CAV1

Rein advanced the clinical development of its lead asset, LTI-03, and aims to initiate a Phase 2 trial for the treatment of idiopathic pulmonary fibrosis (IPF) in the first half of 2025 Positive topline results from Cohort 2 (5 mg BID) of the Phase 1b clinical trial of LTI-03 in IPF patients demonstrated dose dependent effects in five biomarkers evaluated, with four biomarkers achieving statistical significance in the combined Cohort 1 and Cohort 2 data set AUSTIN, Texas, April 7, 2025 /PRNewswire/ -- Rein Therapeutics, Inc. (NASDAQ: RNTX), a biopharmaceutical company advancing a novel pipeline of first-in-class medicines to address significant unmet medical needs in orphan pulmonary and fibrosis indications, today reported financial results for the fourth quarter and full year ended December 31, 2024 and provided a business update. "We've made significant clinical progress during 2024, culminating in promising safety and positive topline data from our Phase 1b trial of LTI-03 in IPF patients, which demonstrated early signs of therapeutic effect. LTI-03 has shown potential to improve lung function and potentially reverse the course of IPF, with its dual mechanism of action on both epithelial cells and fibroblasts gaining increasing support within the medical community," said Brian Windsor, Ph.D., President and Chief Executive Officer of Rein Therapeutics. "With our recent rebranding and renewed mission to combat fibrosis, we are excited to advance our pipeline. We are planning to initiate a Phase 2 study for LTI-03 in IPF in the first half of this year, where we will continue to evaluate the safety, tolerability and efficacy of this promising asset." Recent Clinical and Corporate Highlights and Upcoming Milestones Clinical Updates In November 2024, Rein announced positive topline data from Cohort 2 of the Phase 1b clinical trial evaluating the safety and tolerability of high dose LTI-03 (5 mg BID) and a set of exploratory biomarkers in patients diagnosed with IPF. Four biomarkers showed statistical significance in the combined Cohort 1 and Cohort 2 data set, and five demonstrated dose dependence, indicative of active pharmacodynamics. High dose LTI-03 continued to exhibit a favorable safety profile. A Phase 2 trial of LTI-03 for the treatment of IPF is anticipated to be initiated in the first half of this year, subject to funding. In October 2024, at the 22nd International Colloquium on Lung and Airway Fibrosis (ICLAF), Rein presented two abstracts highlighting preclinical and Phase 1b data for low dose LTI-03 (2.5 mg BID), reinforcing the potential of LTI-03 to improve lung function and reverse the course of IPF. Following inhaled administration of low dose LTI-03 in 12 patients over the course of 14 days, a positive trend was observed in biomarkers with evidence of reduced expression among multiple profibrotic proteins produced by basal-like cells and fibroblasts that contribute to the progression of IPF, including data from three biomarkers (collagen synthesis, inflammation, and fibrogenesis) that were statistically significant. Pre-clinical data further supported the potential therapeutic effectiveness of LTI-03 for IPF through precision cut lung slices (PCLS) performed ex-vivo. The studies demonstrated molecular activity in IPF PCLS explants indicative of fibrosis during five days in culture and LTI-03 broadly attenuated profibrotic proteins and pathways. Also in October 2024, the Company announced entry into an exclusive option agreement with Advancium Health Network for the acquisition of ALRN-6924, a clinical-stage oncology agent for retinoblastoma developed by the Company prior to its 2023 merger with Lung Therapeutics, Inc. Under the terms of the agreement, Rein received an upfront payment from Advancium for the exclusive option to acquire ALRN-6924 and related assets and could receive additional payments for development, regulatory and commercial milestones as well as sales royalties. Corporate Updates In January 2025, the Company rebranded to Rein Therapeutics, Inc. from Aileron Therapeutics, Inc. The new name, logo, website, and branding elements strategically aligns with the Company's sole focus to develop therapies in orphan pulmonary and fibrosis indications, including two Phase 2-ready clinical assets. The Company's common stock began trading under the Nasdaq ticker symbol "RNTX" effective January 13, 2025. Fourth Quarter and Full Year 2024 Financial Results Cash Position: Cash, cash equivalents, and investments on December 31, 2024, were $12.9 million, compared to $17.3 million on December 31, 2023. Research and Development (R&D) Expenses: R&D expenses for the quarter ended December 31, 2024, were $3.3 million, compared to $2.0 million for the quarter ended December 31, 2023. R&D expenses for the full-year 2024 were $14.2 million, compared to $4.0 million for the prior year. The increase in full year R&D expenses was primarily due to the termination of ALRN-6924 in 2023 and additional clinical programs acquired as part of the 2023 merger with Lung Therapeutics, Inc. General and Administrative (G&A) Expenses: G&A expenses for the quarter ended December 31, 2024, were $2.5 million compared to $5.3 million for the quarter ended December 31, 2023. G&A expenses for the full-year 2024 were $13.9 million, compared to $11.4 million for the prior year. The increase in full year G&A expenses was primarily due to increased headcount associated with the 2023 merger of Lung