SAKURA commenced subject randomization and treatments under Protocol 32-007, Amendment #2. Protocol Amendment #3 was developed to extend the overall study duration to 24 months and to introduce open-label treatments with the 880 μg dose to ensure enough safety information would be established to support regulatory filings. The transition from Protocol Amendment #2 to Protocol Amendment #3 resulted in a total of 88 subjects whose data from Month 6 to Month 12 were collected during the Double-Masked PRN Treatment Period under Amendment #2. Under Protocol Amendment #3, subjects who completed the 6-month Double-Masked Treatment Period entered the 6-month Open-Label Treatment Period with 3 IVT injections of open-label 880 μg dose administered at Month 6, Month 8, and Month 10. At Month 12, subjects were assessed to determine if they have achieved clinical benefit. Subjects who did not achieve clinical benefit during the first 12 months of the study concluded participation at the Month 12 visit. Subjects who achieved clinical benefit were invited to continue participating in the study and were eligible to receive open-label 880 μg DE-109 PRN per retreatment criteria on or after Month 12, no more frequently than every 2 months up to Month 22, and completed the study at the Month 24 visit (Open-Label Retreatment Period). The overall study duration was 24 months under Protocol Amendment #3.

Key changes in the Protocol Amendment #4 included:  - Modified the definition of clinical benefit assessed at Month 12  - Clinical benefit was defined as achieving of a VH score of ≤ 0.5+ at both Month 10 and Month 12, without any use of rescue therapy between Months 6 through 12. This adjusted definition reflected what key opinion leaders in the treatment of posterior segment uveitis consider clinical benefit in practice. It also more closely aligned with the primary endpoint of the study (i.e., having a VH score of 0 at Month 5 [modified SUN scale]). If a subject continued to have a VH score of ≥ 1, the subject were discontinued from study participation and could have been treated with additional alternative treatments.  - Clarified the retreatment criteria and the DE-109 dose for the 12-month Open-Label Retreatment Period  - Added a secondary endpoint: “Proportion of subjects with a VH score of 0 or 0.5+ at Month 5 (modified SUN scale)”, i.e., VH 0 or 0.5+ response  - Clarified a secondary endpoint: “Proportion of subjects with a VH score of 0 or at least a 2-unit improvement in VH score at Month 5 (modified SUN scale)”, i.e., VH 0 or 2-unit response

Santen decided to proceed with commercial development of the 440 μg dose for the treatment of non-infectious uveitis of the posterior segment with a planned unmasked analysis of SAKURA Study 1 that was conducted on the 6-month data of the 347 randomized subjects. Based on this decision, the 32-007 protocol was further amended (Amendment #5) to randomize subjects to receive only the 44 μg or the 440 μg dose during the 6-month Double-Masked Treatment Period in Study 2. This amendment also resulted in phasing out the 880 μg dose in the Open-Label Treatment and Retreatment Periods of both SAKURA studies. Specifically, all ongoing SAKURA subjects who had completed the 6-month Double-Masked Treatment Period and were being treated with open-label 880 μg returned to the investigational site at the next scheduled visit and exited from the study. Key changes: For SAKURA Study 1 and Study 2: - The overall sample size of the SAKURA program (Study 1 and Study 2 combined) was adjusted from approximately 500 to approximately 600 subjects - Subjects beyond the Double-Masked Treatment Period (i.e., subjects under the treatment of open-label 880 μg dose in the Open-Label Treatment Period or the Open-Label Retreatment Period) returned to the investigational site at the next scheduled visit and exited the study For SAKURA Study 2 Alone: - Enrollment was limited to the US and India to approximate subject demographics/characteristics of the SAKURA Study 1 subject population - Eligible subjects from the US and India were randomized in a 1:1 ratio to receive either 44 or 440 μg DE-109 and continued treatment through Month 6 after Amendment #5 was in effect - There was no Open-Label Treatment or Retreatment Period - Response rates for the primary endpoint (VH 0 response) were compared between the 44 and 440 μg doses as the primary comparison - All treatment comparisons of the efficacy endpoints between the 880 μg dose and the 44 μg dose were performed for exploratory purposes only