There was an incredible amount of positive data presented at the Angiogenesis 2021 meeting this past February. It’s clear that retina specialists want more: greater efficacy, longer duration of treatment, and minimal side effects. The anti-VEGF space is certainly getting interesting and, in this issue, we would like to discuss a molecule called KSI-301 (Kodiak Sciences). This is an antibody linked to a biopolymer to produce a relatively “massive” compound (950 kDa compared to 48 kDa for ranibizumab) that yields a greater molar dose relative to the currently approved anti-VEGF drugs. Based on preclinical data, this results in an extended intraocular half-life and increased retinal bioavailability, all while having a fast systemic clearance. Dr. Diana Do, a principle investigator for Kodiak Sciences and Professor at Stanford, presented at Angiogenesis some fascinating early results of 130 patients who participated in the Phase 1a/1b studies. She shares some related thoughts below. We also asked Dr. Anthony Joseph from the Ophthalmic Consultants of Boston to provide his keen insights on the data presented. Finally, Kodiak Sciences’ chief medical officer Jason Ehrlich, MD, PhD, weighs in with comments from the company.

Diana V. Do, MD

KSI-301 is a novel intravitreal anti-VEGF antibody biopolymer conjugate (ABC) that has demonstrated extended durability of action across retinal vascular diseases such as wet age-related macular degeneration (wet AMD), diabetic macular edema (DME), and macular edema due to retinal vein occlusion (RVO). Recently, new results from a large phase 1b clinical trial involving 121 treatment-naïve eyes with wet AMD, DME, or RVO (NCT03790852) were shared. The data demonstrate that 2 in every 3 patients treated with KSI-301 are on a 6-month or longer treatment-free interval at year 1 after 3 loading doses. In treatment-naïve wet AMD, KSI-301 treated eyes had rapid and durable improvements in VA and OCT, and eyes improved +5.7 letters to a visual acuity of 20/40. These benefits were achieved with a mean of 2 injections per patient during the 10-month durability assessment phase of the study. This results in only 5 mean injections during year 1. Treatment-naïve DME eyes improved +7.6 to almost 20/32 with a mean of 1 injection per patient during the 10-month durability assessment phase of the study, resulting in only 4 mean injections during year 1.

In addition, treatment-naïve RVO eyes improved +22.2 to better than 20/32, with a mean of 1.7 injections per patient during the 10-month durability assessment phase of the study. RVO eyes received only 4.7 mean injections during year 1. These results are very promising, because they demonstrate the ABC platform’s unique advantages allowing for a higher dose and longer treatment duration. The integrated properties of the ABC platform allow for extended intraocular half-life, excellent bioavailability, deeper inhibitory potential, and fast systemic clearance. Furthermore, KSI-301 has an excellent safety profile thus far with more than 710 total doses given in over 130 subjects. There have been no drug-related serious adverse events. KSI-301 is currently being evaluated in pivotal global clinical trials in wet AMD (DAZZLE), DME (GLEAM and GLIMMER), and RVO (BEACON). If the promising clinical data continue to demonstrate extended durability with KSI-301, this new biologic has the potential to change the treatment paradigm for patients with these vision-threatening retinal diseases.

Anthony Joseph, MD

The year 1 results from the phase 1b study of the KSI-301 anti-VEGF ABC presented at the annual 2021 Angiogenesis, Exudation, and Degeneration meeting offer an exciting look into the future of treating exudative retinal diseases. While there are already proven and safe anti-VEGF agents available on the market, they often depend on high-frequency treatment. The goal for any new platform, including KSI-301, is to match the efficacy and safety profiles of current anti-VEGF agents with improved durability and therefore decreased treatment burden. The data presented at the Angiogenesis meeting suggest that KSI-301 has the potential to offer this durability across retinal vascular diseases with 2 of every 3 patients achieving a 6-month or greater treatment-free interval at year 1 after 3 loading doses. This finding was true for wet AMD, DME, and RVO all while maintaining gains in visual acuity and reduction in OCT thickness. Additionally, the data demonstrated a comparable safety profile to current anti-VEGF medications with most adverse events assessed as mild. Given the recent focus on intraocular inflammation with newer anti-VEGF agents, it is important to note that only 2 adverse events of intraocular inflammation were reported out of 710 injections. Both were cases of trace to 1+ vitreous cells that completely resolved. There were no reports of vasculitis or retinal artery occlusion.

Indeed, these phase 1b results are promising in terms of bringing another tool to the management of exudative retinal diseases, especially in those patients with a high treatment burden. If the ongoing DAZZLE, GLEAM/GLIMMER, and BEACON studies can demonstrate comparable safety and efficacy to aflibercept with significantly increased durability, this medication has the potential to become a valuable weapon in the retina specialist’s arsenal.

Jason Ehrlich, MD, PhD

We believe that the year 1 data for KSI-301 presented at Angiogenesis and the data presented on other late-stage molecules at the meeting continue to support a highly-differentiated durability profile for KSI-301 along with strong efficacy and an encouraging safety profile. We observed that two-thirds of patients in each disease cohort achieve a 6-month or longer treatment-free interval at the 1-year mark – 66% of wet AMD patients, 69% of DME patients, and 66% of RVO patients. Moreover, 78% of wet AMD patients and 84% of DME patients were on a 4-month or longer interval at Year 1, as were 75% of RVO patients. Said differently, an average of only 2.0, 1.0, and 1.7 retreatments were given in the 10 months following the 3 loading doses in AMD, DME, and RVO patients, respectively. Remarkably, 54% of wet AMD patients required only 1 retreatment, and 50% of DME patients required no retreatment in year 1. These results are particularly notable when put into context with that of other anti-VEGF and bispecific agents in clinical trials and those used in everyday clinical practice.

As mentioned by Dr. Do, we truly believe long-acting medicines like KSI-301 have the potential to change the treatment paradigm in these exudative retinal diseases and improve patients’ lives. With that in mind, Kodiak is pursing late-stage development of KSI-301 across all of the major retinal diseases treated with anti-VEGF therapy today. Our wet AMD study, called DAZZLE, is fully recruited with an expected data readout in early 2022, and our GLEAM and GLIMMER studies in DME and BEACON study in RVO are actively recruiting in the United States and worldwide. We are grateful for the enthusiastic support of these studies from the retina physician community.

The phase 1b results also provide clinical validation of our ABC platform technology, which uses molecular engineering to merge the fields of antibody-based and chemistry-based therapeutics. Our pipeline of therapies built on the ABC platform includes a bispecific molecule, KSI-501, that inhibits VEGF and IL-6, which we envision could be important in retinal conditions with an inflammatory component, and triplet molecules, including KSI-601, which combines biologics with small molecules for high-prevalence, multifactorial diseases such as dry AMD and glaucoma. Using trailblazing science, Kodiak hopes to deliver medicines that challenge the status quo within ophthalmology. RP