The Evolution of AMD Therapies

From anti-VEGF to home OCT — the quest for the most promising AMD treatment is on

by April Ingram

Although 2005 may not seem like ancient history — the first iPhone wasn’t available until 2007 — if you were diagnosed with neovascular (wet) age-related macular degeneration (AMD) before then, your prognosis was dismal.

The best available treatment at the time was photodynamic therapy, which, despite best efforts, resulted in the majority of eyes declining to visual acuity of 20/200 or poorer within the first year. Late 2004 saw the approval, and subsequent short lifespan, of intravitreal pegaptanib sodium. And in 2005, Philip Rosenfeld wowed the crowd at the 109th Annual Meeting of the American Academy of Ophthalmology in Chicago, discussing AMD treatment with intravitreal bevacizumab. In a 2006 issue of the New England Journal of Medicine, Rosenfeld and investigators had us all jumping on the nautical-themed (MARINA, HARBOR, ANCHOR) ranibizumab train — and then we were full speed ahead to antivascular endothelial growth factor (anti-VEGF) land.

For years, ranibizumab (LUCENTIS®) held its place of glory on the wet AMD landscape, with, of course, its bevacizumab (Avastin®) cousin stealing a little off-label thunder.

Fast forward to 2011, when aflibercept (Eylea®) entered the scene, and there we had our pillars of anti-VEGF treatment.

The quest for more effective treatments

As we know in all subspecialties of ophthalmology, specifically in retina, we are forever on a quest for more effective, safer, and durable ways to treat our patients.

So, let’s fast forward to current times — when you may be reading this on an iPhone 14, Pro, or Max — and take a look at the ways we are diagnosing and treating AMD and the novel advancements on the horizon. Retina practices are always buzzing with patients, and there seems to be no shortage of ongoing clinical trials.

Two highly sought-after investigators that are at the forefront of recently approved AMD treatments and novel pipeline therapies are Dr. Christina Y. Weng — professor of ophthalmology and the Vitreoretinal Diseases and Surgery Fellowship Program director at the Baylor College of Medicine, and Dr. Charles C. Wykoff — director of research at Retina Consultants of Texas, chairman of research at Retina Consultants of America, and deputy chair of ophthalmology for the Blanton Eye Institute, Houston Methodist Hospital, both in Houston, Texas, USA.

We had a chance to ask Dr. Weng and Dr. Wykoff about the evolution of AMD treatments and what novel therapies they are most excited about that may be coming soon to a clinic near you.

“The current generation anti-VEGF pharmacotherapies aflibercept and ranibizumab, as well as the dual VEGF and ANG2 inhibitor faricimab, are excellent for managing exudative retinal diseases including neovascular AMD,” Dr. Wykoff shared some of the currently available treatments in the US.

He added that a higher dose of a familiar face is also making waves. “Most recently, high-dose aflibercept, 8 mg, has demonstrated improved durability in trials with a potential label update anticipated for later this year,” Dr. Wykoff shared.

Dr. Weng agreed that the durability of high-dose aflibercept has been impressive. “It may allow patients to be treated as infrequently as every 16 weeks with no new safety signals observed.” [Editor’s Note: You can read more about the high-dose Eylea treatment regimen in PIE magazine’s issue 24X.]

New molecules and devices in the pipeline

Of all the data being released, and new molecules and devices being evaluated in the AMD space, we wanted to know if there were certain candidates, in addition to high-dose aflibercept, that Dr. Weng is excited about or watching carefully.

“It’s honestly impossible to pick just one — what excites me the most is that there are so many promising therapeutics being investigated in parallel,” she explained. “Anything that can further elevate the high bar that has been set, whether it’s better efficacy or longer durability, will be a welcome addition to our toolboxes.”

Dr. Weng highlighted a few treatments that are on her watchlist. “I am fascinated by gene therapies, such as RGX-314 and ADVM-022, because they may be able to significantly reduce the treatment burden that challenges so many of our patients,” she continued. “However, their safety needs to be confirmed across larger-scale trials.”

Dr. Wykoff explained the mechanism of these gene therapy options.

“Gene therapies work by creating an intraocular biofactory to produce an anti-VEGF protein,” he said.

“RGX-314 is the most advanced in development, currently enrolling in two phase 3 trials; ADVM-022 and 4D-150 are both intravitreally delivered gene therapies in earlier stages of development.”

RGX-314 is being investigated by REGENXBIO (Maryland, USA) in collaboration with AbbVie (Illinois, USA), as a potential one-time treatment for wet AMD, diabetic retinopathy, and other chronic retinal conditions. RGX-314 gene therapy includes the NAV AAV8 vector containing a gene encoding for a monoclonal antibody fragment designed to inhibit VEGF.

ADVM-022 is Adverum Biotechnologies’ (California, USA) gene therapy product, an AAV vector encoding aflibercept. 4D-150 from 4D Molecular Therapeutics (California, USA) is a dual-transgene, intravitreal gene therapy designed to inhibit four distinct angiogenic factors.

