Prevalence of Macular Atrophy in the MARINA Study of Ranibizumab versus Sham for Neovascular Age-Related Macular Degeneration.

OBJECTIVE: Determine prevalence, progression rates, and associations of newly detectable macular atrophy (MA) in patients with choroidal neovascularization (CNV) secondary to neovascular age-related macular degeneration (nAMD) with/without ranibizumab treatment. DESIGN: Post hoc analysis of MA in patients with occult/minimally classic nAMD who received monthly intravitreal ranibizumab (0.3 or 0.5 mg) or sham injections for 24 months (M) in MARINA, a phase III trial in treatment-naive patients (NCT00056836). PARTICIPANTS: Seven hundred six patients with nAMD: ranibizumab 0.3 mg, n = 236; 0.5 mg, n = 237; sham, n = 233. METHODS: Macular atrophy, assessed by color fundus photographs/fluorescein angiography, was classified as "within," "adjacent," or "nonadjacent" to the original CNV lesion. Factors associated with MA were assessed by multivariate logistic regression. MAIN OUTCOME MEASURES: Prevalence/incidence of newly detectable MA over time, association with CNV area, MA progression rate, association of MA with visual acuity (VA), changes in CNV/leakage area, and factors predictive of new MA at 24M. RESULTS: At 24M, new MA was detected in 36.8%, 40.4%, and 21.0% of eyes for ranibizumab 0.3 mg, 0.5 mg, and sham, respectively, most frequently within the area of the baseline CNV lesion (93.2%, 85.0%, and 69.0%). Rate of MA progression was similar across arms (∼ 0.3 to 0.4 mm/year). There was strong association between absence of fibrosis and detectable MA (odds ratio, 2.7; 95% confidence interval [CI], 1.29-5.56), whereas an association was not identified between detectable MA and baseline VA, baseline fellow eye atrophy, ranibizumab treatment, or change in leakage/CNV area at 24M. Ranibizumab-treated eyes gained VA with (0.3 mg: 5.3 letters [95% CI, -3.3, 13.8]; 0.5 mg: 9.8 [4.7-15.0]) or without new MA (0.3 mg: 6.4 [4.1-8.6]; 0.5 mg: 8.0 [5.3-10.6]), whereas VA in sham-treated eyes deteriorated with/without new MA (-14.7 [-23.6, -5.8] and -14.0 [-16.9, -11.1], respectively). CONCLUSIONS: New MA was more frequently detected in ranibizumab-treated than sham-treated eyes. Macular atrophy progression was similar across arms. Multivariate analysis showed that absence of fibrosis was the only variable associated with increased MA. Regardless of MA presence/location at baseline or throughout the study, ranibizumab-treated eyes showed clinically significant improvements in VA, whereas VA in sham-treated eyes worsened. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Relationship between retinal fluid characteristics and vision in neovascular age-related macular degeneration: HARBOR post hoc analysis.

PURPOSE: To evaluate the relationship between retinal fluid location, amount/severity, and vision with ranibizumab-treated neovascular age-related macular degeneration (nAMD). METHODS: In the phase 3 HARBOR trial (NCT00891735), treatment-naive patients with nAMD received ranibizumab 0.5 or 2.0 mg through month 24. This post hoc analysis included eyes with subretinal fluid (SRF) and/or intraretinal fluid (IRF) at screening, baseline, or week 1, and optical coherence tomography data at months 12 and 24 (n = 917). Outcomes were best-corrected visual acuity (BCVA) change from baseline and proportion of eyes with 20/40 or better vision at months 12 and 24. Eyes were stratified by the location, amount, and/or severity of fluid. RESULTS: At baseline, 86% and 63% of eyes had SRF and IRF, respectively. Among eyes with residual SRF, mean BCVA gains at each time point were greater in eyes with central versus noncentral SRF; location did not affect the odds of having 20/40 or better vision over 24 months. Eyes with 20/40 or better BCVA at month 12 had significantly lower SRF thickness versus eyes with worse vision; however, no difference was apparent at month 24. Vision was comparatively worse in eyes with residual IRF at months 12 and 24; location and severity did not appear to affect this outcome. CONCLUSION: Residual IRF was associated with worse vision outcomes, regardless of location/severity, whereas, despite continued treatment, residual SRF was not associated with worse vision outcome at 24 months, regardless of location/thickness. These data suggest complex relationships between residual fluid, severity, and vision.

