Use of imatinib in treatment of stroke

Abstract

The imatinib may be used in a new dosage regimen in which the imatinib is administered to a patient at a dose of 650 mg / day or higher for at least three consecutive days, and preferably at a starting dose of 1000 mg / day or higher on the first day, and at a dose in the interval of 650 mg / day to 1000 mg / day on subsequent several days. Methods, pharmaceutical compositions and kits for treating stroke are also disclosed.

Description

[0001] This application is a divisional application of the invention patent application with application number 201780013732.6. The application date of the original application is February 27, 2017. The name of the invention is: Use of imatinib in the treatment of stroke. Technical Field

[0002] The present disclosure relates generally to the medical field and stroke treatment, and in particular to novel methods and uses for stroke treatment involving administration of Imatinib or Nilotinib at a prescribed dose for at least 3 consecutive days. Background Art

[0003] A stroke is defined as the sudden death of brain cells in a local area due to interrupted or insufficient blood flow. According to European Cardiovascular Disease Statistics 2012, stroke is the second most common cause of death in Europe: nearly 1.1 million people die each year. More than one in seven women (15%) and one in ten men (10%) die from the disease (Melanie Nichols et al., European Cardiovascular Disease Statistics, 2012 Edition, Department of Public Health, University of Oxford).

[0004] Depending on the causative factor and progression, stroke can be assigned to one of two main types:

[0005] Ischemic stroke, caused by a blockage or clot in a blood vessel supplying blood to the brain. This accounts for the vast majority of all stroke cases.

[0006] Hemorrhagic stroke, which occurs when a blood vessel ruptures. The cause of the rupture may be an aneurysm or an arteriovenous malformation, which may be a birth defect. However, the most common cause is uncontrolled high blood pressure.

[0007] The following disclosure will focus on ischemic stroke, particularly acute ischemic stroke, but is not limited thereto. The goal of all existing treatments for ischemic stroke is to quickly restore blood flow and prevent or at least reduce the likelihood of another stroke. Currently, the only FDA-approved treatment for ischemic stroke is tissue plasminogen activator (tPA, ). tPA works by dissolving clots and improving blood flow to parts of the brain that lack blood flow. tPA can improve the chances of recovery from a stroke if it is administered early. However, tPA is known to have serious side effects, such as increased vascular permeability due to altered blood-brain barrier function, and neurotoxicity. There are indications that when the start of tPA treatment is delayed, the balance between the positive effects of tPA and the side effects becomes unfavorable to the patient. The exact threshold varies, but it is generally recommended to start tPA treatment as soon as possible, preferably no later than 4-5 hours after the stroke. Sometimes even narrower treatment windows are recommended.

[0008] Before administering tPA or other drugs to dissolve the blood clots, it is important to determine whether the patient has had a hemorrhagic stroke or an acute ischemic stroke. In the case of a hemorrhage, thrombolysis can make the condition worse. Symptoms alone are usually not enough to make this distinction, so patients are usually given a CT scan or MRI scan to rule out any intracranial bleeding. Only then can thrombolytic therapy be started. Depending on the resources and diagnostic capabilities available, this may delay the start of thrombolytic therapy, or even cause caregivers to avoid this treatment as a precaution. Furthermore, to be most effective, thrombolysis should be started within 3 hours of the onset of the stroke, preferably as early as possible.

[0009] Thrombolysis is the treatment of choice for acute stroke within 3 to 4.5 hours of symptom onset. Trials have shown that alteplase is superior to placebo 3-4.5 hours after onset, and there is a registry study to support this. Professional recommendations supporting these results have been issued but have yet to be fully accepted. However, there are indications that delayed thrombolytic therapy may be associated with more severe side effects. As a result, patients may not receive the most appropriate treatment due to uncertainty in the diagnosis (ischemic and hemorrhagic stroke), or delays in achieving a diagnosis (delayed access to CT, or lack of necessary equipment), or a combination thereof. In practice, only about 10% of patients receive thrombolytic therapy. Other treatments include mechanical thrombectomy, i.e. the surgical removal or disintegration of a clot, and antiplatelet therapy to prevent the formation of new clots. Cumulative experience shows that thrombectomy significantly increases the chances of recovery, or at least reduces neurological damage after a stroke. Unlike thrombolytic drugs, antiplatelet agents have no effect on clots that are already present. Aspirin is the most commonly used antiplatelet agent, and there is evidence that it is effective for the early treatment of acute ischemic stroke, preferably in combination with dipyridamol.

