TRIGR Therapeutics, Inc.

近期《Nature Reviews Drug Discovery》发表了一篇关于抗血管生成药物的综述，抗血管生成药物对于人们来说可能相对较为熟悉了，特别是以2004年2月26日，人源化抗VEGF单克隆抗体贝伐单抗(Avastin)问世为分界点，抗血管生成药物逐步在肿瘤，眼科中展现出了广泛的应用。尤其是眼科，抗VEGF单一疗法能够显著改善新生血管性AMD和糖尿病性黄斑水肿(DME)患者的视力和生活质量，阿柏西普更是代表着这类眼科疾病治疗的黄金标准。而在肿瘤中靶向VEGF的疗法也成为了多种联用手段的优选方案，其中抗血管生成＋肿瘤免疫检查点抑制剂的组合的治疗效果尤其令人瞩目。而在VEGF在眼科和肿瘤的应用之外，还有其他靶点和其他应用方式可能为血管生成药物的开发提供更广泛的适应途径，该综述对其进行了简单介绍。本文将在该综述的新靶点基础上进一步拓展。非VEGF抗血管生成靶点临床前研究表明，阻断VEGF-VEGFR信号通常会通过缺氧的可能机制引发其他促血管生成因子的过度产生，如FGFs、ANGs、肝细胞生长因子(HGF)、整联蛋白和PDGFs。这些额外的促血管生成因子不是基于抗VEGF的抗血管生成药物的靶点，因此可能提供耐药机制。此外，一些炎性细胞的浸润，也可以产生对VEGF靶点的耐药性。因此应对VEGF的耐药性，理论上来看非VEGF靶点可能提供一种补偿机制，通过使血管生成转向非VEGF依赖性来规避抗VEGF抗体的作用。但不幸的是，没有确凿的证据表明将非VEGF与VEGF一起靶向治疗能提供任何额外的益处。这也是为什么目前的研究还在临床探索阶段。ANG/Tie2血管生成素（ANG）家族与Tie2通路也参与血管形成的重要阶段，如血管重塑和成熟。Ang/Tie2轴使用酪氨酸激酶进行信号转导，在病理过程中ANG2释放更多，因此目前对Ang靶点的开发主要集中在ANG2。Ang2的表达在血管重塑和炎症过程中由内皮细胞增加和释放。Ang2作为血管生成的自分泌早期启动因子，首先破坏静止血管的稳定性，从而使VEGF驱动血管生成新生血管的增殖和趋化迁移。此外，Ang2还激活表达Tie2的单核细胞/巨噬细胞(TEMs ),它们具有自身的促血管生成、促肿瘤发生、促转移和免疫抑制功能，也有关于肿瘤细胞表达Ang2的报道。图：ANG/Tie2通路相关管线统计 来源：doi:10.15252/emmm.36866.88868688666迄今为止，抗Ang2疗法的临床测试仅限于晚期癌症疾病的评估，这些研究显示出令人失望的结果。然而，有临床前证据表明，在围手术期新辅助或辅助治疗中，调节Ang2功能或Tie1/Tie2受体的药物可能更有希望治疗或抑制早期微转移疾病。这种方法的潜在危险警告包括Ang2阻断或Tie2激活增强癌细胞肝转移的可能性。未来将Ang/Tie调节剂与其他疗法(如VEGF/VEGFR2途径抑制剂、常规(或节律)化疗或免疫疗法)相结合的研究可能值得进一步的临床前验证和未来的临床试验评估，以治疗早期疾病。虽然在癌症方面受挫，Ang-2和VEGF-A在驱动血管不稳定方面具有协同作用，来自临床前研究的数据表明，Ang-2阻断与抗VEGF治疗的组合可以有效地减少渗漏、病理性新生血管形成和炎症，从而潜在地改善视网膜和脉络膜疾病的结果。而这一临床转化已经得到很好的落实。其中特别是罗氏的VEGF/Ang2双抗Faricimab已经成功上市，并在AMD、DME等疾病中达到了终点，提升了给药间隔。国内信达的IBI324，奥赛康/蔼睦医疗的ASKG712（ AM712）也是同靶点的有利竞争者。HIF抑制剂HIF（缺氧诱导因子）是一种异二聚体转录因子，由HIF1α和HIF1β亚单位组成。HIF1α由缺氧诱导，HIF1β的组成型表达不依赖于氧水平。由于缺氧是实体瘤的特征之一，这会使得HIF途径经常被激活。除了缺氧，基因突变导致的VHL功能失活（一种肿瘤抑制基因）——例如在RCCs亚群（肾透明细胞癌亚群）和VHL综合征(希佩尔-林道综合征——一种以各种器官的异常血管增生和肿瘤为特征的遗传疾病)——也能够通过稳定作用显著增加HIF表达。重要的是，HIF在促进肿瘤发生和耐药性方面也有多重作用。有趣的是该靶点还是2019年诺贝尔生理学奖的明星靶点，由19年生理学奖得主格雷格·塞门扎（Gregg L. Semenza）发现，并因为他在这方面（理解了细胞在分子水平上感受氧气的基本原理）的贡献而获奖。实际上，HIF-1抑制剂的治疗效果已经在临床前和临床研究中反复得到证实。值得注意的是，阻断哺乳动物雷帕霉素靶蛋白(mTOR)可以抑制HIF 1α-VEGF介导的血管生成途径，表明联合应用mTOR抑制剂和抗VEGF治疗可增强临床疗效。事实上，mTOR抑制剂依维莫司确实改善了接受一线VEGFR靶向TKI lenvatinib治疗的转移性肾细胞癌患者的无进展生存期。最令人瞩目的要属默沙东的Belzutifan (MK-6482，以前称为PT2977)，该药物的疗效令人印象深刻，该药物在)治疗二三线VHL突变型肾细胞癌患者的临床中观察到36.1%的患者对Belzutifan有部分反应，62.3%的患者病情稳定。这一临床数据使得该药物在2021年8月获得FDA批准。然而，在一些研究中，HIF-1抑制剂偶尔不能表现出良好的治疗效果，这也是目前需要解决的问题。一般认为，HIF-1抑制剂的开发方向是①优化HIF-1抑制剂的药代动力学和药效学性质，②寻找多种HIF-1抑制剂的良好组合，③开发一种并行的伴随诊断方法，④通过与其他抗癌策略相结合而协同获得治疗效果。图：处于研发阶段的HIF-1抑制剂 来源：doi:10.3390/cancers13112813Notch抑制剂NOTCH受体是跨膜细胞表面蛋白，控制细胞间通讯、胚胎发生和组织定向。Notch信号控制不同生理过程的稳态，其改变可引起不同的病理状态或疾病，包括遗传性综合征或获得性恶性肿瘤。而目前人类癌症中NOTCH受体的大多数致癌性改变发生在NOTCH1基因。NOTCH1受体及其配体DLL4是血管生成的重要调节因子。DLL4在肿瘤中的高表达发生在血管内皮细胞中，并与存活率降低相关。DLL 4–Notch 1和VEGF–VEGFR 2信号通路在肿瘤微血管网络的形成中相互调节。但是DLL 4–Notch 1的临床转化却并不顺利，尽管具有有效的抗肿瘤活性，但DLL4抑制剂在肝脏、心脏、肺和皮肤中表现出广泛的毒性。OncoMed公司在I期癌症研究中，测试了人源化抗-DLL4抗体demcizumab，但胰腺癌和肺癌的II期研究因毒性和缺乏疗效而中止。又例如MedImmune（后被阿斯利康收购）的DLL4单抗MEDI0639也因为种种原因而被从管线中砍去。还有，RO4929097，MRK003，tarextumab等Notch-DLL4通路抑制剂均未给出较为积极的临床数据。此外，也有研究想要通过Notch1的更上游通路来解决毒性问题，例如SERCA抑制可以有效地控制NOTCH1的运输，并且这种阻断可以在临床前白血病模型中实现，而不会引起明显的心脏毒性，不过SERCA抑制尚且等待临床转化。最有希望的一种开发方向似乎在于DLL 4/VEGF双抗，Mereo BioPharma在收购了OncoMed公司后开始开发DLL 4/VEGF双抗 OMP-305B83（Navicixizumab），2020年Mereo与鼎航医药展开了合作，由鼎航医药获得全球开发和商业化Navi的独家授权。TRIGR Therapeutics（后被Compass Therapeutics收购）也开发了一款VEGF和DLL4双抗药物ES104（TR009），后来将大中华区权益授权给了科望医药。目前正在国内开展针对不可手术切除的局部晚期或转移性结直肠癌（CRC）的1/2期临床试验(NCT05167448)。ES104是目前我国唯一进入临床试验的靶向VEGF和DLL4的双特异性抗体候选药物。图：DLL 4/VEGF双抗作用机理 来源：科望医药官网PlGF胎盘生长因子（PlGF）是个有些争议的靶点，不少研究呈现出完全矛盾的结果，目前对于它在促进肿瘤生长、血管生成和转移中的作用仍不清楚。一些临床前研究表明，PlGF与VEGF具有相同的冗余功能，用抗PlGF抗体抑制PlGF可抑制原发性肿瘤的生长和转移。其他的一些研究却得出了相互矛盾的发现，例如，显示在多种癌症模型中发现PlGF阻断反而会缺少抗血管生成作用。此外，著名的眼科用药阿柏西普可以同时靶向VEGF（A）、PlGF和VEGFB，但阿柏西普在肿瘤用药的疗效还不如贝伐单抗。尽管阿柏西普在多种肿瘤中进行了临床研究，但它只获得了FDA对二线CRC治疗的批准。Oncurious NV开发了一款PlGF单抗TB-403（ RO5323441 ）不过临床开发并不太顺利，与贝伐单抗联合治疗实体瘤的临床研究被终止。此外，TB-403与ranibizumab (Lucentis)联合用于眼科疾病，如新生血管性AMD和DME，但是这些研究似乎也停止了。对于TB-403近期的好消息只有在原位髓母细胞瘤（MB）展现出了较为安全的初步结果，结果据称令人鼓舞：11名复发MB受试者中的7名疾病稳定，这在7名受试者中的4名中稳定持续超过100天。有趣的是，已有研究表明，至少在某些情况下，由于PlGF-VEGF异二聚体的形成，PlGF表达减少而不是促进肿瘤生长，而异二聚体在刺激血管生成方面不如VEGF有效。FGFR成纤维细胞生长因子受体(FGFR)是由四个不同基因(FGFR 1-4)编码的酪氨酸激酶受体(RTKs)家族。这些受体共享相同的典型蛋白质结构，它们的信号轴参与细胞增殖、分化、组织建模和血管生成。第一代非选择性FGFR tki与受体催化位点的ATP结合域结合，但不是激酶选择性的，也靶向其他RTK，如VEGFRs和PDGFRs。这些抑制剂具有同时靶向肿瘤血管生成和增殖的优点，但是它们显示出对FGFR信号通路的适度作用，同时具有多种副作用，这限制了它们在临床实践中的应用。尽管如此，这些治疗药物中的一些已被批准用于治疗几种肿瘤类型，通常与化疗联合使用或在一线治疗失败后使用。为了克服由于非选择性抑制剂的脱靶效应引起的并发症，已经开发了第二代选择性FGFR tki，由于该受体家族不同成员的结构同源性，大多数TKI能够靶向一种以上的FGFR。