Ixoberogene soroparvovec

点击“蓝字”关注我们 编者按：糖尿病视网膜病变（DR）作为糖尿病微血管并发症之一，其隐匿进展与潜在不可逆损伤是DR防控的一大挑战。2025年8月2日于沈阳召开的第二十八次全军内分泌代谢病学术大会上，天津医科大学朱宪彝纪念医院陈莉明教授以“糖尿病视网膜病变机制与诊疗技术进展”为题作精彩报告，系统阐述了多模态影像技术、人工智能（AI）辅助诊断、双靶点药物及新型分子靶点等关键领域的创新成果。该报告为突破DR早期筛查瓶颈、实现精准治疗及深化发病机制研究提供了新视角。 一、DR的流行病学特征与发病机制 全球糖尿病患病人数呈快速增长趋势。2024年，20~79岁人群中糖尿病患者已达5.887亿，预计到2050年将攀升至8.525亿，增幅高达45%。其中，中国成人糖尿病患者人数居全球之首，2024年达1.48亿，预计2050年将增至1.683亿。伴随糖尿病的高发，其常见微血管并发症DR的防控形势亦十分严峻。2020年全球数据显示，DR总患病率为22.27%，其中威胁视力的DR患病率为6.17%，临床显著黄斑水肿患病率为4.07%；值得注意的是，包括中国在内的西太平洋地区情况尤为突出，该地区2020年DR患病人数高达3150万，患病率19.20%[1]。 糖尿病患者在眼底镜下可表现为无DR，也可表现为非增殖性DR（NPDR），后者以微血管异常、视网膜出血、微动脉瘤及静脉串珠等为特征。此外，患者还可能进展为增殖性DR（PDR），其特点是视网膜新生血管形成，后者可能导致视网膜脱离。糖尿病黄斑水肿（DME）在NPDR和PDR中均可发生[2]（图1）。 图1. DR的表现 DR的发病机制可概括为“三重打击”[3,4]：①微血管损伤为核心：持续高血糖导致视网膜毛细血管周细胞凋亡、基底膜增厚，引发血管渗漏（如微动脉瘤、硬性渗出）和闭塞（如棉絮斑）。血管闭塞造成的视网膜缺血会诱导血管内皮生长因子（VEGF）释放，进而导致异常新生血管形成。这些脆弱的新生血管易破裂，引发玻璃体积血和视网膜脱离等严重并发症。②神经血管单元（NVU）损伤：DR的另一关键环节，甚至在血管病变显现之前就已发生，表现为视锥细胞内外节缩短等早期神经元损伤。高血糖通过氧化应激、炎症因子（如IL-6、TNF-α）破坏NVU，导致视网膜神经节细胞凋亡。③ DME：因血-视网膜内屏障破坏，液体渗漏并积聚于黄斑区，可导致中心视力丧失，约3.5%患者需要抗VEGF药物或激光治疗。由此可见，DR不仅是一种血管病变，更是涉及神经血管单元的全局性损伤。 二、多模态影像技术革新与精准筛查体系 01 超广角成像系统：全域可视化与微血管病变分层 超广角成像系统技术优势显著：①全域覆盖：采用“四叶草”拼接模式，实现267°全域覆盖，消除拼接伪影，达成视网膜全域可视化（图2）；②多光谱分层成像：配备全光谱光源，涵盖蓝、绿、红、红外光，并结合自发荧光技术，可同步评估血管渗漏（蓝光）与RPE代谢状态（脂褐质荧光衰减），实现“结构-功能”双重分析。 其精准筛查价值主要体现在：①早期病变捕捉：可检出<100 μm的周边视网膜微动脉瘤及FAZ面积>0.4 mm2的无灌注区，将PDR诊断敏感度提升至92%，有助于早期发现病变，及时干预治疗；②诊疗一体化：可联合OCT测量黄斑水肿厚度，指导抗VEGF药物剂量调整，实现精准诊疗，提高治疗效果[5]。 图2. 超广角成像系统显示的眼底图像 02 免散瞳便携设备& AI：基层筛查的可及性创新 传统眼科筛查面临设备依赖（传统眼底相机体积庞大，仅限大型医院配置）、流程繁琐（散瞳需30分钟以上，且检查后数小时内患者视物模糊，影响生活）、人才缺口（专业眼科医生稀缺）的限制。而免散瞳便携设备突破瓶颈：①免散瞳设计：近红外光+自适应光学技术，瞳孔≥2 mm即可高清成像，突破传统设备依赖散瞳的限制，提升患者依从性，避免散瞳后视力模糊导致的跌倒风险；②超广角成像：单次拍摄覆盖200°~267°视网膜，漏诊率降至<5%，支持周边视网膜无灌注区的早期发现，PDR检出敏感度达92%；③智能质控：实时追踪瞳孔位置与屈光状态，0.4秒自动完成对焦与曝光优化，显著提升日筛查量。 人工智能（AI）存在技术优势，可与设备协同进行闭环管理，助力基层效能提升。在技术方面，多模态深度学习融合眼底彩照与OCT/OCTA数据，可识别55种病变（如微动脉瘤），灵敏度达92%~96%，并自动生成标注病灶的DICOM报告；动态风险评估基于时序数据预测5年DR进展风险（如HbA1c>9%者风险>30%），指导分层干预。在与设备协同形成闭环管理方面，从2秒/例的筛查分级、48小时内的转诊治疗，到自动提醒随访及量化病灶变化，全程高效赋能诊疗。 03 光学相干断层扫描OCT/OCTA技术升级 其优势体现在以下两方面：①超高速扫描与全域成像能力：扫描速度达40万次/秒，为传统设备2倍以上，15秒内可完成24 mm×20 mm、120°眼内角的超广角成像（图3）；全域扫频技术将穿透力提升至14 mm，实现从角膜到玻璃体的全景无拼接成像，突破传统6 mm深度限制。②多模态融合与智能算法：通过三维成像可视化血管网络，定量分析黄斑无灌注区（FAZ面积>0.5 mm2），自动生成血流密度等参数辅助DR分期。 图3. 24 mm OCTA成像 04 精准筛查体系——贾伟平院士牵头DeepDR系列研究 贾伟平教授团队在DR的精准筛查领域开展了深入研究，取得了一系列重要成果（图4）。2021年，该团队开发了DeepDR智能筛查系统，该系统能够对眼底图像质量进行评估，并实现对DR的病变分割与分级诊断[6]。随后，团队于2024年进一步推出了DeepDR Plus智能预警系统，该系统能够精准预测患者未来5年内的DR进展时间与风险，并提供个性化的筛查和干预策略推荐[7]。同年，团队还开发了DeepDR-LLM糖尿病管理大语言模型，该模型能够基于患者的临床信息提供精准的糖尿病管理建议，有效辅助基层的糖尿病诊疗工作[8]。 图4. DeepDR系列研究 三、治疗技术革新与前沿进展 01 多靶点药物与基因治疗 双特异性抗体药物（如Faricimab）：采用“CrossMab”技术，同时靶向VEGF-A与Ang-2。其抗VEGF-A活性抑制新生血管生成，抗Ang-2活性则有助于稳定血管结构（减少周细胞脱落）。注射间隔延长至16周，使DME复发率降低40%，有效解决了传统单靶点药物需频繁注射的痛点[9-11]。 基因疗法（如ADVM-022）：展现出长期稳定表达治疗性蛋白的潜力。单次玻璃体腔注射即可持续抑制VEGF表达≥3年（Ⅲ期临床阶段），为减少治疗负担提供了新策略。 02 长效缓释给药系统 纳米缓释系统：基于载药纳米颗粒（如PLGA）实现药物缓释，效果可持续约6个月，从而减少注射频率。 抗VEGF药物缓释系统（PDS）：采用微型泵装置持续释放雷珠单抗，适用于依从性差的患者。 03 激光治疗技术升级 多点阵列激光（PASCAL）：单次发射25个点，治疗时间缩短至5分钟，疼痛感降低70%。其多点阵列技术实现快速精准光凝，显著提升治疗效率与患者舒适度。克服了传统微脉冲光斑不可见及能量难控的缺陷，并具备多种可个性化设计的阵列扫描模式。 导航激光系统（如Ellex Navilas）：集成AI技术，可规划光凝位点并智能避开黄斑区（图5），使并发症发生率降低50%。 图5. 导航激光系统 04 高精度手术辅助 3D可视化手术系统：集成4K分辨率与景深增强技术，提供放大5倍的清晰术野，膜剥离精度达10 μm，显著提升手术精准度。 四、基础研究：AGGF1通路在视网膜病理性新生血管中的关键发现 陈莉明教授团队今年发表于Nature Communications的研究[12]揭示了血管生成因子AGGF1在DR发病中的核心作用，为治疗提供全新靶点。