BREAKING NEWS: FDA approves faricimab for treatment of wet AMD, DME

The FDA on Friday gave its approval to faricimab (Vabysmo, Genentech) for the treatment of wet age-related macular degeneration (AMD) and diabetic macular edema (DME).

Faricimab, a bispecific monoclonal antibody, is now the first and only FDA-approved drug to target two distinct pathways, Ang-2 and VEGF-A, that often cause retinal disease that may lead to vision loss. In preclinical studies, blocking angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF-A) reduced the vascular leakage/neovascularization, inflammation, and fibrosis.

Faricimab will be available in the United States in the coming weeks.

Genentech also submitted a Marketing Authorization Application for faricimab for the treatment of nAMD and DME, which the European Medicines Agency has accepted.¹

“Vabysmo represents an important step forward for ophthalmology. It is the first bispecific antibody approved for the eye and a major advance in treating retinal conditions such as wet AMD and diabetic macular edema,” Charles Wykoff, MD, PhD, director of research at Retina Consultants of Texas in Houston and a faricimab Phase III investigator, said in a statement. “With Vabysmo, we now have the opportunity to offer patients a medicine that could improve their vision, potentially lowering treatment burden with fewer injections over time.”

According to the news release, the approval is based on positive results across four Phase III studies in wet AMD and DME. The studies consistently showed that patients treated with Vabysmo given at intervals of up to four months achieved non-inferior vision gains versus aflibercept given every two months in the first year. Vabysmo was generally well tolerated in all four studies, with a favorable benefit-risk profile. The most common adverse reaction (≥5%) reported in patients receiving Vabysmo was conjunctival hemorrhage (7%).

In the release, Levi Garraway, MD, PhD, chief medical officer and head of global product development at Genentech, faricimab “provides a new approach to treating vision-threatening retinal conditions through a mechanism of action that targets two pathways simultaneously.”

“This is our second FDA approval in ophthalmology in recent months, underscoring our commitment to people living with retinal conditions,” he added in the statement.

Genentech also submitted a Marketing Authorization Application for faricimab for the treatment of nAMD and DME, which the European Medicines Agency has accepted.¹

In the studies conducted, about half of eligible individuals on faricimab were able to go 4 months between treatments within the first year, and up to three-quarters could go 3 months or longer in the TENAYA and LUCERNE nAMD studies and the YOSEMITE and RHINE DME studies.

Currently, the standard of care for these conditions requires eye injections as often as once every month.

For retina specialists, the approval is welcome news and offers a new treatment option for patients.

Lawrence Singerman, MD, FACS, of Retina Associates of Cleveland and a clinical professor of ophthalmology at Case Western Reserve University and Bascom Palmer Eye Institute, said he has been anticipating the announcement of FDA approval for faricimab.

“After giving presentations of data from the studies, and witnessing those presented by other investigators It is clear to me that this drug offers impressive efficacy and extended duration of action combined with an excellent safety profile,” he said. “This drug should ease the treatment burden on our patients with Wet AMD and DME.”

“The forthcoming availability of faricimab is a refreshing way to kick off 2022 for retina specialists and patients with macular disease alike,” said Andrew A. Moshfeghi, MD, MBA, associate professor of ophthalmology, University of Southern California.

Moshfeghi noted that faricimab appears to offer patients the chance to have more robust control of their macular disease and the potential for a longer treatment benefit.

“Having a new therapy for which approximately half of patients were able to be safely treated as infrequently as every 4 months is a big step forward for patients with chronic macular diseases like nAMD and DME—common conditions that traditionally require very frequent injections (every 1 to 2 months) with standard anti-VEGF monotherapy alone,” he said.

“I think the landscape for faricimab could be an exciting one for both exudative neovascular age-related macular degeneration and diabetic macular edema, particularly with sustaining and extending therapy for patients currently requiring high injection frequency,” said Mark P. Breazzano, MD, an assistant professor of ophthalmology at Wilmer Eye Institute, Retina Division, Johns Hopkins School of Medicine. “The data appear to show efficacy and durability with four-month treatment intervals for many of these patients. However, like any new treatment, it remains important to be cautious and continue monitoring for any safety signals that may follow FDA approval.”

According to Ian C. Han, MD, an associate professor, Institute for Vision Research, Ophthalmology and Visual Sciences, University of Iowa Hospital and Clinics, even with available treatment options, some patients reach a plateau of response to treatment with currently available agents, and the need for frequent office visits for injections continues to be a substantial burden, one that has only been exacerbated with the challenges of the pandemic.

“The current injectable medications on the market target vascular endothelial growth factor (VEGF), which plays a primary role in new blood vessel growth,” he said. “However, we have known for a while now that VEGF levels can modulate over time, and plenty of other factors beyond VEGF play a role in blood vessel formation and stabilization.”

Han noted that faricimab is the first FDA-approved agent to target not only VEGF but the angiopoietin (Ang) and Tie receptor pathway, which plays an important role in vascular stability and permeability.

Identical large, international, multicenter phase 3 trials for both wet AMD (LUCERNE/TENAYA) and DME (YOSEMITE/RHINE) compared faricimab to an available standard care treatment (aflibercept) and demonstrated that the majority of patients could be treated every 3 months or longer, with intervals up to 4 months included in the studies.

