TNFRSF14

8 月 15 日，世界肺癌大会（WCLC）官网公布了本届大会（2024 年 9 月 7 日~9 月 10 日在美国召开）入选摘要详细信息，君实生物自主研发的抗 BTLA 单抗 Tifcemalimab 成功入选大会口头报道，将公布 Tifcemalimab 联合特瑞普利单抗用于难治性广泛期小细胞肺癌（ES-SCLC）的最新临床证据。 最新的Ⅰ/Ⅱ期临床研究（NCT05000684）结果显示：在40例患者中，ORR 为 32.6%， DCR 为 51.2%。 Tifcemalimab 是全球首个进入临床开发阶段（first-in-human）的 BTLA 单抗，目前也是全球该靶点上进度最快的新药。 NCT05000684 是一项多中心、两队列、开放标签的Ⅰ/Ⅱ期临床研究，旨在晚期肺癌（包括非小细胞肺癌和小细胞肺癌）患者中评估 Tifcemalimab 联合特瑞普利单抗治疗的安全性和抗肿瘤活性。 截图来源：Insight数据库 2023 年 ASCO 年会上，该研究首次报告了队列 2——Tifcemalimab 联合特瑞普利单抗用于难治性 ES-SCLC 的初步数据，此次 WCLC 大会上将更新报告该队列的疗效、安全性和生物标志物分析结果。 该队列纳入既往治疗失败的难治性 ES-SCLC 患者，接受 Tifcemalimab（200 mg，Q3W）联合特瑞普利单抗（240 mg，Q3W）治疗，直至疾病进展、出现不可耐受的毒性或完成 2 年治疗。主要终点包括安全性和研究者根据 RECISTv1.1 标准评估的客观缓解率（ORR）。 自 2021 年 8 月至 2023 年 1 月，共入组 43 例难治性 ES-SCLC 患者。中位年龄位 59.0（范围：38~75）岁，男性占比 79.1%（34 例）。44.2%（19 例）患者既往接受了≥2 线系统治疗。截至 2024 年 3 月 14 日，中位随访时间为 11.17 个月。 在抗肿瘤活性方面结果显示： 40 例疗效可评估患者，ORR 为 32.6%，疾病控制率（DCR）为 51.2%。 中位缓解持续时间为 5.7 个月（95% CI 2.0-14.6）。中位无进展生存期（PFS）为 2.8 个月（95% CI 1.4-4.4），中位总生存期（OS）为 12.3 个月（95% CI 7.8-15.7）。 生物标志物分析结果显示，在 PD-L1 或 HVEM 表达阳性的患者中观察到更高的 ORR 和 DCR，将进一步更新生物标志物分析结果。 在安全性方面，39 例 (90.7%) 患者发生了治疗期间出现的不良事件（TEAE），其中≥3 级 TEAE 发生率为 39.5%。最常见的 TEAE 包括贫血（25.6%）、血清肌酸磷酸激酶升高（25.6%）、丙氨酸氨基转移酶升高（23.3%）、COVID-19（23.3%）、高血糖症（23.3%）、低钠血症（20.9%）和甲状腺功能减退（20.9%）。未发生因 TEAE 导致的停药。18 例（41.9%）患者发生免疫相关不良事件（irAE），其中 4 例患者发生了≥3 级 irAE。 综合来看，Tifcemalimab 联合特瑞普利单抗用于难治性 ES-SCLC 显示出极具前景的抗肿瘤活性且安全性可管理，值得在 SCLC 患者中进一步进行临床评估。 目前，Tifcemalimab 已获准进入 III 期临床研究阶段，另有多项联合特瑞普利单抗的 Ib/II 临床研究正在中国和美国同步开展中，覆盖多个瘤种。 据 Insight 数据库显示，Tifcemalimab 在国内已经进入 Ⅰ 期临床的适应症有实体瘤、淋巴瘤、黑色素瘤、肾癌和尿路上皮癌；进入 Ⅰ/Ⅱ 期临床试验的适应症有头颈部鳞状细胞癌、鼻咽癌、非小细胞肺癌、鳞状非小细胞肺癌、非鳞状非小细胞肺癌；进入 Ⅲ 期的适应症有小细胞肺癌和经典型霍奇金淋巴瘤。 封面来源：企业 Logo 免责声明：本文仅作信息分享，不代表 Insight 立场和观点，也不作治疗方案推荐和介绍。如有需求，请咨询和联系正规医疗机构。 PR 稿对接：微信 insightxb 投稿：微信 insightxb；邮箱 insight@dxy.cn 多样化功能、可溯源数据…… Insight 数据库网页版等你体验 点击阅读原文，立刻解锁！

本文研究结果表明，对人群偶发性中风影响不大的两种蛋白似乎会影响偶发性AIS后的MACE，这些关联研究表明，炎症或许是AIS事件后MACE结局的一种促进因素，这或许就进一步强调了其作为新型靶点的重要性。 经历动脉缺血性中风（AIS, arterial ischemic stroke）或短暂性缺血性中风（TIA, transient ischemic stroke）的患者发生二次中风或其它主要心血管不良事件（MACE, major adverse cardiovascular event）的风险会增加，因此识别出其中的风险因素和疗法来预防这些后续事件的发生就显得尤为重要。 近日，一篇发表在国际杂志Stroke上题为“Protein Identification for Stroke Progression via Mendelian Randomization in Million Veteran Program and UK Biobank”的研究报告中，来自布里斯托尔大学等机构的科学家们通过研究识别出了新型遗传和分子风险因素，其或有望揭示新型途径来治疗经历第一次中风后的患者。 文章中，研究人员发现，CCL27和TNFRSF14两种蛋白或许与随后的MACE有关，但却与最初患者的中风无关；众所周知，这些蛋白能激活炎症，而炎症在中风的发生和很多慢性疾病发生过程中扮演着非常关键的角色。本文研究结果表明，当个体发生首次中风后，炎症或许是影响患者MACE结局的一个重要因素。研究者Nimish Adhikari博士说道，尽管此前研究发现了炎症和AIS/MACE事件之间的关联，但我们的研究发现，这些因果性蛋白或许在随后的MACE事件中发挥着重要作用，这或许就会帮助发现潜在的新型药物靶点。 科学家识别出两种能促进人类中风复发的特殊蛋白 图片来源：Stroke (2024). DOI:10.1161/STROKEAHA.124.047103 利用来自两大生物样本库（VA的百万退伍军人计划和英国生物样本库）中的遗传信息和医学历史数据，研究人员进行了祖先特异性全基因组关联性研究（GWAS）来寻找DNA和疾病事件以及随后的AIS和MACE之间的关联。GWAS通常用来确定个体是否首次发生医疗事件，但将这一方法应用于随后的MACE事件或许能提供关于患者中风进展的新见解，这些信息对于治疗性药物的识别非常有价值。文章中，研究人员共对遭受突发性中风的93,422名个体进行了分析，其中51,929名个体随后发生了MACE，45,120名个体随后发生了AIS。 在群体特异性分析中，研究人员观察到了两个重要的遗传突变：rs76472767和rs13294166，前者靠近GWAS 随后会发生MACE的非洲裔祖先机体1号染色体上的RNF220基因；后者则靠近GWAS 随后会发生AIS的相同祖先机体9号染色体的LINC01492基因。Elmore说道，我们利用这些数据来阐明是否存在某些分子与事件发生或随后的发生状态有关，因此，我们就能识别出在炎症中扮演重要角色的特定分子和这些中风及MACE结局之间的关联。尽管在过去三十年里，人群中风的发生率在全球范围内都有所下降，但其仍然是全球人群死亡的第二大原因和引起残疾的第三大原因，同时也是影响全球人群健康的重要公共卫生问题。 