Effect of Residual Retinal Fluid on Visual Function in Ranibizumab-Treated Neovascular Age-Related Macular Degeneration.

PURPOSE: To investigate the relationship between retinal fluid and vision in ranibizumab-treated patients with neovascular age-related macular degeneration (nAMD). DESIGN: Clinical cohort study using post hoc analysis of clinical trial data. METHODS: We assessed data from HARBOR (NCT00891735), a phase III, randomized, controlled trial. We reviewed 917 patients ≥50 years of age with subfoveal nAMD associated with subretinal (SRF) and/or intraretinal fluid (IRF) at baseline, screening, or week 1. The intervention was intravitreal ranibizumab 0.5 or 2.0 mg (all treatment arms pooled). Outcomes included mean best-corrected visual acuity (BCVA) and BCVA change from baseline at months (M) 12 and 24 evaluated by the presence/absence of SRF and/or IRF. RESULTS: Baseline BCVA was higher with residual vs resolved SRF at M12 (mean [95% confidence interval {CI}] 58.8 letters [57.2-60.4] vs 53.5 [52.4-54.5]) and M24 (59.3 letters [57.8-60.8] vs 53.5 [52.5-54.5]). Mean BCVA change (adjusted for baseline) to M12 was greater with residual vs resolved SRF (mean difference [95% CI], +2.4 letters [+0.1 to +4.7]), but lower with residual vs resolved IRF (-3.5 letters [-5.8 to -1.2]). Eyes with residual SRF (no IRF) exhibited the largest mean BCVA gains (M12, +14.1 letters; M24, +13.2 letters), followed by resolved SRF/IRF (M12, +10.6 letters; M24, +10.0 letters), residual SRF/IRF (M12, +7.2 letters; M24, +8.5 letters), and residual IRF only (M12, +5.5 letters; M24, +3.6 letters). CONCLUSIONS: Vision outcomes (adjusted for baseline BCVA) through M24 were better in ranibizumab-treated eyes with residual vs resolved SRF, and worse with residual vs resolved IRF. Presence of residual retinal fluid requires a more complex and nuanced assessment and interpretation in the context of nAMD management.

First-in-human, phase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of RO5126766, a first-in-class dual MEK/RAF inhibitor in patients with solid tumors.

PURPOSE: This phase I study assessed the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, pharmacokinetics, pharmacodynamics, and clinical activity of the first-in-class dual MEK/RAF inhibitor, RO5126766. EXPERIMENTAL DESIGN: Initial dose-escalation was conducted using once daily dosing over 28 consecutive days in 4-week cycles. Further escalation was completed using 2 intermittent dosing schedules [7 days on treatment followed by 7 days off (7on/7off); 4 days on treatment followed by 3 days off (4on/3off)]. RESULTS: Fifty-two patients received RO5126766 at doses of 0.1 to 2.7 mg once daily, 2.7 to 4.0 mg (4 on/3 off), or 2.7 to 5.0 mg (7 on/7 off). The most common DLTs were elevated creatine phosphokinase (CPK) and blurred vision. The MTD for each dosing schedule was 2.25 mg once daily, 4.0 mg (4 on/3 off), and 2.7 mg (7 on/7 off). The dose/schedule recommended for phase II (RP2D) investigation was 2.7 mg (4 on/3 off). Frequent adverse events included rash-related disorders (94.2%), elevated CPK (55.8%), and diarrhea (51.9%). C(max) occurred 1 to 2 hours after dosing and mean terminal half-life was approximately 60 hours. Pharmacodynamic changes included reduced ERK phosphorylation, an increase in apoptosis in tumor tissue, and a reduction in fluorodeoxyglucose (FDG) uptake after 15 days of dosing. Three partial responses were seen: two in BRAF-mutant melanoma tumors and one in an NRAS-mutant melanoma. CONCLUSION: This first-in-human study shows that oral RO5126766 has manageable toxicity, a favorable pharmacokinetic/pharmacodynamic profile, and encouraging preliminary antitumor activity in this population of heavily pretreated patients, achieving tumor shrinkage in around 40% of patients across all dose levels and all tumor types.