Further, Dr. Weng shared her thoughts on OPT-302, an anti-VEGFC/-D being evaluated by Opthea (York, Canada) used as a combination treatment with anti-VEGF-A agents. “OPT-302 has a unique mechanism in its inhibition of VEGF-C and VEGF-D, which can be upregulated by blockade of VEGF-A. When OPT302 was used in combination with ranibizumab in a phase 2 study, patients had superior visual acuity outcomes compared to those who received ranibizumab alone,” she explained. “I look forward to seeing what the ongoing phase 3 trials will show.”

Dr. Wykoff agreed and is excited about what may be the next tool, or combination of tools, to be added to the retinal toolbox. “Looking ahead, next-generation treatments hold substantial promise to move our field forward,” he noted. “For example, OPT-302 inhibits VEGF-C and VEGF-D and in combination with antiVEGF-A therapies is being studied in the two global phase 3 randomized trials, COAST and SHORE. In the preceding phase 2 trial, the addition of OPT-302 to monthly ranibizumab treatment increased visual gain by about 5 letters, underscoring the potential for improved visual outcomes for patients beyond what is achievable with current agents,” he added.

Novel treatments, anyone?

Novel mechanisms of action and more durable treatment options always draw the attention of the AMD crowd. Durability is a hot topic, as it is no secret that patient compliance with frequent intravitreal injections remains a challenge.

EyePoint Pharmaceuticals

(Massachusetts, USA) is conducting trials of EYP-1901, a sustained delivery anti-VEGF (vorolanib) tyrosine kinase inhibitor (TKI), in bioerodible Durasert®. Ocular Therapeutix (Massachusetts, USA) is also in the anti-angiogenic TKI space with OTX-TKI, an investigational bioresorbable, hydrogel implant incorporating axitinib. Clearside Biomedical (Georgia, USA) is also using a proprietary suspension of axitinib, CLS-AX, delivered via their suprachoroidal microinjector.

Dr. Wykoff shared the big potential of these TKI in AMD. “Given that these small molecule inhibitors block signaling through multiple transmembrane receptor tyrosine kinases, it is possible that they may have additional benefits beyond simple fluid reduction as well, such as being anti-fibrosis,” he shared.

Dr. Weng explained why these two have caught her interest. “For similar reasons [unique mechanisms], I am also intrigued by TKIs, such as EYP-1901 and OTX-TKI, which work intracellularly and bind to domains of receptors like VEGFR and PDGRF to inhibit angiogenic activation pathways more broadly. The durability of these agents is on the scale of six to nine months, which could meaningfully alleviate the treatment burden for many,” she discussed.

And what of dry AMD?

Dry AMD remains a hot topic and a tremendous unmet need. But it looks like some hope for patients may be coming soon. “From a dry AMD perspective, we appear to be on the threshold of having access to therapeutics that can slow the progression of geographic atrophy (GA),” Dr. Wykoff explained.

“Pegcetacoplan has a pending PDUFA date of February 26th, and avacincaptad pegol is under FDA review. The introduction of one or both of these medications into the retina landscape would be a meaningful step forward as this progressive, blinding, irreversible disease process has no treatment options currently,” he added.

Taking things one step further, why stop at slowing progression when there may be opportunities to treat geographic atrophy? Annexon Inc. (California, USA) plans to share top line data from their phase 2 ARCHER trial evaluating its anti-C1q candidate, ANX007, in the first half of 2023. And ONL Therapeutics (Michigan, USA) is evaluating ONL1204, a novel, first- in-class small molecule fatty acid synthase (FAS) inhibitor designed to protect key retinal cells, including photoreceptors, from cell death.

The ‘one and done’ strategy is also being studied in eyes with geographic atrophy. Gyroscope Therapeutics (a Novartis company) is investigating a gene therapy (GT005) for geographic atrophy, and Regenerative Patch Technologies (California, USA) has demonstrated safety and efficacy of their subretinally delivered CPCB-RPE1 (human embryonic stem cell-derived retinal pigment epithelial cells seeded on a polymeric substrate) in an early phase trial.

Dr. Wykoff is intrigued by the possibility of pipeline treatments for advanced, dry AMD. “Additional complement modulators under study are also fascinating, including ANX007, which has the potential for neuro-enhancement,” he said. “Finally, next-generation GA treatments including gene therapies, such as GT005, are under development, as well as noncomplement targeting molecules such as ONL1204, which inhibits cell death.”

Home OCT for the win!

In this arena of intravitreal, subretinal, and suprachoroidal AMD treatments, let’s not forget a new device that is a game changer in the management paradigm — home optical coherence tomography (OCT). Providing patients the opportunity to conduct OCTs at home may facilitate highly personalized retreatment decisions, with fewer unnecessary injections and clinic visits.

