A Phase 1/2 Single-ascending and Multiple-ascending Dose, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Study of Subcutaneously Administered ALN-CC5 in Healthy Adult Volunteers and Patients With Paroxysmal Nocturnal Hemoglobinuria
Phase: PHASE1
Conditions: Paroxysmal Nocturnal Hemoglobinuria (PNH)
Sponsor: Alnylam Pharmaceuticals

ALN-CC5                                                             Clinical Study Protocol Amendment 1 for Study ALN-CC5-001 
                                                                                                                                                    Summary of Changes 
 
Alnylam Pharmaceuticals 
Confidential 
1 
 
Amendment 1 Summary of Changes 
Protocol ALN-CC5-001 dated 08 December 2014 
A Phase 1/2 Single-ascending and Multiple-ascending Dose, Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics Study of Subcutaneously Administered 
ALN-CC5 in Healthy Adult Volunteers and Patients with Paroxysmal Nocturnal 
Hemoglobinuria 
 
 
Rationale for amendment 1 
The primary purpose for this protocol amendment
 
 pertaining to study drug 
administration and follow-up of subjects who withdraw from the study; the addition of 
pregnancy and breastfeeding as exclusion criteria; and the plan for the unblinding coding system 
in the event that rapid unblinding becomes necessary. 
The above issues are addressed as follows in this Amendment #1:   
The protocol has been updated to indicate that patients who are withdrawn from the study 
because individual stopping criteria have been met, or the subject/patient requires the use of a 
prohibited medication, which in the opinion of the Sponsor or Investigator, may jeopardize the 
study results or represent a risk to the participant, will receive no further study medication but 
will continue to be followed for safety. 
The protocol wording has been clarified to ensure it is clear that any woman with a positive 
pregnancy test during the study will not receive further study drug and will continue to be 
followed for safety.  Additionally, pregnancy and breastfeeding have been added as exclusion 
criteria. 
The protocol has been updated according to International Conference on Harmonisation 
regulations which state that the coding system in the blinded part of the study will include a 
mechanism permitting rapid unblinding and that the investigator will not be required to discuss 
unblinding with the sponsor if emergent unblinding is necessary. 
A detailed summary of changes is provided in Table 1.  Corrections to typographical errors, 
punctuation, grammar, abbreviations, and formatting are not detailed. 
 

ALN-CC5 
                                                                    Clinical Protocol Amendment 1 for Study ALN-CC5-001 
 
                                           
Summary of Changes 
Alnylam Pharmaceuticals 
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Table 1:  
Amendment 1 Detailed Summary of Changes 
The primary section(s) of the protocol affected by the changes in amendment X are indicated.  The corresponding text has been 
revised throughout the protocol.  Deleted text is indicated by strikeout; added text is indicated by bold font. 
Purpose:   
Include pregnancy and breastfeeding as an exclusion criterion 
Primary change: 
Section 5.2.1, Exclusion Criteria for all Subjects in Part A and Part B 
Added text: 
31. Woman who are pregnant or breastfeeding 
Section(s) also 
containing this 
change: 
 SYNOPSIS 
 Section 5.2.2, Exclusion Criteria for All Patients in Part C (criterion 16) 
 Section 10.1.7.6, Pregnancy Screening 
Purpose:   
Add specification that subjects/patients meeting withdrawal criteria will not receive further study drug and will 
continue to be followed for safety 
Primary change: 
Section 5.3.1 Reason for Withdrawal 
Added text: 
Where a subject/patient meets withdrawal criteria for the study, no further study drug will be administered and, 
wherever possible, such study participants will continue to be followed for safety (see Section 5.3.2). 
Purpose: 
Specify the reasons for withdrawal when no further study drug will be administered 
Primary change: 
Section 5.3.2, Handling of Withdrawals 
Formerly read: 
In the event that a subject/patient withdraws or is withdrawn from the study, the Investigator will inform the Medical 
Monitor and Sponsor immediately.  If there is a medical reason for withdrawal, the subject/patient will remain under the 
supervision of the Investigator for protocol specified safety follow-up procedures.  The SRC will be notified. 
Now reads: 
In the event that a subject/patient withdraws or is withdrawn from the study, the Investigator will inform the Medical 
Monitor and Sponsor immediately.  If a subject/patient is withdrawn because individual stopping criteria have been 
met, the subject/patient requires the use of a prohibited medication, which in the opinion of the Sponsor or 
Investigator, may jeopardize the study results or represent a risk to the participant, or there is another medical 
reason for withdrawal, no further study drug will be administered and the subject/patient will remain under the 
supervision of the Investigator for protocol specified safety follow-up procedures.  The SRC will be notified. 

ALN-CC5 
                                                                    Clinical Protocol Amendment 1 for Study ALN-CC5-001 
 
                                           
Summary of Changes 
Alnylam Pharmaceuticals 
Confidential 
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Purpose:   
Include a mechanism permitting rapid unblinding by the Investigator in emergency situations if it is in the best interest 
of the subject and allowing unrestricted and immediate access to break the treatment code for the Investigator 
Primary change: 
Section 6.6.1, Breaking the blind 
Formerly read: 
In case of emergency, the clinical study site pharmacist will access the randomization list, which contains the study drug 
assignment for the subject.   
If a subject becomes pregnant or seriously ill during the study or follow-up period, the blind should be broken only if 
knowledge of the treatment administered will affect treatment options available for the subject.  Before breaking the 
blind, the Investigator, or designee, should attempt to contact the Medical Monitor and the Sponsor as soon as possible.  If 
the blind should be broken, individuals from the Sponsor, who are not related to the conduct of the study, will assist with 
the unblinding of the subject.  If there is a requirement to unblind subjects at the cohort level, only the subjects in that 
cohort will be unblinded.  
A record of when the blind was broken, who broke the blind, and why it was broken, will be maintained in the TMF.  
Should unblinding occur, it will not have an impact on the planned study analyses. 
Now reads: 
In case of emergency, the clinical study site pharmacist will have access to the randomization list, which contains the 
study drug assignment for subjects.   
The coding system in the blinded part of the study includes a mechanism permitting rapid unblinding.  If the blind 
is prematurely broken, the investigator will promptly document and explain any unblinding to the sponsor.  In 
emergency situations, the investigator may need to break the treatment code immediately, or as quickly as 
possible, if it is in the best interest of the subject; thus, the investigator will have unrestricted and immediate access 
to break the treatment code via the randomization list held by the site pharmacist. 
If a subject becomes pregnant or seriously ill during the study or follow-up period, the blind should be broken only if 
knowledge of the treatment administered will affect treatment options available for the subject.  If possible, before 
breaking the blind, the Investigator, or designee, should attempt to contact the Medical Monitor and the Sponsor.  If there 
is a requirement to unblind subjects at the cohort level, only the subjects in that cohort will be unblinded.  
A record of when the blind was broken, who broke the blind, and why it was broken, will also be maintained in the TMF.  
Should unblinding occur, it will not have an impact on the planned study analyses. 

