Paroxysmal Nocturnal Hemoglobinuria (PNH)
Conditions
Keywords
PNH, RNAi therapeutic
Brief summary
The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of ALN-CC5 in healthy adult volunteers and subjects with PNH
Interventions
DRUGALN-CC5
Single or multiple doses of ALN-CC5 by subcutaneous (sc) injection
DRUGSterile Normal Saline (0.9% NaCl)
calculated volume to match active comparator
Sponsors
Alnylam Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Adequate complete blood counts, liver and renal function * 12-lead electrocardiogram (ECG) within normal limits * Female subjects of child bearing potential agreeing to use a protocol specified method of contraception * Male subjects agreeing to use protocol specified methods of contraception * Willing to provide written informed consent and willing to comply with study requirements
Exclusion criteria
* Any uncontrolled or serious disease, or any medical or surgical condition, that may interfere with participation in the clinical study and/or put the subject at significant risk * Received an investigational agent within 90 days before the first dose of study drug or are in follow-up of another clinical study * History of multiple drug allergies or intolerance to subcutaneous injection * Parts A and B of the study: Used prescription medications within 14 days or 7 half-lives of administration of the first dose of study drug. * History of meningococcal infection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | Part A: through day 658; Part B: through day 532; Part C: through day 280 | Adverse events were reported for single-ascending doses (SAD) or multiple ascending doses (MAD) of ALN-CC5 when administered to healthy adult subjects and of multiple doses (MD) in patients with paroxysmal nocturnal hemoglobinuria (PNH) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in C5 Protein Levels | Part A: through day 70; Part B: through day 140; Part C: through day 140 | Total C5 protein levels were measured in serum samples collected at time points throughout the study using a mass spectrometry-based method. Percentage reduction was calculated relative to baseline levels. A positive value indicates a reduction in C5 protein level from baseline. |
| Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Alternative Pathway (CAP) | Part A: through day 70; Part B: through day 140; Part C: through day 140 | Complement activity was measured in serum samples collected at timepoints throughout the study using the CAP ELISA assay. Percentage reduction was calculated relative to baseline levels. A positive value indicates a reduction in CAP from baseline. |
| Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Classical Pathway (CCP) | Part A: through day 70; Part B: through day 140; Part C: through day 140 | Complement activity was measured in serum samples collected at time points throughout the study using the CCP ELISA assay. Percentage reduction was calculated relative to baseline levels. A positive value indicates a reduction in CCP from baseline. |
| Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (25-mer) | Part A: 0-48 hrs, Day 0; Part B (weekly dosing cohorts): 0-48 hrs, Day 28; Part B (biweekly, weekly/monthly/biweekly/monthly cohorts): 0-48 hrs, Day 84; Part C: 0- 24 hrs, Day 84 | Maximum observed plasma concentration (Cmax) of ALN-CC5 (cemdisiran) 25-mer. |
| Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (23-mer) | Part A: 0-48 hrs, Day 0; Part B (weekly dosing cohorts): 0-48 hrs, Day 28; Part B (biweekly, weekly/monthly/biweekly/monthly cohorts): 0-48 hrs, Day 84; Part C: 0- 24 hrs, Day 84 | Maximum observed plasma concentration (Cmax) of ALN-CC5 (cemdisiran) 23-mer. |
| Pharmacokinetic (PK) Effect of ALN-CC5: T Max (23-mer) | Part A: 0-48 hrs, Day 0; Part B (weekly dosing cohorts): 0-48 hrs, Day 28; Part B (biweekly, weekly/monthly/biweekly/monthly cohorts): 0-48 hrs, Day 84; Part C: 0- 24 hrs, Day 84 | Time of maximum observed plasma concentration (T max) of ALN-CC5 (cemdisiran) 23-mer. |
| Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (25-mer) | Part A: 0-48 hrs, Day 0; Part B (weekly dosing cohorts): 0-48 hrs, Day 28; Part B (biweekly, weekly/monthly/biweekly/monthly cohorts): 0-48 hrs, Day 84; Part C: 0- 24 hrs, Day 84 | Area under the plasma concentration-time curve over the dosing interval zero to time (AUC 0-t) of ALN-CC5 (cemdisiran) 25-mer. |
| Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (23-mer) | Part A: 0-48 hrs, Day 0; Part B (weekly dosing cohorts): 0-48 hrs, Day 28; Part B (biweekly, weekly/monthly/biweekly/monthly cohorts): 0-48 hrs, Day 84; Part C: 0- 24 hrs, Day 84 | Area under the plasma concentration-time curve over the dosing interval zero to time (AUC 0-t) of ALN-CC5 (cemdisiran) 23-mer. |
| Pharmacokinetic (PK) Effect of ALN-CC5: T Max (25-mer) | Part A: 0-48 hrs, Day 0; Part B (weekly dosing cohorts): 0-48 hrs, Day 28; Part B (biweekly, weekly/monthly/biweekly/monthly cohorts): 0-48 hrs, Day 84; Part C: 0- 24 hrs, Day 84 | Time of maximum observed plasma concentration (T max) of ALN-CC5 (cemdisiran) 25-mer. |
Countries
Spain, United Kingdom
Participant flow
Pre-assignment details
A total of 62 subjects who met eligibility criteria were enrolled. Part A includes all Groups receiving a Single Ascending Dose of study drug; Part B includes all Groups receiving Multiple Ascending Doses of study drug; Part C includes the ALN-CC5 Multiple Dose - Eculizumab Treated and ALN-CC5 Multiple Dose - Eculizumab Naive Groups.
