Pharmaceutical compounds for the treatment of atherosclerotic cardiovascular diseases

Abstract

The problem to be solved by the present invention is to provide a targeted anti-inflammatory therapy that reduces the self-perpetuating metabolic inflammation due to local LDL cholesterol in atherosclerotic plaques without significant systemic immunosuppression.SOLUTION: The present invention provides a polypeptide dimer comprising two gp130 - Fc fusion peptides for use in the treatment of ASCVD in human patients, preferably high risk ASCVD in human patients, more preferably very high risk ASCVD in human patients.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a polypeptide dimer comprising two gp130-Fc fusion peptides as components for use in treating atherosclerotic cardiovascular disease (ASCVD) in human patients, as defined in the 2019 ESC / EAS guidelines, particularly Table 4: Mach et al., Eur. Heart J. 41:111 (2020). ASCVD includes low-density lipoprotein (LDL)-driven ASCVD, triglyceride-driven ASCVD, lipoprotein a-driven ASCVD, chronic inflammatory disease-driven ASCVD, or inflammatory ASCVD, which may be accompanied by one or more of familial hypercholesterolemia, chronic kidney disease, diabetes mellitus, blood pressure greater than 180 / 110 mmHg, or human immunodeficiency virus infection.

[0002] Generally, the human patient may be a non-responder to or intolerant to treatment with one or more of: a statin; ezetimibe; an inhibitor of proprotein convertase subtilisin kexin type 9 (PCSK9), preferably an antibody such as alirocumab or evolocumab, or a short interfering RNA such as inclisiran; or lipid apheresis therapy. [Background technology]

[0003] Inflammation is a powerful driver of atherosclerotic cardiovascular disease (ASCVD) (Ross 1999, N. Engl. J. Med. 340:115). There is a significant unmet need for effective therapies for patients with ultra-high-risk ASCVD (as defined in the 2019 ESC / EAS guidelines, particularly Table 4; Mach et al. 2020, Eur. Heart J. 41:111) who experience a high inflammatory burden despite state-of-the-art medical treatment. Such treatments must prevent or reduce inappropriate inflammation while avoiding systemic immunosuppression (Ridker 2017, Circ. Res. 120:617), which increases the risk of infection and does not reduce cardiovascular events (Ridker et al. 2019, N. Engl. J. Med. 380:752). Anti-cytokine therapy is a promising option for treating progressive ASCVD despite lifestyle modifications and optimization of plasma lipid levels (Schuett & Schieffer 2012, Curr. Atheroscler. Rep. 14:187; Ait-Oufella et al. 2019, Arterioscler. Thromb. Vasc. Biol. 39:1510).

[0004] The recent CANTOS trial investigated the anti-interleukin-1β (IL-1β) antibody canakinumab in established human inflammatory ASCVD and demonstrated significant benefit by reducing the rate of recurrent cardiovascular events at the expense of a high incidence of fatal infections (Ridker et al. 2017, N. Engl. J. Med. 377:1119). Interleukin-6 (IL-6) signaling, downstream of IL-1β, has been implicated in atherogenesis (Scheller & Rose-John 2012, Lancet 380:338). IL-6 is a pleiotropic cytokine produced by hematopoietic and non-hematopoietic cells in response to infection and tissue injury. Patients with ASCVD exhibit elevated circulating IL-6 levels, which correlate with clinical activity (Ridker et al. 2016, Circ. Res. 118:145). High plasma levels of IL-6 are associated with a higher risk of future cardiovascular events (Kaptoge et al. 2014, Eur. Heart J. 35:578).