[0010] WO 2007 / 124308 discloses methods and compositions for counteracting the adverse effects of tPA by using platelet-derived growth factor (PDGF) and PDGF receptor antagonism, which are used to prevent or improve the side effects of tPA where thrombolysis is needed, and improve treatment, or extend the treatment window. WO 2007 / 124308 also discloses a combination therapy for treating ischemic stroke using tPA and a PDGF receptor antagonist. Imatinib mesylate is given as an example of a suitable substance for inhibiting PDGF receptors.

[0011] In any case, given the high prevalence of acute ischemic stroke and the serious consequences, such as disability and death, improved treatments and new drugs are needed. Summary of the invention

[0012] One aim is to improve the treatment of acute ischemic stroke, whether it involves surgical removal of a clot or multiple clots (thrombectomy) or pharmacological thrombolytic therapy, such as administration of tissue plasminogen activator, or antiplatelet therapy, or a combination thereof.

[0013] Another aim is to expand the therapeutic window for thrombolysis by enabling the initiation of thrombolytic therapy later than currently recommended.

[0014] Another object is to provide new methods for treating stroke, not limited to acute ischemic stroke, but also applicable to, for example, hemorrhagic stroke.

[0015] After studying the specification and embodiments as well as the appended claims, other objects, corresponding aspects and advantages associated with the technical solutions provided by the present invention will be apparent to those skilled in the art.

[0016] According to a first aspect, the present inventors disclose imatinib ( STI-571, a tyrosine kinase inhibitor) can be used to treat acute ischemic stroke, wherein the imatinib is administered to the patient at a dose of 650 mg / day or higher for at least 3 consecutive days, preferably at least 4 consecutive days, and most preferably at least 5 consecutive days.

[0017] According to an embodiment of the first aspect, the imatinib is administered to the patient at a dose of 700 mg / day or higher, preferably 750 mg / day or higher, more preferably 800 mg / day or higher.

[0018] According to another embodiment freely combinable with the above, said imatinib is administered to the patient before, simultaneously with or after thrombectomy (surgical removal or breakdown of a clot).

[0019] According to another embodiment freely combinable with the above, said imatinib is administered to the patient before, simultaneously with or after thrombolysis (pharmacological breakdown of blood clots).

[0020] According to a preferred embodiment freely combinable with the above, the imatinib is administered to the patient before, during or after thrombectomy and thrombolysis.

[0021] Most preferably, imatinib is administered to a patient as soon as possible, even before it is determined whether the patient has suffered an acute ischemic stroke or a hemorrhagic stroke.

[0022] According to another embodiment freely combinable with the above, the thrombolysis comprises administering a tissue plasminogen activator (tPA), preferably selected from alteplase Reteplase Tenecteplase

[0023] According to a preferred embodiment freely combinable with the above embodiments, the imatinib is administered to the patient at a starting dose of 1000 mg / day or higher on day 1, and at a dose ranging from 650 mg / day to 1000 mg / day on subsequent days.

[0024] Although the initial dose should be higher than the subsequent dose, it is currently envisioned that imatinib should not be administered at a dose higher than 1600 mg / day as the initial dose. In addition, it is envisioned that imatinib should not be administered at a dose higher than 1200 mg / day on any of the consecutive days. According to another embodiment that can be freely combined with the above, the imatinib is administered orally.

[0025] According to an alternative embodiment freely combinable with the above, wherein said imatinib is administered intravenously. It is also envisaged that at least a portion of the initial dose of imatinib is administered intravenously, while subsequent, continuous doses are administered orally.

