Maximum Tolerated Dose of a Humanized Anti–Vascular Endothelial Growth Factor Antibody Fragment for Treating Neovascular Age-Related Macular Degeneration

Presented in part at: Association for Research in Vision and Ophthalmology annual meeting, May, 2001; Fort Lauderdale, Florida; Vitreous Society annual meeting, November, 2001; Fajardo, Puerto Rico; and the 4th International Symposium on Ocular Pharmacology and Pharmaceutics, March, 2002; Seville, Spain.

Received 1 July 2004; accepted 10 January 2005. published online 09 May 2005.

Purpose

To investigate the maximum tolerated dose of ranibizumab administered as a single intravitreal injection.

Design

Open-label, 5-center, uncontrolled, prospective, dose-ranging, interventional case series.

Participants

Twenty-seven patients with subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) with best-corrected Snellen equivalent visual acuity (VA) of 20/100 or worse and considered ineligible for laser photocoagulation or photodynamic therapy.

Methods

A single intravitreal injection of ranibizumab was to be administered at 1 of 6 escalating doses (50, 150, 300, 500, 1000, and 2000 μg), with escalation to the next dose level occurring only after the safety and tolerability of the lower dose level was established through postinjection day 14. Follow-up examinations were performed on postinjection days 1, 3, 7, 14, 42, and 90. Enrollment was stopped if ≥2 patients experienced dose-limiting toxicity.

Main Outcome Measures

The primary safety measures were changes from baseline in VA, intraocular pressure (IOP), intraocular inflammation, and production of antiranibizumab antibody. Dose-limiting toxicity was defined by intraocular inflammation, elevated IOP, reduced VA, or hemorrhage within 90 days after injection.

Results

All patients completed this single intravitreal injection study, and 500 μg of ranibizumab was the maximum tolerated dose. At the higher dose of 1000 μg, significant intraocular inflammation was noted. All adverse events were self-limited, and no infectious endophthalmitis occurred. Aqueous or vitreous ocular inflammation occurred in 12 subjects, with complete resolution within 42 days. In 9 of the subjects, the inflammation was graded as trace to 1+ and required no treatment; in 3 of the subjects, the inflammation was graded as 2+ or 3+, and 2 of the 3 were treated with topical 1% prednisolone acetate. No serum antiranibizumab antibodies were detected. All patients had VA similar or improved compared with baseline values.

Conclusion

The maximum tolerated single dose of ranibizumab in neovascular AMD patients was 500 μg. Single intravitreal injections of ranibizumab up to a dose of 500 μg were safe and well tolerated in this small group of patients.

1 Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami, Miami, Florida

2 Department of Ophthalmology, Jules Stein Eye Institute, UCLA, Los Angeles, California

3 Department of Ophthalmology, Stanford University School of Medicine, Stanford, California

4 Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts

5 Wilmer Ophthalmological Institute, Johns Hopkins University, Baltimore, Maryland

6 Genentech, Inc., South San Francisco, California

Correspondence to Philip J. Rosenfeld, MD, PhD, Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami School of Medicine, 900 NW 17th Street, Miami, FL 33136.

Manuscript no. 240525.

The phase I Ranibizumab Study Group℉s principal investigators and clinical sites are Drs Rosenfeld, Schwartz, Blumenkranz, Miller, and Haller and their respective affiliations.

This study was supported financially by Genentech, Inc., South San Francisco, California.

Drs Rosenfeld, Schwartz, Blumenkranz, Miller, and Haller have received clinical research grants from Genentech, Inc. to perform this study; have indicated support for scientific presentations at meetings and reimbursement for travel expenses from Genentech or competing companies; and have participated in scientific advisory boards to and received honoraria and reimbursement for travel expenses from Genentech, Inc. or competing companies. Drs Reimann, Greene, and Shams are current or former employees of Genentech, Inc. Full financial disclosures have been submitted to the Ophthalmology editorial office.

PII: S0161-6420(05)00287-3

doi:10.1016/j.ophtha.2005.01.043

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