KUS121 for Central Retinal Artery Occlusion

(GION Trial)

Not currently recruiting at 39 trial locations

Overseen By David Eichenbaum, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Kyoto Drug Discovery and Development Co., Ltd.

Must not be taking: Thrombolytics, Fibrinolytics, Prostaglandins

Disqualifiers: Infection, Uncontrolled pressure, Macular abnormality, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: 3 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called KUS121 for individuals with central retinal artery occlusion (CRAO), a serious eye condition that can cause permanent vision loss. The researchers aim to determine if KUS121 can safely and effectively assist those who have experienced sudden vision changes due to this condition. Participants will receive either a low or high dose of KUS121 or a placebo (a harmless substance with no active treatment). Individuals diagnosed with non-arteritic CRAO within the last 48 hours and who have noticeable vision changes may be suitable for this trial. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have had thrombolytic, fibrinolytic, or prostaglandin E1 systemic treatment within 1 month of screening.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot have had thrombolytic, fibrinolytic, or prostaglandin E1 treatments within 1 month of screening.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that KUS121 has been tested for central retinal artery occlusion (CRAO), a condition that can cause serious vision loss. In earlier studies, researchers administered KUS121 to patients to assess its safety. The results indicated that most patients tolerated KUS121 well, with no major side effects reported.

Some patients experienced mild reactions, but these were not serious. Since this trial is in a later phase, KUS121 has already passed earlier safety tests, suggesting it is considered safe enough for broader testing. However, like any treatment, risks may still exist. Participants should discuss any concerns with the trial team. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for CRAO?

Unlike the standard treatments for Central Retinal Artery Occlusion, which often involve ocular massage, hyperbaric oxygen therapy, or clot-busting drugs, KUS121 offers a novel approach. Researchers are excited about KUS121 because it inhibits a specific enzyme linked to cellular energy production, potentially protecting retinal cells from damage. This mechanism of action is different from current options, which primarily aim to restore blood flow. Additionally, KUS121 may offer a non-invasive solution, making it an attractive alternative for patients who may not respond well to existing therapies.

What evidence suggests that KUS121 might be an effective treatment for central retinal artery occlusion?

Research has shown that KUS121 might help treat central retinal artery occlusion (CRAO), a serious condition that can lead to vision loss. In earlier studies, individuals with CRAO who took KUS121 experienced noticeable improvements in vision. This trial will assign participants to different treatment arms, including low-dose and high-dose groups of KUS121. Acting as a neuroprotectant, KUS121 helps protect nerve cells from harm by reducing cellular stress and boosting energy levels, which helps prevent cell death. KUS121 has also been tested in other eye diseases and has shown protection against cell damage. These findings suggest that KUS121 could be a promising treatment for those with sudden CRAO. ^{1 2 3 6 7}

Who Is on the Research Team?

Kunihiro Musashi, MD., Ph.D.

Principal Investigator

Kyoto Drug Discovery ＆ Development Co., Ltd.

Are You a Good Fit for This Trial?

This trial is for men and women over 20 who've had a non-arteritic central retinal artery occlusion (CRAO) within the last 48 hours, with specific inflammation markers within normal ranges. They must have severe vision loss but not complete blindness in one eye and be able to attend clinic visits.

Inclusion Criteria

My eye exam showed swelling or bright spots in the inner layers of my retina.

I am willing and able to follow the study's requirements and can sign the consent form myself or through a legal representative.

I am 20 years old or older.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1 week

Treatment

Participants receive daily intravitreal injections of KUS121 or sham from Day 1 through Day 3

3 days

3 visits (in-person)

Primary Efficacy Assessment

Primary efficacy endpoint is assessed at Week 12, evaluating the gain in BCVA

12 weeks

1 visit (in-person)

Follow-up

Safety evaluation continues until a 12-month follow-up

12 months

What Are the Treatments Tested in This Trial?

Interventions

• KUS121

Trial Overview The study tests two doses of KUS121 via an eye injection against a sham procedure to see if it can help with acute CRAO, which currently has no proven treatment. The goal is to find out if this drug can improve vision safely.

How Is the Trial Designed?

Group I: KUS121 low dose group Experimental Treatment 1 Intervention

Group II: KUS121 high dose group Experimental Treatment 1 Intervention

Group III: Control group Placebo Group 1 Intervention

KUS121 is already approved in United States for the following indications:

Approved in United States as KUS121 for:

• Central Retinal Artery Occlusion (CRAO) under investigation, not yet approved

Who Is Running the Clinical Trial?

