Cosibelimab-ipdl

ZYCUBO ® approved by FDA to treat Menkes disease in the United States; Fortress subsidiary Cyprium Therapeutics closed the sale of its Rare Pediatric Disease Priority Review Voucher (PRV) for $205 million Fortress’ consolidated net income attributable to common stockholders for the first quarter of 2026 was $108.4 million, or $3.44 per common share (basic) and $2.82 per common share (diluted) MIAMI, May 14, 2026 (GLOBE NEWSWIRE) -- Fortress Biotech, Inc. (Nasdaq: FBIO) (“Fortress”), an innovative biopharmaceutical company focused on acquiring and advancing assets to enhance long-term value for shareholders through product revenue, equity holdings and dividend and royalty income, today announced financial results and recent corporate highlights for the first quarter ended March 31, 2026. Lindsay A. Rosenwald, M.D., Fortress’ Chairman, President and Chief Executive Officer, said, “The first quarter of 2026 marked a pivotal period for Fortress, highlighted by significant execution across our portfolio and meaningful progress in enhancing long‑term shareholder value. The FDA approval of ZYCUBO ® for Menkes disease and the subsequent monetization of Cyprium’s PRV for $205 million represent important validation of our business model. We deployed a portion of these proceeds to strengthen our balance sheet through debt reduction, lowering our outstanding principal with Oaktree to $15.0 million. We also continued to expand our pipeline through business development, including Avenue’s acquisition of ATX‑04 from Duke University, a clinically validated program with the potential to address significant unmet need in Pompe disease.” Dr. Rosenwald added, “Looking ahead, we expect to generate increasing royalty revenue from ZYCUBO ® and UNLOXCYT™, along with potential milestone payments across our portfolio. In parallel, AstraZeneca’s regulatory submissions in the EU and Japan for anselamimab (formerly known as CAEL-101), underscore the continued optionality within our partnered assets for potential future sales milestones for Fortress and approval milestones in the U.S. We have a diversified portfolio of commercial, late‑stage, and development‑stage programs and Fortress is well positioned to advance strategic initiatives and drive long‑term value for our shareholders.” Recent Corporate Highlights 1 : Regulatory and Monetization Updates ZYCUBO ® Approved for Menkes Disease; Cyprium Sold PRV for $205 Million. In January 2026, the FDA approved ZYCUBO ® (copper histidinate, formerly known as CUTX-101) for the treatment of Menkes disease in pediatric patients. A PRV was issued at approval and transferred to Cyprium under its agreement with Sentynl Therapeutics, Inc. (“Sentynl”). In March 2026, Cyprium closed the sale of the PRV for gross proceeds of $205 million. Cyprium is also eligible to receive tiered royalties on net sales of ZYCUBO ® and up to approximately $128 million in aggregate sales milestones from Sentynl. In connection with the sale of the PRV, Cyprium redeemed all outstanding shares of its 9.375% Perpetual Preferred Stock pursuant to the previously disclosed terms of such securities. Checkpoint Acquired by Sun Pharma; Fortress Establishes Long-Term Royalty Stream. In May 2025, Fortress’ subsidiary, Checkpoint, was acquired by Sun Pharmaceutical Industries, Inc. (together