ALN-CC5 
                                                                    Clinical Protocol Amendment 1 for Study ALN-CC5-001 
 
                                           
Summary of Changes 
Alnylam Pharmaceuticals 
Confidential 
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Purpose:   
Update to include continued safety follow-up for subjects/patients who become pregnant during this study 
Primary change: 
Section 10.6.1, Pregnancy Reporting 
Formerly read: 
A subject/patient who becomes pregnant during this study must be instructed to stop all study drug administration.  The 
Investigator or Sub-investigator must report a subject/patient or partner pregnancy to the Sponsor or its agency within 
24 hours of being notified of the pregnancy.  Details of the pregnancy will be reported on a Pregnancy Report Form.  The 
subject/patient/partner shall receive any necessary counseling regarding the risks of continuing the pregnancy and the 
possible effects on the fetus.  Monitoring of the subject/patient/partner will continue until the conclusion of the 
pregnancy, and the outcome of the pregnancy will be reported to the Sponsor. 
Now reads: 
A subject/patient who becomes pregnant during this study must be instructed to stop all study drug administration and 
will continue to be followed for safety.  The Investigator or Sub-investigator must report a subject/patient or partner 
pregnancy to the Sponsor or its agency within 24 hours of being notified of the pregnancy.  Details of the pregnancy will 
be reported on a Pregnancy Report Form.  The subject/patient/partner shall receive any necessary counseling regarding 
the risks of continuing the pregnancy and the possible effects on the fetus.  Safety monitoring of the 
subject/patient/partner will continue until the conclusion of the pregnancy, and the outcome of the pregnancy will be 
reported to the Sponsor. 
If, in the opinion of the Investigator, knowledge of the study drug assignment is required to monitor the pregnancy 
for safety, then unblinding procedures detailed in Section 6.6.1 will be followed. 
Section(s) also 
containing this 
change: 
 Section 10.1.7.6, Pregnancy Screening 
Purpose:  Correct typographical errors, punctuation, grammar, and formatting 
These changes are not listed individually. 
 
 
 

ALN-CC5                                                                                                                                                                     Protocol Amendment 2 Study ALN-CC5-001 
 
                                           
16 June 2015 
Alnylam Pharmaceuticals 
Confidential 
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Purpose:   
Clarified the anticipated duration of the study to be  from screening through last subject/patient, last visit 
The primary change occurs in Section 3.1, Overall Study Design 
Formerly read: 
It is anticipated that this study will last for up to 1 year from screening through the last subject/patient, last visit.   
Now reads: 
It is anticipated that this study will last for approximately 1 year from screening through the last subject/patient, last 
visit.   
Section that also contains this change is: 
• Synopsis  
Purpose:   
Increased number of patient in Part C and clarified that approximately 8 of these patients should be on a stable dose of 
eculizumab 
The primary change occurs in Section 3.2, Number of Subjects and Patients 
Formerly read: 
Part C:  Up to 8 patients with PNH who are either naïve to eculizumab treatment or on stable doses of eculizumab 
(as assessed by the Investigator) 
Now reads: 
Part C:  Up to 16 patients with PNH (approximately 8 patients on a stable dose of eculizumab (as assessed by the 
Investigator) 
Section that also contains this change is: 
• Synopsis  
• Section 3.1, Overall Study Design 
Purpose:   
Increased dosing period to approximately 13 weeks and added the possible investigation of biweekly and monthly dosing 
regimens and PK schedules, if recommended by the SRC 
The primary change occurs in Section 3.1.2, Multiple-ascending Dose Phase (Part B) 
Formerly read: 
Subjects will be re-admitted to the clinical study site for administration of each of the 4 remaining weekly doses of study 
drug. 
Now reads: 
Subjects will be re-admitted to the clinical study site for administration of each of the remaining weekly doses of study 
drug over an approximately 13 week treatment period.  If recommended by the SRC, biweekly and monthly dosing 
regimens and corresponding PK schedules may be investigated (Appendix 18.1). 
Section that also contains this change is: 
• Synopsis  

ALN-CC5                                                                                                                                                                     Protocol Amendment 2 Study ALN-CC5-001 
 
                                           
16 June 2015 
Alnylam Pharmaceuticals 
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• Table 11: Pharmacokinetic Time Points for the Multiple-ascending Dose Phase – Weekly, Biweekly, and Monthly Dosing Schedules 
(Part B) 
• Appendix 18.2, Schedules of Assessments for Dosing Regimens for Multiple-ascending Dose (Part B) Cohorts 
Purpose:   
Clarified that Part C of the study may investigate weekly, biweekly, or monthly dosing regimens 
The primary change occurs in Section 3.1.3, Multiple Dose Phase (Part C) 
Added text: 
Weekly, biweekly, or monthly dosing regimens may be investigated.   
Section that also contains this change is: 
• Synopsis  
• Table 12: Pharmacokinetic Time Points for the Multiple Dose Phase (Part C) 
Purpose:   
Updated the inclusion criteria for acceptable methods of contraception for female subjects of childbearing potential  
(Parts A, B, and C) 
The primary change occurs in Section 5.1.1, Inclusion Criteria for all Subjects in Part A and Part B, and Section 5.1.2, Inclusion Criteria for all 
Patients in Part C 
Added text: 
The subject’s male partner has undergone documented vasectomy with documentation of azoospermia (male 
sterilization) and the use of a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used 
with spermicidal foam/gel/film/cream/suppository). 
Added text: 
True abstinence:  when this is in line with the preferred and usual lifestyle of the subject, including female subjects with 
same sex partners. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal 
are not acceptable methods of contraception.  Abstinent subjects have to agree to use one of the above-mentioned 
contraceptive methods, if they start sexual relationships during the study and for up to 5 months after the last dose of 
study drug. 
Section that also contains this change is: 
• Synopsis  

