JP2023170339A - Pharmaceutical composition for treating or preventing dilated cardiomyopathy - Google Patents

Abstract

To provide means for treating or preventing dilated cardiomyopathy.SOLUTION: An IL-13 inhibitor is effective in treating or preventing dilated cardiomyopathy.SELECTED DRAWING: None

Description

The present invention relates to pharmaceutical compositions for treating or preventing dilated cardiomyopathy. More specifically, the present invention relates to a pharmaceutical composition containing an IL-4 receptor α subunit antagonist for treating or preventing dilated cardiomyopathy.

Cardiomyopathy is a disease in which the structure and function of the muscles that make up the heart wall are impaired, resulting in progressive degeneration of the heart muscle. Its main types include dilated cardiomyopathy, hypertrophic cardiomyopathy, and restrictive cardiomyopathy. Dilated cardiomyopathy is a disease in which the ventricles (the two chambers at the bottom of the heart) become enlarged, hypertrophic cardiomyopathy is a disease in which the walls of the ventricles become thick and hard, and restrictive cardiomyopathy is a disease in which the walls of the ventricles become thick and hard. It is a rare type of disease in which the heart becomes hard but not necessarily thick, and other cardiomyopathies also exist. Among these pathological types, dilated cardiomyopathy is the most common pathological condition, but each pathological condition may overlap. However, other heart diseases such as myocardial infarction, ischemia, and valvular heart disease, as well as high blood pressure, eventually cause enlargement and hypertrophy of the ventricles, but the myocardial abnormalities in these cases are not usually referred to as cardiomyopathy.

Dilated cardiomyopathy is characterized by left ventricular dilatation and decreased contractility. Degeneration, atrophy, and fibrosis of the myocardium reduce cardiac contractility and cardiac output. Dilated cardiomyopathy is observed from childhood to adulthood, but the prognosis is as poor as that of a malignant tumor, with a 5-year survival rate of 50%, and it can also cause sudden death. Currently, there is no definitive treatment for dilated cardiomyopathy, and the only option is to prevent the decline in cardiac function with symptomatic medications, and it is also an indication for heart transplantation.

It is estimated that there are approximately 2.4 million heart failure patients in Japan, and patients with dilated cardiomyopathy as an underlying disease account for 15-27% of heart failure hospitalizations. Furthermore, looking at the number of specified disease recipient certificates with dilated cardiomyopathy as a designated intractable disease (Ministry of Health, Labor and Welfare Health Administration Report), 20,387 certified patients were registered in Japan in FY2020, which is 3. It is the most common type of cardiomyopathy, accounting for 82% of all types of cardiomyopathy (https://www.nanbyou.or.jp/entry/5354). In addition, it is characterized by a relatively large number of patients from young to middle age. This is the number of applicants for intractable diseases, and it is estimated that the actual number of patients is more than twice this number.

As causes of dilated cardiomyopathy, inflammation after viral infection, genetic background, autoimmune mechanism, drugs, alcohol, etc. are suspected to be involved (Non-Patent Document 1). In the pathology of dilated cardiomyopathy, fibrosis and remodeling that occur as a result of chronic inflammation of the myocardium play a central role, but the mechanisms are still largely unknown (Non-Patent Document 1, Non-Patent Document 2, Non-Patent Document 3). Traditionally, the immune mechanism involving T lymphocytes, particularly Th1-type inflammation in which inflammatory cytokines such as TNF-α, IL-1β, and IL-6 play the leading role, has been considered to be the main mechanism of dilated cardiomyopathy. However, clinical effects of antibody drugs such as anti-TNF and anti-IL-1β have not been obtained (Non-patent Document 4). Furthermore, although there are reports that the administration of immunosuppressants and large doses of gamma globulin is mildly effective for dilated cardiomyopathy, it has not been put to practical use due to its side effects and cost effectiveness (Non-Patent Document 4). Regarding dilated cardiomyopathy, there are reports pointing out the involvement of Th2 type inflammation and Th17 type inflammation (Non-Patent Document 5), but the specific therapeutic target has not been clarified at all.