Participants by arm
| Arm | Count |
|---|---|
| Placebo - Single Ascending Dose Healthy volunteers received a single dose of placebo (normal saline) | 8 |
| ALN-CC5 50mg - Single Ascending Dose Healthy volunteers received a single dose of ALN-CC5 50mg | 3 |
| ALN-CC5 50mg (Japanese) - Single Ascending Dose Japanese healthy volunteers received a single dose of ALN-CC5 50mg | 3 |
| ALN-CC5 200mg - Single Ascending Dose Healthy volunteers received a single dose of ALN-CC5 200mg | 3 |
| ALN-CC5 200mg (Japanese) - Single Ascending Dose Japanese healthy volunteers received a single dose of ALN-CC5 200mg | 3 |
| ALN-CC5 400mg - Single Ascending Dose Healthy volunteers received a single dose of ALN-CC5 400mg | 3 |
| ALN-CC5 600mg - Single Ascending Dose Healthy volunteers received a single dose of ALN-CC5 600mg | 3 |
| ALN-CC5 600mg (Japanese) - Single Ascending Dose Japanese healthy volunteers received a single dose of ALN-CC5 600mg | 3 |
| ALN-CC5 900mg - Single Ascending Dose Healthy volunteers received a single dose of ALN-CC5 900mg | 3 |
| Placebo - Multiple Ascending Dose Healthy volunteers received multiple doses of placebo (normal saline) per corresponding active drug regimen | 6 |
| ALN-CC5 100mg Weekly - Multiple Ascending Dose Healthy volunteers received weekly doses of ALN-CC5 100mg for 5 doses | 3 |
| ALN-CC5 200mg Weekly - Multiple Ascending Dose Healthy volunteers received weekly doses of ALN-CC5 200mg for 5 doses | 3 |
| ALN-CC5 400mg Weekly - Multiple Ascending Dose Healthy volunteers received weekly doses of ALN-CC5 400mg for 5 doses | 3 |
| ALN-CC5 600mg Biweekly - Multiple Ascending Dose Healthy volunteers received biweekly doses of ALN-CC5 600mg for 7 doses | 3 |
| ALN-CC5 200mg Weekly/Biweekly - Multiple Ascending Dose Healthy volunteers received weekly doses of ALN-CC5 200mg for 5 doses followed by biweekly doses of 200mg for 4 doses | 3 |
| ALN-CC5 200mg Weekly/Monthly - Multiple Ascending Dose Healthy volunteers received weekly doses of ALN-CC5 200mg for 5 doses followed by monthly doses of 200mg for 2 doses | 3 |
| ALN-CC5 Multiple Dose - Eculizumab Treated Patients received weekly doses of ALN-CC5 200mg or ALN-CC5 400mg for up to 12 weeks concomitantly with eculizumab | 3 |
| ALN-CC5 Multiple Dose - Eculizumab Naive Patients naive to eculizumab received weekly doses of ALN-CC5 400mg for 8 doses or ALN-CC5 200mg for 13 doses followed by weekly doses of ALN-CC5 400mg for 4 doses | 3 |
| Total | 62 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 | FG014 | FG015 | FG016 | FG017 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 2 | 0 | 0 | 0 | 0 |
| Overall Study | Pregnancy | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | ALN-CC5 50mg - Single Ascending Dose | ALN-CC5 50mg (Japanese) - Single Ascending Dose | ALN-CC5 200mg - Single Ascending Dose | ALN-CC5 200mg (Japanese) - Single Ascending Dose | ALN-CC5 400mg - Single Ascending Dose | ALN-CC5 600mg - Single Ascending Dose | ALN-CC5 600mg (Japanese) - Single Ascending Dose | ALN-CC5 900mg - Single Ascending Dose | Placebo - Multiple Ascending Dose | Placebo - Single Ascending Dose | ALN-CC5 100mg Weekly - Multiple Ascending Dose | ALN-CC5 200mg Weekly - Multiple Ascending Dose | ALN-CC5 400mg Weekly - Multiple Ascending Dose | ALN-CC5 600mg Biweekly - Multiple Ascending Dose | ALN-CC5 200mg Weekly/Biweekly - Multiple Ascending Dose | ALN-CC5 200mg Weekly/Monthly - Multiple Ascending Dose | ALN-CC5 Multiple Dose - Eculizumab Treated | ALN-CC5 Multiple Dose - Eculizumab Naive | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 6 Participants | 8 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 62 Participants |
| Age, Continuous | 24 years STANDARD_DEVIATION 3.2 | 33 years STANDARD_DEVIATION 7 | 22 years STANDARD_DEVIATION 1.7 | 27 years STANDARD_DEVIATION 5 | 23 years STANDARD_DEVIATION 3.8 | 30 years STANDARD_DEVIATION 6.7 | 30 years STANDARD_DEVIATION 8 | 27 years STANDARD_DEVIATION 5.6 | 27 years STANDARD_DEVIATION 6.3 | 26 years STANDARD_DEVIATION 5 | 32 years STANDARD_DEVIATION 7.6 | 29 years STANDARD_DEVIATION 3.1 | 27 years STANDARD_DEVIATION 2.9 | 29 years STANDARD_DEVIATION 4.2 | 26 years STANDARD_DEVIATION 3.8 | 23 years STANDARD_DEVIATION 6.1 | 44 years STANDARD_DEVIATION 16.9 | 44 years STANDARD_DEVIATION 11.9 | 28.6 years STANDARD_DEVIATION 8.12 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 3 Participants | 0 Participants | 3 Participants | 1 Participants | 2 Participants | 3 Participants | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 15 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) White | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants | 5 Participants | 4 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 39 Participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 3 Participants | 0 Participants | 2 Participants | 4 Participants | 2 Participants | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 2 Participants | 24 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 3 Participants | 2 Participants | 2 Participants | 0 Participants | 3 Participants | 1 Participants | 2 Participants | 6 Participants | 2 Participants | 1 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 1 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk | EG016 affected / at risk | EG017 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 6 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 |
