Latest research brings awareness to new AMD discoveries

By Michelle Dalton, ELS

Ongoing research on treatments and/or causes of age-related macular degeneration (AMD) covers a wide range of approaches and paradigms.

The latest research published in the past three months includes:

• The discovery of a new vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitor;
• The use of optical coherence tomography (OCT) to further delineate those who may need intensive treatment;
• Angiogenic biomarkers;
• Societal influences on treatment.

Here is a summarize some of that latest research.

New inhibitor found

Researchers at Novartis describe a novel strategy for the use of in vivo models of choroidal neovascularization (CNV) that ultimately led to the discovery of acrizanib (LHA510). This small-molecule VEGFR-2 inhibitor has shown potency and efficacy in rodent CNV models, limited systemic exposure after topical ocular administration, multiple formulation options, and an acceptable rabbit ocular pharmacokinetic profile. It is too early to tell if this topical therapy will be successful enough to move into human trials.

Source:J Med Chem. 2018 Feb 5. doi: 10.1021/acs.jmedchem.7b01731. [Epub ahead of print]

Using OCT to manage treatment

A new meta-analysis has evaluated the influence of vitreomacular interface configuration (either vitreomacular adhesion [VMA] or vitreomacular traction [VMT]) on treatment outcomes after intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy.

In total, 9 studies were selected for this meta-analysis, including 2,156 eyes (404 eyes in the VMA/VMT group and 1,752 eyes in the non-VMA/VMT group). In neovascular AMD patients treated with anti-VEGF agents, the VMA/VMT group was associated with poorer visual acuity gains and central macular thickness (CMT) reductions at 1 year. There was no significant difference between 2 groups in the mean best-corrected visual acuity (BCVA) change and the CMT change over 2 years.

The authors noted the limited evidence suggests that vitreomacular interface configuration has a significant influence on the visual acuity gain and CMT reduction at 1 year and injection numbers at 2 years in neovascular AMD patients treated with anti-VEGF agents.

However, they cautioned “the results of this meta-analysis should be interpreted with caution because of the heterogeneity among study designs. Eyes with VMA/VMT on OCT at baseline may require more intensive treatment with decreased response to anti-VEGF agents.”

Source:Medicine (Baltimore). 2017 Dec;96(50):e9345. doi: 10.1097/MD.0000000000009345.

Second OCT study

A second study evaluated the relationship between subfoveal choroidal thickness (SCT) and the development of macular atrophy in eyes with either dry or neovascular AMD (from those enrolled in the TREX-AMD study, NCT01648292). Sixty participants (120 eyes) with treatment-naïve neovascular AMD in at least one eye were included. Subfoveal choroidal thickness was measured by certified reading center graders at baseline using spectral domain OCT.

The baseline SCT was correlated with the presence of macular atrophy at baseline and development of incident macular atrophy by month 18. In general, eyes with AMD and macular atrophy had less SCT than those without macular atrophy, and the lower the baseline SCT, the higher the risk of developing macular atrophy.

Baseline SCT in eyes with macular atrophy was statistically significantly less than in those without macular atrophy in both the dry AMD (P = 0.04) and neovascular AMD (P = 0.01) groups. When the researchers compared the SCT of those who developed macular atrophy to those who did not, there was a statistically significant difference between groups (P = 0.03).

Receiver operating characteristic curve (ROC) analysis showed the cut-off threshold of SCT for predicting the development of macular atrophy in cases without macular atrophy at baseline was 124 μm. Among eyes without macular atrophy at baseline, those with baseline SCT ≤124 μm were 4.3 times more likely to develop macular atrophy (Odds ratio: 4.3, 95% confidence interval: 1.6-12, P = 0.005) than those with baseline SCT >124 μm.

Source: Graefes, Arch Clin Exp Ophthalmol. 2018 Jan 27. doi: 10.1007/s00417-017-3888-2. [Epub ahead of print]

Biomarkers and nAMD

A prospective, noncomparative, interventional case series evaluated angiogenic biomarker expression in the aqueous humor before and after intravitreal bevacizumab (Avastin, Genentech) injections in 23 eyes with neovascular AMD. In these treatment-naïve eyes, aqueous humor samples were obtained by anterior chamber paracentesis at baseline and immediately before each intravitreal bevacizumab injection over the course of 3 monthly treatments.

The researchers evaluated aqueous humor levels of 19 angiogenic biomarkers, and also evaluated BCVA, spectral domain OCT parameters, and intraocular pressure.

They found that despite a decrease in VEGF-A, the aqueous levels of VEGF-C, angiopoietin 2, endothelin 1, follistatin, heparin-binding EGF-like growth factor, hepatocyte growth factor, and interleukin 8 increased significantly after the intravitreal injections.

In their discussion, the authors comment that although increased VEGF production drives the CNV development in this disorder, “in patients with recalcitrant CNV and decreased visual acuity, despite aggressive treatment with anti-VEGF agents, we believe other vascular mediators contribute to CNV.”

At this point, however, no optimal model to measure biomarkers in the eye has garnered unanimous support, and there is still debate surrounding the benefit of performing vitreous biopsies compared to sampling aqueous humor.

They also suggest the increased aqueous levels in their study “may be a consequence of VEGF-A blockage resulting in ischemic injury and upregulation of other angiogenic factors.”

In short, the authors say their findings “suggest a correlative relationship” between VEGF and 7 other biomarkers in the eye with regard to its expression, which may be of therapeutic significance.

Source:Ophthalmology Retina. 2018;2:31-37. doi:10.1016/j.oret.2017.04.004

Societal factors and AMD outcomes

A group of French researchers assessed the impact of societal factors (transportation, living status, daily reading, and social security scheme) on functional outcomes of anti-VEGF treatment in patients with neovascular AMD, and found those factors could contribute to the healing process or sustain disease progression.

The charts of 94 patients with AMD (mean age of 77 years) treated in the Monticelli-Paradis Centre (Marseille, France) were reviewed and phone interviews conducted to assess societal factors. The primary outcome was the impact of family support and disease burden improvement.

Between baseline and month 24, 42.4% of the variability in BCVA was explained by the cumulative effect of the following societal factors: intermittent out-patient follow-up, marital status, daily reading, transportation type, and commuting time. No isolated societal factor significantly correlated with ETDRS BCVA severity at month 24.

A trend to correlation was observed between the EDTRS score at month 24 and the social security scheme (P = 0.076), economic burden (P = 0.075), time between diagnosis and treatment initiation (P = 0.070). A significant correlation was found for the disease burdensome on the patient (P = 0.034) and low-vision rehabilitation (P = 0.014).

This study is one of the first to investigate the impact of new societal criteria. Patients with the highest degree of “societal painfulness” due to treatment (no healthcare insurance or long commuting times to specialists) seem to have better outcomes, perhaps due to a higher motivation and involvement in their own treatment.

The authors are quick to note there may be a bias in their studied population, as French families in southern France are more representative of the Mediterranean countries, “where a family circle is often present, the commuting time to the clinics is longer, and the need for car use is frequent,” which is in contrast to northern France and possibly other countries.

Source:BMC Ophthalmol. 2018 Feb 1;18(1):22. doi: 10.1186/s12886-018-0690-9