但目前只有少数进入临床试验。与非选择性TKIs相比，这些选择性治疗剂的副作用减少了，最显著的副作用表现为FGF23途径的调节，随之发生钙和磷代谢的改变，如高磷血症和组织钙化。与TKIs相比，中和性抗FGFR单克隆抗体的特征在于更高的特异性，由于没有脱靶效应，这可能降低药物毒性。总结——目前尚且离不开VEGF最后，该综述对目前的新靶点进行了总结。尽管进行了广泛的临床前和临床努力，但没有令人信服的证据表明靶向血管生成途径而非VEGF在癌症或眼科疾病中提供治疗益处。虽然HIF和mTOR抑制剂已被批准用于治疗肾细胞癌，但它们的作用至少部分是由VEGF抑制介导的。该综述期望，综述内提到的靶点能够改善目前的情况。扩展阅读:VEGF靶向药物革新参考来源：Shirai Y, Chow CCT, Kambe G, Suwa T, Kobayashi M, Takahashi I, Harada H, Nam JM. 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Targeting oncogenic Notch signaling with SERCA inhibitors. J Hematol Oncol. 2021 Jan 6;14(1):8. doi: 10.1186/s13045-020-01015-9. PMID: 33407740; PMCID: PMC7789735.Saulnier-Sholler G, Duda DG, Bergendahl G, Ebb D, Snuderl M, Laetsch TW, Michlitsch J, Hanson D, Isakoff MS, Bielamowicz K, Kraveka JM, Ferguson W, Carmeliet P, De Deene A, Gijsen L, Jain RK. A Phase I Trial of TB-403 in Relapsed Medulloblastoma, Neuroblastoma, Ewing Sarcoma, and Alveolar Rhabdomyosarcoma. Clin Cancer Res. 2022 Sep 15;28(18):3950-3957. doi: 10.1158/1078-0432.CCR-22-1169. PMID: 35833850; PMCID: PMC9481695.Ghedini GC, Ronca R, Presta M, Giacomini A. Future applications of FGF/FGFR inhibitors in cancer. Expert Rev Anticancer Ther. 2018 Sep;18(9):861-872. doi: 10.1080/14737140.2018.1491795. Epub 2018 Jul 2. PMID: 29936878.Cao, Y., Langer, R. & Ferrara, N. Targeting angiogenesis in oncology, ophthalmology and beyond. Nat Rev Drug Discov (2023). https://doi.org/10.1038/s41573-023-00671-z

Study site initiations in the United States for a randomized Phase 2/3 study of CTX-009 with paclitaxel in patients with Biliary Tract Cancers (BTC) and a Phase 2 of CTX-009 in patients with Colorectal Cancer (CRC) are ongoing; patient enrollment for both studies is expected during the fourth quarter of 2022 Formed a clinical collaboration and supply agreement with Merck to evaluate CTX-471 in combination with KEYTRUDA® (pembrolizumab) in patients with selected solid tumors; patient screening began in November 2022 Initiated preclinical toxicology studies for CTX-8371; IND filing and first in human clinical study are anticipated in the first half of 2023 Cash and marketable securities balance of $120.6 million as of September 30, 2022 Issued and sold an aggregate of 25,000,000 common shares (approximately $80 million in gross proceeds) in a private investment in public company (PIPE) financing to a selected group of institutional investors; the proceeds thereof, combined with the existing cash and marketable securities as of September 30, 2022, are expected to extend the cash runway into 2026 BOSTON, Nov. 09, 2022 (GLOBE NEWSWIRE) -- Compass Therapeutics Inc. (Nasdaq: CMPX), a clinical-stage, oncology-focused biopharmaceutical company developing proprietary antibody-based therapeutics to treat multiple human diseases, today reported third quarter and year-to-date 2022 financial results and provided a corporate update. “We are very pleased to initiate multiple studies, including a Phase 2/3 study of CTX-009 in patients with biliary tract cancer and a phase 2 study in patients with colorectal cancer, while at the same time advancing our CTX-471 and CTX-8371 programs in development” said Thomas Schuetz, M.D., Ph.D., Chief Executive Officer and Scientific Founder of Compass. “Our recent equity financing puts us in a very strong financial position with cash runway well beyond the projected key clinical data and regulatory milestones.” Development Pipeline CTX-009 (DLL4 and VEGF-A bispecific antibody) Following discussions with the United States Food and Drug Administration (FDA), Compass is initiating a randomized Phase 2/3 study of CTX-009 in the United States in combination with paclitaxel in second-line BTC patients. Depending on the results of the study, it could serve as a registrational study (see Clinicaltrials.gov) Compass plans to begin enrollment in a Phase 2 study of CTX-009 in patients with advanced metastatic CRC in the United States in the fourth quarter of 2022 (see Clinicaltrials.gov) CTX-471 (CD137 agonistic monoclonal antibody) The Phase 1b of CTX-471 as a monotherapy in patients with advanced solid tumors who received at least one checkpoint blocker is ongoing. The study is fully enrolled with 4 partial responses (PRs) observed and 3 of the 4 confirmed by RECIST as of September 30, 2022 In September 2022, Compass announced a clinical