Private equity ownership of ophthalmology practices: how does it impact clinical research?

PURPOSE OF REVIEW: To explore the impact of private equity ownership of ophthalmology practices on the success of their clinical research programs. RECENT FINDINGS: Private equity partnership in the clinical research space has been steadily occurring over the past decades. In addition to contract research organizations, private equity groups have also consolidated multiple independent clinical research networks. By investing in an increasing number of retina practices, one private equity group is attempting to create a synergistic relationship between clinical practice and clinical research with the goal of supporting a larger, more robust clinical research network. SUMMARY: Although there are physician concerns about the potential deleterious effects of private equity ownership on clinical research capabilities, private equity support has the potential to be an important stimulus for clinical research growth. VIDEO ABSTRACT: http://links.lww.com/COOP/A48.

C5 Inhibitor Avacincaptad Pegol for Geographic Atrophy Due to Age-Related Macular Degeneration: A Randomized Pivotal Phase 2/3 Trial.

PURPOSE: The complement pathway may play a key role in the pathogenesis of age-related macular degeneration (AMD). The safety and efficacy of avacincaptad pegol (Zimura, IVERIC bio Inc, New York, NY), a C5 inhibitor, were assessed in participants with geographic atrophy (GA) secondary to AMD (GATHER1 Study). DESIGN: International, prospective, randomized, double-masked, sham-controlled, pivotal phase 2/3 clinical trial. PARTICIPANTS: A total of 286 participants with GA secondary to AMD. MAIN OUTCOME MEASURES: The primary efficacy endpoint was the mean rate of change in GA over 12 months measured by fundus autofluorescence (FAF) at 3 timepoints: baseline, month 6, and month 12. RESULTS: The reduction in the mean rate of GA growth (square root transformation) over 12 months was 27.4% (P = 0.0072) for the avacincaptad pegol 2 mg cohort and 27.8% (P = 0.0051) for the avacincaptad pegol 4 mg cohort compared with their corresponding sham cohorts. The results for both dose groups were statistically significant. Avacincaptad pegol was generally well tolerated after monthly administration over 12 months. There were no avacincaptad pegol-related adverse events (AEs) or inflammation. Further, there were no ocular serious AEs (SAEs) and no cases of endophthalmitis. The most frequent ocular AEs were related to the injection procedure. CONCLUSIONS: Intravitreal administration of avacincaptad pegol 2 mg and 4 mg led to a significant reduction of GA growth in eyes with AMD over a 12-month period. Because C5 inhibition theoretically preserves C3 activity, it may offer additional safety advantages. A second confirmatory pivotal clinical trial is underway to confirm the efficacy and safety of avacincaptad pegol in slowing the GA growth (GATHER2 Study).

Phase 1 Study of OPT-302 Inhibition of Vascular Endothelial Growth Factors C and D for Neovascular Age-Related Macular Degeneration.

PURPOSE: OPT-302 is a novel inhibitor of vascular endothelial growth factor (VEGF)-C and VEGF-D. A phase 1 trial assessed the safety of intravitreal OPT-302 as monotherapy or combined with ranibizumab (Lucentis; Genentech, South San Francisco, CA) in patients with neovascular age-related macular degeneration (nAMD). DESIGN: Open-label, dose escalation followed by a randomized dose expansion. PARTICIPANTS: Fifty-one patients with nAMD who were either treatment naïve (n = 25) or previously were treated with anti-VEGF A therapy (n = 26). METHODS: In the dose escalation, groups of 5 patients in 4 cohorts received ascending doses of OPT-302 (0.3 mg, 1 mg, or 2 mg) in combination with ranibizumab (0.5 mg), or as monotherapy (2 mg). In the dose expansion, 31 patients were randomized (3:1) to OPT-302 (2 mg) in combination with ranibizumab (n = 23) or as monotherapy (n = 8). Participants received three intravitreal treatments of OPT-302 once every 4 weeks either with or without ranibizumab. MAIN OUTCOME MEASURES: Safety and tolerability, OPT-302 pharmacokinetics and immunogenicity, effects on best-corrected visual acuity (BCVA), and anatomic changes. RESULTS: Intravitreal OPT-302 with or without ranibizumab was well tolerated with low systemic exposure, no dose-limiting toxicities and no immunogenicity. In patients receiving OPT-302 monotherapy, 7 of 13 (54%) did not require rescue anti-VEGF-A therapy and the mean change in BCVA from baseline to week 12 was +5.6 letters (range, 0-18 letters). Mean BCVA gains from baseline to week 12 following combination OPT-302 with ranibizumab were +10.8 letters (95% confidence interval [CI], 4-17; n = 18) in treatment-naïve patients and +4.9 letters (95% CI, 3-7; n = 19) in previously treated patients, respectively. Corresponding reductions in mean central subfield thickness at week 12 in both groups were -119 µm (95% CI, -176 to -62 µm) and -54 µm (95% CI, -82 to -26 µm), respectively, whilst 50% of treatment-naïve patients also showed no detectable choroidal neovascularization at week 12 on fluorescein angiography. CONCLUSIONS: Intravitreal OPT-302 inhibition of VEGF-C and -D was well tolerated, and OPT-302 combination therapy may overcome an escape mechanism to VEGF-A suppression in the management of nAMD.