[0005] IL-6 exerts multiple functions through two major signaling pathways, both of which require signaling via a preformed dimer of the transmembrane coreceptor gp130 (Scheller et al. 2014, Semin. Immunol. 26:2). In typical signaling, IL-6 uses the membrane-bound IL-6 receptor (IL-6R), which is expressed primarily by hepatocytes and leukocytes. In the trans-signaling pathway, circulating soluble IL-6R (sIL-6R), generated by proteolytic cleavage or alternative splicing, recruits IL-6 to form the IL-6 / sIL-6R complex, which can activate gp130, which is ubiquitously expressed in nearly all somatic cells (Garbers et al. 2018, Nat. Rev. Drug Discov. 17:395). Such ubiquitous trans-signaling is physiologically impeded by excess soluble gp130 isoform (sgp130), which acts as a buffer in the blood (Jostock et al. 2001, Eur. J. Biochem. 268:160). While typical IL-6 signaling has many physiological and anti-infective functions, excessive trans-signaling is observed in many chronic inflammatory conditions. Therefore, specific trans-signaling inhibition has been proposed as an alternative to blocking IL-6 or its receptor to treat chronic inflammation without the adverse effects of systemic immunosuppression (Rose-John et al. 2017, Nat. Rev. Rheumatol. 13:399; Garbers et al. 2018, Nat. Rev. Drug Discov. 17:395). As outlined above, inhibition of IL-1β with canakinumab significantly reduced the recurrence rate of cardiovascular events and reduced IL-6 levels in humans. However, the side effects of systemic immunosuppression caused by canakinumab result in an unfavorable risk / benefit ratio for the treatment of ASCVD (Ridker et al. 2017, N. Engl. J. Med. 377:1119; Palmer et al. 2019, Front. Cardiovasc. Med. 6:90).These results are consistent with the increased rates of opportunistic and severe infections observed with the anti-IL-6R antibody tocilizumab (Rose-John et al. 2017, Nat. Rev. Rheumatol. 13:399). Another potential limitation of complete IL-6 inhibition is the potential increase in triglycerides and LDL cholesterol (Garbers et al. 2018, Nat. Rev. Drug Discov. 17:395).

[0006] EP 1148065 B1 and Jostock et al. 2001 (Eur. J. Biochem. 268:160) describe a fusion protein consisting of two sgp130 domains fused to a crystallizable fragment of human immunoglobulin G1. WO 2008 / 000516 A2 describes an optimized variant of sgp130Fc that has received the international non-proprietary name Olamuxcept and is currently in clinical development by Ferring Pharmaceuticals (Saint-Prex, CH) and I-Mab Biopharma (Shanghai, CN).

[0007] Schuett et al. (2012) (Arterioscler. Thromb. Vasc. Biol. 32:281) showed that patients with coronary artery disease have low plasma levels of endogenous sgp130 and described reduced atherosclerosis with sgp130Fc in a standard mouse atherosclerosis model, in which mice were genetically engineered to lack the LDL receptor and fed a high-fat, high-cholesterol diet to maximize atherosclerosis. However, translating findings from such artificial mouse genetic models to human disease is often unsuccessful, despite the appropriate selection of disease models (Oppi et al. 2019, Front. Cardiovasc. Med. 6:46), due to the many risk factors and behavioral variations that are affected (Seok et al. 2013, PNAS 110:3507; Tsukamoto 2016, Drug Discov. Today 21:529). For example, the two most widely used genetic mouse models of atherosclerosis (Ldlr - / - and Apoe - / - In mice, IL-6 deletion can be atheroprotective (Madan et al. 2008, Atherosclerosis 197:504), and inhibition of IL-6R can attenuate atherosclerotic lesions (Akita et al. 2017, Front. Cardiovasc. Med. 4:84). However, IL-6 ablation may enhance rather than attenuate atherosclerosis in these very models (Ramji & Davies 2015, Cytokine Growth Factor Rev. 26:673), highlighting the complex physiological and pathophysiological functions of IL-6 signaling and the uncertainties inherent in mouse models of complex chronic disease. Summary of the Invention [Problem to be solved by the invention]

[0008] Patients with ASCVD frequently experience disease exacerbations and cardiovascular events despite maximal medical treatment. The challenge is to provide targeted anti-inflammatory therapies that reduce the local LDL cholesterol-driven self-perpetuating metabolic inflammation in atherosclerotic plaques without significant systemic immunosuppression. [Means for solving the problem]

[0009] A solution to this problem is provided by the features of the claims and in particular by a polypeptide dimer comprising two gp130-Fc fusion peptides, as exemplified by olamuxcept, for use in the treatment of ASCVD in a human patient, preferably high-risk ASCVD in a human patient, more preferably very-high-risk ASCVD in a human patient.

