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

Background: Kyoto University Substance (KUS) 121, an ATPase inhibitor of valosin-containing protein, is a novel neuroprotective candidate. It prevents cell death by an innovative mechanism: preserving intracellular ATP concentration and resultantly preventing endoplasmic reticulum stress. We tested the safety and effectiveness of KUS121 in patients with acute central retinal artery occlusion (CRAO), one of the intractable ocular diseases with poor visual prognosis. Methods: 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 to confirm safety. As a secondary endpoint, pharmacokinetics was evaluated. Other key secondary endpoints were: changes in best-corrected visual acuity (BCVA) measured using Early Treatment Diabetic Retinopathy Study chart, visual field scores, and retinal sensitivities between baseline and week 12; and decimal BCVA at week 12. Findings: Administration of KUS121 did not manifest serious adverse events. Plasma concentrations of KUS121 reached the maximum levels 2 h after injection and decreased to zero at 24 h. All 9 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 4 patients (44%) and equal to or better than 0·05 in 7 patients (78%). Interpretation: Intravitreal KUS121 injection for patients with acute CRAO is not only safe but also effective in improving the visual functions, and may be considered a first-line treatment for CRAO. Clinical Trial Number: This trial is registered at University Hospital Medical Information Network clinical trial registry. The registration identification number is 000023979. Funding Statement: The Japan agency for medical research and development, the Ministry of Health, Labor, and Welfare of Japan, and Kyoto Drug Discovery & Development. Declaration of Interests: In relation to this manuscript, Kyoto University applied for patents (PCT/JP PCT/JP2015/055619, WO2014129495 A1, and WO2012014994 A1); HOI, YM, MH, AK, and NY were the inventors in these patents. AK and NY are stock owners of Kyoto Drug Discovery & Development Co., Ltd., a start-up company for the development of VCP modulators. The other authors declare no competing interests. Ethics Approval Statement: This study was an investigator-initiated, phase 1/2, dose-escalation trial conducted at Kyoto University Hospital. It adhered to the tenets of the Declaration of Helsinki and the Ministerial Ordinance on Good Clinical Practice for Drugs, and was approved by an ethics committee (C1201), an Institutional Review Board (K028) in Kyoto University Hospital, and the Pharmaceuticals and Medical Devices Agency of Japan.