Every year, thousands of retina specialists from across the globe gather at Retina Subspecialty Day prior to the annual meeting of the American Academy of Ophthalmology (AAO). This year, the meeting took place in beautiful New Orleans, Louisiana, and we were treated to several excellent clinical trial presentations, interactive point-counterpoint debates, surgical video discussions, and demonstration of cutting-edge technology and surgical techniques. Here is a brief summary of some of these presentations.
Protocol U
While anti-vascular endothelial growth factor (anti-VEGF) monotherapy is effective for a majority of patients with diabetic macular edema (DME), roughly one third of patients will exhibit an incomplete response with persistent loss of vision. This is probably due to other cytokines that are unaffected by VEGF suppression, motivating consideration of corticosteroids. Protocol U of the Diabetic Retinopathy Clinical Research Network (DRCR) sought to evaluate the role of corticosteroids in the treatment of DME. Can a combination of corticosteroid and anti-VEGF therapy help these incomplete responders? Dr Raj Maturi presented these results.
Protocol U was a short-term evaluation of combination dexamethasone and ranibizumab versus ranibizumab monotherapy for the treatment of persistent center-involving DME following anti-VEGF therapy.[1,2] All patients had received three or more prior anti-VEGF injections. Upon enrollment, ranibizumab was administered monthly for three additional months, and if there was persistent edema, patients were randomly assigned to one of two arms. Half of the patients received the 700-μg dexamethasone drug delivery system (DDS) implant in addition to ranibizumab. They could be re-treated with dexamethasone DDS as early as 12 weeks later. The other half received ranibizumab alone.
The primary outcome was the change in mean best-corrected visual acuity (BCVA) at 24 weeks, and unfortunately there was no difference between the groups. However, there were several interesting subgroup analyses. By 6 months, one half of patients in the combination treatment arm had fully resolved edema, compared with only one third of patients in the ranibizumab arm. There was also a trend toward more improvement in the pseudophakic patients receiving combination treatment, perhaps due to acceleration of cataract in the phakic patients. Finally, there was a higher percentage of three-line gainers in the combination arm.
While Protocol U suggests that anti-VEGF monotherapy is still the first-line treatment for patients with DME, the role of corticosteroids still makes sense to most of us, and perhaps a novel drug delivery approach will elucidate this.
HULK
Dr Charlie Wykoff presented the 6-month results of Clearside Biomedical's HULK trial,[3] which is a phase 1/2 clinical trial evaluating the safety and efficacy of suprachoroidal preservative-free Clearside-triamcinolone acetonide (CLS-TA) for center-involving DME. This involves a short (0.9 or 1.1 mm) needle designed to deliver 0.1 mL CLS-TA into the suprachoroidal space at the pars plana. Preliminary studies noted that this enables a high concentration of drug delivery to the retina and choroid with relative sparing of the lens and anterior chamber, substantially less than what is seen with intravitreal TA. The hope is that this provides the efficacy of intravitreal TA without the associated risks for cataract acceleration and ocular hypertension.
This small study enrolled 20 people and divided them into two arms: 10 treatment-naive patients and 10 previously treated with intravitreal anti-VEGF agents and/or corticosteroids, but not within 90 days of enrollment. Treatment-naive patients received intravitreal aflibercept plus 4 mg of CLS-TA at baseline. Previously treated patients received 4 mg of CLS-TA alone at baseline. Re-treatment with 4 mg CLS-TA was given on a monthly as-needed basis. Re-treatment criteria included persistent edema (not substantially improved) or loss of 10+ letters due to DME. Outcome measures at 6 months included mean change in BCVA, central subfield thickness (CST) measured using optical coherence tomography, intraocular pressure (IOP), number of as-needed CLS-TA treatments, and adverse events.
The baseline demographics were fairly typical of patients with DME, with an average visual acuity of 20/50 and an average CST of 473 μM. Patients in the previously treated group received an average of 22 prior anti-VEGF injections. At month 6, the mean gain in BCVA was 5.2 letters overall, with +8.5 letters in the treatment-naive arm and +1.1 letters in the previously treated arm. All patients showed an improvement in central retinal thickness, and an impressive 89% of patients had a 50% or higher reduction in abnormal CST. Ocular hypertension was not a clinically significant issue, even in eyes with monthly injections; only one patient developed an IOP elevation greater than 10 mm Hg from baseline, and no eyes had an IOP greater than 29 mm Hg. No severe adverse events were noted.
While phase 3 studies are currently in process, CLS-TA appeared safe and efficacious for the treatment of DME. Hopefully it will be a useful addition to our armamentarium.
Lampalizumab
It is always disappointing when clinical trial results end up negative, particularly for disease states in which we currently have no therapeutic options for our patients, when the phase 2 results seemed particularly promising, and when the scientific rationale seemed sound.
