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

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, firstin-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.

Fenofibrate Protects against Retinal Dysfunction in a Murine Model of Common Carotid Artery Occlusion-Induced Ocular Ischemia

“…Recently, a new neuroprotective drug (KUS121) has been under clinical trial for CRAO [ 66 ]. CRAO brings acute damages to nerve cells caused by arterial occlusion, and KUS121 is expected to inhibit dysfunction of intracellular organelles, mainly the smooth endoplasmic reticulum, and maintain their activities.…”

A VCP modulator, KUS121, as a promising therapeutic agent for post-traumatic osteoarthritis

“…Consistent with the present study, administration of KUS121 has been shown to mitigate pathologies by reducing ER stress and cell death in several animal models representing conditions such as retinitis pigmentosa 15 , myocardial infarction 16 , ischaemic stroke 20 , and Parkinson’s disease 22 . Moreover, KUS121 has been tested in phase I/II clinical trial for acute central retinal artery occlusion and shown to be safe and efficacious 23 , thereby indicating its promising candidature in the clinical therapy to inhibit the development of PTOA following cartilage injury and other conditions that have been discussed earlier.…”

“…KUS121 has been shown to protect against cell death in animal models of ocular diseases including retinitis pigmentosa 15,17 , macular degeneration 18 , and glaucoma 19 , ischemic diseases including myocardial infarction 16 , ischemic stroke 20 , and retinal artery occusion 21 and Parkinson's disease 22 . Moreover, phase I/II clinical trials show its safety and potential effectiveness in patients with non-arteritic central retinal artery occlusion 23 . ER stress has also been shown to contribute to the degeneration of chondrocytes in the articular cartilage; excessive ER stress induces chondrocyte death in parallel with the severity of OA [24][25][26][27][28] .…”

KUS121 attenuates the progression of monosodium iodoacetate-induced osteoarthritis in rats

“…We recently reported the therapeutic effects of KUS121 on post-traumatic cartilage damage in rats 18 . Among KUSs, KUS121, which has strong protective effects, was safe and effective in a phase 1/2 clinical trial in patients with central retinal artery occlusion 26 .…”