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CLINICAL TRIAL DOWNLOAD: Discussing New Safety Data on GB-102

Early results for a potential 6-month wet AMD treatment.

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Graybug Vision reported results from its phase 1/2a ADAGIO study of GB-102 (sunitinib maleate) for wet AMD at several meetings early this year. The GB-102 depot is designed to continuously inhibit activity of all VEGF receptors for the treatment of wet AMD. Results showed that GB-102 was well tolerated with no dose limiting toxicities, drug-related serious adverse events, or inflammation. Of evaluable patients, 88% were maintained on a single dose of GB-102 at 3 months and 68% percent were maintained on a single dose of GB-102 at 6 months. Graybug Vision says it plans to initiate enrollment of its phase 2b study of GB-102 in 2019. Here, several leaders in the retina field weigh in on the reported safety data.

Mark W. Johnson, MD
University of Michigan, Ann Arbor, Michigan

Although preliminary and based on a small number of patients, the phase 1/2a ADAGIO study results suggest that GB-102 is well tolerated as an intravitreal injection, without significant concerns from a safety perspective. It is premature to judge the durability of VEGF inhibition provided by this depot formulation. However, if these early results hold up in later-phase trials, a potent VEGF inhibitor with a duration of action of 6 months or more would be a welcome addition to our pharmacological toolkit for treating exudative AMD.

Philip J. Rosenfeld, MD
Bascom Palmer Eye Institute, Miami, Florida

When the 7-month results from ADAGIO were presented by David Boyer, MD, at Angiogenesis 2019, I watched with great interest. This long-lasting anti-VEGF therapy has the potential to shake up the current paradigm for anti-VEGF therapy. Dr. Boyer presented sequential escalating doses ranging from 0.25 mg to 2 mg. Prior to enrollment, all patients had at least 3 prior anti-VEGF injections, the eyes were shown to be responsive to anti-VEGF therapy, and there was evidence of macular fluid when treated with GB-102. Prior to the presentation, I was unaware that the microparticles needed to form an aggregate once injected for optimal effectiveness and safety.

Although the results were encouraging with respect to visual acuity and OCT stability, I was concerned that the microparticles were found to migrate into the anterior chamber and cause IOP elevations. Also, the study did not use real-world rescue criteria, meaning that rescue therapy would be given if any macular fluid was present after a month. Rather, the study allowed up to 75 microns of fluid without rescue. Furthermore, we learned that the company is reformulating the microparticles, so that they aggregate better, and then moving into a large phase 2 study without first testing the newly manufactured drug in humans. I understand the financial and time costs associated with testing this newly formulated drug in a small phase 1 protocol, but my opinion is that the company should test it first on a small patient cohort. However, the company is confident that animal testing will suffice. While Graybug will not be the first to do this, there is potential for problems to arise in a large phase 2 study. Once a study goes wrong on a larger scale, companies have a much bigger problem on their hands.

SriniVas R. Sadda, MD
Doheny Eye Institute and University of California–Los Angeles Geffen School of Medicine, Los Angeles, California

The need for frequent anti-VEGF retreatment is a significant burden and barrier for patients undergoing treatment for neovascular AMD as well as these patients’ caregivers. This is supported by real-world data that show that patients are likely being undertreated despite ample evidence and awareness in the community that more treatments on average result in better outcomes. There are a number of new technologies and agents that are being evaluated for the possibility of an increased durability of treatment effect. Because of its apparent excellent safety profile, the GB-102 product appears to be a potentially attractive solution, if the early-phase results can be replicated in future larger studies. It will also be critical to obtain long-term data to evaluate whether the sustained suppression of VEGF by GB-102 has any impact on the development of atrophy and visual function loss over time. RP