Emixustat Hydrochloride for Geographic Atrophy Secondary to Age-Related Macular Degeneration: A Randomized Clinical Trial.

PURPOSE: To determine whether emixustat hydrochloride (emixustat) reduces the rate of enlargement of geographic atrophy (GA) compared with placebo in subjects with age-related macular degeneration (AMD) and to evaluate the safety and tolerability of emixustat over 24 months of treatment. DESIGN: Multicenter, randomized, double-masked, placebo-controlled, phase 2b/3 clinical trial. PARTICIPANTS: Patients with GA secondary to AMD, a visual acuity score of at least 35 letters, and GA with a total area of 1.25 to 18 mm2 were enrolled. METHODS: Subjects were randomized (1:1:1:1) to emixustat 2.5 mg, 5 mg, 10 mg, or placebo, administered orally once daily for 24 months. Visits included screening, baseline, and months 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, and 25. MAIN OUTCOME MEASURES: The primary efficacy end point was the mean annual growth rate of total GA area in the study eye, as measured by a central reading center using fundus autofluorescence (FAF) images. The change from baseline in normal luminance best-corrected visual acuity (NL-BCVA) was a secondary efficacy end point. RESULTS: Of 508 randomized subjects, 320 completed the study. Demographics and baseline characteristics were comparable between treatment groups. On average, GA lesions in the study eye grew at a similar rate in each group (emixustat: 1.69 to 1.84 mm2/year; placebo: 1.69 mm2/year; P ≥ 0.81). Changes in NL-BCVA were also comparable between groups. Subjects with a larger low luminance deficit (LLD) at baseline (≥20 letters) demonstrated a more rapid growth of GA over 24 months. No relationship was observed between the risk-allele status of the AMD-associated single-nucleotide polymorphisms tested and the growth rate of GA. The most common adverse events in emixustat-treated subjects were delayed dark adaptation (55%), chromatopsia (18%), visual impairment (15%), and erythropsia (15%). CONCLUSIONS: Emixustat did not reduce the growth rate of GA in AMD. The most common adverse events were ocular in nature and likely related to the drug's mechanism of action. Data gained from this study over a 2-year period add to the understanding of the natural history of GA and the baseline characteristics affecting the growth rate of GA.

Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer's disease.

BACKGROUND: Noninvasive detection of Alzheimer's disease (AD) with high specificity and sensitivity can greatly facilitate identification of at-risk populations for earlier, more effective intervention. AD patients exhibit a myriad of retinal pathologies, including hallmark amyloid ß-protein (Aß) deposits. METHODS: Burden, distribution, cellular layer, and structure of retinal Aß plaques were analyzed in flat mounts and cross sections of definite AD patients and controls (n = 37). In a proof-of-concept retinal imaging trial (n = 16), amyloid probe curcumin formulation was determined and protocol was established for retinal amyloid imaging in live patients. RESULTS: Histological examination uncovered classical and neuritic-like Aß deposits with increased retinal Aß42 plaques (4.7-fold; P = 0.0063) and neuronal loss (P = 0.0023) in AD patients versus matched controls. Retinal Aß plaque mirrored brain pathology, especially in the primary visual cortex (P = 0.0097 to P = 0.0018; Pearson's r = 0.84-0.91). Retinal deposits often associated with blood vessels and occurred in hot spot peripheral regions of the superior quadrant and innermost retinal layers. Transmission electron microscopy revealed retinal Aß assembled into protofibrils and fibrils. Moreover, the ability to image retinal amyloid deposits with solid-lipid curcumin and a modified scanning laser ophthalmoscope was demonstrated in live patients. A fully automated calculation of the retinal amyloid index (RAI), a quantitative measure of increased curcumin fluorescence, was constructed. Analysis of RAI scores showed a 2.1-fold increase in AD patients versus controls (P = 0.0031). CONCLUSION: The geometric distribution and increased burden of retinal amyloid pathology in AD, together with the feasibility to noninvasively detect discrete retinal amyloid deposits in living patients, may lead to a practical approach for large-scale AD diagnosis and monitoring. FUNDING: National Institute on Aging award (AG044897) and The Saban and The Marciano Family Foundations.