with its subsidiaries and/or associated companies, “Sun Pharma”). Pursuant to the acquisition, Fortress received ~$28 million upfront, with the potential for an additional contingent value right payment of up to $4.8 million and a 2.5% royalty on future net sales of UNLOXCYT™ (cosibelimab-ipdl). UNLOXCYT™ was approved by the FDA in December 2024 to treat metastatic or locally advanced cutaneous squamous cell carcinoma (“cSCC”) in patients who are not candidates for curative surgery or radiation and was commercially launched in January 2026. Commercial Portfolio Updates Journey Medical Expands Payer Access for Emrosi ® . At the end of March 2025, our partner company Journey Medical Corporation (“Journey Medical”) commercially launched Emrosi ® (40mg Minocycline Hydrochloride Modified-Release Capsules, consisting of 10mg immediate release and 30mg extended release pellets), also known as DFD-29, for inflammatory lesions of rosacea. Emrosi ® was approved by the FDA in November 2024 and is available by prescription at specialty pharmacy chains. In April 2026, Journey Medical announced that it secured a contract with a third major group purchasing organization (GPO) for Emrosi ® . As such, payer access for Emrosi ® expanded to over 150 million commercial lives as of April 1, 2026, which equates to approximately 85% of all commercial lives in the United States that have access to Emrosi ® . Journey Medical reported net product revenues of $15.9 million for the first quarter of 2026, compared to net product revenues of $13.1 million for the first quarter ended March 31, 2025. Royalties. In the first quarter of 2026, Cyprium recognized $0.1 million in royalty revenue on net sales of ZYCUBO ® . Clinical Updates Phase 3 CARES Results for Anselamimab (CAEL-101); Regulatory Submission of Prespecified Subgroup Analysis Planned. In July 2025, AstraZeneca announced that anselamimab (formerly known as CAEL-101) did not achieve statistical significance for the primary endpoint in its Phase III Cardiac Amyloid Reaching for Extended Survival (“CARES”) clinical program for Mayo stages IIIa and IIIb AL amyloidosis patients. However, the drug showed clinically meaningful improvement in a prespecified subgroup and was well tolerated. AstraZeneca indicated that the company plans to submit the prespecified subgroup analysis from the CARES trials to regulatory authorities and disclosed regulatory submissions in the EU and Japan. General Corporate: In March 2026, Fortress made aggregate prepayments on its loan with Oaktree, including a prepayment in connection with the sale of the PRV, reducing the outstanding principal balance to $15.0 million. In February 2026, Avenue entered into an exclusive worldwide license agreement with Duke University to acquire patent and know-how rights pertaining to ATX-04 (clenbuterol), a well-characterized small-molecule β2-adrenergic agonist, in clinical development for the treatment of Pompe disease. ATX-04 is a selective β2-adrenergic agonist with human proof-of-concept data demonstrating improved muscle function and enhanced response to enzyme replacement therapy. Avenue anticipates meeting with the FDA in 2026 to discuss and align on the design of a potential single pivotal trial for ATX-04 for Pompe disease. Financial Results: As of March 31, 2026, Fortress’ consolidated cash and cash equivalents totaled $255.8 million, compared to $79.4 million as of December 31, 2025, an increase of $176.5 million during the quarter. Fortress’ consolidated cash and cash equivalents totaling $255.8 million as of March 31, 2026, includes $209.9 million attributable to Fortress and the private subsidiaries, $2.4 million attributable to Avenue, $16.3 million attributable to Mustang Bio and $27.2 million attributable to Journey Medical. Fortress’ consolidated cash and cash equivalents totaled $79.4 million as of December 31, 2025, and includes $35.2 million attributable to Fortress and private subsidiaries, $2.9 million attributable to Avenue, $17.3 million attributable to Mustang and $24.1 million attributable to Journey Medical. Fortress’ consolidated net revenue totaled $16.0 million for the first quarter ended March 31, 2026, of which $15.9 million is generated from Journey Medical’s marketed dermatology products. This compares to consolidated revenue totaling $13.1 million for the first quarter of 2025. Consolidated research and development expenses totaled $0.5 million for the first quarter ended March 31, 2026, compared to $3.9 million for the first quarter ended March 31, 2025. Consolidated selling, general and administrative costs were $15.9 million for the first quarter ended March 31, 2026, compared to $25.7 million for the first quarter ended March 31, 2025. Consolidated net income attributable to common stockholders was $108.4 million, or $3.44 per share (basic) and $2.82 per share (diluted), for the first quarter ended March 31, 2026, compared to net loss attributable to common stockholders of $(12.7) million, or $(0.48) per share basic and diluted for the first quarter ended March 31, 2025. About Fortress Biotech Fortress Biotech, Inc. (“Fortress”) is an innovative biopharmaceutical company focused on acquiring and advancing assets to enhance long-term value for shareholders through product revenue, equity holdings and dividend and royalty income. The company has a portfolio of multiple marketed prescription pharmaceutical products and programs in development at Fortress, at its majority-owned and majority-controlled partners and subsidiaries and at partners and subsidiaries it founded and in which it holds significant minority ownership positions. Fortress’ portfolio is being commercialized and developed for various therapeutic areas including oncology, dermatology, and rare diseases. Fortress’ model is focused on leveraging its significant biopharmaceutical industry expertise and network to further expand and advance the company’s portfolio of product opportunities. Fortress has established partnerships with some of the world’s leading academic research institutions and biopharmaceutical companies to maximize each opportunity to its full potential, including AstraZeneca, City of Hope, Nationwide Children’s Hospital, Columbia University, Dana-Farber Cancer Center and Sentynl Therapeutics. For more information, visit . Forward-Looking Statements Statements in this press release that are not descriptions of historical facts are “forward-looking statements” within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934, as amended. The words “anticipates,” “believes,” “can,” “continue,” “could,” “estimates,” “expects,” “intends,” “may,” “might,” “plans,” “potential,” “predicts,” “should,” or “will” or the negative of these terms or other comparable terminology are generally intended to identify forward-looking statements. These forward-looking statements are based on management’s current expectations and are subject to risks and uncertainties that could negatively affect our business, operating results, financial condition and stock price. Factors that could cause actual results to differ materially from those currently anticipated include risks relating to: our growth strategy, financing and strategic agreements and relationships; our need for substantial additional funds and uncertainties relating to financings; uncertainty related to the timing and amounts expected to be realized from future milestone, contingent value right, royalty or similar future revenue streams, if at all; our ability to identify, acquire, close and integrate product candidates successfully and on a timely basis; our ability to attract, integrate and retain key personnel; the early stage of product candidates under development; the results of research and development activities; uncertainties relating to preclinical and clinical testing; our ability to obtain regulatory approval for products under development; our ability to successfully commercialize products for which we receive regulatory approval or receive royalties or other distributions from third parties; our ability to secure and maintain third-party manufacturing, marketing and distribution of our and our partner companies’ products and product candidates; government regulation; patent and intellectual property matters; competition; as well as other risks described in our SEC filings. We expressly disclaim any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in our expectations or any changes in events, conditions or circumstances on which any such statement is based, except as may be required by law, and we claim the protection of the safe harbor for forward-looking statements contained in the Private Securities Litigation Reform Act of 1995. The information contained herein is intended to be reviewed in its totality, and any stipulations, conditions or provisos that apply to a given piece of information in one part of this press release should be read as applying mutatis mutandis to every other instance of such information appearing herein. Company Contact: Jaclyn Jaffe Fortress Biotech, Inc. (781) 652-4500 ir@fortressbiotech.com Media Relations Contact: Tony Plohoros 6 Degrees (908) 591-2839 tplohoros@6degreespr.com FORTRESS BIOTECH, INC. AND SUBSIDIARIES Unaudited Condensed Consolidated Balance Sheets ($ in thousands except for share and per share amounts) March 31, December 31, 2026 2025 ASSETS Current assets Cash and cash equivalents $ 255,841 $ 79,381 Accounts receivable, net 24,992 29,783 Inventory 9,292 9,624 Other receivables - related party 516 158 Prepaid expenses and other current assets 4,839 4,895 Total current assets 295,480 123,841 Property, plant and equipment, net 2,426 2,519 Operating lease right-of-use asset, net 11,822 12,302 Restricted cash 1,220 1,220 Equity investments, at fair value 18,707 17,660 Intangible assets, net 26,479 27,605 Other assets 740 401 Total assets $ 356,874 $ 185,548 LIABILITIES AND STOCKHOLDERS’ EQUITY Current