collaboration and supply agreement with Merck to evaluate CTX-471 in combination with KEYTRUDA® (pembrolizumab) in patients who have progressed following initial response to a PD-1 regimen As of November 2022, Compass has begun screening patients in the combination arm of the study CTX-8371 (PD-1 and PD-L1 bispecific antibody) GMP manufacturing campaign was completed, and non-human primate toxicology studies were initiated IND filing and initiation of a first-in-human clinical study are anticipated in the first half of 2023 Financial Results for Third Quarter and Nine Months Ended September 30, 2022 Cash Position As of September 30, 2022, cash and marketable securities were $120.6 million as compared to $144.5 million as of December 31, 2021; Compass used $23.0 million of cash to fund operations in the first nine months of 2022. In November 2022, Compass increased its cash position by approximately $76 million, after deducting fees to the placement agents and other offering expenses, from a PIPE financing that generated gross proceeds of approximately $80 million. Net Loss Net loss for the third quarter ended September 30, 2022, was $12.0 million or $0.12 per common share, compared to $6.0 million or $0.10 per common share for the same period in 2021. Net loss for the nine months ended September 30, 2022, was $27.6 million or $0.27 per common share, compared to $69.2 million or $1.26 per common share for the same period in 2021. In 2021, Compass recorded $50.6 million of in-process Research and Development (R&D) expense related to the acquisition of Trigr Therapeutics, Inc. Excluding this expense, the net loss for the first nine months of 2021 would have been $18.6 million, or $0.34 per common share. R&D Expenses R&D expenses were $9.8 million for the third quarter ended September 30, 2022, as compared to $3.2 million for the same period in 2021, an increase of $6.6 million, or 210%. R&D expenses were $20.1 million for the nine months ended September 30, 2022, as compared to $10.8 million for the same period in 2021, an increase of $9.3 million, or 86%. The increase from 2021 for the quarter and year was primarily attributable to increased development program expenses, predominantly related to CTX-009. General and Administrative (G&A) Expenses G&A expenses were $2.8 million for the third quarter ended September 30, 2022, as compared to $2.7 million for the same period in 2021, an increase of $0.1 million, or 4%. G&A expenses were $8.7 million for the nine months ended September 30, 2022, as compared to $7.5 million for the same period in 2021, an increase of $1.2 million, or 16%. The increase from 2021 for the quarter and year was primarily attributable to increased stock compensation expense. About Compass Therapeutics Compass Therapeutics, Inc. is a clinical-stage, oncology-focused biopharmaceutical company developing proprietary antibody-based therapeutics to treat multiple human diseases. Compass’s scientific focus is on the relationship between angiogenesis, the immune system, and tumor growth. Compass’s pipeline of novel product candidates is designed to target multiple critical biological pathways required for an effective anti-tumor response. These include modulation of the microvasculature via angiogenesis-targeted agents, induction of a potent immune response via activators on effector cells in the tumor microenvironment, and alleviation of immunosuppressive mechanisms used by tumors to evade immune surveillance. Compass plans to advance its product candidates through clinical development as both standalone therapies and in combination with proprietary pipeline antibodies based on supportive clinical and nonclinical data. Compass was founded in 2014 and is headquartered in Boston, Massachusetts. For more information, visit the Compass Therapeutics, Inc. website at . We periodically provide other information for investors on our corporate website, . This includes press releases and other information about financial performance, information on corporate governance, and details related to our annual meeting of stockholders. We intend to use our website as a means of disclosing material non-public information and for complying with our disclosure obligations under Regulation FD. Accordingly, investors should monitor our website, in addition to following