| other Total, other adverse events | 6 / 8 | 0 / 3 | 3 / 3 | 2 / 3 | 2 / 3 | 3 / 3 | 3 / 3 | 2 / 3 | 3 / 3 | 6 / 6 | 2 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 2 / 3 | 3 / 3 | 3 / 3 | 3 / 3 |
| serious Total, serious adverse events | 0 / 8 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 6 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 |
Outcome results
Primary
Number of Participants With Adverse Events
Adverse events were reported for single-ascending doses (SAD) or multiple ascending doses (MAD) of ALN-CC5 when administered to healthy adult subjects and of multiple doses (MD) in patients with paroxysmal nocturnal hemoglobinuria (PNH)
Time frame: Part A: through day 658; Part B: through day 532; Part C: through day 280
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo - Single Ascending Dose | Number of Participants With Adverse Events | At least 1 TEAE leading to discontinuation | 0 Participants |
| Placebo - Single Ascending Dose | Number of Participants With Adverse Events | At least 1 Treatment Emergent Adverse Event (TEAE) | 6 Participants |
| Placebo - Single Ascending Dose | Number of Participants With Adverse Events | At least 1 Serious Adverse Event (SAE) | 0 Participants |
| ALN-CC5 50mg - Single Ascending Dose | Number of Participants With Adverse Events | At least 1 Treatment Emergent Adverse Event (TEAE) | 0 Participants |
| ALN-CC5 50mg - Single Ascending Dose | Number of Participants With Adverse Events | At least 1 Serious Adverse Event (SAE) | 0 Participants |
| ALN-CC5 50mg - Single Ascending Dose | Number of Participants With Adverse Events | At least 1 TEAE leading to discontinuation | 0 Participants |
| ALN-CC5 50mg (Japanese) - Single Ascending Dose | Number of Participants With Adverse Events | At least 1 Serious Adverse Event (SAE) | 0 Participants |
| ALN-CC5 50mg (Japanese) - Single Ascending Dose | Number of Participants With Adverse Events | At least 1 Treatment Emergent Adverse Event (TEAE) | 3 Participants |
| ALN-CC5 50mg (Japanese) - Single Ascending Dose | Number of Participants With Adverse Events | At least 1 TEAE leading to discontinuation | 0 Participants |
| ALN-CC5 200mg - Single Ascending Dose | Number of Participants With Adverse Events | At least 1 TEAE leading to discontinuation | 0 Participants |
| ALN-CC5 200mg - Single Ascending Dose | Number of Participants With Adverse Events | At least 1 Treatment Emergent Adverse Event (TEAE) | 2 Participants |
| ALN-CC5 200mg - Single Ascending Dose | Number of Participants With Adverse Events | At least 1 Serious Adverse Event (SAE) | 0 Participants |
| ALN-CC5 200mg (Japanese) - Single Ascending Dose | Number of Participants With Adverse Events | At least 1 Serious Adverse Event (SAE) | 0 Participants |
| ALN-CC5 200mg (Japanese) - Single Ascending Dose | Number of Participants With Adverse Events | At least 1 Treatment Emergent Adverse Event (TEAE) | 2 Participants |
| ALN-CC5 200mg (Japanese) - Single Ascending Dose | Number of Participants With Adverse Events | At least 1 TEAE leading to discontinuation | 0 Participants |
| ALN-CC5 400mg - Single Ascending Dose | Number of Participants With Adverse Events | At least 1 TEAE leading to discontinuation | 0 Participants |
| ALN-CC5 400mg - Single Ascending Dose | Number of Participants With Adverse Events | At least 1 Treatment Emergent Adverse Event (TEAE) | 3 Participants |
| ALN-CC5 400mg - Single Ascending Dose | Number of Participants With Adverse Events | At least 1 Serious Adverse Event (SAE) | 0 Participants |
| ALN-CC5 600mg - Single Ascending Dose | Number of Participants With Adverse Events | At least 1 TEAE leading to discontinuation | 0 Participants |
| ALN-CC5 600mg - Single Ascending Dose | Number of Participants With Adverse Events | At least 1 Treatment Emergent Adverse Event (TEAE) | 3 Participants |
| ALN-CC5 600mg - Single Ascending Dose | Number of Participants With Adverse Events | At least 1 Serious Adverse Event (SAE) | 0 Participants |
| ALN-CC5 600mg (Japanese) - Single Ascending Dose | Number of Participants With Adverse Events | At least 1 Treatment Emergent Adverse Event (TEAE) | 2 Participants |
| ALN-CC5 600mg (Japanese) - Single Ascending Dose | Number of Participants With Adverse Events | At least 1 Serious Adverse Event (SAE) | 0 Participants |
| ALN-CC5 600mg (Japanese) - Single Ascending Dose | Number of Participants With Adverse Events | At least 1 TEAE leading to discontinuation | 0 Participants |
| ALN-CC5 900mg - Single Ascending Dose | Number of Participants With Adverse Events | At least 1 Serious Adverse Event (SAE) | 0 Participants |