Therapeutics, Inc. and severance expense following the merger closure and increased facilities and other expenses as a result of the merger, offset by a decrease in professional fees. Net Loss: Net loss for the quarter ended December 31, 2024 was $41.0 million, compared to $7.3 million for the quarter ended December 31, 2023. The basic and diluted net loss per share for the quarter ended December 31, 2024, was $1.89 compared to a net loss per share of $1.54 for the quarter ended December 31, 2023. The increase in net loss in 2024 is mainly due to a non-cash impairment charge of $37.0 million related to aligning the carrying value of LTI-01 to the fair value. Excluding the non-cash charge, net loss per share for the fourth quarter ended December 31, 2024, was a loss of $0.26. The basic and diluted net loss per share for the full-year 2024 was $3.51, or an adjusted net loss per share of $1.53 excluding the non-cash impairment charge, compared to a net loss per share of $3.42 for the full-year 2023. About Rein Therapeutics Rein Therapeutics is a clinical-stage biopharmaceutical company advancing a novel pipeline of first-in-class therapies to address significant unmet medical needs in orphan pulmonary and fibrosis indications. Rein's lead product candidate, LTI-03, is a novel, synthetic peptide with a dual mechanism targeting alveolar epithelial cell survival as well as inhibition of profibrotic signaling. Rein's second product candidate, LTI-01, is a proenzyme that has completed Phase 1b and Phase 2a clinical trials for the treatment of loculated pleural effusions. LTI-01 has received Orphan Drug Designation in the U.S. and E.U. and Fast Track Designation in the U.S. For more information, please visit the company's website at reintx.com, or follow them on LinkedIn and X. Forward-Looking Statements This press release may contain forward-looking statements of Rein Therapeutics, Inc. ("Rein", the "Company", "we", "our" or "us") within the meaning of the Private Securities Litigation Reform Act of 1995, including statements with respect to: the timing and expectation of a Phase 2 clinical trial of LTI-03; and future expectations, plans and prospects for the Company. We use words such as "anticipate," "believe," "estimate," "expect," "hope," "intend," "may," "plan," "predict," "project," "target," "potential," "would," "can," "could," "should," "continue," and other words and terms of similar meaning to help identify forward-looking statements, although not all forward-looking statements contain these identifying words. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including risks and uncertainties related to: changes in applicable laws or regulations; the possibility that the Company may be adversely affected by other economic, business, and/or competitive factors, including risks inherent in pharmaceutical research and development, such as: adverse results in the Company's drug discovery; preclinical and clinical development activities; the risk that the results of preclinical studies and early clinical trials may not be replicated in later clinical trials, including in a Phase 2 trial of LTI-03, or that partial results of a trial will be indicative of the full results of the trial; the Company's ability to enroll patients in its clinical trials; and the risk that any of its clinical trials may not commence, continue or be completed on time, or at all; decisions made by the U.S. Food and Drug Administration and other regulatory authorities; investigational review boards at clinical trial sites and publication review bodies with respect to its development candidates; the Company's ability to obtain, maintain and enforce intellectual property rights for its platform and development candidates; competition; the Company's ability to obtain additional funding and the sufficiency of the Company's cash resources, after financing, to fund its planned activities for the periods anticipated and the Company's ability to manage unplanned cash requirements; and general economic and market conditions; as well as the risks and uncertainties discussed in the "Risk Factors" section of the Company's Annual Report on Form 10-K for the year ended December 31, 2024, which is on file with the United States Securities and Exchange Commission (the "SEC") and in subsequent filings that the Company files with the SEC. These forward-looking statements should not be relied upon as representing the Company's view as of any date subsequent to the date of this press release, and we expressly disclaim any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law. Rein Investor Relations & Media Contact: Argot Partners [email protected] 212-600-1902 SOURCE Rein Therapeutics, Inc. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Vol.01 -CD47靶点概述- 图1 CD47的简史 CD47的结构特点 CD47(也称为IAP、MER6或OA3)是一种细胞表面整合素相关糖蛋白，属于免疫球蛋白(Ig)超家族，有多种异构体。在结构上，由高度糖基化的N端细胞外结构域(ECD)、5次跨膜结构域和短的C端结构域(CTD)组成。其ECD包含V-set免疫球蛋白超家族结构域，可与配体结合，而CTD存在可变剪接。这种结构使得CD47能够在细胞表面发挥功能，并与多种配体和蛋白质相互作用。 图2 小鼠和人CD47的基因和蛋白质结构 CD47的氨基酸序列 Extracellular Helical Cytoplasmic 19-141,198-207,257-268 142-162,177-197,208-228,236-256, 269-289 163-176,229-235,290-323 CD47的蛋白异构体 CD47亚型：CD47 mRNA经历选择性剪接形成五种亚型，产生多种异构体，人有5种，小鼠有10种，差异源于基因外显子数量不同。还可经翻译后修饰，如糖基化、糖胺聚糖修饰、焦谷氨酸修饰、蛋白水解切割等产生不同蛋白形式。 图3 CD47的可变剪接和翻译后修饰可产生多种CD47蛋白形式 功能差异：不同异构体表达具有组织特异性，在细胞适应生理病理变化、记忆巩固等过程中发挥作用，但在某些功能上存在争议，其胞质尾和各结构域也有不同功能。 表1 CD47亚型和结构域的功能 CD47的配体及功能 CD47能与多种配体和蛋白结合，在细胞功能调节中意义重大。 ①信号调节蛋白α(SIRPα)：CD47与SIRPa结合可保护造血干细胞和红细胞不被吞噬，在肿瘤免疫逃逸中起关键作用，还参与癌症干性维持和免疫耐药等过程。 ②血小板反应蛋白1(TSP1)：CD47与TSP1结合可调节下游信号，影响细胞凋亡、增殖、黏附等过程，还抑制血管生成、炎症反应和血小板激活聚集，对肿瘤生长和转移有抑制作用。 ③SIRPc：也能与CD47结合，但其结合亲和力比SIRPa低约十倍。在T细胞的跨内皮迁移、白细胞迁移和T细胞增殖中发挥重要作用。 此外，CD47还能与多种整合素(如αIIbβ3、α2β1等)、窖蛋白-1(caveolin-1)、血管内皮生长因子受体2(VEGFR2)和NADPH氧化酶1(NOX1)相互作用，在不同细胞中调节细胞黏附、迁移、增殖等过程。在细胞质中，CD47与BNIP3、PLIC-1、ENO1、AKAP13和G蛋白等结合，参与细胞死亡、迁移和增殖等调控。 图4 CD47结构及其配体蛋白 表2 CD47相关/相互作用蛋白及其主要功能的完整列表 Vol.02 -CD47的调控与功能- CD47的细胞功能 CD47是一种多功能蛋白，广泛存在于免疫细胞(树突状细胞DC、巨噬细胞、单核细胞和T细胞等)中，在调节细胞和代谢可塑性方面具有关键的细胞自主功能。 图5 CD47在调节细胞可塑性和代谢可塑性中的细胞自主功能 CD47的调控机制 CD47在转录、转录后和翻译后水平受多种因素调控，如转录因子、细胞因子、miRNAs、lncRNAs等，且翻译后修饰影响其功能。 图6 CD47表达的调节和修饰 CD47的免疫系统功能 CD47在固有免疫和适应性免疫中均有重要作用，其与SIRPα相互作用，构成细胞间通讯系统，对免疫系统功能双向调节，抑制巨噬细胞等的吞噬作用，影响肿瘤免疫逃逸。 图7 先天免疫和适应性免疫中的CD47 CD47相关信号通路 图8 CD47调节的细胞内信号通路 Vol.03 -CD47在癌症及肿瘤微环境中的作用- CD47在癌症中的作用 在多种恶性肿瘤中高表达CD47，与预后不良相关，促进肿瘤发生和转移，在血液肿瘤和实体瘤中均发挥重要作用。调控CD47的表达和相关信号通路，可通过多种机制影响肿瘤细胞命运，如调节巨噬细胞吞噬、激活抗肿瘤免疫反应、诱导肿瘤细胞凋亡等。 CD47在肿瘤微环境中的作用 通过与肿瘤浸润细胞相互作用，影响肿瘤细胞的免疫逃逸，CD47与TSP-1的相互作用也影响肿瘤微环境的代谢和肿瘤生长。 CD47的功能串扰 CD47的经典和非经典功能之间存在串扰，共同调节细胞复杂反应。因其在多种癌症中高表达，阻断CD47-SIRPα相互作用成为潜在癌症治疗策略，但CD47在正常细胞广泛表达，治疗时会产生脱靶毒性，限制临床应用。 图9 CD47的经典和非经典作用 Vol.04 -CD47的靶向治疗及临床进展- 图10 CD47/SIRPα临床试验时间表和主要进展 CD47作为免疫检查点阻断 CD47-SIRPa作为免疫检查点，阻断其相互作用可促进巨噬细胞吞噬肿瘤细胞，激活免疫系统。 图11 阻断肿瘤细胞中CD47/SIRPα的作用机制 CD47作为预后标志物 CD47 可作为肝细胞癌、肺鳞状细胞癌、胰腺癌、甲状腺癌的预后标志物。 图12 CD47 作为多种癌症的预后标志物 CD47的抗体研发与临床应用 多种抗CD47抗体处于临床试验阶段，单独或联合治疗展现出一定疗效，联合治疗方式多样，可增强治疗效果。 图13 基于CD47的免疫治疗作用机制 (1)单克隆抗体：抗CD47单克隆抗体(如Hu5F9-G4、B6H12、MIAP410)和抗SIRPa单克隆抗体可阻断CD47-SIRPa相互作用，增强巨噬细胞吞噬作用，部分已进入临床试验阶段。 (2)重组融合蛋白：如ALX148、IMM01、TTI-621，通过融合SIRPa胞外域和抗体Fc片段，增强免疫反应，部分已在临床试验中评估其治疗癌症的效果。 (3)双特异性抗体(BSAb)：同时靶向CD47和其他抗原，如IMM2902、D3L-001等，在多种癌症治疗中展现出潜力。 (4)miRNA：如miR-133a、miR-222等，通过结合CD47mRNA的3'-UTR抑制其表达，影响肿瘤细胞增殖、迁移等，但存在脱靶效应等问题。 (5)小分子抑制剂：如GramicidinA、AP-III-a4等，通过干扰CD47-SIRPa结合或调节相关蛋白合成发挥作用，为癌症治疗提供了新方向。 (6)肽类：靶向CD47或SIRPa的肽类(如Pep-20、RS-17、SP5等)可破坏CD47-SIRPa信号通路，具有低免疫原性等优势。 (7)工程化T细胞和巨噬细胞：CD47-CAR-T细胞和CAR-巨噬细胞可增强对癌细胞的杀伤作用，是癌症免疫治疗的新途径。 表3 靶向CD47的临床药物清单 Vol.05 -CD47在疾病中的应用进展- 图14 癌症基因组图谱(TCGA)数据库的CD47的表达水平 CD47在血液肿瘤中的应用进展 淋巴瘤：在B细胞淋巴瘤如弥漫大B细胞淋巴瘤(DLBCL)和慢性淋巴细胞白血病(CLL)中，CD47高表达，抑制其表达可增强巨噬细胞的吞噬作用。在DLBCL中，黄连素可下调CD47，增强吞噬并清除癌细胞；在CLL中，CD47抗体可促进肿瘤细胞凋亡。在T细胞淋巴瘤(TCL)中，CD47表达可变，靶向CD47-SIRPa可增强吞噬、改善生存，且CD47能促进TCL转移。 髓系肿瘤：在急性髓系白血病(AML)和慢性髓系白血病(CML)中，白血病干细胞(LSC)中CD47表达增加，与不良预后相关。在AML中，CD47与FLT3-ITD突变密切相关。在多发性骨髓瘤(MM)中，多数患者CD47高表达，阻断CD47可激活巨噬细胞，清除MM细胞。 CD47在实体瘤中的应用成果 肺癌：在小细胞肺癌(SCLC)和非小细胞肺癌(NSCLC)中，CD47均高表达，与肿瘤分期、转移、复发和患者生存相关。在NSCLC中，CD47高表达与中性粒细胞凋亡和吞噬减少有关，阻断CD47-SIRPa信号通路可抑制肿瘤生长。 胶质母细胞瘤(GBM)：GBM细胞中CD47高表达，与干细胞特性和不良预后相关。CD47敲除可增加巨噬细胞对肿瘤细胞的吞噬，联合放疗或化疗可增强治疗效果。 乳腺癌：乳腺癌患者中，高CD47水平与低生存率相关。在三阴乳腺癌(TNBC)中，联合注射STING配体cGAMP和CD47抗体可抑制肿瘤生长。 卵巢癌：在子宫内膜异位症相关卵巢癌(EAOC)中，CD47高表达与肿瘤分级和预后不良相关，抑制CD47可逆转其促进细胞增殖、迁移和抑制吞噬的作用。 胆管癌(CCA)：CD47在CCA中的表达高于在HCC中。CD47-SIRPα轴的中断增强了所有巨噬细胞亚型的巨噬细胞吞噬作用，从而抑制了CCA的生长和转移。 食管癌：在食管鳞状细胞癌(ESCC)中，43.2%的患者CD47高表达，且癌组织中CD47表达高于癌旁组织。CD47高表达与淋巴结转移、预后不良相关。 胃癌：早期胃癌患者中49.6%高表达CD47，CD47阳性患者5年生存率较低。其表达与巨噬细胞浸润、不良临床结局及对氟尿嘧啶辅助化疗的抵抗相关。 结直肠癌：35.3%的原发性结直肠癌患者病变中，癌细胞表达CD47。CD47阳性患者总生存时间短，其表达与肿瘤侵袭、转移及不良病理特征相关。 肝癌：在常规肝细胞癌(HCC)中，21.7%的肝细胞癌患者CD47高表达，与病理特征和不良预后相关，阻断CD47可增强巨噬细胞对HCC细胞的吞噬。 胆囊癌：17.4%的胆囊癌患者表达CD47，与血管侵犯、神经侵犯等不良临床病理特征相关，在肿瘤发生发展中起重要作用。 胰腺癌：61.3%的胰腺导管腺癌患者肿瘤细胞CD47高表达，与不良预后相关。在胰腺神经内分泌肿瘤中也高表达。 CD47在非肿瘤性疾病中的免疫疗法 借鉴癌症免疫疗法原理，CD47在多种非肿瘤性疾病治疗中展现潜力。 ①在动脉粥样硬化中，CD47表达与病情相关，阻断CD47可减轻炎症、缩小斑块； ②在神经系统疾病方面，参与神经元发育调节，在脑出血、脑缺血和阿尔茨海默病等病症中，阻断CD47能发挥神经保护等作用； ③在肌肉干细胞中，CD47与细胞增殖相关，或可用于对抗肌肉萎缩； ④在糖尿病领域，CD47与1型糖尿病发病有关，阻断它可能改善胰岛素分泌； ⑤在自身免疫性疾病中，CD47-SIRPα参与疾病发展，调节其功能或为治疗提供方向。 Vol.06 -CD47靶向治疗的挑战与应对策略- 表4 靶向CD47的已终止的临床试验 面临挑战 ①由于CD47在造血系统广泛表达，靶向治疗可能对正常细胞的损伤导致免疫系统过度激活和脱靶毒性，如贫血、溶血等不良反应。 ②CD47不是唯一的免疫逃逸检查点分子，CD47-SIRPa阻断触发吞噬作用不足，单独靶向效果可能不佳，在实体瘤中的疗效也有限。 ③肿瘤细胞会对CD47靶向治疗产生耐药性，且存在肿瘤异质性和免疫抑制细胞干扰。 ④目前缺乏可靠的预测生物标志物来选择适合CD47靶向治疗的患者，需开发有效的检测方法并确定相关阈值。 图15 针对CD47的治疗方法存在挑战以及潜在的非预期副作用 应对策略 设计与红细胞结合弱的CD47抗体，或基于肿瘤细胞与红细胞差异设计抗体；靶向SIRPa或isoQC等，减少对正常血细胞的影响；现有癌症研究模型各有局限，需结合多种模型优势推动研究；未来应探索CD47抑制剂与新型靶向疗法、癌症疫苗联合治疗，同时优化药物递送以减少副作用。 关于仁域生物 成都仁域生物成立于2019年1月，是一家专注基因工程抗体技术和天然抗体库开发的公司，拥有优化的噬菌体展示抗体库技术和现代化的骆驼/羊驼养殖免疫基地。 公司核心技术平台包括全球最大的6000+天然驼源纳米抗体库(总库容＞3×10^12)、肿瘤细胞系免疫的骆驼免疫库、万亿级大容量全人源噬菌体展示scFv抗体库(总库容＞1×10^12)。 可为客户提供14天、100%成功率的先导抗体分子发现服务，彻底解决传统抗体定制的周期长、失败率高、成本高三大难题。目前已经成功完成300+靶点抗体筛选项目！ 科研专用—万亿级天然抗体库产品 （一步到位，轻松搭建基因工程抗体平台） protocol 获取 / 产品咨询 邮箱｜find@renyubio.com 电话｜19136178673 地址｜成都市经开区科技产业孵化园 关注我们，持续更新相关内容 参考文献 Che Z, Wang W, Zhang L, Lin Z. Therapeutic strategies targeting CD47-SIRPα signaling pathway in gastrointestinal cancers treatment. J Pharm Anal. 2025 Jan;15(1):101099.  Chen C, Lu F, Huang H, Pan Y. Translating CD47-targeted therapy in gastrointestinal cancers: Insights from preclinical to clinical studies. iScience. 2024 Nov 26;27(12):111478.  Polara R, Ganesan R, Pitson SM, Robinson N. Cell autonomous functions of CD47 in regulating cellular plasticity and metabolic plasticity. Cell Death Differ. 2024 Oct;31(10):1255-1266.  Liu Y, Weng L, Wang Y, Zhang J, Wu Q, Zhao P, Shi Y, Wang P, Fang L. Deciphering the role of CD47 in cancer immunotherapy. J Adv Res. 2024 Sep;63:129-158.  Jiang C, Sun H, Jiang Z, Tian W, Cang S, Yu J. Targeting the CD47/SIRPα pathway in malignancies: recent progress, difficulties and future perspectives. Front Oncol. 2024 Jul 5;14:1378647.  Xing L, Wang Z, Feng Y, Luo H, Dai G, Sang L, Zhang C, Qian J. The biological roles of CD47 in ovarian cancer progression. Cancer Immunol Immunother. 2024 Jun 4;73(8):145. Tang XX, Shimada H, Ikegaki N. A Perspective on the CD47-SIRPA Axis in High-Risk Neuroblastoma. Curr Oncol. 