[0010] Olamuxcept can be administered to human patients diagnosed with ASCVD, and it has now been found to be devoid of any apparent side effects caused by the treatment. Surprisingly, specific therapeutic inhibition of IL-6 trans-signaling by olamuxcept in established atherosclerotic lesions has been found to unexpectedly reduce atherosclerotic burden and local inflammatory activity in human patients with ultra-high-risk ASCVD, with high efficacy despite maximal medical treatment. The finding that olamuxcept can result in clinically significant regression of established atherosclerotic plaques and arterial wall inflammation in these patients, despite optimized therapy and lifestyle, is surprising. The previously reported effects of olamuxcept in mouse models of atherosclerosis (Schuett et al. 2012, Arterioscler. Thromb. Vasc. Biol. 32:281) were achieved by massively inducing atherosclerosis and administering olamuxcept as the sole agent in mice fed a high-fat, high-cholesterol diet, resulting in an environment genetically predisposed to severe atherosclerosis due to artificial deletion of the LDL receptor. However, in human patients without artificial deletion of the LDL receptor, olamuxcept demonstrated clinically meaningful effects as add-on therapy in optimized treatment settings, exerting strikingly beneficial effects on key parameters of ASCVD that are not clearly adequately targeted by the best available ASCVD drugs, such as PCSK9 inhibitors or statins. Preferably, these key parameters are those defined in the 2019 ESC / EAS guidelines (Mach et al. 2020, Eur. Heart J. 41:111).

[0011] The polypeptide dimers of the present invention comprise two gp130-Fc monomers, each monomer having at least 90% sequence identity to SEQ ID NO: 1. Preferably, the monomers comprise a gp130 D6 domain comprising amino acids 585-595 of SEQ ID NO: 1 and an Fc domain hinge region comprising amino acids 609-612 of SEQ ID NO: 1. More preferably, the monomers do not comprise a linker between the gp130 portion and the Fc portion, but rather the gp130 portion is directly linked to the Fc portion, as is the case with olamuxcept. Furthermore, the present invention provides polypeptide dimers, particularly olamuxcept, for use in methods for treating human patients diagnosed with ASCVD, high-risk ASCVD, or very-high-risk ASCVD.

[0012] Preferably, the human patient is a non-responder to or intolerant to treatment with one or more of statins, ezetimibe, inhibitors of proprotein convertase subtilisin kexin type 9 (PCSK9), or lipid apheresis therapy. Optionally, the human patient may suffer from, for example, LDL cholesterol-driven ASCVD, triglyceride-driven ASCVD, lipoprotein a-driven ASCVD, chronic inflammatory disease-driven ASCVD, inflammatory ASCVD, familial hypercholesterolemia, chronic kidney disease, diabetes mellitus, blood pressure greater than 180 / 110 mmHg, or human immunodeficiency virus infection.

[0013] The present invention provides polypeptide dimers, exemplified by olamuxcept, for use in treating ASCVD in a human patient, preferably high-risk ASCVD in a human patient, more preferably very-high-risk ASCVD in a human patient. As used herein, the polypeptide dimer comprises or consists of two gp130-Fc monomers, each monomer having at least 90% sequence identity to SEQ ID NO: 1, preferably comprising a gp130 D6 domain comprising amino acids 585-595 of SEQ ID NO: 1 and an Fc domain hinge region comprising amino acids 609-612 of SEQ ID NO: 1, and more preferably comprising no linker between the gp130 and Fc portions.

[0014] The polypeptide dimers described herein are believed to inhibit excessive IL-6 trans-signaling by selectively targeting and neutralizing the IL-6 / sIL-6R complex, thus inhibiting IL-6 trans-signaling only at desirable therapeutic concentrations while leaving intact typical signal transduction and many of its physiological functions, as well as its acute inflammatory defense mechanisms. The polypeptide dimers have now been found to have similar efficacy to global IL-6 blockade, for example, with the anti-IL-6R antibody tocilizumab or the anti-IL-6 antibody sirukumab, but with significantly fewer side effects, particularly without general immunosuppression.

