Intravitreally injected anti-VEGF drugs are undergoing investigation as researchers look for new treatment options.
From the pages of Modern Retina.
Reviewed by David S. Boyer, MD.
When treating diabetic retinopathy (DR) the current approach for physicians remains medical management, specifically maintaining control of blood sugar, blood pressure, and lipids and smoking cessation.
Remarkably, for each 1% decrease in the A1c, the risk of complications decreases by 28% to 35%, according to David S. Boyer, MD, adjunct clinical professor of Ophthalmology, University of Southern California Keck School of Medicine, Los Angeles.
The question then arises: why are additional treatments needed for patients with diabetic eye diseases? The answer is that despite the latest advances in anti-vascular endothelial growth factor (VEGF), a small group of patients do not achieve improved vision. Boyer pointed out that 40% of eyes have a suboptimal response to monthly intravitreal VEGF injections.
Numerous intravitreally injected anti-VEGF drugs for DR with different mechanism of action are undergoing investigation. These include aflibercept (Regeneron/Bayer), OPT-302 (Opthea), THR-149 (Oxurion), KSI (Kodiak), and PDS/ranibizumab (Genentech), as well as multiple biosimilar drugs that work on controlling VEGF-A and VEGF-B.
Orally administered drugs for diabetic eye disease are also under study. These include APX3330 (Ocuphire), a ref-1 inhibitor; BAY1101042 (Bayer), a guanylate cyclase activator; AKST4290 (Alkahest), a CCR3 eotaxin inhibitor; RG7774 (Roche), a CB2 receptor; and HCB 1019 (Inflamax), connexin 43, all of which are for treating DR, and RZ402 (Rezolute), plasma kallikrein for diabetic macular edema (DME).
The hope, according to Boyer, is that the oral agents will help reduce the number of injections administered and provide visual improvements.
Topical therapies are also in the pipeline: SFO-166 (OcuTerra), an integrin in a phase 2 study; and OCS-01 (Oculis), a steroid in a phase 1 study.
High-dose (8 mg) aflibercept, currently in a phase 3 trial, may be active for a longer duration and provide better drying. The drug demonstrated excellent safety without toxicity. The treatments were extended out to 12 and 16 weeks with 8.8 and 7.9 letter gains, respectively, with decreased frequency of injections.
Regenix Bio’s RGX-314, a gene therapy injected into the suprachoroid, provides a long duration of action and a 2-step or greater improvement in the Diabetic Retinopathy Severity Score (DRSS) in 33% of patients at month 3 and in 47% of patients at month 6. These improvements were achieved with 1 injection. The therapy works by reducing blood vessel formation by providing ocular cells with the ability to produce an anti-VEGF fab and has not demonstrated any inflammation. “This is one of the most exciting treatments available for DR,” Boyer stated.
Opthea’s OPT-302 is an intravitreally injection combination therapy targeting DME that inhibits VEGF-C and VEGF-D. When used in combination with an anti-VEGF-A therapy VEGFR-2 and VEGFR-3 signaling are blocked completely. In a small post-hoc analysis, the mean change in the best-corrected visual acuity (BCVA) from baseline to week 12 was 6.4 letters when OPT-302 was injected with 2 mg of aflibercept compared with 3.4 letters with aflibercept alone. In addition, the number of patients who gained 10 or more letters with the combination therapy was much higher than with aflibercept alone, i.e., 27.3% versus 0%, respectively.
Genentech’s PDS insert is a long-acting drug. In the phase III noninferiority PAGODA study, 550 patients with DME were randomized to PDS 100 mg/ml that was refilled at 6-month intervals or ranibizumab 0.5 mg. The change in the BCVA at week 64 compared with baseline is the primary endpoint. These results are forthcoming.
“This approach decreases the treatment burden tremendously,” Boyer said.
PAVILION, a second study of the efficacy and safety of PDS is also under way in patients with moderately severe or severe nonproliferative DR without DME. The primary endpoint is the percentage of patients with a marked improvement of more than 2 steps in the DRSS at 1 year of treatment. Patients will be treated once every 6 months and hopefully reduce disease progression. [Editor’s note: Following this presentation, Genentech put their diabetic trials on hold because of failure of the insert.]
Kallikreins, which are serin proteases, also may provide better drying and visual improvements and may be used alone or in combination with anti-VEGF therapy. They are currently being evaluated as an intravitreal injection and also as oral agents.
“Diabetic retinopathy is a multifactorial disease. I am hoping that these new agents that are in clinical testing will be able to improve vision, decrease frequency of injections, allow easier routes of administration or improve diabetic retinopathy severity allowing us to take better care of our patients with diabetic eye disease,” Boyer concluded.