2024 Jun 1;31(6):3212-3226. Wu F, Pang H, Li F, Hua M, Song C, Tang J. Progress in cancer research on the regulator of phagocytosis CD47, which determines the fate of tumor cells (Review). Oncol Lett. 2024 Apr 9;27(6):256.  Zhang T, Wang F, Xu L, Yang YG. Structural-functional diversity of CD47 proteoforms. Front Immunol. 2024 Feb 15;15:1329562.  Xu Y, Jiang P, Xu Z, Ye H. Opportunities and challenges for anti-CD47 antibodies in hematological malignancies. Front Immunol. 2024 Feb 23;15:1348852. Isenberg JS, Montero E. Tolerating CD47. Clin Transl Med. 2024 Feb;14(2):e1584.  Chen Q, Guo X, Ma W. Opportunities and challenges of CD47-targeted therapy in cancer immunotherapy. Oncol Res. 2023 Nov 15;32(1):49-60.  Wang C, Feng Y, Patel D, Xie H, Lv Y, Zhao H. The role of CD47 in non-neoplastic diseases. Heliyon. 2023 Nov 29;9(12):e22905.  Lau APY, Khavkine Binstock SS, Thu KL. CD47: The Next Frontier in Immune Checkpoint Blockade for Non-Small Cell Lung Cancer. Cancers (Basel). 2023 Oct 31;15(21):5229.

GREENFIELD, Ind., Feb. 13, 2025 /PRNewswire/ -- Elanco Animal Health Incorporated issued the following statement regarding its commitment to clear veterinary and pet owner education following a promotional practices warning letter from U.S. Food and Drug Administration (FDA). At Elanco, we are dedicated to helping veterinarians and pet owners help pets live longer, healthier, more active lives. Delivering new innovation to the marketplace and ensuring we clearly communicate with veterinarians and pet owners about how to safely and effectively use these products is a key part of that goal. The U.S. FDA recently issued a Warning Letter to Elanco related to statements in Zenrelia™ (ilunocitinib tablets) promotional materials. The FDA uses these letters to notify companies of their positions and provide an opportunity to respond and make voluntary changes. We appreciate the FDA's perspective and are working quickly to review and update Zenrelia promotional materials as appropriate. Importantly, this letter is not related to the in-market product use experience; we are very pleased with Zenrelia's real-world performance. We appreciate the opportunity to work closely with the FDA to resolve the issues as we continue to help veterinarians and pet owners understand how their patients and pets can benefit from this exciting new product. Elanco does not expect the adjustments to the promotional materials to have a material impact on Zenrelia revenue. The company continues to expect accelerating organic constant currency revenue growth to mid-single digits in 2025. The entire FDA letter follows. For full prescribing information for Zenrelia, including the boxed warning, speak with your veterinarian, call 1 888 545 5973 or visit . INDICATIONS Zenrelia is a prescription medication used to control itching and inflammation associated with skin allergies for dogs over 12 months of age. IMPORTANT SAFETY INFORMATION See package insert including the Boxed Warning. For full prescribing information speak with your veterinarian, call 1 888 545 5973 or visit . WARNING: VACCINE-INDUCED DISEASE AND INADEQUATE IMMUNE RESPONSE TO VACCINES. Based on results of the vaccine response study, dogs receiving Zenrelia are at risk of fatal vaccine-induced disease from modified live virus vaccines and inadequate immune response to any vaccine. Discontinue Zenrelia for at least 28 days to 3 months prior to vaccination and withhold Zenrelia for at least 28 days after vaccination. Dogs should be up to date on vaccinations prior to starting Zenrelia. Do not use in dogs less than 12 months old or dogs with a serious infection. Dogs should be monitored for the development of infections because Zenrelia may increase the chances of developing an infection. Neoplastic conditions (benign and malignant) were observed during clinical studies. The most common side effects were vomiting, diarrhea and tiredness. Zenrelia has not been tested in dogs used for breeding, pregnant, or lactating dogs and has not been evaluated in combination with glucocorticoids, cyclosporine, or other immune suppressive drugs. ABOUT ELANCO Elanco Animal Health Incorporated (NYSE: ELAN) is a global leader in animal health dedicated to innovating and delivering products and services to prevent and treat disease in farm animals and pets, creating value for farmers, pet owners, veterinarians, stakeholders and society as a whole. With 70 years of animal health heritage, we are committed to breaking boundaries and going beyond to help our customers improve the health of animals in their care, while also making a meaningful impact on our local and global communities. At Elanco, we are driven by our vision of Food and Companionship Enriching Life and our Elanco Healthy Purpose™ sustainability pillars – all to advance the health of animals, people, the planet and our enterprise. Learn more at . The complete text of the letter from the U.S. Food & Drug Administration follows: Elanco Animal Health Attention: Jeffrey Simmons President and CEO, Elanco Animal Health USA 2500 Innovation Way Greenfield, Indiana 46140 Re: NADA 141-585, Zenrelia™ (ilunocitinib tablets) CMS #: 695170 WARNING LETTER Dear Mr. Simmons: The U.S. Food and Drug Administration (FDA) has reviewed your promotional communications for Zenrelia (ilunocitinib tablets) including your veterinarian product website,1 the consumer directed website,2 your Product Brochure and Itch Tracker,3 which is linked on both websites, and a slide deck titled "Reach for Zen: New Relief for Dogs