“Faricimab has the potential to decrease the treatment burden for patients with two conditions that we see the most (wet AMD and DME). It also represents an important step in moving beyond "just anti-VEGF" for treatment of these conditions, potentially paving the way for other drugs in the pipeline,” Han said. “As always with a new drug, ophthalmologists will need to translate the protocols from clinical trials to their everyday practice, including the varying treatment schedules (between one to four months in the phase 3 studies).”

Han added FDA-approval is a necessary and important step to bringing a new treatment to clinic.

“As we have recently been reminded, clinicians will need to evaluate the efficacy (and safety) of faricimab in their own patients to decide on the best treatment among the several now available for wet AMD and DME,” he said.

Study history

Faricimab met its primary endpoints for a variety of studies: TENAYA and LUCERNE and its extension study AVONELLE X, which assessed the long-term safety and efficacy of faricimab for the treatment of wet AMD. YOSEMITE and RHINE as well as the extension study RHONE X measured the safety and efficacy of faricimab for the treatment of DME.

Extension studies AVONELLE X and RHONE X are still underway to determine the long-term safety and efficacy of wet AMD and DME, respectively. RHONE X is expected to conclude in August of 2023, and AVONELLE X is expected to conclude in August of 2024.^2,3

The COMINO and BALATON trials are currently evaluating the safety and efficacy of faricimab in patients with macular edema secondary to central retinal vein occlusion (RVO) and branch RVO. The study is expected to conclude in fall of 2023.⁴

TENAYA and LUCERNE trials

The results of the phase III TENAYA and LUCERNE trials showed that faricimab met the primary efficacy endpoints of noninferiority to aflibercept (Eylea, Regeneron Pharmaceuticals) in the change in the best-corrected visual acuity (BCVA), durability, and safety for treating patients with neovascular age-related macular degeneration (AMD), according to Robyn Guymer, a professor of ophthalmology at Melbourne University and deputy director of the Centre for Eye Research Australia in Melbourne.

These 2 clinical trials are large identical randomized, double-masked, investigations that are evaluating the dual inhibition of angiopoietin-2 and vascular endothelial growth factor-A by faricimab.

Patients in these 112-week studies were treatment-naïve and randomized 1:1 to faricimab 6.0 mg up to every 16 weeks after 4 initial every-4-week doses or aflibercept 2.0 mg every 8 weeks after 3 initial every-4-week doses.

After the initial dosing and assessments of the disease activity, the patients receiving faricimab were treated at fixed intervals, ie, every 16 weeks, every 12 weeks, or every 8 weeks.

The patients treated with faricimab then followed a personalized treatment interval, that is, a protocol-driven treat-and-extend regimen with interval adjustment that was based on individualized treatment responses as assessed by the prespecified anatomic and functional criteria at study drug dosing visits up to week 108.

The primary efficacy endpoint was the change in the BCVA compared with baseline averaged over weeks 40, 44, and 48 and compared with aflibercept.

The secondary safety endpoints were the proportions of patients treated every 8, every 12, and every 16 weeks; the proportion of patients who had increases of 15 letters or more or who did not have losses of 15 letters or more; and the changes in the BCVA and central subfield thickness (CST) over time.

The safety endpoints were the incidence and severity and non-ocular adverse events.

YOSEMITE and RHINE trials

The 1-year results of the ongoing 2-year YOSEMITE and RHINE trials showed favorable results for faricimab for treating diabetic macular edema (DME). The visual gains achieved with every-16-week dosing were non-inferior to those of aflibercept (Eylea, Regeneron Pharmaceuticals) dosed every 8 weeks.

The anatomic gains also favored faricimab compared with aflibercept. Faricimab also demonstrated a good safety profile with very low rates of inflammation.

The YOSEMITE and RHINE trials, which are identical, randomly assigned double-masked studies compared the efficacy, durability, and safety of faricimab with aflibercept in patients with center-involving DME who were either treatment-naïve or received previous treatment with anti-VEGF therapy.

Patients were randomly assigned 1:1:1 to faricimab 6.0 mg every 8 weeks (Q8W) after 6 initial every-4-week Q4W doses; faricimab 6.0 mg treated according to a personalized treatment interval (PTI) based on the treat-and-extend concept after 4 initial very-4-week doses; or aflibercept 2.0 mg every 8 weeks after 5 initial every-4-week doses.

The primary efficacy endpoint was the mean change in the best-corrected visual acuity (BCVA) from baseline averaged over study weeks 48, 52, and 56. The secondary endpoints were the proportion of patients with a 2-step or more improvement in the Early Treatment Diabetic Retinopathy Diabetic Retinopathy Severity Scale (ETDRS-DRSS) from baseline, the proportion of patients with a 15 or greater gain in ETDRS letters from baseline, the change in central subfield thickness (CST) from baseline, and the proportion of patients in the PTI arm receiving doses every 4, every 8, every 12, or every 16 weeks at 1 year.

References

1. FDA accepts application for Roche's faricimab for the treatment of neovascular age-related macular degeneration (NAMD) and diabetic macular edema (DME). Roche. https://www.roche.com/investors/updates/inv-update-2021-07-29b.htm

2. A study to evaluate the long-term safety and tolerability of Faricimab in participants with neovascular age-related macular degeneration. https://clinicaltrials.gov/ct2/show/NCT04777201

3. A study to evaluate the long-term safety and tolerability of Faricimab in participants with diabetic macular edema. https://clinicaltrials.gov/ct2/show/NCT04432831

4. A study to evaluate the efficacy and safety of Faricimab in participants with macular edema secondary to branch retinal