KUS121 / KDDD - LARVOL DELTA

KUS121, a novel VCP modulator, attenuates atherosclerosis development by reducing ER stress and inhibiting glycolysis through the maintenance of ATP levels in endothelial cells. (PubMed, Atherosclerosis) - "KUS121 can be a new therapeutic option for atherosclerotic diseases by maintaining intracellular ATP levels, leading to the attenuation of ER stress and glycolysis in plaque endothelium."

Journal • Atherosclerosis • Cardiovascular • Inflammation • APOE • CASP3 • ERN1

Valosin-containing protein modulator KUS121 protects retinal neurons in a rat model of anterior ischemic optic neuropathy. (PubMed, Sci Rep) - "Mechanistically, the neuroprotective effect of KUS121 can be attributed to the suppression of endoplasmic reticulum stress, as evidenced by reduced expression of the C/EBP homologous protein, a marker of endoplasmic reticulum stress, following ischemic injury. Conclusively, KUS121 is promising as a therapeutic option for ischemic optic neuropathy and other ischemia-related neurodegenerative conditions."

Journal • Preclinical • Cardiovascular • CNS Disorders • Ocular Inflammation • Ophthalmology • Optic Neuritis • Pain

GION: A Study of the Efficacy and Safety of KUS121 in Participants With Acute Non-Arteritic Central Retinal Artery Occlusion (CRAO) (clinicaltrials.gov) - P2 | N=75 | Active, not recruiting | Sponsor: Kyoto Drug Discovery and Development Co., Ltd. | Recruiting ➔ Active, not recruiting | Trial completion date: Sep 2025 ➔ Dec 2025 | Trial primary completion date: Dec 2024 ➔ Mar 2025

Enrollment closed • Trial completion date • Trial primary completion date • Retinal Disorders

The effect of KUS121, a novel VCP modulator, against ischemic injury in random pattern flaps. (PubMed, PLoS One) - "We examined the mRNA expression of Ddit3 (CHOP) and Casp3 (caspase-3) on day one after the surgery; mRNA expression of both genes appeared to decrease in the KUS121 group, as compared with the control group, although differences between groups were not significant. Thus, in a random pattern flap, KUS121 reduces ER stress and the number of apoptotic cells, thereby reducing ischemic damage of the flap."

Journal • Cardiovascular • CASP3 • DDIT3

A novel VCP modulator, KUS121, attenuates atherosclerosis progression by maintaining intracellular ATP and mitigating ER stress in endothelial cells (ESC 2024) - "KUS121 can be a new therapeutic option for atherosclerotic diseases by maintaining intracellular ATP levels and attenuating ER stress-induced apoptosis and inflammation in plaque endothelium."

Atherosclerosis • Cardiovascular • Congestive Heart Failure • Coronary Artery Disease • Dyslipidemia • Heart Failure • APOE • ICAM1

GION: A Study of the Efficacy and Safety of KUS121 in Participants With Acute Non-Arthritic Central Retinal Artery Occlusion (CRAO) (clinicaltrials.gov) - P2 | N=75 | Recruiting | Sponsor: Kyoto Drug Discovery and Development Co., Ltd. | Not yet recruiting ➔ Recruiting

Enrollment open • Retinal Disorders

GION: A Study to Evaluate the Efficacy and Safety of Intravitreal KUS121 in Participants With Acute Non-Arthritic Central Retinal Artery Occlusion (CRAO) (clinicaltrials.gov) - P2 | N=75 | Not yet recruiting | Sponsor: Kyoto Drug Discovery and Development Co., Ltd.

New P2 trial • Retinal Disorders

KUS121, a VCP modulator, has an ameliorating effect on acute and chronic heart failure without calcium loading via maintenance of intracellular ATP levels. (PubMed, Biomed Pharmacother) - "KUS121 ameliorated HF by a mechanism totally different from that of conventional catecholamines. We propose that KUS121 is a promising new option for the treatment of HF."

Journal • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology

Neuroprotection for Nonarteritic Central Retinal Artery Occlusion: Lessons from Acute Ischemic Stroke. (PubMed, Clin Ophthalmol) - "Also, neuroprotective research in AIS has been extensive, and newer drugs tested, including Uric acid, Nerinetide, and Otaplimastat, with promising results...Efforts in the field of neuroprotection for NA-CRAO should focus on better imaging to delineate the penumbra after an acute episode of NA-CRAO (using a combination of high-definition optical coherence angiography and electrophysiology). Also, research should explore details of pathophysiologic mechanisms involved in NA-CRAO, allowing for further neuroprotective intervention, and closing the gap between preclinical and clinical neuroprotection."