[0026] According to a second aspect, the present inventors provide a method for treating acute ischemic stroke, wherein imatinib ( STI-571, a tyrosine kinase inhibitor) is administered to the patient at a dose of 650 mg / day or more for at least 3 consecutive days, preferably at least 4 consecutive days, and most preferably at least 5 consecutive days.

[0027] According to an embodiment of the second aspect, imatinib is administered to the patient at a dose of 700 mg / day or higher, preferably 750 mg / day or higher, more preferably 800 mg / day or higher.

[0028] According to another embodiment freely combinable with the above, imatinib is administered to the patient before, simultaneously with or after thrombectomy.Thrombectomy is here understood as any surgical removal or breakdown of a clot, whatever the method used.

[0029] According to another embodiment, freely combinable with the above, imatinib is administered to the patient before, simultaneously with or after thrombolysis.Thrombolysis is here understood as the pharmacological breakdown of a blood clot, regardless of the specific drug or pharmacological treatment used.

[0030] According to a preferred embodiment freely combinable with the above, imatinib is administered to the patient before, during or after thrombectomy and thrombolysis.

[0031] Most preferably, imatinib is administered to a patient as soon as possible, even before it is determined whether the patient has suffered an acute ischemic stroke or a hemorrhagic stroke.

[0032] According to another embodiment freely combinable with the above, wherein the thrombolysis comprises administering a tissue plasminogen activator (tPA) (selected from alteplase Reteplase Tenecteplase

[0033] According to a preferred embodiment that can be freely combined with the above, the imatinib is administered to the patient at a starting dose of 1000 mg / day or higher on the first day, and at a dose in the range of 650 mg / day to about 1000 mg / day on the following days. Although the starting dose should be higher than the subsequent dose or multiple doses, it is currently envisioned that imatinib should not be administered at a dose higher than 1600 mg / day as the starting dose. In addition, it is envisioned that imatinib should not be administered at a dose higher than 1200 mg / day on any of the consecutive days.

[0034] According to another embodiment freely combinable with the above, imatinib is administered orally.

[0035] According to an alternative embodiment, freely combinable with the above, imatinib is administered intravenously. It is also envisaged that at least a portion of the initial dose of imatinib is administered intravenously, while subsequent, continuous doses are administered orally.

[0036] The steps of any method disclosed herein do not have to be performed in the exact order disclosed, unless explicitly stated.

[0037] Particular embodiments include pharmaceutical compositions for intravenous administration comprising a dosage range of 400-1200, preferably 800-1000 mg of imatinib in a solution suitable for intravenous administration, for example in a 0.8-1.0% NaCl solution, such as 500 ml of a 0.9% NaCl solution.

[0038] The pharmaceutical composition for intravenous administration can be prepared in a hospital pharmacy, intensive care unit or bedside (care point). Imatinib should be stored away from heat sources, moisture and light. Preferably, imatinib is provided in a lyophilized form, stored in a sealed dark glass vial, and may be mixed with one or more suitable stabilizers. When preparing a composition for intravenous administration, lyophilized imatinib is reconstituted by adding sterile WFI or saline, and added to a solution for intravenous administration at a desired concentration.

[0039] Therefore, a particular embodiment is the use of a pharmaceutical composition suitable for intravenous administration in the treatment of stroke, said composition comprising imatinib and optionally adjuvants and excipients.

[0040] Another embodiment is a kit comprising imatinib, preferably in lyophilized form, and a solution suitable for reconstitution of lyophilized imatinib, and a solution suitable for intravenous administration, and optional adjuvants and excipients. In a specific embodiment, imatinib is provided in a dose of 400 mg and 800 mg in a separate vial, and the solution suitable for intravenous administration is a 0.8-1.0% NaCl solution, preferably a 0.9% NaCl solution, to be provided in a container, such as a flexible bag with a capacity of 50 ml, 100 ml, 250 ml, 500 ml or 1000 ml, preferably 500 ml.

[0041] It is currently preferred to administer imatinib intravenously, but when imatinib is available in tablet form, it is envisaged that the initial dose of imatinib is administered intravenously at least during the first day of treatment, while imatinib is administered orally during the remaining treatment period. Therefore, another embodiment is a kit comprising a solution of 1000 mg imatinib in 500 ml of 0.9% NaCl, and n*400 mg imatinib tablets, wherein n is an integer between 2 and 4.

