Kenneth Bender, PharmD, MA

In what investigators characterized as the first study to use whole genome sequencing (WGS) in a large cohort of patients with early onset drusen 

 (EODM), both common and rare genetic variants are implicated, and the condition appears more likely an early manifestation of 

"(The study) allowed for the evaluation of both common and rare variants, and revealed insights into biological disease pathways that may contribute to EODM," wrote Anita de Breuk, MD, Department of Ophthalmology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands, and colleagues.

Although environmental factors could contribute to EODM, de Breuk and colleagues considered the early manifestation an indicator that genetic factors play a prominent role. They suspected, in particular, rare and highly penetrant variants for the early appearance of AMD characteristics.

To examine the possible contribution of common AMD-associated variants and identify potential disease-causing rare variants, the investigators identified a population of 90 unrelated patients with EODM, all but 1 drawn from the European Genetic Database (EUGENDA). The criteria included any sign of age-related maculopathy diagnosed ≤55 years of age, or severe signs of AMD diagnosed between 56 and 65 years of age.

From this population, the study cohort was constituted with 49 patients having no rare, potential causative variants in the complement genes CFH, CFI, C3, C9 and CFB. A case-control cohort to reference the genetic risk score (GRS) distribution included 925 individuals without AMD ≥65 years of age, 577 early/intermediate AMD patients, and 1155 advanced AMD patients.

WGS was performed in all participants, and 52 variants previously associated with AMD were extracted from the dataset. The investigators calculated an overall GRS which included all 52 variants; a complement GRS which included 19/52 complement-related variants; and a lipid GRS including 7/52 lipid-related variants. Multiple filtering steps were applied to identify potential disease-causing variants in the EODM patients.

de Breuk and colleagues demonstrated that the 52 AMD associated variants contributed to EODM, especially variants located in the complement pathway. The latter finding follows on their previous study of rare variants in the Complement Factor H genes in patients with EODM.

In addition, they identified 26 rare genetic variants predicted to be pathogenic, with

prediction tools and corroborating literature, which are predominantly located in the complement and lipid metabolism pathways. Also, in their evaluation of 18 genes causing inherited retinal dystophies that can mimic AMD characteristics, de Breuk and colleagues identified 11 potential deleterious variants in 8 of the patients with EODM but not manifesting retinal dystrophy.

"We consider EODM as an early manifestation of AMD, which is a multifactorial disease," de Breuk and colleagues wrote. "In some EODM cases a high GRS based on the AMD-associated variants may already explain the disease. In other cases where the GRS is low and where we did not find potential deleterious rare variants in the studied candidate genes, the cause may lie in other genomic regions or in genes that were not evaluated in this study."

"Common and Rare Variants in Patients With Early Onset Drusen Maculopathy"

The earlier study by de Breuk and colleagues examining variants in the complement pathway, 

"Evaluating the Occurrence of Rare Variants in the Complement Factor H Gene in Patients With Early-Onset Drusen Maculopathy

Articles

Whole genome sequencing suggests both common and rare variants contribute to early onset drusen maculopathy.

Multiple Genetic Variants Likely Underlie Early Onset Drusen Maculopathy

 is exceedingly low, according to 2 recent pharmacovigilance investigations of the agents by separate groups of investigators in China. Both studies accessed US postmarketing data in the Food and Drug Administration's Adverse Event Reporting System (FAERS).

The study searching specifically for any reported ocular side effects was led by Shenyin Zhu, PhD, Chief Pharmacist, Department of Pharmacy, The First Affiliated Hospital of Chongquing Medical University, Chongquing, China. The other study, seeking to establish a broad adverse event profile for the agents, was conducted by Professor Ying Zou, Research Division of Clinical Pharmacology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China, and colleagues.

Both investigator groups acknowledged previous studies which have indicated that evolocumab and alirocumab are safe and well tolerated; and Zhu and colleagues noted that ocular side effects were not among the adverse events emerging in the New Drug Application (NDA) clinical trials which occurred with the frequency or severity to warrant inclusion in the approved labeling.In Zou's findings, they represented approximately 0.25% of all adverse events reported to FAERS, grouped by system organ class.