with Atopic Dermatitis4" and noted false or misleading claims and representations about the safety and effectiveness of Zenrelia. These promotional communications misbrand Zenrelia within the meaning of the Federal Food, Drug, and Cosmetic Act (FD&C Act). FD&C Act section 502(a) [21 U.S.C. 352(a)] and section 502(n) [21 U.S.C. 352(n)]; see also section 201(n) [21 USC 321(n)]. It is a prohibited act to distribute a misbranded product in interstate commerce. FD&C Act section 301(a) [21 U.S.C. 331(a)]. This violation is especially concerning from a public health perspective because the misleading promotional communications create a misleading impression regarding the safety and effectiveness of Zenrelia, which is a recently-approved veterinary drug in the Janus Kinase (JAK) inhibitor drug class. Background Zenrelia is indicated for "control of pruritus associated with allergic dermatitis and control of atopic dermatitis in dogs at least 12 months of age."5 Zenrelia's FDA-approved Prescribing Information (PI) contains a boxed and bolded warning of the risk of "fatal vaccine-induced disease from modified live virus vaccines and inadequate immune response to any vaccine" in dogs receiving Zenrelia. Therefore, the boxed warning states to discontinue Zenrelia for at least 28 days to 3 months prior to vaccination and withhold Zenrelia for at least 28 days after vaccination. The PI contains additional warning language including: "Dogs should be monitored for the development of infections because Zenrelia may increase susceptibility to opportunistic infections, including demodicosis, interdigital furunculosis, coccidiosis, and pneumonia, and exacerbation of subclinical or uncomplicated infections (see Target Animal Safety and Adverse Reactions)." … "Zenrelia may cause a progressive or persistently decreased hematocrit, hemoglobin, and/or red blood cell count without a corresponding increase in absolute reticulocyte count (see Target Animal Safety)." "New neoplastic conditions (benign and malignant) were observed in dogs treated with Zenrelia during clinical studies (see Adverse Reactions)." The PI contains additional adverse event, warning, precaution, and contraindication information.6 False or Misleading Claims Prescription drug advertisements and labeling (promotional communications) misbrand a drug if they are false or misleading in any particular. See FD&C Act sections 502(a),(n) (21 U.S.C 352(a),(n)). The determination of whether a promotional communication is misleading includes, among other things, not only representations made or suggested in the promotional communication, but also the extent to which the promotional communication fails to reveal facts material in the light of its representations or material with respect to consequences that may result from the use of the drug as recommended or suggested in the promotional communication. See FD&C Act section 201(n) (21 U.S.C 321(n)) and 21 CFR 202.1(e)(5) . Omitted Information The websites mentioned above and the Product Brochure and Itch tracker omit the phrase "from modified live virus vaccines" from the boxed warning found in the Important Safety Information (ISI) sections. The Vaccine Response Study in the Target Animal Safety section of the PI describes a dog that was administered Zenrelia that developed lethargy, depression, poor body condition, and weakness after receiving a modified live virus (MLV) vaccination and was subsequently euthanized. This dog was later diagnosed with adenoviral hepatitis and pancreatitis that "were concluded to be vaccine-induced, secondary to Zenrelia-induced immunosuppression." Omitting the phrase "from modified live virus vaccines" in promotional material is misleading because the fatal vaccine-induced disease occurred after administration of a MLV DHPP vaccination,7 a core vaccination for all dogs.8 Therefore, the phrase "from modified live virus vaccines" provides material facts that may be relevant to prescribing veterinarians and dog owners. In the ISI section of the consumer-directed website and on page one of the Product Brochure and Itch Tracker, the specific time period to withhold Zenrelia before and after vaccination is omitted (i.e., at least 28 days to 3 months prior to vaccination and at least 28 days after vaccination) and replaced with the phrase "for a time period before and after vaccination." The specific time frame is also omitted from a 30-second video found on the veterinarian product website.9 The phrase "for a time period before and after vaccination" is misleading because it does not provide necessary information to the pet owner. The Safety section of the Zenrelia veterinarian website contains only the statements "Read the entire package insert before using this drug, including the Boxed Warning" and "In clinical trials, the most observed adverse events were vomiting, diarrhea, and lethargy." There is no mention of fatal vaccine-induced disease from MLV vaccines or inadequate immune response to any vaccines. We acknowledge that clicking on the box titled "Explore Zenrelia's safety data" directs the reader to another webpage where more safety information is presented. However, this Safety section is also missing information about the risk of fatal vaccine-induced disease from MLV vaccines or inadequate immune response to any vaccines, as well as safety information from the Warnings section of the PI like monitoring for the development of infections, the risk of decreased