1. CEDAR 150998-005 and SEQUOIA 150998-006 Protocol Amendment Summary
April 2016

2. Protocol Amendment Summary Amendment 2 Title: Safety and Efficacy of Abicipar Pegol (AGN ) in Patients With Neovascular Age-related Macular Degeneration Protocol and Amendment 2 Date of Amendment: April 2016

3. Amendment Summary
This summary includes changes made to Protocol / Amendment 1 (approved March 2015).
Following is a summary of content-oriented changes that were made to each section of the protocol, and a brief rationale for these changes.
Minor editorial and document formatting revisions have not been summarized.

4. Summary of Changes Section Revision Rationale Title Page (page 2)
Updated title of Allergan Signatory
Administrative change
Protocol Summary, Duration, Visit Schedule, General Statistical Methods and Types of Analyses;
Figure 1;
Sections 3, 5.6.2, , 7, , 8.7
Updated study duration from 100 to weeks throughout protocol to reflect change in study duration
Based on the MHRA’s comment to have last follow up visit occur at least 5 human vitreous half-lifes of the study drug, either abicipar or ranibizumab, whichever is longer. Abicipar’s vitreous half-life is longer than ranibizumab, it is estimated to be 12 days.
Protocol Summary, Endnote;
Table 1, footnote “l”;
Sections 5.6, 5.9
Clarified that preparation for all treatment administration procedures, including sham injections, will follow a standard protocol defined in procedure manual
Clarification that details of the pre- treatment patient preparation procedure are provided in the procedure manual

5. Summary of Changes Section Revision Rationale
Protocol Summary, Key Ocular Inclusion Criteria (study eye);
Section 4.3, Criterion 4
Revised inclusion criterion as follows: Presence of active subfoveal and/or juxtafoveal CNV (1 to micron from the center) secondary to AMD assessed by fluorescein angiogram. In addition, presence of retinal fluid on optical coherence tomography (OCT) and/or fluorescein leakage under the fovea as assessed by the investigator at screening and confirmed by the central reading center prior to baseline (day 1).
Revised language for purposes of clarification only
Protocol Summary, Key Ocular Exclusion Criteria (either eye);
Section 4.4, criterion 8
Revised exclusion criterion as follows: Active periocular, ocular, or /intraocular infection at baseline (day 1)

6. Summary of Changes Section Revision Rationale
Protocol Summary, Key Ocular Exclusion Criteria (study eye);
Section 4.4, criterion 18
Revised exclusion criterion as follows: Previous or concurrent macular laser treatment for macular drusen
Revised language for purposes of clarification only
Section 4.4, criterion 21
Revised exclusion criterion as follows: Structural damage to the center of the macula that is likely to preclude improvement in BCVA following the resolution of macular edema, including atrophy of the RPE, or retinal fibrosis/scarring as assessed by the investigator at screening and confirmed by the central reading center prior to baseline (day 1) including any of the following:
Macular hole stage 3 or 4
Atrophy of the RPE
Retinal fibrosis or scarring

7. Summary of Changes Section Revision Rationale Table 1
Added week 104 as study exit or early termination visit, week 100 will be a study assessment visit without study treatment for all treatment groups
Based on the MHRA’s comment to have last follow up visit occur after at least 5 human vitreous half- lifes of the study drug, either abicipar or ranibizumab, whichever is longer. Abicipar’s vitreous half-life is longer than ranibizumab, it is estimated to be 12 days.
Visit windows for weeks 4 through 24, weeks 28 through 48, weeks 52 through 96, and weeks 100 through 104/early exit has been changed from ±5 days to ±7 days; accompanying footnote “p” was updated to include that the minimum interval between 2 study visits ≥ 20 days.
The visit windows have been updated to accommodate site operations; while all indicated study procedures (including study treatment administration) are intended to be completed in the same visit, this footnote clarifies post-baseline visit dates and visit windows, in particular if the study treatment is administered on a different day as the other baseline (day 1) procedures and further clarifies that the minimum interval between 2 study visits should be at least 20 days.