研究发现，PDR患者玻璃体液中AGGF1水平显著升高，在氧诱导视网膜病变小鼠模型中，AGGF1与新生血管内皮细胞共定位，通过激活TNFSF12/FN14通路，上调CyclinA2、CyclinD1等细胞周期蛋白，促进血管异常增殖与炎症反应。干预实验证实，内皮细胞特异性敲除AGGF1可减少氧诱导视网膜病变（OIR）小鼠病理性新生血管，降低血管渗漏与巨噬细胞浸润；抗AGGF1抗体与抗VEGF药物联用增效显著；钠-葡萄糖共转运蛋白2抑制剂（SGLT2i）早期干预可下调AGGF1及其下游蛋白，延缓病变进展。这一发现不仅揭示了内皮细胞AGGF1依赖的视网膜病理性新生血管形成机制，更为缺血性视网膜病变提供了靶向AGGF1或SGLT2i早期干预的新策略（图6）。 图6. AGGF1介导DR病变的核心机制与靶向干预策略 五、总结 超广角成像系统实现了视网膜全域的可视化，并能够结合AI算法，在拍摄瞬间自动对病变程度进行分级。利用AI辅助诊断对糖尿病患者进行视网膜摄影筛查并远程解读结果，显著提升了基层医院的筛查覆盖率和诊断准确性。在治疗领域，靶向VEGF-A/Ang-2的双特异性抗体药物在保留抗VEGF抑制新生血管作用的同时，新增了抗Ang-2以稳定血管的功能。第三代微脉冲激光采用“打孔机”式点阵治疗模式，能在有效保护健康组织的前提下，促进病变区域的自我修复。 参考文献 （上下滑动可查看） 1.Teo ZL, et al. Ophthalmology. 2021; 128(11): 1580-1591. 2.Antonetti DA, et al. Nat Rev Endocrinal. 2021; 17(4): 195-206. 3.Goldney J, et al. Diabetologia. 2023; 66(10): 1832-1845. 4.Wong TY, et al. Nat Rev Dis Primers. 2016; 2: 16012. 5.Patel SN, et al. Ther Adv Ophthalmol. 2020; 12: 2515841419899495. 6.Dai L, et al. Nat Commun. 2021; 12(1): 3242. 7.Dai L, et al. Nature Medicine. 2024; 30(2): 584-594. 8.Li J, et al. Nat Med. 2024; 30(10): 2886-2896. 9.Shirley M. Drugs. 2022; 82(7): 825-830. 10.Bressler SB, et al. JAMA Ophthalmol. 2016; 134(3): 278-285. 11.Curry BA, et al. Ophthalmol Ther. 2020; 9(1): 87-101. 12.Cheng Y, et al. Nat Commun. 2025; 16(1): 1332. 声明：本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。 最新《国际糖尿病》读者专属微信交流群建好了，快快加入吧！扫描左边《国际糖尿病》小助手二维码（微信号：guojitnb），回复“国际糖尿病读者”，ta会尽快拉您入群滴！ （来源：《国际糖尿病》编辑部） 版权声明 版权属《国际糖尿病》所有。欢迎个人转发分享。其他任何媒体、网站未经授权，禁止转载。

REDWOOD CITY, Calif., April 15, 2025 (GLOBE NEWSWIRE) -- Adverum Biotechnologies, Inc. (Nasdaq: ADVM), a clinical-stage company pioneering the use of gene therapy to preserve sight for life in highly prevalent ocular diseases, today reported financial results for the fourth quarter and full year 2024. The company also provided pipeline highlights and updates to anticipated milestones. “We believe Ixo-vec is poised to redefine the standard of care for patients with wet AMD as a potential best-in-class, one-and-done gene therapy. Ixo-vec offers the potential for life-long vision preservation and a favorable safety profile and is overwhelmingly preferred by patients over today’s treatment, as evidenced by our LUNA 52-week and OPTIC 4-year data,” stated Laurent Fischer, M.D., president and chief executive officer of Adverum Biotechnologies. “2025 is off to a strong start with the initiation of our first pivotal trial, ARTEMIS. Designed to enhance the potential for clinical, regulatory and commercial success, ARTEMIS will evaluate a broad patient population, including treatment naïve patients and patients with a high treatment burden, to provide confidence to retina specialists to prescribe Ixo-vec, if approved, across the spectrum of wet AMD patients. We look forward to sharing the design of our second pivotal trial, AQUARIUS, and to presenting long-term follow-up data from LUNA later this year.” Ixo-vec Program Highlights Initiated ARTEMIS, the first-ever registrational intravitreal gene therapy trial in patients with wet AMD ARTEMIS is designed to derisk the clinical, regulatory and commercial path to approval. The inclusion of both treatment-experienced and treatment-naïve patients is expected to increase the speed of enrollment and generate a broad registrational dataset representative of real-world patient demographics to inform prescribers.ARTEMIS is a