Understanding the Benefits of Bispecific Ang-2/VEGF-A Inhibition for Exudative Retinal Diseases

Charles C. Wykoff, MD, PhD, is the director of research at Retina Consultants of Texas, chairman of research and clinical trials at Retina Consultants of America, and deputy chair of ophthalmology for the Blanton Eye Institute at Houston Methodist Hospital in Texas. His research interests are focused on topics relevant to vitreoretinal surgery such as retinal detachment and macular surgery, and on the relationship between angiogenesis and retinal vascular diseases, including AMD, venous occlusive diseases, and diabetic retinopathy.

What is the rationale for targeting angiopoietin-2 (Ang-2) and vascular endothelial growth factor A (VEGF-A) to treat exudative retinal diseases?

Anti-VEGF-A monotherapy has proven to be an incredibly valuable treatment for the management of several type of exudative retinal diseases. It has set a high bar in terms of treatment optimization in this area. However, data from an extensive body of basic science and clinical research indicate that multiple pathways beyond VEGF are involved in the pathogenesis of these blinding diseases. In particular, findings from clinical studies that included patients with DME, diabetic retinopathy, and neovascular (wet) AMD show that upregulation of Ang-2 and concurrent decreased activity of the Tie2 transmembrane receptor tyrosine kinase leads to destabilization of the retinal vasculature.^1,2 This vascular disruption may exacerbate the clinical outcomes of DME and neovascular AMD. 

For years in our field, there has been high interest in studies targeting the Ang-2 pathway and some of those investigations have built on the clinical benefits achieved with VEGF inhibition. Faricimab is the first agent approved by the US Food and Drug Administration (FDA) that targets both VEGF-A and the Ang-2 pathway in the management of ocular diseases, specifically DME and neovascular AMD. 

Studies show that dual inhibition of Ang-2 and VEGF-A improves both structural and functional outcomes for patients with neovascular AMD and DME.^3-5 What are the mechanisms of action underlying Ang-2 and VEGF-A inhibition?  

Before the approval of faricimab, all of our available treatments blocked VEGF-A alone. Faricimab inhibits both VEGF-A and Ang-2 via completely distinct mechanisms of action that involve different receptors and produce different cellular effects.

When you block the VEGF-A pathway, the goal is to silence the downstream cascade of events that result from VEGF upregulation. Blocking Ang-2 allows Ang-1 to activate the Tie2 receptor, thereby restoring its effects. 

When activated by Ang-1, Tie2 initiates a homeostatic drive toward vascular stability¹ through supporting pericyte survival and increased integrity of endothelial cell tight junctions. These effects account for the improved integrity of the blood-retinal barrier that we see in diabetic retinopathy patients who have developed DME.⁶ This pathway is independent of the VEGF-A signaling pathway. When we inhibit Ang-2 in preclinical models, that seems to translate into a more robust VEGF-A inhibition effect. Manipulating both pathways simultaneously appears to be additive.^3-5  

Based on recent phase 3 data, what do we know about the safety, efficacy, and durability of dual Ang-2/VEGF-A inhibition with faricimab?^3-5,7

The fact that faricimab has been approved for both neovascular AMD and DME is a clinically meaningful milestone.² This is important not only because we can now treat both diseases, but also because 4 large phase 3 trials are now underway across which we can analyze efficacy and safety signals. Faricimab has already been studied in 2 large randomized phase 3 programs. One of these is the largest phase 3 DME program to date with more than 1800 patients enrolled and treated with this faricimab.^3,4 Ocular inflammatory events with faricimab were mostly mild or moderate through year 1 and comparable to those observed with intravitreal aflibercept in the YOSEMITE (ClinicalTrials.gov Identifier: NCT03622580; 31% vs 33%) and RHINE trials (ClinicalTrials.gov Identifier: NCT03622593; 43% vs 36%).³

The main efficacy take-home message from these 2 trials is the signal for treatment durability with faricimab. The 1-year data showed that more than 50% of patients were able to go 16 weeks or longer between treatments and more than 70% of patients were able to extend the treatment interval by 12 weeks or longer.^3,4 Top-line 2-year data for YOSEMITE and RHINE trials showed improvement over what was achieved in year 1. By year 2, approximately 60% of patients treated with faricimab were able to extend treatment to every 4 months and approximately 80% of patients were able to extend treatment to every 3 months.⁷

These are meaningful proportions of patients and they appear to be larger than what we would expect to see in routine clinical practice. Nevertheless, we should recognize that these trials were not designed to allow aflibercept to be given at an extended interval.

To date, I think the anatomic signals, especially in the DME program, support the durability signal we are seeing. Even though we are dosing 70% of patients receiving faricimab in the personalized treatment interval arm every 3 months or less, we are achieving better anatomic outcomes than those seen in patients receiving aflibercept administered every other month through year 1.³ Not only are we seeing reduced dosing frequency, but we are also achieving better anatomic outcomes, which truly speaks to increased durability.

In clinical practice, the interval between doses can be highly dependent on the individual patient phenotype. In the clinic, it is not unusual to have patients who can extend the interval between treatments to 3 months with our current anti-VEGF therapies. That said,  I am hoping faricimab will shift the duration of treatment effect for all patients. For example, could patients who need monthly dosing with one of our current agents now go 6 or 8 weeks between treatments? Can all patients go longer? Even an incremental increase in the intervals between dosing can be tremendously valuable for patients.

We will continue to learn more about the durability signal associated with faricimab over time as we use it in the real world and as additional trial results become available. In particular, findings from long-term extension studies following the phase 3 trials and from the ongoing phase 3 retinal vein occlusion trials would be interesting.  

How will Ang-2/VEGF inhibition be incorporated into the treatment paradigm? 

In the beginning, I think faricimab will be incorporated into the treatment paradigm the way most new drugs in the past have been incorporated: it will first be used for patients with a suboptimal outcome on previous therapy, which is defined most commonly as persistent fluid. An important question is whether we can achieve better anatomic and visual outcomes with faricimab in patients who were previously getting monthly therapy. The second population of patients who may benefit from faricimab are those who have a dry retina but leak again at a given interval (6, 8, or 10 weeks after therapy) and want to increase the interval between their treatments. Giving those patients an extra 2, 4, or 8 weeks would be a valuable transition. Once we are comfortable using faricimab to treat patients with more challenging eyes, it will be used more frequently in patients who are treatment-naive as long as the safety signals continue to be consistent with our current agents.

What is next on the horizon for Ang-2/VEGF inhibition? What additional data should clinicians should watch for?

Many important data sets will be coming. Investigators of the faricimab retinal vein occlusion studies BALATON (ClinicalTrials.gov Identifier: NCT04740905) and COMINO (ClinicalTrials.gov Identifier: NCT04740931) may be reporting their findings over the course of the next year. There are also ongoing extension studies, including Rhone-X (ClinicalTrials.gov Identifier: NCT04432831) and AVONELLE-X (ClinicalTrials.gov Identifier: NCT04777201) which will have long-term data, a study of faricimab dosed monthly in patients with DME who are underrepresented and treatment-naive (ClinicalTrials.gov Identifier: NCT05224102), and ongoing clinical trials looking extensively at biomarkers to better characterize the clinical impact of manipulating the Ang-2/Tie-2 pathway, such as the ALTIMETER trial in patients with DME who are treatment-naive (ClinicalTrials.gov Identifier: NCT04597918). We have a lot more to learn and more data will be coming that may help us to identify the most fruitful avenues of investigation in this setting.