| ALN-CC5 900mg - Single Ascending Dose | Number of Participants With Adverse Events | At least 1 TEAE leading to discontinuation | 0 Participants |
| ALN-CC5 900mg - Single Ascending Dose | Number of Participants With Adverse Events | At least 1 Treatment Emergent Adverse Event (TEAE) | 3 Participants |
| Placebo - Multiple Ascending Dose | Number of Participants With Adverse Events | At least 1 Serious Adverse Event (SAE) | 0 Participants |
| Placebo - Multiple Ascending Dose | Number of Participants With Adverse Events | At least 1 Treatment Emergent Adverse Event (TEAE) | 6 Participants |
| Placebo - Multiple Ascending Dose | Number of Participants With Adverse Events | At least 1 TEAE leading to discontinuation | 0 Participants |
| ALN-CC5 100mg Weekly - Multiple Ascending Dose | Number of Participants With Adverse Events | At least 1 Serious Adverse Event (SAE) | 0 Participants |
| ALN-CC5 100mg Weekly - Multiple Ascending Dose | Number of Participants With Adverse Events | At least 1 TEAE leading to discontinuation | 0 Participants |
| ALN-CC5 100mg Weekly - Multiple Ascending Dose | Number of Participants With Adverse Events | At least 1 Treatment Emergent Adverse Event (TEAE) | 2 Participants |
| ALN-CC5 200mg Weekly - Multiple Ascending Dose | Number of Participants With Adverse Events | At least 1 Serious Adverse Event (SAE) | 0 Participants |
| ALN-CC5 200mg Weekly - Multiple Ascending Dose | Number of Participants With Adverse Events | At least 1 TEAE leading to discontinuation | 0 Participants |
| ALN-CC5 200mg Weekly - Multiple Ascending Dose | Number of Participants With Adverse Events | At least 1 Treatment Emergent Adverse Event (TEAE) | 3 Participants |
| ALN-CC5 400mg Weekly - Multiple Ascending Dose | Number of Participants With Adverse Events | At least 1 Treatment Emergent Adverse Event (TEAE) | 3 Participants |
| ALN-CC5 400mg Weekly - Multiple Ascending Dose | Number of Participants With Adverse Events | At least 1 Serious Adverse Event (SAE) | 0 Participants |
| ALN-CC5 400mg Weekly - Multiple Ascending Dose | Number of Participants With Adverse Events | At least 1 TEAE leading to discontinuation | 0 Participants |
| ALN-CC5 600mg Biweekly - Multiple Ascending Dose | Number of Participants With Adverse Events | At least 1 Treatment Emergent Adverse Event (TEAE) | 3 Participants |
| ALN-CC5 600mg Biweekly - Multiple Ascending Dose | Number of Participants With Adverse Events | At least 1 TEAE leading to discontinuation | 0 Participants |
| ALN-CC5 600mg Biweekly - Multiple Ascending Dose | Number of Participants With Adverse Events | At least 1 Serious Adverse Event (SAE) | 0 Participants |
| ALN-CC5 200mg Weekly/Biweekly - Multiple Ascending Dose | Number of Participants With Adverse Events | At least 1 Serious Adverse Event (SAE) | 0 Participants |
| ALN-CC5 200mg Weekly/Biweekly - Multiple Ascending Dose | Number of Participants With Adverse Events | At least 1 Treatment Emergent Adverse Event (TEAE) | 2 Participants |
| ALN-CC5 200mg Weekly/Biweekly - Multiple Ascending Dose | Number of Participants With Adverse Events | At least 1 TEAE leading to discontinuation | 0 Participants |
| ALN-CC5 200mg Weekly/Monthly - Multiple Ascending Dose | Number of Participants With Adverse Events | At least 1 Treatment Emergent Adverse Event (TEAE) | 3 Participants |
| ALN-CC5 200mg Weekly/Monthly - Multiple Ascending Dose | Number of Participants With Adverse Events | At least 1 Serious Adverse Event (SAE) | 0 Participants |
| ALN-CC5 200mg Weekly/Monthly - Multiple Ascending Dose | Number of Participants With Adverse Events | At least 1 TEAE leading to discontinuation | 0 Participants |
| ALN-CC5 Multiple Dose - Eculizumab Treated | Number of Participants With Adverse Events | At least 1 Serious Adverse Event (SAE) | 0 Participants |
| ALN-CC5 Multiple Dose - Eculizumab Treated | Number of Participants With Adverse Events | At least 1 TEAE leading to discontinuation | 0 Participants |
| ALN-CC5 Multiple Dose - Eculizumab Treated | Number of Participants With Adverse Events | At least 1 Treatment Emergent Adverse Event (TEAE) | 3 Participants |
| ALN-CC5 Multiple Dose - Eculizumab Naive | Number of Participants With Adverse Events | At least 1 Serious Adverse Event (SAE) | 0 Participants |
| ALN-CC5 Multiple Dose - Eculizumab Naive | Number of Participants With Adverse Events | At least 1 Treatment Emergent Adverse Event (TEAE) | 3 Participants |
| ALN-CC5 Multiple Dose - Eculizumab Naive | Number of Participants With Adverse Events | At least 1 TEAE leading to discontinuation | 0 Participants |
Secondary
Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in C5 Protein Levels
Total C5 protein levels were measured in serum samples collected at time points throughout the study using a mass spectrometry-based method. Percentage reduction was calculated relative to baseline levels. A positive value indicates a reduction in C5 protein level from baseline.