US-based study evaluating a single administration of Ixo-vec (6E10 vg/eye) compared to on-label aflibercept (2mg) every 8 weeks in approximately 284 patients with wet AMD.The primary endpoint is mean change from baseline of best corrected visual acuity (BCVA) at one year (average of weeks 52 and 56) with a non-inferiority margin of -4.5 letters.Per FDA guidance, all patients will receive three loading doses of aflibercept prior to receiving Ixo-vec. Patients in both arms will be eligible for supplemental injections of aflibercept and will receive prophylactic steroid eye drops.ARTEMIS is the first of two planned Phase 3 registrational trials to evaluate Ixo-vec in patients with wet AMD. Details on the second similar global study, AQUARIUS, are forthcoming. Presented Phase 2 LUNA 52-week trial results LUNA data support selection of 6E10 dose with topical eyedrops for pivotal program, providing evidence of potential best-in-class efficacy with favorable long-term safety.6E10 dose in LUNA maintained visual and anatomic endpoints and continued to demonstrate potential best-in-class injection-free rates and reduction in injection burden.Aflibercept levels were in the therapeutic range similar to those observed in OPTIC.Ixo-vec was well tolerated, with local steroids effectively managing inflammation at both the higher 2E11 dose and the “go-forward” 6E10 dose.Results from the LUNA pre-specified Patient Preference Survey demonstrate overwhelming preference for Ixo-vec over prior anti-VEGF therapies and for the acceptability of the topical steroid prophylaxis. Presented OPTIC 4-year trial results Despite significant treatment need at baseline, patients in OPTIC continued to experience long-term benefit from Ixo-vec through at least 4 years of follow up, including maintenance of vision, durability of anatomical improvements and sustained reduction in anti-VEGF treatment burden.Stable aflibercept levels have been demonstrated as long as measured, up to 5 years post treatment.Ixo-vec at 2E11 was generally well tolerated and demonstrated a favorable safety profile. Long-term data establish a 10-fold safety margin from highest dose tested in wet AMD to the 6E10 dose selected for Phase 3. Other Ixo-vec updates “Nonclinical Study of Ixo-vec Gene Therapy for nAMD Supports Efficacy for a Human Dose of 6E10 vg/eye and Staggered Dosing of Fellow Eyes” published in Molecular Therapy – Methods and Clinical Development. This study supports staggered contralateral dosing of Ixo-vec, and dosing Ixo-vec at the 6E10 dose explored in LUNA, in patients with wet AMD. Upcoming Anticipated Milestones 2H 2025 Initiate the global AQUARIUS Phase 3 trial4Q 2025 Present Phase 2 LUNA two-year long-term follow-up data Financial Results for the Three Months Ended December 31, 2024 Cash, cash equivalents and short-term investments were $125.7 million as of December 31, 2024, compared to $153.2 million as of September 30, 2024, and $96.5 million as of December 31, 2023. Adverum expects its cash, cash equivalents and short-term investments to fund operations into the second half of 2025. Research and development expenses were $24.1 million for the three months ended December 31, 2024, compared to $15.3 million for the same period in 2023. Research and development expenses increased due to higher material