Biosimilar SB15 versus reference aflibercept in neovascular age-related macular degeneration: 1-year and switching results of a phase 3 clinical trial

NCT04450329 | SB15 vs. Reference Aflibercept Trial | Sadda SR et al. (2023)

Sadda SR, Bradvica M, Vajas A, et al. Biosimilar SB15 versus reference aflibercept in neovascular age-related macular degeneration: 1-year and switching results of a phase 3 clinical trial. BMJ Open Ophthalmology, 2023; 8:e001561.

Locations

56 study centres in 10 countries

Study Period

Not reported

Study Design

Phase 3, randomized, double-masked, multicenter, parallel-group, biosimilarity trial

Study Population

Characteristic:

Type of AMD:

2 (Wet AMD)

AMD Stage:

3 (Late)

Total Sample Size:

449 randomized patients

Age:

Phase 3, randomized, double-masked, multicenter, parallel-group, biosimilarity trial

Sex (Male) n%:

Not explicitly reported

Experimental Group

Intervention Therapy:

Intravitreal SB15 (biosimilar aflibercept) 2 mg every 8 weeks after 3 monthly loading doses

Dose & Frequency:

2 mg intravitreal injection every 4 weeks (Weeks 0, 4, 8), followed by every 8 weeks up to Week 56

Age (Years):

73.7 ± 8.05

Number of Patients:

224 randomized and treated

Male N %:

106 (47.3%)

Patients Followed Up:

215

Control Group

Intervention Therapy:

Intravitreal reference aflibercept (Eylea) 2 mg every 8 weeks after 3 monthly loading doses

Dose & Frequency:

2 mg intravitreal injection every 4 weeks (Weeks 0, 4, 8), followed by every 8 weeks up to Week 56

Age (Years):

74.3 ± 8.09

Number of Patients:

225 randomized and treated

Male N %:

132 (58.7)

Patients Followed Up:

210

Follow-up Time: 56 weeks

Outcomes

Durability

Not reported

Vision

Best-Corrected Visual Acuity (BCVA)
The least squares (LS) mean BCVA change at Week 56 (Primary Outcome):
• SB15/SB15: +7.4 (SE 0.93) letters
• AFL/AFL: +7.0 (SE 1.29) letters
• Difference: 0.4 letters (95% CI -2.5 to 3.2).

Vision Maintaining
Proportion of patients gaining ≥15 letters at Week 56:
• SB15/SB15: 26.4%
• AFL/AFL: 17.8%
• Adjusted risk difference: 8.2% (95% CI -1.38 to 17.86)

Proportion of patients losing <15 letters:
• SB15/SB15: 95.8%
• AFL/AFL: 98.0%
• Adjusted risk difference: -2.4% (95% CI -6.18 to 1.40)

Other

Vision-related Quality of Life (QoL)
NEI VFQ-25 composite score
Change in NEI VFQ-25 composite score
from baseline at week 56:
• SB15/SB15: 4.1 (SE 12.27)
• AFL/AFL: 4.1 (SE 12.57)

Immunognicity

Incidence of treatment-induced or treatment-boosted ADAs up to week 32 were low and comparable between treatment groups:
• SB15: 2 of 210 (1.0%)
• AFL, 0 of 209 (0.0%)

After week 32, treatment-induced in 1 of 96 (1.0%) participants in the AFL/ AFL treatment group but in none of the participants in the SB15/SB15 and AFL/SB15 treatment groups.

Pharmokinetics

• Serum concentrations (Ctrough and Cmax) were comparable between SB15 and AFL treatment groups before switching.
• After re-randomisation at week 32, Ctrough measured predose at week 40 and week 56 were below the limit of quantification (BLQ; 5.00 ng/mL) for all treatment groups.

Anatomic

Central Subfield Thickness (CST)
The least squares (LS) mean CST reduction at Week 56:
• SB15/SB15: -119.2 (SE 4.36) µm
• AFL/AFL: -126.6 (SE 6.15) µm
• Difference: 7.4 µm (95% CI -6.11 to 20.96)

Total Retinal Thickness (TRT)
The least squares (LS) mean TRT reduction at Week 56:
• SB15/SB15: -132.4 (SE 7.19) µm
• AFL/AFL: -136.3 (SE 10.1) µm
• Difference: 3.9 µm (95% CI -18.35 to 26.10).

Choroidal Neovascularization (CNV)
The LS mean changes from baseline in CNV area size to Week 56:
• SB15/SB15: −1.26 (SE 0.281) mm2
• AFL/AFL: −1.09 (SE 0.392) mm2
• Difference: −0.17 (95% CI −1.036 to 0.705) mm2

Retinal Fluid
Study participants with subretinal pigment epithelial (RPE) fluid at week 56:
• SB15/SB15: 24.1%
• AFL/AFL: 24.8%
Presence of intraretinal or subretinal fluid at Week 56:
• SB15/SB15: 47.2%
• AFL/AFL: 48.5%
• Adjusted risk difference: - 1.5 (95% CI -13.25 to 10.19)

Safety

Treatment-emergent AEs (TEAEs)
Patients with any TEAE:
• SB15/SB15: 36.5%
• AFL/AFL: 29.8%
Patients with ocular TEAE (study eye):
• SB15/SB15: 9.1%
• AFL/AFL: 2.9%
• Most common: cataract and visual acuity reduced
Patients with non-ocular TEAE:
• SB15/SB15: 25.1%
• AFL/AFL: 23.1%
• Most common: Hypertension

Serious ocular TEAEs
Patients with serious ocular TEAEs in the study eye:
• SB15/SB15: 0.5%
• AFL/AFL: 1.0%
Patients with serious non-ocular TEAEs:
• SB15/SB15: 4.1%
• AFL/AFL: 4.8%

Adverse Event of Special Interest (AESI)
Patients with ocular AESI:
• SB15/SB15: 1.4%
• AFL/AFL: 1.0%
Patients with non-ocular AESI:
• SB15/SB15: 0.9%
• AFL/AFL: 1.9%

Outcomes

Conclusion

The biosimilar SB15 demonstrated comparable efficacy, safety, and immunogenicity to reference aflibercept in nAMD patients up to 56 weeks. Switching from aflibercept to SB15 maintained clinical efficacy and safety.

Risk of Bias Assessment for Primary Outcome

Randomization Process

Low risk

Note: “Participants, investigators and other study personnel remained masked throughout the study period…” although there is no information on randomization.
“Baseline demographics and baseline disease characteristics were comparable between the SB15 and AFL treatment groups”

Missing Outcome Data

Low risk

Note: Evidence of the primary outcome data analysis was not biased by missingness (sensitivity analysis): data analysis using per-protocol set

Selection of the Reported Results

Low risk Note: Registration with protocol

Deviations from Intended Observations

Low risk Note: “Participants, investigators and other study personnel remained masked throughout the study period…” “All analyses of efficacy endpoints were performed on the FAS or mFAS and based on available data.”

Measurement of the Outcome

Some concerns Note: “Participants, investigators and other study personnel remained masked throughout the study period…” As a multiple site study, there may be assessment diversity on BCVA through the different sites.

Overall

Some concerns