ALN-CC5                                                                                                                                                                     Protocol Amendment 2 Study ALN-CC5-001 
 
                                           
16 June 2015 
Alnylam Pharmaceuticals 
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Purpose:   
Updated the inclusion criteria for acceptable methods of contraception for male subjects if the male subject’s partner 
could become pregnant (Parts A, B, and C) 
The primary change occurs in Section 5.1.1, Inclusion Criteria for all Subjects in Part A and Part B, and Section 5.1.2, Inclusion Criteria for all 
Patients in Part C 
Added text:  
True abstinence: when this is in line with the preferred and usual lifestyle of the subject, including male subjects with 
same sex partners.  Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception.  Abstinent subjects have to agree to use one of the 
above-mentioned contraceptive methods, if they start sexual relationships during the study and for up to 5 months after 
the last dose of study drug. 
Section that also contains this change is: 
• Synopsis  
Purpose:   
Clarified exclusion criteria for HIV infection, HCV infection, or chronic HBV infection 
The primary change occurs in Section 5.2.2, Exclusion Criteria for All Patients in Part C 
Added text: 
Known clinical laboratory evidence or clinical diagnosis of HIV infection, HCV infection, or chronic HBV infection (as 
shown by HBsAg positivity). 
Section that also contains this change is: 
• Synopsis  
Purpose:   
Increased number of patients in the study due to the increase in the number of patients in Part C 
The primary change occurs in Section 11.1, Sample Size and Randomization  
Formerly read: 
Up to 68 participants (60 subjects and 8 patients) are expected be enrolled in the study (including optional cohorts). 
Now reads: 
Up to 76 participants (60 subjects and 16 patients) are expected be enrolled in the study (including optional cohorts). 
Section that also contains this change is: 
• Synopsis  
• Section 3.2, Number of Subjects and Patients 

ALN-CC5                                                                                                                                                                     Protocol Amendment 2 Study ALN-CC5-001 
 
                                           
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Alnylam Pharmaceuticals 
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Purpose:   
Corrected the blood volume for Part B and Part C 
The primary change occurs in Section 10.1.6, Maximum Blood Volume  
Formerly read: 
Part A:  up to 400 mL over the course of 70 days 
Part B:  up to 500 mL over the course of 140 days 
Part C:  up to 500 mL over the course of 140 days
 
Now reads: 
Part A:  up to 500 mL over the course of 70 days 
Part B:  up to 600 mL over the course of 140 days 
Part C:  up to 800 mL over the course of 140 days 
Purpose:   
Clarified the timing of vaccinations 
The primary change occurs in Section 10.1.8, Part A and Part B Vaccination Specifications 
Added text: 
Subjects who were not previously vaccinated will be vaccinated with meningococcal group ACWY conjugate 
vaccine and meningococcal group B vaccine.  Vaccinations should be administered within the 90 day 
screening period according to the following plan (Note:  Vaccination day is not the same as Study Day): 
Purpose:   
Removed 15-minute PK timepoint 
The primary change occurs in Tables 10, 11 and 12, Pharmacokinetic Time Points for Parts A, B, and C, respectively 
Purpose:  Correct typographical errors, punctuation, grammar, abbreviations, and formatting 
These changes are not listed individually. 
 
 
 

ALN-CC5                                                                  Protocol Amendment 3 Summary of Changes ALN-CC5-001 
                                                                                                                                                    13 November 2015 
 
Alnylam Pharmaceuticals 
Confidential 
1 
ALN-CC5-001 
Summary of Changes 
Protocol Amendment 3, dated 13 November 2015 
A Phase 1/2 Single-ascending and Multiple-ascending Dose, Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics Study of Subcutaneously Administered 
ALN-CC5 in Healthy Adult Volunteers and Patients with Paroxysmal Nocturnal 
Hemoglobinuria 
Rationale for the amendment 
The primary purpose of this amendment is to extend study drug dosing through 39 weeks in the 
multiple-dose phase in patients with paroxysmal nocturnal hemoglobinuria (PNH; Part C).  An 
extension of the dosing is supported by
 
 
 
 
 
Schedules of Assessments were added and pharmacokinetic time points were updated to 
align with the new dosing regimens. 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
In Part C, a maximum of 3 cohorts comprised of at least 4 patients each will be enrolled to 
permit an assessment of the effect of cohort-based dose modifications in this patient population 
during longer-term dosing.  During the dosing period, the SRC will meet at regular intervals to 
review ongoing safety, tolerability, and available PD data from Part B and Part C, including 
degree of complement inhibition and clinically meaningful suppression of intravascular 
hemolysis as evaluated by LDH levels (Part C only).  Based on these reviews, the SRC will 
recommend cohort initiation and the dose and dosing regimen to be administered to patients in 
the cohort or all patients in Part C.  To further reduce patient burden in Part C, ALN-CC5 may be 
administered at home between visits to the clinical study center by a home healthcare provider.  
Since safety information is analyzed locally at the clinical study center, patient safety will be 

ALN-CC5                                                                  Protocol Amendment 3 Summary of Changes ALN-CC5-001 
                                                                                                                                                    13 November 2015 
 
Alnylam Pharmaceuticals 
Confidential 
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maintained.  To implement a more feasible study design in this amendment, after completing the 
13 week dosing period, patients in Cohort 1 may transition to extended dosing on a modified 
regimen provided the Day 140/ET study visit has not been completed; these patients will resume 
ALN-CC5 administration at a dose and regimen recommended by the SRC. 
Additionally, in Part A and B, unblinding will occur at the cohort level.  In Part B and C of the 
study, editorial and minor administrative errors identified since protocol amendment 2, dated 
16 June 2015, were corrected and editorial changes were made to improve protocol clarity and to 
align with the adaptive design features of the study.  Study assessments and visits were 
harmonized with the new dosing regimens that may be investigated and antidrug antibody 
assessments added.  Intermediate overnight visits to the clinical study center were removed to 
reduce the burden of visits to the clinical study center on patients.  The Schedule of Assessments 
from Part B (5 weekly doses), which was inadvertently removed in protocol amendment 2, was 
incorporated back into the protocol. 
A detailed summary of the changes is provided in Table 1.  Minor administrative updated and 
corrections to typographical errors, abbreviations, and formatting are not detailed.  

