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).

Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy.

REVERSE is a randomized, double-masked, sham-controlled, multicenter, phase 3 clinical trial that evaluated the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON). A total of 37 subjects carrying the m.11778G>A (MT-ND4) mutation and with duration of vision loss between 6 to 12 months were treated. Each subject's right eye was randomly assigned in a 1:1 ratio to treatment with rAAV2/2-ND4 (GS010) or sham injection. The left eye received the treatment not allocated to the right eye. Unexpectedly, sustained visual improvement was observed in both eyes over the 96-week follow-up period. At week 96, rAAV2/2-ND4-treated eyes showed a mean improvement in best-corrected visual acuity (BCVA) of -0.308 LogMAR (+15 ETDRS letters). A mean improvement of -0.259 LogMAR (+13 ETDRS letters) was observed in the sham-treated eyes. Consequently, the primary end point, defined as the difference in the change in BCVA from baseline to week 48 between the two treatment groups, was not met (P = 0.894). At week 96, 25 subjects (68%) had a clinically relevant recovery in BCVA from baseline in at least one eye, and 29 subjects (78%) had an improvement in vision in both eyes. A nonhuman primate study was conducted to investigate this bilateral improvement. Evidence of transfer of viral vector DNA from the injected eye to the anterior segment, retina, and optic nerve of the contralateral noninjected eye supports a plausible mechanistic explanation for the unexpected bilateral improvement in visual function after unilateral injection.

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.

Pegaptanib 1-year systemic safety results from a safety-pharmacokinetic trial in patients with neovascular age-related macular degeneration.

OBJECTIVE: To characterize the safety, tolerability, and pharmacokinetics of the pegylated anti-vascular endothelial growth factor (VEGF) aptamer pegaptanib sodium in subfoveal choroidal neovascularization secondary to age-related macular degeneration (AMD). DESIGN: Prospective 2-cohort study: (1) open-label cohort and (2) randomized, double-masked, uncontrolled multicenter trial. PARTICIPANTS: In the combined cohorts, 147 subjects with any angiographic subtype of subfoveal choroidal neovascularization secondary to AMD and best-corrected visual acuities (VAs) in the study eye of 20/40 to 20/320 and in the fellow eye of 20/800 or better received pegaptanib sodium. INTERVENTION: Subjects were randomized to receive intravitreous pegaptanib sodium (1 mg or 3 mg [3- and 10-fold higher than the 0.3-mg approved dose]) every 6 weeks for 54 weeks. MAIN OUTCOME MEASURES: Safety assessments included blood chemistries, urinalyses, vital signs, electrocardiograms, serum antipegaptanib antibody assays, adverse events, VAs, and intraocular pressures. After the first, fourth, and eighth injections, serial blood samples were obtained for quantification of pegaptanib plasma concentrations. RESULTS: No antipegaptanib immunoglobulin G (IgG) or IgM antibodies were detected. Few systemic adverse events were noted. Mild or moderate ocular adverse events related to the injection procedure were reported in most patients. Pegaptanib did not accumulate in plasma after multiple doses; systemic exposures were similar after the first, fourth, and eighth doses. The mean apparent terminal half-life was 10 days. Evaluation of blood pressure (BP) and urine protein, both of which are known to be affected by systemic VEGF inhibition, indicated no evidence of a pegaptanib treatment effect on these parameters. Mean BP at the end of year 1 remained below 140 mmHg (systolic) and 90 mmHg (diastolic), levels considered hypertension by the American College of Cardiology. CONCLUSIONS: At doses up to 10-fold higher than the 0.3-mg dose approved for the treatment of AMD, pegaptanib sodium was well tolerated, with no detectable clinical evidence of systemic VEGF inhibition (i.e., no clinically meaningful changes in proteinuria or mean BP) and no clinically relevant ocular inflammation. Most ocular adverse events were related to the injection procedure itself and were mild or moderate in severity.

Use of an olmesartan medoxomil-based treatment algorithm for hypertension control.

Hypertension guidelines recommend a stepped-care approach that starts with titration of the initial agent followed by the addition of other agents, as necessary, to achieve goal blood pressure. This study assessed the effectiveness of an antihypertensive treatment algorithm with olmesartan medoxomil as the initial agent. This was a 24-week, open-label trial in patients (N=201) with mean seated diastolic blood pressure of 90-109 mm Hg. Following placebo run-in, all patients received olmesartan medoxomil 20 mg/d for 4 weeks. At subsequent 4-week intervals, the regimen was modified in patients with blood pressure >130/85 mm Hg: up-titration of olmesartan medoxomil to 40 mg/d; addition of hydrochlorothiazide 12.5 mg/d; up-titration of hydrochlorothiazide to 25 mg/d; addition of amlodipine besylate 5 mg/d; and up-titration of amlodipine besylate to 10 mg/d. Patients who achieved blood pressure < or =130/85 mm Hg at any point exited the study with no further follow-up. At Week 24, reductions in blood pressure from baseline were 33.7/18.2 mm Hg. Altogether, 87.7% of patients reached the goal blood pressure of < or =130/85 mm Hg and 93.3% achieved a blood pressure of < or =140/90 mm Hg. Thus, an antihypertensive algorithm with olmesartan medoxomil as the initial agent controlled blood pressure in the majority of patients, but with >60% of patients also requiring the use of a thiazide diuretic or a thiazide and a calcium channel blocker.

Antihypertensive efficacy of olmesartan medoxomil, a new angiotensin II receptor antagonist, as assessed by ambulatory blood pressure measurements.

Olmesartan medoxomil is a new angiotensin II receptor blocker. In this randomized, double-blind, placebo-controlled study, the efficacy and safety of olmesartan medoxomil was assessed in 334 patients with moderate to severe essential hypertension. Patients were randomized to receive placebo; 5, 20, or 80 mg olmesartan medoxomil q.d.; or 2.5, 10, or 40 mg olmesartan medoxomil b.i.d. Ambulatory and cuff blood pressure were measured prior to and after 8 weeks of treatment. Treatment with olmesartan medoxomil resulted in a significant placebo-adjusted reduction of mean 24-hour ambulatory diastolic blood pressure of 9.6 mm Hg, 12.2 mm Hg, and 10.6 mm Hg in the 5-, 20-, and 80-mg q.d. groups, respectively. Corresponding reductions in mean ambulatory systolic blood pressure were 14.5 mm Hg, 16.5 mm Hg, and 15.4 mm Hg. Similar reductions of diastolic and systolic blood pressure were seen with b.i.d. dosing. The diastolic trough-to-peak ratios of the q.d. doses of olmesartan medoxomil ranged from 57%-70%, indicating 24-hour effectiveness. The safety profile of olmesartan medoxomil was similar to that of placebo. Olmesartan medoxomil appears to be a safe and effective once-a-day treatment for hypertension.