alexa 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.
Clinical Sciences

Clinical Sciences

Cardiovascular Pharmacology: Open Access

Author(s): Mnch G, BoivinJahns V, Holthoff HP, Adler K, Lappo M,

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Abstract 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 2008-007745-31. This article was published in Eur J Heart Fail and referenced in Cardiovascular Pharmacology: Open Access

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