liabilities Accounts payable and accrued expenses $ 92,986 $ 47,125 Income taxes payable 5,418 356 Common stock warrant liabilities — 1 Operating lease liabilities, short-term 2,221 2,127 Partner company notes payable, short-term 2,500 — Other current liabilities 268 135 Total current liabilities 103,393 49,744 Notes payable, long-term, net 36,878 52,417 Operating lease liabilities, long-term 12,028 12,672 Partner company redeemable perpetual preferred liability — 7,085 Other long-term liabilities 2,201 1,447 Total liabilities 154,500 123,365 Commitments and contingencies Stockholders’ equity (deficit) Cumulative redeemable perpetual preferred stock, $0.001 par value, 15,000,000 authorized, 5,000,000 designated Series A shares, 3,427,138 shares issued and outstanding as of March 31, 2026 and December 31, 2025, respectively, liquidation value of $25.00 per share 3 3 Common stock, $0.001 par value, 200,000,000 shares authorized, 33,186,671 and 31,364,094 shares issued and outstanding as of March 31, 2026 and December 31, 2025, respectively 33 31 Additional paid-in-capital 785,851 783,891 Accumulated deficit (623,679 ) (734,052 ) Total stockholders' equity attributed to the Company 162,208 49,873 Non-controlling interests 40,166 12,310 Total stockholders' equity 202,374 62,183 Total liabilities and stockholders' equity $ 356,874 $ 185,548 FORTRESS BIOTECH, INC. AND SUBSIDIARIES Unaudited Condensed Consolidated Statements of Operations ($ in thousands except for share and per share amounts) Three Months Ended March 31, 2026 2025 Revenue Product revenue, net $ 15,921 $ 13,139 Other revenue 117 — Net revenue 16,038 13,139 Operating expenses Cost of goods - (excluding amortization of acquired intangible assets) 6,218 4,790 Amortization of acquired intangible assets 1,126 1,065 Research and development 540 3,938 Selling, general and administrative 15,893 25,663 Total operating expenses 23,777 35,456 Loss from operations (7,739 ) (22,317 ) Other income (expense) Interest income 570 490 Interest expense and financing fee (3,368 ) (2,805 ) Gain on sale of priority review voucher, net of expenses 158,873 — Change in fair value of partner company derivative liability (7,085 ) — Gain (loss) on common stock warrant liabilities 1 (47 ) Other income (expense) 1,042 (12 ) Total other income (expense) 150,033 (2,374 ) Income (loss) before income tax expense 142,294 (24,691 ) Income tax expense 5,132 — Net income (loss) 137,162 (24,691 ) Attributable to non-controlling interests (26,789 ) 14,107 Net income (loss) attributable to Fortress $ 110,373 $ (10,584 ) Preferred A dividends declared and paid and/or cumulated, and Fortress' share of subsidiary deemed dividends (2,008 ) (2,131 ) Net income (loss) attributable to common stockholders $ 108,365 $ (12,715 ) Net income (loss) per common share attributable to common stockholders - basic $ 3.44 $ (0.48 ) Net income (loss) per common share attributable to common stockholders - diluted $ 2.82 $ (0.48 ) Weighted average common shares outstanding - basic 31,540,595 26,450,218 Weighted average common shares outstanding - diluted 38,412,716 26,450,218 ____________________ 1 This press release references products being developed or commercialized by Fortress, by Fortress’ private or public subsidiaries (referred to herein as “subsidiaries” or “partner companies”) and by entities with whom one of the foregoing parties has a significant business relationship, such as an exclusive license or an ongoing product-related payment obligation (such entities referred to herein as “partners”). The words “we”, “us” and “our” may refer to Fortress individually, to one or more of our subsidiaries and/or partner companies, or to all such entities as a group, as dictated by context.

