Steven Francom

A Phase IIIb Study to Evaluate the Safety of Ranibizumab in Subjects with Neovascular Age-related Macular Degeneration

OBJECTIVE To evaluate the safety and efficacy of intravitreal ranibizumab in a large population of subjects with neovascular age-related macular degeneration (AMD). DESIGN Twelve-month randomized (cohort 1) or open-label (cohort 2) multicenter clinical trial. PARTICIPANTS A total of 4300 subjects with angiographically determined subfoveal choroidal neovascularization (CNV) secondary to AMD. METHODS Cohort 1 subjects were randomized 1:1 to receive 0.3 mg (n = 1169) or 0.5 mg (n = 1209) intravitreal ranibizumab for 3 monthly loading doses. Dose groups were stratified by AMD treatment history (treatment-naïve vs. previously treated). Cohort 1 subjects were retreated on the basis of optical coherence tomography (OCT) or visual acuity (VA) criteria. Cohort 2 subjects (n = 1922) received an initial intravitreal dose of 0.5 mg ranibizumab and were retreated at physician discretion. Safety was evaluated at all visits. MAIN OUTCOME MEASURES Safety outcomes included the incidence of ocular and nonocular adverse events (AEs) and serious adverse events (SAEs). Efficacy outcomes included changes in best-corrected VA over time. RESULTS Some 81.7% of cohort 1 subjects and 49.9% of cohort 2 subjects completed the 12-month study. The average total number of ranibizumab injections was 4.9 for cohort 1 and 3.6 for cohort 2. The incidence of vascular and nonvascular deaths during the 12-month study was 0.9% and 0.7% in the cohort 1 0.3 mg group, 0.8% and 1.5% in the cohort 1 0.5 mg group, and 0.7% and 0.9% in cohort 2, respectively. The incidence of death due to unknown cause was 0.1% in both cohort 1 dose groups and cohort 2. The number of vascular deaths and deaths due to unknown cause did not differ across cohorts or dose groups. Stroke rates were 0.7%, 1.2%, and 0.6% in the 0.3 mg and 0.5 mg groups and cohort 2, respectively. At month 12, cohort 1 treatment-naïve subjects had gained an average of 0.5 (0.3 mg) and 2.3 (0.5 mg) VA letters and previously treated subjects had gained 1.7 (0.3 mg) and 2.3 (0.5 mg) VA letters. CONCLUSIONS Intravitreal ranibizumab was safe and well tolerated in a large population of subjects with neovascular AMD. Ranibizumab had a beneficial effect on VA. Future investigations will seek to establish optimal dosing regimens for persons with neovascular AMD. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Safety and efficacy of ocrelizumab in combination with methotrexate in MTX-naive subjects with rheumatoid arthritis: the phase III FILM trial

Objective To determine the efficacy and safety of ocrelizumab (OCR) with methotrexate (MTX) in MTX-naive rheumatoid arthritis (RA) patients. Methods In a randomised, double-blind, controlled trial, patients received placebo+MTX (MTX; n=210), OCR 200 mg×2+MTX (OCR 200; n=200) or OCR 500 mg×2+MTX (OCR 500; n=203). OCR/placebo (two intravenous infusions) was given on days 1 and 15, with fixed re-treatment scheduled at weeks 24/26, 52/54 and 76/78. Due to early termination of OCR dosing, there was no formal primary end point analysis (change from baseline in modified total Sharp score (ΔmTSS) at week 104). Analyses are reported for week 52 outcomes. Results At week 52, treatment with OCR+MTX compared with MTX alone reduced progression of joint damage (mean (SD) change in ΔmTSS: OCR 200, 0.66 (4.51); OCR 500, 0.27 (2.91); MTX alone, 1.59 (4.82); p=0.001 and p=0.003, respectively vs MTX alone) and improved clinical signs and symptoms (American College of Rheumatology 20 response: OCR 200, 73.0%; OCR 500, 71.0%; MTX alone, 57.5%; p<0.005 for each OCR vs MTX alone). Serious infection rates per 100 patient-years were similar with OCR 200 and MTX alone (2.6 (95% CI 0.9 to 6.1) and 3.0 (1.1 to 6.5), respectively), but higher with OCR 500 (7.1 (3.9 to 11.9)). Conclusions OCR 200 mg and 500 mg with MTX in MTX-naive patients with RA were effective in inhibiting joint damage progression and improving RA signs and symptoms. OCR 500 mg with MTX was associated with an increased rate of serious infections.

