title: Administration of the cyclic peptide COR-1 in humans (phase I study): ex vivo measurements of anti-β1-adrenergic receptor antibody neutralization and of immune parameters.
abstract: OBJECTIVE
  A novel concept for the treatment of heart failure is the neutralization of antibodies against the β(1)-adrenergic receptor (anti-β(1)AR-ab). In a rat model of autoimmune cardiomyopathy, the cyclic peptide COR-1 (given i.v. once monthly) neutralized anti-β(1)AR-abs and prevented anti-β(1)AR-ab-induced myocardial damage, and completely reverted cardiac dysfunction over 3-6 months.
  
  
  RESULTS
  A clinical phase I trial was designed as a single-blinded, placebo-controlled study. Fifty human volunteers received COR-1 or matching placebo as a single i.v. administration with ascending doses (10-240 mg). Primary endpoints were safety and tolerability, while the pharmacokinetic profile of COR-1 was assessed as a secondary endpoint. All five investigated dose groups were well tolerated; no drug-related side effects occurred. Pharmacokinetics revealed a favourable profile with an almost complete plasma clearance within 60 min after administration. Pharmacodynamic investigation showed dose-dependent efficacy with almost complete scavenging of pathological anti-β(1)AR-abs ex vivo at the two highest doses. No anti-COR-1 autoantibodies occurred. No other effects on the immune system (such as an increase of crucial cytokines) were observed up to 43 days after drug administration, nor upon incubation of anti-β(1)AR-ab-positive patient blood samples with COR-1 ex vivo.
  
  
  CONCLUSIONS
  COR-1 was shown to be safe after i.v. administration in vivo; no relevant side effects occurred. Efficacy was estimated from ex vivo investigation of the potency to neutralize specific anti-β(1)-AR-abs.
  
  
  BACKGROUND
  NCT 01043146, Eudra CT 2008-007745-31.
authors.affiliation: Corimmun GmbH, Martinsried, Germany.
authors.forename: Götz
authors.initials: G
authors.lastname: Münch
authors.forename: Valerie
authors.initials: V
authors.lastname: Boivin-Jahns
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Holthoff
authors.forename: Kristin
authors.initials: K
authors.lastname: Adler
authors.forename: Mariola
authors.initials: M
authors.lastname: Lappo
authors.forename: Stephan
authors.initials: S
authors.lastname: Truöl
authors.forename: Heidrun
authors.initials: H
authors.lastname: Degen
authors.forename: Nina
authors.initials: N
authors.lastname: Steiger
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Lohse
authors.forename: Roland
authors.initials: R
authors.lastname: Jahns
authors.forename: Martin
authors.initials: M
authors.lastname: Ungerer
mesh_terms: D018674:Adrenergic Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D000328:Adult; D000704:Analysis of Variance; D000818:Animals; D019540:Area Under Curve; D001323:Autoantibodies / Q000276:immunology; D016207:Cytokines; D005260:Female; D006333:Heart Failure / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D006439:Hemodynamics; D006801:Humans; D007107:Immune System / Q000187:drug effects* / Q000276:immunology; D008297:Male; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D011941:Receptors, Adrenergic / Q000187:drug effects*; D016037:Single-Blind Method
chemical_list: D018674:Adrenergic Antagonists; D001323:Autoantibodies; D016207:Cytokines; D010456:Peptides, Cyclic; D011941:Receptors, Adrenergic