production and bioanalytics expenses and higher compensation expenses in preparation for Phase 3 clinical trials. Stock-based compensation expense included in research and development expenses was $1.2 million for the fourth quarter of 2024. General and administrative expenses were $18.5 million for the three months ended December 31, 2024, compared to $11.7 million for the same period in 2023. General and administrative expenses increased due to increases in a non-cash tenant improvement allowance made available to a subtenant for our North Carolina premises and higher consultant fees. Stock-based compensation expense included in general and administrative expenses was $2.0 million for the fourth quarter of 2024. Net loss was $40.9 million, or $1.96 per basic and diluted share, for the three months ended December 31, 2024, compared to $24.5 million, or $2.42 per basic and diluted share for the same period in 2023. About Ixo-vec in Wet AMD Adverum is developing ixoberogene soroparvovec (Ixo-vec, formerly referred to as ADVM-022), its clinical-stage gene therapy product candidate, for the treatment of wet AMD. Ixo-vec utilizes a proprietary vector capsid, AAV.7m8, carrying an aflibercept coding sequence under the control of a proprietary expression cassette. Unlike other ophthalmic gene therapies that require surgery to administer the gene therapy under the retina (sub-retinal approach), Ixo-vec is designed to be administered as a one-time IVT injection in the physician’s office, deliver long-term efficacy, reduce the burden of frequent anti-VEGF, optimize patient compliance and improve vision outcomes for patients with wet AMD. In recognition of the need for new treatment options for wet AMD, FDA granted Fast Track and Regenerative Medicine Advanced Therapy (RMAT) designations for Ixo-vec for the treatment of wet AMD. Ixo-vec has also received PRIME designation from the EMA and the Innovation Passport from the United Kingdom’s Medicines and Healthcare Products Regulatory Agency for the treatment of wet AMD. About Adverum Biotechnologies Adverum Biotechnologies (NASDAQ: ADVM) is a clinical-stage company that aims to establish gene therapy as a new standard of care for highly prevalent ocular diseases with the aspiration of developing functional cures to restore vision and prevent blindness. Leveraging the capabilities of its proprietary intravitreal platform, Adverum is developing durable, single-administration therapies, designed to be delivered in physicians’ offices, to eliminate the need for frequent ocular injections to treat these diseases. Adverum is evaluating its novel gene therapy candidate, ixoberogene soroparvovec (Ixo-vec, formerly referred to as ADVM-022), as a one-time, IVT injection for patients with neovascular or wet age-related macular degeneration. Additionally, by overcoming the challenges associated with current treatment paradigms for debilitating ocular diseases, Adverum aspires to transform the standard of care, preserve vision, and create a profound societal impact around the globe. For more information, please visit www.adverum.com. Forward-looking Statements Statements contained in this press release regarding events or results that may occur in the future are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Such statements