Pegzilarginase

编者按：过去的2024年，在美国FDA批准的所有小分子新药中，药明康德支持了其中6款的生产，占19%；自2018年以来，美国FDA所批准的所有小分子新药中，18%由药明康德赋能，这意味着几乎每5个美国FDA批准的小分子新药中，就有1个得到了药明康德的支持。作为创新赋能者、客户信赖的合作伙伴以及全球医药及生命科学行业的贡献者，药明康德将持续通过独特的“CRDMO”业务模式，助力更多合作伙伴，为全球病患带来突破性创新疗法。根据PDUFA的目标日期，预计2025年5月，美国FDA将对3款创新药物的批准做出监管决定。本文将对这些疗法进行相关介绍。▲5月美国FDA可能批准的新药（点击可见大图）活性成分：Pegzilarginase适应症：精氨酸酶缺乏症（ARG1-D）公司名称：Immedica PharmaPegzilarginase是一种重组人体精氨酸酶，可促进体内精氨酸代谢。这种酶替代疗法可快速、持续地降低血浆中精氨酸及其毒性代谢物的水平，同时改善临床症状。Pegzilarginase已在欧盟和英国获得批准，用于治疗成人、青少年和2岁及以上儿童的精氨酸酶缺乏症。根据2024年2月发表在eClinicalMedicine杂志上的3期临床研究结果，共有32名患者入组该研究并接受随机分组，其中21名患者接受了pegzilarginase治疗，11名患者接受了安慰剂治疗。研究结果显示，在第24周时，接受pegzilarginase治疗的患者血浆精氨酸（pArg）的几何平均值从354.0 μmol/L显著降低至86.4 μmol/L，而安慰剂组患者的pArg水平仅从464.7 μmol/L降至426.6 μmol/L（95% CI：-67.1%至-83.5%；p<0.0001）。此外，pegzilarginase治疗使90.5%的患者pArg水平恢复正常，而安慰剂组中这一比例为0%。在功能性活动能力方面，pegzilarginase治疗也显示出显著的临床改善效果。这些疗效在随后的24周持续治疗中得以长期维持。在安全性方面，pegzilarginase耐受性良好，不良事件大多为一过性且严重程度为轻度或中度。活性成分：Telisotuzumab vedotin（Teliso-V）适应症：非小细胞肺癌（NSCLC）公司名称：艾伯维Teliso-V是一款靶向c-Met的抗体偶联药物（ADC），以微管蛋白抑制剂MMAE作为毒性有效载荷。该疗法在2022年1月获FDA突破性疗法认定，治疗非小细胞肺癌。艾伯维于2024年10月为teliso-V提交了一份生物制品许可申请（BLA），以寻求加速批准该疗法用于治疗c-Met蛋白过度表达的经治局部晚期或转移性非鳞状NSCLC成人患者，这些患者肿瘤的表皮生长因子受体（EGFR）为野生型。该BLA得到了LUMINOSITY临床2期试验数据的支持，该试验旨在评估teliso-V在c-Met过表达NSCLC患者中的安全性和有效性。之前公布的独立中心审评（ICR）分析结果显示，肿瘤c-Met高度表达和中度表达患者的总缓解率分别为35%和23%。此外，其他终点显示了有意义的临床结局，包括c-Met高度表达和中度表达患者的中位缓解持续时间分别为9个月和7.2个月，中位总生存期分别为14.6个月和14.2个月。Teliso-V的安全性特征与既往结果一致，未发现新的安全性问题。Teliso-V单药治疗的不良事件通常为可控且耐受良好。活性成分：Acoltremon（AR-15512）适应症：干眼症公司名称：AlconAR-15512是一款局部TRPM8激动剂，是治疗干眼症体征和症状的潜在“first-in-class"候选产品。AR-15512在两项关键性3期临床试验COMET-2和COMET-3中均取得了积极结果，这两项试验旨在评估该疗法的疗效和安全性。分析显示，在上述两项研究中，AR-15512均达到主要终点。在这两项研究中，共有超过930例干眼症受试者入组，并以1：1的比例随机分配至AR-15512组或溶剂对照组。试验的主要终点为在第14天时，未麻醉Schirmer评分（泪液生成指标）至少增加10 mm的受试者比例达到统计学显著性（p<0.0001）。这些数据与AR-15512的已知作用机制一致。此外，次要终点的数据表明，与对照组相比，AR-15512可快速起效并持续促进泪液产生，最早在第1天出现，并持续至第90天。总体而言，AR-15512耐受性良好，且未报告任何严重眼部不良事件。参考资料：[1] BLA for pegzilarginase in the treatment of arginase 1 deficiency (ARG1-D) accepted for priority review by the U.S. FDA. Retrieved April 15, 2025 from https://www.immedica.com/en/press/bla-pegzilarginase-treatment-arginase-1-deficiency-arg1-d-accepted-priority-review-us-fda[2] Russo, Rossana Sanchez et al. “Efficacy and safety of pegzilarginase in arginase 1 deficiency (PEACE): a phase 3, randomized, double-blind, placebo-controlled, multi-centre trial.” EClinicalMedicine vol. 68 102405. 12 Jan. 2024, doi:10.1016/j.eclinm.2023.102405[3] AbbVie Submits Biologics License Application to the FDA for Telisotuzumab Vedotin (Teliso-V) in Previously Treated Non-Small Cell Lung Cancer. Retrieved April 15, 2025 fromhttps://www.prnewswire.com/news-releases/abbvie-submits-biologics-license-application-to-the-fda-for-telisotuzumab-vedotin-teliso-v-in-previously-treated-non-small-cell-lung-cancer-302261263.html[4] Alcon Announces Positive Topline Results From Phase 3 COMET Trials of AR-15512, a Novel Topical Drug Candidate for Dry Eye. Retrieved April 15, 2025 from https://www.alcon.com/media-release/alcon-announces-positive-topline-results-phase-3-comet-trials-ar-15512-novel-topical免责声明：本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

Reported positive interim pharmacokinetic ("PK") and safety data in Phase 1 trial of SPY001 in November 2024 and strengthened the balance sheet with a $230 million public offering Continued execution towards expected milestones across portfolio, with interim Phase 1 data readouts for SPY002 and SPY003 on-track for the second quarter and second half of 2025, respectively Remain on track for initiation of Phase 2 platform trial in ulcerative colitis ("UC") in mid-2025 with SPY001 (α4β7), followed by SPY002 (TL1A), SPY003 (IL-23), and combinations thereof, with initial monotherapy results expected in 2026 Announced indication expansion into rheumatoid arthritis ("RA") with SPY002, with expected Phase 2 trial initiation in mid-2025 and top-line results in 2026 $603 million of cash, cash equivalents, and marketable securities as of December 31, 2024, with expected runway into the second half of 2028 WALTHAM, Mass., Feb. 27, 2025 /PRNewswire/ -- Spyre Therapeutics, Inc. ("Spyre" or the "Company") (NASDAQ:SYRE), a clinical-stage biotechnology company utilizing best-in-class antibody engineering, dose optimization, and rational therapeutic combinations to target improved efficacy and convenience in the treatment of inflammatory bowel disease ("IBD") and other immune-mediated diseases, today announced its fourth quarter and full year 2024 financial results and provided program and corporate updates. "In 2024, we initiated first-in-human studies for three of our next-generation antibodies and delivered outstanding interim Phase 1 results for SPY001, which underscore