A Study to Investigate the Safety, Tolerability, Pharmacokinetics and Efficacy of BC 007 in Healthy Subjects

Study Overview
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Brief Summary
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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
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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

Official Title
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A Three-part, Randomized Study to Investigate the Safety, Tolerability, Pharmacokinetics and Efficacy of BC 007 in Healthy, Young Subjects and Elderly Subjects

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: BC 007
* Drug: NaCl 0.9 %


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (main): 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). 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). Female subjects are postmenopausal (verified by an appropriate serum FSH level and amenorrhea for at least one year). 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. 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. 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). Coagulation variables, uric acid, ALT, AST, alkaline phosphatase (ALP), GGT, bilirubin and creatinine must be within the normal laboratory reference ranges at screening. Thyroid-stimulating hormone (TSH) must be within the normal laboratory reference range at screening. Exclusion Criteria (main): 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. Any history or current intake of beta blockers. Any history of allergic reactions.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BC 007 (15, 50, 150, 300, 450, 750, 1350, 1200 mg)<br>Part A: BC 007 at doses of 15, 50 and 150 mg or matching placebo administered as i.v. bolus + infusion of 20 min (Cohorts 1 to 4). The sentinel pair of each cohort will be dosed without bolus. NaCl 0.9% (matching placebo) administered as i.v. bolus + infusion of 20 min (Part A: Cohorts 1 to 4). Part B: BC 007 at doses of 50 and 150 mg administered (Cohort 1) or a single dose < 50 mg or 150 mg (Cohort 2) as i.v. bolus + infusion of 20 min is administered to GPCR autoantibody positive subjects. The first subject in each dosing period of Cohort 1 will be dosed without bolus. Part C: BC007 administered at doses of 300 mg (Cohort 1), 450 mg (Cohort 2), 750 mg (Cohort 3), 1350 mg (Cohort 4) as i.v. bolus + infusion of 40 min to GPCR autoantibody positive subjects. The first three subjects in each dosing period of Cohort 1-4 will be dosed without bolus. In Cohort 5 BC007 dose of 1200 mg will be administered as a continuous infusion of 20 min. | Drug: BC 007<br> <br> Drug: NaCl 0.9 %<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment |  | 24 hours post dose | 
| Part B: Conversion rate from positive GPCR AAB to negative immune status |  | 24 hours post dose | 
| Part C: Conversion rate from positive GPCR AAB to negative immune status |  | 24 hours and 8-12 days post dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 |  | 24 hours post dose | 
| 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 |  | 24 hours post dose | 
| Part A, B and C: AUC from time zero to 24 hour post-dose (AUC0-24) derived from BC 007 plasma concentrations |  | 24 hours post dose | 
| Part A, B and C: Maximum observed plasma concentration (Cmax) derived from BC 007 plasma concentrations |  | 24 hours post dose | 
| Part A, B and C: Apparent terminal half-life (t1/2) derived from BC 007 plasma concentrations |  | 24 hours post dose | 
| Part A, B and C: Nominal time of Cmax (tmax) derived from BC 007 plasma concentrations |  | 24 hours post dose | 
| Part A, B and C: Plasma clearance (CL) derived from BC 007 plasma concentrations |  | 24 hours post dose | 
| Part A, B and C: Volume of distribution during terminal phase (Vz) derived from BC 007 plasma concentrations |  | 24 hours post dose | 
| Part A, B and C: Terminal elimination rate constant (λz) derived from BC 007 plasma concentrations |  | 24 hours post dose | 
| A, B and C: Cumulative amount of unchanged drug excreted into urine (Ae) |  | 24 hours post dose | 
| A, B and C: Fraction of intravenous administered drug that is excreted unchanged in urine (fe) |  | 24 hours post dose | 
| Part A, B and C: Renal clearance (CLR) of BC 007 |  | 24 hours post dose | 
| Part A, B and C: Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment |  | 24 hours post dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Autoantibodies, Heart Failure, Fatigue Syndrome, Chronic, Idiopathic Pulmonary Hypertension, Cardiomyopathies