Cardiovascular disease still accounts for the greatest number of deaths worldwide. PCSK9-inhibition reduces the risk of cardiovascular events by regulation of the LDL (low density lipoprotein) receptor, one of the transporters of cholesterol in blood. The protein PCSK9 binds to the LDL-cholesterol receptor and enhances its degradation, which leads to the reduced clearance of LDL-cholesterol and a higher risk of atherosclerosis.
So far, blocking PCSK9 was clinically limited by the need for frequent injections with therapeutic antibodies and economically restricted by their high cost. As a promising novel strategy, active immunotherapy that induces a long-lasting PCSK9-specific antibody response may overcome these disadvantages to reduce the burden of cardiovascular disease as the major cause of death in the developed world. On the basis of this innovative concept AFFiRiS AG (Vienna, Austria) developed two products, AT04A and AT06A, which were tested at the Medical University of Vienna (Dept. of Clinical Pharmacology). Results of the first in-human study of this immunotherapy actively targeting PCSK9 are now available.
72 healthy individuals with slightly elevated LDL-cholesterol (75 to 200 mg/dl) were enrolled in three parallel treatment groups. Participants were randomized to receive AT04A, AT06A or placebo. Immunizations were administered as three priming immunizations at four-weekly intervals. In a second part of the study, 50 participants received a booster immunization at week 60 with a follow-up until week 90, including an interim analysis at week 70. The primary study objective was safety and tolerability of AT04A and AT06A with immunogenicity and efficacy as secondary, exploratory study objectives.
Both immunotherapies, AT04A and AT06A, were safe and well tolerated. No significant difference in the safety profile was observed between active and placebo treatment groups with the exception of injection site reactions. These local reactions – typical for vaccinations – were the most frequently reported adverse events (63.3%) and were more common in the active treatment groups. Injection site reactions were usually of mild to moderate severity, transient and not interfering with activities of daily living. More than 90% of individuals who received AT04A or AT06A developed a PCSK9-specific antibody response, which was readily reactivated after booster immunization at week 60. The mean LDL-cholesterol reduction after the booster was 13.3% at week 70 when comparing AT04A with placebo. Over the entire study period of 90 weeks, the difference in LDL-cholesterol reduction between AT04A and placebo was statistically highly significant (p<0.0001). The maximum individual reduction in LDL-cholesterol was up to 37% from baseline and was associated with a high immune response against PCSK9. LDL-cholesterol reduction persisted for at least 30 weeks after the boost immunization supporting the long-term effect of this therapy.
Prof. Martin Bauer, clinical investigator of the study and expert in clinical pharmacology, presented these results at the “Late Breaking Pharmacological Science” Session of the European Society of Cardiology (ESC) Congress on August 25th 2018 in Munich. “Specific active immunotherapy is a novel and interesting approach to target PCSK9,” stated Prof. Bauer. “This was the first study to show the feasibility and safety of a specific active immunotherapy to reduce LDL-cholesterol in humans. Proof-of-concept was achieved for AT04A.”
An optimized formulation of AT04 with enhanced immunogenicity was developed and this promising candidate, called AT04B, will be tested in a next clinical trial. To fully exploit the potential of AT04B, the next study will be tested in a hyperlipidemic population in order to optimize dose, treatment schedule and efficacy. If successful, this would be the first time that an immunotherapy actively targets elevated cholesterol with long lasting efficacy to reduce the risk for coronary heart disease.
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