Taku Wakabayashi, MD, PhD
Wills Eye Hospital
The panel discussion on gene therapy and diabetic retinopathy at Macula 2022 was moderated by Michael A. Klufas, MD, and covered important topics in the treatment of diabetic retinopathy. The panelists were Ajay E. Kuriyan, MD, Yoshihiro Yonekawa, MD, and Sunir J. Garg, MD, from Wills Eye hospital.
Treatment of severe non-proliferative diabetic retinopathy
Dr. Klufas first asked the panelists if they consider treatment of patients with severe non-proliferative diabetic retinopathy (NPDR) without obvious diabetic macular edema (DME). Increasing attention has been directed recently to the early treatment of severe NPDR, given the outcomes of the RISE/RIDE, Protocol W, and PANORAMA studies. All the panelists agreed on the potential benefit of anti-VEGF in preventing the progression of diabetic retinopathy and vision-threatening complications, but Dr. Kuriyan pointed out that the barrier to initiating anti-VEGF treatment for NPDR may include the relatively low percentage of patients who develop serious vision-threatening complications and the potential for patients to recover vision even after visual impairment due to complications, and Dr. Yonekawa mentioned the human-factors in initiating invasive treatment with potential procedure-related complications and other implications of injection treatments.
Dr. Klufas next introduced ongoing clinical trials, including the Port Delivery System (PDS) for NPDR (the PAVILION study) and RGX-314 suprachoroidal gene therapy for NPDR and mild PDR (the ALTITUDE study) and asked if the panelists would treat NPDR if a one-time treatment such as these could be offered. Dr. Yonekawa answered that both treatments may be good potential options, although more data are needed. The panelists agreed that there are many uncertainties regarding the treatment of NPDR, such as the benefits, frequency, endpoint, and delivery methods, and we need to wait for future research to provide answers.
The role of steroids in diabetic macular edema
Dr. Klufas next presented a 52-year-old male with DME in the left eye (visual acuity 20/200) who was lost to follow-up for one year after a history of PRP. The right eye was NLP secondary to NVG/TRD six years prior. He asked what the panelists would do for the left eye? Dr. Garg answered that he would perform anti-VEGF treatment. Dr. Klufas showed that the patient underwent three bevacizumab injections, but the patient’s vision remained 20/200 without any improvement in the edema. What do you do next?
Dr. Kuriyan answered that switching to another anti-VEGF therapy may be a reasonable approach because the patient had seen no improvement despite three injections. The patient subsequently underwent three aflibercept injections, but again did not show any improvement in vision or edema. Next, Dr. Kuriyan suggested steroids. The patient then underwent a dexamethasone implant, the edema completely resolved, and the patient’s vision improved to 20/60.
Dr. Klufas mentioned that in Protocol U, which compared the addition of a dexamethasone implant to ranibizumab, there were no overall differences in visual outcomes. However, Dr. Yonekawa commented that, in the subgroup of pseudophakic patients, there was a trend toward better visual outcomes with combination treatment. Dr. Garg and Dr. Kuriyan also mentioned that some patients who are refractory to anti-VEGF therapy may benefit from steroids.
Treatment of PDR: PRP or anti-VEGF?
Dr. Klufas next presented a 29-year-old phakic male with proliferative diabetic retinopathy (PDR). The patient had had type 1 diabetes mellitus for 20 years and Dr. Klufas asked the panelists for their preferred treatment choices.
Dr. Garg answered that these days he would start with anti-VEGF therapy. The patient underwent three anti-VEGF injections, and the DR severity scale improved and Dr. Klufas asked about subsequent treatment. Dr. Kuriyan answered that he would perform panretinal photocoagulation (PRP) because he is strongly concerned about the loss to follow-up (LTFU) and the consequent irreversible vision loss. He mentioned the study from Wills Eye Hospital regarding LTFU in PDR patients. In this study, nearly 25% of PDR patients were LTFU, and patients who received anti-VEGF showed worse anatomic and visual outcomes after being LTFU compared with patients who received PRP.
Dr. Klufas then revealed that the patient was indeed LTFU for six months after three injections, then presented again and fluorescein angiography showed worsening neovascularization. Dr. Garg and Dr. Yonekawa said that they would start PRP immediately in this case. Dr. Klufas mentioned that the data from Protocol S showed that only 61% of patients completed a five-year visit. The panelists agreed that continuous anti-VEGF is effective only if the patient returns for regular follow-up.
The role of anti-VEGF injections in the treatment of NPDR and PDR is expanding; however, patient understanding and maintaining clinic visits are key to maintaining vision. PRP remains an important part of diabetic retinopathy treatment. The panelists emphasized that patients are human beings, and a personalized decision should be made for each individual patient after sufficient discussion.