中风会继续不成比例地影响不同种族、社会经济和地理线的人群，从而就会进一步加剧高收入国家和低收入国家的卫生不平等状况，识别出开发新型治疗干预性措施的新型药物靶点来阻断中风的进展，或许能让数百万人免于中风相关的残疾和死亡。目前研究人员并不清楚是否靶向作用中风的其它可修饰风险因素就能帮助开发新型疗法来帮助那些经历第一次中风的患者进行治疗。研究人员期待将这一研究扩展到除中风以外的其它心脏代谢健康研究中。 综上，本文研究结果表明，对人群偶发性中风影响不大的两种蛋白似乎会影响偶发性AIS后的MACE，这些关联研究表明，炎症或许是AIS事件后MACE结局的一种促进因素，这或许就进一步强调了其作为新型靶点的重要性。（生物谷Bioon.com） 参考文献： Andrew R. Elmore, MPH, Nimish Adhikari, BSc, April E. Hartley, PhD, et al. Protein Identification for Stroke Progression via Mendelian Randomization in Million Veteran Program and UK Biobank, Stroke (2024). DOI: 10.1161/STROKEAHA.124.047103

Topline results from planned Phase 2 trial of AVTX-009 in hidradenitis suppurativa expected in 2026Cash on hand of approximately $110 million as of March 31, 2024 with expected cash runway into 2027 WAYNE, Pa. and ROCKVILLE, Md., May 13, 2024 (GLOBE NEWSWIRE) -- Avalo Therapeutics, Inc. (Nasdaq: AVTX), today announced business updates and financial results for the first quarter of 2024. “Over the past month we have made considerable progress toward initiating our planned Phase 2 trial of AVTX-009 in hidradenitis suppurativa. Our experienced team has been working closely with subject matter experts on trial enabling activities, and we plan to have the trial underway this year,” said Dr. Garry Neil, Chief Executive Officer and Chairman of the Board. “Our main focus remains on the initiation of the Phase 2 trial in hidradenitis suppurativa. Upon trial initiation, we plan to expand our focus to include the evaluation and announcement of a second indication, as well as pursuing the development of a next generation anti-IL-1β mAb.” Program Updates and Milestones: AVTX-009: Anti-IL-1β monoclonal antibody (mAb) targeting inflammatory diseases. Avalo is pursuing the development of AVTX-009 in hidradenitis suppurativa and expects topline data from its planned Phase 2 trial in hidradenitis suppurativa in 2026.In addition to hidradenitis suppurativa, Avalo plans to develop AVTX-009 in at least one other chronic inflammatory indication. Next Generation anti-IL-1β mAb. Avalo is pursuing a next generation anti-IL-1β with an extended half-life. Quisovalimab (AVTX-002): Anti-LIGHT mAb targeting immune-inflammatory diseases. Avalo is conducting a strategic review of the quisovalimab program. AVTX-008: B and T Lymphocyte Attenuator (BTLA) agonist fusion protein targeting immune dysregulation disorders. Avalo is conducting a strategic review of the AVTX-008 program. First Quarter 2024 Financial Update: As of March 31, 2024, Avalo had $110.2 million in cash and cash equivalents. In March 2024, the Company closed a private placement investment for up to $185.0 million in gross proceeds, including an initial upfront gross investment of $115.6 million. The Company could receive up to an additional $69.4 million of gross proceeds upon the exercise of the warrants issued in the financing. The Company’s current cash on hand is expected to fund operations through the data readout of our planned Phase 2 trial in hidradenitis suppurativa and into 2027. For the three months ended March 31, 2024, Avalo generated a net loss of $121.3 million. The increase in net loss as compared to the