Compass’s press releases, SEC filings, and public conference calls and webcasts. Forward-Looking Statements This press release contains forward-looking statements. Statements in this press release that are not purely historical are forward-looking statements. Such forward-looking statements include, among other things, references to Compass’s financial position to continue advancing its product candidates, expectations about Compass’s cash runway lasting into 2026, business and development plans, and statements regarding Compass’s product candidates, their development, regulatory plans with respect thereto and therapeutic potential thereof, planned interactions with regulatory authorities, and planned clinical development. Actual results could differ from those projected in any forward-looking statements due to numerous factors. Such factors include, among others, Compass’s ability to raise the additional funding it will need to continue to pursue its business and product development plans, the inherent uncertainties associated with developing product candidates and operating as a development stage company, Compass’s ability to identify additional product candidates for development, Compass’s ability to develop, complete clinical trials for, obtain approvals for and commercialize any of its product candidates, competition in the industry in which Compass operates and market conditions. These forward-looking statements are made as of the date of this press release, and Compass assumes no obligation to update the forward-looking statements, or to update the reasons why actual results could differ from those projected in the forward-looking statements, except as required by law. Investors should consult all of the information set forth herein and should also refer to the risk factor disclosure set forth in the reports and other documents Compass files with the SEC available at including without limitation Compass’s latest Form 10-Q and subsequent filings with the SEC. Investor Contact Mario Corso, Investor Relations ir@compasstherapeutics.com Media Contact Anna Gifford, Communications Manager media@compasstherapeutics.com 617-500-8099 Compass Therapeutics, Inc. and Subsidiaries Consolidated Statement of Operations (unaudited) (In thousands, except per share data) Three Months Ended september 30, Nine Months Ended September 30, 2022 2021 2022 2021 Operating expenses: Research and development $ 9,791 $ 3,154 $ 20,069 $ 10,763 General and administrative 2,807 2,700 8,698 7,500 In-process R&D — — — 50,618 Total operating expenses 12,598 5,854 28,767 68,881 Loss from operations (12,598 ) (5,854 ) (28,767 ) (68,881 ) Other income (expense), net 623 (121 ) 1,136 (306 ) Loss before income tax expense (11,975 ) (5,975 ) (27,631 ) (69,187 ) Income tax expense — — — (13 ) Net loss $ (11,975 ) $ (5,975 ) $ (27,631 ) $ (69,200 ) Net loss per share - basic and diluted $ (0.12 ) $ (0.10 ) $ (0.27 ) $ (1.26 ) Basic and diluted weighted average shares outstanding 101,010 61,694 100,939 55,003 Compass Therapeutics, Inc. and Subsidiaries Consolidated Balance Sheets (In thousands, except par value) September 30, 2022 (unaudited) December 31, 2021 Assets Current assets: Cash and cash equivalents $ 16,481 $ 144,514 Short-term marketable securities 104,121 — Prepaid expenses and other current assets 1,952 2,591 Total current assets 122,554 147,105 Property and equipment, net 1,708 2,243 Operating lease, right-of-use ("ROU") asset 3,256 4,089 Other assets 320 320 Total assets $ 127,838 $ 153,757 Liabilities and Stockholders' Equity Current liabilities: Accounts payable $ 2,761 $ 867 Accrued expenses 5,742 8,775 Operating lease obligations, current portion 1,075 989 Total current liabilities 9,578 10,631 Operating lease obligations, long-term portion 2,144 3,048 Total liabilities 11,722 13,679 Stockholders' equity: Common stock, $0.0001 par value: 300,000 shares authorized; 101,286 and 101,303 shares issued at June 30, 2022 and December 31, 2021, respectively; 100,967 and 100,832 shares outstanding at June 30, 2022 and December 31, 2021, respectively 10 10 Additional paid-in-capital 377,967 373,657 Accumulated other comprehensive loss (641 ) Accumulated deficit (261,220 ) (233,589 ) Total stockholders' equity 116,116 140,078 Total liabilities and stockholders' equity $ 127,838 $ 153,757

