Safety and effectiveness of a novel neuroprotectant, KUS121, in patients with non-arteritic central retinal artery occlusion: An open-label, non-randomized, first-in-humans, phase 1/2 trial

Hanako Ohashi Ikeda, Yuki Muraoka, Masayuki Hata, Eriko Sumi, Takafumi Ikeda, Takayuki Nakagawa, Hiroyasu Abe, Harue Tada, Satoshi Morita, Akira Kakizuka, Nagahisa Yoshimura, Akitaka Tsujikawa, Hanako Ohashi Ikeda, Yuki Muraoka, Masayuki Hata, Eriko Sumi, Takafumi Ikeda, Takayuki Nakagawa, Hiroyasu Abe, Harue Tada, Satoshi Morita, Akira Kakizuka, Nagahisa Yoshimura, Akitaka Tsujikawa

Abstract

Kyoto University Substance (KUS) 121, an ATPase inhibitor of valosin-containing protein, is a novel neuroprotectant. We tested the safety and effectiveness of KUS121 in patients with acute central retinal artery occlusion (CRAO). We conducted an investigator-initiated, first-in-humans, phase 1/2 clinical trial. Nine patients with non-arteritic CRAO symptoms lasting for 4-48 h were enrolled. These patients received daily intravitreal injections of KUS121 for 3 days: 25 μg (low-dose) in the first three patients and 50 μg (high-dose) in the next six patients. The primary endpoint was the safety of the drug. As a secondary endpoint, pharmacokinetics was evaluated. Other key secondary endpoints were changes in best-corrected visual acuity (BCVA), measured using the Early Treatment Diabetic Retinopathy Study chart, visual field scores, and retinal sensitivities between baseline and week 12; and decimal BCVA at week 12. Administration of KUS121 did not result in serious adverse events. All nine patients (100%) showed significant improvement of BCVA. Average readable letter counts, visual field scores, and retinal sensitivities also improved. Decimal BCVA at week 12 was better than 0.1 in four patients (44%) and equal to or better than 0.05 in seven patients (78%). This first-in-humans clinical trial provides support for the safety and efficacy of intravitreal KUS121 injection. To substantiate the safety and effectiveness for patients with acute CRAO, further larger scale clinical studies will be needed.

Conflict of interest statement

With regard to this manuscript, Kyoto University applied for patents (WO2015129809 (Pharmaceutical Composition for Treatment of Ischemic Eye Disease) and WO2012014994A1 (Naphthalene derivative)); HOI, YM, MH, AK, and NY were the inventors of these patents. H.O.I. renounced the right of fees before the start of the clinical study. A.K. and N.Y. are stock owners of Kyoto Drug Discovery & Development Co. Ltd., a start-up company for the development of VCP modulators. This does not alter our adherence to the policies of PLOS ONE on sharing data and materials. The other authors declare no competing interests.

Figures

Fig 1. Trial profile.
Fig 1. Trial profile.
IVT: intravitreal injection of KUS121, KUS: Kyoto University Substance.
Fig 2. Time course of visual acuity.
Fig 2. Time course of visual acuity.
(A) Time course of the average logMAR tested on the ETDRS chart. (B) Time course of logMAR tested on the ETDRS chart for the nine patients enrolled in the trial. (C) Time course of the average readable ETDRS letter counts. (D) Time course of the readable ETDRS letter counts for the nine patients enrolled in the trial. Dotted line: low-dose group, full line: high-dose group. #: patient with patent cilioretinal artery in the objective eye, logMAR: logarithm of the minimum angle of resolution, ETDRS: Early Treatment Diabetic Retinopathy Study.
Fig 3. Visual field and retinal sensitivity…
Fig 3. Visual field and retinal sensitivity changes from baseline to week 12 in individual patients.
(A, B) Comparison of area on the visual field (V4e in A, I4e in B) (C, D) Comparison of visual field (C) and Esterman disability (D) scores on the visual field (V4e isopter). (E-G) Comparison of retinal sensitivity (central 8 points in E, middle 8 points in F, peripheral 8 points in G). #: patient with patent cilioretinal artery in the objective eye.

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