[0015] The polypeptide dimers described herein preferably comprise a gp130-Fc monomer having a sequence corresponding to SEQ ID NO: 1. In certain embodiments, the polypeptide dimers described herein comprise a polypeptide having at least 90%, 95%, 97%, 98%, 99%, or 99.5% sequence identity to SEQ ID NO: 1. Preferably, the polypeptide dimers described herein comprise a polypeptide having at least 90%, 95%, 97%, 98%, 99%, or 99.5% sequence identity to amino acids 1 to 595 of SEQ ID NO: 1, which corresponds to the gp130 sequence. Preferably, the Fc domain is an IgG1 or IgG4 Fc domain. Preferably, the polypeptide comprises the gp130 D6 domain (particularly, amino acid residues TFTTPKFAQGE: amino acids 585 to 595 of SEQ ID NO: 1), amino acid residues AEGA of the Fc domain hinge region (amino acids 609 to 612 of SEQ ID NO: 1), and does not comprise a linker between the gp130 portion and the Fc portion. In a preferred embodiment, the present disclosure provides a polypeptide dimer comprising two monomers having an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 1, wherein the amino acid sequence comprises a gp130 D6 domain, an AEGA Fc domain hinge region, and no linker is present between the gp130 portion and the Fc portion. In some embodiments, the present invention provides a composition comprising a plurality of polypeptides described herein (e.g., a plurality of polypeptide monomers and / or polypeptide dimers described herein).

[0016] The polypeptide-dimer of the present invention is intended for use in parenteral administration, such as intravenous infusion or subcutaneous injection. Suitable formulations include those containing a surfactant, particularly a non-ionic surfactant such as a polysorbate surfactant (e.g., polysorbate 20). The formulation may also contain a buffer and a sugar. An exemplary buffer is histidine. An exemplary sugar is sucrose. Thus, suitable formulations may contain polysorbate 20 (e.g., 0.01-1 mg / mL, 0.02-0.5 mg / mL, 0.05-0.2 mg / mL), histidine (e.g., 0.5 mM-250 mM, 1-100 mM, 5-50 mM, 10-20 mM), and sucrose (e.g., 10-1000 mM, 20-500 mM, 100-300 mM, 150-250 mM).

[0017] The polypeptide dimer of the present invention is typically administered at a dose of 60 mg to 1 g, preferably 150 mg to 600 mg, and is typically administered once every 1 to 4 weeks, preferably once every 1 to 2 weeks.

[0018] The present examples demonstrate that olamuxcept can be administered to patients with ASCVD without significant side effects. Surprisingly, specific therapeutic inhibition of IL-6 trans-signaling with olamuxcept in established, very high-risk ASCVD patients (as defined in the current recommended guidelines, the 2019 ESC / EAS Guidelines, Table 4; Mach et al. 2020, Eur. Heart J. 41:111) reduced atherosclerotic burden and local inflammatory activity despite maximal (tolerated) medical therapy and unexpectedly extensive treatment. In particular, olamuxcept can reduce intima-media thickness (IMT), atherosclerotic plaques, and arterial wall inflammation, as measured by cellular infiltration of atherosclerotic plaques.

[0019] Thus, the present invention is suitable for use in treating human patients with ASCVD, preferably high-risk ASCVD, more preferably very-high-risk ASCVD, wherein the human patient is preferably a non-responder to or intolerant to treatment with one or more of a statin, ezetimibe, a PCSK9 inhibitor (preferably an antibody such as alirocumab or evolocumab, or a short interfering RNA such as inclisiran), or lipid apheresis therapy.