Time frame: Part A: through day 70; Part B: through day 140; Part C: through day 140
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo - Single Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in C5 Protein Levels | 15.88 percentage reduction | Standard Error 2.61 |
| ALN-CC5 50mg - Single Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in C5 Protein Levels | 77.61 percentage reduction | Standard Error 3.249 |
| ALN-CC5 50mg (Japanese) - Single Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in C5 Protein Levels | 73.44 percentage reduction | Standard Error 2.885 |
| ALN-CC5 200mg - Single Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in C5 Protein Levels | 93.17 percentage reduction | Standard Error 0.898 |
| ALN-CC5 200mg (Japanese) - Single Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in C5 Protein Levels | 88.62 percentage reduction | Standard Error 0.565 |
| ALN-CC5 400mg - Single Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in C5 Protein Levels | 94.60 percentage reduction | Standard Error 1.378 |
| ALN-CC5 600mg - Single Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in C5 Protein Levels | 97.62 percentage reduction | Standard Error 0.902 |
| ALN-CC5 600mg (Japanese) - Single Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in C5 Protein Levels | 95.47 percentage reduction | Standard Error 0.306 |
| ALN-CC5 900mg - Single Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in C5 Protein Levels | 97.49 percentage reduction | Standard Error 0.252 |
| Placebo - Multiple Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in C5 Protein Levels | 24.302 percentage reduction | Standard Error 5.9546 |
| ALN-CC5 100mg Weekly - Multiple Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in C5 Protein Levels | 94.959 percentage reduction | Standard Error 0.6087 |
| ALN-CC5 200mg Weekly - Multiple Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in C5 Protein Levels | 98.297 percentage reduction | Standard Error 0.4901 |
| ALN-CC5 400mg Weekly - Multiple Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in C5 Protein Levels | 98.428 percentage reduction | Standard Error 0.2 |
| ALN-CC5 600mg Biweekly - Multiple Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in C5 Protein Levels | 98.695 percentage reduction | Standard Error 0.1612 |
| ALN-CC5 200mg Weekly/Biweekly - Multiple Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in C5 Protein Levels | 98.683 percentage reduction | Standard Error 0.3165 |
| ALN-CC5 200mg Weekly/Monthly - Multiple Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in C5 Protein Levels | 96.870 percentage reduction | Standard Error 1.8851 |
| ALN-CC5 Multiple Dose - Eculizumab Treated | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in C5 Protein Levels | 96.057 percentage reduction | Standard Error 1.3728 |
| ALN-CC5 Multiple Dose - Eculizumab Naive | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in C5 Protein Levels | 98.187 percentage reduction | Standard Error 0.2586 |
Secondary
Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Alternative Pathway (CAP)
Complement activity was measured in serum samples collected at timepoints throughout the study using the CAP ELISA assay. Percentage reduction was calculated relative to baseline levels. A positive value indicates a reduction in CAP from baseline.
Time frame: Part A: through day 70; Part B: through day 140; Part C: through day 140
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo - Single Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Alternative Pathway (CAP) | 18.823 percentage reduction | Standard Error 4.302 |
| ALN-CC5 50mg - Single Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Alternative Pathway (CAP) | 49.321 percentage reduction | Standard Error 5.6718 |
| ALN-CC5 50mg (Japanese) - Single Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Alternative Pathway (CAP) | 26.337 percentage reduction | Standard Error 5.2159 |
| ALN-CC5 200mg - Single Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Alternative Pathway (CAP) | 64.435 percentage reduction | Standard Error 2.3138 |
| ALN-CC5 200mg (Japanese) - Single Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Alternative Pathway (CAP) | 47.628 percentage reduction | Standard Error 3.174 |
| ALN-CC5 400mg - Single Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Alternative Pathway (CAP) | 58.525 percentage reduction | Standard Error 5.5782 |
| ALN-CC5 600mg - Single Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Alternative Pathway (CAP) | 72.517 percentage reduction | Standard Error 7.5442 |
| ALN-CC5 600mg (Japanese) - Single Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Alternative Pathway (CAP) | 58.914 percentage reduction | Standard Error 13.0568 |
| ALN-CC5 900mg - Single Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Alternative Pathway (CAP) | 66.097 percentage reduction | Standard Error 7.6113 |
| Placebo - Multiple Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Alternative Pathway (CAP) | 25.419 percentage reduction | Standard Error 5.9153 |
| ALN-CC5 100mg Weekly - Multiple Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Alternative Pathway (CAP) | 63.224 percentage reduction | Standard Error 4.5313 |
| ALN-CC5 200mg Weekly - Multiple Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Alternative Pathway (CAP) | 78.028 percentage reduction | Standard Error 5.6692 |
| ALN-CC5 400mg Weekly - Multiple Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Alternative Pathway (CAP) | 70.618 percentage reduction | Standard Error 6.7831 |
| ALN-CC5 600mg Biweekly - Multiple Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Alternative Pathway (CAP) | 68.367 percentage reduction | Standard Error 0.975 |
| ALN-CC5 200mg Weekly/Biweekly - Multiple Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Alternative Pathway (CAP) | 77.079 percentage reduction | Standard Error 1.4564 |
| ALN-CC5 200mg Weekly/Monthly - Multiple Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Alternative Pathway (CAP) | 76.470 percentage reduction | Standard Error 8.1563 |
| ALN-CC5 Multiple Dose - Eculizumab Treated | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Alternative Pathway (CAP) | 25.951 percentage reduction | Standard Error 25.1389 |
| ALN-CC5 Multiple Dose - Eculizumab Naive | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Alternative Pathway (CAP) | 77.558 percentage reduction | Standard Error 5.9434 |
Secondary
Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Classical Pathway (CCP)
Complement activity was measured in serum samples collected at time points throughout the study using the CCP ELISA assay. Percentage reduction was calculated relative to baseline levels. A positive value indicates a reduction in CCP from baseline.