8. Summary of Changes Section Revision Rationale Table 1
The timing for specular microscopy (at selected sites) was set to a fixed visit at week 32. The accompanying footnote “i” was updated to reflect this change
The timing for specular microscopy has been set to a fixed visit for consistency across sites
Section 1
Updated to include additional support for dosing regimens used in the study
Revised language for purposes of clarification only
Section 3
Updated the minimum and maximum number of visits scheduled
Revised based on adding visit at week 104
Section 3.1
Updated to include purpose of monitoring.
Revised language for purposes of clarification only
Section 4.4, criterion 3
Updated exclusion criterion to refer to povidone iodine solution
Section
Updated to include use of condoms as preferred method of contraception for male patients participating in the study
To specify male contraceptive measures

9. Summary of Changes Section Revision Rationale Section 4.5.2
Removed topical ocular corticosteroids from prohibited medication list
Use of topical ocular corticosteroids is not likely to impact study outcome
Section 5.6.2
Added clarification to criteria for escape to standard of care as follows: Persistent fluid (subretinal and intraretinal) by OCT, judged to be the cause of the BCVA loss (not explained by reasons other than the progression of neovascular AMD)
Revised language for purposes of clarification only
Updated as follows: Patients who escape to standard of care will be required to complete the study exit procedures indicated at the week /early exit visit and will be reevaluated at the subsequent follow-up visits: 1) 4 or 8 weeks after receiving first standard-of-care treatment for BCVA, CRT, and adverse event assessments, 2) approximately 16 weeks after the last study medication injection for immunogenicity, BCVA, CRT, and adverse events assessments, and 3) approximately 52 and 100 weeks after baseline for BCVA, CRT, and adverse event assessment.
Revised to include evaluation at approximately 52 and weeks after baseline based on DSMC recommendations.

10. Summary of Changes Section Revision Rationale Section 6.4.3.4
Added: In addition, a post-injection safety follow-up phone call (up to 3 days following the office visit) should be performed for all enrolled patients after the administration of each study treatment. The post-injection safety follow- up may be completed in-office for patients who participate in blood sample collection for PK analysis.
Added for consistency with other sections of protocol
Section 7.3.1
Added that if non-inferiority for both abicipar arms is established, that superiority testing of abicipar over ranibizumab will be performed
Updated to reflect changes to the statistical analysis plan
Section 7.3.2
Analysis updated to be based on ANCOVA with baseline BCVA as a covariate
Section 7.3.3
Updated to describe additional analyses if non-inferiority for both abicipar arms is established
Updated to align with FDA’s comments at the end-of- Phase 2 meeting
Section 7.3.4
Removed reference to SAS®
This detail is covered in statistical appendix

11. Summary of Changes Section Revision Rationale
Sections 8.3.1, , , and
Revise 3-field color imaging to Field 2 for each mention of dilated color fundus photography (screening and week 24, 52, and source documents)
For consistency with the requirement stated in central reading center charter
Sections 8.3.9, , and
Removed specular microscopy at weeks 28, 36, 40, 44, 48, 52.
For consistency with change to Table 1
Section
Revised specular microscopy to be prior to study medication administration at week 32
Section
Updated week 100 visit procedures to reflect changes to Table 1 based on addition of week 104/exit visit
For consistency with changes to Table 1 and addition of week 104/early exit
Section
New section to list visit procedures at week 104/early exit

12. Summary of Changes Section Revision Rationale Section 8.7
Updated as follows: Patients who discontinue early due to other reasons will be required to complete the study exit procedures indicated at the week 104/early exit visit and will be reevaluated at the subsequent follow-up visits: 1) approximately 16 weeks after the last study medication injection or 100 weeks from baseline whichever occurs earlier for immunogenicity, BCVA, CRT, and adverse events assessments, and 2) approximately 52 and 100 weeks after baseline for BCVA, CRT, and adverse event assessments.
Revised to include evaluation at approximately 52 and 100 weeks after baseline based on DSMC recommendations
Section
Added the following: If local policy does not allow storage of used study medication vials, the site may destroy the used vials per their local policy, but must keep the kit box for the detailed inventory of the study medication.
Revised language for accommodating the local policy of handling the used study medication
Section
Added abbreviations for the following: ANCOVA, PDT, and PEG
Included abbreviations that were either added or not previously defined.
Note: Stricken text was removed and underlined text was added

13. Thank you