various doses of vofatamab ("cold antibody") to assess the impact of pre-dosing on tumor uptake and will inform the dosing regimen for the remainder of the trial. The Company anticipates providing a preliminary clinical data update in 2024. FPI-2059 The Phase 1, non-randomized, open-label clinical trial of FPI-2059 in patients with solid tumors expressing NTSR1 is intended to investigate safety, tolerability and pharmacokinetics and to establish the recommended Phase 2 dose. Site initiation and patient screening is ongoing. Fusion plans to provide guidance on timelines for the FPI-2059 program following site activations and initial experience with patient screening and patient enrollment. Recent Updates In February, Fusion announced the acquisition of a Phase 2 program for 225Ac-PSMA I&T, a radiopharmaceutical targeting mCRPC now known as FPI-2265. In connection with the acquisition, Fusion announced gross proceeds of $60.0 million in a private placement of its common shares. New and existing investors in the private placement financing include Avidity Partners, Federated Hermes Kaufmann Funds, a fund affiliated with Deerfield Management Company, L.P., Invus, Perceptive Advisors, and Woodline Master Fund LP. In January, Fusion and BWXT Medical announced an actinium-225 partnership to scale supply for developing targeted alpha therapies. Under the preferred partner agreement, BWXT Medical will provide predetermined amounts of Fusion's actinium supply needs at volume-based pricing. Actinium-225 is an alpha-emitting isotope used in targeted alpha therapies (TATs) that combine the isotope with specific tumor-seeking targeting vectors to kill cancer cells while minimizing the impact to healthy tissues. Fourth Quarter 2022 Financial Results Cash and Investments: As of December 31, 2022, Fusion held cash, cash equivalents and investments of $186.6 million, compared to cash, cash equivalents and investments of $220.8 million as of December 31, 2021. Fusion expects its existing cash, cash equivalents and investments as of December 31, 2022, plus the proceeds of the recently announced private placement, will be sufficient to fund operations into the first quarter of 2025. Collaboration Revenue: For the fourth quarter of 2022, Fusion recorded $0.1 million of revenue under the AstraZeneca collaboration agreement, compared to $0.6 million for the same period in 2021. R&D Expenses: Research and development expenses for the fourth quarter of 2022 were $17.6 million, compared to $11.8 million for the same period in 2021. The increase was primarily due to manufacturing-related milestone payments to our collaboration partners that occurred during the fourth quarter of 2022, as well as increased personnel-related costs. G&A Expenses: General and administrative expenses for the fourth quarter of 2022 were $6.9 million, compared to $6.3 million for the same period in 2021. The increase was primarily due to an increase in personnel-related costs. Net Loss: For the fourth quarter of 2022, Fusion reported a net loss of $24.6 million, or $0.55 per share, compared with a net loss of $17.2 million, or $0.40 per share, for the same period in 2021. Presentations at AACR Annual Meeting 2023 Fusion announced that it will present data from three preclinical studies in poster presentations at the American Association for Cancer Research (AACR) Annual Meeting being held in Orlando, Fla., April 14-19, 2023. Title: NTSR1-targeted alpha therapeutic [Ac-225]-FPI-2059 induces growth inhibition in a preclinical colorectal tumor model Session: Theranostics and Radionuclides / Pharmacologic Approaches Session Date and Time: Tuesday April 18, 2023, 1:30 PM - 5:00 PM ET Location: Poster Section 19 Abstract Number: 5045 Title: TEM-1 targeted alpha therapeutic [Ac-225]-FPI-1848 induces regression in pre-clinical sarcoma xenograft models Session: Theranostics and Radionuclides / Pharmacologic Approaches Session Date and Time: Tuesday April 18, 2023, 1:30 PM - 5:00 PM ET Location: Poster Section 19 Abstract Number: 5041 Title: EGFRvIII-targeted alpha therapy shows significant therapeutic efficacy as both a single-agent and in combination with standard of care against preclinical GBM models Session: Late-Breaking Research: Experimental and Molecular Therapeutics 3 Session Date and Time: Wednesday April 19, 2023, 9:00 AM - 12:30 PM ET Location: Poster Section 35 Abstract Number: LB313 The posters will be available on Fusion's website following the presentations. For more details about the AACR Annual Meeting, please visit: . About Fusion Fusion Pharmaceuticals is a clinical-stage oncology company focused on developing next-generation radiopharmaceuticals as precision