The failure of KSI-301 to achieve non-inferiority compared to aflibercept in the DAZZLE trial, with a six-letter difference in vision between the arms, hurt (page 6). Much hope was built around this anti-VEGF biopolymer conjugate and its inferred ability to dramatically extend intervals between treatments. 

While this promise stemmed from sound preclinical models and a Phase Ib trial, the Achilles heel was the absence of a control arm. Nevertheless, KSI-301 showed a signal for meaningful durability, with 59 percent of patients extending to a 20-week interval at year one. 

But, neovascular age-related macular degeneration is heterogeneous and some patients need more anti-VEGF treatment than others. Therefore, because the shortest retreatment interval after three loading doses was 12 weeks, it appears that most of the 30 percent of patients on q12-week dosing in DAZZLE probably would’ve benefited from more frequent dosing. 

More difficult to understand is the apparent difference in drying capability between KSI-301 and aflibercept during the loading doses. This deserves further analysis. 

Fortunately, KSI-301 still has a path to regulatory approval, so long as the team incorporates learnings from DAZZLE into the ongoing trials in diabetic macular edema and the ongoing pivotal trials are successful.

Unquestionably, gene therapy for ophthalmic diseases holds great promise. The approval of voretigene neparvovec-rzyl (VN) for patients with biallelic RPE65 mutations was a watershed moment in medicine. 

Since its 2017 approval, ongoing analyses into previously under-appreciated anatomic sequelae may have implications for other gene therapy programs, report Xuan Cao, MD, and Aaron Nagiel, MD, PhD (page 22). 

Harnessing gene therapy to create an intraocular, anti-VEGF biofactory to treat exudative retinal diseases is exciting. Early data from the ALTITUDE trial of RGX-314 in diabetic retinopathy seem encouraging, as Dennis Marcus, MD, and colleagues discuss (page 16). We must incorporate learnings from challenges related to inflammation, and even hypotony, with other ophthalmic gene therapies in other disease states as we advance these incredible therapeutics. 

Even after an agent passes the rigors of regulatory approval and gains market access, meaningful safety events may sometimes only be appreciated with widespread clinical use, as was the case with brolucizumab. 

As the proverb goes, The proof of the pudding is in the eating. In drug development for retinal diseases, we must ground ourselves in the reality that proof of efficacy and long-term safety can only be determined through well-designed, controlled studies and, ultimately, widespread clinical utilization. I can’t wait to try the pudding. RS