JERUSALEM, July 18, 2022 (GLOBE NEWSWIRE) -- Entera Bio Ltd. (NASDAQ: ENTX), a leader in the development of orally delivered peptides and therapeutic proteins, announced today the execution of the following key milestones: The U.S. Food and Drug Administration (FDA) has granted Entera’s request for a Type C Meeting based on the revised phase 3 registrational study for lead clinical asset, EB613 (oral formulation of PTH (1-34, teriparatide), as the first oral anabolic drug to treat post-menopausal women with osteoporosis. The meeting is expected in H2 2022Following its End of Phase 2 Meeting with the FDA, Entera designed the pivotal study for EB613 as an 18 month double blind placebo-controlled study, followed by a 6-month open label transition to alendronate for all patientsThe study’s primary endpoint employs the Foundation for the National Institutes of Health Bone Quality Program (FNIH BQP) total hip Bone Mineral Density (BMD) as a surrogate endpoint to evaluate fracture risk. FDA re-confirmed that with a well-designed BMD study, EB613 approval would not require a fracture studyIn line with her increased executive role since earlier this year, Ms. Miranda Toledano, Entera Board Member and industry veteran with over 20 years of experience succeeds Dr. Spiros Jamas as Chief Executive Officer FDA Acceptance of Type C Meeting: Phase 3 Design of EB613 Under Review During Entera’s End of Phase 2 Meeting, FDA’s Division of Endocrinology remarked on the FNIH BQP published meta-regression analysis which is based on patient-level BMD and fracture incidence data from more than 22 placebo-controlled fracture endpoint studies across all classes of osteoporosis drugs, including teriparatide. The FNIH BQP data indicate that changes in Total Hip BMD (in contrast to lumbar spine or femoral neck BMD measurements) provides a superior surrogate marker of an osteoporosis drug’s effects on vertebral, nonvertebral and all site fracture risk. The FNIH BQP BMD data and Surrogate Threshold Effects (STEs) are in the process of qualification by the FDA to become the first surrogate endpoint for fracture risk reduction1. FDA suggested that Entera explore the FNIH BQP STEs and the design of a placebo-controlled study as an alternative to the originally contemplated non-inferiority design versus Forteo.® Entera has since submitted to the FDA, as part of its Type C briefing documents, a revised Phase 3 protocol. The study is expected to be an 18-month randomized, double-blind, multicenter study comparing the effects of oral PTH (1-34, teriparatide) EB613 vs. placebo on BMD in post-menopausal women with osteoporosis at high risk of fracture, followed by a 6-month open-label extension where all patients will be transitioned to alendronate, a standard of care anti-resorptive therapy. 1 Black DM et. al. The Lancet. Diabetes & Endocrinology 2020 Eastell R et. al. JBMR 2021FDA Approves Biomarker Qualification Plan for the First Surrogate Endpoint in Anti-Osteoporosis Drug Trials, June 1st, 2022, https://www.fnih.org/news/announcements/fda-approves-biomarkers-qualification-plan-first-surrogate-endpoint-anti Patients will be randomized in a 2:1 ratio to receive blinded treatments with either EB613 (N=400) 2.5mg dose of oral PTH or Placebo (N=200). The 6-month extension phase of the study is intended to provide information on the transition from EB613 to a standard anti-resorptive therapy which has been shown to maintain or augment the increases in BMD following injectable PTH therapies, to preserve blinding of the prior therapy and to ensure that patients randomized to the placebo arm also receive an osteoporosis treatment. The primary objective or endpoint of the phase 3 study will evaluate the effect of daily oral EB613 treatment on percent change in Total Hip BMD over 18 months versus placebo. Statistical methods will compare the observed treatment effect compared to pre-defined STEs associated with vertebral fracture, all site fracture and nonvertebral fracture risk reduction. The study will also look at secondary endpoints including changes in lumbar spine and femoral neck BMD and EB613’s effects on biochemical markers of bone formation and resorption. “In the past months, Entera has invested a considerable amount of time aligning our proposed Phase 3 study with FDA’s EOP2 guidance, with the