[0020] As used herein, a "non-responder" is a human patient who demonstrates a partial or complete lack of expected response to appropriate therapy, alone or in combination with other therapies, at appropriate doses according to current guidelines. For example, a biomarker for non-response to statins, ezetimibe, and / or PCSK9 inhibitors is an insufficient or absent reduction in LDL cholesterol levels in blood and / or plasma and / or serum. Current LDL cholesterol treatment goals for ASCVD are defined, for example, by the 2019 ESC / EAS guidelines (Mach et al. 2020, Eur. Heart J. 41:111). The efficacy of LDL cholesterol-lowering drugs can vary not only between drug classes but also within the same drug class, as observed with the variable efficacy of statins, which lower LDL cholesterol by approximately 30% to 55% at the same maximum dose of 80 mg (Illingworth 2000, Med. Clin. North Am. 84:23). Adding ezetimibe to simvastatin therapy can be expected to further reduce LDL cholesterol by up to approximately 25% (Cannon et al. 2015, N. Engl. J. Med. 372:2387). Anti-PCSK9 antibodies, in addition to statin therapy, can be expected to reduce LDL cholesterol by approximately 60% (Sabatine et al. 2017, N. Engl. J. Med. 376:1713; Schwartz et al. 2018, N. Engl. J. Med. 379:2097). Therefore, the definition of non-response in a particular patient or group depends on the type and dose of medication and, if applicable, concomitant medications, but can be determined by a practitioner of ordinary skill in the art, such as the treating physician, based on objective guidelines and published literature.

[0021] Thus, a human patient according to the present invention may be a patient who has received a statin, ezetimibe, and / or a PCSK9 inhibitor before receiving a polypeptide dimer for use in treatment according to the present invention. Preferably, a human patient who is a non-responder to treatment with a statin, ezetimibe, and / or a PCSK9 inhibitor does not exhibit a reduction in blood levels of LDL cholesterol and / or plasma levels of LDL cholesterol and / or serum levels of LDL cholesterol to the extent that would be expected according to current guidelines, recommended dosages of the respective agents, and / or outcomes of clinical trials investigating changes in LDL cholesterol levels during treatment with the respective agents, for example, using current guidelines, recommended dosages of the respective agents, and / or outcomes of clinical trials investigating changes in LDL cholesterol levels during treatment with the respective agents.

[0022] As used herein, "intolerance" refers to partial or complete intolerance of a drug, requiring a dose reduction or discontinuation of treatment. Side effects may vary among different drugs in the same class. For example, the most common side effects of statins include muscle pain, tenderness, or weakness (statin-associated muscle symptoms); headache; dizziness; gastrointestinal problems; fatigue / weakness; sleep problems; itching; elevated liver enzyme levels; or low platelet counts. Similar side effects are observed with ezetimibe. Frequently observed side effects during treatment with antibodies against PCSK9 (e.g., evolocumab) include flu-like symptoms, vomiting, upper respiratory tract infections, and back and joint pain. Some combinations of the above drug therapies may also lead to a combination of side effects and poor tolerance, as well as patient compliance, making maximally tolerated ASCVD treatment less than optimal.

[0023] Administration of olamxcept according to the present invention exhibits a different, primarily anti-inflammatory mechanism of action and a highly favorable side effect profile, which is particularly advantageous given the surprisingly potent therapeutic effect of olamxcept on very high-risk ASCVD as demonstrated in the Examples.

[0024] Human patients with ASCVD to be treated with a gp130-Fc fusion peptide such as olamuxcept may suffer from, for example, LDL cholesterol-driven ASCVD, triglyceride-driven ASCVD, lipoprotein a-driven ASCVD, chronic inflammatory disease-driven ASCVD, inflammatory ASCVD, familial hypercholesterolemia, chronic kidney disease, diabetes mellitus, blood pressure greater than 180 / 110 mmHg, or human immunodeficiency virus infection. [Example]

[0025] Example 1: Administration of Olamxcept in the Treatment of Human Patients Diagnosed with Very High Risk ASCVD Olamuxcept (600 mg intravenously [i.v.], administered every other week for 6 weeks and every other week for 10 weeks, respectively), a representative polypeptide dimer containing two gp130-Fc fusion peptides, was administered to two patients who suffered from very high-risk ASCVD despite optimal treatment. Administration of olamuxcept was found to unexpectedly reduce IMT, plaque size, and arterial wall inflammation in these patients.

[0026] Drug administration: Olamxcept (manufactured by Ferring Pharmaceuticals A / S; Copenhagen, Denmark) was administered intravenously within 1 hour at a clinical trial dose of 600 mg every other week for 6 weeks (4 infusions total) to patient 1 and every other week for 10 weeks (6 infusions total) to patient 2. The half-life of olamxcept is 4.7 days. Patients were monitored for 3 hours (first 2 infusions) or 1 hour (subsequent infusions) for infusion reactions.

