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Sunil S Patel, Joel Naor, Almas Qudrat, Diana V Do, Desiree Buetelspacher, hong liang, D. Victor Perlroth; 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(9):3670.
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Real world vision outcomes of anti-VEGF therapy are limited by the high treatment burden of existing agents. KSI-301 is a novel antibody biopolymer conjugate that inhibits VEGF. Its design optimized both size and molar dose to improve intraocular durability. With a molecular weight of 950 kDa achieved by site-specific conjugation of an antibody to an 800 kDa branched phosphorylcholine biopolymer, KSI-301 demonstrates high bioavailability to key ocular tissues (retina and choroid/RPE), has high affinity for VEGF (KD 6.75 pM), and is delivered via standard intravitreal injection. In the rabbit ocular pharmacokinetic model KSI-301 has ocular tissue half-lives of 10+ days in the retina and 12.5+ days in the choroid in comparison to 3-4 days for Lucentis and 4-5 days for Eylea. This first-in-human study sought to evaluate initial safety and tolerability of KSI-301, and to establish a maximum tolerated dose. Bioactivity was evaluated by measuring visual function and retinal anatomy.
Previously-treated or naïve subjects with DME were eligible. In this open-label, single ascending dose study, study eyes received one intravitreal injection of KSI-301 (1.25 mg, 2.5 mg, or 5 mg) and were then followed for 12 weeks. The primary endpoint was Week 2. Three subjects were enrolled in each cohort; dose escalation was based on review by a DSMC.
Nine subjects were enrolled. The Phase 1 study met its objective of safety and tolerability. At the primary endpoint, no drug-related adverse events, no intraocular inflammation, and no dose-limiting toxicities were observed. All dose levels were well tolerated. After a single dose of KSI-301, rapid-onset, high-magnitude improvements in BCVA with corresponding reductions in macular thickness on OCT were observed at all dose levels. The patients are continuing to be followed through 12 weeks.
A single intravitreal injection of KSI-301 was safe and well tolerated at all dose levels tested. Bioactivity was demonstrated at all dose levels providing a preliminary proof-of-concept for KSI-301 in retinal vascular diseases and for the antibody biopolymer conjugate approach. The results support continued clinical development of KSI-301; a multiple-dose Phase 1b study in patients with wet AMD, DME, or RVO is now underway, and a series of Phase 2 studies in wet AMD and DME is being planned.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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