[0042] Other aspects and embodiments will become apparent to one skilled in the art upon examination of the drawings and the following detailed description and examples. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] The present invention and its embodiments will now be described by way of example with reference to the accompanying drawings, in which:

[0044] Figure 1The logical features of the clinical study are shown. The first arrow from the left indicates "A total of 60 patients were recruited between February 2011 and November 2014". The second arrow from the left indicates "All patients who started intravenous thrombolysis within 4.5h: stroke onset to start: median 1h25m range: 0h35m to 4h25m". The third arrow from the left represents "25 patients who received mechanical thrombectomy, ended within 7h45min: stroke onset to end: median 4h38m range: 2h25m to 7h45m". The fourth arrow from the left represents "43 patients randomized to imatinib (17 as controls): stroke onset to first dose: median 4h00m range: h5m-11h54min".

[0045] Figure 2 A graph showing the plasma concentration of imatinib (ng / ml) over time (Day 0 to Day 6) for three different doses of 400, 600 and 800 mg is shown. D0 = 3 h after the first dose; D1-D5 = before the morning dose of Days 1-5; D6 = morning of Day 6. For each 600 mg and 800 mg D0-D2, N = 14; for each 400 mg and for each 600 mg and 800 mg D3-D6, N = 1.

[0046] Figure 3 Mean results according to the National Institute of Health Stroke Scale (NIHSS) are shown.

[0047] Figure 4 Results according to the modified Rankin scale are shown. A score of 0-2 indicates functional independence. DETAILED DESCRIPTION

[0048] Before describing the present invention, it is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims and their equivalents.

[0049] It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0050] Furthermore, where applicable, the term "about" is used to indicate a deviation of + / - 2% from a given value, preferably a deviation of + / - 5% from a given value, and most preferably a deviation of + / - 10% from a given value.

[0051] Tyrosine kinase inhibitors (TKIs) are biologically active, usually aromatic, small molecules that are currently being investigated for the treatment of cancer, inflammatory, metabolic, proliferative, and neurodegenerative diseases. Tyrosine kinase inhibitors can bind to the active site of TK receptors to prevent phosphorylation and, by doing so, inhibit, modulate, or regulate signal transduction, often with cytostatic activity. Some potent kinase inhibitors are selective for certain TK receptors and less selective for others. For example, some compounds are potent and selective inhibitors of vascular endothelial growth factor receptor (VEGFR) receptor kinases, but weak inhibitors of platelet-derived growth factor receptor (PDGFR) tyrosine kinases and epidermal growth factor receptor (EGFR) tyrosine kinases.

[0052] As of today, eight TKI drugs, including imatinib and gefitinib, have been approved by the Food and Drug Administration for use in humans. One TKI, Toceranib (Palladia), was recently approved for the treatment of cancer in dogs. Erlotinib (Tarceva), like gefitinib, inhibits EGFR. Lapatinib (Tykerb) is a dual inhibitor of EGFR and a subclass known as human EGFR type 2. EGFR is not the only growth factor targeted. Sunitinib (Sutent) has multiple targets and inhibits PDGFR and VEGF.

[0053] Other tyrosine kinase inhibitors are more specific. Sorafenib (Nexavar) targets a complex pathway that gives rise to the kinase signaling cascade. Another small molecule tyrosine kinase inhibitor, Nilotinib (Tasigna), also inhibits the fusion protein bcr-abl and is often prescribed when patients are resistant to imatinib. Nilotinib also targets the PDGF receptor. There are indications that nilotinib is more potent than imatinib, for example, 10-30 times more potent than imatinib in inhibiting Bcr-Abl tyrosine kinase activity. Nilotinib is currently marketed as 150 mg and 200 mg hard gelatin capsules. It is envisioned that the discoveries made in clinical studies with imatinib, and the subsequent identification of new and surprising uses for imatinib and new approaches for treating stroke, may also be converted to nilotinib with appropriate dose adjustments.