[0027] Pre-study assessment and patient phenotype: Patient characteristics are detailed in Table 1. Patient 1 was a 42-year-old Caucasian male (body mass index [BMI]: 37 kg / m 2Patient 2 was a 64-year-old Caucasian woman (BMI: 37 kg / m²) with an ultra-high risk of ASCVD (antinuclear antibodies [ANA] and antineutrophil cytoplasmic antibodies [ANCA] negative). Patient 3 had a history of recurrent stroke and was receiving maximal medical treatment consisting of evolocumab, atorvastatin, aspirin, metoprolol, amlodipine, hydrochlorothiazide, doxasozine, and vitamin D. 2 She also had very high-risk ASCVD (ANA / ANCA-negative) and a history of coronary artery disease. She had a previous right carotid endarterectomy. Her medications consisted of evolocumab, aspirin, metoprolol, amlodipine, hydrochlorothiazide, candesartan, pantoprazole, and vitamin D. Despite maximally tolerated treatment, both patients were at high risk for future vascular events associated with advanced ASCVD.

[0028] Imaging of atherosclerosis: Clinical evaluation and non-invasive imaging include ultrasound and 18 Fluorodeoxyglucose positron emission tomography / computed tomography ( 18 FDG PET / CT was used. In patient 1, screening for ASCVD included ultrasound examination of the carotid arteries and abdominal aorta. Both carotid arteries were scanned proximal to the carotid bifurcation, at the bifurcation, and at the internal and external carotid arteries using a 7.5 MHz frequency probe in B-mode, pulsed Doppler mode, and color mode. IMT of the arterial wall was assessed in a plaque-free area 1 cm proximal to the common carotid bulb. The abdominal aorta was scanned at a 5 MHz frequency to detect atherosclerotic plaque. Ultrasound-measured IMT can predict cardiovascular outcomes (Polak et al. 2011, N. Engl. J. Med. 365:213). In patient 2, screening for inflammatory ASCVD included ultrasound examination of the carotid arteries and abdominal aorta. 18 It consisted of an FDG PET / CT examination. 18FDG PET / CT has shown great potential in noninvasively visualizing, quantifying, and characterizing atherosclerotic inflammation and is emerging as a suitable surrogate endpoint for clinical trials of novel anti-atherosclerotic therapeutics (Tarkin et al. 2014, Nat. Rev. Cardiol. 11:443). Target-to-background ratios (TBRs) were calculated as previously described by van Wijk et al. 2014, J. Am. Coll. Cardiol. 64:1418).

[0029] Safety and metabolic parameters: In two patients with ASCVD, 600 mg of olamuxcept was safely administered every other week for 6 weeks (Patient 1) and 10 weeks (Patient 2). No clinical or laboratory adverse events were observed during or after treatment (Table 1). Although sIL-6R levels remained unchanged, serum IL-6 concentrations increased slightly, reflecting olamuxcept's additional sgp130 buffering capacity for the IL-6 / sIL-6R complex (Table 1). Administration of olamuxcept did not alter normal serum high-sensitivity C-reactive protein (hsCRP) levels in Patient 1, but transiently reduced elevated hsCRP levels in Patient 2 by 64–70% at 3 days postinfusion and by 50% at 7 days postinfusion (Table 2). As expected with selective inhibition of IL-6 trans-signaling, serum levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, LDL cholesterol, triglycerides, and lipoprotein(a) [Lp(a)] showed no clear trends or changes during olamuxcept treatment (Table 2). This contrasts with the common anabolic side effects (increased serum triglyceride and cholesterol levels, as well as increased body weight) observed with anti-IL-6 or anti-IL-6R agents, which inhibit both canonical and trans-signaling (Garbers et al. 2018, Nat. Rev. Drug Discov. 17:395).