support of our clinical and statistical team, world-renowned scientific and clinical leaders in osteoporosis drug development, and representative institutional review boards. We are appreciative of FDA’s inputs and believe that the current Phase 3 design is a much de-risked pivotal study pathway and enables us to continue to study a similar patient population, based on T-Score and other criteria, as in our Phase 2 dose ranging study which met its 3-month biomarker and 6-month BMD endpoints. We look forward to providing updates to you on the outcome of our conversation with FDA later this year,” said Miranda Toledano, Entera’s Chief Executive Officer. CEO Transition Entera’s Board of Directors appointed Miranda Toledano as Chief Executive Officer (CEO) as of July 15th, 2022, succeeding Dr. Spiros Jamas. Chairman of the Board Mr. Jerry Lieberman said, “The management transition reflects a strategic reorientation of Entera as we embark on pivotal clinical development and ongoing strategic discussions. I am thrilled to announce Miranda as our new CEO. Her fundamental understanding of Entera’s pipeline and transaction-focused track record in the industry is aligned to the current stage of the Company. Her contributions as an independent board member for the last 4 years also demonstrate her passion and commitment to establishing Entera as a leading biopharmaceutical entity. On behalf of Entera’s Board, we would like to recognize and thank Dr. Spiros Jamas for his contributions to Entera and advancement to success across our core programs.” Ms. Toledano stated, “We are laser focused on unlocking the value of Entera’s oral delivery platform and core therapeutic assets. Both of our lead oral PTH drug candidates, EB613 for the treatment of osteoporosis and EB612 for the treatment of hypoparathyroidism are highly differentiated with the potential to meaningfully change the treatment paradigm and the lives of patients in their respective indications. I am excited to take on the challenge of leading Entera at this critical time and help the Company forge forward which is why I first took more executive responsibility a few months ago. We believe that Entera’s science has poised it as one of the leading entities in transforming the profile of therapeutic proteins to an oral route of administration. We further believe that this is especially valuable in chronically treated indications such as osteoporosis where most patients are under-treated because of the high cost and their reluctance to take injectable drugs. EB613 is positioned as a viable anabolic (bone formation) option to potentially lower the risk of fractures for a much wider population of post-menopausal osteoporotic women versus SC injected PTH drugs. We believe EB613 will deliver a tablet form (oral) PTH to fulfill the promise of this validated therapeutic class.” Dr. Jamas said, “I’m very proud of the significant progress we made advancing Entera’s lead oral PTH asset, EB613 for the treatment of osteoporosis towards a pivotal Phase 3 study, including successfully completing the Phase 2 study. We demonstrated and presented data on the utility of Entera’s oral delivery platform with other peptides, filed IP on a new and improved oral delivery platform and strengthened the management team. I support this transition and have full confidence that the team will realize Entera’s full potential.” Ms. Toledano has served as a Member of the Board of Directors at Entera since 2018, and as Member of the Scientific Advisory Committee since February 2022. In May 2022, she also joined as Entera’s Chief Business Officer and Chief Financial Officer. Previously, Miranda served as Chief Operating Officer, Chief Financial Officer, and Director of TRIGR Therapeutics, an oncology focused, clinical stage bispecific antibody company acquired by Compass Therapeutics (Nasdaq: CMPX) in June 2021 just 3 years after its establishment with her co-founder George Uy. At TRIGR, Miranda oversaw the clinical development of lead asset TR009 (now CTX-009) and led strategic execution, including a $117 million China License Transaction and acquisition by CMPX. Previously, Ms. Toledano served as Head of Healthcare Investment Banking at MLV & Co. (acquired by B. Riley FBR & Co.), where she completed biotech equity financings (IPOs, ATMs, and