Use of nintedanib for treating castleman disease

Abstract

The invention relates to the use of a tyrosine kinase inhibitor, specifically nintedanib or one of the pharmaceutically acceptable salts thereof, for the treatment of Castleman disease or the prevention or treatment of one of its complications.

Description

[0001] Use of nintedanib for the treatment of Castleman disease

[0002] The invention relates to the use of a tyrosine kinase inhibitor, namely nintedanib or one of its pharmaceutically acceptable salts, in the treatment of Castleman disease or the prevention or treatment of one of its complications.

[0003] State of the art

[0004] Castleman disease is a rare, non-cancerous, non-communicable, and non-hereditary disease of the lymph nodes. There are several forms: idiopathic multicentric (also called disseminated), multicentric associated with the HHV-8 virus, or unicentric (also called localized).

[0005] The idiopathic multicentric form can manifest at any age, but generally affects adults over 40 years of age. It is characterized by a deterioration of general condition, accompanied by anemia, thrombocytosis, an elevation of C-reactive protein and polyclonal hypergammaglobulinemia.

[0006] The form associated with the HHV-8 virus presents a clinical picture similar to that of severe forms of idiopathic multicentric Castleman disease, with some particularities such as the frequency of Kaposi lesions and a risk of hemophagocytosis.

[0007] The unicentric form of Castleman disease affects only one group of lymph nodes. This is the most common form, primarily affecting children and young adults. It is characterized by localized, non-inflammatory, and painless lymphadenopathy, usually discovered incidentally or through self-examination.

[0008] Castleman disease, particularly in its unicentric form, can lead to compression of the lymph nodes by the lymphadenopathy, and the development of potentially fatal autoimmune (such as paraneoplastic pemphigus, bronchiolitis obliterans or myasthenia gravis) or neoplastic (follicular dendritic cell sarcoma) complications.

[0009] Current drug treatments, such as corticosteroids, B-cell therapies (rituximab), IL-6 receptor antibodies (siltuximab, tocilizumab), and cyclophosphamide, target inflammatory forms of Castleman disease and are ineffective in unicentric, non-inflammatory forms. Localized radiotherapy may be recommended, but its short- and long-term toxicity limits its use, particularly in certain locations and in young patients. Surgery, especially in unicentric cases, remains the preferred option and aims for complete excision of the lesion. However, immediate complications can arise due to the highly vascular nature of the lesions. Therefore, the risk of pre- or postoperative hemorrhage is significant.In some patients, excision is not feasible or is considered too difficult due to the location of the tumor, the contiguous involvement of vital structures, or the hemorrhagic nature of the lesion.

[0010] There is therefore a marked need for treatment of Castleman disease, particularly in patients with unresectable or only partially resectable unicentric Castleman disease.

[0011] Summary of the invention

[0012] To address this need, the inventors now propose using nintedanib or one of its pharmaceutically acceptable salts.

[0013] An object of the invention is therefore a tyrosine kinase inhibitor, which is nintedanib or one of its pharmaceutically acceptable salts, for its use in the treatment of Castleman disease or the prevention or treatment of one of its complications.

[0014] Preferably, the tyrosine kinase inhibitor is nintedanib esylate.

[0015] It is preferably used in the treatment of non-inflammatory forms of Castleman disease or in the prevention or treatment of one of its complications.

[0016] Advantageously, Castleman disease is unicentric Castleman disease, more specifically it may be unresectable or partially resectable unicentric Castleman disease.

[0017] Nintedanib or one of its pharmaceutically acceptable salts is particularly useful for reducing tumor volume and, if necessary, enabling surgery.

[0018] It is also useful in the treatment of skin or lung involvement associated with Castleman disease, particularly in the treatment of paraneoplastic pemphigus (PNP) or bronchiolitis obliterans (BO).

[0019] It is also useful in reducing the risk of developing follicular dendritic cell sarcoma. Detailed description of the invention

[0020] The invention aims to treat Castleman's disease, or to prevent or treat one of its complications.