Time frame: Part A: through day 70; Part B: through day 140; Part C: through day 140
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo - Single Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Classical Pathway (CCP) | 18.417 percentage reduction | Standard Error 2.7684 |
| ALN-CC5 50mg - Single Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Classical Pathway (CCP) | 46.953 percentage reduction | Standard Error 2.8152 |
| ALN-CC5 50mg (Japanese) - Single Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Classical Pathway (CCP) | 43.615 percentage reduction | Standard Error 6.0458 |
| ALN-CC5 200mg - Single Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Classical Pathway (CCP) | 72.939 percentage reduction | Standard Error 3.4838 |
| ALN-CC5 200mg (Japanese) - Single Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Classical Pathway (CCP) | 63.582 percentage reduction | Standard Error 2.5038 |
| ALN-CC5 400mg - Single Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Classical Pathway (CCP) | 72.809 percentage reduction | Standard Error 1.5589 |
| ALN-CC5 600mg - Single Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Classical Pathway (CCP) | 87.307 percentage reduction | Standard Error 1.375 |
| ALN-CC5 600mg (Japanese) - Single Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Classical Pathway (CCP) | 70.830 percentage reduction | Standard Error 11.7722 |
| ALN-CC5 900mg - Single Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Classical Pathway (CCP) | 80.646 percentage reduction | Standard Error 4.2849 |
| Placebo - Multiple Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Classical Pathway (CCP) | 25.419 percentage reduction | Standard Error 6.2753 |
| ALN-CC5 100mg Weekly - Multiple Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Classical Pathway (CCP) | 72.340 percentage reduction | Standard Error 3.4211 |
| ALN-CC5 200mg Weekly - Multiple Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Classical Pathway (CCP) | 86.031 percentage reduction | Standard Error 4.1209 |
| ALN-CC5 400mg Weekly - Multiple Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Classical Pathway (CCP) | 88.821 percentage reduction | Standard Error 6.3222 |
| ALN-CC5 600mg Biweekly - Multiple Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Classical Pathway (CCP) | 80.126 percentage reduction | Standard Error 1.6075 |
| ALN-CC5 200mg Weekly/Biweekly - Multiple Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Classical Pathway (CCP) | 89.145 percentage reduction | Standard Error 1.9147 |
| ALN-CC5 200mg Weekly/Monthly - Multiple Ascending Dose | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Classical Pathway (CCP) | 75.938 percentage reduction | Standard Error 7.2788 |
| ALN-CC5 Multiple Dose - Eculizumab Treated | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Classical Pathway (CCP) | 21.333 percentage reduction | Standard Error 20.2816 |
| ALN-CC5 Multiple Dose - Eculizumab Naive | Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Classical Pathway (CCP) | 87.606 percentage reduction | Standard Error 4.9981 |
Secondary
Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (23-mer)
Area under the plasma concentration-time curve over the dosing interval zero to time (AUC 0-t) of ALN-CC5 (cemdisiran) 23-mer.
Time frame: Part A: 0-48 hrs, Day 0; Part B (weekly dosing cohorts): 0-48 hrs, Day 28; Part B (biweekly, weekly/monthly/biweekly/monthly cohorts): 0-48 hrs, Day 84; Part C: 0- 24 hrs, Day 84
Population: All healthy volunteers/patients who received at least one dose of study drug, and who had evaluable plasma or urine PK concentration. For the ALN-CC5 Multiple Dose - Eculizumab Naive group, Day 84 plasma samples were not collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (23-mer) | 258 h*ng/mL | Standard Deviation 58.6 |
| ALN-CC5 50mg - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (23-mer) | 277 h*ng/mL | Standard Deviation 40.9 |
| ALN-CC5 50mg (Japanese) - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (23-mer) | 2290 h*ng/mL | Standard Deviation 362 |
| ALN-CC5 200mg - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (23-mer) | 2470 h*ng/mL | Standard Deviation 505 |
| ALN-CC5 200mg (Japanese) - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (23-mer) | 5450 h*ng/mL | Standard Deviation 1630 |
| ALN-CC5 400mg - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (23-mer) | 10040 h*ng/mL | Standard Deviation 3200 |
| ALN-CC5 600mg - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (23-mer) | 9720 h*ng/mL | Standard Deviation 2260 |
| ALN-CC5 600mg (Japanese) - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (23-mer) | 21540 h*ng/mL | Standard Deviation 9930 |
| ALN-CC5 900mg - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (23-mer) | 16.0 h*ng/mL | Standard Deviation 7.71 |
| Placebo - Multiple Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (23-mer) | 22.3 h*ng/mL | Standard Deviation 9.03 |
| ALN-CC5 100mg Weekly - Multiple Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (23-mer) | 88.8 h*ng/mL | Standard Deviation 8.95 |
| ALN-CC5 200mg Weekly - Multiple Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (23-mer) | 14520 h*ng/mL | Standard Deviation 2290 |
| ALN-CC5 400mg Weekly - Multiple Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (23-mer) | 2420 h*ng/mL | Standard Deviation 668 |
| ALN-CC5 600mg Biweekly - Multiple Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (23-mer) | 1700 h*ng/mL | Standard Deviation 219 |
| ALN-CC5 200mg Weekly/Biweekly - Multiple Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (23-mer) | 2930 h*ng/mL | Standard Deviation 13 |
Secondary
Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (25-mer)
Area under the plasma concentration-time curve over the dosing interval zero to time (AUC 0-t) of ALN-CC5 (cemdisiran) 25-mer.
