Effect of Serial Infusions of CER-001, a Pre-β High-Density Lipoprotein Mimetic, on Coronary Atherosclerosis in Patients Following Acute Coronary Syndromes in the CER-001 Atherosclerosis Regression Acute Coronary Syndrome Trial

Nicholls, Stephen J.; Andrews, Jordan; Kastelein, John J.P.; Merkely, Béla; Nissen, Steven E.; Ray, Kausik K.; Schwartz, Gregory G.; Worthley, Stephen G.; Keyserling, Constance H.; Dasseux, Jean-Louis; Griffith, Liddy; Kim, Susan W.; Janssan, A.; Giovanni, Giuseppe Di; Pisaniello, Anthony D.; Scherer, Daniel; Psaltis, Peter J.; Butters, Julie

doi:10.1001/jamacardio.2018.2121

Cited by 149 publications

(94 citation statements)

References 42 publications

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“…Future research on HDL-based therapeutic approaches for AD will benefit from the considerable safety and efficacy data gathered from clinical trials using HDL formulations, including recombinant apoA-I proteins, apoA-I mimetics, and plasma-derived apoA-I, all of which were developed to treat atherosclerosis [62,63]. CER-001 and MDCO-216 are recombinant proteins of the wildtype and Milano sequences of apoA-I, respectively, which were both well tolerated as infusions in phase II clinical trials but were unsuccessful in meeting the primary endpoint of reduced atherosclerosis [64][65][66]. ApoA-I mimetic peptides, such as D-4F and L-4F, were developed to overcome the production difficulties associated with full-length recombinant proteins and improve oral bioavailability.…”

Section: Discussionmentioning

confidence: 99%

ApoA-I deficiency increases cortical amyloid deposition, cerebral amyloid angiopathy, cortical and hippocampal astrogliosis, and amyloid-associated astrocyte reactivity in APP/PS1 mice

et al. 2019

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Background Alzheimer’s disease (AD) is defined by amyloid beta (Aβ) plaques and neurofibrillary tangles and characterized by neurodegeneration and memory loss. The majority of AD patients also have Aβ deposition in cerebral vessels known as cerebral amyloid angiopathy (CAA), microhemorrhages, and vascular co-morbidities, suggesting that cerebrovascular dysfunction contributes to AD etiology. Promoting cerebrovascular resilience may therefore be a promising therapeutic or preventative strategy for AD. Plasma high-density lipoproteins (HDL) have several vasoprotective functions and are associated with reduced AD risk in some epidemiological studies and with reduced Aβ deposition and Aβ-induced inflammation in 3D engineered human cerebral vessels. In mice, deficiency of apoA-I, the primary protein component of HDL, increases CAA and cognitive dysfunction, whereas overexpression of apoA-I from its native promoter in liver and intestine has the opposite effect and lessens neuroinflammation. Similarly, acute peripheral administration of HDL reduces soluble Aβ pools in the brain and some studies have observed reduced CAA as well. Here, we expand upon the known effects of plasma HDL in mouse models and in vitro 3D artery models to investigate the interaction of amyloid, astrocytes, and HDL on the cerebrovasculature in APP/PS1 mice . Methods APP/PS1 mice deficient or hemizygous for Apoa1 were aged to 12 months. Plasma lipids, amyloid plaque deposition, Aβ protein levels, protein and mRNA markers of neuroinflammation, and astrogliosis were assessed using ELISA, qRT-PCR, and immunofluorescence. Contextual and cued fear conditioning were used to assess behavior. Results In APP/PS1 mice, complete apoA-I deficiency increased total and vascular Aβ deposition in the cortex but not the hippocampus compared to APP/PS1 littermate controls hemizygous for apoA-I. Markers of both general and vascular neuroinflammation, including Il1b mRNA, ICAM-1 protein, PDGFRβ protein, and GFAP protein, were elevated in apoA-I-deficient APP/PS1 mice. Additionally, apoA-I-deficient APP/PS1 mice had elevated levels of vascular-associated ICAM-1 in the cortex and hippocampus and vascular-associated GFAP in the cortex. A striking observation was that astrocytes associated with cerebral vessels laden with Aβ or associated with Aβ plaques showed increased reactivity in APP/PS1 mice lacking apoA-I. No behavioral changes were observed. Conclusions ApoA-I-containing HDL can reduce amyloid pathology and astrocyte reactivity to parenchymal and vascular amyloid in APP/PS1 mice. Electronic supplementary material The online version of this article (10.1186/s13195-019-0497-9) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