prior period was primarily driven by the excess of warrant fair value over private placement proceeds. The warrants did not satisfy the conditions to be accounted for as an equity instrument and therefore were classified as a liability upon issuance. The initial fair value of the warrants at issuance was $194.9 million, which exceeded the upfront gross proceeds of $115.6 million, resulting in a $79.3 million loss recognized for the three months ended March 31, 2024. The fair value of the warrant liability was estimated using a Black-Scholes option-pricing model and the key variable input driving the fair value was the closing stock price of $21.75 on March 28, 2024, which was the initial valuation date, as well as the last trading day of the first quarter of 2024. Because the warrants are carried at fair value, future changes in fair value will be recognized in other (expense) income, net at each reporting period until the warrants are either exercised or expired. In addition, Avalo’s acquisition of AlmataBio, Inc. was accounted for as an asset acquisition resulting in the recognition of $27.5 million of acquired in-process research and development (“IPR&D”) expense. Finally, we recognized $9.2 million of private placement transaction expenses within other expense. Net loss per share of common stock decreased as a result of the increase in the shares outstanding from the first quarter of 2023, partially offset by the increase in net loss. Consolidated Balance Sheets(In thousands, except share and per share data) March 31, 2024 December 31, 2023 (unaudited) Assets Current assets: Cash and cash equivalents$110,177 $7,415 Other receivables 35 136 Prepaid expenses and other current assets 997 843 Restricted cash, current portion 4 1 Total current assets 111,213 8,395 Property and equipment, net 1,882 1,965 Goodwill 10,502 10,502 Restricted cash, net of current portion 131 131 Total assets$123,728 $20,993 Liabilities, mezzanine equity and stockholders’ (deficit) equity Current liabilities: Accounts payable$916 $446 Accrued expenses and other current liabilities 7,383 4,172 Warrant liability 194,901 — Contingent consideration 12,500 — Total current liabilities 215,700 4,618 Royalty obligation 2,000 2,000 Deferred tax liability, net 162 155 Derivative liability 5,670 5,550 Other long-term liabilities 1,281 1,366 Total liabilities 224,813 13,689 Mezzanine equity: Series C Preferred Stock—$0.001 par value; 34,326 and 0 shares of Series CPreferred Stock authorized at March 31, 2024 and December 31, 2023,respectively; 22,358 and 0 shares of Series C Preferred Stock issued andoutstanding at March 31, 2024 and December 31, 2023, respectively 11,457 — Series D Preferred Stock—$0.001 par value; 1 and 0 shares of Series D PreferredStock authorized at March 31, 2024 and December 31, 2023, respectively; 1 and 0shares of Series D Preferred Stock issued and outstanding at March 31, 2024 andDecember 31, 2023, respectively — — Series E Preferred Stock—$0.001 par value; 1 and 0 shares of Series E PreferredStock authorized at March 31, 2024 and December 31, 2023, respectively; 1 and 0shares of Series E Preferred Stock issued and outstanding at