Time frame: Part A: 0-48 hrs, Day 0; Part B (weekly dosing cohorts): 0-48 hrs, Day 28; Part B (biweekly, weekly/monthly/biweekly/monthly cohorts): 0-48 hrs, Day 84; Part C: 0- 24 hrs, Day 84
Population: All healthy volunteers/patients who received at least one dose of study drug, and who had evaluable plasma or urine PK concentration. For the ALN-CC5 Multiple Dose - Eculizumab Naive group, Day 84 plasma samples were not collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (25-mer) | 6.63 h*ng/mL | Standard Deviation 3.71 |
| ALN-CC5 50mg - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (25-mer) | 7.50 h*ng/mL | Standard Deviation 4.65 |
| ALN-CC5 50mg (Japanese) - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (25-mer) | 182 h*ng/mL | Standard Deviation 101 |
| ALN-CC5 200mg - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (25-mer) | 198 h*ng/mL | Standard Deviation 113 |
| ALN-CC5 200mg (Japanese) - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (25-mer) | 287 h*ng/mL | Standard Deviation 67.2 |
| ALN-CC5 400mg - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (25-mer) | 574 h*ng/mL | Standard Deviation 15.6 |
| ALN-CC5 600mg - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (25-mer) | 444 h*ng/mL | Standard Deviation 78.2 |
| ALN-CC5 600mg (Japanese) - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (25-mer) | 757 h*ng/mL | Standard Deviation 154 |
| ALN-CC5 900mg - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (25-mer) | 10.5 h*ng/mL | Standard Deviation 1.31 |
| Placebo - Multiple Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (25-mer) | 15.8 h*ng/mL | Standard Deviation 3.82 |
| ALN-CC5 100mg Weekly - Multiple Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (25-mer) | 40.6 h*ng/mL | Standard Deviation 8.44 |
| ALN-CC5 200mg Weekly - Multiple Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (25-mer) | 843 h*ng/mL | Standard Deviation 472 |
| ALN-CC5 400mg Weekly - Multiple Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (25-mer) | 110 h*ng/mL | Standard Deviation 11.6 |
| ALN-CC5 600mg Biweekly - Multiple Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (25-mer) | 93.5 h*ng/mL | Standard Deviation 60.7 |
| ALN-CC5 200mg Weekly/Biweekly - Multiple Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (25-mer) | 203 h*ng/mL | Standard Deviation 51 |
Secondary
Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (23-mer)
Maximum observed plasma concentration (Cmax) of ALN-CC5 (cemdisiran) 23-mer.
Time frame: Part A: 0-48 hrs, Day 0; Part B (weekly dosing cohorts): 0-48 hrs, Day 28; Part B (biweekly, weekly/monthly/biweekly/monthly cohorts): 0-48 hrs, Day 84; Part C: 0- 24 hrs, Day 84
Population: All healthy volunteers/patients who received at least one dose of study drug, and who had evaluable plasma or urine PK concentration. For the ALN-CC5 Multiple Dose - Eculizumab Naive group, Day 84 plasma samples were not collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (23-mer) | 27.2 ng/mL | Standard Deviation 4.35 |
| ALN-CC5 50mg - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (23-mer) | 30.4 ng/mL | Standard Deviation 4.21 |
| ALN-CC5 50mg (Japanese) - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (23-mer) | 144 ng/mL | Standard Deviation 39.1 |
| ALN-CC5 200mg - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (23-mer) | 178 ng/mL | Standard Deviation 38.1 |
| ALN-CC5 200mg (Japanese) - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (23-mer) | 384 ng/mL | Standard Deviation 183 |
| ALN-CC5 400mg - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (23-mer) | 787 ng/mL | Standard Deviation 473 |
| ALN-CC5 600mg - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (23-mer) | 710 ng/mL | Standard Deviation 250 |
| ALN-CC5 600mg (Japanese) - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (23-mer) | 1500 ng/mL | Standard Deviation 966 |
| ALN-CC5 900mg - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (23-mer) | 32.0 ng/mL | Standard Deviation 15.4 |
| Placebo - Multiple Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (23-mer) | 44.7 ng/mL | Standard Deviation 18.1 |
| ALN-CC5 100mg Weekly - Multiple Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (23-mer) | 178 ng/mL | Standard Deviation 17.9 |
| ALN-CC5 200mg Weekly - Multiple Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (23-mer) | 1080 ng/mL | Standard Deviation 243 |
| ALN-CC5 400mg Weekly - Multiple Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (23-mer) | 167 ng/mL | Standard Deviation 41 |
| ALN-CC5 600mg Biweekly - Multiple Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (23-mer) | 103 ng/mL | Standard Deviation 8.48 |
| ALN-CC5 200mg Weekly/Biweekly - Multiple Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (23-mer) | 242 ng/mL | Standard Deviation 78.5 |
Secondary
Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (25-mer)
Maximum observed plasma concentration (Cmax) of ALN-CC5 (cemdisiran) 25-mer.
