Clinical trial NCT02955420: A Study to Investigate the Safety, Tolerability, Pharmacokinetics and Efficacy of BC 007 in Healthy Subjects
Official title: A Three-part, Randomized Study to Investigate the Safety, Tolerability, Pharmacokinetics and Efficacy of BC 007 in Healthy, Young Subjects and Elderly Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteers
Keywords: Autoantibodies
Heart Failure
Fatigue Syndrome, Chronic
Idiopathic Pulmonary Hypertension
Cardiomyopathies
Lead sponsor: Berlin Cures GmbH
Sponsor class: INDUSTRY
First posted: 2016-11-04
Enrollment: 74
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Berlin Cures develops BC 007 to treat patients suffering from diseases (chronic heart failure, pulmonary hypertension, chronic fatigue syndrome etc.) which are associated with functional autoantibodies (AAB) directed against G-protein coupled receptors (GPCR).

The first part of the study (part A) is designed to evaluate the safety and tolerability of ascending doses of BC 007. The study part is blinded and placebo controlled in order to better discriminate possible safety signals. The assessment of safety and tolerability in an elderly cohort is a bridge to dosing elderly GPCR AAB positive subjects in part B. The subjects in part A are confirmed to be GPCR AAB negative.

The objective of the second part of the study (part B) is to evaluate the efficacy of BC 007 in neutralizing AAB against GPCR shortly after dosing compared to baseline and to find the optimal dose for the neutralization of the AAB in all individuals. This dose shall be taken to progress into a Phase II/III trial with beta1-adrenergic receptor-AAB positive patients suffering from chronic heart failure.

Detailed description: Part A

Primary objective is:

* To assess safety and tolerability of BC 007 after a single ascending intravenous (i.v.) bolus + infusion in healthy, young and elderly subjects.

Secondary objectives are:

* To determine the pharmacokinetic plasma and urine profiles of BC 007 in healthy, young and elderly subjects.

Part B

Primary objective is:

* To assess the neutralizing potency of BC 007 against GPCR autoantibodies alpha -1 adrenergic receptor, beta-1 adrenergic receptor, beta-2 adrenergic receptor or endothelin-A-receptor following ascending i.v. bolus + infusion.

Secondary objectives are:

* To assess safety and tolerability of BC 007 after a single ascending i.v. bolus + infusion in GPCR AAB (α(1)-adrenergic receptor AAB, ß(1)-adrenergic receptor AAB, ß(2)-adrenergic receptor AAB or endothelin-A-receptor AAB) positive healthy elderly subjects.
* To determine the pharmacokinetic plasma and urine profiles of BC 007 in GPCR AAB (α(1)-adrenergic receptor AAB, ß(1)-adrenergic receptor AAB, ß(2)-adrenergic receptor AAB or endothelin-A-receptor AAB) positive healthy elderly subjects.

Part C

Primary Objective

* To assess the neutralizing potency of BC 007 against GPCR autoantibodies alpha-1 adrenergic receptor (α(1)-AR AAB), beta-1 adrenergic receptor (ß(1)-AR AAB), beta-2 adrenergic receptor (ß(2)-AR AAB) or endothelin-A-receptor (ETA AAB) following ascending i.v. bolus + infusion.

Secondary Objectives

* To assess safety and tolerability of BC 007 after a single ascending i.v. bolus + infusion in GPCR AAB (α(1)-AR AAB, ß(1)-AR AAB, ß(2)-AR AAB or ETA AAB) positive healthy elderly subjects.
* To determine the pharmacokinetic plasma and urine profiles of BC 007 in GPCR AAB (α(1)-AR AAB, ß(1)-AR AAB, ß(2)-AR AAB or ETA AAB) positive healthy elderly subjects.

Explorative Objective

* To investigate the pharmacokinetic plasma and urine profiles of BC 007 metabolites in GPCR AAB (α(1)-AR AAB, ß(1)-AR AAB, ß(2)-AR AAB or ETA AAB) positive healthy elderly subjects

Eligibility criteria: Inclusion Criteria (main):

