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; 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是在工作年龄人群中失明的主要原因。反VEGF代理人目前是 护理DME，但这些治疗远非最佳：患者需要在第一次注射8-12次玻璃体内注射 一年，并继续定期随访和待遇。这些患者还必须花费大量 管理糖尿病和其他合并症的时间 - 最近的一项研究报告说，普通DME患者的医疗保健约为30 一年访问几天。因此，他们很难平衡工作和疾病管理。因此， DME患者的现实结果明显比由于治疗不足而导致的对照试验结果差得多 和后续行动的损失。迫切需要更长的疗法。 药物效率的持续时间由3个关键因素确定：药物效力，影响最低有效性 浓度（MEC）；药物半衰期（T1/2），这决定了其代谢的速度；最初的药物剂量 确定它可以持续多长时间，直到达到MEC。改善这些因素的好处已得到验证：1）Aflibercept 杠杆二价比ranibizumab更高的效能，并使持续时间更长（双月与每月）； 2）广泛的研究表明，增加药物的流体动力半径（RH）会按比例延长 玻璃半衰期和多个程序正在开发以利用这一原则； 3）布洛妥珠单抗采用了很多 剂量高于批准的抗VEGF药物，并报告了最近在湿AMD的3阶段试验中持续时间更长。 尽管这些计划提供了通过理性生物工程来提高药物持续时间的可行性，但它们各自铲球 一个因素，仅实现了增量改善（持续时间〜3个月）。同时改善所有3个因素 解锁戏剧性的改进，但极为挑战。 该SBIR的目的是开发一种新型的多价聚合物结合物的治疗性适体偶联物 首次改善所有3个药物持续时间因素，从而使DME明显更长地持续治疗。为此 结束时，能力团队在Apatmer Discover中积累了丰富的经验。我们以前已经开发了 粒子显示方法可显着改善纠正性能。我们也表现出色 初步研究以证明构建多价聚合物偶联的可行性。而且，我们做了 进一步改进，直接筛选具有卓越稳定性和性能的完全修改的适体 与以前的适体相比。我们合作者的专业知识完成了我们在适体发现方面的专业知识 在DME临床前研究和临床试验中。如果成功，该项目有可能带来更高效的 以及对DME患者的负担得起的治疗。