ApoA-I deficiency increases cortical amyloid deposition, cerebral amyloid angiopathy, cortical and hippocampal astrogliosis, and amyloid-associated astrocyte reactivity in APP/PS1 mice

et al. 2019

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“…We show that long-term genetically increased circulating apoA-I levels do not protect from CAD, a finding consistent with the cardiovascular associations in two trials of apoA-I infusion products (MDCO-216 and CER-001) that led to the termination of development of those products. 10,11 Thus, randomized evidence of both the short-term, transient increase in circulating concentration of apoA-I arising from apoA-I infusions and the life-long increase caused by genetic variants fails to provide evidence in support of a protective role of apoA-I in CAD.…”

Section: Discussionmentioning

confidence: 99%

“…9 Recent results from phase II randomized controlled trials (RCTs) of apoA-I that used MDCO-216 (recombinant apoA-I-Milano) and CER-001 (recombinant wild-type apoA-I) infusions suggest that the initial optimism may be misplaced. 10,11 Trials of MDCO-216 and CER-001 failed to identify a beneficial effect of apoA-I infusion on the regression of coronary atherosclerosis as measured by intravascular ultrasonography, 10,11 resulting in the termination of the development of these apoA-I products. A third apoA-I infusion therapy, CSL112, representing a modified form of native apoA-I from human plasma, is currently underway in a large phase III RCT (AEGIS-II; ClinicalTrials.gov Identifier: NCT03473223), which seeks to assess the efficacy of CSL112 on the risk of cardiovascular events.…”

Section: Introductionmentioning

confidence: 99%

Genetic variation in apolipoprotein A-I concentrations and risk of coronary artery disease

Karjalainen

Holmes

Wang

et al. 2019

Preprint

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Rationale: Apolipoprotein A-I (apoA-I) infusions represent a potential novel therapeutic approach for the prevention of coronary artery disease (CAD) with phase III cardiovascular outcome trials currently underway. Although circulating apoA-I levels inversely associate with risk of CAD, the evidence base of this representing a causal relationship is lacking.Objective: To assess the causal role of apoA-I in CAD using human genetics. Methods and Results:We identified a variant (rs12225230) in APOA1 locus that associated with circulating apoA-I concentrations at GWAS significance (P<5x10 -8 ) in 20,370 Finnish participants and meta-analyzed our data with a previous genome-wide association study of apoA-I. We obtained genetic estimates of CAD from UK Biobank and CARDIoGRAMplusC4D (totaling 122,733 CAD cases) and conducted a two-sample Mendelian randomization analysis. We compared our genetic findings to observational associations of apoA-I with risk of CAD in 918 incident CAD cases among 11,535 individuals from population-based prospective cohorts. We also summarized the available evidence from randomized controlled trials (RCTs) of apoA-I infusion therapies reporting CAD events. ApoA-I was associated with a lower risk of CAD in observational analyses (HR 0.81; 95%CI: 0.75, 0.88; per 1-SD higher apoA-I), with the association showing a dose-response relationship. Rs12225230 associated with apoA-I concentrations (per-C allele beta 0.076 SD; SE: 0.013; P=1.5x10 -9 ) but not with potential confounders. In Mendelian randomization analyses, apoA-I was not related to risk of CAD (OR 1.13; 95%CI: 0.98, 1.30 per 1-SD higher apoA-I), which was different to the observational association (P-het<0.001). RCTs of apoA-I infusions did not show an effect on the risk of CAD.

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“…CER-001 has already reached Phase III for the treatment of patients with genetic HDL deficiencies. However, CER-001 has failed in Phase II trial for the treatment of patients with coronary atherosclerosis following acute coronary syndromes (Nicholls et al, 2018). The results show that CER-001 did not produce plaque regression in statin-treated patients following acute coronary syndrome (Nicholls et al, 2018).…”

Section: B Drugs In Clinical Trialsmentioning

confidence: 97%

Targeting Foam Cell Formation in Atherosclerosis: Therapeutic Potential of Natural Products

et al. 2019

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Effect of Serial Infusions of CER-001, a Pre-β High-Density Lipoprotein Mimetic, on Coronary Atherosclerosis in Patients Following Acute Coronary Syndromes in the CER-001 Atherosclerosis Regression Acute Coronary Syndrome Trial

Abstract: ClinicalTrials.gov Identifier: NCT2484378.

Cited by 149 publications

References 42 publications

ApoA-I deficiency increases cortical amyloid deposition, cerebral amyloid angiopathy, cortical and hippocampal astrogliosis, and amyloid-associated astrocyte reactivity in APP/PS1 mice

ApoA-I deficiency increases cortical amyloid deposition, cerebral amyloid angiopathy, cortical and hippocampal astrogliosis, and amyloid-associated astrocyte reactivity in APP/PS1 mice

Genetic variation in apolipoprotein A-I concentrations and risk of coronary artery disease

Targeting Foam Cell Formation in Atherosclerosis: Therapeutic Potential of Natural Products

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