Ang-2/VEGF-A Inhibition Synergistic Effect in DME and AMD


Anat Loewenstein, MD, MHA, explores dual Ang-2/VEGF-A inhibition in the management of diabetic macular edema and exudative age-related macular degeneration.

Anat Loewenstein, MD, MHA: Hello. My name is Anat Loewenstein. I am the chair of the Department of Ophthalmology at the Tel Aviv Medical Center and vice dean of the Sackler Faculty of Medicine at Tel Aviv University in Tel Aviv, Israel.

The rationale in targeting both Ang-2 [angiopoietin‐2] and VEGF [vascular endothelial growth factor] in the management of neovascular macular degeneration and diabetic macular edema results from the fact that both Ang-2 and VEGF are implicated in the pathogenesis of these diseases. We know that Ang-2 levels are increased in retinal diseases as compared to control, specifically very much so in diabetic retinal disease. Elevated Ang-2 levels lead to vascular leakage and neovascularization by sensitizing blood vessels to the effect of VEGF-A. Elevated levels of Ang-2 cause displacement of Ang-1 on type 2, inhibiting type 2 activation. This increases Ang-2 expression, which primes the blood vessels for angiogenesis and sensitizes them to cytokines, such as VEGF-A. And we all know that elevated VEGF-A levels cause vascular leakage and promote neovascularization.

The YOSEMITE and RHINE were randomized, double-masked, multicenter studies that were designed to evaluate the efficacy and safety of faricimab vs aflibercept. Following a loading dose, patients received treatment either q8 [every 8 weeks] for aflibercept as per the label, or in 1 of 2 regimens for faricimab. The first regimen was [every 8] weeks and the second was according to a personalized treatment interval [PTI] in which patients received treatment according to their disease activity. The results of the YOSEMITE and RHINE studies showed that faricimab met the primary end point, demonstrating advantages in durability potential in anatomy vs aflibercept. The best corrected visual acuity gains from baseline with faricimab dosed every 8 weeks, or up to every 16 weeks, were noninferior to aflibercept dosed per the label every 8 weeks. There were better anatomical outcomes with faricimab vs aflibercept. This was seen when you looked at the change in central subfield thickness favoring faricimab, showing absence of diabetic macular edema in more patients, and showing absence of intraretinal fluid in more patients. Dosing up to every 16 weeks in the PTI dosing arm showed a durability of [every 16 weeks] in more than 50% of the patients. More than 70% of the patients achieved a durability of more than 12 weeks.

The results for YOSEMITE and RHINE showed extended durability for faricimab, meaning that patients with diabetic macular edema can potentially be treated less often with this new drug. The ability to treat patients less often has a tremendous impact on their quality of life and on the ability of the patient, physician, and the system to provide the exact treatment the patient needs by the way of having less burden and, as a result, increased compliance. The studies showed that even though there was a longer interval possible between treatments, the results are noninferior to the results with the comparator.

The design of the TENAYA and LUCERNE studies was recently presented at the Angiogenesis, Exudation, and Degeneration 2021 virtual symposium. TENAYA and LUCERNE were randomized, double-masked, multicenter studies that were designed to evaluate the efficacy and safety of faricimab vs aflibercept. Patients were randomized equally to either aflibercept given as per the global label of every 8 weeks following the loading dose, which was given after 3 months, or the faricimab up to [every 16] weeks, after 4 monthly doses in length. Patients in the faricimab arm were assessed for activity, and the drug was given according to disease activity. This allowed for evaluation of the possibility to lengthen the time interval between doses according to the activity of the disease in the particular patient.

The results of the TENAYA and LUCERNE studies were presented at the Angiogenesis 2021 meeting and showed that these double-blind, randomized trials met the primary end point, with faricimab demonstrating the ability to be extended over 12 weeks in 80% of the patients in the first year. Regarding visual acuity, the results showed noninferiority of faricimab with extended interval between doses as compared to aflibercept given bimonthly, [every 8] weeks. In addition, the studies showed durability of up to 16 weeks in 45% of the patients and the ability to extend the dosing to more than 12 weeks in almost 80% of the patients. The results of these studies showed meaningful reduction in central subfield thickness with faricimab given up to 16 weeks, which was comparable to aflibercept given every 8 weeks. Regarding safety, faricimab was well tolerated, with intraocular inflammation rates being only about 2% in the faricimab arms.

The results of the TENAYA and LUCERNE studies have significant implications for the treatment of our patients with neovascular macular degeneration. We know from all of the previous trials that in order to manage neovascular macular degeneration, we need to see the patients very often and to treat them with at least 8 injections yearly for the visual acuity to stay stable following the initial increase in visual acuity. Now, we finally have the ability to lengthen the interval between doses, thus allowing the patients decreased burden and improved quality of life. In these elderly patients, it is crucial to lower their need to get injections by way of having a drug that has a longer duration. This has the potential to increase their compliance, to enable the system and the physician to cope with the burden, as well as the patient and their caregiver, and thus improve the final outcome.

Transcript edited for clarity.

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