Study Assessing Safety, Immunogenicity and LDLc -Lowering Activity of 2 PCSK9 Targeting AFFITOPE Vaccines in Healthy Subjects (AFF012)

A Single-blind Phase 1 Study Assessing the Safety, Immunogenicity and Low Density Lipoprotein Cholesterol (LDLc)-Lowering Activity of 2 Different Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Targeting AFFITOPE® Vaccines in Healthy Subjects

Study AFF012 is a single blind, single-center, randomized, placebo-controlled, parallel group, phase I clinical trial of repeated administration by subcutaneous injection of a single dose of one of two different proprotein convertase subtilisin/kexin type 9 targeting AFFITOPE® vaccines or Placebo. This study will assess Safety, Immunogenicity and low density lipoprotein cholesterol-lowering activity of the two vaccines.

72 healthy subjects are divided into three test groups (2 treatment groups, 1 placebo group), each consisting of 24 subjects. The subjects are randomized to receive either of two AFFITOPEs® (AT04A or AT06A, adsorbed to 1 mg aluminium oxyhydroxide) or placebo (1 mg aluminium oxyhydroxide).

The study consists of 3 parts, part A, encompassing Visit 1 to Visit 8, covering 3 priming immunizations at a dose of 15μg at days 0, 28 and 56 and the immediate observation period extending to day 140; the prolonged observation period: part B, encompassing Visit 9 and Visit 10 at days 273 and 365; and part C consisting of 7 visits (V11 to V17). Study participants having received 3 priming vaccinations and having completed part B will receive in part C one boost immunization at a dose of 75μg, which will be applied one year after the 3rd immunization (day 420). Probands will proceed directly from part A to part B and to part C. Continuation of parts B and C will be considered based on the part A results, primarily the immunological results. The following scenarios apply (provided that there is no safety issue). None of the two treatment groups exhibits a vaccine-specific antibody response over the placebo group at Visit 8 - this will lead to termination of the trial. One of the two groups fails to exhibit a vaccine-specific antibody response over the placebo group at Visit 8 - this will lead to its discontinuation; the other treatment group and the placebo group will be continued.

Study Overview

• Status: Completed
• Conditions: Hypercholesterolemia
• Intervention / Treatment: Biological: AFFITOPE® AT04A+adjuvant; Biological: AFFITOPE® AT06A+adjuvant; Biological: Adjuvant without active component

• Study Type: Interventional
• Enrollment (Actual): 72
• Phase: Phase 1

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Medical University of Vienna

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Subjects ≥ 18 years of age at time of study entry.
2. Fasting LDLc at screening.
3. Fasting triglycerides at screening.
4. Body weight > 50 kg and a body mass index (BMI) between 19 and 35.

Exclusion Criteria:

1. Treatment/change in treatment with medications known to influence HDLc, LDLc and total cholesterol concentrations
2. Planned life-style changes during the study period like increasing aerobic exercise activity, attempting to lose body weight or changing the smoking status.
3. History of autoimmune diseases.
4. History of malignancy
5. Active or passive vaccination
6. Blood donation
7. History of severe hypersensitivity reactions and anaphylaxis.
8. History of allergic bronchial asthma.
9. Acquired or hereditary immunodeficiency.
10. Prior and/or current treatment with immune modulating drugs:
11. Subject has taken prescription lipid-regulating drugs
12. Treatment prior to screening with the following drugs: vitamin A derivatives and retinol derivatives for dermatologic treatment or any other drug known to influence cholesterol Levels
13. Infection with the human immunodeficiency Virus,Hepatitis B (HBsAg) or Hepatitis C.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AFFITOPE® AT04A+adjuvant; 3 injections of 15µg AFFITOPE® AT04A+adjuvant once every 4 weeks and 1 boost immunization at a dose of 75μg, which will be applied one year after the 3rd immunization	Biological: AFFITOPE® AT04A+adjuvant; subcutaneous injection
Experimental: AFFITOPE® AT06A+adjuvant; 3 injections of 15µg AFFITOPE® AT06A+adjuvant once every 4 weeks and 1 boost immunization at a dose of 75μg, which will be applied one year after the 3rd immunization	Biological: AFFITOPE® AT06A+adjuvant; subcutaneous injection
Placebo Comparator: Adjuvant without active component; 3 injections of Placebo once every 4 weeks and 1 boost immunization which will be applied one year after the 3rd immunization	Biological: Adjuvant without active component; subcutaneous injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurence of any Serious Adverse Event (SAE)	Evaluation of SAE being unlikely, possibly, probably or definitely related to the study vaccines Occurence of any Grade 3 or higher adverse Event (AE) Occurence of solicited local AEs Occurence of solicited systemic AEs Occurence of unsolicited non-serious AEs	21 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immunological activity of AFFITOPE® AT04A: Titer of vaccination-induced antibodies	Titer of vaccination-induced antibodies directed towards peptide components of the vaccine, the carrier, and the target proprotein convertase subtilisin/kexin type 9	21 months
Immunological activity of AFFITOPE® AT06A: Titer of vaccination-induced antibodies	Titer of vaccination-induced antibodies directed towards peptide components of the vaccine, the carrier, and the target proprotein convertase subtilisin/kexin type 9	21 months
Mean Levels of Low Density Lipoprotein Cholesterol (LDLc)	Change from baseline	21 months
Mean Levels of High Density Lipoprotein Cholesterol (HDLc)	Change from baseline	21 months
Mean Levels of Very Low Density Lipoprotein (VLDL)	Change from baseline	21 months
Mean Levels of Total Cholesterol (TC)	Change from baseline	21 months
Mean Levels of Triglycerides (TG)	Change from baseline	21 months
Mean Levels of PCSK9	Change from baseline	21 months
Correlation analysis: Relating the strength of antibody responses to Lipid lowering effects	Relating the strength of antibody responses to Lipid lowering effects	21 months

Collaborators and Investigators

• Sponsor: Affiris AG
• Collaborators: Medical University of Vienna
• Investigators: Principal Investigator: Markus Zeitlinger, MD, Medical University of Vienna

Publications and helpful links

General Publications

• Zeitlinger M, Bauer M, Reindl-Schwaighofer R, Stoekenbroek RM, Lambert G, Berger-Sieczkowski E, Lagler H, Oesterreicher Z, Wulkersdorfer B, Luhrs P, Galabova G, Schwenke C, Mader RM, Medori R, Landlinger C, Kutzelnigg A, Staffler G. A phase I study assessing the safety, tolerability, immunogenicity, and low-density lipoprotein cholesterol-lowering activity of immunotherapeutics targeting PCSK9. Eur J Clin Pharmacol. 2021 Oct;77(10):1473-1484. doi: 10.1007/s00228-021-03149-2. Epub 2021 May 10.

Study record dates

Study Major Dates

• Study Start: July 1, 2015
• Primary Completion (Actual): May 1, 2016
• Study Completion (Actual): August 31, 2017

Study Registration Dates

• First Submitted: July 24, 2015
• First Submitted That Met QC Criteria: July 24, 2015
• First Posted (Estimate): July 27, 2015

Study Record Updates

• Last Update Posted (Actual): October 20, 2017
• Last Update Submitted That Met QC Criteria: October 19, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Hypercholesterolemia
• Other Study ID Numbers: AFFiRiS 012; 2015-001719-11 (EudraCT Number)