Suprachoroidal Delivery of Small Molecules, Nanoparticles, Gene and Cell Therapies for Ocular Diseases

Abstract

Suprachoroidal drug delivery technology has advanced rapidly and emerged as a promising administration route for a variety of therapeutic candidates, in order to target multiple ocular diseases, ranging from neovascular age-related macular degeneration to choroidal melanoma. This review summarizes the latest preclinical and clinical progress in suprachoroidal delivery of therapeutic agents, including small molecule suspensions, polymeric entrapped small molecules, gene therapy (viral and nonviral nanoparticles), viral nanoparticle conjugates (VNCs), and cell therapy. Formulation customization is critical in achieving favorable pharmacokinetics, and sustained drug release profiles have been repeatedly observed for multiple small molecule suspensions and polymeric formulations. Novel therapeutic agents such as viral and nonviral gene therapy, as well as VNCs, have demonstrated promise in animal studies. Several of these suprachoroidally-administered therapies have been assessed in clinical trials, including small molecule suspensions of triamcinolone acetonide and axitinib, viral vector RGX-314 for gene therapy, and VNC AU-011. With continued drug delivery research and optimization, coupled with customized drug formulations, suprachoroidal drug delivery may address large unmet therapeutic needs in ophthalmology, targeting affected tissues with novel therapies for efficacy benefits, compartmentalizing therapies away from unaffected tissues for safety benefits, and achieving durability to relieve the treatment burden noted with current agents.

Vascular Endothelial Growth Factor Antagonists: Promising Players in the Treatment of Neovascular Age-Related Macular Degeneration

“…Suprachoroidal delivery can target therapy to affected chorioretinal tissues for potential efficacy benefits, compartmentalizing it away from unaffected vitreous and anterior segment tissues for potential safety benefits, and achieve durability through the use of insoluble suspension formulations. 65 This approach was assessed with proof of concept therapy, CLS-TA or Xipere, a proprietary suspension of triamcinolone, for uveitic macular edema, culminating in a successful phase 3 clinical trial; durability was demonstrated in an extension study, with a new drug application planned for 2021. 66 In preclinical studies of axitinib, compared to intravitreal administration, suprachoroidal administration resulted in much greater targeted levels of axitinib in retinal and choroidal tissues, with lower levels in the vitreous and anterior segment, which could minimize the risk of off-target effects.…”

“… 66 In preclinical studies of axitinib, compared to intravitreal administration, suprachoroidal administration resulted in much greater targeted levels of axitinib in retinal and choroidal tissues, with lower levels in the vitreous and anterior segment, which could minimize the risk of off-target effects. 65 …”

Ocular Therapeutics and Molecular Delivery Strategies for Neovascular Age-Related Macular Degeneration (nAMD)

“…It is an invasive route and causes difficulty to patients, but alternative clinical outcomes are bleak at present [ 4 , 5 ]. Various administrative routes are explored, such as periocular, suprachoroidal, sub-retinal, systemic, and topical routes for the delivery of small molecules, biologics, and gene therapy [ 6 ]. Molecular therapies such as cell therapy and gene therapy are in focus due to their restoration ability [ 7 , 8 , 9 , 10 ].…”

Patient preferences in retinal drug delivery

“…Treatment non-compliance can worsen the overall prognosis of RVDs by breaking the necessary continuation of treatment required to keep neovascularization in check 6 . However, recent developments in small molecule anti-angiogenic drugs provide potential treatments for these RVDs that could utilize less invasive drug delivery systems, such as eye drops, oral tablets, and subconjunctival or suprachoroidal injections 7 – 10 . Non-invasive treatment options also avoid the rare but serious risks of adverse events with IVT injections, notably endophthalmitis 11 .…”