Cardiomyopathy Treatment Guidelines 2018 (Japanese Circulation Society/Japan Heart Failure Society Joint Guidelines) https://www.j-circ.or.jp/cms/wp-content/uploads/2018/08/JCS2018_tsutsui_kitaoka.pdf Imanaka-Yoshida K. Inflammation in myocardial disease: From myocarditis to dilated cardiomyopathy. Pathol Int. 2020 Jan;70(1):1-11. doi: 10.1111/pin.12868. Epub 2019 Nov 5. PMID: 31691489.Pathology International .2020;70:1-11 Stephenson E, Savvatis K, Mohiddin SA, Marelli-Berg FM. T-cell immunity in myocardial inflammation: pathogenic role and therapeutic manipulation. Br J Pharmacol. 2017 Nov;174(22):3914-3925. doi: 10.1111/bph. 13613. Epub 2016 Oct 4. PMID: 27590129; PMCID: PMC5659997 Kadhi A, Mohammed F, Nemer G. The Genetic Pathways Underlying Immunotherapy in Dilated Cardiomyopathy. Front Cardiovasc Med. 2021 Apr 14;8:613295. doi: 10.3389/fcvm.2021.613295. PMID: 33937353; PMCID: PMC8079649 Jain A, Norton N, Bruno KA, Cooper LT Jr, Atwal PS, Fairweather D. Sex Differences, Genetic and Environmental Influences on Dilated Cardiomyopathy. J Clin Med. 2021 May 25;10(11):2289. doi: 10.3390/jcm10112289 .PMID: 34070351; PMCID: PMC8197492

The present invention aims to provide a means for treating or preventing dilated cardiomyopathy.

The present inventor administered dupilumab, an IL-4 receptor α subunit antagonist, to patients suffering from dilated cardiomyopathy and associated cardiomegaly (CTR). After ~4 weeks, the dyspnea disappeared, and the stubborn edema in the lower legs that had persisted up to that point also disappeared, and blood tests conducted 8 weeks after administration showed that serum BNP, a sensitive indicator of heart failure, normalized. They found that CTR improved, and by auscultation, they found that the crepitus in the lower lungs due to pulmonary congestion associated with congestive heart failure also disappeared. That is, the inventors discovered that an IL-4 receptor α subunit antagonist is effective for treating or preventing dilated cardiomyopathy, and completed the present invention. Although we do not wish to be bound by any theory, periostin, an inflammatory indicator of IL-4 and IL-13, has been suggested as a factor involved in myocardial fibrosis/remodeling. To treat or prevent cardiomyopathy, IL-13 inhibitors, such as IL-4 receptor alpha subunit antagonists, are effective.

That is, the present invention includes, but is not limited to, the following inventions.
[1]
A pharmaceutical composition comprising an IL-13 inhibitor for treating or preventing dilated cardiomyopathy.
[2]
A pharmaceutical composition comprising an IL-13 inhibitor for treating or preventing symptoms of heart failure associated with dilated cardiomyopathy.
[3]
A pharmaceutical composition comprising an IL-13 inhibitor for treating or preventing hyperBNPemia associated with dilated cardiomyopathy.
[4]
The pharmaceutical composition according to any one of [1] to [3], wherein the IL-13 inhibitor is an IL-4 receptor α subunit antagonist.
[5]
The pharmaceutical composition according to [4], wherein the IL-13 inhibitor is an IL-4 receptor α subunit antagonist.
[6]
The pharmaceutical composition according to [5], wherein the IL-4 receptor α subunit antagonist is an IL-4/IL-13 receptor antagonist.
[7]
The IL-4/IL-13 receptor antagonist is an anti-IL-4/IL-13 receptor antagonist comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 2. The pharmaceutical composition according to [6], which is a 13 receptor antibody or an antigen-binding fragment thereof.
[8]
The pharmaceutical composition according to [7], wherein the anti-IL-4/IL-13 receptor antibody is dupilumab.
[9]
A method for treating or preventing dilated cardiomyopathy by administering a pharmaceutical composition comprising an IL-13 inhibitor to a subject suffering from dilated cardiomyopathy.

