Genetic Biomarkers for the Response to Anti-VEGF (Vascular Endothelial Growth Factor).Treatment in Wet Age-related Macular Degeneration (Wet ARMD)

Age-Related Macular Degeneration (ARMD) is the most common cause of blindness in the adult population of the Western World. It affects the macula - the region of the retina most rich in photoreceptors and responsible for central vision. The ethiology of ARMD remains poorly understood. Population-based studies have demonstrated a complex ethiology, with contributions from a combination of genetic and environmental factors.

Two major forms of ARMD are clinically distinguishable: the dry and wet form. The latter represents the more aggressive clinical subgroup, and is characterized by the abnormal growth of new blood vessels (neovascularization) under the macula, thus leading to the accumulation of fluid under the retina, bleeding, progression to fibrosis, and finally loss of central vision.

The pathogenesis of this neovascularization is not fully understood, although the VEGF pathway is well known to be involved in angiogenesis and was implicated in the development of the new vessels under the macula. The VEGFs are the most specific and potent stimulators of the angiogenesis.

Molecules that bind and inactivate the VEGF have been developed for the treatment of ARMD and they are applied in ARMD clinic through intra vitreal injections.The difference seen in response to anti VEGF treatment for ARMD between the patients is suggestive for the presence of factors influencing the effect of the drug. Some of these could be genetic variants within genes involved in ARMD pathogenesis or VEGF pathway. Few associations with markers within genes previously found to be related with the pathogenesis of ARMD have been found. It remains unknown whether variants involved in the anti VEGF treatment response could influence the therapeutic outcome.

The purpose of this trial is to evaluate the association between a panel of selected polymorphic markers in the VEGF pathway and the response to therapy with anti VEGF antibody for ARMD. The hypothesis is that the individual genotype influences the response to the anti VEGF. This can lead to identification of genetic biomarkers allowing treatment individualization and optimization of the visual outcomes.

Study Overview

• Status: Completed
• Conditions: Age-Related Macular Degeneration
• Intervention / Treatment: Device: Genotype analysis

Detailed Description

Age-Related Macular Degeneration (ARMD) is the most common cause of blindness in the adult population of the Western World. It affects the macula - the region of the retina most rich in photoreceptors and responsible for central vision.

Despite this manifest importance, the ethiology of ARMD remains poorly understood. Population-based studies have demonstrated a complex ethiology, with contributions from a combination of genetic and environmental factors. Genome-wide association studies revealed the presence of loci associated with susceptibility in a wide range of genes, including genes involved in the complement system, cholesterol homeostasis, growth factor diffusion and angiogenesis. Smoking has been identified as a major environmental factor.

Two major forms of ARMD are clinically distinguishable: the dry and wet form. The latter represents the more aggressive clinical subgroup, and is characterized by the abnormal growth of new blood vessels (neovascularization) under the macula, thus leading to the accumulation of fluid under the retina, bleeding, progression to fibrosis, and finally loss of central vision.

The pathogenesis of this neovascularization is not fully understood, although the VEGF pathway is well known to be involved in angiogenesis and was implicated in the development of the new vessels under the macula. The VEGFs are the most specific and potent stimulators of the angiogenesis. VEGF-A is a 45kD glycoprotein binding to transmembrane tyrosine kinase receptors, VEGFRs, which activates a cascade of downstream factors. VEGF-A has the strongest pro-angiogenic effect in the retina by promoting proliferation, sprouting and tubing of the endothelial cells. It can bind to at least two receptors -VEGFR1 and VEGFR2, although the most of the proangiogenic activity appears to be mediated through VEGFR2. Expression of a VEGFR2 isoform that lacks both the intracellular signaling domain and the transmembrane domain, represents a soluble form of the receptor, inactivating VEGF extracellularly.

Similarly, molecules that bind and inactivate the VEGF have been developed for the treatment of ARMD and they are applied in ARMD clinic through intra vitreal injections. These include antibodies, a recombinant receptor fusion protein and a synthetic aptamer. The anti-VEGFA antibodies - ranibizumab and bevacizumab, off-label, have been associated with limited side-effects and significant therapeutic improvement, and became the standard in the treatment of the wet form of ARMD. Indeed, for example in the first clinical trials for ranibizumab, monthly injections of ranibizumab demonstrated an average gain in visual acuity of 6.6 and 10.7 ETDRS letters after 24 months. However, currently most clinical centres apply modified treatment protocols. Commonly used is an initial loading dose of three consecutive monthly injections and subsequent follow-up and administration of additional injections depending on the evolution of visual acuity, optical coherence tomography and fluorescein angiography data . 25% of the ARMD patients show significant improvement of the visual acuity, 70% maintain or show slightly increased visual acuity, and the remaining 5 percent of the patients fail to respond to the treatment and continue to loose vision.

The difference seen in response to anti VEGF treatment for ARMD between the patients is suggestive for the presence of factors influencing the effect of the drug. Some of these could be genetic variants within genes involved in ARMD pathogenesis or VEGF pathway. Few associations with markers within genes previously found to be related with the pathogenesis of ARMD have been found. It remains unknown whether variants involved in the anti VEGF treatment response could influence the therapeutic outcome.

