Efficacy, Safety, and Immunogenicity of Sun’s Ranibizumab Biosimilar in Neovascular Age-Related Macular Degeneration: A Phase 3, Double-Blind Comparative Study

CTRI/2020/09/027629 | Not reported | Ghosh AK et al. (2024)

Ghosh, A. K., Nikumbh, U. S., Shukla, C. K., Laul, R. S., Dixit, A., Mahapatra, S. K., Nayak, S., Shah, U. M., Parwal, S., Venkatapathy, N., Radhakrishnan, N., Kelgaonkar, A., Saxena, S., Mishra, D., Dave, V. P., Khan, P., Saswade, M. R., Shantilal, M. S., Ramasamy, K., Sreekanta, S., Rajurkar, M., Doshi, M., Behera, S., Patel, P., Dhawan, S., Lakhwani, L. Efficacy, Safety, and Immunogenicity of Sun’s Ranibizumab Biosimilar in Neovascular Age-Related Macular Degeneration: A Phase 3, Double-Blind Comparative Study. Ophthalmology Therapeutics, 2024; 13:1369–1382.

Locations

19 centers across India

Study Period

October 2020 – October 2021

Study Design

Phase 3, randomized, double-blind, parallel-arm, multicenter comparative study

Study Population

Characteristic:

Type of AMD:

2 (Wet AMD)

AMD Stage:

3 (Late)

Total Sample Size:

161 randomized (Sun’s Ranibizumab: 107, Reference Ranibizumab: 54)

Age:

Phase 3, randomized, double-blind, parallel-arm, multicenter comparative study

Sex (Male) n%:

96 (59.6%)

Experimental Group

Intervention Therapy:

Sun’s Ranibizumab 0.5 mg

Dose & Frequency:

0.5 mg intravitreal injection every 4 weeks for 16 weeks (4 total doses)

Age (Years):

65.5 ± 9.8

Number of Patients:

107

Male N %:

62 (57.9%)

Patients Followed Up:

100

Control Group

Intervention Therapy:

Reference Ranibizumab (Accentrix) 0.5 mg

Dose & Frequency:

0.5 mg intravitreal injection every 4 weeks for 16 weeks (4 total doses)

Age (Years):

67.9 ± 9.3

Number of Patients:

Male N %:

34 (63.0%)

Patients Followed Up:

Follow-up Time: 16 weeks

Outcomes

Durability

Not reported

Vision

Proportion Losing <15 Letters BCVA
From baseline to week 16 (Primary Outcome):
• Sun’s Ranibizumab: 99%
• Reference Ranibizumab: 100%
• Difference = -1.0% (95% CI: -2.51 to 0.61, p > 0.9999).
Proportion Gaining ≥15 Letters BCVA
From baseline to week 16:
• Sun’s Ranibizumab: 43%
• Reference Ranibizumab: 37%
• Difference = 6% (p = 0.4267).
Mean Change in BCVA (ETDRS Letters)
From baseline to week 16:
• Sun’s Ranibizumab: +15.7 ± 10.5
• Reference Ranibizumab: +14.6 ± 8.8
• Difference = +1.1 letters (p = 0.5275).

Other

N/A

Immunognicity

One patient in the reference ranibizumab group tested positive for anti-ranibizumab antibodies, with no neutralizing antibodies detected.

Pharmokinetics

Not reported

Anatomic

Change in Central Macular Thickness (CMT)
From baseline to week 16:
• Sun’s Ranibizumab: -100.9 ± 143.1 µm
• Reference Ranibizumab: -107.3 ± 141.6 µm
• Difference = +6.4 µm (p = 0.7946).

Safety

Treatment-emergent AEs (TEAEs)
• Sun’s Ranibizumab: 6/107, 5.6%
• Reference Ranibizumab: 5/54, 9.3%
Ocular-related AEs
• Sun’s Ranibizumab: 0
• Reference Ranibizumab: 2/54, 3.7%.
Non-ocular AEs Gastrointestinal disorders:
• Sun’s Ranibizumab: 1/107, 0.9%
• Reference Ranibizumab: 3/54, 5.6%
Infections and infestations:
• Sun’s Ranibizumab: 3/107, 2.8%
• Reference Ranibizumab: 3/54, 5.6%
Metabolism and nutrition disorders:
• Sun’s Ranibizumab: 1/107, 0.9%
• Reference Ranibizumab:1/54, 1.9%
Hypertension:
• Sun’s Ranibizumab: 2/107, 1.9%
• Reference Ranibizumab: 0

Serious Adverse Events (SAEs)
Three SAEs in the Reference Ranibizumab group (dyspepsia, urinary tract infection, hyponatremia), none related to the drug.

Outcomes

Conclusion

Sun’s Ranibizumab demonstrated therapeutic equivalence to reference ranibizumab in patients with nAMD, with similar efficacy, safety, and immunogenicity profiles over 16 weeks.

Risk of Bias Assessment for Primary Outcome

Randomization Process

Low risk

Note: “The randomisation schedule was generated centre-wise by the sponsor using statistical analysis system (SAS) version 9.4 software before the start of the study.” “Baseline demographic and disease characteristics were similar between the two groups…”

Missing Outcome Data

Some concerns

Note: There is no evidence that the result was not biased by missing outcome data. However, the missingness is unlikely depend on the true value.

Selection of the Reported Results

Low risk Note: Registration with the protocol.

Deviations from Intended Observations

High risk Note: “Patients, investigators and the sponsor’s study team were blinded throughout the study regarding the assigned treatment.” However, no ITT or mITT was announced in the paper for the data analysis. The excluded patients (6.1%) may have potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomized.

Measurement of the Outcome

Some concerns Note: This is a double-masked study. However, this is a multiple-site study. There is no information on if the primary outcome assessment is consistent across all sites. However, assessment of the outcome could not have been influenced by knowledge of intervention received.

Overall

High risk