This certified CME activity is designed for retina specialists and eye care professionals involved in the medical management of patients with retina disorders.
This continuing medical education activity is supported through an educational grant from Genentech.
Evolve Medical Education LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.
Credit Designation Statement
Evolve Medical Education LLC designates this enduring material for a maximum of 0.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Faculty and Disclosures
It is the policy of Evolve that faculty and other individuals who are in the position to control the content of this activity disclose any real or apparent conflict of interests relating to the topics of this educational activity. Evolve has full policies in place that will identify and resolve all conflicts of interest prior to this educational activity.
The following faculty members have the following financial relationships with commercial interests:
Editorial Support Disclosures:
The staff and planners involved in this activity have no financial relationships with commercial interests.
This program will focus on the basics of pigment epithelial detachment and treatment options as well as the latest in available neovascular age-related macular degeneration therapies and select investigative agents in the pipeline nearing FDA approval.
The natural history of PED is that they will lead to progressive vision loss, with 50% of affected patients losing greater than 3 lines of visual acuity (VA) after 1 year without treatment. In addition, patients with PED also are a higher risk for ocular comorbidities such as vision loss, disciform scars, and retinal pigment epithelium (RPE) tears.1-3
Multiple retrospective studies demonstrate a reduction in size of PEDs after intravitreal anti-VEGF treatment.2-5
PEDs that demonstrate suboptimal response to anti-VEGF therapy present a unique challenge in the management of nAMD.6-10 Prospective and post-hoc analysis have demonstrated that both ranibizumab and aflibercept are effective in treating PEDs secondary to nAMD.11
Options include switching anti-VEGF therapy or increasing the dose or frequency of anti-VEGF therapy employed.10 HARBOR showed that PED resolved more frequently in the 2.0-mg group but this did not correlate with VA gains, which were not significant between the 0.5-mg IVL and 2.0-mg IVL groups.11 Multiple retrospective studies evaluated switching agents, and no pattern of visual improvement can be attributed to switching anti-VEGF agents, despite anatomical improvements.6-10
PEDs have been shown to decrease in volume over time with continued anti-VEGF therapy, and there is no correlation between reduction in PED height and VA improvements. Complete flattening of PEDs may yield an unfavorable outcome due to the development of macular atrophy with resolution.12,13
Volumetric analysis of OCT demonstrates a decrease in PED volume and height with an increase in basal diameter. This suggests that PEDs flatten and widen with minimal changes in volume overtime, and that they may be protective against RPE tear.12,13
PEDs with a height greater than 400 to 600 microns suggest an increase in the risk for RPE tear development,14,11 and evidence suggests a trend in RPE tears occurring in the first 3-months of anti-VEGF therapy.15,16
However, more frequent injections during the 12- to 24-month period following an RPE tear can result in continued VA gains.11
These images show an 82-year-old man with nAMD in his right eye who was treated with five injections of bevacizumab. At first presentation, his VA 20/70 OD and 20/30 OS.
He developed RPE tear after one bevacizumab injection and his VA declined to 20/300 in his right eye. He continued monthly anti-VEGF therapy and his VA improved to 20/150 OD.
Current treatment options for nAMD requires regular anti-VEGF injections. However, patient adherence to follow-up over 5 years is poor for various reasons.17 A study by Boulanger-Scemama and colleagues to analyze adherence to follow-up over 5 years among patients treated in a tertiary health care center with intravitreal ranibizumab for exudative AMD found that three factors were associated with failure to follow up: high age at baseline (82.2 vs. 76.5 years, P < .001), poor best-corrected visual acuity (BCVA) at baseline (42.5 vs. 51.0 letters, P= .020), and long distance from home to hospital (132 vs. 17.1km, P< .001).
A total of 201 patients were included, and the rate of loss to follow-up during the 5-year period was 57% (115/201). Fifty-eight patients lost to follow-up completed the questionnaire. The main reasons reported by patients for follow-up discontinuation were long distance from home to hospital (51.7%, 30/58), subjective dissatisfaction with the benefits of intravitreal injections (34.5%, 20/58), and the excessive burden of periodic follow-up visits (24.1%, 14/58).