our portfolio's potential to revolutionize the treatment of IBD. Looking ahead, we are progressing our suite of therapeutics into a groundbreaking Phase 2 platform study in ulcerative colitis, which is designed to test both monotherapies and combination therapies with the potential for unified quarterly subcutaneous dosing in maintenance," said Cameron Turtle, DPhil., Chief Executive Officer. "Additionally, the expansion of SPY002 into a Phase 2 rheumatoid arthritis trial this year represents a key step in addressing a pressing unmet need in a disease that affects millions across the globe. We are well-positioned and well-capitalized to deliver a series of value-inflecting catalysts, including three Phase 1 readouts expected in 2025 and four Phase 2 proof-of-concept readouts expected in 2026." Development Pipeline Overview and Update The Company's approach combines best-in-class antibody engineering, dose optimization, and rational therapeutic combinations with the goal of maximizing efficacy, safety, and convenience in the treatment of IBD and other immune-mediated diseases. IBD is a chronic condition characterized by inflammation within the gastrointestinal tract, including two main disorders: UC and Crohn's disease ("CD"). In the United States, it is estimated that approximately 2.4 million individuals are diagnosed with IBD. RA is a chronic inflammatory autoimmune condition that primarily affects the joints but also other parts of the body. It is characterized by pain, stiffness, and swelling of one or more joints and can progress from mild swelling of the joints in early stages to severe deformations of the feet, ankles, and hands in late/severe stages. RA affects more than 1.5 million individuals in the United States. The Company has four programs in nonclinical and clinical development, three of which are targets in IBD validated by third parties. The fourth program is an undisclosed target. All three validated targets offer the potential for safe and effective treatment of UC and CD, with infrequent, subcutaneous maintenance dosing as a monotherapy or in rational combinations. The Company is also planning to study its anti-TL1A program in additional indications outside IBD, beginning with RA. SPY001 – a highly potent and selective investigational monoclonal antibody targeting α4β7, engineered with half-life extension technology and formulated at high concentration with the goal of maximizing efficacy and enabling infrequent, subcutaneous maintenance dosing. In November 2024, interim healthy volunteer data from a Phase 1 trial were presented, demonstrating a favorable safety profile, a meaningfully differentiated PK profile relative to vedolizumab with half-life estimates greater than 90 days supporting potential Q6M maintenance dosing, and complete occupancy of α4β7 receptors out to 12 weeks at a single dose of 300mg. Longer-term data from this Phase 1 trial will be presented at a medical meeting later this year. Based on these interim results, Spyre plans to advance SPY001 to a Phase 2 clinical trial in UC patients in mid-2025. SPY002 – a program with two highly potent and selective, investigational anti-TL1A monoclonal antibodies, engineered with half-life extension technology and formulated at high concentration with the goal of maximizing efficacy and enabling infrequent, subcutaneous maintenance dosing. The Company believes TL1A has emerged as one of the most promising targets in IBD and broader immunology indications. In January 2025, the Company announced its intent to study one of its anti-TL1A antibodies in RA, with Phase 2 trial initiation expected in mid-2025 and topline results in 2026. With class-leading potency and half-life established in preclinical studies, SPY002 has the potential to become the first-in-class and best-in-class anti-TL1A treatment for RA. In December 2024, the Company initiated first-in-human ("FIH") trials of both SPY002 candidates, with healthy volunteer interim data expected in the second quarter of 2025. If successful, the Company expects one or more SPY002 candidates would then advance to Phase 2 clinical trials. In October 2024, preclinical data for both SPY002 development candidates were presented at the United European Gastroenterology Week ("UEGW") Congress demonstrating superior or comparable in vitro potency to first-generation anti-TL1As, as well as a pharmacokinetic half-life of 24 days in non-human primates ("NHPs"), which represents a two to three-fold increase compared to these same first-generation anti-TL1As. SPY003 – a highly potent and selective investigational monoclonal antibody targeting the p19 subunit of IL-23, engineered with half-life extension technology and formulated at