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Case Report: Arterial Wall Inflammation in Atherosclerotic Cardiovascular Disease is Reduced by Olamkicept (sgp130Fc).

ABSTRACT: Inflammation is a strong driver of atherosclerotic cardiovascular disease (ASCVD). There is a large unmet need for therapies that prevent or reduce excessive inflammation while avoiding systemic immunosuppression. We showed previously that selective inhibition of pro-inflammatory interleukin-6 (IL-6) trans-signalling by the fusion protein olamkicept (sgp130Fc) prevented and reduced experimental murine atherosclerosis in low-density lipoprotein receptor-deficient (Ldlr ^-/-) mice on a high-fat, high-cholesterol diet independently of low-density lipoprotein (LDL) cholesterol metabolism. Therefore, we allowed compassionate use of olamkicept (600 mg intravenously biweekly for 10 weeks) in a patient with very-high-risk ASCVD. Despite optimal LDL cholesterol under maximum tolerated lipid-lowering treatment, the patient had a remaining very high risk for future cardiovascular events related to significant arterial wall inflammation with lipoprotein (a) [Lp(a)]-cholesterol as the main contributor. ¹⁸Fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸FDG PET/CT) measurements were performed before and after the treatment period. Olamkicept reduced arterial wall inflammation in this patient without interfering with lipoprotein metabolism. No clinical or laboratory side effects were observed during or after treatment with olamkicept. Our findings in this patient matched the results from our mechanistic study in Ldlr ^-/- mice, which were extended by additional analyses on vascular inflammation. Olamkicept may be a promising option for treating ASCVD independently of LDL cholesterol metabolism. A Phase II trial of olamkicept in ASCVD is currently being prepared.

SUBMITTER: Schulte DM

PROVIDER: S-EPMC9218605 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Case Report: Arterial Wall Inflammation in Atherosclerotic Cardiovascular Disease is Reduced by Olamkicept (sgp130Fc).

Schulte Dominik M DM Waetzig Georg H GH Schuett Harald H Marx Marlies M Schulte Berenice B Garbers Christoph C Lokau Juliane J Vlacil Ann-Kathrin AK Schulz Juliane J Seoudy Anna K AK Schieffer Bernhard B Rosenstiel Philip P Seeger Marcus M Laudes Matthias M Rose-John Stefan S Lützen Ulf U Grote Karsten K Schreiber Stefan S

Frontiers in pharmacology 20220609

Inflammation is a strong driver of atherosclerotic cardiovascular disease (ASCVD). There is a large unmet need for therapies that prevent or reduce excessive inflammation while avoiding systemic immunosuppression. We showed previously that selective inhibition of pro-inflammatory interleukin-6 (IL-6) trans-signalling by the fusion protein olamkicept (sgp130Fc) prevented and reduced experimental murine atherosclerosis in low-density lipoprotein receptor-deficient (<i>Ldlr</i> <sup>-/-</sup>) mice ...[more]

PMID: 35754497

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Project description:Background and aimsThe burden and outcomes of inflammation in patients with atherosclerotic cardiovascular disease (ASCVD) are not well defined beyond the controlled settings of trials and research cohorts.MethodsThis was an observational study of ASCVD adults undergoing C-reactive protein testing in Stockholm's healthcare (2007-21). After excluding C-reactive protein tests associated with acute illness or medications/conditions that bias C-reactive protein interpretation, systemic inflammation was evaluated over a 3-month ascertainment window. Determinants of C-reactive protein ≥ 2 mg/L were explored with logistic regression. C-reactive protein categories were compared via negative-binomial/Cox regression for subsequent healthcare resource utilization and occurrence of major adverse cardiovascular events, heart failure hospitalization, and death.ResultsA total of 84 399 ASCVD adults were included (46% female, mean age 71 years, 59% with C-reactive protein ≥ 2 mg/L). Female sex, older age, lower kidney function, albuminuria, diabetes, hypertension, and recent anaemia were associated with higher odds of C-reactive protein ≥ 2 mg/L. The use of renin-angiotensin system inhibitors, antiplatelets, and lipid-lowering therapy was associated with lower odds. Over a median of 6.4 years, compared with C-reactive protein < 2 mg/L, patients with C-reactive protein ≥ 2 mg/L had higher rates of hospitalizations, days spent in hospital, outpatient consultations, and dispensed medications (P < .05 for all). They also had a higher rate of major adverse cardiovascular events [hazard ratio (HR) 1.30; 95% confidence interval (CI) 1.27-1.33], heart failure (HR 1.24; 95% CI 1.20-1.30), and death (HR 1.35; 95% CI 1.31-1.39). Results were consistent across subgroups and granular C-reactive protein categories and robust to the exclusion of extreme C-reactive protein values or early events.ConclusionsThree in five adults with ASCVD have systemic inflammation, which is associated with excess healthcare resource utilization and increased rates of cardiovascular events and death.

Dataset Information

Case Report: Arterial Wall Inflammation in Atherosclerotic Cardiovascular Disease is Reduced by Olamkicept (sgp130Fc).

Publications

Case Report: Arterial Wall Inflammation in Atherosclerotic Cardiovascular Disease is Reduced by Olamkicept (sgp130Fc).

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