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

Abstract

Background and Objective BC 007 is a substance with a novel and innovative mode of action for the first-time causal treatment of chronic heart failure, associated with the occurrence of autoantibodies against the β1-adrenoceptor, and other diseases of mostly the heart and vascular system, being accompanied by the occurrence of functionally active agonistic autoantibodies against G-protein-coupled receptors (f GPCR-AAb). The proposed mechanism of action of BC 007 is the neutralisation of these pathogenic autoantibodies which stimulate the respective receptor. To evaluate the safety, tolerability, pharmacokinetics and mode of action of BC 007, single intravenous infusions of increasing concentration were given to healthy young males and healthy elderly autoantibody-negative and autoantibody-positive participants of both sexes. Methods This study was subdivided into three parts. Part A was a single-centre, randomised, double-blind, placebo-controlled safety and tolerability study including healthy young male autoantibody-negative Whites (N = 23) and Asians (N = 1), testing doses of 15, 50 and 150 mg BC 007 (Cohorts 1-3) and elderly male and female Whites (N = 8), testing a dose of 150 mg BC 007 (Cohort 4), randomly assigned in a 3:1 ratio to BC 007 or placebo. Open-label Part B included f GPCR-AAbpositive subjects (50 and 150 mg BC 007, Cohorts 1 and 2, respectively). Open-label Part C included f GPCR-AAb-positive subjects for testing doses of 300, 450, 750, 1350 mg and 1900 mg BC 007. Lower doses were either given as an infusion or divided into a bolus plus infusion up to a dose of 300 mg followed by a constant bolus of 150 mg up to a dose of 750 mg, while at doses of 1350 mg and 1900 mg it was a slow infusion with a constant infusion rate. Infusion times increased with increasing dose from 20 min (15, 50 or 150 mg) to 40 min (300, 450 or 750 mg), 75 min (1350 mg) and 105 min (1900 mg). Results The mean observed BC 007 area under the concentration-time curve (AUC 0-24) increased with increasing dose in a dose proportional manner (slope estimate of 1.039). No serious adverse events were observed. Drug-related adverse events were predominantly the expected mild-to-moderate increase in bleeding time (aPTT), beginning with a dose of 50 mg, which paralleled the infusion and returned to normal shortly after infusion. f GPCR-AAb neutralisation efficiency increased with increasing dose and was achieved for all subjects in the last cohort. Conclusion BC 007 is demonstrated to be safe and well tolerated. BC 007 neutralised f GPCR-AAb, showing a trend for a dose-response relationship in elderly healthy but f GPCR-AAb-positive subjects. ClinicalTrials.gov Registration Number NCT02955420.

Aptamer BC 007 - Efficient binder of spreading-crucial SARS-CoV-2 proteins

“…Just using an existing developed aptamer in an “ trial and error set-up ”, might, especially in view of the medical urgency, also lead to valuable medicines that could be used very quickly in the combat against SARS-CoV-2. BC 007 had already undergone all preclinical and clinical toxicity and tolerability tests, without showing any toxicity, as well as an expected application accompanying anti-coagulatory effect [ 22 ]. The latter would, in view of the increased risk of COVID-19 associated thromboembolic events, be of additional advantage.…”

“…As its actual purpose is to neutralise pathogenic autoantibodies against G-protein coupled receptors [ 18 ] as they especially occur in diseases of the heart and circulatory system (for review see (Düngen et al., 2020)) and because it is currently in phase II of the clinical testing (NCT04192214), BC 007, is being given via slow infusion over e.g. one hour, circumventing its short in vivo half-life of 3–11 min (NCT02955420) [ 22 ]. In this way, the pharmacokinetics can excellently be controlled in the clinic, which is a fact that would also be of great benefit in the case of COVID-19 use.…”

“…In its current purpose BC 007 is able to neutralise pathogenic autoantibodies [ 18 , 19 ] as they occur in diseases of the heart and circulatory system [ 20 ] (for review see Düngen et al., 2020 [ 21 ]), and is already in phase II of the clinical testing (NCT04192214). In phase I (NCT02955420) it showed an excellent safety profile [ 22 ]. In the case of SARS-CoV-2 growth inhibition, re-purposing can be easily organised.…”

Aptamers against Immunoglobulins: Design, Selection and Bioanalytical Applications

“…These aptamers usually block the Fab domain of the antibody, thereby inhibit the binding between the autoantibody and the target, such as proteins, DNA or receptors. Aptamers were selected to detect Multiple Sclerosis (MS) [ 13 , 14 ], Systematic Lupus Erythematosus (SLE) [ 81 ], Dilated Cardiomyopathy (DCM), Chagas’ Cardiomyopathy (ChCM), Peripartum Cardiomyopathy (PPCM) [ 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 ], Extreme Insulin Resistance (type B) (T2DM) [ 90 , 91 ] and Myastenia gravis (MG) [ 92 , 93 , 94 , 95 , 96 ] with high affinity (K D ≈ 1.2–75 nM) at an early stage of the diseases. Moreover, 2′-F-Py (2′-fluoro pyrimidine) and 2′-A-Py (2′-amino pyrimidine) bases were widely used to increase the nuclease resistance of the aptamer.…”

Aptamer BC 007’s Affinity to Specific and Less-Specific Anti-SARS-CoV-2 Neutralizing Antibodies

“…BC 007 is currently in phase 2a of clinical testing in heart failure patients. In phase 1 of clinical testing, BC 007 showed excellent safety and tolerability profiles [ 2 ].…”