Phase 3 Study Finds Ranibizumab Biosimilar Ximluci Equivalent to Lucentis in nAMD

The ranibizumab biosimilar XSB-001 (Ximluci; STADA Arzneimittel AG) demonstrated biosimilarity to the originator (Lucentis) in a phase 3 trial in neovascular age-related macular degeneration (nAMD). According to the authors, the study met its primary endpoint, change from baseline in best-corrected visual acuity (BCVA) at week 8, and there were “no clinically meaningful differences” in safety or immunogenicity.

Targeting pathologic neovascularization with intravitreal injections of vascular endothelial growth factor (VEGF) inhibitors is the standard treatment for nAMD, a leading cause of visual impairment in older adults. Ranibizumab is a monoclonal antibody fragment targeting VEGF originally approved by the FDA in 2005. In November 2022 the biosimilar XSB-001 was approved by the European Medicines Agency.

The trial was conducted across 15 countries including the United States and randomized 582 patients to receive either the biosimilar or reference product every 4 weeks for 52 weeks. Patients were newly diagnosed with active subfoveal choroidal neovascularization (CNV) secondary to nAMD.

Difference in Change From Baseline in BCVA Within Equivalence Margins

The primary efficacy endpoint was the change from baseline in BCVA assessed by early treatment diabetic retinopathy study (ETDRS) letters at week 8. At week 8, the least-squares (LS) mean change in BCVA from baseline was 4.6 (standard error, 0.5) ETDRS letters in the biosimilar group and 6.4 (SE, 0.5) letters in the reference product group. Both 90% and 95% CIs for the difference between treatments were within the predefined equivalence margin of +/- 3.5 letters.

Although the study met its primary efficacy endpoint at week 8, the authors noted, “small between-group differences in mean BCVA in favor of reference ranibizumab were observed over the 52-week study. These between-group differences in BCVA did not increase over time, were all less than 3 ETDRS letters, and were similar to those observed in previous large clinical trials of nAMD.” At week 52, LS mean change in BCVA was 6.4 (SE, 0.8) letters and 7.8 (SE, 0.8) letters in the biosimilar and originator groups. The 90% CI for the difference between treatments was -3.3 to 0.4, and the 95% CI was -3.6 to 0.7.

The vast majority of patients, 95% receiving XSB-001 and 96% receiving the reference product, had a loss of fewer than 15 letters at week 52. The authors also reported similar results between groups for additional secondary efficacy endpoints, such as change from baseline in central foveal thickness, CNV leakage area, CNV size, and amount of subretinal fluid.

“No Clinically Meaningful Differences” in Safety or Immunogenicity

In the XSB-001 and reference ranibizumab groups, 47 and 49 patients discontinued the study. Of those, 5 in the biosimilar group and 10 in the reference product group discontinued due to an adverse event, and 1 in each group was due to lack of efficacy.

The total incidence of treatment-emergent adverse events (TEAEs) was “comparable” between treatment groups, 68% and 71% of patients. Thirty-six percent of patients in each group experienced ocular TEAEs, most of which were mild and not considered to be related to the study treatment. Four patients in each group experienced a serious ocular TEAE, all of which were considered to be related to the study treatment. One patient in the biosimilar group and 2 patients in the reference ranibizumab group discontinued treatment due to ocular TEAEs. Approximately 10% of patients in each group experienced a non-ocular serious TEAE, which led to treatment discontinuation in 2 patients receiving XSB-001 and 5 patients receiving the reference product.

According to the authors, the incidence of anti-drug antibodies (ADAs) was similar between groups. At baseline 4% and 3% of patients in the biosimilar and reference product groups were positive for ADAs, and 11% and 13% were positive at week 52. Neutralizing antibodies were detected in “a minority of ADA-positive patients.” At week 52, 25% of patients receiving the biosimilar who were ADA-positive and 22% of patients receiving the reference product were ADA-positive.

The authors concluded the ranibizumab biosimilar XSB-001 demonstrated biosimilarity to the reference product in patients with nAMD, and treatment with XSB-001 for 52 weeks had “a safety profile similar to the reference product.”

Reference

Loewenstein A, Czumbel N, Ernest J, Dusová J, Pearlman J, Nowosielska A. Randomized trial of biosimilar XSB-001 versus reference ranibizumab in patients with neovascular age-related macular degeneration. Ophthalmol Retina. 2023:S2468-6530(23)00204-X. doi:10.1016/j.oret.2023.05.005