follow-ons) totaling over $4 billion in aggregate value. Earlier in her career, Ms. Toledano served as vice president in the investment group of Royalty Pharma. Ms. Toledano is also a member of the board of directors of Journey Medical (Nasdaq: DERM) and NEXGEL (Nasdaq: NXGL). Ms. Toledano holds a B.A. in Economics from Tufts University and an MBA in Finance and Entrepreneurship from the NYU Stern School of Business. About EB613 Parathyroid hormone (PTH) is an 84-amino acid hormone and the primary regulator of calcium and phosphate metabolism in bone and kidney. EB613 is an oral formulation of synthetic hPTH (1-34), (teriparatide), a peptide consisting of the first 34 amino acids of PTH which represent the functional region. Subcutaneous Forteo® (teriparatide injection) has been the leading anabolic treatment of osteoporosis since 2002. EB613 utilizes Entera’s oral drug delivery platform which promotes enteric absorption and stabilizes teriparatide in the gastrointestinal tract. Entera’s Oral PTH formulations have been administered collectively to a total of 225 subjects in two Phase 1 studies and 3 phase 2 studies (including 35 in 2 phase 2 hypoparathyroidism studies). The most recent study was a dose ranging Phase 2 study in postmenopausal women with low bone mass. This study met primary and key secondary endpoints and was presented in a late-breaker oral presentation at the ASBMR 2021 conference. For the primary efficacy endpoint: a statistically significant increase in P1NP (a bone formation marker) at 3 months was achieved. A significant dose response was observed for 0.5, 1.0, 1.5 and 2.5 mg oral PTH doses on P1NP, Osteocalcin and bone mineral density (BMD). Subjects receiving the 2.5 mg dose of EB613 showed significant increases in dose-related BMD at the lumbar spine, total hip, and femoral neck at 6 months. Subjects receiving the 2.5 mg dose of EB613 daily for 6 months had a significant placebo adjusted increase of 3.78% in lumbar spine BMD (p<0.008) which is similar to the 3.9% increase in lumbar spine BMD seen with Forteo® in clinical studies reported in the literature2. Increases in total hip and femoral neck BMD were greater than those previously reported with Forteo®. EB613 exhibited an excellent safety profile, with no drug related serious adverse events. The most common adverse events included mild nausea, moderate back pain, moderate headache, and moderate upper abdominal pain. 2 Leder BZ et.al. JCEM 2015 About Entera Bio Entera is a leader in the development of orally delivered large molecule therapeutics for use in areas with significant unmet medical need where adoption of injectable therapies is limited due to cost, convenience and compliance challenges for patients. The Company’s proprietary, oral drug delivery technology is designed to address the technical challenges of poor absorption, high variability, and the inability to deliver large molecules to the targeted location in the body through the use of a synthetic absorption enhancer to facilitate the absorption of large molecules, and protease inhibitors to prevent enzymatic degradation and support delivery to targeted tissues. The Company’s most advanced product candidates, EB613 for the treatment of osteoporosis and EB612 for the treatment of hypoparathyroidism are in clinical development. The Company recently completed the phase 2 study for EB613. Entera also licenses its technology to biopharmaceutical companies for use with their proprietary compounds and, to date, has established a collaboration with Amgen Inc. For more information on Entera Bio, visit www.enterabio.com. Cautionary Statement Regarding Forward Looking Statements Various statements in this press release are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 (PSLRA). All statements (other than statements of historical facts) in this press release regarding our prospects, plans, financial position, business strategy and expected financial and operational results may constitute forward-looking statements. Words such as, but not limited to, “anticipate,” “believe,” “can,” “could,” “expect,” “estimate,” “design,” “goal,” “intend,” “may,” “might,” “objective,” “plan,” “predict,” “project,” “target,” “likely,” “should,” “will,” and “would,” or the negative of these terms and similar expressions or words, identify forward-looking