Zhu and colleagues point out that ocular adverse events have been reported in some clinical trials, albeit less than in the placebo group of the ODYSSEY trial.They did find 1 

 reporting an occurrence in 2.9% of those taking alirocumab, compared to 1.9% in the placebo group.In addition, they point to some associations of ocular disorders with disordered plasma cholesterol levels; and reason the possibility that these might also arise with the therapeutic effect of PCSK9 inhibitors lowering LDL-C levels.

With the possibility that ocular adverse effects may have been reported in the larger population after marketing, despite not being detected in the premarketing trials, Zhu and colleagues applied a disproportionality analysis for ocular reports among the FAERS.

"This study is the first disproportionality analysis of ocular disorders with PCSK9 inhibitors using an extensive pharmacovigilance database," Zhu and colleagues indicated.

They also indicate, in the introduction of the published study, that theirs is likely the only analysis for a possible association.

A total of 103,531 reports involving at least one PCSK9 inhibitor were found in the FAERS.Their initial analysis suggested that PCSK9 inhibitors were associated with higher reporting of increased lacrimation (Information Component [IC], 0.27; 95% CI, 0.02-0.45, and Reporting Odds Ratio [ROR] 1.21, 95% CI, 1.04-1.40); and "eye operation"—which is not further described—with IC 0.66 (95% CI, 0.04-1.10), and ROR 1.60 (95% CI, 1.11-2.30). They also attribute some disproportionate reporting of "seasonal allergy" to persons receiving the agents.

In further analysis, Zhu and colleagues found that the positive signal of increased lacrimation disappeared after excluding other lipid-lowering drugs. Both investigator groups found the relative lack of ocular effects and the general safety profiles were similar for evolocumab and alirocumab.

Ocular Disorders Associated With PCSK9 Inhibitors: A Pharmacovigilance Disproportionality Analysis

Adverse Event Profiles of PCSK9 Inhibitors Alirocumab and Evolocumab: Data Mining of the FDA Adverse Event Reporting System

Pharmacovigilance studies sifting through FDA adverse event reports confirm ocular side effects from PCSK9 inhibitors are infrequent and minor.

Adverse Event Data Mining Finds Few Ocular Side Effects From PCSK9 Inhibitors

neovascular age-related macular degeneration (nAMD)

 supported controlled studies that suggest it may not be necessary to achieve absence of subretinal fluid (SRF) for good visual outcomes with intravitreal anti-vascular endothelial growth factor (anti-VEGF) treatment.

Chang-Hao Yang, MD, PhD, Department of Opthamology, National Taiwan University, Taipei, Taiwan, and colleagues cited studies that have examined alternative treatment regimens, such as treat-and-extend (T&E) and pro re nata (PRN), to reduce the number of injections without compromising visual gains; but pointed out that few have addressed the impact of fluid tolerance on the treatment outcomes of nAMD in real world treatment settings..

"Our primary objective in the current study was to determine whether fluid tolerance in the implementation of intravitreal aflibercept treamtent affects anatomical or functional outcomes in nAMD patients presenting recurrent or persistent retinal fluid," they wrote.

The investigators retrospectively collected medical records of patients at a single treatment center, with a total of 90 treated eyes in 90 patients meeting criteria for inclusion in the study between January 2016 and July 2019. 

Patients had demonstrated persistent or recurrent retinal fluid from month 3 to month 18. Those with less than 18 months of follow-up were excluded from the study. Also excluded were patients with polypoidal choroidal vasculopathy, epiretinal membrane, diabetic retinopathy, or maculopathies other than nAMD. If both eyes of a patient met inclusion criteria, only the more affected eye was included in the study.

Patients were treated under the discretion of the attending physician, most with an extended PRN regimen. Inference of "tolerance" of retinal fluid, either intraretinal (RF) or SRF, was based on whether or not the patient received anti-VEGF injection when retinal fluid was detected at their examination.

Levels of tolerance were calculated from the duration between clinic visits before treatment was deemed necessary to maintain visual outcomes. A "fluid tolerance ratio" was determined from the summed duration of the fluid-tolerant periods divided by the total duration of fluid retention throughout the entire follow-up period. Fluid tolerance was categorized as strict (zero tolerance, requiring therapy to achieve dry retina with absence of both SRF and IRF); intermediate (tolerance ratio of less than 30%), and relaxed (tolerance ratio of 30% or greater).

The primary outcomes were best-corrected visual acuity (BCVA) and central retinal thickness (CRT), including retinal fluids, measured at baseline and at visits at 3, 6, 12 and 18 months.

