A Phase 1/2 Study of an Investigational Drug, ALN-CC5, in Healthy Adult Volunteers and Patients With PNH

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

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

Study Overview

• Status: Completed
• Conditions: Paroxysmal Nocturnal Hemoglobinuria (PNH)
• Intervention / Treatment: Drug: ALN-CC5; Drug: Sterile Normal Saline (0.9% NaCl)

• Study Type: Interventional
• Enrollment (Actual): 62
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain
    • Clinical Trial Site
• United Kingdom
  • Leeds, United Kingdom
    • Clinical Trial Site
  • Leeds, United Kingdom
    • Covance Clinical Research Unit
  • London, United Kingdom
    • Richmond Pharmacology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Sterile Normal Saline (0.9% NaCl)	Drug: Sterile Normal Saline (0.9% NaCl); calculated volume to match active comparator
Active Comparator: ALN-CC5	Drug: ALN-CC5; Single or multiple doses of ALN-CC5 by subcutaneous (sc) injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	Part A: through day 658; Part B: through day 532; Part C: through day 280

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Part A: through day 70; Part B: through day 140; Part C: through day 140
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.	Part A: through day 70; Part B: through day 140; Part C: through day 140
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.	Part A: through day 70; Part B: through day 140; Part C: through day 140
Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (25-mer)	Maximum observed plasma concentration (Cmax) of ALN-CC5 (cemdisiran) 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
Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (23-mer)	Maximum observed plasma concentration (Cmax) of ALN-CC5 (cemdisiran) 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
Pharmacokinetic (PK) Effect of ALN-CC5: T Max (25-mer)	Time of maximum observed plasma concentration (T max) of ALN-CC5 (cemdisiran) 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
Pharmacokinetic (PK) Effect of ALN-CC5: T Max (23-mer)	Time of maximum observed plasma concentration (T max) of ALN-CC5 (cemdisiran) 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
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.	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
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.	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

Collaborators and Investigators

• Sponsor: Alnylam Pharmaceuticals
• Investigators: Study Director: Nader Najafian, MD, Alnylam Pharmaceuticals

Publications and helpful links

General Publications

• Badri P, Jiang X, Borodovsky A, Najafian N, Kim J, Clausen VA, Goel V, Habtemariam B, Robbie GJ. Pharmacokinetic and Pharmacodynamic Properties of Cemdisiran, an RNAi Therapeutic Targeting Complement Component 5, in Healthy Subjects and Patients with Paroxysmal Nocturnal Hemoglobinuria. Clin Pharmacokinet. 2021 Mar;60(3):365-378. doi: 10.1007/s40262-020-00940-9. Erratum In: Clin Pharmacokinet. 2022 Jun;61(6):919.

Study record dates

Study Major Dates

• Study Start: January 1, 2015
• Primary Completion (Actual): April 1, 2016
• Study Completion (Actual): August 1, 2017

Study Registration Dates

• First Submitted: January 23, 2015
• First Submitted That Met QC Criteria: January 28, 2015
• First Posted (Estimate): February 2, 2015

Study Record Updates

• Last Update Posted (Actual): March 30, 2020
• Last Update Submitted That Met QC Criteria: March 17, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: RNAi therapeutic; PNH
• Additional Relevant MeSH Terms: Urologic Diseases; Urological Manifestations; Bone Marrow Diseases; Hematologic Diseases; Urination Disorders; Anemia; Proteinuria; Anemia, Hemolytic; Myelodysplastic Syndromes; Hemoglobinuria; Hemoglobinuria, Paroxysmal
• Other Study ID Numbers: ALN-CC5-001