statements. Forward-looking statements are based upon current expectations that involve risks, changes in circumstances, assumptions and uncertainties. Forward-looking statements should not be read as a guarantee of future performance or results and may not be accurate indications of when such performance or results will be achieved. Important factors that could cause actual results to differ materially from those reflected in Entera’s forward-looking statements include, among others: changes in our interpretation of the 3-month biomarker data from the Phase 2 clinical trial of EB613, the timing of data readouts from the Phase 2 clinical trial of EB613, the full results of the Phase 2 clinical trial of EB613 and our analysis of those full results, the FDA’s interpretation and review of our results from and analysis of our Phase 2 trial of EB613, unexpected changes in our ongoing and planned preclinical development and clinical trials, the timing of and our ability to make regulatory filings and obtain and maintain regulatory approvals for our product candidates; the potential disruption and delay of manufacturing supply chains, loss of available workforce resources, either by Entera or its collaboration and laboratory partners, due to travel restrictions, lay-offs or forced closures or repurposing of hospital facilities; impacts to research and development or clinical activities that Entera is contractually obligated to provide, such as those pursuant to Entera’s agreement with Amgen; overall regulatory timelines, if the FDA or other authorities are closed for prolonged periods, choose to allocate resources to review of COVID-19 related drugs or believe that the amount of Phase 2 clinical data collected are insufficient to initiate a Phase 3 trial, or a meaningful deterioration of the current political, legal and regulatory situation in Israel or the United States; the availability, quality and timing of the data from the Phase 2 clinical trial of EB613 in osteoporosis patients; the size and growth of the potential market for EB613 and Entera’s other product candidates including any possible expansion of the market if an orally delivered option is available in addition to an injectable formulation; the scope, progress and costs of developing Entera’s product candidates including EB612 and GLP-2; Entera’s reliance on third parties to conduct its clinical trials; Entera’s expectations regarding licensing, business transactions and strategic collaborations; Entera’s operation as a development stage company with limited operating history; Entera’s ability to continue as a going concern absent access to sources of liquidity; Entera’s expectations regarding its expenses, revenue, cash resources, liquidity and financial condition; Entera’s ability to raise additional capital; Entera’s interpretation of FDA feedback and guidance and how such guidance may impact its clinical development plans; Entera’s ability to obtain and maintain regulatory approval for any of its product candidates; Entera’s ability to comply with Nasdaq’s minimum listing standards and other matters related to compliance with the requirements of being a public company in the United States; Entera’s intellectual property position and its ability to protect its intellectual property; and other factors that are described in the “Cautionary Statement Regarding Forward-Looking Statements,” “Risk Factors”, “Management’s Discussion and Analysis of Financial Condition and Results of Operations” sections of Entera’s more recent annual, quarterly and current report and other documents filed by Entera with the SEC and available free of charge on the SEC’s website at http://www.sec.gov. There can be no assurance that the actual results or developments anticipated by Entera will be realized or, even if substantially realized, that they will have the expected consequences to, or effects on, Entera. Therefore, no assurance can be given that the outcomes stated in such forward-looking statements and estimates will be achieved. The information in this release is provided only as of the date of this release, and Entera undertakes no obligation, to update or revise publicly any forward-looking statements, whether as a result of new information, future events or otherwise, except to the extent required by law.