Fully modified bispecific aptamer for effective wet AMD combination treatment

PROJECT ABSTRACT Wet Age related Macular Degeneration AMD is the leading cause of new blindness among people who are or older The current standard of care for wet AMD is anti Vascular Endothelial Growth Factor VEGF agents such as Lucentis Eylea and Avastin used off label These anti VEGF agents inhibit VEGF mediated angiogenesis and effectively stop or even reverse the vision loss for most patients Despite being the best treatment currently available it has two critical shortcomings limited near term vision gain and poor long term vision maintenance major cost and treatment burden First despite continued treatment only of the patient gain andgt lines of vision over the first months after years most patients start losing vision again and eventually dropping to pre treatment levels Second patients must return to the clinic every to months for intravitreal injections a specialized uncomfortable and costly procedure that represents significant treatment burden Combination therapies which combine an anti VEGF agent with disease modifying agents that target other important biomarkers such as PDGF and Ang have shown great promise in further improving efficacy and or reducing treatment burden However they require the use of multiple therapeutic agents and sometimes multiple injections which further increase the cost and treatment burden In order to address this shortcoming the ideal next generation wet AMD treatment should meet the following criteria a small in size in order to achieve high molar dosage and longer duration of efficacy and facilitate tissue penetration b devoid of immunogenicity and immune stimulatory effects in order to ensure long term safety c suitable for complex formulation in order to facilitate future development in slow release or topical administration technologies d most importantly capable of inhibiting multiple biomarkers with one molecule in order to improve efficacy without increasing treatment burden and cost Aptamers are single stranded oligonucleotides that bind to molecular targets in a manner similar to monoclonal antibodies mAbs Although aptamers were invented much more recently than mAbs they have already shown significant potential in wet AMD treatment Macugen the first anti VEGF agent approved by FDA for wet AMD treatment is an aptamer Fovista an anti PDGF aptamer is the most advanced combination treatment program There is also an anti complement C aptamer Zimura currently in Phase II III trial The purpose of this SBIR is to develop highly stable bispecific aptamers that may serve as the optimal combination treatment for wet AMD 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 developed the method to screen for the optimal linker for a bispecific aptamer Moreover we have made further improvement to directly screen for fully modified aptamers that may enable longer duration of efficacy Our expertise in aptamer discovery is complemented by our collaboratorsandapos expertise in wet AMD animal model and clinical trials If successful this project has the potential of bringing more efficacious and affordable treatment to wet AMD patients NARRATIVE Wet Age related Macular Degeneration wet AMD is the leading cause of new blindness among people who are or older Anti VEGF therapeutics such as Eylea and Lucentis are the standard treatment and are effective in improving vision in the near term However the vision gain typically plateaus soon and patients will later start to lose vision again despite continued treatment We propose to create a highly stable bispecific aptamer that can target multiple biomarkers thus both further improving treatment efficacy and potentially reducing treatment burden by extending the duration of efficacy