Our Science

Vantage Biosciences is at the forefront of targeting the root cause of inflammation in Diabetic Retinopathy and Metabolic Dysfunction-Associated Steatohepatitis.

Diabetic Eye Disease

Retinopathy, with or without macula oedema, is one of the most prevalent complications of diabetes affecting up to 382 million people Worldwide.1,2 In the USA, one third of diabetics over 40 years old have retinopathy; a sixth of these have threatened vision.3

Treatment of retinopathy today is challenged by:
  • The difficulties in delivering medicines to the eye in an effective, convenient, and patient-compliant manner.
    ‍
    Current standard of care – an array of anti-VEGF drugs which share a singular mechanism of action and require invasive intravitreal injection of drug on a regular basis.
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  • An evolving understanding of disease pathobiology providing an excellent opportunity for an exploratory study of a new therapeutic option with improved biological insight and important role in the root cause of disease pathology.

Although effective at reducing the risk of vision loss in various ophthalmic disorders, these drugs are not suitable for the broad-based treatment of earlier stages of disease, where superior compliance can be anticipated with an oral drug.

It is now clear they target the microvascular sequalae of disease progression rather than the initiating cause - injury of the integrated neurovascular unit (retinal neurons, and glia, along with pericytes and endothelia of the adjacent microvasculature) by direct neuroinflammatory insult.4
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Evidence now points to this inflammatory process being driven by oxidized and NO2 species (ROS/RNS), overproduction of inflammatory cytokines and chemokines, aberrant growth factor signalling and disruption of the blood retinal barrier (BRB).4

Human eye anatomy, retina, optic disc artery and vein

Diabetic Eye Disease

Retinopathy, with or without macula oedema, is one of the most prevalent complications of diabetes affecting up to 382 million people Worldwide.1,2 In the USA, one third of diabetics over 40 years old have retinopathy; a sixth of these have threatened vision.3

Human eye anatomy, retina, optic disc artery and vein
Treatment of retinopathy today is challenged by:
  • The difficulties in delivering medicines to the eye in an effective, convenient, and patient-compliant manner.

    Current standard of care – an array of anti-VEGF drugs which share a singular mechanism of action and require invasive intravitreal injection of drug on a regular basis.
  • An evolving understanding of disease pathobiology. Current standard of care – an array of anti-VEGF drugs which share a singular mechanism of action - requires intravitreal injection of drug on a regular basis.

Although effective at reducing the risk of vision loss in various ophthalmic disorders, these drugs are not suitable for the broad-based treatment of earlier stages of disease, where superior compliance can be anticipated with an oral drug.

It is now clear they target the microvascular sequalae of disease progression rather than the initiating cause - injury of the integrated neurovascular unit (retinal neurons, and glia, along with pericytes and endothelia of the adjacent microvasculature) by direct neuroinflammatory insult.4
‍
Evidence now points to this inflammatory process being driven by oxidized and NO2 species (ROS/RNS), overproduction of inflammatory cytokines and chemokines, aberrant growth factor signalling and disruption of the blood retinal barrier (BRB).4

Pathologic changes to retinal neuro-vascular unit in diabetes
Retinal Neuro-Vascular Unit
Image Source: JCI Insight. 2017;2(14):e93751. https://doi.org/10.1172/jci.insight.93751.
Vantage Biosciences believes that amine oxidase copper-containing 3 (AOC-3; also known as vascular adhesion protein 1) is a central player orchestrating this pathological cascade, specifically that which is upregulated in the neurovascular unit of the eye.5,6