｜中肽生化内容团队编辑环肽药物作为一类介于传统小分子和生物大分子之间的特殊分子形态，近年来在全球创新药研发管线中的占比稳步提升。通过引入环化结构，这类药物在保留多肽高特异性和高亲和力的基础上，显著提高了对蛋白酶的稳定性和结构预限制性，从而在调节蛋白质相互作用（PPI）等难成药靶点上展现出独特的优势。随着icotrokinra的获批，环肽技术在改善药物代谢动力学性质、探索非注射给药途径等方面的实际潜力得到了更多实证。从全球环肽资产的全景分布来看，目前的研发重点正从天然产物的简单修饰转向基于噬菌体展示（phage display）技术和de novo设计的系统化开发。在研管线广泛覆盖了自身免疫、肿瘤、代谢性疾病以及抗感染等多个核心领域，体现出差异化的技术路径和商业价值。通过梳理当前的管线梯队，可以客观观察到不同研发平台在分子量控制、跨膜渗透性优化以及长效化修饰等关键指标上的真实进展，进而评估该类资产在未来医药市场中的竞争地位。1. MK‑0616（Enlicitide）图片来源：Wikipedia开发商：默沙东环肽结构特征Enlicitide（MK‑0616）是一个围绕口服吸收目标进行深度工程化改造的宏环肽，而且是非常独特的三环肽，其结构特征体现为多层次化学设计的叠加，包含如下特征：✔ 三环肽✔ 吲哚结构✔ (S)-2-甲基脯氨酸✔ 氟取代✔ 季胺结构✔ 特殊的合环结构适应症与临床✔ 高胆固醇血症（Hypercholesterolemia）临床研究：CORALreef Lipids（NCT05952856，III期）这项三期研究受试者为高胆固醇血症成年人，研究目的为评估 Enlicitide 在此人群中的 LDL‑C 降幅和安全性。✔ 杂合子家族性高胆固醇血症（Heterozygous Familial Hypercholesterolemia, HeFH）临床研究：CORALreef HeFH（NCT05952869，III期）✔ 在既有降脂治疗基础上仍需额外降低 LDL‑C 的成人临床研究：CORALreef Add‑On（NCT06450366，III期）研究对象包括正在使用他汀或其他降脂药（ezetimibe、bempedoic acid）的成年人，专门针对仍需额外降低 LDL‑C 的患者所进行的加用研究✔ 具有动脉粥样硬化性心血管事件风险的成年人（ASCVD‑risk adults）临床研究：CORALreef Outcomes（NCT06008756，III期）机理MK‑0616 的作用机理与已上市的抗体类 PCSK9 抑制剂一致，其分子能够直接与 PCSK9 的 LDL（低密度脂蛋白）受体结合域发生结合，从而阻断 PCSK9 与 LDL 受体之间的相互作用。这种结合可使 PCSK9 失去降解 LDL 受体的能力，使更多 LDL 受体得以在肝细胞表面存留并回收 LDL‑C，最终导致血浆 LDL‑C 水平下降。递送方式：口服从药代动力学层面，enlicitide已有早期临床试验提供了直接证据：在健康受试者中，口服给予 10–300 mg 的 MK‑0616 能使血浆游离 PCSK9 水平降低超过 93%。MK‑0616 的注册路径全部基于口服给药。所有临床试验采用的是 Enlicitide Decanoate 的口服片剂。这使得 MK‑0616 成为迄今推进最靠前的口服 PCSK9 抑制剂。相较于注射型 PCSK9 抗体治疗方式，口服剂型拥有更高的依从性、更低的使用门槛，并有可能将 PCSK9 抑制剂从特殊用药带入初级干预药物的层级。开发意义从行业视角看，Enlicitide 是第一个真正进入注册性阶段的口服宏环肽药物，也是第一个有机会实现口服 PCSK9 抑制的品种。这意味着大尺寸蛋白–蛋白相互作用靶点首次能够通过口服肽类药物进行调控。更重要的是，三个 LDL‑C 关键试验的成功完成与大型心血管终点试验的稳步推进共同构成了一个即将进入申报期的证据体系，使其成为未来可能改变降脂治疗模式的战略级药物。相关公开资料显示，MK‑0616 进入 Phase 3 后的进展顺利，并已被业内视为下一阶段监管申报的候选品种。2. BT5528开发商：Bicycle Therapeutics环肽结构特征BT5528 是Bicycle Therapeutics 所开发的 Bicycle® Toxin Conjugate（BTC），其本质可视为PDC（Peptide-Drug Conjugate, 多肽药物偶联物）。其受体识别模块为一个 bicyclic peptide（双环肽），能够特异性结合 EphA2，并与细胞毒素 monomethyl auristatin E（MMAE）通过可切割连接子（protease‑cleavable linker）连接。BT5528 的结构与传统 PDC 最大的不同，在于它的 “P”与“D”两部分都是肽类结构。传统 PDC 通常由一段识别肽连接一个小分子毒素，而在 BT5528 中，靶向部分本身是一个双环肽（bicyclic peptide），而毒素 MMAE 也是一个肽源性的细胞毒素。再加上中间的多肽 spacer 和可切割肽链连接子，BT5528 呈现出的是肽‑肽偶联的整体架构，而不是传统的肽‑小分子偶联。✔ 双环肽（bicyclic peptide）：靶向 EphA2✔ MMAE（monomethyl auristatin E）细胞毒素：作为载荷，与肽偶联✔ 蛋白酶可切割连接子（protease‑cleavable peptide linker）：连接肽与 MMAE 的关键结构✔ Spacer：β‑Ala‑Sar10多肽，环肽与连接子之间，用于结构衔接✔ EphA2 结合模块：双环肽本体用于识别 EphA2 高表达肿瘤环肽特征：通过1,3,5-triazinane (1,3,5-三氮杂环己烷)，与直链肽前体上的三个半胱氨酸类似物Cys((CH2)2COOH)侧链的羧基结合，从而形成双宏环的化学结构。适应症与临床✔ EphA2 高表达的晚期实体瘤临床研究：BT5528‑100（NCT04180371，I/II 期），研究对象为EphA2 高表达的既往已知类型的晚期实体瘤，包括卵巢癌、尿路/膀胱癌、非小细胞肺癌、头颈癌、三阴性乳腺癌、胃/上消化道癌等多类实体瘤。机理BT5528属于一种 Bicycle Toxin Conjugate（BTC）。其双环肽部分识别并结合肿瘤细胞表面的 EphA2。EphA2 是多种实体瘤中高表达的细胞表面受体。双环肽结构通过其特定的空间构象与 EphA2 的细胞外结构域发生高亲和力结合，使 BT5528 能够在 EphA2 高表达的肿瘤组织中实现选择性富集。当双环肽将 BT5528 锚定于 EphA2 阳性肿瘤细胞后，连接子在肿瘤环境中被蛋白酶切割，从而释放细胞毒素 MMAE ，MMAE 进入细胞后作用于微管系统，从而杀伤肿瘤细胞并递送方式BT5528 的给药方式在为静脉注射（IV）。