A study by Maguire et al described outcomes 5 years after initiation of treatment with bevacizumab or ranibizumab for nAMD among patients enrolled in CATT.
This graph shows the distribution of VA over time for 647 patients. The authors concluded that vision gains during the first 2 years of the trial were not maintained at 5 years. However, 50% of eyes had VA 20/40 or better, confirming anti-VEGF therapy as a major long-term therapeutic advance for nAMD.
VA was obtained for 647 (71%) of 914 living patients with average follow-up time 5.5 years. The mean number of examinations for AMD care after the clinical trial ended was 25.3, and the mean number of treatments in the study eye was 15.4. Most (60%) patients were treated ≥1 times with a drug other than their randomly assigned drug. At the 5-year visit, 50% of study eyes had VA 20/40 or better and 20% had VA 20/200 or worse. Mean change in VA was −3 letters from baseline and −11 letters from 2 years. Among 467 eyes with fluorescein angiography, mean total lesion area was 12.9 mm2, a mean of 4.8 mm2 larger than at 2 years. GA was present in 213 (41%) of 515 gradable eyes and was subfoveal in 85 (17%). Among 555 eyes with spectral domain OCT, 83% had fluid (61% intraretinal, 38% subretinal, and 36% sub-retinal pigment epithelium). Mean foveal total thickness was 278 μm; a decrease of 182 μm from baseline and 20 μm from 2 years. An abnormally thin retina at the foveal center (<120 μm) was present in 36%. Between 2 and 5 years, the group originally assigned to ranibizumab for 2 years lost more VA than the bevacizumab group (−4 letters; P= .008). Otherwise, there were no statistically significant differences in VA or morphological outcomes between drug or regimen groups.18
New treatments may help alleviate the nAMD treatment burden. This image shows the current and emerging anti-VEGF agents, their format, molecular structure, molecular weight, and clinical dose used for treating wet AMD.19-27
Note the large size of bevacizumab and aflibercept. It was once hypothesized that large molecules, if delivered intravitreally, would not be able to penetrate the retina to treat choroidal neovascularization (CNV). Clearly that theory has been disproven and both bevacizumab and aflibercept are effective agents in treating wet AMD.21,23,26,27 Also, note, the small molecular weight of brolucizumab.24,25 This allows a high dose to be delivered. Finally, abicipar is a DARPin platform that is distinct from the other agents. DARPin molecules are a novel class of binding proteins with the potential to overcome some limitations of antibody-based therapeutics. DARPin molecules are small, highly stable proteins that contain engineered ankyrin repeat domain(s) and can be selected to bind any given target protein with high specificity and affinity.20
Brolucizumab, an anti-VEGF for the treatment of nAMD, was approved by the FDA in October 2019. The recommended dose for brolucizumab is 6 mg monthly (approximately every 25-31 days) for the first three doses, followed by one dose of 6 mg every 8 to 12 weeks.28
HAWK and HARRIER, two phase 3, double-masked, multicenter, active-controlled, randomized trials, compared brolucizumab with aflibercept to treat nAMD that included 1,817 patients with untreated, active choroidal neovascularization due to AMD in the study eye. Patients were randomized to intravitreal brolucizumab 3 mg (HAWK only) or 6 mg or aflibercept 2 mg. After loading with 3 monthly injections, brolucizumab-treated eyes received an injection every 12 weeks (q12w) and were interval adjusted to every 8 weeks (q8w) if disease activity was present; aflibercept-treated eyes received q8w dosing.28
At week 48, each brolucizumab arm demonstrated noninferiority to aflibercept in BCVA change from baseline (least squares [LS] mean, +6.6 [6 mg] and +6.1 [3 mg] letters with brolucizumab vs. +6.8 letters with aflibercept [HAWK]; +6.9 [brolucizumab 6 mg] vs. +7.6 [aflibercept] letters [HARRIER]; P< .001 for each comparison).
Greater central subfield thickness reductions from baseline to week 48 were observed with brolucizumab 6 mg versus aflibercept in HAWK (LS mean 172.8 mm vs. 143.7 mm; P= .001) and HARRIER (LS mean 193.8 mm vs. 143.9 mm; P< .001).