Yang and colleagues reported that the relaxed group required fewer injections than the strict group (4.92 vs 7.50 injections) and presented a similar reduction in retinal thickness (-57.7 vs -71.65 μm), while having similar final visual acuity.

"A fluid-tolerant approach provides comparable gains in visual acuity," Yang and colleagues wrote. They noted that "reducing the number of injections may also improve adherence to therapy."

The investigators point out that retinal fluid is not always associated with neovascular activity, and cite several studies detecting the presence SRF or IRF without active vascular leakage. They also notethat there is some risk that additional injections could exacerbate the process of degeneration.

Yang and colleagues encouraged consideration of the different circumstances which may contribute to presence and tolerance of residual retinal fluid, and the possible feasibility of fewer anti-VEGF injections.

The impact of retinal fluid tolerance on the outcomes of neovascular age-related macular degeneration treated using aflibercept: A real-world study

Higher tolerance of retinal fluid in neovascular AMD corresponded to needing fewer anti-VEGF treatment injections for same visual outcomes.

Tolerance of Some Retinal Fluid Requires Less Anti-VEGF Therapy

 was found to have become less common in Finland over 4 decades, in a national population study which attributes the trend to improved diagnostic tools, earlier diagnoses, and new therapy options.

Petri Purola, MS, SILK, of the department of opthalmology and faculty of medicine and health technology at Tampere University in Finland, and colleagues found that there have been few studies which have evaluated the prevalence of AMD and its relation to visual impairment and new therapies.Those few, they noted, had the limitations of using single site populations, and/or were clinical trials with short follow-up periods, or had restricted the cohort to those with legal blindness due to AMD.

"Hence, there is a need for a comprehensive, population-based evaluation of trends in VI due ot AMD and the impact of new treatment options on the VI of AMD patients," Purola and colleagues wrote.

To fill in what they characterize as a "gap in knowledge", the investigators conducted a population study with over 30,000 visually impaired persons with AMD as the main diagnosis for visual impairment, drawn from the Finnish Register of visual impairment data from 1980 - 2019. The number of persons treated with intravitreal injections was obtained from hospital data at the Finnish Institute for Health and Welfare.

Purola and colleagues reported that although there had been a doubling of the incidence of reported visual impairment between the 1980s and the 2010s, the rate then plateaued, and has trended lower since 2012. The investigators also found a trend of decreasing severity of reported visual impairment over the studied time period; while that the mean age of onset had increased. The declining prevalence of visual impairment from AMD was apparent in all age groups except those 85 years and older; and the prognosis of VI had improved over the 4 decades.

"What was most remarkable, however, was the stagnation of the incidence and prevalence in the 2010s; in fact, even some decline was observed in younger age groups," Purola and colleagues remarked.

The prevalence of reported visual impairment was significantly higher in females than males, however, across decades and with age-adjustment. The investigators found no significant differences in visual impairment grades between sexes; and, after considering effect of longer life expectancy of females and looking for, but not finding undertreatment of exudative AMD among females, they concluded that females are at greater risk for visual impairment due to AMD.

Purola and colleagues attribute the overall favorable trend of reduced prevalence of visual impairment from AMD to several factors, including that the number of patients treated with intravitreal injections increased 40-fold during the period of 2005 - 2019.

"Today, we can say that exudative AMD treatment has been revolutionized by the introduction of intravitreal anti-VEGF drugs," Puola and colleagues enthused; but with a caveat. "Despite this development, undertreatment is frequent and the availability of treatment and protocols differs between clinics."

In addition to pharmacotherapeutic progress,the investigators cite other studies which have suggested that healthier lifestyles have contributed to the favorable trend. They also noted that many public campaigns have likely succeeded in making persons more aware of the symptoms, and prompted them to seek diagnosis and treatment.

Purola and colleagues pointed out that non-exudative AMD remains without effective treatment options, and is a significant cause for visual impairment in developed countries. "Therefore, it is important to evaluate the amount and burden of VI caused by the disease in order to improve health care and treatment," they concluded.

Visual impairment due to age-related macular degeneration during 40 years in Finland and the impact of novel therapies

Finnish population study attributes reduction in visual impairment from AMD to improved diagnostic tools, earlier diagnoses, and new therapies.