Conjugate Active in Exudative Retinal Diseases

SAN FRANCISCO — A multitargeted anti-VEGF therapy achieved sustained improvement in vision and reduced retinal thickening in patients with three different types of exudative retinal disease, data from an early clinical trial showed.

Within 16 weeks of intravitreal injection, the antibody biopolymer conjugate (ABC) KSI-301 led to improvements in best corrected visual acuity (BCVA) of 5.4 to 21.3 letters and mean reductions in central subsurface thickness (CST) of 72 to 353 µm. The therapy demonstrated beneficial effects in patients with neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME), or retinal vein occlusion (RVO).

The vast majority of patients did not require retreatment during the first 3 months of follow-up, reported Charles C. Wykoff, MD, PhD, of Retina Consultants of Houston, reported at the American Academy of Ophthalmology meeting.

“Antibody biopolymer conjugates are a new design platform for long-durability intravitreal medicines,” said Wykoff. “KSI-301 has achieved important milestones, including excellent safety, strong efficacy, and remarkable biological durability.”

“The ongoing phase Ib study has been extended to 18 months to collect additional durability outcomes,” he added. “The pivotal DAZZLE study is KSI-301 versus aflibercept (Eylea) in treatment-naive wet AMD is now recruiting.”

The design of KSI-301 addresses both durability and efficacy of intravitreal therapy for retinal diseases. The ABC consists of an IgG1 antibody with inert immune effector function covalently linked to a branched, high-molecular weight, optically clear phosphorylcholine polymer, said Wykoff. Upon intravitreal injection, KSI-301 simultaneously targets all VEGF-A isoforms, in contrast to currently available anti-VEGF therapies that have single targets.

“Intraocularly, the goal is to maximize biological activity by leveraging size and a 3.5-molar greater VEGF binding capacity than aflibercept, to achieve an intraocular concentration at three months estimated to be one thousand-fold that of aflibercept” he said. “In other words, go bigger to last longer.”

In a phase Ia study involving nine patients with severe previously treated DME, a single injection of KSI-301 led to rapid, “high-magnitude” responses that lasted for 12 weeks. Eight of the nine patients met prespecified criteria for response. No intraocular inflammation or drug-related adverse events were reported.

Wykoff reported findings from a phase Ib trial of 105 patients, with equal distribution of nAMD, DME, and RVO. The patients were randomized 1:3 to two different doses of KSI-301. The primary outcomes were safety, efficacy, and durability of treatment effect. Treating physicians had the discretion to retreat any patient whose condition met predefined criteria for “significant disease activity.”

At baseline mean BCVA ranged from 54.9 to 66.8 ETDRS letters, 17-47% of the patients had BCVA of 20/40 or better, and mean CST ranged from 426 to 675 µm.

All three treatment groups improved from baseline to 16 weeks, including increased BCVA (letters) and decreased CST:

• nAMD: +5.4, -72 µm
• DME: +8.4, -140 µm
• RVO: +21.3, -353 µm

A durability assessment suggested an interval of 3 to >5 months for patients with nAMD, >3 months for DME, and 2-3 months for RVO.

One of 25 evaluable patients with nAMD was retreated before 3 months, two were retreated at 3 months, and the rest had passed the 3-month mark without retreatment. Among 11 evaluable patients with DME, two were retreated at 3 months, none before 3 months. All 15 patients with evidence of diabetic retinopathy at baseline had stable disease or improvement within 12 weeks of treatment with KSI-301, said Wykoff.

In the RVO group, seven patients were retreated at or before 3 months, and five of nine evaluable patients had passed the 3-month mark without retreatment.

Wykoff said no intraocular inflammation or ocular severe adverse events (SAEs) had occurred to date in any study eye, and no drug-related AEs have been reported. Most AEs were considered mild, consistent with the profile of other intravitreal anti-VEGF agents. Four patients had a total of eight non-ocular SAEs unrelated to study medication.