Developing a multivalent agent for long-lasting treatment of diabetic macular edema

开发用于长期治疗糖尿病黄斑水肿的多价药物

• 批准号: 10324534
• 负责人: Qiang Gong
• 金额: $ 22.47万
• 依托单位: APTITUDE MEDICAL SYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10324534
• 关键词: Adopted; Affect; Affinity; Age; Angiopoietin-2; Animal Model; Aptitude; Binding; Biological; Biomedical Engineering; Blindness; Chronic; Clinical; Clinical Trials; Combined Modality Therapy; Complement; Computer Models; Disease Management; Dose; Equilibrium; Exudative age-related macular degeneration; Funding; Half-Life; Health Care Visit; Human; Hyaluronic Acid; In Vitro; Injections; Link; Maximum Tolerated Dose; Measures; Metabolic Clearance Rate; Methods; Modeling; Molecular Sieve Chromatography; Mus; Nucleic Acids; Oryctolagus cuniculus; Outcome; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Polymers; Publishing; Radial; Regimen; Reporting; Rest; Safety; Schedule; Small Business Innovation Research Grant; Solubility; Testing; Therapeutic; Time; Time Management; Toxic effect; Translating; Vascular Endothelial Growth Factors; Work; aging population; aptamer; arm; bevacizumab; comorbidity; design; diabetes management; diabetic; dosage; drug efficacy; efficacy testing; experience; follow-up; improved; indexing; intravitreal injection; light scattering; macular edema; meetings; next generation; novel; novel strategies; particle; phase III trial; pre-clinical research; programs; prototype; ranibizumab; standard of care; systemic toxicity

PROJECT ABSTRACT DME is the leading cause of blindness in the working age population. The anti-VEGF agents are currently the standard of care for DME, but these treatments are far from optimal: patients need to receive 8-12 intravitreal injections in the first year and continue regular follow-up and treatment for the rest of their lives. These patients also have to spend significant time managing diabetes and other comorbidities – a recent study reported that an average DME patient has ~30 healthcare visit days a year. It is therefore extremely difficult for them to balance work and disease management. Consequently, the real-world outcomes of DME patients are significantly worse than the results from controlled trials due to under-treatment and loss to follow-up. Longer-lasting therapeutics are urgently needed. The duration of drug efficacy is determined by 3 key factors: drug potency, which affects the minimum effective concentration (MEC); drug half-life (t1/2), which determines how fast it is metabolized; initial drug dosage, which determines how long it can last until it reaches MEC. The benefits of improving these factors are validated: 1) Aflibercept leveraged bivalency to achieve higher potency than Ranibizumab and enabled a longer duration (bimonthly vs. monthly); 2) extensive studies have shown that increasing the hydrodynamic radius (RH) of a drug proportionally elongates its vitreous half-life, and multiple programs are being developed to leverage this principle; 3) Brolucizumab adopted a much higher dose than the approved anti-VEGF agents and reported a longer duration in the recent phase 3 trials in wet AMD. While these programs proved the feasibility to improve drug duration through rational bioengineering, they each tackles one factor and only achieved incremental improvement (~3-month duration). Simultaneously improving all 3 factors may unlock dramatic improvement but is extremely challenging. The purpose of this SBIR is to develop a novel multivalent polymer conjugate of therapeutic aptamers that simultaneously improve all 3 factors of drug duration for the first time, enabling significantly longer-lasting treatment for DME. To that end, the Aptitude team has accumulated extensive experience in aptamer discovery. We have previously developed the Particle Display method that significantly improves the aptamer performance. We have also performed significant preliminary studies to prove the feasibility of constructing multivalent polymer conjugates. Moreover, we have made further improvement to directly screen for fully modified aptamers that possess superior stability and performance compared to the previous aptamers. Our expertise in aptamer discovery is complemented by our collaborators' expertise in DME preclinical research and clinical trials. If successful, this project has the potential of bringing more efficacious and affordable treatment to DME patients.

项目摘要 DME 是导致劳动年龄人口失明的主要原因。抗VEGF药物是目前的标准药物 护理 DME，但这些治疗方法远非最佳：患者首次需要接受 8-12 次玻璃体内注射 年并在余生中继续定期随访和治疗。这些患者还需要花费大量的费用 管理糖尿病和其他合并症的时间——最近的一项研究报告称，一名 DME 患者平均有约 30 次医疗保健 一年中的访问天数。因此，他们很难平衡工作和疾病管理。因此， 由于治疗不足，DME 患者的现实结果明显比对照试验的结果差 以及后续的损失。迫切需要更持久的治疗方法。 药物疗效的持续时间由 3 个关键因素决定： 药物效力，影响最低有效剂量 浓度（MEC）；药物半衰期（t1/2），决定其代谢速度；初始药物剂量， 决定它到达 MEC 之前可以持续多长时间。改善这些因素的好处已得到验证：1) 阿柏西普 利用二价来实现比雷珠单抗更高的效力，并实现更长的持续时间（双月与每月）； 2) 广泛的研究表明，增加药物的流体动力学半径 (RH) 会成比例地延长其药效 玻璃体半衰期，并且正在开发多个项目来利用这一原理； 3) Brolucizumab 采用了很多 在最近的湿性 AMD 3 期试验中，该药物的剂量比已批准的抗 VEGF 药物更高，并且持续时间更长。 虽然这些计划证明了通过合理的生物工程延长药物持续时间的可行性，但它们各自解决了 一个因素，并且仅实现了渐进式改进（约 3 个月的持续时间）。同时改善所有 3 个因素可能会 实现显着的改进，但极具挑战性。 该 SBIR 的目的是开发一种新型的治疗性适体多价聚合物缀合物，同时 首次改善了药物持续时间的所有 3 个因素，从而使 DME 的治疗效果显着延长。对此 由此，Aptitude团队在适配体发现方面积累了丰富的经验。我们之前开发过 显着提高适配体性能的粒子显示方法。我们也做出了重大贡献 初步研究证明构建多价聚合物缀合物的可行性。此外，我们还做了 进一步改进直接筛选具有优异稳定性和性能的完全修饰的适体 与之前的适配体相比。我们在适体发现方面的专业知识与我们合作者的专业知识相辅相成 从事DME临床前研究和临床试验。如果成功，该项目有可能带来更有效的 为 DME 患者提供负担得起的治疗。