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The relentlessly increasing worldwide cases of diabetic retinopathy continues to fuel strong interest in improving the efficacy and durability of therapy.
Beginning in the 1970s, for about 30 years laser photocoagulation was the only therapy for diabetic retinopathy (DR.) Subsequently, intravitreal steroids were the only pharmacological treatment until intravitreal anti-VEGF agents became widely available. Anti-VEGF agents were a game-changer and they’ve been the mainstay of DR/diabetic macular edema treatment for about 15 years.
Various types of molecules with different vascular endothelial growth factor isomer affinities have been developed in this time. The recent approval of intravitreal faricimab, an inhibitor of both vascular endothelial growth factor A and angiopoietin 2, was a milestone in the mechanism of action of commercially available DR therapeutics. When considering upcoming treatments, it’s helpful to first recognize some of the basic strategies for expanding the repertoire of pharmacologic treatment. Besides targeting various molecular pathways, options include repurposed therapies effective for other diseases, different doses or combinations of existing treatments, alternative pharmacologic vehicles and alternative routes of delivery. In addition, new surgical technologies and techniques can also be developed. DR therapy is evolving on nearly all of these fronts.
Evolution of anti-VEGF therapies
Ranibizumab, the monoclonal antibody fragment that binds to all isomers of VEGF-A, has more recently been incorporated into a sustained-delivery device, surgically implanted through the sclera, for long-term intravitreal drug delivery. This Port Delivery System, or Susvimo (Genentech/Roche), is refillable in the clinic. On the heels of its approval for neovascular age-related macular degeneration, the Phase III Pagoda and Pavilion trials are evaluating its use for DME and DR, respectively.1,2 These trials are comparing monthly ranibizumab with PDS refilled every 24 weeks after a monthly loading-dose regimen. The primary endpoint is best-corrected visual acuity. Results are expected in October. Aflibercept binds to all isomers of VEGF-A as well as VEGF-B and placental growth factor. In the wake of the VIVID, VISTA and DRCR Retina Network Protocol T trials,3,4 it remains a mainstay of DR therapy. As with other anti-VEGF agents, many retina specialists have anecdotally observed that a higher dose of intravitreal aflibercept seems to improve its efficacy against DME compared to the Food and Drug Administration-approved 2-mg dose. The Phase II/III PHOTON trial in DME is comparing 8-mg aflibercept injections q12 or q16 weeks (each in separate arms) with 2-mg injections q8 weeks. The primary outcome is BCVA change at 48 weeks.
Biosimilars emerge
While ranibizumab and aflibercept are very effective for treating DR, one ongoing drawback is their high costs. The U.S. patent for ranibizumab expired in 2020, while aflibercept’s will expire in 2023. As a result, several companies outside the United States have developed biosimilars for ranibizumab, which are intended to provide the same therapeutic benefit at reduced cost. Per the World Health Organization, biosimilars are biotechnical products comparable in quality and performance to already approved reference products. Unlike generic drugs, which are chemically synthesized according to a drug’s established formula, biosimilars are manufactured with living cells according to a reverse-engineered representation of the original drug. Hence, biosimilars may be more immunogenic; their inherent deviation from the original synthetic process may lead to variations in quality. Since the approval last year of the ranibizumab biosimilar SB11, now known as Byooviz (Samsung Bioepis) for nAMD, macular edema due to retinal vein occlusion and myopic choroidal neovascularization, we expect to see FDA-approved biosimilars for DR in the near future. A number of other biosimilars for nAMD are in development, and one biosimilar developer, Celltrion Healthcare, has initiated a trial of CT-P42, an aflibercept biosimilar, in DME.
Gene Therapy
This has been a very active area for investigative treatment to treat exudative disease, as the following programs illustrate.
• ADVM-022. Using gene therapy to potentially increase the durability of intravitreally administered anti-VEGF agents, ADVM-022 (Adverum Biotechnologies) is an adeno-associated virus vector capsid (AAV.7m8) carrying an aflibercept coding sequence controlled by an expression cassette. It’s designed to be delivered as a one-time intravitreal injection. INFINITY is a Phase II trial evaluating the safety and efficacy of ADVM-022 for DME, in which patients received a single intravitreal injection of aflibercept 2 mg on day one, followed an ADVM-022 injection one week later. They were also prophylactically treated with topical difluprednate for 10 weeks. There were 12, 13 and nine patients in high-dose ADVM-022, low-dose ADVM-022, and control (serial aflibercept injections only) arms, respectively. The 24- week primary endpoint was time to worsening of DME activity (that is, time to requiring a supplemental aflibercept injection). By 24 weeks, only 25 percent of the high-dose and 39 percent of the low-dose groups required any supplemental aflibercept. However, unfortunately, more than 80 percent of the low-dose and 90 percent of the high-dose patients had intraocular inflammation, including around 10 percent of whom had posterior IOI—although none had vasculitis. More than half of the patients treated with ADVM-022 had iris-related events, including transillumination defects and synechiae, and a quarter of high-dose patients had hypotony. INFINITY is expected to conclude by year-end.
• RGX-314. Representing innovations in both gene therapy and alternative routes of drug delivery, RGX-314 (RegenxBio) is an AAV8 vector encoding an anti-VEGF monoclonal antibody fragment that is being studied for subretinal or suprachoroidal delivery. Based on Phase I and II results in nAMD, the Phase II ALTITUDE trial is evaluating RGX-314 on the Diabetic Retinopathy Severity Scale at 48 weeks in patients with nonproliferative DR or mild proliferative DR without center-involved DME.10 The trial, expected to be completed in early 2023, is evaluating two doses of RGX314 delivered suprachoroidally using the RegenxBio Suprachoroidal Space (SCS) Microinjector, which could be employed for in-office injections. Results from the first cohort of 15 patients getting the lower dose of RGX-314, compared to five controls, suggest good tolerability of RGX-314, with a few reports of conjunctival hyperemia or hemorrhage. One patient developing mild episcleritis; none developed IOI.11 Treated patients demonstrated stable BCVA and one-third had at least a two-step improvement in DRSS. While these results are encouraging, some authors propose that suprachoroidal AAV8 may induce a different immune response than intravitreal therapy, with a greater potential for vitritis and chorioretinitis.12. Several additional molecular pathways relevant to DR are being studied, but few of the corresponding drugs have reached or shown positive results at the Phase II stage. OPT302 (Opthea) is an intravitreally injected anti-VEGF R3 receptor fusion protein that acts as a “trap” molecule to block VEGF-C and VEGF-D. A Phase IIa trial evaluated a combination of OPT-302 and aflibercept in patients with persistent CI-DME follow.