Berlin Cures announces the start of the phase IIa trial for its β1-adrenoceptor autoantibody (β1-AAb) neutralizing ssDNA product BC 007. β1-AAbs have been identified as a relevant pathogenic cause of heart failure. BC 007 is now being tested as the first causative drug for patients with β1-AAb associated heart failure.
Heart failure is one of the most common causes of death in Western society and is becoming increasingly global. Its socioeconomic impact is enormous, equivalent to the impact caused by cancer. Although there has been progress in the treatment over the last decades, the largely symptomatic treatment has produced little to no resounding success curb this problem. With the discovery of agonistically acting autoantibodies which target G protein-coupled receptors (GPCR-AAb) such as the β1-adrenoceptor (β1-AAb) in heart failure, one of the main causal pathogenic principles was identified. The removal of these autoantibodies via an extracorporeal method, the immunoadsorption, already showed its enormous benefit for the patients as summarized by M. Dandel and colleagues in 2012 in Eur J Heart Fail (14:1374)
However, immunoadsorption has never been approved as a standard therapy for a variety of reasons related to patient burden and / or therapy costs. With the discovery of BC 007, an DNA-based therapeutic able to neutralize these autoantibodies in-vivo after infusion, a completely new option for widely applicable future causal treatment has opened. A successfully completed clinical phase I trial (NTC02955420) already included elderly, healthy but GPCR-AAb positive tested subjects. Here BC 007 neutralized the GPCR-AAbs in a dose-dependent manner (for more detail see J. Müller, The DNA-Based Drug BC 007 Neutralizes Agonistically Acting Autoantibodies Directed Against G Protein–Coupled Receptors– Successful Mode of Action Demonstrated in Clinical Phase 1 Trial, Chimica Oggi – Chemistry Today – vol. 37(2), Monographic special issue: Oligonucleotides & Peptides, 2019).
These phase I safety tests showed the excellent tolerability of BC 007 and the lack of clinically relevant side effects. Transient elevated aPTT to subclinical values, paralleling the infusion, were observed in some subjects especially at the higher dosing. BC 007 is rapidly metabolized down to its nucleic bases degradation products beta-aminoisobutyric acid and uric acid, beginning shortly after start of infusion as shown by Davideit and colleagues in 2019 in Eur J Drug Metab Pharmacokinet.
Now, in phase IIa, the temporal persistence of the β1-autoantibody neutralization after BC 007 infusion will be evaluated in chronic heart failure patients with reduced ejection fraction. Safety and the pharmacokinetic profile in patients will also be tested. It is a two-arm randomized, open-label study including twenty treated patients versus ten controls.
BC 007 is now being tested as the first causative drug for patients with β1-AAb associated heart failure.