Efficacy and Safety of Biosimilar FYB201 Compared With Ranibizumab in Neovascular Age-Related Macular Degeneration

Recently the FDA approved the first interchangeable biosimilar for use in ophthalmology, ranibizumab-eqrn. Biosimilars are biologic drugs that are highly similar in their physical, chemical, and biological properties to the FDA-approved reference drug. The approval process requirements include analytical studies to demonstrate that the biosimilar product is highly similar to the reference drug, animal studies to assess toxicity, and a clinical study to demonstrate the safety, purity, and potency of the biosimilar product compared to the reference product. The clinical trial only needs to be for one indication for which the reference product is licensed to obtain FDA approval for all prior indications of the reference drug. To obtain an “interchangeable” designation there must be no additional risk or reduced efficacy when the patient is switched back and forth between the biosimilar and reference drug. Biosimilars with an interchangeable designation may be substituted without the approval of the physician who prescribed the reference product, very similar to how generic drugs are substituted for brand-name drugs.

This study was a prospective, multicentered, evaluation-masked, parallel-group, 48-week, phase 3 randomized clinical trial that included a single eye of 477 patients with treatment-naïve, subfoveal choroidal neovascularization secondary to age-related macular degeneration randomized to reference ranibizumab or ranibizumab-egrn every 4 weeks. The primary endpoint was change in best corrected visual acuity (BCVA) by Early Treatment Diabetic Retinopathy Study letters from baseline to 8 weeks, immediately prior to the third scheduled injection. 

Efficacy

At week 8, there was a mean change of +5.1 EDTRS letters in the ranibizumab-eqrn group and +5.6 EDTRS letters in the reference ranibizumab group. The ANCOVA least squares mean difference in EDTRS letters at 8 weeks was -0.4 (90% CI of -1.6 to 0.9) ETDRS letters, within the predefined equivalence margin of -3.5 to 3.5 ETDRS letters. At week 24, there was a mean change from baseline of +6.9 (ranibizumab-eqrn) and +7.1 (reference ranibizumab) ETDRS letters. The ANCOVA least squares mean difference in EDTRS letters at 24 weeks was -0.0 (90% CI of -1.6 to 1.5) ETDRS letters. At week 48, there was a mean change from baseline of +7.8 (ranibizumab-eqrn) and +8.0 (reference ranibizumab) ETDRS letters. The ANCOVA least squares mean difference in ETDRS letters at 48 weeks was -0.1 (90% CI of -1.8 to 1.7) ETDRS letters. Secondary outcomes including the foveal central subfield thickness as assessed by SD-OCT showed similar outcomes between the groups with a mean reduction from baseline of 180.4 mm (ranibizumab-eqrn) and 181.6 mm (reference ranibizumab) at 24 weeks and 182.9 mm (ranibizumab-eqrn) and 190.9 mm (reference ranibizumab) at 48 weeks. The ANCOVA least squares mean difference in foveal central subfield was -5.91 mm (90% CI of -22.62 to 10.80 mm) at 24 weeks and 3.68 mm (90% CI of -13.28 to 20.63 mm) at 48 weeks.

Safety

The frequency and severity of adverse events were similar between ranibizumab-eqrn and reference ranibizumab. The most frequent adverse events were cataract (0.0% and 2.1%), retinal pigmented epithelium tear (0.4% and 1.3%), reduced visual acuity (0.0% and 1.3%), punctate keratitis (0.0% and 0.8%), vitreous hemorrhage (0.4% and 0.4%), eye pain (0.8% and 0.0%), and increased intraocular pressure (1.3% and 0.8%) for the biosimilar and reference drug, respectively. Iridocyclitis developed in 1 patient (0.8%) in the ranibizumab-eqrn arm. Systemic adverse events were also similar between the two groups.

Immunogenicity and Pharmacokinetics

Anti-drug antibodies were detected in 14 patients (5.9%) in each arm over the study period. The patient that developed iridocyclitis was negative for anti-drug antibodies. Systemic concentrations of ranibizumab-eqrn and reference drug were similar after the first and sixth injections.

The first FDA-approved interchangeable biosimilar anti-VEGF is equivalent in efficacy and safety compared to the reference drug in this clinical trial. There have been some concerns raised within the retina community regarding switching stable, well-controlled patients to a different medication. Some insurances have already mandated biosimilar ranibizumab-eqrn use prior to the reference drug use.