Best-corrected visual acuity gain and central subfield thickness reduction observed at the end of the core study were maintained to Week 24 of the extension study. There was no indication of difference in the safety profile of the brolucizumab 6 mg drug product intended for commercialization and the brolucizumab 3 mg or 6 mg drug product used in the Phase III clinical trials.
Brolucizumab is a ∼26 kDa humanized single-chain Fv antibody fragment inhibitor of VEGF-A, with a concentration of 120 mg/ml. In the Phase III HAWK (NCT02307682) and HARRIER (NCT02434328) trials, brolucizumab 6 mg was non-inferior to aflibercept in terms of visual outcome at Week 48 and >50% of brolucizumab 6 mg-treated eyes were maintained on a q12w dosing interval through Week 48. Anatomic outcomes also favored brolucizumab over aflibercept.
Brolucizumab is a ∼26 kDa humanized single-chain Fv antibody fragment inhibitor of VEGF-A, with a concentration of 120 mg/ml. In the Phase III HAWK (NCT02307682) and HARRIER (NCT02434328) trials, brolucizumab 6 mg was non-inferior to aflibercept in terms of visual outcome at Week 48 and >50% of brolucizumab 6 mg-treated eyes were maintained on a q12w dosing interval through Week 48. Anatomic outcomes also favored brolucizumab over aflibercept.
Drug substance and drug product manufacturing changes have been implemented for brolucizumab in order to scale-up the manufacturing process and to modify the brolucizumab formulation intended for commercialization, respectively. The FDA recommended to include into the Biologic License Application clinical data of at least 50 subjects (who were previously treated with brolucizumab in the HAWK and/or HARRIER studies) treated for an additional 6 months with the brolucizumab product intended for commercialization to support comparability. To address this recommendation, the objective of the current HAWK extension study was to collect additional data on safety and efficacy of the brolucizumab 6 mg commercialized drug product in patients with nAMD previously treated in the HAWK study, to support comparability to the brolucizumab 6 mg drug product used in Phase III clinical studies.
The HAWK extension study was a 24-week, double-masked, multicenter study of patients with neovascular age-related macular degeneration who completed the 96-week HAWK core study. Patients who completed the 96-week HAWK core study, regardless of treatment group (brolucizumab 3 mg, brolucizumab 6 mg or aflibercept 2 mg) and dosing regimen (q12w/q8w), were eligible for inclusion in the extension study provided Visit 26/Week 96 in the core study was ≤12 weeks from the baseline visit in the extension study.
The HAWK extension study was a 24-week, double-masked, multicenter study of patients with neovascular age-related macular degeneration who completed the 96-week HAWK core study. Patients who completed the 96-week HAWK core study, regardless of treatment group (brolucizumab 3 mg, brolucizumab 6 mg or aflibercept 2 mg) and dosing regimen (q12w/q8w), were eligible for inclusion in the extension study provided Visit 26/Week 96 in the core study was ≤12 weeks from the baseline visit in the extension study.
Patients were excluded if they received a standard of care treatment regimen for nAMD, or received treatment with any of the following, after completion of the core study: investigational treatment for nAMD in the study eye; intraocular/periocular injections of steroids in the study eye; or systemic anti-VEGF therapy. Patients were also excluded if they experienced stroke or myocardial infarction within 3 months of the baseline visit of the extension study. The study eye was the same eye that received either brolucizumab or aflibercept treatment in the core study.
The brolucizumab 6 mg drug product intended for commercialization was used in this study. Changes to the excipients within the drug product were made i.e. increase in pH from ∼6.8 to ∼7.2 and decrease in polysorbate concentration from 0.05% to 0.02%. Although the drug substance remains unchanged, an optimized manufacturing scale for brolucizumab drug substance was introduced.
All patients were planned to receive three intravitreal injections of either brolucizumab 6 mg or aflibercept 2 mg. Key endpoint measures included change in best-corrected visual acuity and central subfield thickness from baseline, and incidence and characteristics of treatment emergent adverse events.
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Overall, there was no indication of a difference in the efficacy profile of the brolucizumab 6 mg drug for commercialization, with no relevant differences seen in functional and anatomical outcomes between the end of the core study (at Week 96) and the end of the extension study (additional Week 24).
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Overall, there was no indication of a difference in the efficacy profile of the brolucizumab 6 mg drug for commercialization, with no relevant differences seen in functional and anatomical outcomes between the end of the core study (at Week 96) and the end of the extension study (additional Week 24).
Overall, the safety results of this extension study did not provide any indication that there was a difference in the safety profile of brolucizumab 6 mg drug product intended for commercialization and the brolucizumab 3 mg or 6 mg drug product used in Phase III clinical studies.
The authors conclude that the safety and efficacy with the intended commercial formulation of brolucizumab 6 mg in nAMD patients was consistent with that observed in the HAWK and HARRIER Phase III studies.
Source: You can read the full article on Current Eye Research
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