hematocrit, hemoglobin, and/or red blood cell count, and the risk of new neoplastic conditions.10 Misrepresented Study Results The veterinarian product website makes misleading claims about the results of the Vaccine Response Study. In the "Vaccinations FAQs" section of the website, under the question "What is vaccine-induced disease?" the response in part states "After the label was finalized, PCR testing confirmed this dog had Infectious Canine Hepatitis due to infection with canine adenovirus type 1 (CAV-1), which is genetically distinct from the strain of CAV-2 used in the MLV. Furthermore, this dog developed clinical signs of hepatitis (hematemesis) prior to receiving its first MLV. CAV-1 is highly contagious and difficult to kill with routine disinfectants; it is unknown how this dog became exposed or if it was a carrier prior to entering the bio-secure facility used for this study." This claim is repeated on page 33 of the "Reach for Zen" slide deck. This information is in direct conflict with the PI and Freedom of Information (FOI) summary for Zenrelia, which concluded that the dog in the study had vaccine-induced adenoviral hepatitis and pancreatitis secondary to Zenrelia-induced immunosuppression. We are aware that Elanco submitted polymerase chain reaction (PCR) data to support this claim but, as discussed in a meeting with CVM on November 21, 2024, this data, in its current form, does not confirm that CAV-1, and not CAV-2, is present in the liver tissue from the dog in question. The PCR assay did not include CAV-2 primers and was not validated, and there were no results from PCR analysis of the pancreas. As suggested at the November 21, 2024 meeting, Elanco can submit any additional data it has to support this claim in a supplemental application. However, at this time, these claims are misleading because they contradict the conclusions of the Vaccine Response Study, which served as the basis of the boxed warning. If Elanco takes the position that the boxed warning on the currently approved product labeling is false and misleading, the appropriate approach is to submit a supplemental new animal drug application with supporting information to amend the product labeling. The Safety section of the Zenrelia veterinarian website also contains information about adverse reactions seen in the field studies conducted for approval,11 accessible by clicking on the boxes titled "US atopic dermatitis study vs placebo" and "US allergic dermatitis study vs placebo". However, the adverse reaction data found on the website is not consistent with the information found in the Zenrelia PI. For example, for the Control of Pruritus Associated with Allergic Dermatitis study, the PI states that diarrhea was reported in 26 (12.2%) dogs and urinary tract infections were reported in 13 (6.3%) Zenrelia treated dogs, while the Zenrelia website reports these numbers as 19 (9.2%) and 3 (1.5%), respectively. The adverse reaction data was reviewed and verified by the FDA as part of the approval process. The statements on the Zenrelia website are therefore false and misleading because they misrepresent the safety profile of Zenrelia. Additional Comments We offer the following additional comments about the promotion of Zenrelia: Your product websites and Product Brochure state that there are "visible improvements in allergic itch from day one." Neither effectiveness study (i.e., Control of Atopic Dermatitis or Control of Pruritus Associated with Allergic Dermatitis) supporting FDA approval assessed the speed of action of Zenrelia. According to the FOI summary, in the Control of Atopic Dermatitis study, treatment success12 on Day 28 was identified as the primary effectiveness endpoint. Pruritus Visual Analog Scale (PVAS) scores were also assessed at other time points, but they were considered secondary endpoints. This study did demonstrate that the estimated mean PVAS scores were lower in the Zenrelia group compared to placebo on Day 1, however, this difference was relatively small, and it is unknown if it represented a clinically identifiable difference in pruritus in the treatment group compared to the placebo group. Therefore, it cannot be concluded that the difference in PVAS scores indicates that Zenrelia improved pruritus compared to placebo on Day 1. In the Control of Pruritus Associated with Allergic Dermatitis study, the primary effectiveness endpoint was treatment success13 on at least 5 of the first 7 days of treatment. In this study, PVAS scores were assessed on Days 1 through 7, but the estimated mean PVAS score in the Zenrelia group was not lower than the placebo group until after Day 1, beginning on Day 2. Your product Detailer14 makes the claim "77% of Zenrelia-treated dogs returned to normal versus 53% of Apoquel treated dogs." The head-to-head study comparing treatment with Zenrelia to treatment with Apoquel showed that Zenrelia had similar efficacy as Apoquel on day 28, which was the primary effectiveness endpoint. The claim in the Detailer is based on PVAS scores on Day 112 of the study, which was a secondary endpoint. When multiple endpoints are tested statistically, the Type I error rate (the probability of erroneously concluding an effect when the truth is that there is no effect) may be inflated. Therefore, the p-values associated with the analyses of the multiple secondary endpoints should not be interpreted as evidence of statistically significant differences. We acknowledge you note with an asterisk