[0021] Definitions

[0022] The term "patient" refers to a human subject, who may be an adult or a child, having a diagnosis of one of the forms of Castleman disease, preferably unicentric Castleman disease.

[0023] The term "treatment" refers to curative or symptomatic treatment aimed at relieving or slowing the onset or development of one or more symptoms of the disease, or one of its complications.

[0024] The term "prevention" refers to reducing the risk of developing one or more of the symptoms of the disease or one of its complications.

[0025] The term "pharmaceutically acceptable" is used here to refer to compounds that are suitable for use in contact with human tissues without toxicity, irritation, or excessive allergic reaction.

[0026] The nintedanib

[0027] Nintedanib refers to 3-Z-[l-(4-(N-((4-methyl-piperazine-l-yl)-methylcarbonyl)-N-methyl-aminojanilino)-1-phenylmethylene]-6-methoxycarbonyl-2-indolinone, with formula A,

[0028] Patent application W02004 / 013099 discloses its monoethanesulfonate (esylate) salt, which is particularly suitable for pharmaceutical compositions. Other salt forms, such as those shown in patent application WO 2007 / 141283, are also useful here.

[0029] A mixture of nintedanib in free base form and one of its pharmaceutically acceptable salts, such as nintedanib esylate, can also be used here.

[0030] Castleman disease and its complications

[0031] Castleman disease is understood here as encompassing three forms: idiopathic multicentric (also called disseminated), multicentric associated with HHV-8, and unicentric (also called localized). According to a preferred approach, the aim is to treat unicentric Castleman disease most effectively. This form is typically characterized by a single, hypervascularized lymph node mass.

[0032] Patients with Castleman disease are at risk of multiple complications.

[0033] The invention aims to prevent or treat these complications, in particular which may be skin and / or lung complications, or more generally autoimmune complications.

[0034] These complications include an inflammatory syndrome, particularly common in multicentric and / or plasmacytic forms, whether idiopathic or associated with HHV-8. An inflammatory syndrome can also complicate or even reveal a localized form. Clinically, it may present with fever, weight loss, and, in children, growth retardation. Laboratory findings include microcytic, aregenerative anemia, thrombocytopenia or thrombocytosis, hypoalbuminemia, hypergammaglobulinemia, and a marked elevation of CRP.

[0035] Another complication is paraneoplastic pemphigus (PNP). This is a bullous disease associated with autoantibodies against cutaneous intercellular substances, causing skin and mucous membrane lesions. Pulmonary involvement, manifesting as bronchiolitis obliterans, can lead to severe respiratory failure. This complication appears to be particularly common in Asian populations. PNP is sometimes diagnosed before Castleman disease. In this case, systematic screening for Castleman disease is essential, as its neutralization is crucial for achieving sustained remission of PNP. More generally, several types of skin lesions can be observed as complications of Castleman disease.

[0036] In addition to skin lesions caused by PNP, specific lesions can occur, most often a single, nodular lesion whose biopsy reveals lymphoid and plasmacytic infiltration. Glomerular hemangiomas can also be observed. In the skin lesions of the Asian or Polynesian form, multiple, infiltrated, slightly pigmented lesions may be found, corresponding to a clinical presentation of these specific lesions.

[0037] Pulmonary involvement is also a frequent complication, which the present invention aims to treat or prevent. This pulmonary involvement includes interstitial lymphoid pneumonia, bronchiolitis obliterans or organizing pneumonia, and bilateral infiltrates accompanying hemophagocytic syndrome.

[0038] Other complications include neuropathies, such as peripheral neuropathy or polyradiculoneuritis.

[0039] Myasthenia gravis (MG), an autoimmune disease of the neuromuscular junction, is another observed complication.

[0040] AA amyloidosis remains a possible complication.

[0041] Finally, the tumor lesions observed in Castleman disease are often associated with proliferations of follicular dendritic cells, which can evolve into a sarcoma.

