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

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 collaboratorsandapos; 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.NARRATIVE 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. In consequence, 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. We propose to create a novel multivalent polymer conjugate of therapeutic aptamers, which has the potential to dramatically prolong drug duration and reduce treatment burden.