that "PVAS <2; p::Q.Q5. Secondary end point p values are not adjusted for multiple testing; therefore, caution should be exercised in interpretation." However, this information is located in much smaller font at the bottom of the page and its inclusion in the Detailer does not mitigate the misleading impression made by the claim, which is presented prominently in large font in the center of the page. See 21 CFR 202.1(e)(7)(viii). Your product Detailer claims that "Results of multiple other studies demonstrate very similar safety profiles between Zenrelia and Apoquel." The Zenrelia PI has a boxed warning regarding the risk of fatal vaccine-induced disease from modified live vaccines and inadequate immune response to any vaccine as well as additional warning language regarding the risk of progressive or persistently decreased hematocrit, hemoglobin, and/or red blood cell count without a corresponding increase in absolute reticulocyte count, while the Apoquel PI does not. Therefore, the claim of "similar safety profiles between Zenrelia and Apoquel" may be misleading. Conclusion and Requested Response For the reasons discussed above, your websites, Product Brochure and Itch Tracker, and slide deck titled "Reach for Zen" misbrand Zenrelia within the meaning of the FD&C Act. FD&C Act section 502(a), (21 U.S.C. 352(a)); section 502(n) [21 U.S.C. 352(n)]; section 201(n) (21 U.S.C. 321(n));, and 21 CFR 202.1(e)(5). Introducing or delivering misbranded new animal drugs for introduction into interstate commerce violates section 301(a) of the FD&C Act [21 U.S.C. 331(a)]. This letter is not intended to be an all-inclusive statement of violations that may exist in connection with your products. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations. It is your responsibility to ensure that your firm complies with all requirements of federal law and FDA regulations. This letter notifies you of our concerns and provides you an opportunity to address them. Failure to adequately address this matter may lead to legal action, including without limitation, seizure, and injunction. Within fifteen (15) working days of receipt of this letter, please submit a written response addressing the concerns described in this letter, listing all promotional communications for Zenrelia that contain representations like that described above, and explaining any plan for discontinuing use of such communications, or for ceasing distribution of Zenrelia. If you cannot complete the above requested actions within fifteen (15) working days, state the reason for the delay and the time within which you will complete them. If you believe that your products are not in violation of the FD&C Act, please include in your submission to us your reasoning and any supporting information for our consideration within 15 working days from the date of receipt of this letter. Please direct your response to the undersigned at the Food and Drug Administration, Center for Veterinary Medicine, Division of Pharmacovigilance and Surveillance, 12225 Wilkins Ave, MPN II Room E436, Rockville, Maryland 20852. Please send a courtesy copy by email to [email protected]. All correspondence should include a subject line that clearly identifies the submission as a Response to Warning Letter # 695170. If you have any questions, please contact Dr. Christopher Loss by email at [email protected]. Sincerely, Linda Walter-Grimm, DVM Director, Division of Pharmacovigilance and Surveillance Office of Surveillance and Compliance Center for Veterinary Medicine 1 (last accessed on 1.27.25) 2 (last accessed on 1.27.25) 3 Identified by Elanco as PM-US-24-0697 4 Identified by Elanco as PM-US-24-1330 and submitted to the Drug Experience Report (DER) portal under cover of form 2301 on October 2, 2024. 5 FDA-approved package insert (PI) for Zenrelia 6 The risk information reproduced in this letter is only for background information related to the letter's subject matter and does not necessarily represent the risk information that should be included in any promotional communications. 7 The DHPP vaccine contains canine distemper virus (CDV), canine adenovirus (CAV-2), canine parainfluenza (CPiV), and canine parvovirus (CPV). 8 A Core Vaccination is recommended for all dogs irrespective of lifestyle, unless there is a specific medical reason not to vaccinate according to the American Animal Hospital Association. 9 Identified by Elanco as PM-US-24-0930 10 We recognize some of this information is found in the ISI section at the bottom of the main veterinarian website and linked webpage. However, due to the location and small size of the text, this information is not comparably noticeable or conspicuous compared to the benefit information. See 21 CFR 202.1(e)(7)(viii). 11 The two field studies conducted for approval were the field study for Control of Atopic Dermatitis and the field study for Control of Pruritus Associated with Allergic Dermatitis. 12 Treatment success for each dog was defined as at least a 50% reduction from baseline (Day 0) in owner- assessed PVAS score for pruritus or at least a 50% reduction from baseline in investigator assessed CADESI-4 (Canine Atopic Dermatitis Extent and Severity Index version 4) score for skin lesions. 