[0054] More TKIs are being developed, although the process is slow and more drugs are ultimately abandoned during the clinical phase than are approved. There are currently three TKIs showing promise in clinical trials. Bosutinib targets the abl and src kinases. Neratinib, like lapatinib, inhibits EGFR and human EGFR type 2. Vatalanib inhibits both VEGFR and PDGFR.

[0055] According to a first aspect, the present inventors disclose imatinib ( STI-571, a tyrosine kinase inhibitor) can be used to treat acute ischemic stroke, wherein the imatinib is administered to the patient at a dose of 650 mg / day or more for at least 3 consecutive days, preferably at least 4 consecutive days, and most preferably at least 5 consecutive days. The exact dose can be adjusted by the treating physician and adapted to the severity of the condition, the patient's age and sex, weight and other details of the patient.

[0056] According to an embodiment of the first aspect, the imatinib is administered to the patient at a dose of 700 mg / day or higher, preferably 750 mg / day or higher, more preferably 800 mg / day or higher.

[0057] According to another embodiment freely combinable with the above, the imatinib is administered to the patient before, simultaneously with or after thrombectomy. The term "thrombectomy" is used herein to define any surgical and / or mechanical removal or disintegration of a clot. In the United States, the FDA has approved three types of mechanical thrombectomy devices: embolic coils, aspiration devices, and extraction stents. Other devices and methods currently under development are also included in the definition of thrombectomy used herein.

[0058] According to another embodiment that can be freely combined with the above, the imatinib is administered to the patient before, at the same time or after thrombolysis. The term "thrombolysis" is used here to define any pharmacological decomposition of blood clots. The most commonly used thrombolytic therapy drug is tissue plasminogen activator (tPA), but there are also alternative drugs that can achieve the same effect. Thrombolysis may involve injecting thrombolytic drugs through an intravenous (IV) line or through a long catheter that delivers the drug directly to the site of occlusion. If the patient is administered thrombolytic drugs within 12 hours after a stroke, the chances of survival and recovery from an acute ischemic stroke will be significantly improved. Ideally, thrombolytic therapy should be performed within the first 30 minutes after arriving at the hospital. Most preferably, imatinib is administered to the patient as soon as possible, even before determining whether the patient suffers from an acute ischemic stroke or a hemorrhagic stroke.

[0059] Both thrombectomy and thrombolysis are emergency treatments and should be given as soon as possible. For practical reasons, thrombolytic therapy is usually started before thrombectomy can be performed, but as described under the heading "Summary of the Invention", the steps of any method disclosed herein do not have to be performed in the exact order disclosed unless explicitly stated.

[0060] According to a preferred embodiment freely combinable with the above, the imatinib is administered to the patient before, during or after thrombectomy and thrombolysis. More preferably, imatinib is administered to the patient as soon as possible, even before determining whether the patient suffers from acute ischemic stroke or hemorrhagic stroke. The advantage of doing so is that such administration of imatinib improves the efficacy of the patient, and in addition, makes it possible to delay the start of thrombolytic therapy in the event of the following circumstances, and outside the recommended window, such as delays in the patient's arrival at the hospital, or delays in making a correct diagnosis, or delays in determining that the patient suffers from ischemic stroke rather than hemorrhagic stroke, for example due to delays in obtaining access to CT or MRI equipment.

[0061] According to another embodiment freely combinable with the above, the thrombolysis comprises administering a tissue plasminogen activator (tPA), preferably selected from alteplase Reteplase Tenecteplase Although the present disclosure focuses on the tPA drug described above, other drugs currently under development and awaiting approval may also be used in combination therapy.

[0062] According to a preferred embodiment that can be freely combined with the above embodiment, the imatinib is administered to the patient at a starting dose of 1000 mg / day or higher on the first day, and at a dose in the range of 650 mg / day to 1000 mg / day in the following days. Although the starting dose should be higher than the subsequent dose, it is currently envisioned that imatinib should not be administered at a dose higher than 1600 mg / day as the starting dose. In addition, it is envisioned that imatinib should not be administered at a dose higher than 1200 mg / day on any of the consecutive days. Similarly, the exact dose can be adjusted by the treating physician and adapted to the severity of the disease, the age and sex of the patient, the weight and other details of the patient.