ALN-CC5                                                             
                                                              Protocol Amendment 3 Summary of Changes ALN-CC5-001 
 
                                           
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Alnylam Pharmaceuticals 
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Table 1:  
Amendment 3 Detailed Summary of Changes 
The primary section(s) of the protocol affected by the changes in the amendment are indicated.  The corresponding text has been 
revised throughout the protocol.  Deleted text is indicated by strikeout; added text is indicated by bold font. 
Purpose:   
 
Primary change: 
Section 2.3, Exploratory Objectives 
Now reads: 
 
 
Other sections affected 
by this change: 
 Protocol Synopsis 
 Section 9.3.4, 
 
 Section 11.3.5, Exploratory Analysis 
 All Schedule of Assessment Tables for Part C (Table 3, Table 20, Table 21, and Table 22) 
Purpose:   
Evaluate less frequent dosing regimens and lower doses in Part B and update and add Schedules of Assessments and 
PK time point tables to align with new dosing regimens 
Primary change: 
Section 3.1.2, Multiple-ascending Dose Phase (Part B) 
Now reads: 
Part B of the study will be performed in a randomized (3:1), placebo-controlled, double-blind design to assess MAD of 
ALN-CC5 in healthy subjects (Figure 2).   
Subjects will be screened from -90 to -2 days before dose administration.  Eligible subjects will be admitted to the 
clinical study site on Day -1 to determine continued eligibility and for pretreatment assessments.  Subjects will be 
randomized on Day 0 and will receive an initial dose of study drug.  Subjects will be discharged from the clinical study 
site following the completion of the 24 hourshour postdose follow-up assessments.  Subjects will be readmitted to the 
clinical study site for administration of each of the remaining weekly doses of study drug over an approximately 13 
week treatment period.  If recommended by the SRC, biweekly and monthly dosing regimens and corresponding PK 
schedules may be investigated (Appendix 18.2).  Following completion of the 24 hours postdose followup assessments, 
subjects will be discharged from the clinical study site.Subjects will return to the clinical study site on an outpatient 
basis at the time points in the Schedule of Assessments (Table 2, Table 15, Table 16, Table 17, Table 18, and Table 
19) forand PK table (Table 11 and Table 12) for study drug administration and safety, tolerability, PK, and PD 
monitoring through SC doses administered over an approximately 13 week treatment periodover the treatment period 
and for postdose follow-up.  For subjects with serum complement activity below normal range at the last postdose 
follow-up visit (Day 140), monitoring visits will occur every 28±7 days until serum complement activity is within the 
normal reference range for all subjects in that cohort as assessed by CAP ELISA.  
 
 
 

ALN-CC5                                                             
                                                              Protocol Amendment 3 Summary of Changes ALN-CC5-001 
 
                                           
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Alnylam Pharmaceuticals 
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Other section affected 
by this change: 
 Protocol Synopsis 
 Figure 2, Multiple-ascending Dose Phase – Weekly Dosing (Part B) Flow Diagram 
 Table 2: Schedule of Assessments for Multiple-ascending Dose Cohorts (Part B) – 5 Weekly Doses 
 Table 11: Pharmacokinetic Time Points for Multiple-ascending Dose Cohorts (Part B) – Weekly Dosing 
 Table 12: Pharmacokinetic Time Points for the Multiple-ascending Dose Phase (Part B) – Other Dosing 
Schedules 
 Table 15: Schedule of Assessments for Multiple-ascending Dose Cohorts (Part B) – 13 Weekly Doses 
 Table 16: Schedule of Assessments for Multiple-ascending Dose Cohorts (Part B) – Once Every 2 Weeks 
Dosing 
 Table 17: Schedule of Assessments for Multiple-ascending Dose Cohorts (Part B) – Monthly Dosing 
 Table 18: Schedule of Assessments for Multiple-ascending Dose Cohorts (Part B) – 5 Weekly Doses Followed 
by Once Every 2 Weeks Dosing 
 Table 19: Schedule of Assessments for Multiple-ascending Dose Cohorts (Part B) – 5 Weekly Doses Followed 
by Monthly Dosing 
Purpose:   
Evaluate less frequent dosing regimens in Part C, update and add Schedules of Assessments and PK time point tables to 
align with new dosing regimens, and permit ALN-CC5 administration at home between visits to the clinical study center 
by a home healthcare provider 
Primary change: 
Section 3.1.3, Multiple Dose Phase (Part C) 
Now reads: 
Part C of the study will be conducted in patients with PNH in an open-label design to assess multiple doses of ALN-
CC5.  The start of Part C and the study drug dose will depend on SRC review of safety, tolerability, and available PD 
data from Part A and Part B (Figure 3).  A maximum of 3 cohorts, comprised of at least 4 patients each, will be 
enrolled in Part C.  Overall, patients in Part C will undergo a maximum of 39 weeks of ALN CC5 dosing. 
Patients will be screened from -90 to -2 days before dose administration.  Patients will have a consultation at the clinical 
study site on Day -1 to determine continued eligibility and for pretreatment assessments.  Patients will be admitted and 
dosed on Day 0.  Patients will be discharged from the clinical study site following the completion of the 24 hourshour 
postdose follow-up assessments.  Patients will return to the clinical study site at the time points in the Schedule of 
Assessments (Table 3, Table 20, Table 21, and Table 22) on an outpatient basis for each of the remaining doses ofand 
PK table (Table 13 and Table 14) for study drug administration and for safety, tolerability, PK, and PD monitoring 
at specified time points over an approximately 13 weekthe treatment period through the lastand for postdose follow-up 
visit (Day 140).  Weekly, biweekly.  For patients with serum complement activity below normal range at the last 
postdose follow-up visit, monitoring visits will occur every 28±7 days until serum complement activity is within the 