Dual Antagonism of PDGF and VEGF in Neovascular Age-Related Macular Degeneration: A Phase IIb, Multicenter, Randomized Controlled Trial.

PURPOSE: To assess the safety and efficacy of E10030 (Fovista; Ophthotech, New York, NY), a platelet-derived growth factor (PDGF) antagonist, administered in combination with the anti-vascular endothelial growth factor (VEGF) agent ranibizumab (Lucentis; Roche, Basel, Switzerland) compared with ranibizumab monotherapy in patients with neovascular age-related macular degeneration (nAMD). DESIGN: Phase IIb global, multicenter, randomized, prospective, double-masked, controlled superiority trial. PARTICIPANTS: Four hundred forty-nine patients with treatment-naïve nAMD. METHODS: Participants were randomized in a 1:1:1 ratio to 1 of the following 3 intravitreal treatment groups: E10030 0.3 mg in combination with ranibizumab 0.5 mg, E10030 1.5 mg in combination with ranibizumab 0.5 mg, and sham in combination with ranibizumab 0.5 mg (anti-VEGF monotherapy). Drugs were administered monthly in each of the groups for a total duration of 24 weeks. MAIN OUTCOME MEASURES: The prespecified primary end point was the mean change in visual acuity (VA; Early Treatment Diabetic Retinopathy [ETDRS] letters) from baseline to 24 weeks. RESULTS: No significant safety issues were observed in any treatment group. The E10030 (1.5 mg) combination therapy regimen met the prespecified primary end point of superiority in mean VA gain compared with anti-VEGF monotherapy (10.6 compared with 6.5 ETDRS letters at week 24; P = 0.019). A dose-response relationship was evident at each measured time point commencing at 4 weeks. Visual acuity outcomes favored the E10030 1.5 mg combination therapy group regardless of baseline VA, lesion size, or central subfield thickness on optical coherence tomography. All clinically relevant treatment end points of visual benefit (≥15 ETDRS letter gain, final VA ≥20/40 or ≥20/25) and visual loss (≥1 ETDRS line loss, ≥2 ETDRS line loss, final VA ≤20/125 or ≤20/200) favored the E10030 1.5 mg combination group. CONCLUSIONS: In this phase IIb clinical trial, a 62% relative benefit from baseline was noted in the E10030 1.5 mg combination therapy group compared with the anti-VEGF monotherapy group. A favorable safety and efficacy profile of E10030 combination therapy for nAMD was evident across multiple clinically relevant end points. This highly powered study provides strong rationale for a confirmatory phase III clinical trial.

Multifocal choroiditis and panuveitis presenting with progressive equatorial linear streaks: evolution of Schlaegel lines documented with multimodal imaging.

PURPOSE: To describe the progressive, peripheral linear streaks of the equatorial retina, known as Schlaegel lines, in multifocal choroiditis and panuveitis (MCP). METHODS: A case report of a 13-year-old girl with MCP showed progression of retinal linear streaks. Extensive systemic and ophthalmologic investigations were performed. RESULTS: Linear streaks in MCP showed progression before the institution of immunomodulatory treatment. Infrared imaging showed hyperreflectivity of the lesions with surrounding hyporeflectivity. Optical coherence tomography showed elevated and irregular hyperreflectivity of the retinal pigment epithelium and choroidal hyperreflectivity. These findings, including the clinical progression before immunomodulatory therapy and negative systemic evaluation for infectious entities, are consistent with MCP. CONCLUSION: Patients with linear streaks in the setting of atypical MCP can progress and should be treated with adequate systemic corticosteroids and immunomodulatory agents. This case is unique in that it shows the evolution of Schlaegel lines using a multimodal imaging approach. Multimodal imaging can provide ancillary evidence of disease activity.