Despite the remarkable advances seen in the treatment landscape for neovascular age-related macular degeneration (nAMD) and retinal vascular diseases such as diabetic macular edema (DME) and retinal vein occlusion (RVO), a substantial unmet need continues to be the availability of treatment options that can improve visual acuity with a significantly reduced number of injections. Currently available anti-vascular endothelial growth factor (anti-VEGF) therapies have a high treatment burden, and this, along with other interlinked factors such as transportation requirements, health comorbidities, or insurance coverage challenges, can result in undertreatment. Undertreatment, in turn, means that the outcomes seen in pivotal clinical studies are hard to replicate in clinical practice.¹ The recent FDA approval of brolucizumab (Beovu; Novartis) has brought the practice of retina a step in the right direction because it will potentially enable around half of nAMD patients to maintain adequate disease control with every-3-month dosing (after 3 monthly loading doses). Other agents in late stage clinical development like abicipar pegol (Allergan) or faricimab (Roche/Genentech) are also targeting 2- to 3-month or 2- to 4-month dosing.

The antibody biopolymer conjugate (ABC) platform is a novel approach to producing potent and effective drugs designed to have enhanced intraocular durability and subsequent clinical effect. KSI-301 is a first-in-class bioconjugate that combines a recombinant, full-length, humanized and immunologically inert anti-VEGF monoclonal antibody, with a high molecular weight phosphorylcholine-based biopolymer, designed to provide extended ocular half-life and increased tissue bioavailability. Similar to currently available anti-VEGF therapies, KSI-301 binds human VEGF-A with a high binding affinity (KD 6.75 pM), higher than its cognate receptors (VEGFR1 and VEGFR2), preventing downstream signaling and inhibiting both proangiogenic and propermeability activities, as seen in nAMD and retinal vascular disorders.³ The optically clear phosphorylcholine biopolymer is covalently bound through site-specific conjugation to the antibody, which results in an intentionally high molecular weight of 950 kDa. Preclinical pharmacokinetic studies in rabbits have demonstrated KSI-301’s extended ocular half-life of 10-12 days when compared to 3-4 days for ranibizumab or 4-5 days for aflibercept.⁴ At the same time, preclinical data also demonstrate that KSI-301 has rapid systemic clearance when it leaves the eye. The molecular properties of KSI-301 as compared to other anti-VEGF biologics are shown in Figure 1. Importantly, KSI-301 is injected intravitreally using typical clinical procedures and equipment.

In a phase 1 single ascending dose escalation study (1.25 mg to 5 mg), 9 patients with DME were enrolled. The primary endpoint was safety at week 2, with extended follow-up to week 12. Every dose level was well tolerated through the week 12 follow-up period with no dose limiting toxicities, no drug-related adverse event, and no intraocular inflammation. A rapid-onset, high-magnitude and durable treatment response was seen in all dose levels tested; pooled best corrected visual acuity (BCVA) gains of +9 ETDRS letters and central subfield thickness (CST) reductions of -121 microns were seen by the end of the study.⁴

Currently a phase 1b open-label study designed to evaluate the safety, efficacy, and durability of KSI-301 in treatment-naïve patients with nAMD, DME/DR, and RVO (approximately 120 patients) is ongoing. Patients are randomized to receive 3 initial monthly injections of either 2.5 mg or 5 mg KSI-301, after which additional treatment is given on an as-needed basis when the study eye meets disease specific, protocol-defined retreatment criteria. As of results available in November 2019, the ocular safety of KSI-301 has been excellent with no reports of intraocular inflammation and no drug-related adverse events after 338 doses. A rapid and sustained response to treatment, measured as improvements in BCVA and CST by optical coherence tomography (OCT) across the 3 phenotypically variable retinal diseases (nAMD, DME, and RVO) has been seen (Figure 2). Most importantly, extended durability is being demonstrated with over 90% of nAMD eyes being extended to 3 months or longer after the last loading dose without receiving retreatment. Indeed, most nAMD patients have not received their first retreatment until 5 or even 6 months after the last loading dose. Promising durability results are also being observed in DME, where 72% of the treated eyes have been extended to 4 months or longer, and in RVO, where half of treated eyes have been extended to 3 months or longer.

Clinical development of KSI-301 is advancing rapidly, with a 2-year pivotal trial in nAMD now under way and actively recruiting. In this study, called DAZZLE (NCT04049266), KSI-301 is given to treatment-naïve wAMD patients every 3 to 5 months, compared to aflibercept every 2 months after a loading phase. Additional studies in other retinal vascular diseases (RVO, DME, and nonproliferative diabetic retinopathy) are planned to begin in 2021. The RVO studies of KSI-301 are expected to compare every-8-week or less often KSI-301 to monthly aflibercept, and the DME study is expected to compare every 3 to 6-month KSI-301 to every-other-month aflibercept. In nonproliferative diabetic retinopathy, a dosing regimen of every 4 or 6 months, with no loading doses, is expected to begin testing in 2021.

If these clinical trials are successful, KSI-301 will be an office-based intravitreal anti-VEGF treatment that represents an even bigger step toward more durable therapy and will hopefully deliver the promise of good, long-term maintenance of visual gains with less treatment burden. RP

REFERENCES

1. Holekamp NM, Liu Y, Yeh WS, et al. Clinical utilization of anti-VEGF agents and disease monitoring in neovascular age-related macular degeneration. Am J Ophthalmol. 2014;157(4):825-833.
2. Holz FG, Tadayoni R, Beatty S, et al. Key drivers of visual acuity gains in neovascular age-related macular degeneration in real life: findings from the AURA study. Br J Ophthalmol. 2016;100(12):1623-1628.
3. Liang H, Huang X, Ngo W, et al. KSI-301: An anti-VEGF antibody biopolymer conjugate with extended half-life for treatment of neovascular retinal diseases. Invest Ophthalmol Vis Sci. 2018;59:211.
4. Patel SS, Naor J, Qudrat A, et al. Phase 1 first-in-human study of KSI-301: a novel anti-VEGF antibody biopolymer conjugate with extended durability. Invest Ophthalmol Vis Sci. 2019;60:3670.