March 31, 2024 andDecember 31, 2023, respectively — — Stockholders’ (deficit) equity: Common stock—$0.001 par value; 200,000,000 shares authorized at March 31,2024 and December 31, 2023; 1,034,130 and 801,746 shares issued andoutstanding at March 31, 2024 and December 31, 2023, respectively 1 1 Additional paid-in capital 343,881 342,437 Accumulated deficit (456,424) (335,134) Total stockholders’ (deficit) equity (112,542) 7,304 Total liabilities, mezzanine equity and stockholders’ (deficit) equity$123,728 $20,993 The consolidated balance sheets as of March 31, 2024 and December 31, 2023 have been derived from the reviewed and audited financial statements, respectively, but do not include all of the information and footnotes required by accounting principles accepted in the United States for complete financial statements. Consolidated Statements of Operations (In thousands, except per share data) Three Months EndedMarch 31, 2024 2023 Revenues: Product revenue, net$— $475 Total revenues, net — 475 Operating expenses: Cost of product sales (80) 551 Research and development 2,116 6,008 Acquired in-process research and development 27,538 — General and administrative 3,193 2,708 Total operating expenses 32,767 9,267 (32,767) (8,792) Other expense: Excess of warrant fair value over private placement proceeds (79,276) — Private placement transaction costs (9,220) — Change in fair value of derivative liability (120) (180) Interest income, net 100 (949) Other expense, net — (26) Total other expense, net (88,516) (1,155) Loss before taxes (121,283) (9,947) Income tax expense 7 8 Net loss and comprehensive loss$(121,290) $(9,955) Net loss per share of common stock, basic and diluted1$(141) $(204) 1 Amounts for prior periods presented have been retroactively adjusted to reflect the 1-for-240 reverse stock split effected on December 28, 2023. The unaudited consolidated statements of operations for the three months ended March 31, 2024 and 2023 have been derived from the reviewed financial statements, but do not include all of the information and footnotes required by accounting principles generally accepted in the United States for complete financial statements. About AVTX-009 AVTX-009 is a humanized monoclonal antibody (IgG4) that binds to interleukin-1β (IL-1β) with high affinity and neutralizes its activity. IL-1β is a central driver in the inflammatory process. Overproduction or dysregulation of IL-1β is implicated in many autoimmune and inflammatory diseases. IL-1β is a major, validated target for therapeutic intervention. There is evidence that inhibition of IL-1β could be effective in hidradenitis suppurativa and a variety of inflammatory diseases in dermatology, gastroenterology, and rheumatology. About quisovalimab (AVTX-002) Quisovalimab is a fully human monoclonal antibody (mAb), directed against human LIGHT (Lymphotoxin-like, exhibits Inducible expression, and competes with Herpes Virus Glycoprotein D for Herpesvirus Entry Mediator (HVEM), a receptor expressed by T lymphocytes). There is increasing evidence that the dysregulation of the LIGHT-signaling network which includes LIGHT, its receptors HVEM and LTβR and the downstream