IL-13 inhibitors can effectively treat or prevent dilated cardiomyopathy.

The present invention, in one aspect, relates to a pharmaceutical composition comprising an IL-13 inhibitor for treating or preventing dilated cardiomyopathy. In the present invention, treatment refers to bringing about improvement or disappearance of pathological conditions and/or symptoms. In the present invention, prevention refers to preventing, suppressing, or delaying the occurrence of symptoms, or reducing the risk of occurrence of symptoms.

In this invention, dilated cardiomyopathy refers to (1) left ventricular A group of diseases characterized by diffuse systolic dysfunction and (2) left ventricular enlargement, excluding those that fall under secondary cardiomyopathy, which is secondary to an underlying disease or systemic abnormality and exhibits similar pathology. refers to a group of diseases caused by Whether a subject is suffering from dilated cardiomyopathy can be determined based on symptoms, auscultation, chest X-ray examination, electrocardiography, echocardiography, blood tests, etc. according to known diagnostic criteria. Since dilated cardiomyopathy is characterized by impaired left ventricular contraction, for example, left ventricular drive factor (LVEF) can be used as an index for improvement in dilated cardiomyopathy, but other known indexes can also be used. .

The present invention, from one aspect, relates to a pharmaceutical composition containing an IL-13 inhibitor for treating or preventing heart failure associated with dilated cardiomyopathy.
In the present invention, heart failure refers to any type of cardiac dysfunction, according to the Joint Guidelines for Diagnosis and Treatment of Acute and Chronic Heart Failure (JCS 2017/JHFS 2017), the Japanese Circulation Society/Japan Heart Failure Society. In other words, it is a clinical syndrome in which dyspnea, fatigue, and edema appear as a result of substrate and/or functional abnormalities occurring in the heart and the failure of the compensatory mechanism of cardiac pump function, resulting in decreased exercise tolerance. Symptoms of heart failure in the subject can be determined according to known diagnostic criteria by auscultation, chest X-ray examination, electrocardiography, echocardiography, blood test, motor function test, etc. Various symptoms of heart failure associated with dilated cardiomyopathy, ie, heart failure caused by dilated cardiomyopathy, can be treated or prevented.

The present invention, from one aspect, relates to a pharmaceutical composition containing an IL-13 inhibitor for treating or preventing hyperBNPemia associated with dilated cardiomyopathy.
The inventors have discovered that IL-13 inhibitors can treat or prevent not only the pathology of dilated cardiomyopathy, but also hyperBNPemia in subjects suffering from dilated cardiomyopathy. BNP (brain natriuretic peptide) is an indicator of the load on the heart. HyperBNPemia refers to the concentration of BNP in serum or plasma exceeding the normal value of 40 pg/mL, particularly 100 pg/mL or higher, 200 pg/mL or higher, 400 pg/mL or higher, This refers to cases where the concentration is 500 pg/mL or higher, or 1000 pg/mL or higher.