[0030] Efficacy of Olamxcept Treatment: In Patient 1, who had atherosclerosis due to elevated LDL cholesterol and Lp(a) (Table 2), IMT in the carotid artery increased slightly, and atherosclerotic plaques were detected in the abdominal aorta (Figure 1). After four biweekly infusions of olamuxcept, IMT decreased from 0.93 mm to 0.86 mm in the right carotid artery and from 0.98 mm to 0.89 mm in the left carotid artery (3 months vs. baseline) (Figure 1A, B). Additionally, the atherosclerotic plaques in the abdominal aorta completely disappeared with olamuxcept treatment (Figure 1C, D).

[0031] Patient 2 presented with atherosclerosis due to LDL cholesterol, Lp(a), and hsCRP. Therefore, we investigated the carotid arterial wall inflammation before and after olamxcept administration. 18 FDG PET / CT images (six biweekly injections, Table 2) were compared. Plaque macrophage density was measured by PET. 18 The resulting signal has been shown to correlate with FDG uptake (Tarkin et al. 2014, Nat. Rev. Cardiol. 11:443), and the mean and maximum target-to-background ratio (TBR mean and TBR max ) at baseline 18 Arterial wall inflammation detected by FDG PET / CT was significantly reduced after 3 months with six infusions of olamuxept ( Figure 2 ).

[0032] In summary, specific therapeutic inhibition of IL-6 trans-signaling in established ASCVD reduced both atherosclerotic burden and local inflammatory activity in two human patients with very high-risk ASCVD despite maximal medical treatment and unexpectedly extensive therapy.

[0033] Patient 1 did not have elevated serum CRP levels. Nevertheless, the anti-cytokine therapy olamuxcept surprisingly reduced IMT and atherosclerotic plaque burden. Therefore, elevated CRP levels, which indicate inflammatory activity, may not be necessary as a biomarker for selecting patients for olamuxcept treatment of ASCVD.

[0034] The specificity and efficacy of olamuxcept as a trans-signaling inhibitor were highlighted by the lack of changes in lipid levels, particularly Lp(a) (Table 2). Because olamuxcept does not directly inhibit the induction of acute-phase proteins such as CRP (Hoge et al. 2013, J. Immunol. 190:703), the decrease in hsCRP in patient 2 is currently interpreted as reflecting a decrease in disease activity in atherosclerotic lesions. [Brief explanation of the drawings]

[0035] [Figure 1] Inhibition of IL-6 transduction signaling reduces intima-media thickness and atherosclerotic plaque size in advanced atherosclerosis. This figure shows representative images of ultrasound evaluations of patient 1 at baseline and 12 weeks after initiation of olamuxcept treatment (four intravenous infusions of 600 mg every other week; Table 1). (A) Pretreatment intima-media thickness (IMT): right carotid artery 0.93 mm, left 0.98 mm (not shown); (B) Posttreatment IMT: right 0.86 mm, left 0.89 mm (not shown); (C) Pretreatment abdominal aorta showing atherosclerotic plaque; (D) Same region of abdominal aorta after resolution of atherosclerotic plaque under olamuxcept treatment. [Figure 2]Inhibition of IL-6 trans-signaling reduces arterial wall inflammation and macrophage infiltration of atherosclerotic plaques in advanced atherosclerosis. This figure shows arterial wall inflammation in the carotid artery of patient 2 (A) at baseline and (B) 11 weeks after initiation of olamuxcept treatment (six intravenous infusions of 600 mg every other week; Table 1). Representative computed tomography (CT) scans, 18-fluorodeoxyglucose positron emission tomography (18FDG PET), and fusion images (18FDG PET / CT) highlight the regions of interest with thick circles (arteries) and thin circles (veins). The mean and maximum target-to-background ratios (TBRmean and TBRmax) are shown below. DETAILED DESCRIPTION OF THE INVENTION

[0036] [Table 1]

[0037] [Table 2]

[0038] [Table 3]

[0039] [ka] [ka] [ka]

Claims

1. A polypeptide dimer comprising two gp130-Fc monomers, each monomer having at least 90% sequence identity to SEQ ID NO:1, for use in treating a human patient with atherosclerotic cardiovascular disease (ASCVD).

2. 10. The polypeptide-dimer of claim 1 for use in the manufacture of a medicament for the treatment of a human patient with ASCVD.