checkpoint BTLA, is a disease-driving mechanism in autoimmune and inflammatory reactions in barrier organs. Therefore, we believe reducing LIGHT levels can moderate immune dysregulation in many acute and chronic inflammatory disorders. Quisovalimab previously demonstrated proof of concept in COVID-19 induced acute respiratory distress syndrome including reduction in mortality and respiratory failure, as well as a positive signal in patients with Crohn’s Disease. About AVTX-008 AVTX-008 is a fully human B and T Lymphocyte Attenuator (BTLA) agonist fusion protein in the IND-enabling stage. AVTX-008 is differentiated by having specific binding to BTLA, with no binding to LIGHT or CD160. AVTX-008 also has high-serum stability and solubility. About Avalo Therapeutics Avalo Therapeutics is a clinical stage biotechnology company focused on the treatment of immune dysregulation. Avalo’s lead asset is AVTX-009, an anti-IL-1β mAb, targeting inflammatory diseases. Avalo’s pipeline also includes quisovalimab (anti-LIGHT mAb) and AVTX-008 (BTLA agonist fusion protein). For more information about Avalo, please visit www.avalotx.com. Forward-Looking Statements This press release may include forward-looking statements made pursuant to the Private Securities Litigation Reform Act of 1995. Forward-looking statements are statements that are not historical facts. Such forward-looking statements are subject to significant risks and uncertainties that are subject to change based on various factors (many of which are beyond Avalo’s control), which could cause actual results to differ from the forward-looking statements. Such statements may include, without limitation, statements with respect to Avalo’s plans, objectives, projections, expectations and intentions and other statements identified by words such as “projects,” “may,” “might,” “will,” “could,” “would,” “should,” “continue,” “seeks,” “aims,” “predicts,” “believes,” “expects,” “anticipates,” “estimates,” “intends,” “plans,” “potential,” or similar expressions (including their use in the negative), or by discussions of future matters such as: the intended use of the proceeds from the private placement; integration of AVTX-009 into our operations; drug development costs, timing of trial results and other risks, including reliance on investigators and enrollment of patients in clinical trials; reliance on key personnel; regulatory risks; general economic and market risks and uncertainties, including those caused by the war in Ukraine and the Middle East; and those other risks detailed in Avalo’s filings with the Securities and Exchange Commission, available at www.sec.gov. Actual results may differ from those set forth in the forward-looking statements. Except as required by applicable law, Avalo expressly disclaims any obligations or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in Avalo’s expectations with respect thereto or any change in events, conditions or circumstances on which any statement is based. For media and investor inquiries Christopher Sullivan, CFO Avalo Therapeutics, Inc. ir@avalotx.com410-803-6793 or Chris BrinzeyICR WestwickeChris.brinzey@westwicke.com339-970-2843