Vascular Safety of Ranibizumab in Patients With Diabetic Macular Edema: A Pooled Analysis of Patient-Level Data From Randomized Clinical Trials

Importance Patients with diabetic macular edema (DME) are at high risk of vascular complications, including stroke and myocardial infarction (MI). Concerns have been raised that intravitreal dosing of vascular endothelial growth factor inhibitors in DME could be associated with an increase in cardiovascular and cerebrovascular adverse events. Objective To evaluate the cardiovascular and cerebrovascular safety of ranibizumab, 0.5 mg and 0.3 mg, compared with sham with and without laser in DME. Data Sources Patient-level data from 6 randomized, double-masked, sham- and laser-controlled clinical trials. Study Selection Company-sponsored (Genentech or Novartis) studies in DME completed as of December 31, 2013. Data Extraction and Synthesis Pairwise comparisons (ranibizumab, 0.5 mg, vs sham and laser; ranibizumab, 0.3 mg, vs sham) were performed using Cox proportional hazard regression (hazard ratios, 95% CIs) and rates per 100 person-years. Data analysis was conducted from June 1 to July 15, 2015. Main Outcomes and Measures Standardized Medical Dictionary for Regulatory Activities queries and extended searches were prospectively defined to identify relevant safety end points, including arterial thromboembolic events, MI, stroke or transient ischemic attack, vascular deaths, and major vascular events as defined by the Antiplatelet Trialists’ Collaboration (APTC). Results Overall, 936 patients were treated with ranibizumab, 0.5 mg; 250 patients with ranibizumab, 0.3 mg; and 581 patients with sham/laser. The hazard ratios associated with all pairwise comparisons included 1 for all key cardiovascular and cerebrovascular safety end points. For ranibizumab, 0.5 mg, vs sham/laser and ranibizumab, 0.3 mg, vs sham, the hazard ratios were, respectively, arterial thromboembolic events, 1.05 (95% CI, 0.66-1.68) and 0.78 (95% CI, 0.43-1.40); MI, 0.84 (95% CI, 0.41-1.72) and 0.94 (95% CI, 0.43-2.06); stroke or transient ischemic attack, 0.94 (95% CI, 0.44-1.99) and 0.53 (95% CI, 0.19-1.42); stroke (excluding transient ischemic attack), 1.63 (95% CI, 0.65-4.07) and 0.59 (95% CI, 0.14-2.46); vascular death, 2.17 (95% CI, 0.57-8.29) and 2.51 (95% CI, 0.49-12.94); and APTC-defined events, 1.09 (95% CI, 0.63-1.88) and 1.00 (95% CI, 0.51-1.96). Conclusions and Relevance This pooled analysis includes 1 of the largest patient-level data sets on treatment of DME with ranibizumab. Although still underpowered to detect small differences for infrequent events, such as stroke, the findings suggest that intravitreous ranibizumab does not increase the risk of systemic vascular events. However, uncertainty remains for patients with DME who are at high risk for vascular disease and were not included in these trials.