ALN-CC5                                                             
                                                              Protocol Amendment 3 Summary of Changes ALN-CC5-001 
 
                                           
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normal reference range as assessed by CAP ELISA. 
In Part C, ALN-CC5 may be administered at home between visits to the clinical study center by a home 
healthcare provider trained in the administration of ALN-CC5.  Patients will return to the clinical study center 
every other month for assessments; however, in between, visits can be completed by a home healthcare provider. 
After the last dose of study drug, eligible patients may transition to a Phase 2an open-label extension study immediately 
after administration of the last dose of study drug or obtain standard of care treatment. 
Other section affected 
by this change: 
 Protocol Synopsis 
 Section 7.5, Study Drug Administration 
 Table 3: Schedule of Assessments for Multiple-dose Cohorts (Part C) – 13 Weekly Doses (Cohort 1) 
 Table 13: Pharmacokinetic Time Points for the Multiple Dose Phase (Part C) – 13 Weekly Doses (Cohort 1) 
 Table 14: Pharmacokinetic Time Points for the Multiple Dose Phase (Part C) – 5 Weekly Doses Followed by 
Once Every 2 Weeks Dosing or Followed by Monthly Dosing (Cohort 2 and Cohort 3) 
 Table 20: Schedule of Assessments for Multiple-dose Cohorts (Part C) – 5 Weekly Doses Followed by Once 
Every 2 Weeks Dosing (Cohort 2 and Cohort 3) 
 Table 21: Schedule of Assessments for Multiple-dose Cohorts (Part C) – 5 Weekly Doses Followed by Monthly 
Dosing (Cohort 2 and Cohort 3) 
 Table 22: Schedule of Assessments for Multiple-dose Cohorts (Part C) – All Cohorts (Day 91 through PD 
Follow-up) 
Purpose:   
Updated the treatment and study duration 
Primary change: 
Section 3.1.5, Treatment and Study Duration 
Now reads: 
A single SC dose of study drug will be administered in Part A.  In Part B and Part C, respectively, study drug 
will be administered over a maximum of a 13 or a 39 week period.  It is anticipated that this study will last for a 
maximum of 2 years from screening through the last subject/patient, last visit.  End of study is defined as last 
subject/patient, last visit.  It is anticipated that the duration of study participation for a subject/patient will be 
454 days (65 weeks). 
Other sections affected 
by this change: 
 Protocol Synopsis 
 Section 10.1.6, Maximum Blood Volume 

ALN-CC5                                                             
                                                              Protocol Amendment 3 Summary of Changes ALN-CC5-001 
 
                                           
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Purpose:   
Extend study drug dosing through 39 weeks in the multiple-dose phase in patients with PNH in Part C, enroll a 
maximum of 3 cohorts comprised of at least 4 patients and permit SRC recommended cohort initiation and dose 
modifications, and permit patients in Cohort 1 to transition to extended dosing on a modified regimen provided the Day 
140/ET study visit has not been completed 
Primary change: 
Section 4.3, Study Drug Dosing and Regimen Modifications in Part C 
Now reads: 
Part C will be initiated if the SRC, based on their expert clinical experience in treating PNH patients, determines 
that the safety, tolerability, and available PD (C5 levels and complement activity) data derived from Part A and 
Part B is clinically meaningful and the risk-benefit assessment is favorable. 
Figure 4 illustrates the cohort enrollment and dose and dosing regimen modification plan for Part C.  A 
maximum of 3 cohorts, comprised of at least 4 patients each, will be enrolled.  The SRC will meet at regular 
intervals (approximately every 8 weeks) to review ongoing safety, tolerability, and available PD data from Part B 
and Part C to recommend cohort initiation and to determine the dose and dosing regimen to be administered to 
all patients in a cohort or all patients in Part C.  During the dosing period, the SRC may also recommend the 
ALN-CC5 dose and regimen be modified for all patients, based on the degree of complement inhibition and 
clinically meaningful suppression of intravascular hemolysis as evaluated by LDH (Part C only).  Part C does not 
include sentinel dosing.   
Dosing in Cohort 1 may initiate after SRC review of data from Part A and Part B at a dose no greater than the 
highest safe and tolerated dose explored in Part B.  Initially, 13 weekly doses of ALN-CC5 will be administered.  
After completing the 13 week dosing period, patients in Cohort 1 may transition to extended dosing on a 
modified regimen provided the Day 140/ET study visit has not been completed; these patients will resume ALN-
CC5 administration at a dose and regimen recommended by the SRC. 
Dosing in Cohort 2 may initiate after SRC review of data from subjects in Part B, Cohorts 4, 5, and 6, who 
completed ≥10 weeks of dosing.  Additionally, dosing in Cohort 2 may initiate after SRC confirmation that 
clinically meaningful suppression of intravascular hemolysis (evaluated by LDH levels) has occurred in at least 4 
patients in Part C, Cohort 1, who completed ≥8 weeks of dosing.  Initially, ALN-CC5 will be administered once 
weekly for 5 doses. 
Dosing in Cohort 3 may initiate to further explore dose and dosing regimens after ≥4 patients in Part C, Cohort 2 
complete ≥13 weeks of dosing data have been evaluated by the SRC.  Initially, ALN-CC5 will also be 
administered once weekly for 5 doses. 
After an initial dosing period (5 or 13 weekly doses), the SRC may recommend a dose or dosing regimen 
modification.  The regimen can be modified in Cohorts 1, 2, and 3 to once every 2 weeks or once monthly dosing, 
or weekly dosing continued.  The SRC may also determine that de-escalation to a lower dose and regimen or re-
escalation to a higher dose and regimen is appropriate.  Overall, patients in Part C will undergo a maximum of 
39 weeks of ALN CC5 dosing. 

