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AMB-05X for DME and nAMD

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Disease and Prevalence

DME is a serious complication of diabetic retinopathy (DR) the most common cause of vision loss in patients with diabetes. The prevalence of DME is >1M in the US and ~20M worldwide (1-3). DME is characterized by swelling or thickening of the macula due to sub- and intra-retinal accumulation of fluid in the macula triggered by the breakdown of the blood-retinal barrier (BRB). DME can occur at any stage of DR and cause distortion of visual images and a decrease in visual acuity (4). Intravitreal administration of anti-VEGF agents is currently the mainstay of therapy for both early and advanced stages of DR/DME.

nAMD is an eye disease that destroys the macula, the part of the retina in the back of the eye that allows for central vision, fine detail discrimination, and color vision. It is the leading cause of vision loss among people 50 years of age and older. There are two types of AMD: dry and wet. The majority of afflicted patients have dry AMD wherein layers of the macula become thinner over time and leads to vision problems. But an estimated 10% of people with AMD have the wet/neovascular/exudative type. nAMD typically follows dry AMD and involves abnormal blood vessels growing under the macula. These vessels leak blood and fluids into layers of the retina, including the macula causing a bulge in the retina. The leaking blood vessels can also cause scar tissue to form and damage retinal cells. The macular distortion and fibrosis compromises central vision.  nAMD is the leading cause of vison loss in people over 60 (2) and affects about 20M people worldwide (1-3,6).

Pathogenesis and AMB-05X Mechanism of Action

In DME, hyperglycemia is considered to play an important role in the pathogenesis of retinal microvascular damage. Evidence of apoptosis of pericytes triggered by high glucose leads to localized outpouching of capillary walls. This process is associated with microaneurysm formation, an early clinical sign of DR (4). In addition to pericyte loss, apoptosis of endothelial cells and thickening of the basement membrane are also detected during the pathogenesis of DR. Inflammation, at least in part instigated by retinal glial cell activation, is considered a major contributor to these pathogenic events.  Altogether, they lead to retinal ischemia/hypoxia and upregulation of VEGF amongst other factors including CSF1.  VEGF is known to be a key factor involved in the angiogenesis and vascular permeability of progressive disease.  Increased CSF1 levels are thought to contribute to both the inflammatory, angiogenic, and vascular leak components and, consequently, the unique attenuation of all of these parameters by AMB-05X may afford broad, enhanced efficacy including those with suboptimal anti-VEGF/anti-angiogenic responses.

In nAMD, pathologic choroidal neovascular membranes (CNVM) develop under the retina. These new abnormal blood vessels emerging from the choroid grow through the Bruch membrane and sometimes the retinal pigment epithelium (RPE).  Not only does this lead to vision loss, but the CNVM can leak fluid/blood and, if left untreated, cause a centrally blinding disciform scar.  Upregulated VEGF contributes to the abnormal neovascularization and anti-VEGF therapies can attenuate that vessel growth, but generally not the scar formation.  CSF1 has been shown to be upregulated in vitreal and aqueous fluids in nAMD (7) and CSF1 has demonstrated anti-fibrotic activity in multiple tissues and recent data additionally implicates this factor in the neovascular and vascular leak components of nAMD (AMB data and 8).

Current Treatment & Unmet Need

Anti-VEGF therapies administered intravitreally (IVT) are the mainstay of treatment for DME and nAMD.  The predominantly utilized drugs are Lucentis (ranibizumab, a Fab) and Eylea (aflibercept, a VEGF trap Fc fusion protein).  While these therapies provide substantial benefit, many patients experience suboptimal responses, and a significant unmet medical need remains:

DME:

  • ~23% patients have persistent edema after 2 years of monthly Lucentis injection and ~60% patients were suboptimal responders even after 10 injections (9).

  • Incomplete resolution of macular edema was noted in approximately 1/3 of participants receiving anti-VEGF therapy (including ranibizumab, aflibercept, and bevacizumab) at 1 and 2 years (10).

nAMD:

  • Approximately 1/3 of patients don’t respond well to anti-VEGF therapy (likely due to macular fibrosis) (11).

  • Nearly 50% of patient eyes on anti-VEGF therapy developed some fibrosis by 2 years (12).

In January of this year, VABYSMO (Faricimab) was approved for DME & nAMD.  It is a humanized bispecific antibody that acts by binding to VEGF-A and Ang-2. Inhibition of VEGF-A suppresses endothelial cell proliferation, neovascularization and vascular permeability. Inhibition of Ang-2 is thought to promote vascular stability and desensitize blood vessels to the effects of VEGF-A.  Administration is Q4W for several cycles prior to longer-term dosing intervals.

AMB-05X Differentiation

AMB-05X is a novel MOA therapeutic candidate for which AmMax Bio and others have shown, in multiple preclinical models of DME and nAMD, neovascular and edema efficacy that is as good or better than potent anti-VEGF agents and, unlike an anti-VEGF or anti-Ang2 intervention, has demonstrated anti-fibrotic activity.  Accordingly, AMB-05X represents a first-in-class drug for the substantial proportion of poor- or non-responders to current therapy. AMB-05X has a proprietary formulation presumably allowing intravitreal administrations at >3 month intervals.

References

  1. Friedman DS et al., Arch Ophthalmology 2004 , 122: 564-572

  2. Wong WL et al., Lancet Global Health 2014 (2): 106-116

  3. Varma R et al., JAMA Ophthalmol. 2014;132(11):1334-1340

  4. Wang W, Lo ACY, Int J Mol Sci 19:1816, 2018

  5. Pagan & Kozarsky, May 2020 WebMD

  6. Bright Focus Foundation. Age-Related Macular Degeneration: Facts & Figures 2021 (https://www.brightfocus.org/macular/article/age-related-macular-facts-figures)

  7. Zhou Y et al., Invest Ophthalmol. Vis Sci. 2021;62(3):37

  8. Schwarzer P et al., Am J Pathol. 190:2:Feb 2020

  9. Blinder K et al., Clin Ophthalmology 11, 2017: 393-401

  10. Wells JA et al., Ophthalmology 2016 6;123(6):1351–1359

  11. Little K et al., EBioMedicine 38, 2018: 283-291

  12. Daniel E et al., Ophthalmology 2014, 121(3): 656-666

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AMB-05X is a fully human, inhibitory anti-CSF1R mAb that represents a first-in-class therapeutic for the treatment of diabetic macular edema (DME) and neovascular (or “wet”) age-related macular degeneration (nAMD or wet AMD).  AMB-05X is unique in that it may attenuate inflammation, vascular leak, and fibrosis - all of which are core to the clinical deficits in these common retinal diseases.