Macular Degeneration: Time to Focus on Vision

The approval of pegcetacoplan intravitreal injection (Syfovre, Apellis Pharmaceuticals) has—at long last—offered retina specialists and their patients a therapy to slow the progression of geographic atrophy (GA). Given that no prior treatment existed for GA, this new arrival has the potential to revolutionize care.

But what if we could do more than slow disease progression? Quality of life and vision are what patients value most in their day-to-day activities, and many have difficulty adhering to a treatment regimen that can only prevent an already advanced problem from getting worse. This article reviews several devices and therapies currently in the pipeline that are aimed at improving vision.

SURGICAL INTERVENTIONS

Subretinal Implant

The Prima System (Pixium Vision; Figure 1) is a subretinal implant designed to provide a photovoltaic substitute for photoreceptors. Once implanted, the device electrically stimulates the residual inner retinal neurons to elicit functional prosthetic (or bionic) central vision in combination with remaining natural peripheral vision.¹

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Figure 1. Diagram depicting the implantation of the Prima System into the eye.
Image courtesy of Samsara Vision

A team of investigators in France published a study in the Journal of Neural Engineering involving three patients to evaluate the effects of this device on neurosensory macular structures;² they used spectral-domain OCT to measure changes in retinal thickness (RT) and the distance between the electrodes and the retinal inner nuclear layer (INL). Although the total RT above the implant decreased (average 39 µm ± 12 µm) during a 3-month postoperative period, no significant changes were observed beyond that point up to 36 months follow-up.² Moreover, no structural or functional adverse events were observed, and the distance between the INL and the implant remained stable up to 36 months.

Following these preliminary findings, the European-based PRIMAvera clinical trial completed surgeries on 38 study participants as of December 2022.¹ The primary endpoint is change in VA of 0.2 logMAR or more from baseline after 1 year. The study is also evaluating device- and procedure-related adverse events with up to 3 years of follow-up.

The FDA granted breakthrough device designation to the Prima System in March to expedite its development, assessment, and review.¹ A readout of data from the PRIMAvera study to verify safety and efficacy is expected later this year.

SING-IMT

The smaller-incision new-generation implantable miniature telescope (SING-IMT, Samsara Vision; Figure 2) is designed to help patients regain a portion of the central vision that is lost due to late-stage AMD.³ It works by magnifying images viewed directly ahead of the patient by 2.7 times and projecting these images onto undamaged portions of the macula.³ The device is implanted during an outpatient cataract surgery that involves only a small corneal incision ranging in size from 6.5 mm to 7.5 mm.

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Figure 2. The SING-IMT implant used in the feasibility trial was 2 mm x 2 mm in size and 30 µm thick.
Images courtesy of Samsara Vision

The CONCERTO trial to evaluate the safety and efficacy of the implant for patients with late-stage AMD completed its first procedures in the United States last year. The study will enroll a total of 100 patients 65 years of age or older with nonactive neovascularization and bilateral central scotomas and those with fovea-involving GA or disciform scar. Each patient will receive the implant in one eye. In addition, patients will be required to undergo postoperative rehabilitation and training to strengthen their vision.

The first surgeries of the study have gone smoothly,⁴ with plans to continue working with the FDA toward gaining approval to market SING-IMT in the United States.

RPE REGENERATION

CPCB-RPE1

A type of implant that uses retinal pigment epithelium (RPE) cell therapy, the California Project to Cure Blindness Retinal Pigment Epithelium 1 (CPCB-RPE1, Regenerative Patch Technologies; Figure 3), is also in development to attempt to restore in vision lost from macular degeneration.⁵ The implant is composed of an investigational human embryonic stem cell (hESC)-derived RPE monolayer that is seeded on a synthetic substrate.

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Figure 3. This fundus photograph shows the CPCB-RPE1 implant in the eye.
Image courtesy of Regenerative Patch Technologies

The phase 1/2a feasibility study enrolled 16 participants, split between two cohorts (median age 78 years, range 69–85 years), who underwent implantation in their worse seeing eye (VA of 20/200) with CPCB-RPE1. The implant is 3.5 mm x 6.25 mm in size, and the study procedure was completed using 23-gauge vitrectomy, custom surgical forceps, and an operating microscope with or without intraoperative OCT. Low-dose tacrolimus was prescribed during the 68-day period leading up to the procedure to achieve immunosuppression.

A 1-year follow-up report showed positive preliminary safety and tolerability data, with no unexpected serious adverse events. Four participants in cohort 1 experienced serious ocular adverse events, including retinal hemorrhage, edema, focal retinal detachment, and RPE detachment.⁶

The study was not designed to evaluate efficacy, but the researchers reported that four treated eyes experienced an increase of BCVA of > 5 letters (range 6–13 letters). Although not statistically significant, a larger proportion of treated eyes experience BVCA gains compared with untreated eyes.⁶

RG6501

RG6501 (OpRegen) is an RPE cell transplant therapy (Figure 4) being developed by Lineage Cell Therapeutics in collaboration with Genentech and Roche. RG6501 is administered via a single subretinal injection and works to slow, stop, and potentially reverse RPE cell loss in areas of the GA lesions. Like CPCB-RPE1, it is composed of RPE cells derived from hESC.⁷

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Figure 4. Effects of treatment with RG6501 shown on OCT, including reappearnce of the outer nuclear layer and external limiting membrane, greater hyperreflectivity visible at the retinal pigment epithelium/Bruch membrane, and weaker choroidal hypertransmission. Presented at the Association for Research in Vision and Opthalmology.
Image courtesy of OpRegen

Positive safety and tolerability data up to 1 year from the phase 1/2a clinical trial showed that the majority of adverse events associated with this therapy were mild (87% in cohorts one to three, 93% in cohort 4).⁸ The most common were related to the surgical procedure, including conjunctival hemorrhage/hyperemia (n = 17) and epiretinal membrane (n = 16). No cases of rejection, acute or delayed intraocular inflammation, or sustained IOP increases following subretinal delivery of RP6501 have been reported.⁸

Preliminary efficacy data showed that participants in cohort four (n = 12) experienced improvement in visual acuity from baseline, with an average gain of 7.6 letters at 1 year; three patients from cohort four experienced VA gains of 15 letters or greater at 1 year.⁸ Five patients for whom RG6501 was delivered to most or all of the GA area, including the fovea, experienced an average gain of 12.8 letters, with improvements in retinal structure evidenced on spectral-domain OCT.

Enrollment in a phase 2a clinical trial of RG6501 is ongoing (NCT05626114).^7,9

THE FUTURE IS BRIGHT

At end of the day, improving vision and quality of life is a top priority for physicians and their patients. These therapies are still in early stages of development, but we have much to look forward to in the future of therapies for macular degeneration.