ALN-CC5                                                             
                                                              Protocol Amendment 3 Summary of Changes ALN-CC5-001 
 
                                           
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Patients with confirmed PNH and on stable doses of eculizumab (as assessed by the Investigator) will continue 
receiving treatment concomitantly with ALN-CC5 at a dose and regimen determined by the SRC.  These patients 
will receive their last dose of eculizumab when at least 2 consecutive measurements of C5 levels demonstrate a 
degree of suppression consistent with complement inhibition (as determined by the SRC during review of data 
from Part A and Part B).  Patients who are naïve to eculizumab treatment may begin ALN-CC5 administration 
at a dose and regimen determined by the SRC. 
Other sections affected 
by this change: 
 Figure 4, Study Drug Dosing in the Multiple-dose Phase (Part C) 
 Section 11.3, Statistical Methodology 
 All Schedules of Assessment and PK Time Point tables for Part C (Table 3, Table 13, Table 14, Table 20, Table 
21, and Table 22) 
Purpose:   
In Part A and B, unblinding will occur at the cohort level 
Primary change: 
Section 6.6, Randomization and Blinding 
Now reads: 
Part A and Part B will be conducted in a randomized 3:1 (ALN CC5:placebo), double-blinded, placebo-controlled 
manner.   
The study subjects, Investigators, Medical Monitors, and members of the study team at the Sponsor and at the Contract 
Research Organization(s) (CROs), clinical study site personnel, and members of the SRC will remain blinded to the 
treatment assignment at least throughout the decisionmaking time points and until end of study for each subjectuntil all 
subjects in a cohort (see Table 6)complete PD follow-up. 
Other sections affected 
by this change: 
 Protocol Synopsis 
Purpose:   
Specify immunogenicity assessment criteria 
Primary change: 
Section 10.1.7.3, 
 
Now reads: 
 
 
 
Details regarding the processing, shipping, and analysis of the samples will be provided in the Laboratory 
Manual. 
Other sections affected 
by this change: 
 Protocol Synopsis 
 All Schedule of Assessment tables 

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                                                              Protocol Amendment 3 Summary of Changes ALN-CC5-001 
 
                                           
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Purpose:   
Extended minimum time permitted for concomitant antibiotic treatment through PD follow-up period in Part A and B 
Primary change: 
Section 10.1.9, Prophylactic Antibiotic Administration and Compliance Check 
Now reads: 
Ciprofloxacin will be administered in accordance with the manufacturer’s instructions.  Antibiotic compliance checks 
will be performed at the time points in the Schedule of Assessments.   
Subjects participating in Part A and Part B will be treated with prophylactic ciprofloxacin (according to standard 
practice at the clinical study sites) from start of dosing with study drug (ALN-CC5 and at least until Day 21 (SAD part) 
and Day 35 (MAD part) or placebo) until serum complement activity, as assessed by CAP ELISA, for all subjects in 
the cohort returns to within the normal reference range as assessed by CAP ELISA. 
Patients in Part C will receive antibiotics at the discretion of the investigator. 
Full detailsDetails of antibiotic compliance methodology will be described in the Study Operations 
Manual/Procedures. 
Other sections affected 
by this change: 
 Protocol Synopsis 
 All Schedule of Assessment tables for Parts A and B 
 

ALN-CC5  
 
Clinical Study Protocol ALN-CC5-001 
 
 Amendment 4 Summary of Changes_16 August 2016 
 
Alnylam Pharmaceuticals 
Confidential 
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ALN-CC5-001 Protocol Amendment 4  
Summary of Changes dated 16 August 2016 
A Phase 1/2 Single-ascending and Multiple-ascending Dose, Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics Study of Subcutaneously Administered 
ALN-CC5 in Healthy Adult Volunteers and Patients with Paroxysmal Nocturnal 
Hemoglobinuria 
 
Rationale for Protocol Amendment 
Protocol ALN-CC5-001 is an ongoing study.  Although subjects and patients are no longer being 
enrolled or treated in this study, subjects and patients continue to be followed in accordance with 
the protocol.  The primary purpose of this amendment is to update the timing of treatment 
unblinding for healthy subjects in Parts A and B to avoid unnecessarily prolonged prophylaxis 
antibiotic treatment in normal healthy volunteers who have been assigned placebo, and in 
ALN-CC5 exposed subjects who have recovered to complement activity within the reference 
range.  This change in the unblinding procedure is based on the observed pharmacodynamic 
duration of ALN-CC5 plus the unblinding of treatment at the cohort level, which have 
necessitated all healthy subjects in a cohort to continue daily antibiotics and clinic visits every 28 
days regardless of treatment assignment (ALN-CC5 or placebo) and the level of complement 
activity (as assessed by complement alternative pathway [CAP] enzyme-linked immunosorbent 
assay [ELISA]).  Currently, the protocol requires that all subjects in a cohort complete 
pharmacodynamic (PD) follow-up in the study before the unblinding of that cohort.  With this 
amendment to the protocol, unblinding of investigators and individual subjects to treatment 
assignment will occur at a minimum of 9 months after a subject receives his or her last dose of 
study drug.  If an individual subject’s complement functional activity as measured by CAP 
ELISA is within the reference range, prophylactic antibiotics will be stopped after unblinding 
and that subject will have completed the study.  If an individual subject who received ALN-CC5 
has a CAP ELISA result that has not returned to within the reference range after unblinding, then 
prophylactic antibiotics will continue and the subject will be required to attend follow-up visits 
until the CAP ELISA result returns to within the reference range.  Unblinding the treatment 
assignment of individual subjects in this manner will maintain the safety of subjects, as it will 
allow for subjects to discontinue daily prophylactic antibiotic use and follow-up clinic visits. 
In addition, clarifications are being implemented in this amendment as outlined below: 
 Increased the anticipated time for screening through the last subject/patient from a 
maximum of 2 years to a maximum of 3 years and increased the anticipated duration 
of study participation for a subject/patient to 665 days (1 year and 10 months) due to 
the observed PD duration of ALN-CC5.  
 Removed hepatitis B core antibodies from the viral serology section of the protocol, 
as this was only in a single location in the protocol and was included in error. 
 Corrected the start of AE collection for Part B to begin after the first dose of ALN-
CC5 to align with Section 10.4 of the protocol. 

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Clinical Study Protocol ALN-CC5-001 
 
 Amendment 4 Summary of Changes_16 August 2016 
 
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 Increased the estimated total  protocol-specified blood volume for Part C from 800 
mL to 900 mL over the duration of the study.  This is a result of the estimated blood 
volume required for the lactate dehydrogenase analysis being determined to be more 
than originally estimated. 
 Aligned the hemoglobinuria evaluation to Day -1 and Day 1 (not Day 0) and the 
coagulation sampling to every 2 weeks followed by once monthly starting at Day 84. 
 Removed a reference to Cohort 1in the footnotes in Table 3 and Table 22 for 
alignment with Section 4.3 of the protocol. 
A detailed summary of changes is provided in Table 1.  Corrections to typographical errors, 
punctuation, grammar, abbreviations, and formatting are not detailed. 

