A Study of ALN-PCSSC in Participants With Homozygous Familial Hypercholesterolemia (HoFH) (ORION-2)

An Open-Label, Single-Arm, Multicenter Pilot Study to Evaluate Safety, Tolerability, and Efficacy of ALN-PCSSC in Subjects With Homozygous Familial Hypercholesterolemia (HoFH)

The purpose of this study is to assess the safety, tolerability, and efficacy of ALN-PCSSC in participants with homozygous familial hypercholesterolemia.

Study Overview

• Status: Completed
• Conditions: Homozygous Familial Hypercholesterolemia
• Intervention / Treatment: Drug: ALN-PCSSC; Drug: Standard of Care

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands
    • Research Site 231001
• South Africa
  • Johannesburg
    • Parktown, Johannesburg, South Africa, 2193
      • Research Site 227001
• United States
  • California
    • Los Angeles, California, United States, 90001
      • Research Site 201001

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Males and females, ≥12 years of age with a diagnosis of homozygous familial hypercholesterolemia by genetic confirmation or a clinical diagnosis based on a history of an untreated low-density lipoprotein cholesterol (LDL-C) concentration >500 mg/deciliter (dL) [13 millimoles/liter (mmol/L)] together with either xanthoma before 10 years of age or evidence of heterozygous familial hypercholesterolemia in both parents.
• Stable on a low-fat diet.
• Stable on pre-existing, lipid-lowering therapies (such as statins, cholesterolabsorption inhibitors, bile-acid sequestrants, or combinations thereof) for at least 4 weeks with no planned medication or dose change for the duration of study participation.
• Fasting central lab LDL-C concentration >130 mg/dL (3.4 mmol/L) and triglyceride concentration <400 mg/dL (4.5 mmol/L).
• Body weight of 40 kilograms (kg) or greater at screening.

Exclusion Criteria:

• LDL or plasma apheresis within 8 weeks prior to the screening visit, and no plan to receive it during the study because of the attendant difficulty in maintaining stable concentrations of LDL-C while receiving apheresis.
• Use of mipomersen or lomitapide therapy within 5 months of screening.
• Previous treatment with monoclonal antibodies directed towards PCSK9 within 8 weeks of screening.

The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: ALN-PCSSC; 300 milligrams (mg) administered subcutaneous (SC) on Day 1. Participants with a mean serum proprotein convertase subtilisin/kexin type 9 (PCSK9) levels not suppressed by >70% at Day 60 or Day 90, as compared to baseline, will receive a second dose at Day 90 or Day 104, respectively, based on PCSK9 levels from the previous visit. Participants also received standard of care as background therapy.

Drug: ALN-PCSSC; ALN-PCSSC is a small interfering ribonucleic acid (siRNA) that inhibits PCSK9 synthesis and is given as SC injections.; Other Names: PCSK9 synthesis inhibitor; Drug: Standard of Care; Included maximally-tolerated statin therapy and/or other low density lipoprotein-cholesterol (LDL-C)-lowering therapies.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage Change From Day 1 to Day 90 in LDL-C	Due to the small number of subjects, and the fact that the data are not normally distributed, the data are presented as descriptive statistics with no inferential and limited summary statistics presented.	Day 1, Day 90
Percentage Change From Day 1 to Day 180 (or Final Visit) in LDL-C		Day 1, Day 180 (or Final Visit)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in LDL-C		Day 1, Day 90, Day 180 (or Final Visit)
Percentage Change From Day 1 to Day 60 and to Day 90 in PCSK9		Day 1, Day 60, Day 90
Absolute Change From Day 1 to Day 60 and to Day 90 in PCSK9		Day 1, Day 60, Day 90
Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Total Cholesterol		Day 1, Day 90, Day 180 (or Final Visit)
Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Total Cholesterol		Day 1, Day 90, Day 180 (or Final Visit)
Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Triglycerides		Day 1, Day 90, Day 180 (or Final Visit)
Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Triglycerides		Day 1, Day 90, Day 180 (or Final Visit)
Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in HDL-C		Day 1, Day 90, Day 180 (or Final Visit)
Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in HDL-C		Day 1, Day 90, Day 180 (or Final Visit)
Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Non-HDL-C		Day 1, Day 90, Day 180 (or Final Visit)
Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Non-HDL-C		Day 1, Day 90, Day 180 (or Final Visit)
Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in VLDL-C		Day 1, Day 90, Day 180 (or Final Visit)
Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in VLDL-C		Day 1, Day 90, Day 180 (or Final Visit)
Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Apolipoprotein A1		Day 1, Day 90, Day 180 (or Final Visit)
Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Apolipoprotein A1		Day 1, Day 90, Day 180 (or Final Visit)
Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Apolipoprotein B		Day 1, Day 90, Day 180 (or Final Visit)
Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Apolipoprotein B		Day 1, Day 90, Day 180 (or Final Visit)
Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Lipoprotein-a	The reported percent change value is the per participant calculated Mean.	Day 1, Day 90, Day 180 (or Final Visit)
Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Lipoprotein-a		Day 1, Day 90, Day 180 (or Final Visit)

Collaborators and Investigators

• Sponsor: The Medicines Company
• Investigators: Principal Investigator: Kees Hovingh, MD, PhD, Department of Vascular Medicine, Academic Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): December 13, 2016
• Primary Completion (Actual): October 8, 2018
• Study Completion (Actual): October 8, 2018

Study Registration Dates

• First Submitted: November 10, 2016
• First Submitted That Met QC Criteria: November 10, 2016
• First Posted (Estimate): November 15, 2016

Study Record Updates

• Last Update Posted (Actual): May 18, 2020
• Last Update Submitted That Met QC Criteria: May 14, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Lipid Metabolism, Inborn Errors; Hyperlipoproteinemias; Hypercholesterolemia; Hyperlipoproteinemia Type II
• Other Study ID Numbers: MDCO-PCS-16-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No