Innovative therapies for neovascular age-related macular degeneration

ABSTRACT

Introduction: Investigational anti-VEGF treatments for neovascular age-related macular degeneration (nAMD) aim to improve visual outcomes and reduce treatment burden; these include long-acting agents, combination strategies, topical agents, sustained-release, and genetic therapies.

Areas covered: The authors provide a comprehensive review of investigational therapies for nAMD, focusing on therapies currently in clinical trial.

Expert opinion: Long-acting anti-VEGF agents have demonstrated promising results in phase 3 studies, and include Brolucizumab, a single-chain antibody fragment, and Abicipar, a designed ankyrin repeat protein (DARPin). Other unique anti-VEGF agents in current trials include Conbercept – a fusion protein of the VEGF receptor domains, KSI-301 – an anti-VEGF antibody biopolymer conjugate, and OPT-302 – an inhibitor of VEGF-C/D. Strategies to activate the Tie-2 receptor, some in combination with VEGF inhibition, are of interest, with recent trials of Faricimab, ARP-1536, and nesvacumab. Topical anti-VEGF ± anti-PDGF agents, such as pazopanib, squalamine lactate, regorafenib, and LHA510 have shown limited efficacy and/or have not been advanced, although PAN-90806 continues to advance with promising initial results. Sustained-release anti-VEGF treatments, to address treatment burden, include the ranibizumab Port Delivery System, GB-102, NT-503, hydrogel depot, Durasert, and ENV1305. Similarly, genetic therapies, including RGX-314 and ADVM-022, aim to provide sustained anti-VEGF expression from the retina.

KEYWORDS:

• Age-related macular degeneration
• vascular endothelial growth factor
• abicipar pegol
• brolucizumab
• conbercept
• X-82
• Tie-2 receptor
• faricimab
• nesvacumab
• gene therapy
• RGX-314
• ADVM-022

Acknowledgments

This work was undertaken in Dr. Ciulla’s role as Volunteer Clinical Professor at Indiana University School of Medicine, and does not reflect the views or opinions of Clearside Biomedical or management.

Declaration of interest

T Ciulla is an employee of Clearside Biomedical and was formerly employed by Spark Therapeutics and Ophthotech. PU Dugel is on the scientific advisory board of Alcon Surgical, Genentech, MacuSight, Novartis, NeoVista, ArticDx, Alcon Pharmaceutical, AMO, Novartis, Thrombogenics, Santen, Ophthotech, Lux BioScience, Digisight, Roche, Acucela, Stealth Biotherapeutics, Lutronic, Avalanche, TrueVision, Alimera, Orbis International, Annidis, Neurotech, Aerpio, DOSE Medical, Omeros, Shire Human Genetics, Opthea, Graybug Vision, CDR-Life, and Clearside Biomedical. He has also acted as a consultant for Bausch and Lomb Surgical and Medical, Genentech, Alcon Surgical and Pharmaceutical, NeoVista, MacuSight, ArticDx, ORA, Novartis, Allergan, Regeneron, Santen Inc, QLT, Inc., Abbott/AMO, Thrombogenics, Ophthotech, Lux Bioscience, DigiSight,Genentech, Roche, TopCon, Acucela, Pentavision, ORA, Stealth Biotherapeutics, Annidis, Clearside Biomedical, Optovue, Neurotech, Lutronic, Alimera Sciences, DOSE Medical, Aerpio, Omeros, Shire Human Genetics, Ophthea, Spark Therapeutics, Graybug Vision, Zeiss Group, Irenix, ByeOnics, Clearside Biomedical, PanOptica, Chengdu Kanghong Biotechnology, SciFluor Life Sciences, Boehringer Ingelheim, Kodiak Sciences, Oculis SA, pSivida Corporation, Amgen Inc, Aerie Pharmaceutical, Pieris Pharmaceutical, Gemini Pharmaceutical, Ionis, RegenexBio, Reneuron and Abfero. He is also a minor stockholder for Alimera, Aerpio, Annidis, ArctixDx, Digisight, Irenix, Ophthotech, Clearside Biomedical, PanOptica, and TrueVision. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

One referee has received lecture fees and consultancy honoraria from Allergan, Alimera, Bayer, Novartis, Roche. They also participate in studies conducted by Samsung, Novartis, and GlaxoSmithKline. Another referee gives presentations for Bayer, Novartis and Heidelberg Engineering and has served on advisory boards for Bayer and Novartis. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Article Highlights

• Despite impressive advancements in the treatment of neovascular age-related macular degeneration over the past two decades with anti-vascular endothelial growth factor (anti-VEGF) therapy, there is great need to reduce the treatment burden from frequent injections.

• Brolucizumab and abicipar pegol are two novel anti-VEGF agents that demonstrated promising results with 12-week dosing in phase 3 clinical trials. Conbercept, another anti-VEGF agent that has been approved in China, is undergoing phase 3 trials in the United States.

• Faricimab is a bispecific antibody targeting both VEGF-A and angiopoietin-2, which is now in phase 3 trials after 12 and 16-week dosing was non-inferior to monthly ranibizumab in phase 2 trials.

• Topical anti-VEGF therapy so far has failed to reduce the need for rescue intravitreal anti-VEGF injections in clinical trials, though PAN-90806 is currently being studied in phase 1/2 trials.

• The ranibizumab Port Delivery System is in phase 3 studies after the phase 2 LADDER study demonstrated the majority of patients were maintained for 6 months or more without requiring an initial medication refill. Other sustained-release anti-VEGF delivery treatments such as GB-102, hydrogel depot, Durasert, and ENV1305 are in earlier phase studies.

• Several viral vector-based genetic therapies under study aim to relieve the burden of persistent anti-VEGF therapy, with potential for a one-time treatment.

This box summarizes the key points contained in the article.

Additional information

Funding

This manuscript has not been funded.