ALN-CC5 
Clinical Study Protocol ALN-CC5-001 
 
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Table 1:  
Protocol Amendment 4 Detailed Summary of Changes 
The primary section(s) of the protocol affected by the changes in Protocol Amendment 4 are indicated.  The corresponding text has 
been revised throughout the protocol.  Deleted text is indicated by strikeout; added text is indicated by bold font. 
Purpose:  Updated the timing of treatment unblinding and follow-up period for healthy subjects in Parts A and B  
The primary change occurs in Section 6.6, Randomization and Blinding 
Now reads: 
The study subjects, Investigators, Medical Monitors, and members of the study team at the Sponsor and at the Contract 
Research Organization(s) (CROs), clinical study site personnel, and members of the SRC will remain blinded to the 
treatment assignment until all subjects in a cohort complete PD followupfor a minimum of 9 months after a 
subject receives his or her last dose of study drug.  If an individual subject’s complement functional 
activity as measured by CAP ELISA is within the reference range, prophylactic antibiotics will be 
stopped after unblinding and that subject will have completed the study.  If an individual subject who 
received ALN-CC5 has a CAP ELISA result that has not returned to within the reference range after 
unblinding, then prophylactic antibiotics will continue and the subject will be required to attend follow-
up visits until the CAP ELISA result returns to within the reference range.  
Section(s) also containing this change: 
 Synopsis 
 Table 1:  Schedule of Assessments for Single-ascending Dose Cohorts (Part A) 
 Table 2:  Schedule of Assessments for Multiple-ascending Dose Cohorts (Part B) – 5 Weekly Doses 
 Section 3.1.1, Single-ascending Dose Phase (Part A) 
 Section 3.1.2, Multiple-ascending Dose Phase (Part B) 
 Section 10.1.9, Prophylactic Antibiotic Administration and Compliance Check 
 Table 15:  Schedule of Assessments for Multiple-ascending Dose Cohorts (Part B) – 13 Weekly Doses 
 Table 16:  Schedule of Assessments for Multiple-ascending Dose Cohorts (Part B) – Once Every 2 Weeks Dosing 
 Table 17:  Schedule of Assessments for Multiple-ascending Dose Cohorts (Part B) – Monthly Dosing 
 Table 18:  Schedule of Assessments for Multiple-ascending Dose Cohorts (Part B) – 5 Weekly Doses Followed by Once Every 2 Weeks 
Dosing 
 Table 19:  Schedule of Assessments for Multiple-ascending Dose Cohorts (Part B) – 5 Weekly Doses Followed by Monthly Dosing 

ALN-CC5 
Clinical Study Protocol ALN-CC5-001 
 
Amendment 4 Summary of Changes_16 August 2016 
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Purpose:  Increased the anticipated time for screening through the last subject/patient and for the duration of study participation for a 
subject/patient 
The primary change occurs in Section 3.1.5, Treatment and Study Duration 
Now reads: 
A single SC dose of study drug will be administered in Part A.  In Part B and Part C, respectively, study drug will be 
administered over a maximum of a 13 or a 39 week period.  It is anticipated that this study will last for a maximum of 
2 years 3 years from screening through the last subject/patient, last visit.  End of study is defined as last subject/patient, 
last visit.  It is anticipated that the duration of study participation for a subject/patient will be 665 days (1 year and 10 
months)454 days (65 weeks). 
Section(s) also containing this change:  
 Synopsis 
Purpose:  Aligned the start time of AE collection time for Part B with Section 10.4 of the protocol  
The primary change occurs in Table 2: Schedule of Assessments for Multiple-ascending Dose Cohorts (Part B) – 5 Weekly Doses 
Now reads: 
Under the Review/record AEs assessment, removed ‘X’ at Screening and inserted ‘X’ starting at Day 0  
Purpose:  Increased the blood volume for Part C from 800 mL to 900 mL  
The primary change occurs in Section 10.1.6, Maximum Blood Volume 
Now reads: 
The maximum total blood volume that will be collected from subjects and patients participating in this study will be 
documented in the Study Manual/Procedures.  Maximum total blood volume according to study part is as follows: 
• Part A:  up to 500 mL over the course of 70 days 
• Part B:  up to 600 mL over the course of 140 days 
• Part C:  up to 800 mL 900 mL over the course of approximately 1 year 
Purpose:  Removed hepatitis B core antibodies from the viral serology section of the protocol for alignment within the protocol 
The primary change occurs in Section 10.1.7.4, Viral Serology 
Now reads: 
Serology will be performed at the time points in the Schedule of Assessments.  During screening, subjects and patients 
will be tested for HIV I and II antibody, HBsAg, hepatitis B core antibodies, and anti HCV.  Results of the assessments 
will not be entered into the study database.  If a subject/patient is confirmed positive for any of these tests, the 
subject/patient will be referred for further examination, counseling, or treatment and is not eligible for the study. 