NCT04180371 试验的给药频率为每周一次（QW）或每两周一次（Q2W）。 开发意义BT5528 通过双环肽结构实现对 EphA2 的高亲和力识别，并以可切割连接子将肽源性细胞毒素 MMAE 精准递送至肿瘤细胞。其早期临床研究显示，BT5528 在多种 EphA2 高表达的晚期实体瘤中展现了可管理的安全性和初步抗肿瘤活性。这些结果为 Bicycle Toxin Conjugate（BTC）这一新型分子形式提供了临床可行性的初步验证，体现出以合成双环肽为基础构建偶联毒素药物的潜在发展价值。3. BT8009 (Zelenectide pevedotin)图片来源：Bicycle Therapeutics开发商：Bicycle Therapeutics环肽结构特征同BT5528一样，BT8009 (Zelenectide pevedotin) 同样属于 Bicycle Therapeutics 的 Bicycle Toxin Conjugate（BTC），其靶向结构是一个高度选择性的双环肽（bicyclic peptide），用于结合 Nectin‑4（肿瘤表面黏附分子）。其机构包括如下模块：✔ 双环肽（bicyclic peptide），结合Nectin-4;✔ 用于连接肽与毒素的可切割连接子（val‑cit‑PABC）✔ 细胞毒素 MMAE（monomethyl auristatin E）适应症与临床✔ Nectin‑4 高表达的晚期实体瘤临床研究：BT8009‑100（NCT04561362，I/II 期）针对Nectin‑4 表达相关的晚期实体瘤，包括尿路上皮癌、胰腺癌、乳腺癌、非小细胞肺癌、胃癌、食管癌、头颈癌、卵巢癌等。✔ 局部晚期或转移性尿路上皮癌（la/mUC）临床研究：Duravelo‑2（NCT06225596，II/III 期），针对局部晚期或转移性尿路上皮癌的注册性研究，并作为化疗对照的比较组之一。✔ 转移性尿路上皮癌（单药与联合 pembrolizumab）临床研究：Duravelo‑1（NCT04561362 的扩展部分）机理BT8009 的受体靶向部分是一个双环肽，可选择性结合 Nectin‑4。Nectin‑4 是一种位于细胞表面的黏附分子，它在多种肿瘤组织中常见高表达，包括尿路上皮癌、肺癌、上消化道肿瘤、卵巢癌、乳腺癌以及头颈部肿瘤等。BT8009与Nectine-4结合后，可切割连接子在肿瘤微环境中被特定蛋白酶分解，释放出毒素MMAE（monomethyl auristatin E），通过抑制微管使细胞停止分裂并最终死亡。递送方式：静脉注射静脉给药，包括每周一次、每两周一次或 21 天周期的 D1+D8 给药方案。开发意义BT8009 展示了 Bicycle Toxin Conjugate（BTC）技术在 Nectin‑4 靶向肿瘤中的应用潜力，其双环肽结构赋予药物小分子级别的组织穿透性与高度选择性的肿瘤富集能力。早期临床数据显示，BT8009 在转移性尿路上皮癌中展现出明确的抗肿瘤活性和良好耐受性，部分研究观察到高达 45% 的客观缓解率（ORR）。基于这些结果，FDA 已与开发方就其 II/III 期注册性研究达成一致，使 BT8009 成为首批可能进入加速审批路径的 BTC 类候选药物之一。4. BT7480图片来源：Biopharma PEG图片来源：WO2025125648开发商：Bicycle Therapeutics环肽结构特征BT7480 是一种由三个双环肽（bicyclic peptides）组成的分子，包括：✔ 一个双环肽靶向 Nectin‑4✔ 两个双环肽靶向 CD137（4‑1BB）（免疫细胞表面共刺激受体）三个双环肽通过一个三臂 PEG₃（branched trimeric PEG）连接子进行连接，是一个完全化学合成的多肽免疫激动剂结构。适应症与临床✔ Nectin‑4 表达相关的晚期实体瘤临床研究：NCT05163041（I/II期）研究的实体瘤包括非小细胞肺癌、尿路上皮癌、头颈鳞癌、宫颈癌、食管癌、胃癌、卵巢癌、乳腺癌等多种 Nectin‑4 阳性肿瘤机理BT7480 的出现，为多肽药物在“结构复杂性”与“机制功能性”的融合设计提供了一个清晰范式。它既不同于传统意义上仅承担识别功能的环肽，也不同于体积更大、构象受限的融合蛋白或抗体药物。BT7480 以完全化学合成的方式，将三个功能精确分区的双环肽结构域组合成一个整体分子，通过结构域分离的策略同时实现肿瘤靶向与免疫激活两个目的，其结构布局在功能逻辑上已接近、甚至重构了双抗式（bispecific）的作用模式。在分子层面，BT7480 由一个靶向 Nectin‑4 的双环肽结构域和两个靶向 CD137 的双环肽结构域构成。Nectin‑4 是多种实体瘤中高度表达的黏附分子，而 CD137（4‑1BB）则是活化 T 细胞与 NK 细胞表面的关键共刺激受体。BT7480 的设计使其能够在肿瘤细胞（Nectin‑4）与免疫细胞（CD137）之间实现空间上的共缀合（co‑ligation），从而将免疫激活信号精准定位在肿瘤局部。这种设计与传统依赖单一肽段承担全部功能的 GLP‑1/GIP 类多受体激动剂不同，而是通过物理结构域分离，使每一部分均承担清晰、独立且可控的药理任务。围绕 CD137 的激动策略，是 BT7480 的另一核心价值。CD137 作为 TNF（肿瘤坏死因子）受体家族成员，其激活需要聚合，但以往的 CD137 激动抗体由于系统性激活导致的肝毒性，长期阻碍了临床推进。BT7480 以小分子双环肽为基础，通过噬菌体展示筛选、亲和力成熟与化学优化获得能够结合 CD137 的环肽模板，再与识别 Nectin‑4 的环肽通过三臂连接子拼接，使 CD137 的聚合仅在肿瘤部位被触发，实现了肿瘤局部免疫激活而避免系统性副作用。最终形成的 BT7480 分子，实现了“靶向 + 激活”功能的物理隔离与空间耦合，为 CD137 激动剂的发展提供了新的结构途径。递送方式：静脉注射开发意义BT7480 代表了 Bicycle Therapeutics 的肿瘤定向免疫激动剂（Bicycle TICA®）平台首次进入人体研究，利用三个双环肽同时连接肿瘤细胞的 Nectin‑4 与免疫细胞的 CD137，实现精准的局部免疫激活机制。在早期临床结果中，BT7480 显示出良好的耐受性与初步抗肿瘤活性，包括未确认的部分缓解（PR）与多例超过 8 个月的长期稳定疾病（SD）。由于其机制与结构均完全不同于传统抗体和 ADC，BT7480 被视为 BTC / TICA 类药物在实体瘤免疫激活方向的重要验证性项目，并已进入持续推进的临床阶段。5. PL8177开发商：Palatin Technologies多肽结构特征PL8177 是7个氨基酸组成的环肽，其中5个氨基酸残基参加了环肽结构的构成，Glu侧链的羧基与Dap (Diaminopropionic acid) 侧链的氨基形成了侧链-侧链酰胺环化。适应症与临床✔ 活动性溃疡性结肠炎（Active Ulcerative Colitis, UC）临床研究：NCT05466890 (IIa期)，双盲、随机、安慰剂对照试验，采用口服结肠递送方案，在轻中度活动性溃疡性结肠炎患者中进行 8 周治疗，评估其安全性、PK/PD、肠黏膜愈合与临床缓解效果。机理PL8177 的作用机制属于对 melanocortin‑1 受体（MC1R）的选择性激动。在结肠局部释放后，MC1R 激动所触发的生物学效应能够调节黏膜免疫状态，使局部炎症从“损伤模式”向“修复模式”转化，并推动炎症分辨过程，而不是像传统免疫抑制剂那样抑制免疫反应本身。这一机制的实现依赖其结肠定向递送体系：Phase 1 研究显示口服 PL8177 能够在结肠局部达到有效暴露，同时几乎不进入血液循环，从而以最小系统暴露的方式降低全身不良反应风险，实现了以局部免疫调节为核心的治疗策略。