13 Treatment success for each dog was defined as at least a 50% reduction from baseline (Day 0) in owner- assessed PVAS score for pruritus on at least 5 out of the first 7 days of treatment 14 Identified by Elanco as PM-US-24-1164, submitted to the DER under cover of form 2301 on September 23, 2024. U.S. Food and Drug Administration MPN 2, Room E436 12225 Wilkins Avenue Rockville, MD 20852 Zenrelia, Elanco and the diagonal bar logo are trademarks of Elanco or its affiliates. © 2025 Elanco or its affiliates. PM-US-25-0265 Cautionary Statement Regarding Forward-Looking Statements This statement contains forward-looking statements within the meaning of the federal securities laws, including, without limitation, statements concerning product launches and our 2025 full year organic constant currency revenue growth expectations. These forward-looking statements are based on our current expectations and assumptions regarding our business, the economy and other future conditions. Because forward-looking statements relate to the future, by their nature, they are subject to inherent uncertainties, risks and changes in circumstances that are difficult to predict. As a result, our actual results may differ materially from those contemplated by the forward-looking statements. Important risk factors that could cause actual results to differ materially from those in the forward-looking statements include regional, national or global political, economic, business, competitive, market and regulatory conditions, including but not limited to the following operating in a highly competitive industry; the success of our research and development (R&D) and licensing efforts; the impact of disruptive innovations and advances in veterinary medical practices, animal health technologies and alternatives to animal-derived protein; competition from generic products that may be viewed as more cost-effective; changes in regulatory restrictions on the use of antibiotics in farm animals; an outbreak of infectious disease carried by farm animals; risks related to the evaluation of animals; consolidation of our customers and distributors; the impact of increased or decreased sales into our distribution channels resulting in fluctuations in our revenues; our dependence on the success of our top products; our ability to complete acquisitions and divestitures and to successfully integrate the businesses we acquire; our ability to implement our business strategies or achieve targeted cost efficiencies and gross margin improvements; manufacturing problems and capacity imbalances, including at our contract manufacturers; fluctuations in inventory levels in our distribution channels; our dependence on sophisticated information technology systems and infrastructure, including the use of third-party, cloud-based technologies, and the impact of outages or breaches of the information technology systems and infrastructure we rely on; the impact of weather conditions, including those related to climate change, and the availability of natural resources; demand, supply and operational challenges associated with the effects of a human disease outbreak, epidemic, pandemic or other widespread public health concern; the loss of key personnel or highly skilled employees; adverse effects of labor disputes, strikes and/or work stoppages; the lack of availability or significant increases in the cost of raw materials; risks related to our presence in foreign markets; the potential impact that actions by activist shareholders could have on the pursuit of our business strategies; actions by regulatory bodies, including as a result of their interpretation of studies on product safety; the possible slowing or cessation of acceptance and/or adoption of our farm animal sustainability initiatives; the impact of increased regulation or decreased governmental financial support related to the raising, processing or consumption of farm animals; risks related to the modification of foreign trade policy; the impact of litigation, regulatory investigations, and other legal matters, including the risk to our reputation and the risk that our insurance policies may be insufficient to protect us from the impact of such matters; challenges to our intellectual property rights or our alleged violation of rights of others; misuse, off-label or counterfeiting use of our products; and unanticipated safety, quality or efficacy concerns and the impact of identified concerns associated with our products. For additional information about the factors that could cause actual results to differ materially from forward-looking statements, please see the company's latest Form 10-K and Form 10-Qs filed with the Securities and Exchange Commission. Although we have attempted to identify important risk factors, there may be other risk factors not presently known to us or that we presently believe are not material that could cause actual results and developments to differ materially from those made in or suggested by the forward-looking statements contained in this statement. Any forward-looking statement made by us in this statement speaks only as of the date thereof. Factors or events that could cause our actual results to differ may emerge from time to time, and it is not possible for us to predict all of them. We undertake no obligation to publicly update or to revise any forward-looking statement, whether as a result of new information, future developments or otherwise, except as may be required by law. Investor Contact: Tiffany Kanaga (765) 740-0314 [email protected] Media Contact: Colleen Parr Dekker (317) 989-7011 [email protected] SOURCE Elanco Animal Health WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED