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Administration of the cyclic peptide COR‐1 in humans (phase I study): ex vivo measurements of anti‐β 1 ‐adrenergic receptor antibody neutralization and of immune parameters
Author(s) -
Münch Götz,
BoivinJahns Valerie,
Holthoff HansPeter,
Adler Kristin,
Lappo Mariola,
Truöl Stephan,
Degen Heidrun,
Steiger Nina,
Lohse Martin J.,
Jahns Roland,
Ungerer Martin
Publication year - 2012
Publication title -
european journal of heart failure
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.149
H-Index - 133
eISSN - 1879-0844
pISSN - 1388-9842
DOI - 10.1093/eurjhf/hfs118
Subject(s) - medicine , ex vivo , pharmacokinetics , pharmacodynamics , pharmacology , in vivo , placebo , tolerability , heart failure , clinical endpoint , immune system , clinical trial , immunology , adverse effect , pathology , alternative medicine , microbiology and biotechnology , biology
Aims 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. Methods and 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. Trial registration : NCT 01043146, Eudra CT 2008‐07745‐31.