ASRS 2024: Dr. Judy Kim reviews studies on the new second-generation anti-VEGF therapies, aflibercept and faricimab
Judy Kim, MD, professor of ophthalmology, Jean and Tom Walter endowed distinguished chair in ophthalmology at UT Southwestern Medical Center in Dallas, Texas, and ASRS Foundation president, talks about the 2024 American Society of Retina Specialists (ASRS) Annual Meeting that took place in July 2024. She provided highlights from a session that she moderated.
Question:
You moderated a session at the ASRS 2024 Annual Meeting titled “Expert Panel: Faricimab and Aflibercept Eight milligrams in Diabetic Retinopathy.” Can you provide some highlights and key takeaways from the studies presented during this session?
Judy E. Kim, MD:
In my session, we had 6 great papers on faricimab and aflibercept 8 mg in managing diabetic macular edema and diabetic retinopathy.
The first paper was an efficacy and safety of faricimab in ALTIMETER, which is a phase 2b, open-label, single-arm study that explored the biomarkers of ANG-2 inhibition in patients with diabetic macular edema.
This paper was presented by Dr. Chirag Jhaveri. This trial involved monthly faricimab injections for 6 months in treatment-naive patients with diabetic macular edema. At baseline, and at week 16, aqueous chamber (AC) taps were done and multimodal imaging were performed to study ocular and aqueous biomarkers. The patients in the study were categorized into high or low macular leakage based on fluorescein angiogram.
The study found that eyes with high macular leakage had higher levels of ANG-2 and other immune regulators in the aqueous. But, interestingly, all of these were significantly improved by week 16 after monthly injections with faricimab. Dr. Jhaveri concluded that the improvement in visual acuity anatomy as well as aqueous biomarkers studied suggest vascular stability with the dual VEGF as well as ANG-2 inhibition with faricimab.
The next paper was presented by Dr. Michael Ip, a study entitled “Greater Reduction in Hard Exudates with Faricimab Versus Aflibercept in patients with Diabetic Macular Edema: Biomarker Study Results from the Phase 3 YOSEMITE and RHINE trials.”
As you know, studies in the past have shown that presence of hard exudates portend of worse visual acuity prognosis in eyes with diabetic macular edema. In this study, using RHINE and YOSEMITE data in a post-hoc analysis, the effect of hard exudates on visual acuity and central subfield thickness, as well as the effect of faricimab versus aflibercept 2 mg were studied in terms of hard exudates. In this study, the 6 mm ETDRS, early treatment diabetic retinopathy scale, grid on color fundus photographs were graded by the Wisconsin Reading Center and PRISP-specified time points for analysis were determined to be at baseline, week 16, week 52, and week 96.
Dr. Ip reported that patients with hard exudates had a slower improvement in visual acuity and center subfield thickness in the initial 6 months, but by year 1 and 2 in YOSEMITE and RHINE trials, it didn’t matter; visual acuity was similar in all groups. But overall, a smaller percentage had residual hard exudates when treated with faricimab compared to aflibercept 2 mg. The results may reflect improved vascular stability with faricimab, which is dual inhibition.
Then came the exciting late-breaking results presented by Dr. Arshad Khanani. He gave a paper entitled “Four-Year Outcomes of Faricimab in Diabetic Macular Edema: First Time Safety and Efficacy Results From the RHONE-X Long-Term Extension Trial.”
In this study, patients who had completed YOSEMITE and RHINE trials for diabetic macular edema were followed for 2 additional years, and this is the RHONE-X trial, in a treat and extend regimen with faricimab with up to 16 week re-injections.
In the trial, there were 1,400 patients in the study with a retention rate of 82%, which is not bad. Not only were the visual acuity and central subfield thickness on OCT improved in YOSEMITE and RHINE, and were maintained in RHONE-X, but also more than 90% of eyes had absence of diabetic macular edema, which was defined as central subfield thickness less than 325 microns by the end of the 4-year study.
Dr. Arshad Khanani reported that overall, 80% of patients achieved every 12 week or longer dosing at the end of RHONE-X trial at 4 years with good safety profiles as well.
Then Dr. Jordana Fein reported on intraocular pressure, or IOP outcomes, with aflibercept 8 mg and 2 mg in patients with diabetic macular edema through week 48 of phase 2/3 PHOTON trial. As you know, aflibercept 8 mg dose is 70 microliters, 0.07 mL, while 2 mg aflibercept is dosed at 50 microliters. They were wondering with this larger volume, is there an IOP concern?
In this study, bilateral IOP was measured using same method throughout the PHOTON study, and at baseline, 8% of the patients had history of glaucoma. The study found that 3 eyes had to get AC tap at the time of treatment to lower IOP, but overall 7.7% of eyes in the 8 mg group and 16% in the 2 mg group required IOP lowering medications.
The study found that the mean change in pre-dose IOP from baseline to week 48 was less than 1 mm mercury and was similar in the study and untreated fellow eye. She concluded that there was no drift toward IOP elevation over time with the higher volume 8 mg aflibercept, so it may seem safe that we can use this higher volume.
Dr. Dennis Marcus then presented a 48-week outcomes in aflibercept 8 mg-treated and 2 mg-treated patients by prior diabetic macular edema treatment status, whether they had prior DME treatment or did not have prior DME treatment. This was a subgroup analysis of the phase 2/3 PHOTON trial as well.
There were 44% of eyes in the PHOTON trial that had prior DME treatment with a washout period of about 3 to 4 months. The study looked at baseline ocular characteristics and they found that it was comparable in eyes with or with that prior DME treatment. But the study found that visual acuity gains at week 48 were greater in patients in eyes without prior DME treatment compared to eyes with prior DME treatment, suggesting that those eyes that had prior DME treatment may have more chronic or refractory cases.
Also, a higher proportion of eyes without prior DME treatment achieved a 2-step or greater diabetic retinopathy severe scale improvement compared to those with prior DME treatment. Overall, 90% of eyes in the trial maintained Q12 week or better dosing regardless of whether they had prior DME treatment or not. This is actually really promising.
Last but not least, Dr. Diana Do presented a paper entitled “Outcomes of Patients With DME and Baseline BCVA of 20/50 or Worse, or 20/40 or Better, Treated With Aflibercept 8 mg and 2 mg in the Phase 2/3 PHOTON Trial in Patients With DME.”
As you know, Protocol T of Diabetic Retinopathy Clinical Research Retina Network sometime ago found that when 3 agents, bevacizumab, ranibizumab, and aflibercept 2 mg, were compared, all 3 agents were equally great in improving visual acuity when the patient had baseline visual acuity of 20/32 or 20/40. However, when looked at in eyes with 20/50 or worse visual acuity of baseline, aflibercept 2 mg was superior compared to the other 2 agents.
This study looked at, how does aflibercept 8 mg do? The study found that aflibercept 8 mg also improved visual acuity and central subfield thickness and OCT. But regardless of baseline visual acuity, it didn’t matter whether the patient had 20/32 or 20/40 vision or 20/50 or worse vision, and it was equivalent to aflibercept 2 mg.
Overall, this session was really exciting because we’re learning more and more about these 2 new second-generation anti-VEGF agents, namely faricimab and aflibercept 8 mg and how they compare to our historic agents as well. Wat we are finding is that these studies show efficacy, safety, as well as durability of these newer second-generation anti-VEGF agents. I believe this is great news for our patients who are refractory to prior-generation anti-VEGF or those wanting to reduce treatment burden by using these longer durable agents as well. It’s great news for us retina specialists to be able to have more agents that we can provide treatment for our patients and keep them seen for a lifetime.
