Dinner panel speakers from L-R: Dr Srinivas Sadda, Professor Robyn Guymer AM, Dr Jia Hui Lee, Professor Paul Mitchell AO, Professor Adrian Fung, and Dr Peter Westenskow.
The critical role and effectiveness of dual angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF) inhibition in treating retinal diseases was the topic of discussion at a dinner for ophthalmologists attending RANZCO (Royal Australian New Zealand College of Ophthalmologists) Congress in Adelaide.
The dinner presentation was moderated by Professor Adrian Fung (Sydney), who led a panel comprising retinal specialist Dr Srinivas Sadda (California, United States), Roche researcher Dr Peter Westenskow (Basel, Switzerland), Professor Paul Mitchell AO (Sydney), Professor Robyn Guymer AM (Melbourne), and Dr Jia Hui Lee (Melbourne).
Combination Therapy
Dr Sadda, Director of Artificial Intelligence and Imaging Research at the Doheny Eye Institute and President of the Association for Research in Vision and Ophthalmology (ARVO), presented evidence for the effectiveness of dual angiopoietin-2 (Ang-2) and VEGF inhibition in treating retinal diseases, specifically focussing on faricimab’s (Vabysmo) mechanism of action.
Dr Sadda explained that Ang-2 is “upregulated in a variety of different retinal diseases” including diabetic retinopathy and retinal vein occlusion.
Drawing on preclinical studies, Dr Sadda highlighted how the combination of Ang-2 and VEGF inhibition shows synergistic benefits in reducing vascular leakage. “Mechanistically, I think there really is a theoretical benefit for this combination,” he said, observing its positive outcomes in both neovascular age-related macular degeneration (nAMD) and diabetic macular oedema (DMO) trials.
Particularly notable was faricimab’s effectiveness in treating pigment epithelial detachments (PEDs), which Dr Sadda described as “the hardest component of exudation or fluid to resolve for patients”.
He explained that faricimab’s ability to reduce the macular leakage area; reduce hyperreflective foci, potentially indicating decreased inflammation; and lower the incidence of central epiretinal membrane development “could reflect improved vascular stability that’s provided by this type of inhibition”.
Looking ahead, Dr Sadda suggested that longer-term studies might reveal disease-modifying effects of Ang-2 inhibition that could impact patients’ ongoing treatment needs. “You fundamentally change something about the biology of disease that can impact the patient’s long-term need for therapy,” he concluded.
If you inhibit the VEGF/Ang-2 axis… you can significantly delay the fibrosis, so you can stabilise the blood vessels early and make sure that they don’t become fibrotic
Role of Ang-2 Pathway
Dr Westenskow then delved into the critical role of the Ang-2 pathway in retinal diseases, explaining that while Ang-2 is significantly elevated across various proliferative retinal diseases, its counterpart angiopoietin-1 (Ang-1) remains stable. “Ang-1 is the good guy in the situation… it keeps vessels in a healthy state,” Dr Westenskow said.
He outlined how Ang-2 acts as a crucial priming factor for VEGF activity. “It helps prepare the way for VEGF to find its receptor by stripping off the pericytes… and it also eats the matrix that covers the endothelial cells, sort of like the plastic that coats electrical wire,” he explained. This process enables both VEGF and Ang-2 to access their receptors on endothelial cells, leading to vessel leakage and inflammation.
Dr Westenskow presented data from studies using a mouse model with spontaneous subretinal neovascularisation. At the five-week mark, while anti-VEGF therapy alone showed diminished effectiveness, Ang-2 inhibition maintained its therapeutic impact. The combination therapy demonstrated particular promise in preventing fibrosis, as visualised using a novel biomarker technique.
“If you inhibit the VEGF/Ang-2 axis… you can significantly delay the fibrosis, so you can stabilise the blood vessels early and make sure that they don’t become fibrotic,” Dr Westenskow reported.
The dual mechanism of faricimab works by blocking both VEGF and Ang-2, allowing Ang-1 to bind to its receptor. Theoretically, this promotes vessel stabilisation by reestablishing the blood-retinal barrier and encouraging pericyte coverage.
Dr Westenskow concluded that by maintaining both pericyte coverage and the protective matrix around blood vessels, vessel stabilisation is achieved, potentially explaining the extended treatment intervals observed in clinical practice.
Complex Cases
Following these two presentations Prof Guymer, Prof Mitchell, and Dr Lee discussed several complex case studies demonstrating their approaches to managing patients with nAMD and DMO, and sharing their professional learnings.
One study presented by Prof Guymer, demonstrated that “AMD is not all about VEGF”, sparking further discussion on the role of fibrosis and atrophy in vision loss.
Prof Guymer told the audience that a patient can have a good anti-VEGF response but still lose vision from atrophy and fibrosis and “a huge number of patients in studies get fibrosis if you look long enough”.
“We really need something other than anti-VEGF and, in my mind, that’s why I’m really interested in faricimab,” she said.
She said subretinal hyperreflective material (SHRM) increases the risk of fibrosis and because of this, “it would be a good idea” to include patients with SHRM in a trial of antifibrotic therapies.
Real-World Data
Prof Mitchell presented Australian real-world data on the use of faricimab in treatment naive patients presenting to his Westmead Sydney clinic with nAMD and DMO over the past 12 months. Unusually, his clinic manages about 900 patients with nAMD and even more with DMO, seeing about 250 new patients annually with these conditions and “a huge amount of diabetic proliferative retinopathy causing bad outcomes”.
His clinic collected data on 111 patients and 121 eyes with nAMD treated with faricimab and reported that after loading doses the average treat and extend was 11 weeks; 59% could get to 12 weeks, and 14% could get to 16 weeks.
At the time of presenting, the mean duration of treatment was 32 weeks and Prof Mitchell said best corrected visual acuity had improved by about seven letters and central subretinal thickness (CST) had also improved.
He said the results showed that “in the real world we can achieve the same outcomes as the clinical trial”.
In Prof Mitchell’s study of 127 patients, 181 eyes with DMO, 23 % had proliferative diabetic retinopathy. He reported that after “a relatively short follow-up to date”, following loading doses of a mean three to four weeks, 50% of patents were extended beyond 12 weeks, and 20% to 16 weeks.
He reported an increase in BCVA of six to seven letters, and reduced CST.
The dinner was sponsored by Roche.
