Diabetic macular edema (DME) and neovascular age-related macular degeneration (nAMD) are the leading causes of irreversible blindness in the U.S., with 4 million adults actively affected and 10 million more at risk of severe retinal vascular disease.

A new drug, faricimab, recently received FDA approval for treatment of both conditions following the publication of primary results in four major phase 3 clinical trials.

As reported in The Lancet, faricimab met non-inferiority endpoints compared to the drug aflibercept in all four studies in addition to demonstrating robust vision gains, anatomical improvements and potentially longer intervals between dosing.

"It's quite unusual to obtain simultaneous FDA approval for two common diseases, and I think it speaks to how well suited this particular drug is for the job of treating exudative retinal diseases," says Dr. Charles Wykoff, a Houston Methodist ophthalmologist and the principal investigator of the two nearly identical DME trials, YOSEMITE and RHINE.

Evolving new treatments

Anti-vascular endothelial growth factor A (anti-VEGF-A) medications, delivered into the eye by intravitreal injection, can prevent vision loss in the majority of patients and improve vision in many patients with nAMD or DME.

"The approval of these drugs in 2004 really was a remarkable breakthrough," Dr. Wykoff says. "The epidemiology of blindness and the prognosis for a new diagnosis of nAMD and DME have changed dramatically because of these therapeutics."

Despite the effectiveness of anti-VEGF-A medications, certain drawbacks made treatment adherence and widespread adoption a significant challenge.

"Patients typically require an injection every four to 12 weeks, often indefinitely," Dr. Wykoff says. "It turns out that is a substantial burden for patients, caregivers and eye care providers alike and a limitation of current therapeutics that has prevented us from fully realizing the potential of these drugs in the real world. Many of these patients face significant comorbidities and mobility issues related to advanced age or conditions associated with diabetes."

Medications whose therapeutic effects last longer and which require fewer doctor's appointments could go a long way toward reducing the treatment burden, improving compliance and alleviating the high personal and systemic costs of preventable blindness, researchers theorized.

How faricimab works

Faricimab is an angiopoietin-2 (Ang2) and VEGF-A bispecific antibody that blocks two key signaling pathways implicated in the pathogenesis of exudative retinal diseases including nAMD and DME.

In pre-clinical studies and three Phase II clinical trials, concluded in 2019, dual pathway inhibition demonstrated the potential for increased vascular stability and greater reductions in vascular leakage, neovascularization and inflammation over VEGF-A inhibition alone.

"We know from decades of research that inhibiting VEGF-A leads to reductions in downstream pathologic signaling that drives vascular leakage and neovascularization," explains Dr. Wykoff. "Blocking Ang2 leads to an entirely distinct effect inside of the eye with the aim of restoring normal processes that occur in healthy eyes."

By inhibiting Ang2, native Ang1 is able to bind to the Tie2 transmembrane receptor, leading to increased intracellular signaling that improves vascular leakage and drives stabilization of the blood retinal barrier, reductions in inflammation and improved cell survival.

"It is our hope that these effects will lead to improved outcomes and durability of action," says Dr. Wykoff.

Indeed, the approach appears to produce a more sustained effect than anti-VEGF-A monotherapies, with faricimab demonstrating efficacy at up to 16-week intervals. In the future, additional studies are planned to examine the potential to extend treatment intervals even further in some patients.

Unique study design

The DME trials were the first to incorporate a flexible, individualized treatment interval-approach in a double-masked manner. Nearly 1,900 patients across 353 sites worldwide were randomly assigned to receive either faricimab every eight weeks, faricimab per personalized treatment intervals (PTI) or aflibercept every eight weeks.

"We wanted to test the durability of this novel drug using methods common in clinical practice, where you treat consistently until you achieve optimal outcomes, then titrate the frequency to what an individual patient needs," Dr. Wykoff explains.

By the end of the one-year study period, more than 50% of patients in the PTI groups could go 16 weeks between treatments without losing vision gains, and 70% could go 12 weeks or longer.

"Importantly, all the markers used to assess treatment efficacy, including measures of dryness, retinal thickness and intraretinal fluid, showed more than adequate treatment for DME, and the results from many of the anatomic analyses favored faricimab over aflibercept," Dr. Wykoff says. "So we were able to dose less frequently with this new drug while achieving improved anatomic outcomes in eyes with DME."

In the nAMD studies, TENAYA and LUCERNE, led by Dr. Jeffrey Heier of Ophthalmic Consultants of Boston, 1,300 patients from 271 sites worldwide were randomly assigned to receive faricimab up to every 16 weeks or aflibercept every 8 weeks. By the end of the one-year study period, 80% of patients receiving the new drug maintained their best corrected visual acuity at 12-week or longer intervals and 45% maintained it at 16-week intervals.

In January, Vabysmo (faricimab-svoa) became the only injectable eye medicine approved simultaneously in the U.S. for nAMD and DME, with flexible dosing regimens based on patient need. Vabysmo is manufactured by Genentech, a subsidiary of F. Hoffmann-La Roche, which funded the studies.