Preclinical work has shown that selective inhibition of AOC-3 in the eye:
  • Reduces leukocyte infiltration, vessel occlusion, hypoxia, ischemia, aneurysm and vascular damage in the neurovascular unit at the retinal-endothelial barrier
  • Reduces production of reactive oxygen species localised in the vessel wall and downregulates associated ROS-activated signalling pathways, thereby reducing inflammation
  • Reduces local release of endogenously-generated, protein cross-linking reactive compounds that contribute to the vascular dysfunction found in the diabetic retinaI inhibition of AOC-3 with VX-01 significantly decreases leukocyte infiltration within the retina
  • Duh EJ, Sun JK, Stitt AW. Diabetic retinopathy: current understanding, mechanisms, and treatment strategies. JCI Insight. (2017) 2:e93751
  • Yau JW, Rogers SL, Kawasaki R, Lamoureux EL, Kowalski JW, Bek T, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. (2012) 35:556–64
  • Zhang X, Saaddine JB, Chou CF, Cotch MF, Cheng YJ, Geiss LS, et al. Prevalence of diabetic retinopathy in the United States, 2005–2008. JAMA. (2010) 304:649–56
  • Sinclair SH, Schwartz SS. Diabetic Retinopathy-An Underdiagnosed and Undertreated Inflammatory, Neuro-Vascular Complication of Diabetes. Front Endocrinol (Lausanne). (2019) 3;10:843
  • Boyer DS, Rippmann JF, Ehrlich MS, Bakker RA, Chong V, Nguyen QD. Amine oxidase copper-containing 3 (AOC3) inhibition: a potential novel target for the management of diabetic retinopathy. Int J Retina Vitreous. 2021 Apr 12;7(1)
  • Almulki L, Noda K, Nakao S, Hisatomi T, Thomas KL, Hafezi-Moghadam A. Localization of vascular adhesion protein-1 (VAP-1) in the human eye. Exp Eye Res. 2010 Jan;90(1):26-32

Metabolic Dysfunction-Associated Steatohepatitis (MASH)

Affecting over 35 million people globally, MASH is a subgroup of metabolic dysfunction-associated fatty liver disease (MAFLD), where excessive fat buildup is accompanied by liver cell injury and inflammation.

  • MASH is the 2nd leading cause of liver transplantation in the US
  • 25% of patients with MASH develop cirrhosis over nine years
Inhibition of AOC-3 has been demonstrated to:
  • Block persistent hepatic inflammation via reduction of leukocyte recruitment into the liver
  • Blunt hepatic fibrosis by reducing stellate cell activation and migration of fibroblasts to hepatic fibrotic scar
  • Control hepatic glucose handling via reduction of GLUT expression on the cell membrane
  • Alter lipid uptake and reduce steatosis
Preclinical and clinical work has shown that selective inhibition of AOC-3 in MASH:
  • Results in significant, dose dependent improvements in key markers of liver injury
  • Protects against high fat diet induced steatosis
  • Results in significant reduction in liver inflammation and fibrosis

VX-01

Our orally available small molecule inhibitor has a dual mechanism of action, targeting leukocyte trafficking and pro-inflammatory products of local amine oxidation.

VX-01 is suitable for daily oral chronic dosing to ensure that intraocular concentrations of the drug achieve profound, persistent inhibition of AOC-3 in the neurovascular unit. Previous clinical studies using AOC-3 inhibitors to treat diabetic eye diseases (1,2)  were confounded using drug doses that, although effective against soluble AOC-3 circulating in plasma, were insufficient to cross the blood-retina barrier and block AOC-3 in the eye.

Diabetic Retinopathy

VX-01 is suitable for daily oral chronic dosing to ensure that intraocular concentrations of the drug achieve profound, persistent inhibition of AOC-3 in the neurovascular unit. Previous clinical studies using AOC-3 inhibitors to treat diabetic eye diseases (1,2)  were confounded using drug doses that, although effective against soluble AOC-3 circulating in plasma, were insufficient to cross the blood-retina barrier and block AOC-3 in the eye.

MASH

VX-01 is suitable for oral chronic dosing and is a first in class inhibitor of AOC-3 that targets multiple drivers of MASH. VX-01 significantly reduces liver fibrosis markers and blunts disease drivers that lead to MASH, including inflammation, fibrosis, glucose and lipid uptake.

VX-01 Pipeline Timeline

Global Rights are owned by Vantage

Global Rights are owned by Vantage