high concentration with the goal of maximizing efficacy and enabling infrequent, subcutaneous maintenance dosing. In October 2024, preclinical data for SPY003 were presented for the first time at UEGW, demonstrating comparable potency to risankizumab, as well as a pharmacokinetic half-life of 30 days in NHPs, greater than three-fold compared to risankizumab. These data also demonstrated that SPY003 exhibits high selectivity and affinity for IL-23 and potently inhibits downstream cellular signaling. SPY003 remains on track to initiate a FIH trial in the first quarter of 2025, with healthy volunteer interim data expected in the second half of 2025. Rational Combinations – the Company plans to investigate combinations of our proprietary antibodies in nonclinical studies and clinical trials in order to evaluate whether combination therapy can potentially lead to best-in-class efficacy in IBD, with less frequent dosing. In February 2025, new preclinical data for SPY120 were presented at the 20th Congress of the European Crohn's and Colitis Organisation, demonstrating that the combined inhibition of TL1A and α4β7 is superior to either monotherapy in mouse models of colitis and that coadministration of SPY001 and SPY002 demonstrated no drug effects on PK in NHPs. In October 2024, preclinical data for SPY130 and SPY230 were presented at UEGW, demonstrating enhanced efficacy and pharmacodynamics with SPY003 in combination with SPY001 and with SPY002. The Company expects to initiate a Phase 2 clinical trial in 2025 that is intended to include each of its rational combinations, as well as all three of its lead monotherapy programs. Recent Corporate Updates In December 2024, Spyre was added to the Nasdaq Biotechnology Index. In November 2024, the Company raised $230 million in gross proceeds from a public offering of common stock with broad participation from both new and existing investors, extending cash runway into the second half of 2028. In October 2024, the Company announced the appointment of Sheldon Sloan, M.D., M. Bioethics, as Chief Medical Officer. Dr. Sloan's 25+ years of experience in both large pharmaceutical and small biotech companies, featuring an extensive track record of program leadership in the field of Inflammation and Immunology, will be invaluable to guide the Company as it advances its potentially best-in-class IBD portfolio. Fourth Quarter 2024 Financial Results Cash Position: As of December 31, 2024, Spyre had cash, cash equivalents, and marketable securities of $603.1 million. Net cash used in operating activities was $37.2 million for the fourth quarter of 2024. In November 2024, the Company raised $230 million in gross proceeds, before deducting $14.2 million in underwriting discounts, commissions, and other offering expenses, from a public offering of common stock. Research and Development (R&D) expenses: R&D expenses totaled $50.5 million for the fourth quarter of 2024 and $33.7 million for the fourth quarter of 2023. The increase was primarily driven by nonclinical and clinical development, as well as manufacturing expenses, for the Company's pipeline candidates. General and Administrative (G&A) expenses: G&A expenses totaled $10.8 million for the fourth quarter of 2024 and $14.1 million for the fourth quarter of 2023. The decrease was driven by higher stock compensation expense related to the Spyre acquisition in the fourth quarter of 2023. Other income (expense): Other income totaled $5.0 million for the fourth quarter of 2024 primarily driven by interest earned on the Company's cash and marketable securities. For the fourth quarter of 2023, other expense totaled $17.3 million, primarily driven by an increase in the Company's CVR liability related to the increased likelihood of certain milestone payments related to pegzilarginase reimbursement in European markets, partially offset by interest earned on the Company's cash and marketable securities. Net Loss: Net loss totaled $56.3 million and $63.2 million for the fourth quarters of 2024 and 2023, respectively, which includes non-cash stock compensation expense of $9.2 million and $17.3 million for the fourth quarters of 2024 and 2023, respectively. About Spyre Therapeutics Spyre Therapeutics is a clinical-stage biotechnology company that aims to create next-generation inflammatory bowel disease (IBD) and other immune-mediated disease products by combining best-in-class antibody engineering, dose optimization, and rational therapeutic combinations. Spyre's pipeline includes investigational extended half-life antibodies targeting α4β7, TL1A, and IL-23. For more information, please visit . Safe Harbor / Forward Looking Statements This press release contains "forward-looking" statements