Kyoto Drug Discovery and Development Co., Ltd.

Lead Sponsor

Trials

1

Recruited

80+

Published Research Related to This Trial

A 29-year-old male experienced sudden vision loss due to central retinal artery occlusion while having an optic disk melanocytoma, indicating that such tumors can lead to significant retinal vascular issues.

The study suggests that the rapid visual loss may result from tumor necrosis rather than malignant transformation, highlighting the need for careful monitoring of patients with optic disk melanocytoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Central retinal artery occlusion secondary to optic disk melanocytoma. Rishi, P., Venkatesh, R.[2022]

A 48-year-old woman experienced a central retinal artery occlusion with sparing of the cilioretinal artery just one day after undergoing laser-assisted in situ keratomileusis (LASIK) surgery, highlighting a rare postoperative complication.

Despite the occlusion, the fovea remained intact and perfused due to the presence of the cilioretinal artery, which may have helped preserve some visual function, as indicated by her visual acuity of 20/40 in the affected eye.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CENTRAL RETINAL ARTERY OCCLUSION WITH CILIORETINAL ARTERY SPARING AFTER LASER-ASSISTED IN SITU KERATOMILEUSIS. Francis, AW., Zhu, I., Borirakchanyavat, S., et al.[2021]

In a rat model of retinal ischemic injury, the compound KUS121 significantly reduced retinal cell death and preserved visual function, indicating its potential as a neuroprotective treatment.

KUS121 was effective both when administered systemically and through intravitreal injection, with the latter showing equal or better efficacy, suggesting it could be a promising therapy for ischemic retinal diseases by modulating endoplasmic reticulum stress.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

KUS121, a VCP modulator, attenuates ischemic retinal cell death via suppressing endoplasmic reticulum stress. Hata, M., Ikeda, HO., Kikkawa, C., et al.[2018]

In a first-in-humans phase 1/2 clinical trial involving 9 patients with acute central retinal artery occlusion, KUS121 was found to be safe, with no serious adverse events reported after daily intravitreal injections for 3 days.

All patients showed significant improvements in best-corrected visual acuity, with 44% achieving a decimal BCVA better than 0.1 by week 12, indicating that KUS121 may be an effective neuroprotectant for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Ikeda, HO., Muraoka, Y., Hata, M., et al.[2020]

The study examined 6 cases of sudden vision loss characterized by a central scotoma, revealing ischemic edema in the eye and cotton wool bodies in some patients, indicating potential retinal damage.

Fluorescein angiography showed delays in blood flow to the choroid and central retinal artery, suggesting that carotid artery circulatory insufficiency may contribute to macular injury through choroidal artery obstruction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Acute insufficiency of the chorioretinal circulation]. Saraux, H., Laroche, L., Le Hoang, P.[2006]

In a rat model of retinal ischemia, the NMDA receptor antagonist MK-801 showed significant protective effects on retinal thickness and ganglion cell counts at a dose of 10 mg/kg, indicating its potential efficacy in preventing retinal damage after elevated intraocular pressure.

MK-801 also reduced DNA fragmentation and tissue responses associated with ischemia/reperfusion injury, suggesting that targeting NMDA receptors could be a promising strategy to mitigate retinal neuron apoptosis and improve outcomes after ischemic events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ameliorative effect of MK-801 on retinal ischemia. Lam, TT., Siew, E., Chu, R., et al.[2013]

Substance P-like nerve fibers were found to surround the central retinal artery in rabbits, indicating a specific nerve supply to this artery.

In contrast, no nerve fibers were detected in the central retinal vein or retinal blood vessels, suggesting that these structures are innervated by different nerve systems, with the artery receiving peripheral nerve innervation and the retinal vessels being controlled by the central nervous system.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Substance P-like immunoreactivity in the central retinal artery of the rabbit. Kumagai, N., Yuda, K., Kadota, T., et al.[2019]

Transluminal Nd:YAG laser embolysis (TYE) was successfully used in two cases of branch retinal artery occlusion (BRAO), leading to the complete removal of the embolus and significant improvement in visual acuity.

