Clinical tolerability and safety profile of CER-001, a novel bio-engineered pre-β HDL-mimetic, across the clinical development programme

Background: The main protective effect of HDL against atherosclerosis is its ability to mobilise cholesterol from lipid-rich atherosclerotic plaques. Cerenis Therapeutics has developed CER-001, an engineered discoidal particle comprising recombinant human ApoA-I and phospholipids mimicking the natural nascent, discoidal pre- HDL particle. In preclinical studies, CER-001 promotes cholesterol efflux from macrophages and from atherosclerotic plaques. In clinical trials in patients with familial hypercholesterolaemia or hypoalphalipoproteinaemia, CER-001 reduced carotid wall thickness and enhanced ex vivo cholesterol efflux capacity, thus affecting atherosclerotic burden. Several clinical development programs are underway. Purpose: To report the clinical tolerability and safety findings observed with CER-001 across the clinical development programs performed to date. Methods: Adverse event (AE), serious AE (SAE) and other safety-related data were collated to evaluate the safety profile of CER-001 to determine whether any specific treatment-related AEs emerge as clinical experience with the product increases. Results: In the Phase I study, no treatment-related AEs were reported with single IV doses of CER-001 (0.25 to 45 mg/kg). There were no deaths, SAEs or AEs that led to withdrawal. There were no adverse findings associated with CER-001, relative to placebo, on vital signs, ECGs, clinical chemistry, haematology, immunogenicity and coagulation parameters. In multiple dose studies involving CER-001 (3 to 12 mg/kg), there have been no unusual or particularly concerning AEs reported to date. After six administrations, one each week, in post-ACS patients, no antibodies against ApoA-I were detected at 6 months. AE data from 530 subjects in Phase II studies, including type and incidence of AEs, SAEs and AEs causing withdrawal from study treatment, shows a safety profile comparable with placebo except for infusion reactions, which occurred more frequently with CER-001. Treatment-related infusion reactions occurred in 16 of 410 subjects (4%) treated with CER-001 in Phase II studies. These were reversible in all cases and either resolved spontaneously or after management with antihistamines, steroids and/or IV fluids. In studies evaluating liver enzymes (ALT, AST), no 3-times upper limit of normal elevations were seen during CER-001 therapy. Conclusions: To date, CER-001 appears to have a clinical safety profile similar to placebo in terms of type and incidence of AEs, SAEs and AEs causing withdrawal from study treatment. CER-001 was not associated with any adverse impact on hepatic safety. Not unusually, a slightly higher incidence of infusion reactions has been reported and clinical study sites should be aware of the possibility of infrequent infusion reactions and be prepared to provide supportive care if necessary. Safety support is continuing with CER-001 clinical development for short- and long-term treatment.