Time frame: Part A: 0-48 hrs, Day 0; Part B (weekly dosing cohorts): 0-48 hrs, Day 28; Part B (biweekly, weekly/monthly/biweekly/monthly cohorts): 0-48 hrs, Day 84; Part C: 0- 24 hrs, Day 84
Population: All healthy volunteers/patients who received at least one dose of study drug, and who had evaluable plasma or urine PK concentration. For the ALN-CC5 Multiple Dose - Eculizumab Naive group, Day 84 plasma samples were not collected.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (25-mer) | 14.4 ng/mL | Standard Deviation 2.33 |
| ALN-CC5 50mg - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (25-mer) | 13.5 ng/mL | Standard Deviation 4.38 |
| ALN-CC5 50mg (Japanese) - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (25-mer) | 69.8 ng/mL | Standard Deviation 22.8 |
| ALN-CC5 200mg - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (25-mer) | 93.9 ng/mL | Standard Deviation 30.8 |
| ALN-CC5 200mg (Japanese) - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (25-mer) | 111 ng/mL | Standard Deviation 6.56 |
| ALN-CC5 400mg - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (25-mer) | 166 ng/mL | Standard Deviation 42.7 |
| ALN-CC5 600mg - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (25-mer) | 217 ng/mL | Standard Deviation 73.1 |
| ALN-CC5 600mg (Japanese) - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (25-mer) | 261 ng/mL | Standard Deviation 79.5 |
| ALN-CC5 900mg - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (25-mer) | 21.0 ng/mL | Standard Deviation 2.62 |
| Placebo - Multiple Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (25-mer) | 31.5 ng/mL | Standard Deviation 7.64 |
| ALN-CC5 100mg Weekly - Multiple Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (25-mer) | 81.2 ng/mL | Standard Deviation 16.9 |
| ALN-CC5 200mg Weekly - Multiple Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (25-mer) | 283 ng/mL | Standard Deviation 17 |
| ALN-CC5 400mg Weekly - Multiple Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (25-mer) | 61.7 ng/mL | Standard Deviation 24.1 |
| ALN-CC5 600mg Biweekly - Multiple Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (25-mer) | 47.3 ng/mL | Standard Deviation 16.4 |
| ALN-CC5 200mg Weekly/Biweekly - Multiple Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (25-mer) | 74.1 ng/mL | Standard Deviation 22 |
Secondary
Pharmacokinetic (PK) Effect of ALN-CC5: T Max (23-mer)
Time of maximum observed plasma concentration (T max) of ALN-CC5 (cemdisiran) 23-mer.
Time frame: Part A: 0-48 hrs, Day 0; Part B (weekly dosing cohorts): 0-48 hrs, Day 28; Part B (biweekly, weekly/monthly/biweekly/monthly cohorts): 0-48 hrs, Day 84; Part C: 0- 24 hrs, Day 84
Population: All healthy volunteers/patients who received at least one dose of study drug, and who had evaluable plasma or urine PK concentration. For the ALN-CC5 Multiple Dose - Eculizumab Naive group, Day 84 plasma samples were not collected.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: T Max (23-mer) | 8.00 hr |
| ALN-CC5 50mg - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: T Max (23-mer) | 8.00 hr |
| ALN-CC5 50mg (Japanese) - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: T Max (23-mer) | 8.00 hr |
| ALN-CC5 200mg - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: T Max (23-mer) | 6.00 hr |
| ALN-CC5 200mg (Japanese) - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: T Max (23-mer) | 12.00 hr |
| ALN-CC5 400mg - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: T Max (23-mer) | 4.00 hr |
| ALN-CC5 600mg - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: T Max (23-mer) | 1.00 hr |
| ALN-CC5 600mg (Japanese) - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: T Max (23-mer) | 6.00 hr |
| ALN-CC5 900mg - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: T Max (23-mer) | 1.00 hr |
| Placebo - Multiple Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: T Max (23-mer) | 1.00 hr |
| ALN-CC5 100mg Weekly - Multiple Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: T Max (23-mer) | 1.00 hr |
| ALN-CC5 200mg Weekly - Multiple Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: T Max (23-mer) | 7.00 hr |
| ALN-CC5 400mg Weekly - Multiple Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: T Max (23-mer) | 4.00 hr |
| ALN-CC5 600mg Biweekly - Multiple Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: T Max (23-mer) | 8.00 hr |
| ALN-CC5 200mg Weekly/Biweekly - Multiple Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: T Max (23-mer) | 7.55 hr |
Secondary
Pharmacokinetic (PK) Effect of ALN-CC5: T Max (25-mer)
Time of maximum observed plasma concentration (T max) of ALN-CC5 (cemdisiran) 25-mer.
Time frame: Part A: 0-48 hrs, Day 0; Part B (weekly dosing cohorts): 0-48 hrs, Day 28; Part B (biweekly, weekly/monthly/biweekly/monthly cohorts): 0-48 hrs, Day 84; Part C: 0- 24 hrs, Day 84
Population: All healthy volunteers/patients who received at least one dose of study drug, and who had evaluable plasma or urine PK concentration. For the ALN-CC5 Multiple Dose - Eculizumab Naive group, Day 84 plasma samples were not collected.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: T Max (25-mer) | 0.50 hr |
| ALN-CC5 50mg - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: T Max (25-mer) | 0.50 hr |
| ALN-CC5 50mg (Japanese) - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: T Max (25-mer) | 0.50 hr |
| ALN-CC5 200mg - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: T Max (25-mer) | 0.50 hr |
| ALN-CC5 200mg (Japanese) - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: T Max (25-mer) | 0.50 hr |
| ALN-CC5 400mg - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: T Max (25-mer) | 0.50 hr |
| ALN-CC5 600mg - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: T Max (25-mer) | 0.50 hr |
| ALN-CC5 600mg (Japanese) - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: T Max (25-mer) | 1.00 hr |
| ALN-CC5 900mg - Single Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: T Max (25-mer) | 1.00 hr |
| Placebo - Multiple Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: T Max (25-mer) | 1.0 hr |
| ALN-CC5 100mg Weekly - Multiple Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: T Max (25-mer) | 1.0 hr |
| ALN-CC5 200mg Weekly - Multiple Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: T Max (25-mer) | 0.75 hr |
| ALN-CC5 400mg Weekly - Multiple Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: T Max (25-mer) | 0.50 hr |
| ALN-CC5 600mg Biweekly - Multiple Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: T Max (25-mer) | 1.00 hr |
| ALN-CC5 200mg Weekly/Biweekly - Multiple Ascending Dose | Pharmacokinetic (PK) Effect of ALN-CC5: T Max (25-mer) | 1.00 hr |