Up-and-coming AMD treatments: From intravitreal injections to gene therapy

Reviewed by Dr Christina Y. Weng.

Retinal treatment is a rapidly evolving field. Dr Christina Y. Weng, an associate professor of ophthalmology and surgical retina fellowship programme director at Baylor College of Medicine in Houston, Texas, United States, recently shared some stand-out therapies for macular degeneration.

Two hundred million individuals worldwide are affected by macular degeneration, most of whom have dry age-related macular degeneration (AMD). About 5 million of the affected people have the most advanced form of the disease: namely, geographic atrophy (GA).

There is currently no approved treatment for dry AMD, but Dr Weng is excited that this scenario is close to changing. “Treatment of dry AMD and GA is perhaps the greatest unmet need in our field,” Dr Weng said. “However, that is not for lack of trying.”

Dry AMD is an extremely complex disease that has been investigated using a number of different approaches. One of these, over-activation of the complement cascade, has become a target of therapeutic interest, she explained.

Two molecules have proved to be of special interest in late-stage clinical trials. One of the molecules, pegcetacoplan, blocks the over-activation at the level of C3 in the cascade. C3 is the point of convergence of all three complement pathways: alternative, classical and lectin.

The second molecule, avacincaptad pegol, works further downstream and blocks at the level of C5. These molecules are injected intravitreally monthly or every other month in patients with GA.

In the Phase 2 FILLY trial, patients randomised to pegcetacoplan experienced a 20–29% reduction in growth rate of the GA lesions. Dr Weng believes that this is an exciting result. “We may finally have a treatment to offer these patients that can help them preserve their visual acuity for a longer period of time,” she said.

Wet AMD

In contrast to dry AMD, several effective intravitreally injected treatments are currently available for the wet form of the disease. The downside to this approach is that patients must undergo frequent injections for indefinite periods of time. “This heavy treatment burden is not sustainable for many patients and contributes to sub-optimal visual acuity outcomes,” Dr Weng said.

Looking past intravitreal injections, patients will have access to a number of therapies on the horizon that will ease the treatment burden. One of these is Susvimo, a port delivery system with ranibizumab (Genentech) that was recently approved by the US Food and Drug Administration. This surgical implant is a reservoir that is implanted into the vitreous cavity and slowly releases concentrated forms of ranibizumab over longer periods of time.

Faricimab (Roche) is a recently approved bispecific antibody that targets two distinct pathways. One part of the molecule blocks vascular endothelial growth factor (VEGF)-A; the other part of the molecule blocks angiopoietin-2 (Ang-2), which is also involved in angiogenesis.

OTX-TKI (axitinib intravitreal implant, Ocular Therapeutix) is an intravitreal hydrogel containing a tyrosine kinase inhibitor; this product releases the drug in the eye over a period of 6 months or longer. Dr Weng explained that tyrosine kinase inhibitors have a broader activity compared with anti-VEGF drugs.

At-home monitoring using optical coherence tomography, which is operated by patients, is a recently introduced evolution in imaging. This technology not only provides patient surveillance but also allows retinal changes associated with AMD to be recognised earlier than might happen through scheduled in-clinic examinations, thus facilitating earlier appropriate treatment. According to Dr Weng, this may allow for more personalised treatment.

Gene therapy

Gene therapy has been a huge step in many arenas in medicine, and this is especially true in ophthalmology. “This is science fiction turned into reality,” Dr Weng said.

One gene therapy has been approved for use in ophthalmology for RPE65 deficiency-associated retinal dystrophy. Investigators are currently trying to determine whether gene therapy can be applied to other more common diseases, such as AMD.

“We are leveraging the biofactory concept; that is, injecting a transgene into the eye and allowing the eye to then produce its own supply of anti-VEGF therapy,” Dr Weng stated. “If that works, this could potentially be a one-and-done treatment that would significantly reduce or even eliminate the patient’s treatment burden.”

A few different routes of administration are being considered in gene therapy for AMD—not just intravitreal or suprachoroidal, but also via a subretinal route. This latter route would require a vitrectomy and a catheter, with gene therapy injected into the subretinal space.

In addition to the dry and wet forms of AMD, diabetic diseases are other potential targets in ophthalmic gene therapy.

Christina Y. Weng, MD, MBA

E: Christina.Weng@bcm.edu

This article is adapted from Dr Weng’s presentation at the virtual Real World Ophthalmology 2021 meeting. Dr Weng is a consultant to Allergan/AbbVie; Alcon; Alimera Sciences; Novartis; Genentech; Regeneron; D.O.R.C.; and Regenxbio.