Subjects

• Inclusion criteria:
  • Adults aged 50 years or older with acute subfoveal choroidal neovascularization secondary to nAMD
  • BCVA of 20/32 to 20/320 (78-24 ETDRS letters)
  • Total area of choroidal neovascularization of more than 50% of the total lesion area
  • Intraretinal fluid, subretinal fluid, or both affecting the center subfield (circle with a 1mm diameter centered on the fovea)
• Exclusion criteria:
  • Total lesion size of more than 12 disc areas

Randomization Scheme/Study Interventions

• Randomized 1:1:1 to:
  • Aflibercept 2 mg every 8 weeks after three monthly loading doses (2q8)
  • Aflibercept 8 mg every 12 weeks after three monthly loading doses (8q12)
  • Aflibercept 8 mg every 16 weeks after three monthly loading doses (8q16)
• Dose regimen modification (DRM) criteria for shortening or extending intervals were applied during the trial based on BCVA and CRT changes.

Results

• 1012 patients were randomized, 936 completed week 48, and 869 completed week 96. Baseline characteristics between groups were similar.
• Vision:
  • Aflibercept 8 mg met the primary efficacy endpoint and showed non-inferior BCVA for both dosing regimens.
  • BCVA change from baseline (least square means): 2q8: +7.0 at week 48, +6.6 at week 96; 8q12: +6.1 at week 48, +5.6 at week 96; 8q16: +5.9 at week 48, +5.5 at week 96.
• Drying:
  • The pooled aflibercept 8 mg arms had statistically superior drying (no fluid in the center subfield) compared to aflibercept 2 mg at week 16, after an equivalent number of monthly loading doses (63% vs 52% dry for 8 mg and 2 mg, respectively).
  • Mean CST change from baseline (least square means): 2q8: -136 at week 48, -147 at week 96; 8q12: -147 at week 48, -152 at week 96; 8q16: -147 at week 48, -149 at week 96.
• Dosing interval:
  • Most aflibercept 8mg maintained their assigned dosing interval at week 48: 79% of patients assigned to q12 and 77% assigned to q16 remained at q12 and q16, respectively, at week 48.
  • At week 96: 8q12 group: The last completed interval was 12 or more weeks for 87% of patients and 20 weeks for 31% of patients; the last assigned interval was 24 weeks for 25% of patients and 20 or more weeks for 41% of patients. 8q16 group: The last completed interval was 16 or more weeks for 79% of patients randomized to 8q16 and 20 weeks for 48% of patients; the last assigned interval was 24 weeks for 31% of patients and 20 or more weeks for 53% of patients.
• Mean number of injections at week 96: 2q8: 12.8 injections; 8q12: 9.7 injections; 8q16: 8.2 injections.
• Safety: Comparable between aflibercept 8 mg and 2 mg at 48 and 96 weeks.

PULSAR Extension Study

• Design: Open label optional extension study from week 96 to week 156. Patients in the 2q8 group in PULSAR were switched to aflibercept 8 mg every 12 weeks (2mg→8mg group). Patients in the 8q12 or 8q16 groups in PULSAR were continued at their last assigned dosing interval (8mg group). DRM criteria were set for shortening or extending intervals in 2-week increments (to a minimum of 8 weeks and a maximum of 24 weeks).
• Results:
  • Vision: 2mg→8mg group: Mean BCVA of 66.9 letters at week 96, and 65.1 letters at week 156; 8mg group: Mean BCVA of 66.9 letters at week 96, and 64.2 letters at week 156.
  • Central Retinal Thickness (least square mean change from baseline, in microns): 2mg→8mg group: -145; 8mg group: -148.
  • Number of injections from week 96 through week 156: 2mg→8mg group: 4.7; 8mg group: 3.8.
  • Dosing Interval: 2mg→8mg group: The last completed dosing interval was 12 weeks or longer in 83% of patients and 16 weeks or longer in 37% of patients; the last assigned dosing interval was 20 weeks or longer in 16% of patients. 8mg group: The last completed dosing interval was 12 weeks or longer in 79% of patients and 20 weeks or longer in 39% of patients; the last assigned dosing interval was 20 weeks or longer in 40% of patients.
• Conclusions:
  • Functional and anatomic gains observed in PULSAR were largely maintained through week 156 in the extension study.
  • The mean BCVA and CRT were comparable between the 2mg→8mg group (patients randomized to 2mg in PULSAR) and the 8mg group (patients randomized to 8mg in PULSAR), with fewer injections and longer intervals in the 8mg group.
  • Similar safety profile between groups.