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Purpose:  Aligned the hemoglobinuria evaluation to Day -1 and Day 1 (not Day 0) 
The primary change occurs in Table 20: Schedule of Assessments for Multiple-dose Cohorts (Part C) – 5 Weekly Doses Followed by Once Every 
2 Weeks Dosing (Cohort 2 and Cohort 3) 
Now reads: 
Under the Hemoglobinuria evaluation, added an ‘X’ at Day -1 and Day 1 and removed ‘X’ at Day 0 
Purpose:  Aligned the coagulation sampling to every 2 weeks followed by once monthly starting at Day 84 
The primary change occurs in Table 3: Schedule of Assessments for Multiple-dose Cohorts (Part C) – 13 Weekly Doses (Cohort 1) 
Added text: 
Under the Biochemistry, hematology, and coagulation assessment,  added a cross-reference the appropriate footnote 
Section(s) also containing this change: 
 Table 20: Schedule of Assessments for Multiple-dose Cohorts (Part C) – 5 Weekly Doses Followed by Once Every 2 Weeks Dosing 
(Cohort 2 and Cohort 3) 
 Table 21: Schedule of Assessments for Multiple-dose Cohorts (Part C) – 5 Weekly Doses Followed by Monthly Dosing (Cohort 2 and 
Cohort 3) 
Purpose:  Removed reference to Cohort 1 for alignment within the protocol 
The primary change occurs in Table 3: Schedule of Assessments for Multiple-dose Cohorts (Part C) – 13 Weekly Doses (Cohort 1) 
Now reads: 
After completing the 13 week dosing period, patients in Cohort 1 may transition to extended dosing on a modified 
regimen provided the Day 140/ET study visit has not been completed; these patients will resume ALN-CC5 
administration at a dose and regimen recommended by the SRC 
Section(s) also containing this change: 
 Table 22: Schedule of Assessments for Multiple-dose Cohorts (Part C) – All Cohorts (Day 91 through PD Follow-up) 
Purpose:  Correct typographical errors, punctuation, grammar, abbreviations, and formatting 
These changes are not listed individually. 
 

ALN-CC5  
 
Clinical Study Protocol ALN-CC5-001 
 
Amendment 5 Summary of Changes_12 June 2017 
 
Alnylam Pharmaceuticals 
Confidential 
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ALN-CC5-001 Protocol Amendment 5 
Summary of Changes dated 12 June 2017 
A Phase 1/2 Single-ascending and Multiple-ascending Dose, Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics Study of Subcutaneously Administered 
ALN-CC5 in Healthy Adult Volunteers and Patients with Paroxysmal Nocturnal 
Hemoglobinuria 
 
Rationale for Protocol Amendment 
The protocol is being amended primarily to revise the study follow-up period, with the objective 
of reducing the risks associated with long-term antibiotic exposure, while ensuring subject and 
patient safety.  Per the current protocol, study participants administered ALN-CC5 receive 
prophylactic ciprofloxacin to minimize susceptibility to meningococcal infections during the 
follow-up period until their serum complement activity is within the normal reference range.  To 
date, several study participants with near-normal complement activity have been required to 
receive long-term prophylactic ciprofloxacin.  
To potentially balance the health risks of slightly reduced complement activity with the risks of 
long-term ciprofloxacin use, this protocol amendment will require that participants continue in 
follow-up until serum complement activity is within the normal reference range OR until the 
Safety Review Committee makes a recommendation on a case-by-case basis to discontinue 
follow-up and prophylactic ciprofloxacin treatment, whichever is sooner. The decision cannot be 
made until after completion of the last postdose follow-up visit. 
A detailed summary of changes is provided in Table 1.  Corrections to typographical errors, 
punctuation, grammar, abbreviations, and formatting, including administrative changes noted in 
Protocol Administrative Change #3 (dated 28 October 2016) are not detailed. 
 

ALN-CC5 
Clinical Study Protocol ALN-CC5-001 
Amendment 5 Summary of Changes_12 June 2017 
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Table 1:  
Protocol Amendment 5 Detailed Summary of Changes 
The primary section(s) of the protocol affected by the changes in the protocol amendment are indicated.  The corresponding text has 
been revised throughout the protocol.  Deleted text is indicated by strikeout; added text is indicated by bold font. 
Purpose:  Added an alternative threshold for discontinuation from study follow-up 
The primary change occurs in Section 3.1.1 Single Ascending Dose Phase (Part A) 
Now reads:  For subjects with serum complement activity below normal range at the last postdose follow up visit (Day 70), monitoring visits will 
occur until serum complement activity is within the normal reference range as assessed by CAP ELISA or until the SRC makes a decision on 
a case-by-case basis to discontinue follow-up, whichever is sooner (see Section 3.5.3.).  The decision cannot be made until after 
completion of the last postdose follow-up visit.   
Section(s) also containing a similar change:  
Synopsis
Table 1:  Schedule of Assessments for Single-ascending Dose Cohorts (Part A)
Table 2:  Schedule of Assessments for Multiple-ascending Dose Cohorts (Part B) – 5 Weekly Doses
Table 3:  Schedule of Assessments for Multiple-dose Cohorts (Part C) – 13 Weekly Doses (Cohort 1)
Table 15: Schedule of Assessments for Multiple-ascending Dose Cohorts (Part B) – 13 Weekly Doses
Table 16: Schedule of Assessments for Multiple-ascending Dose Cohorts (Part B) – Once Every 2 Weeks Dosing
Table 17: Schedule of Assessments for Multiple-ascending Dose Cohorts (Part B) – Monthly Dosing
Table 18: Schedule of Assessments for Multiple-ascending Dose Cohorts (Part B) – 5 Weekly Doses Followed by Once Every 2 Weeks
Dosing
Table 19: Schedule of Assessments for Multiple-ascending Dose Cohorts (Part B) – 5 Weekly Doses Followed by Monthly Dosing
Table 22: Schedule of Assessments for Multiple-dose Cohorts (Part C) – All Cohorts (Day 91 through PD Follow-up)
Section 1.9.3, Risk Mitigation Strategy
Section 3.1.2, Multiple Ascending Dose Phase (Part B)
Section 3.1.3, Multiple Dose Phase (Part C)
Section 6.6, Randomization and Blinding
Section 10.1.9, Prophylactic Antibiotic Administration and Compliance Check
Purpose:  To indicate that another purpose of the Safety Review Committee (SRC) Meetings is to determine whether a study participant may be 
discontinued from study follow-up 
The primary change occurs in Section 3.5.3 Timing and Purpose of Review Meetings 
Added text: To balance the health risks of slightly reduced complement activity with the risks of long-term ciprofloxacin use, the SRC will 

ALN-CC5 
Clinical Study Protocol ALN-CC5-001 
 
Amendment 5 Summary of Changes_12 June 2017 
Alnylam Pharmaceuticals 
Confidential 
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also determine whether study follow-up and prophylactic ciprofloxacin treatment will be discontinued in subjects or patients with 
complement activity below the normal range.  The decision cannot be made until after completion of the last postdose follow-up visit. 
Purpose:  Correct typographical errors, punctuation, grammar, abbreviations, and formatting[, including administrative changes, if appropriate] 
These changes are not listed individually.