The authors concluded that brolucizumab was noninferior to aflibercept in visual function at week 48, and more than 50% of brolucizumab 6 mg treated eyes were maintained on q12w dosing interval through week 48. Anatomic outcomes favored brolucizumab over aflibercept.
The BCVA achieved by brolucizumab at week 48 (primary endpoint) was maintained at Week 96.29
In addition, 82% and 75% of those patients who reached week 48 on a q12w 6 mg brolucizumab interval remained on q12w dosing through week 96. Though not reported directly, since 56% of eyes in HAWK and 51% in HARRIER reached 48 weeks at q12w dosing, this would imply that of the total cohort 46% of eyes in HAWK and 38% of eyes in HARRIER maintained q12w dosing.30
Abicipar, which is currently under investigation for treatment of nAMD, was tested in two global pivotal phase 3 trials, CEDAR and SEQUOIA, against the standard of care (ranibizumab given every 4 weeks [q4w]) in the following two ways: three monthly loading doses and then q8w or two monthly loading doses followed by a bimonthly dose and then q12w. Of note, the primary outcome for this study was not mean change in BCVA but rather the percent of eyes maintaining VA.31,32
In both the SEQUOIA and CEDAR studies, abicipar met the prespecified primary endpoint of the proportion of patients with stable vision at week 52 and demonstrated statistical noninferiority to q4w ranibizumab for both the 12- and 8-week dosing regimens. Noninferiority was demonstrated for abicipar despite substantially fewer injections required for q12w and q8w abicipar vs q4w ranibizumab with six, eight, and 13 injections required, respectively. In each trial, more than 91% of patients had stable vision on the q12w dosing regimen.
The Port Delivery System (PDS) for extended release of ranibizumab was well-tolerated and improved BCVA versus monthly injections in a phase 1 trial. The device received fast-track designation from FDA and is being studied in an FDA phase 3 clinical trial.33-35
The nonbiodegradable refillable port is placed beneath the conjunctiva, and the reservoir is refilled via subconjunctival opening using a custom refill needle. The device is designed to provide constant levels of ranibizumab.33,34
The current design of the device requires it be surgically implanted in an ambulatory surgery center or hospital operating room at the present time. Refills are performed in the office.
The figure shows the LADDER study, an FDA phase 2 clinical trial of the PDS to evaluate the efficacy, safety and pharmacokinetics of three different formulations of ranibizumab delivered via PDS implant compared with monthly intravitreal injection of ranibizumab in participants with subfoveal nAMD.36,37
The results of the LADDER study show that the median time to refill for the 100 mg/mL dose of ranibizumab was 15.0 months, and 80% of patients went at least 6 months without requiring a refill. The results for the other two doses of ranibizumab used in the PDS show that this occurs in a dose-dependent fashion.37
Only the 100 mg/mL dose of ranibizumab will be used in the phase 3 clinical trial, ARCHWAY.38
When looking at mean change in BCVA, it is important to remember that all eyes included in the LADDER clinical trial had already received at least three anti-VEGF injections, so the PDS with ranibizumab can be described as a maintenance strategy.39
Looking at mean change in Central Foveal Thickness (CFT), once again it is evident that the PDS is a maintenance strategy.39
ARCHWAY is the clinical trial designed for the 100 mg/mL dose of ranibizumab in the PDS. Note the mandatory refills every 6 months as well as the opportunity for rescue injections at each of the two visits prior to the 6-month time point.38 Enrollment is complete and are results pending.
Also note that all patient in the PDS arm will rollover to the PORTAL study, a phase 3, multicenter, long-term extension study of safety and efficacy.40 This is an extension of the LADDER phase 2 study which allows patients who were in the control group to receive the PDS implant. Enrollment is complete, and results are pending.
This activity reviewed the currently available anti-VEGF agents plus therapeutic agents under investigation, which could greatly expand the nAMD treatment options. Additionally, advances being made in sustained delivery of these agents may further help with treatment adherence.