A study demonstrated that the single nucleotide polymorphism (SNP) in VEGFR1 rs7993418 (TAC codon) form is associated to resistance to the anti VEGF therapy in carcinoma patients. This specific genotype leads to an increased expression of the VEGFR1 without changing the amino acid content of the protein. The increased VEGFR1 protein is most likely due to higher efficiency of messenger ribonucleic acid (mRNA) translation.

The purpose of this trial is to evaluate the association between a panel of selected polymorphic markers in the VEGF pathway and the response to therapy with anti VEGF antibody for ARMD. The hypothesis is that the individual genotype influences the response to the anti VEGF. This can lead to identification of genetic biomarkers allowing treatment individualization and optimization of the visual outcomes.

• Study Type: Interventional
• Enrollment (Actual): 501
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, 1020
    • CHU Brugmann

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with the wet form of ARMD who receive or have received in the past anti VEGF intra vitreal injections

Exclusion Criteria:

• Patients whi had received treatments other than anti VEGF, before the use of anti-VEGF
• Patients without follow-up
• Patients receiving anti-VEGF because of another pathology than ARMD

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: wet ARMD patients; Patients with the wet form of ARMD who receive or have received in the past anti VEGF intra vitreal injections. Diagnosis of wet ARMD is made based on clinical data-visual acuity, fundus presence of subretinal fluid and/or haemorrhage and/or hard exudates, fundus photographs -color and red free, optical coherence tomography (SD-OCT), fluorescein angiography and indocyanine green angiography showing the presence and activity of subretinal neovascularisation.

Device: Genotype analysis; After signing informed consent, a blood sample is taken and DNA extracted according to standard procedures. The samples are genotyped with the Mass Array iPlex Gold. Processing of the data is done using the previously described protocol by Lambrechts and co. Statistical analysis will be done to evaluate the association between the different genetic variants and the clinical outcomes collected during the standard of care follow-up for ARMD.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Snellen visual acuity test result	The visual acuity test is used to determine the smallest letters you can read on a standardized chart (Snellen chart).	Baseline
Snellen visual acuity test result	The visual acuity test is used to determine the smallest letters you can read on a standardized chart (Snellen chart).	3 months after treatment
Snellen visual acuity test result	The visual acuity test is used to determine the smallest letters you can read on a standardized chart (Snellen chart).	6 months after treatment
Snellen visual acuity test result	The visual acuity test is used to determine the smallest letters you can read on a standardized chart (Snellen chart).	12 months after treatment
Number of injections received per year		1 year
Central foveal thickness (µm)	Measured by optical coherence tomography (Heidelberg & Zeiss)	Baseline
Central foveal thickness (µm)	Measured by optical coherence tomography (Heidelberg & Zeiss)	3 months after treatment
Central foveal thickness (µm)	Measured by optical coherence tomography (Heidelberg & Zeiss)	6 months after treatment
Central foveal thickness (µm)	Measured by optical coherence tomography (Heidelberg & Zeiss)	12 months after treatment
Presence of Intra Retinal Cysts (yes/no)	Tested by optical coherence tomography (Heidelberg & Zeiss)	Baseline
Presence of Intra Retinal Cysts (yes/no)	Tested by optical coherence tomography (Heidelberg & Zeiss)	3 months after treatment
Presence of Intra Retinal Cysts (yes/no)	Tested by optical coherence tomography (Heidelberg & Zeiss)	4 months after treatment
Presence of Subretinal Fluid (yes/no)	Tested by optical coherence tomography (Heidelberg & Zeiss)	Baseline
Presence of Subretinal Fluid (yes/no)	Tested by optical coherence tomography (Heidelberg & Zeiss)	3 months after treatment
Presence of Subretinal Fluid (yes/no)	Tested by optical coherence tomography (Heidelberg & Zeiss)	4 months after treatment
Presence of Pigment Epithelial Detachment (yes/no)	Tested by optical coherence tomography (Heidelberg & Zeiss)	Baseline
Presence of Pigment Epithelial Detachment (yes/no)	Tested by optical coherence tomography (Heidelberg & Zeiss)	3 months after treatment
Presence of Pigment Epithelial Detachment (yes/no)	Tested by optical coherence tomography (Heidelberg & Zeiss)	4 months after treatment

Collaborators and Investigators

• Sponsor: Brugmann University Hospital
• Investigators: Principal Investigator: Laurence Postelmans, MD, CHU Brugmann

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2013
• Primary Completion (Actual): January 18, 2018
• Study Completion (Actual): January 18, 2018

Study Registration Dates

• First Submitted: April 25, 2016
• First Submitted That Met QC Criteria: May 2, 2016
• First Posted (Estimate): May 4, 2016

Study Record Updates

• Last Update Posted (Actual): January 23, 2018
• Last Update Submitted That Met QC Criteria: January 18, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Keywords: VEGF; wet ARMD; intra vitreal injections
• Additional Relevant MeSH Terms: Eye Diseases; Retinal Degeneration; Retinal Diseases; Macular Degeneration
• Other Study ID Numbers: CHUB-SAMBA

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No