1. The subject is a healthy, male, non-smoker or slight/occasional smoker (less than or equal to 10 cigarettes per day), 18 to 45 years of age (Cohorts 1 to 3, Part A).
2. The subject is a healthy, male or female, non-smoker or slight/occasional smoker (less than or equal to10 cigarettes per day), 55 to 70 years of age (Cohort 4 \[only in Part A\] and Part B).
3. Female subjects are postmenopausal (verified by an appropriate serum FSH level and amenorrhea for at least one year).
4. The subject has a body mass index (BMI) range of 18.5 to 29.9 kg/m2 inclusive, (healthy young males as well as elderly subjects) and weighs at least 50 kg and \< 100 kg.
5. The subject is positive for either one or the combination of GPCR α(1)- adrenergic receptor AAB, ß(1)-adrenergic receptor AAB, ß(2)-adrenergic receptor AAB and endothelin-A-receptor AAB (Part B only) at (pre-) screening prior to enrolment.
6. The subject is negative for GPCR α(1)-adrenergic receptor AAB, ß(1)-adrenergic receptor AAB, ß(2)-adrenergic receptor AAB and endothelin-A-receptor AAB at (pre-)screening prior to enrolment (Part A only).
7. Coagulation variables, uric acid, ALT, AST, alkaline phosphatase (ALP), GGT, bilirubin and creatinine must be within the normal laboratory reference ranges at screening.
8. Thyroid-stimulating hormone (TSH) must be within the normal laboratory reference range at screening.

Exclusion Criteria (main):

1. Any history or evidence of any clinically significant cardiovascular, gastrointestinal, endocrinologic, hematologic, hepatic, immunologic, metabolic (specifically gout), urologic, pulmonary, neurologic, dermatologic, psychiatric, renal, and/or other major disease or malignancy, as judged by the Investigator.
2. Any history or current intake of beta blockers.
3. Any history of allergic reactions.

Primary outcomes:
measure: Part A: Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment
timeFrame: 24 hours post dose
measure: Part B: Conversion rate from positive GPCR AAB to negative immune status
timeFrame: 24 hours post dose
measure: Part C: Conversion rate from positive GPCR AAB to negative immune status
timeFrame: 24 hours and 8-12 days post dose
Secondary outcomes:
measure: Part A, B and C: Area under the plasma concentration time curve (AUC) from time zero to the last quantifiable concentration (AUC0-t) derived from BC 007 plasma concentrations
timeFrame: 24 hours post dose
measure: Part A, B and C: Area under the plasma concentration time curve (AUC) from time zero extrapolated to infinity (AUC0-inf) derived from BC 007 plasma concentrations
timeFrame: 24 hours post dose
measure: Part A, B and C: AUC from time zero to 24 hour post-dose (AUC0-24) derived from BC 007 plasma concentrations
timeFrame: 24 hours post dose
measure: Part A, B and C: Maximum observed plasma concentration (Cmax) derived from BC 007 plasma concentrations
timeFrame: 24 hours post dose
measure: Part A, B and C: Apparent terminal half-life (t1/2) derived from BC 007 plasma concentrations
timeFrame: 24 hours post dose
measure: Part A, B and C: Nominal time of Cmax (tmax) derived from BC 007 plasma concentrations
timeFrame: 24 hours post dose
measure: Part A, B and C: Plasma clearance (CL) derived from BC 007 plasma concentrations
timeFrame: 24 hours post dose
measure: Part A, B and C: Volume of distribution during terminal phase (Vz) derived from BC 007 plasma concentrations
timeFrame: 24 hours post dose
measure: Part A, B and C: Terminal elimination rate constant (λz) derived from BC 007 plasma concentrations
timeFrame: 24 hours post dose
measure: A, B and C: Cumulative amount of unchanged drug excreted into urine (Ae)
timeFrame: 24 hours post dose
measure: A, B and C: Fraction of intravenous administered drug that is excreted unchanged in urine (fe)
timeFrame: 24 hours post dose
measure: Part A, B and C: Renal clearance (CLR) of BC 007
timeFrame: 24 hours post dose
measure: Part A, B and C: Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment
timeFrame: 24 hours post dose
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: PAREXEL International GmbH, Early Phase Clinical Unit Berlin
Study officials:
affiliation: Parexel
name: Angela Sinn, Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Becker NP, Haberland A, Wenzel K, Gottel P, Wallukat G, Davideit H, Schulze-Rothe S, Honicke AS, Schimke I, Bartel S, Grossmann M, Sinn A, Iavarone L, Boergermann JH, Prilliman K, Golor G, Muller J, Becker S. A Three-Part, Randomised Study to Investigate the Safety, Tolerability, Pharmacokinetics and Mode of Action of BC 007, Neutraliser of Pathogenic Autoantibodies Against G-Protein Coupled Receptors in Healthy, Young and Elderly Subjects. Clin Drug Investig. 2020 May;40(5):433-447. doi: 10.1007/s40261-020-00903-9.