This technique appears to be a promising therapeutic option for BRAO caused by visible emboli, although further experience and studies are needed to establish its efficacy and safety on a larger scale.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transluminal Nd: YAG laser embolysis for branch retinal artery occlusion: Case report. Zhang, W., An, N., Zhang, X., et al.[2023]

KUS121, a novel valosin-containing protein modulator, effectively protects retinal cells from ischemic injury by inhibiting ATP depletion and reducing endoplasmic reticulum (ER) stress, as demonstrated in a rat model.

Intravitreal injections of KUS121 significantly reduced retinal cell death and inner retinal thinning, while preserving visual functions, indicating its potential as a therapeutic strategy for ischemic retinal diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modulation of valosin-containing protein by Kyoto University Substances (KUS) as a novel therapeutic strategy for ischemic neuronal diseases. Hata, M., Ikeda, HO.[2020]

CKLP1, a novel ocular hypotensive agent, was found to be safe for use in Dutch-belted pigmented rabbits, showing no observable histological changes after 90 days of topical application.

The pharmacokinetic profile indicated that CKLP1 is converted to its active form, levcromakalim, in the eye, with low systemic absorption, suggesting it effectively lowers intraocular pressure with minimal side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological and pharmacokinetic profile of the novel ocular hypotensive prodrug CKLP1 in Dutch-belted pigmented rabbits. Roy Chowdhury, U., Kudgus, RA., Rinkoski, TA., et al.[2023]

This nationwide study identified 3464 cases of central retinal artery occlusion (CRAO) in Korea, revealing an incidence rate of 1.80 per 100,000 person-years, with a higher rate in men (2.15) compared to women (1.47).

The incidence of CRAO significantly increases with age, peaking at 10.08 per 100,000 person-years in individuals aged 80 to 84, indicating that older adults are at a greater risk for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nationwide incidence of clinically diagnosed central retinal artery occlusion in Korea, 2008 to 2011. Park, SJ., Choi, NK., Seo, KH., et al.[2014]

The crude incidence rate of central retinal artery occlusion (CRAO) in Japan is 5.84 per 100,000 person-years, which is higher than rates reported in other countries, indicating a significant public health concern in the context of Japan's aging population.

Men are 1.40 times more likely to experience CRAO than women, with incidence rates of 6.85 per 100,000 person-years for men compared to 4.88 for women, highlighting the need for targeted healthcare strategies for at-risk groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nationwide incidence of central retinal artery occlusion in Japan: an exploratory descriptive study using the National Database of Health Insurance Claims (2011-2015). Kido, A., Tamura, H., Ikeda, HO., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7018138/

Safety and effectiveness of a novel neuroprotectant, KUS121 ... We tested the safety and effectiveness of KUS121 in patients with acute central retinal artery occlusion (CRAO). We conducted an investigator- ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/32053676/

An open-label, non-randomized, first-in-humans, phase 1/2 ... KUS121 showed no serious adverse events and all patients had significant improvement in visual acuity, supporting its safety and efficacy.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT06178055

NCT06178055 | A Study of the Efficacy and Safety ... This study evaluates KUS121's efficacy and safety for acute non-arteritic CRAO, a severe vision loss condition, using a sham-controlled, double-masked design.

4. atherosclerosis-journal.com atherosclerosis-journal.com/article/S0021-9150(25)00121-2/fulltext

KUS121, a novel VCP modulator, attenuates ... KUS121 reduces atherosclerosis by reducing ER stress, inhibiting glycolysis, and maintaining ATP levels in endothelial cells. It also reduces macrophage burden.

5. nature.com nature.com/articles/s41598-020-77735-2

A VCP modulator, KUS121, as a promising therapeutic ... KUS121 has been shown to protect against cell death in animal models of ocular diseases including retinitis pigmentosa, macular degeneration, ...

6. researchgate.net researchgate.net/publication/339246595_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_12_trial

(PDF) Safety and effectiveness of a novel neuroprotectant, ... We tested the safety and effectiveness of KUS121 in patients with acute central retinal artery occlusion (CRAO). We conducted an ...

7. clinicaltrials.llu.edu clinicaltrials.llu.edu/trials/study-efficacy-and-safety-kus121-participants-acute-non-arteritic-central-retinal-artery-occlusion-crao

A Study of the Efficacy and Safety of KUS121 in Participants ... The objective of this GION study is to evaluate the efficacy and safety of KUS121 intravitreal (IVT) injection in participants with acute non-arteritic CRAO.