medicines. Fusion connects alpha particle emitting isotopes to various targeting molecules to selectively deliver the alpha emitting payloads to tumors. Fusion's clinical portfolio includes: FPI-2265 targeting prostate specific membrane antigen (PSMA) for metastatic castration resistant prostate cancer currently in a Phase 2 trial; FPI-1434 targeting insulin-like growth factor 1 receptor currently in a Phase 1 trial; FPI-1966, targeting the fibroblast growth factor receptor 3 (FGFR3), currently in a Phase 1 trial; and FPI-2059, a small molecule targeting neurotensin receptor 1 (NTSR1), currently in a Phase 1 trial. In addition to a robust proprietary pipeline, Fusion has a collaboration with AstraZeneca to jointly develop novel targeted alpha therapies (TATs) and combination programs between Fusion's TATs and AstraZeneca's DNA Damage Response Inhibitors (DDRis) and immuno-oncology agents. Fusion has also entered into a collaboration with Merck to evaluate FPI-1434 in combination with Merck's KEYTRUDA® (pembrolizumab) in patients with solid tumors expressing IGF-1R. To support Fusion's growing pipeline of TATs, the company has signed strategic actinium supply agreements with TRIUMF, Niowave, Inc. and BWXT Medical. Forward-Looking Statements This press release contains "forward-looking statements" for purposes of the safe harbor provisions of The Private Securities Litigation Reform Act of 1995, including but not limited to the statements regarding Fusion Pharmaceuticals Inc.'s (the "Company") future business and financial performance. For this purpose, any statements contained herein that are not statements of historical fact may be deemed forward-looking statements. Without limiting the foregoing, the words "expect," "plans," "anticipates," "intends," "will," and similar expressions are also intended to identify forward-looking statements, as are expressed or implied statements with respect to the Company's potential drug candidates, including any expressed or implied statements regarding the successful development of its product candidates. Actual results may differ materially from those indicated by such forward-looking statements as a result of risks and uncertainties, including but not limited to the following: there can be no guarantees that the Company will advance any clinical product candidate or other component of its potential pipeline to the clinic, to the regulatory process or to commercialization; management's expectations could be affected by unexpected patient recruitment delays or regulatory actions or delays; uncertainties relating to, or unsuccessful results of, clinical trials, including additional data relating to the ongoing clinical trials evaluating its product candidates; the Company's ability to obtain additional funding required to conduct its research, development and commercialization activities; changes in the Company's business plan or objectives; the ability of the Company to attract and retain qualified personnel; competition in general; and the Company's ability to obtain, maintain and enforce patent and other intellectual property protection for its product candidates and its discoveries. Such forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause actual results to be materially different from any future results, performance or achievements expressed or implied by such statements. These and other risks which may impact management's expectations are described in greater detail under the heading "Risk Factors" in the Company's quarterly report on Form 10-Q for the quarter ended September 30, 2022, as filed with the SEC and in any subsequent periodic or current report that the Company files with the SEC. All forward-looking statements reflect the Company's estimates only as of the date of this release (unless another date is indicated) and should not be relied upon as reflecting the Company's views, expectations or beliefs at any date subsequent to the date of this release. While Fusion may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so, even if the Company's estimates change. Investors and others should note that Fusion communicates with its investors and the public using the Fusion website, , including, but not limited to, company disclosures, investor presentations, SEC filings, and press releases. The information that Fusion posts on this website could be deemed to be material information. As a result, Fusion encourages investors, media and others interested to review the information that Fusion posts there on a regular basis. Contact: Amanda Cray Senior Director of Investor Relations & Corporate Communications (617) 967-0207 cray@fusionpharma.com Company Codes: NASDAQ-NMS:FUSN