FRI0223 Long-term targeted safety event rates in ra patients following initiation of rituximab: interim analysis from sunstone registry

Background Rituximab (RTX) is used for the treatment of rheumatoid arthritis (RA) in patients (pts) with an inadequate response to anti-TNF therapy. Long-term safety data on real world RTX use in RA are limited. Objectives To describe the frequency of targeted safety events in an observational cohort of RA pts initiating RTX in the US. Methods SUNSTONE is a prospective observational cohort study designed to evaluate the safety of RTX in RA pts in the real-world setting. Pts are evaluated and treated according to their physician’s standard practice and followed at standard of care visits every 6 mo. All pts were required to receive ≥1 RTX course but could subsequently receive other RA therapies including biologic DMARDs. Pts are assessed at baseline and at follow-up visits every ≤6 mo. Data collection focuses on targeted adverse events (AEs) (significant infections [infections that meet serious AE criteria or require IV antibiotics], cardiovascular thrombotic events, seizures, deaths), and pregnancies. Pts are followed for 5 y (regardless of time of RTX discontinuation) or until death, withdrawal of consent or loss to follow-up. Interim analysis results (Oct 5, 2012) are presented (study completion expected 2014). Baseline demographic and disease characteristics, and safety events captured during follow-up are summarized. For calculating incidence rates, only the 1st event is counted and follow-up is censored at 1st event, as in similar studies [1-3]. Rates per 100 pt-yrs (PY) are reported. The follow-up period includes the entire study period, even after RTX discontinuation or start of another therapeutic agent. Results Overall, 994 pts (3608 PY) received RTX (82% female; median age 58 y; median disease duration 9 y; 72% RF+). Mean follow-up was 3.6 y; mean number of RTX courses was 3.9; 72% received ≥2 courses. Significant infections were reported in 184 pts, with a corresponding incidence rate of 5.7 (95% CI: 4.9–6.6) per 100 PY. Respiratory, skin/soft tissue and abdominal/gastrointestinal infections were the most common infections observed. No cases of progressive multifocal leukoencephalopathy or tuberculosis were reported. Overall, 60 deaths were reported (1.7/100 PY; 95% CI 1.3–2.1). Cardiovascular disease, malignancy and infection were the most common causes of death. Incidence rates per 100 PY (95% CI) of other safety events were: myocardial infarction 0.6 (0.4–0.9), cerebrovascular accident 0.5 (0.3–0.8), pulmonary embolism 0.3 (0.1–0.5), deep vein thrombosis 0.4 (0.2–0.6) and seizures 0.1 (0.1–0.3). Seven pregnancies were reported. Conclusions This interim analysis gives a preliminary summary of the frequency of targeted safety events from the SUNSTONE registry of RA patients who had an inadequate response to anti-TNF therapy and initiated RTX treatment. Although impossible to control all methodologic differences between SUNSTONE and other observational studies examining the incidence rates for the events of interest in RA pts, these data appear consistent with rates reported from other studies [1-4]. References Curtis et al. Ann Rheum Dis 2011;70:1401; Nguyen-Khoa et al. Semin Arthritis Rheum 2012;42:119; Dixon et al. Arthritis Rheum 2007;56:2905; Dixon et al. Arthritis Rheum 2007;56:2896 Disclosure of Interest: D. Furst Grant/research support from: Abbott, Actelion, Amgen, BMS, Gilead, GSK, NIH, Novartis, Pfizer, Roche/Genentech, UCB, Consultant for: Abbott, Actelion, Amgen, BMS, BiogenIdec, Centocor, CORRONA, Gilead, GSK, NIH, Novartis, Pfizer, Roche/Genentech, UCB, Speakers bureau: Abbott, Actelion, UCB (CME ONLY), K. Winthrop Grant/research support from: Pfizer, Consultant for: Genentech Inc., Pfizer, UCB, K. Alexander Shareholder of: Roche, Employee of: Genentech Inc., A. Vashishtha Employee of: Genentech Inc., S. Francom Employee of: Genentech Inc., K. Saag Grant/research support from: ACR; Ardea; Savient; Takeda; Regeneron, Consultant for: Ardea; Rengeneron; Takeda; Savient