include but are not limited to statements regarding: the potential of Ixo-vec to redefine treatment standards as a potential best-in-class, one-and-done gene therapy; the therapeutic and commercial potential of Ixo-vec; potential benefits of Ixo-vec, including the potential for life-long vision preservation and its favorable long-term safety profile; the ability to generate data that provides confidence to retina specialists to prescribe Ixo-vec; plans and milestones related to Adverum’s product candidates, including the planned initiation of the global AQUARIUS Phase 3 trial and the presentation of LUNA Phase 2 two-year long-term follow-up data; Adverum’s cash sufficiency and runway; the potential of Ixo-vec to redefine the standard of care for patients with wet AMD; the ability to establish gene therapy as a standard of care for wet AMD patients and other statements that are not a historical fact. Actual results could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, including risks inherent to, without limitation: Adverum’s novel technology, which makes it difficult to predict the timing of commencement and completion of clinical trials; regulatory uncertainties; enrollment uncertainties; the results of early clinical trials not always being predictive of future clinical trials and results; the potential for future complications or side effects in connection with use of Ixo-vec; and risks associated with market conditions. Additional risks and uncertainties facing Adverum are set forth under the caption “Risk Factors” and elsewhere in Adverum’s Securities and Exchange Commission (SEC) filings and reports, including Adverum’s most recent Annual Report on Form 10-K and subsequent filings with the SEC. All forward-looking statements contained in this press release speak only as of the date on which they were made. Adverum undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law. Corporate & Investor Inquiries:Adverum Investor RelationsEmail: ir@adverum.com Media:Jason Awe, Ph.D.Executive Director, Corporate CommunicationsEmail: jawe@adverum.com Adverum Biotechnologies, Inc.Selected Consolidated Balance Sheet Data(In thousands) December 31 December 31 2024 2023(Restated) Cash and cash equivalents, and marketable securities$125,691 $96,526 Total assets 179,841 155,768 Total current liabilities 22,898 19,981 Total stockholders' equity 70,714 67,222 Adverum Biotechnologies, Inc.Condensed Consolidated Statements of Operations(In thousands except per share data) Three months ended December 31, Years ended December 31, 2024 2023(Restated) 2024 2023(Restated) (Unaudited) (1) License revenue$- $- $1,000 $3,600 Operating expenses: Research and development 24,095 15,278 77,041 77,486 General and administrative 18,523 11,670 63,118 55,056 Total operating expenses 42,618 26,948 140,159 132,542 Operating loss (42,618) (26,948) (139,159) (128,942) Other income, net 1,687 1,311 8,232 5,748 Net loss before income taxes (40,931) (25,637) (130,927) (123,194) Income tax provision - 1,133 - 1,078 Net loss (40,931) (24,504) (130,927) (122,116) Net loss per share — basic and diluted$(1.96) $(2.42) $(6.62) $(12.11) Weighted-average common shares outstanding - basic and diluted 20,898 10,121 19,782 10,082 (1) Derived from Adverum’s annual audited consolidated financial statements.