递送方式：口服PL8177是一种选择性 melanocortin‑1 receptor（MC1R）激动剂，归类为 melanocortin 多肽类药物（melanocortin receptor agonist）。它采用口服结肠递送（oral colon‑delivered）体系，定向结肠递送，减少系统暴露，用于在局部发挥抗炎与组织修复相关作用，而非免疫抑制。开发意义PL8177 展示了 MC1R 激动在肠道局部炎症疾病中的新型应用路径，通过结肠定向释放实现作用部位与系统暴露的分离，从而减少传统免疫抑制剂常见的安全性问题。在活动性 UC 的 Phase 2a 研究中，PL8177 显示出显著的临床缓解、黏膜改善与优异安全性，公开数据中无治疗相关不良事件。这些结果使 PL8177 成为 MC1R 口服治疗在肠道炎症疾病领域的首个验证性成果，并促使开发者已开启与大型药企的许可与合作洽谈。6. Certepetide（CEND-1）开发商：Lisata Therapeutics多肽结构特征Certepetide 来源于 iRGD（CRGDKGPDC）序列，是一个9个氨基酸组成的环状多肽。其结构特征为通过两个半胱氨酸残基形成二硫键，构建稳定的环状构象。该序列包含典型的 RGD 基序，可与整合素（αvβ3/αvβ5）结合，并在蛋白酶裂解后暴露 C-end Rule（CendR）基序，从而获得与 neuropilin-1（NRP-1）结合的能力。这种结构赋予其“先结合整合素、再激活组织穿透通路”的双阶段功能特征。适应症与临床✔ 胰腺导管腺癌（Pancreatic Ductal Adenocarcinoma, PDAC）临床研究：ASCEND（II期，NCT05042128），在一线化疗基础上联合 certepetide，评估客观缓解率、无进展生存期等指标。已披露数据中 ORR 约45%，对照组约19%，mPFS 约7.5个月，对照组约4.7个月。✔ 胆管癌（Cholangiocarcinoma）临床研究：（NCT05628064，II期），已获得孤儿药资格认定，正在推进，用于评估其在胆道系统肿瘤中的增敏作用。✔ 晚期实体瘤临床研究：NCT03517176 （Phase 1b/2），评估 certepetide 联合化疗在晚期实体瘤中的安全性与初步疗效；NCT04958811（Phase 1b/2），在多种晚期实体瘤中评估其作为递送增强剂的作用。机理Certepetide 的作用机制属于肿瘤组织穿透增强（tumor penetration enhancer）。Certepetide 首先通过其序列中的 RGD 结构与肿瘤血管和肿瘤细胞表面的αv 整合素结合。结合后，该多肽在肿瘤微环境中被蛋白酶切割，使其C端暴露出能够与 neuropilin-1 结合的结构，从而激活一种内吞-跨细胞运输通路。该通路能够在肿瘤组织中形成类似通道的结构，显著提高共给药药物（如化疗药物）在肿瘤内部的分布和渗透深度。其核心作用并不直接杀伤肿瘤细胞，而是通过改变药物在肿瘤组织内的空间分布，提高局部有效暴露，从而增强已有治疗方案的疗效。递送方式：静脉注射Certepetide 作为辅助性多肽药物，与化疗或其他抗肿瘤药物联合使用，通过静脉给药实现全身分布，但其功能主要在肿瘤局部发挥。其作用依赖肿瘤特异性的整合素表达和NRP-1通路激活，因此具有一定的组织选择性。开发意义Certepetide 提供了一种区别于传统靶向治疗与细胞毒药物的开发路径，其核心在于通过调控肿瘤组织结构与药物分布，提高既有疗法的有效性。该策略针对实体瘤中普遍存在的药物渗透受限问题，尤其在胰腺癌等高基质、低血供肿瘤中具有明确理论基础。已有 II 期数据显示其在联合治疗中可提高缓解率并延长无进展生存期，提示该类递送增强型多肽具有成为肿瘤治疗新辅助模块的潜力。同时，该机制具有与多种治疗手段（化疗、放疗、免疫治疗）组合的兼容性，为后续联合策略提供了空间。7. Balixafortide （POL6326）开发商：Spexis（原 Polyphor）多肽结构特征Balixafortide的化学结构非常特殊，它由16个氨基酸残基组成，通过Cys2和Cys9的侧链巯基形成二硫键，与此同时，其[Ala1-Arg7]-的部分和[His16-Tyr8]的部分，通过N对N, C对C的方式进行对接环化，从而产生了肼（红色部分）和1,2-diketone（蓝色部分）的特殊结构，并赋予Balixafortide极为特殊的双环结构。适应症与临床✔ 转移性胰腺导管腺癌（PDAC）临床研究：NCT06981806（I期），联合 cosibelimab（PD-L1 抗体），用于标准治疗失败后的转移性 PDAC。计划入组 24 例，主要目标为确定最大耐受剂量（MTD）及推荐 II 期剂量（RP2D）。机理Balixafortide 的作用机制为 CXCR4 受体拮抗。CXCR4 是肿瘤细胞与肿瘤微环境中重要的趋化因子受体，与其配体 CXCL12（SDF-1）共同参与肿瘤细胞迁移、免疫逃逸及肿瘤微环境重塑。Balixafortide 通过与 CXCR4 结合，阻断 CXCL12-CXCR4 信号轴，从而干扰肿瘤细胞向转移部位的趋化迁移，并影响肿瘤相关免疫细胞的募集与分布。在免疫治疗联合策略中，该机制还可能通过改变肿瘤微环境中免疫抑制状态，提高免疫细胞浸润，从而增强免疫检查点抑制剂的疗效。递送方式：静脉注射开发意义Balixafortide 代表了一类针对肿瘤微环境趋化信号通路的多肽药物，其开发重点在于调控肿瘤细胞迁移及免疫微环境，而非直接细胞毒作用。CXCR4 作为肿瘤转移和免疫抑制的重要节点，在多种实体瘤中具有明确生物学基础。尽管其在乳腺癌 III 期研究中未取得阳性结果，但后续在胰腺癌等高度免疫抑制肿瘤中的早期探索仍在进行。当前可见临床活动主要集中在小规模早期研究，提示该项目仍处于机制验证与适应症再定位阶段。8. Rusfertide（PTG-300 / TAK-121）开发商： Protagonist Therapeutics / 武田制药多肽结构特征Rusfertide 是17个氨基酸残基组成的环肽，其中Cys6-Cys16之间形成二硫键。Rusfertide的N端经过了异戊酰基修饰。其Lys8的侧链还通过gama glutamic acid进行了棕榈酸（16碳脂肪酸）的脂化修饰。适应症与临床✔ 真性红细胞增多症（Polycythemia Vera, PV）临床研究：VERIFY（NCT05210790，III期）：rusfertide 联合标准治疗使临床应答率超过安慰剂组两倍；Takeda 公布的数据为 77.0% vs 32.9%，并达到主要终点和全部四个关键次要终点；THRIVE（NCT06033586，III期）：是一项开放标签长期延长期研究，用于评估 rusfertide 的长期安全性和疗效持续性。✔ 当前进展：rusfertide 的 NDA 已被 FDA 受理并授予 Priority Review，PDUFA 目标日期位于 2026 年第三季度。机理Rusfertide 的作用机制属于 hepcidin 模拟。其核心在于模拟内源性 hepcidin 对 ferroportin 的调控作用，降低铁从肠道和储存组织向血液循环的输出，从而减少可用于红细胞生成的铁供给，最终抑制过度红细胞生成并维持血细胞比容控制。该机制调控的是铁代谢上游环节，而不是直接抑制骨髓细胞增殖。递送方式：皮下注射开发意义Rusfertide 是当前最接近上市的环肽项目之一，其意义首先在于它验证了环肽可以作为全身性铁代谢调节药物进入后期临床并冲击上市。在真性红细胞增多症中，传统管理长期依赖放血和细胞减灭治疗，而 rusfertide 通过 hepcidin 模拟这一全新机制，从铁供给端限制红细胞生成，为疾病控制提供了新的治疗路径。