The Spectri and Chroma studies evaluated the safety and efficacy of lampalizumab, an anti-complement factor D monoclonal antibody fragment, for the treatment of geographic atrophy. The phase 2 MAHALO study[4] suggested a 20% reduction in the growth of atrophy in treated patients and an impressive 44% reduction in patients positive for the complement factor I biomarker. In fact, the growth rate reduction appeared to be driven entirely by the cohort of patients positive for complement factor I (CFI+). However, this was a small study of 129 patients.
The follow-up phase 3 studies[5] were presented by Dr Jeffrey Heier at the meeting. Over 1800 patients were enrolled to two study arms: lampalizumab 10 mg every 4 weeks or every 6 weeks, as compared with sham injections every 4 weeks or every 6 weeks. CFI+ patients were targeted during enrollment. The primary outcome was the mean change in area of atrophy, measured by fundus autofluorescence at 48 weeks. Unfortunately, this was not met in either study—neither for the cohorts as a whole nor for the CFI+ subgroups.
HAWK and HARRIER: Brolucizumab
Switching gears, Dr Pravin Dugel gave what was certainly one of the most buzzworthy presentations of the meeting, on the outcomes of the phase 3 HAWK and HARRIER trials.[6]
These studies examined the efficacy of the novel single-chain variable fragment, a 26 kDa anti-VEGF molecule, in neovascular age-related macular degeneration (AMD). The investigators enrolled over 1800 patients with treatment-naive neovascular AMD in 48-week, multicenter, randomized, double-masked trials comparing brolucizumab versus aflibercept. Upon enrollment, all patients were treated with three monthly injections of their assigned medication. Following this, eyes in the brolucizumab arm were treated every 12 weeks, with an option to reduce this to every 8 weeks on the basis of disease activity. Eyes in the aflibercept arm were dosed every 8 weeks following the loading phase.
Overall, brolucizumab met the goal of noninferiority compared with aflibercept. Moreover, more than one half of the eyes in the brolucizumab arm were maintained on every-12-week injections. At both 4 and 11 months compared with aflibercept, roughly a third fewer brolucizumab-treated patients had persistent intraretinal fluid on optical coherence tomography (P < .0001). There were no new adverse-event signals. These studies will continue on through week 96 and are expected to conclude in the middle of 2018.
Retinal Detachment Outcomes: IRIS® Registry
The IRIS® (Intelligent Research in Sight) Registry is a robust data registry run by the AAO and recognized as a qualified clinical data registry by the Centers for Medicare & Medicaid Services. The goal is to provide the ophthalmic community with quality of care, benchmark data, and practice patterns. The database is the largest such registry in the world, with over 119 million unique visits from more than 32 million patients in the past 3 years.
The registry includes 135,050 eyes of 127,631 unique patients who received one or more retinal detachment surgery. The database can be filtered by several variables, including diagnostic (ICD) and procedure (CPT) codes. Dr George Williams focused on noncomplex detachments treated with scleral buckling (CPT 67107) and/or vitrectomy (CPT 67108); retinal detachments associated with proliferative vitreoretinopathy (CPT 67113) and cases treated with pneumatic retinopexy (CPT 67110) were not included in this analysis.[7] This cohort totaled 82,069 eyes of 79,350 patients. Bilateral detachment was noted in 3.4% of patients. Follow-up data at 3, 6, and 12 months were available for about one third of these patients (ie, 24,968 patients). The majority (88%) of these eyes received vitrectomy with or without scleral buckle, with the remainder (12%) treated with scleral buckle alone. Younger patients and male patients were more likely to receive a primary buckle. To determine the single-operation success rate, this cohort was evaluated for the need for subsequent surgery associated with CPT codes 67107, 67108, and 67113. Dr Williams presented that the rate of reoperation, regardless of procedure, was 12.1%, including 12.2% for scleral buckles and 11.8% for vitrectomy with or without scleral buckling.
In a separate presentation, Dr Richard Kaiser presented the 12-month single-surgery success rates for eyes with high-risk or complex retinal detachment.[8] This included patients with multiple breaks (4067 patients), a total detachment (2944 patients), proliferative vitreoretinopathy (1225 patients), or giant retinal tears (407 patients). Overall, nearly 13% of eyes needed additional surgery for recurrent detachment. The rate was even higher for patients with preoperative proliferative retinopathy (16%) and giant retinal tear (18%).
Together, these two presentations provide information on how we are performing as a specialty, but moreover they demonstrate the ability of the IRIS database to analyze real-world data. Over time, this powerful tool will certainly be used more and more frequently to help answer questions, provide feedback for improvement, and help us to maximize outcomes for our patients.
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Cite this: Spotlight on Retinal Diseases - Medscape - Jan 17, 2018.
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