Journal • Review • Age-related Macular Degeneration • Cardiovascular • Gene Therapies • Ischemic stroke • Macular Degeneration • Ophthalmology • Retinal Disorders • ANGPT1 • XIAP

KUS121, an ATP-Retaining VCP Modulator, Exerts Renoprotective Effects in Ischemia-Reperfusion Injury With Enhancing Endoplasmic Reticulum-Associated Degradation (KIDNEY WEEK 2022) - "Furthermore, KUS121 recovered from stagnation of CD3delta caused by Eeyarestatin I known as an ERAD inhibitor. Conclusion These findings indicate that KUS121 may contribute to protect renal tubular cells from ER stress-induced injury, suggesting that KUS121 could be a novel and promising therapeutic compound against ischemia-associated AKI."

Acute Kidney Injury • Cardiovascular • Chronic Kidney Disease • Nephrology • Renal Disease • Reperfusion Injury • CASP3 • CD3D • ERN1 • LCN2 • XBP1

Development of new neuroprotective treatment for retinal diseases—a phase 1/2 clinical trial on central retinal artery occlusion with KUS121 (ARVO 2022) - "We confirmed the efficacy and safety of KUS121 in preserving the visual function of patients with CRAO. We are currently preparing for the next phase of clinical trials. Additionally, KUS121 is being developed as a therapeutic agent for other retinal diseases such as age-related macular degeneration."

Clinical • P1/2 data • Age-related Macular Degeneration • Glaucoma • Inherited Retinal Dystrophy • Macular Degeneration • Ocular Inflammation • Ophthalmology • Retinal Disorders • Retinitis Pigmentosa

A Novel VCP modulator KUS121 exerts renoprotective effects in ischemia-reperfusion injury with retaining ATP and restoring ERAD-processing capacity. (PubMed, Am J Physiol Renal Physiol) - "These findings indicate that KUS 121 can protect renal tubular cells from ER stress-induced injury, suggesting that KUS121 could be a novel and promising therapeutic compound for ischemia-associated AKI."

Journal • Acute Kidney Injury • Chronic Kidney Disease • Nephrology • Renal Disease • Reperfusion Injury • CASP3 • CD3D • XBP1

A NOVEL ATP-RETAINING COMPOUND, KUS121, ENHANCES ER-ASSOCIATED DEGRADATION AND EXERTS RENOPROTECTIVE EFFECTS AGAINST ACUTE KIDNEY INJURY. (ISN-WCN 2022) - "These results indicate that a VCP-modulator KUS121 attenuates I/R injury in mice at least in part through the activation of ERAD, and may suggest that the administration of KUS121 could become a novel and promising therapeutic strategy for ischemia-associated AKI."

Acute Kidney Injury • Cardiovascular • Chronic Kidney Disease • Ischemic stroke • Myocardial Infarction • Nephrology • Renal Disease • Reperfusion Injury • CASP3 • CD3D • XBP1

KUS121 attenuates the progression of monosodium iodoacetate-induced osteoarthritis in rats. (PubMed, Sci Rep) - "Moreover, intra-articular administration of KUS121 more prominently reduced the apoptosis of the affected chondrocytes. These results demonstrate that KUS121 protects chondrocytes from stress-induced cell death in vitro and in vivo, and indicate that KUS121 is a promising novel therapeutic agent to prevent the progression of OA."

Journal • Preclinical • Immunology • Osteoarthritis • Pain • Rheumatology • SOX9 • TNFA

KUS121, a new VCP modulator, retains ATP and reduces renal deficiency reperfusion injury (JSN 2021) - No abstract available

Reperfusion Injury

[VIRTUAL] Elucidation of neuroprotective mechanism of valosin-containing protein modulators against retinal ganglion cell damage (ARVO 2021) - "These results suggested that KUSs protect retinal ganglion cells by suppressing the upregulated Edn1 and Ednrb expression."

Age-related Macular Degeneration • Glaucoma • Inherited Retinal Dystrophy • Macular Degeneration • Ocular Inflammation • Ophthalmology • Retinal Disorders • Retinitis Pigmentosa • EDN1 • THY1

A VCP modulator, KUS121, as a promising therapeutic agent for post-traumatic osteoarthritis. (PubMed, Sci Rep) - "Collectively, these results demonstrated that KUS121 protected chondrocytes from cell death through the inhibition of excessive ER stress. Therefore, KUS121 would be a new, promising therapeutic agent with a protective effect on the progression of PTOA."

Journal • Immunology • Osteoarthritis • Pain • Rheumatology • MMP13

KUS121, a valosin-containing protein modulator, attenuates ischemic stroke via preventing ATP depletion. (PubMed, Sci Rep) - "Administration of KUS121 in these models improved functional deficits and reduced brain infarction volume after transient focal cerebral ischemia in both C57BL/6 and B-17 mice. These results indicate that KUS121 could be a novel type of neuroprotective drug for ischemic stroke."

Journal • Cardiovascular • Ischemic stroke

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. (PubMed, PLoS One) - "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."

Clinical • Journal • P1/2 data • Diabetes • Diabetic Macular Edema • Diabetic Retinopathy • Macular Edema • Metabolic Disorders • Ophthalmology • Retinal Disorders