[0042] The invention makes it possible to reduce the risk, delay the onset, and / or slow the development of at least one of these complications.

[0043] Treatment efficacy can be monitored by determining the decrease in TLG (Total Lesion Glycolysis), which can be measured following a PET scan. This index is defined by the following formula: TLG = Average SUV x MTV, where SUV (Standardized Uptake Value) is the ratio of the radioactive tracer concentration to the activity injected into the patient, divided by the patient's mass (a dimensionless quantity), and MTV (Metabolic Tumor Volume) represents the Metabolic Tumor Volume.

[0044] In a preferred embodiment, administration of nintedanib or one of its pharmaceutically acceptable salts according to the invention reduces tumor volume to such an extent as to allow for surgical excision, preferably complete excision. Preferably, the reduction in tumor volume is at least 15%, preferably at least 20%, preferably even at least 30%, or even at least 40%. Most advantageously, the reduction in tumor volume is at least 30%.

[0045] An improvement in overall survival is thus expected, particularly in patients with unicentric Castleman disease, unresectable or only partially resectable before treatment.

[0046] Treatment method

[0047] Described here is a method for treating Castleman disease or for preventing or treating one of its complications, in a patient, in which the patient is administered nintedanib or one of its pharmaceutically acceptable salts.

[0048] The therapeutically effective amount and dosage may depend on the patient's age and weight, the route of administration, and the stage of disease development.

[0049] Administration can be carried out, for example, orally, intravenously, subcutaneously, rectally, by inhalation, or any other suitable route.

[0050] Oral administration is preferred. Nintedanib or one of its pharmaceutically acceptable salts can then typically be formulated in combination with pharmaceutically acceptable excipients, within a pharmaceutical composition which may be, for example, a capsule, a tablet, a syrup or a solution.

[0051] According to one embodiment of the invention, nintedanib, or one of its pharmaceutically acceptable salts, is administered at a daily dose of 50 mg to 400 mg, preferably 100 to 300 mg. Preferably, the patient receives a dose of 100 to 150 mg twice daily of nintedanib or one of its pharmaceutically acceptable salts.

[0052] A pharmaceutical composition useful for treating Castleman disease or for preventing or treating one of its complications is also described. This pharmaceutical composition comprises nintedanib or one of its pharmaceutically acceptable salts, in combination with at least one pharmaceutically acceptable excipient. Typically, the pharmaceutical composition may include 100 or 150 mg of nintedanib or one of its pharmaceutically acceptable salts.

[0053] The administration is typically planned for a period of at least one month, preferably for at least about 3 months, even more preferably for at least about 6 months, and even more preferably for at least 12 months.

[0054] In a particularly preferred embodiment, the patient receives nintedanib or one of its pharmaceutically acceptable salts such as nintedanib esylate orally, at a dose of 100 to 150 mg twice daily, for a period of at least about 3 months, preferably at least 6 months, and preferably still at least 12 months.

[0055] Nintedanib or one of its pharmaceutically acceptable salts such as nintedanib esylate, can be administered alone or in combination with another active substance, for example corticosteroids, treatments targeting B lymphocytes, such as rituximab, antibodies targeting the IL6 axis such as siltuximab, or tocilizumab, and / or cyclophosphamide.

[0056] The examples below illustrate the invention without limiting its scope.

[0057] Example 1:

[0058] A 50-year-old woman diagnosed with unicentric Castleman disease underwent incomplete surgical resection, subsequently developing paraneoplastic pemphigus (PNP) which was complicated by bronchiolitis obliterans (BO). Due to treatment-resistant lung involvement, the patient was eventually administered nintedanib esylate, 150 mg twice daily, orally.

[0059] An improvement in BO was observed. After 12 months of treatment with nintedanib esylate, the patient showed, in particular, an improvement in total lung capacity and DLCO (diffusing capacity of carbon monoxide), as well as an improvement in the walking test (going from 38% to 60% of the theoretical value).