The pharmaceutical composition of the present invention includes an IL-13 inhibitor. IL-13 inhibitor refers to a drug that inhibits the function of IL-13 in a living body, such as a drug that inhibits the function or expression of the IL-13 gene or IL-13 protein, and antagonizes the ligand of the IL-13 receptor. Examples include drugs, IL-13 receptor antagonists, and the like. Examples of drugs that inhibit the function or expression of the IL-13 gene or IL-13 protein include low molecular weight compounds that inhibit the function or expression of the IL-13 gene or IL-13 protein, and suppresses the expression of the IL-13 gene. Examples include siRNA (small interfering RNA), shRNA (short hairpin RNA), miRNA (micro RNA), antisense nucleic acids, and expression vectors capable of expressing these polynucleotides. Examples of drugs that antagonize IL-13 receptor ligands include antibodies that specifically bind to IL-13 or antigen-binding fragments thereof. Examples of the IL-13 receptor antagonist include antibodies that specifically bind to the IL-13 receptor or binding fragments thereof. Because IL-13 and IL-4 receptors share an α subunit, IL-13 inhibitors include drugs that inhibit both IL-4 and IL-13 receptors. Examples of drugs that inhibit both IL-4 receptors and IL-13 receptors include IL-4 receptor α subunit antagonists. An IL-4 receptor α subunit antagonist refers to a drug that antagonizes the ligand of the IL-4 receptor α subunit and blocks or inhibits the function of the IL-4 receptor. The IL-4 receptor α subunit antagonist is preferably an antibody or antigen-binding fragment thereof that specifically binds to the IL-4 receptor α subunit. The IL-4 receptor α subunit antagonist may be an IL-4/IL-13 receptor antagonist that acts as an antagonist for both the IL-4 receptor and the IL-13 receptor. . Preferred examples of IL-4/IL-13 receptor antagonists include anti-IL-4 receptor antagonists comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 2. /IL-13 receptor antibody or an antigen-binding fragment thereof, and a more preferred example is dupilumab or an antigen-binding fragment thereof.

The pharmaceutical composition of the present invention can be formulated into any form such as a powder formulation, granule formulation, tablet, capsule, or injection formulation. Pharmaceutical compositions of the invention can be formulated using, in addition to the IL-4 receptor alpha subunit antagonist, pharmaceutically acceptable additives well known to those skilled in the art. Pharmaceutically acceptable additives include surfactants, stabilizers, pH adjusters, solubilizing agents, and the like. As the surfactant, polysorbate such as polysorbate 80 can be suitably used. As the stabilizer, L-histidine, L-histidine hydrochloride hydrate, L-arginine hydrochloride, etc. can be suitably used. As the pH adjuster, acetates such as sodium acetate hydrate, glacial acetic acid, and the like can be suitably used. As the solubilizing agent, sucrose such as refined white sugar can be suitably used.

The dosage form and dosage of the pharmaceutical composition of the present invention can be appropriately determined by those skilled in the art, taking into consideration the age, weight, etc. of the subject. The pharmaceutical compositions of the invention can be administered, for example, systemically or locally, for example subcutaneously, intravenously, or intranasally. The pharmaceutical compositions of the invention can be administered at doses ranging from 0.1 mg to 600 mg, from 100 mg to 400 mg, from 150 mg, 200 mg, 250 mg, 300 mg or 350 mg, for example as an IL-4 receptor alpha subunit antagonist. can. Typically, the pharmaceutical composition of the present invention is administered subcutaneously at an initial dose of 600 mg as an IL-4 receptor alpha subunit antagonist, followed by subsequent subcutaneous administration of 300 mg at two-week intervals.

The pharmaceutical composition of the present invention may contain one or more additional agents in addition to the IL-4 receptor α subunit antagonist, as long as the desired effect is achieved. Alternatively, the pharmaceutical composition containing the IL-4 receptor α subunit antagonist of the present invention may be supplemented with an additional drug or It may also be administered in combination with a pharmaceutical composition. In the present invention, concomitant administration means administering separate pharmaceutical compositions and drugs or pharmaceutical compositions simultaneously or sequentially.

In one aspect, the present invention provides a method for treating or preventing dilated cardiomyopathy by administering a pharmaceutical composition comprising an IL-4 receptor α subunit antagonist to a subject suffering from dilated cardiomyopathy. Also related.

The present invention will be explained in detail in the following examples, but the present invention is not limited to the examples.