3. The polypeptide-dimer for use according to claim 1 or 2, wherein the ASCVD is very high-risk ASCVD.

4. 4. The polypeptide-dimer for use according to any one of claims 1 to 3, wherein the monomer comprises a gp130 D6 domain comprising amino acids 585 to 595 of SEQ ID NO: 1, an Fc domain hinge region comprising amino acids 609 to 612 of SEQ ID NO: 1, and wherein the monomer does not comprise a linker between the gp130 portion and the Fc portion.

5. 5. The polypeptide-dimer of any one of claims 1 to 4 for use in the treatment of a human patient with ASCVD, wherein said human patient is a non-responder to or intolerant to treatment with one or more of the following: a statin, ezetimibe, and an inhibitor of proprotein convertase subtilisin / kexin type 9 (PCSK9 inhibitor).

6. A polypeptide-dimer for use in therapy according to any one of claims 1 to 5, characterized in that the human patient is unresponsive to or intolerant to a combination of a statin and ezetimibe.

7. 7. The polypeptide-dimer for use in therapy according to any one of claims 1 to 6, characterized in that the human patient is unresponsive to or intolerant to a combination of a statin and a PCSK9 inhibitor.

8. 8. The polypeptide-dimer for use in therapy according to any one of claims 1 to 7, characterized in that the human patient is unresponsive to or intolerant to a combination of ezetimibe and a PCSK9 inhibitor.

9. 9. The polypeptide-dimer for use in therapy according to any one of claims 1 to 8, characterized in that the human patient is unresponsive to or intolerant to a combination of a statin, ezetimibe and a PCSK9 inhibitor.

10. 10. The polypeptide-dimer for use in therapy according to any one of claims 1 to 9, characterized in that the human patient is classified as a non-responder to one or more of a statin, ezetimibe, and a PCSK9 inhibitor based on the detection of a biomarker for non-response.

11. 11. The polypeptide dimer for use in treatment according to any one of claims 1 to 10, wherein the biomarker for non-response to treatment with one or more of a statin, ezetimibe and a PCSK9 inhibitor is an insufficient reduction in blood levels of LDL cholesterol and / or plasma levels of LDL cholesterol and / or serum levels of LDL cholesterol compared to objective expectations based on current guidelines, recommended dosages of the respective agents and / or therapeutic targets in the outcome of clinical trials investigating changes in LDL cholesterol levels during treatment with the respective agents.

12. A polypeptide-dimer for use in therapy according to any one of claims 1 to 11, characterized in that the human patient is unresponsive to or intolerant of lipid apheresis therapy.

13. 13. The polypeptide dimer for use in therapy according to any one of claims 1 to 12, characterized in that the use reduces one or more of atherosclerotic plaque size, intima-media thickness, and inflammation in the arterial wall.

14. 14. A polypeptide-dimer for use in therapy according to any one of claims 1 to 13, characterized in that the ASCVD is low-density lipoprotein-induced ASCVD, triglyceride-induced ASCVD, lipoprotein a-induced ASCVD, chronic inflammatory disease-induced ASCVD, or inflammatory ASCVD.

15. 15. The polypeptide-dimer for use in therapy according to any one of claims 1 to 14, characterized in that the human patient has one or more of the following: familial hypercholesterolemia, chronic kidney disease, diabetes mellitus, blood pressure above 180 / 110 mmHg, and human immunodeficiency virus infection.

16. 16. The polypeptide-dimer for use in therapy according to any one of claims 1 to 15, characterized in that said use comprises a dosage of said polypeptide-dimer of 60 mg to 1 g, preferably 150 to 600 mg.

17. The polypeptide-dimer for use in therapy according to any one of claims 1 to 16, characterized in that the use is administered once every 1 to 4 weeks, preferably once every 1 to 2 weeks.

18. 1. A method for treating atherosclerotic cardiovascular disease (ASCVD) in a human patient, said method comprising administering to a patient in need thereof a therapeutically effective amount of a polypeptide dimer comprising two gp130-Fc monomers, each monomer having at least 90% sequence identity to SEQ ID NO:1.

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