within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. All statements contained in this press release, other than statements of historical fact are forward-looking statements. These forward-looking statements include statements regarding the Company's future results of operations and financial position; its business strategy, including the Company's ability to successfully develop best-in-class and/or first-in-class therapeutics for IBD, RA, or other immune-mediated diseases that meaningfully improve both efficacy and convenience compared to today's standard of care; the SPY001 Phase 1 trial final data readouts not being consistent with or being different than the interim Phase 1 results; the sufficiency of the Company's funding to support the development of its assets, including expectations of cash runway extending into the second half of 2028; the length of time that the Company believes its existing cash resources will fund its operations; estimated market sizes and potential growth opportunities; its nonclinical and future clinical development activities; clinical trial designs and related regulatory feedback; further clinical evaluation of therapeutic combinations; the potential efficacy, tolerability, convenience, commercial viability and safety profile of its product candidates, including in combinations; the planned dosing regimen for SPY001 and our other product candidates, including the potential for a Q6M dosing profile; the potential therapeutic benefits and economic value of its product candidates as monotherapies or in combinations and their extended half-life; the timing for initiation of nonclinical studies and clinical trials, including the commencement of FIH and Phase 2 trials; and the planned expansion of SPY002 into RA, including timing thereof. The words "believe," "may," "will," "potentially," "estimate," "continue," "anticipate," "predict," "target," "intend," "could," "would," "should," "project," "plan," "expect," the negatives of these terms, and similar expressions that convey uncertainty of future events or outcomes are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. These forward-looking statements are subject to a number of risks, uncertainties and assumptions, including the expected or potential impact of macroeconomic conditions, including U.S. elections inflationary pressures, rising interest rates, general economic slowdown or a recession, changes in monetary policy, the prospect of a shutdown of the U.S. federal government, volatile market conditions, financial institution instability, as well as geopolitical instability, including the ongoing military conflict in Ukraine, conflict in Israel and surrounding areas, and geopolitical tensions in China on the Company's operations, the potential impacts of the BIOSECURE Act bill if passed into law and those risks described in the Company's Quarterly Reports on Form 10-Q, Annual Reports on Form 10-K, as well as in other filings and reports that the Company makes from time to time with the Securities and Exchange Commission. Moreover, the Company operates in a very competitive and rapidly changing environment, and new risks emerge from time to time. It is not possible for the Company's management to predict all risks, nor can the Company assess the impact of all factors on the business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in any forward-looking statements it may make. In light of these risks, uncertainties, and assumptions, the forward-looking events and circumstances discussed in this press release may not occur and actual results could differ materially and adversely from those anticipated or implied in the forward-looking statements. You should not rely upon forward-looking statements as predictions of future events. Although the Company believes that the expectations reflected in the forward-looking statements are reasonable, the Company cannot guarantee that the future results, levels of activity, performance or events and circumstances reflected in the forward-looking statements will be achieved or occur. The Company undertakes no obligation to update publicly any forward-looking statement for any reason after the date of this press release to conform these statements to actual results, to reflect changes in the Company's expectations, or otherwise, except as required by law. You should read press release with the understanding that the Company's actual results, levels of activity, performance, events, outcomes, and the timing of results and outcomes, and other circumstances may be materially different from what the Company expects. SOURCE Spyre Therapeutics, Inc. 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