Phase I dose-escalation study of the safety, pharmacokinetics, and pharmacodynamics of the MEK inhibitor RO4987655 (CH4987655) in patients with advanced solid tumors.

PURPOSE: This phase I study of the mitogen-activated protein/extracellular signal-regulated kinase inhibitor RO4987655 (CH4987655) assessed its maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, pharmacokinetic/pharmacodynamic profile, and antitumor activity in patients with advanced solid tumors. PATIENTS AND METHODS: An initial dose escalation was conducted using a once-daily dosing schedule, with oral RO4987655 administered at doses of 1.0 to 2.5 mg once daily over 28 consecutive days in 4-week cycles. Doses were then escalated from 3.0 to 21.0 mg [total daily dose (TDD)] using a twice-daily dosing schedule. RESULTS: Forty-nine patients were enrolled. DLTs were blurred vision (n = 1) and elevated creatine phosphokinase (n = 3). The MTD was 8.5 mg twice daily (TDD, 17.0 mg). Rash-related toxicity (91.8%) and gastrointestinal disorders (69.4%) were the most frequent adverse events. The pharmacokinetic profile of RO4987655 showed dose linearity and a half-life of approximately 4 hours. At the MTD, target inhibition, assessed by suppression of extracellular signal-regulated kinase phosphorylation in peripheral blood mononuclear cells, was high (mean 75%) and sustained (90% of time >IC(50)). Of the patients evaluable for response, clinical benefit was seen in 21.1%, including two partial responses (one confirmed and one unconfirmed). 79.4% of patients showed a reduction in fluorodeoxyglucose uptake by positron emission tomography between baseline and day 15. CONCLUSION: In this population of heavily pretreated patients, oral RO4987655 showed manageable toxicity, a favorable pharmacokinetics/pharmacodynamics profile, and promising preliminary antitumor activity, which has been further investigated in specific populations of patients with RAS and/or RAF mutation driven tumors.

The safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of RO5068760, an MEK inhibitor, in healthy volunteers: assessment of target suppression.

RO5068760, a substituted hydantoin, represents a new class of potent, highly selective, non-adenosine triphosphate (ATP)-competitive MEK1/2 inhibitors. The study aimed to determine the safety/tolerability, pharmacokinetics, and pharmacodynamics of single ascending doses of RO5068760 in human healthy volunteers. All participants received a single dose followed by 48 hours of pharmacokinetics, pharmacodynamics, and safety/tolerability assessments. The pharmacodynamics were measured by changes in ERK phosphorylation (pERK) in peripheral blood mononuclear cells, ex vivo stimulated by phorbol 12-myristate 13-acetate (PMA). Forty-eight participants received 6 doses (50, 100, 200, 400, 600, 800 mg). RO5068760 was well tolerated up to 800 mg. There were no clinically significant safety findings, including laboratory, electrocardiogram, ophthalmological assessment, and fecal occult blood tests. Of the total 13 adverse events (n = 12), 11 were mild, 2 were moderate, and none were severe, and only 5 were considered by the investigator as possibly related to treatment. RO5068760 was absorbed with a t(max), of 2 hours. Disposition appeared to be biphasic with a terminal elimination t(1/2) of 5 to 9 hours. The variability was moderate to high, ranging from 38% to 62% for C(max) and 41% to 69% AUC. Within the dose range tested, pERK inhibition was relatively modest with a mean maximal pERK suppression of 55%.