The Notal Home OCT from Notal Vision (Tel Aviv, USA) could significantly impact the way we manage our AMD patients, said Dr. Weng. “It is a small, portable device that patients can self-operate from the comforts of their own home. Leveraging a proprietary artificial- intelligence algorithm, it can detect subtle anatomical changes (that could indicate disease activity) and alert the treating physician,” she explained.

“The DRCR Retina Network is developing a protocol that will compare Home OCT-guided treatment versus a more standard treat-and-extend approach for wet AMD patients,” added Dr. Weng. “I suspect we will learn a tremendous amount from this upcoming clinical trial.”

Consider what matters most to your patients

We can conduct the trials and review the data, but it is important to remember that in addition to treating the eye with AMD, the decisions being made impact the patient as a whole, their quality of life, and very often the lives of their families.

Dr. Weng shared some vital advice, recognizing the importance of good communication and relationships with patients. “Always remember to look beyond the Snellen acuity chart hanging in your exam lane,” she advised. “In my early career, I have learned that while patients appreciate knowing their visual acuity, seeing their OCT images, and understanding their disease, what they care about most is being able to watch their granddaughter on stage at her dance recital, drive to the neighborhood grocery store without having to bother their children, and read for pleasure or livelihood,” she continued.

“It can be easy for us to get lost in the weeds of molecules and data points galore. But at the end of the day, preserving patients’ ability to do the things they love is the common goal we all share,” enthused Dr. Weng.

In addition to the wider range of treatment options currently available for AMD patients, Dr. Wykoff is looking forward to the direction that AMD treatment is headed and the opportunities that may soon be available. “It is a fascinating and exciting time in retina, and our patients have a brighter future than ever,” he said.

As more treatment options move closer to entering the clinical space — with different modes of delivery, safety profiles, and mechanisms of action, Dr. Weng offered some key advice to retina specialists. “Keep yourself up-to-date, and don’t get ‘stuck’ in your comfort zone. Wet AMD is a rapidly evolving area, and there will likely be many new therapeutics emerging over the next decade, some of which will inevitably

Contributing Doctors

Dr. Christina Y. Weng , MD, MBA, is a professor of ophthalmology and the vitreoretinal diseases & surgery fellowship program director at the Baylor College of Medicine in Houston, Texas. She has a faculty appointment at the Level 1 trauma center, Ben Taub General Hospital. Dr. Weng was a prior recipient of the Dan B. Jones Teaching Award. She graduated cum laude from Northwestern University and then went on to medical school at the University of Michigan, where she was elected to the Alpha Omega Alpha (AOA) Medical Society. While in Ann Arbor, Dr. Weng pursued an MBA degree from the University of Michigan-Ross School of Business and graduated with high distinction. She completed her ophthalmology residency at the Wilmer Eye Institute-Johns Hopkins University and her surgical retina fellowship at the Bascom Palmer Eye Institute-University of Miami. Dr. Weng is involved with multiple clinical trials, including the DRCR. net diabetic retinopathy trials and the AGTC Phase 1/2 intravitreal gene therapy study for X-linked retinoschisis. She also leads numerous research studies in her areas of interest: clinical/surgical outcomes, medical economics, healthcare quality metrics, and telemedicine.

christina.weng@bcm.edu

Dr. Charles C. Wykoff , MD, PhD, is the director of research at Retina Consultants of Texas, chairman of research at Retina Consultants of America, and deputy chair of ophthalmology for the Blanton Eye Institute, offer additional advantages over what our current agents do,” she shared. charleswykoff@gmail.com

She added that doing your own homework is key. “Evaluate each one critically for yourself, independent of outside influence. While always considering safety first, if the drug/ device appears promising, consider offering it to your patients who could benefit [from it],” Dr. Weng concluded.

Houston Methodist Hospital. He received his baccalaureate from MIT, PhD from Oxford University while on a Marshall Scholarship, and MD from Harvard Medical School. Dr. Wykoff completed his ophthalmology residency and vitreoretinal fellowship at Bascom Palmer Eye Institute where he served as Chief Resident/CoDirector of Ocular Trauma and received a Heed Fellowship and the Ronald G. Michels Award. He is an active medical and surgical retina specialist. Dr. Wykoff is passionate about translational research, clinical trial design, and accelerating drug-development programs. He has published over 250 peer-reviewed manuscripts, serves as principal investigator for dozens of clinical trials, and frequently speaks at national and international academic meetings. He serves on multiple scientific and medical advisory boards, safety monitoring committees, and global steering committees for endeavors spanning the innovative process from early to late-stage developments. He is the president of the Vit-Buckle Society (20212023), serves on the American Society of Retina Specialists Board of Directors, is a founding member of the Ophthalmology Retina Editorial Board, and is the chief medical editor for Retina Specialist . He has been awarded multiple Achievement, Honor and Senior Honor Awards, including the ASRS Young Investigator and the AAO Secretariat Awards. His guiding philosophy is to build and strengthen innovative, ethical teams focused on developing new approaches to improving outcomes for blinding diseases.