[0060] Example 2: Open, uncontrolled, multicenter phase II trial

[0061] Patients

[0062] For this trial, patients aged 18 years or older are selected, whose diagnosis of unicentric Castleman disease has been established after biopsy (hyaline-vascular histology). The selected patients have unresectable or only partially resectable lesions, or for whom surgery has been refused.

[0063] Potential complications such as paraneoplastic pemphigus (PNP), bronchiolitis obliterans (BO), and myasthenia gravis (MG) are investigated using clinical markers (signs or symptoms of PNP, BO, and MG) and laboratory tests (PNP: screening for anti-ICS, dsgl and 3, and antiplakin antibodies; MG: screening for anti-AChR and MusK antibodies). If skin lesions suggestive of PNP are present, a skin biopsy (fixed and frozen sample) is performed. If BO is suspected, a pulmonary function test is conducted. The patient also undergoes an assessment of their performance status and potential comorbidities (chronic liver disease, chronic kidney disease, and coagulation disorders).He also undergoes a basic routine biological assessment (complete blood count, serum electrolytes, BUN, serum creatinine, liver enzymes, total conjugated bilirubin, PT and TTP, serum fibrinogen, urine protein sample (proteinuria / creatininuria), serum C-reactive protein, serum electrophoresis). A baseline positron emission tomography and PET-CT scan are performed.

[0064] Study design

[0065] These patients are administered nintedanib esylate, in the form of oral capsules (Ofev®), at a dose of 150 mg, twice a day, for a period of 6 months.

[0066] Treatment evaluation

[0067] The efficacy of nintedanib in reducing total lesion glycolysis (TLG) in Castleman disease lesions is being evaluated. A very good response is defined as a reduction of at least 30% in TLG as measured by 18F-FDG PET / CT at months 3 and 6. The size and metabolism of disease-related lesions are also being assessed, and lesion resectability is being estimated after 3 and 6 months of treatment. Furthermore, the progression and occurrence of complications related to autoimmune diseases (including paraneoplastic pemphigus, bronchiolitis obliterans, and myasthenia gravis) are being monitored.

Claims

Demands 1. Tyrosine kinase inhibitor, which is nintedanib or one of its pharmaceutically acceptable salts, for use in the treatment of Castleman disease or the prevention or treatment of any of its complications, in which Castleman disease is unicentric Castleman disease.

2. The tyrosine kinase inhibitor for its use according to claim 1, the tyrosine kinase inhibitor being nintedanib esylate.

3. The tyrosine kinase inhibitor for its use according to claim 1 or 2, wherein Castleman disease is unresectable or partially resectable unicentric Castleman disease.

4. The tyrosine kinase inhibitor for its use according to any one of claims 1 to 3, wherein the inhibitor is in the form of a pharmaceutical composition suitable for oral administration.

5. The tyrosine kinase inhibitor for its use according to any one of claims 1 to 4, wherein the inhibitor is in the form of a pharmaceutical composition suitable for administration at a daily dose of 50mg to 400mg, preferably 100 to 300mg.

6. The tyrosine kinase inhibitor for its use according to claim 5, wherein the inhibitor is in the form of a pharmaceutical composition suitable for administration at a dose of 100 to 150 mg twice daily.

7. The tyrosine kinase inhibitor for its use according to any one of claims 1 to 6, to decrease tumor volume and, where appropriate, enable surgery.

8. The tyrosine kinase inhibitor for its use according to any one of claims 1 to 6, in the treatment of skin or lung damage associated with Castleman disease.

9. The tyrosine kinase inhibitor for its use according to claim 8, in the treatment of paraneoplastic pemphigus (PNP) or bronchiolitis obliterans (BO).

10. The tyrosine kinase inhibitor for its use according to any one of claims 1 to 6, to reduce the risk of developing follicular dendritic cell sarcoma.

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