The results of administering Dupixent (trade name: Manufacturer: Sanofi), a pharmaceutical composition containing dupilumab, to Patient 1 are shown below.
Patient 1 has been suffering from dilated cardiomyopathy (DCM) for more than 10 years and associated cardiac enlargement (CTR: cardiothoracic ratio, which is the cardiothoracic ratio on chest X-ray images.The most commonly used imaging indicator of cardiac hypertrophy is He was a man in his 50s who had been diagnosed with 78% of the symptoms (less than 50% is considered normal). Patient 1 had dilated cardiomyopathy and also had symptoms of severe heart failure (left ventricular ejection fraction (LVEF) was 35% on echocardiography during the stable phase), and as the heart failure worsened, he developed symptoms of congestive heart failure. He had repeated bouts of difficulty breathing. In addition, patient 1 usually has difficulty breathing, palpitations, and fatigue even during mild daily tasks, and was diagnosed with persistent heart function classification NYHA grade 3. There was a history of hospitalization due to Furthermore, over the last 6 years for which patient 1 has records of test values, his plasma BNP, which is an indicator of cardiac stress, has always been high, ranging from 200 to 500 even during stable periods and over 1000 (normally 40 pg/m or less) during heart failure. He also showed BNPemia. In addition, patient 1 had no clear asthma attacks, and secondary cardiomyopathy was excluded.

In February 2021, with Patient 1's consent, administration (subcutaneous administration) of the brand name Dupixent, a pharmaceutical composition containing dupilumab, was started. Dupilumab was administered subcutaneously at an initial dose of 600 mg, followed by subcutaneous administration of 300 mg at two-week intervals. The results are shown in Table 1 below. Dyspnea disappeared 3 to 4 weeks after administration and continued. Stubborn lower leg edema also disappeared. Eight weeks after administration, blood tests showed that serum BNP, a sensitive indicator of heart failure, normalized for the first time to less than 40, and X-ray CTR improved from 78% to 71%, and auscultation showed that pulmonary congestion associated with congestive heart failure was observed. The crepitus in the lower lungs also disappeared. In addition, as of March 2022, he is continuing to administer dupilumab by self-injection, and his BNP has remained below 40, his CTR has reached 65%, and his LVEF (left ventricular ejection fraction on echocardiography) has reached 48%. Improved. Breathing difficulties and fatigue were also significantly reduced. There were no side effects due to dupilumab administration.As mentioned above, when dupilumab was administered to patients with severe dilated cardiomyopathy, it was significantly effective in a relatively short period of time, and it was shown that it was effective not only for patients with dilated cardiomyopathy but also for patients with dilated cardiomyopathy. It was shown that heart failure and hyperBNPemia associated with cardiomyopathy improved or disappeared. It is noteworthy that hyperBNPemia normalized early, and this type of treatment course has never been seen with other treatments in dilated cardiomyopathy. It was suggested that it acts on the underlying mechanism of heart failure.

Claims (8)

A pharmaceutical composition comprising an IL-13 inhibitor for treating or preventing dilated cardiomyopathy. A pharmaceutical composition comprising an IL-13 inhibitor for treating or preventing symptoms of heart failure associated with dilated cardiomyopathy. A pharmaceutical composition comprising an IL-13 inhibitor for treating or preventing hyperBNPemia associated with dilated cardiomyopathy. The pharmaceutical composition according to any one of claims 1 to 3, wherein the IL-13 inhibitor is an IL-4 receptor α subunit antagonist. The pharmaceutical composition according to claim 4, wherein the IL-13 inhibitor is an IL-4 receptor α subunit antagonist. The pharmaceutical composition according to claim 5, wherein the IL-4 receptor α subunit antagonist is an IL-4/IL-13 receptor antagonist. The IL-4/IL-13 receptor antagonist is an anti-IL-4/IL-13 receptor antagonist comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 2. 7. The pharmaceutical composition according to claim 6, which is a 13 receptor antibody or an antigen-binding fragment thereof. 8. The pharmaceutical composition according to claim 7, wherein the anti-IL-4/IL-13 receptor antibody is dupilumab.