[0063] According to a specific embodiment, imatinib is formulated and administered to a patient as follows: 800 mg of imatinib is dissolved in a NaCl solution, such as 500 ml of 0.9% NaCl, or other suitable intravenous solution, and administered to the patient over about 12 hours. After this initial dose, 400 mg of imatinib in 500 ml of a suitable intravenous solution is administered over a continuous 12-hour period. This is equivalent to a starting dose of 1200 mg / day on day 1, and 800 mg / day on each of the consecutive days.

[0064] According to another embodiment that can be freely combined with the above, the imatinib is administered orally. Oral administration forms include but are not limited to tablets, capsules, caplets, suspensions and solutions. A technician in the field of galenic chemistry can prepare suitable oral administration forms without undue burden.

[0065] According to an alternative embodiment that can be freely combined with the above, the imatinib is administered intravenously. Intravenous administration forms include conventional intravenous injection solutions, such as saline (0.9% sodium chloride sterile water), hypotonic saline (0.45% or 0.33% sodium chloride sterile water), hypertonic saline (3-5% sodium chloride sterile water), glucose water, glucose saline and electrolyte solutions, such as Ringer's solution. Imatinib is preferably administered by adding the required dose to a physiological saline solution, for example, 650mg imatinib is added to 500ml of saline. For example, imatinib can be administered at a concentration such as 400mg / 500ml, 500mg / 500ml, 600mg / 500ml, 700mg / 500ml and 800mg / 500ml intravenous injection solution.

[0066] However, depending on the patient's condition, the treating physician may prescribe the addition of imatinib to another intravenous solution. Furthermore, a person skilled in the art of galenic chemistry is able to prepare a suitable intravenous administration form without undue burden.

[0067] It is also contemplated that at least a portion of an initial dose of imatinib is administered intravenously, while subsequent, continuous doses are administered orally.

[0068] Based on the findings obtained with imatinib, it is also envisaged that nilotinib can be used in the same manner with appropriate adjustment of the dose. Therefore, according to an additional aspect, the inventors provide the use of nilotinib in the treatment of acute ischemic stroke, wherein the nilotinib is administered to a patient at a dose of 200 to 600 mg / day or more for at least 3 consecutive days, preferably at least 4 consecutive days, and most preferably at least 5 consecutive days.

[0069] Furthermore, the nilotinib may be administered to a patient at a dose of 300 mg / day or more, preferably 400 mg / day or more, more preferably 600 mg / day or more.

[0070] Preferably, nilotinib is administered to the patient before, simultaneously with, or after thrombectomy, before, simultaneously with, or after thrombolysis. Preferably, nilotinib is administered to a patient who is undergoing or has undergone thrombectomy and thrombolysis. Most preferably, nilotinib is administered to the patient as soon as possible and before it has been determined whether the patient has an ischemic stroke or a hemorrhagic stroke.

[0071] In the above aspects related to the use of nilotinib, the thrombolysis comprises administering an agent selected from alteplase Reteplase Tenecteplase tissue plasminogen activator (tPA).

[0072] According to another embodiment freely combinable with any of the above embodiments relating to nilotinib, the nilotinib is administered to the patient at a starting dose of 500 mg / day or higher on day 1, and at a dose ranging from 300 mg / day to 500 mg / day on the following days. The nilotinib is administered orally or intravenously, preferably intravenously. According to a specific embodiment, at least a portion of the starting dose is administered intravenously, and continuous doses are administered orally.

[0073] According to a second aspect, the present inventors provide a method for treating acute ischemic stroke, wherein imatinib ( STI-571, a tyrosine kinase inhibitor) is administered to the patient at a dose of 650 mg / day or more for at least 3 consecutive days, preferably at least 4 consecutive days, and most preferably at least 5 consecutive days.

[0074] According to an embodiment of the second aspect, imatinib is administered to the patient at a dose of 700 mg / day or higher, preferably 750 mg / day or higher, more preferably 800 mg / day or higher.

[0075] According to another embodiment, freely combinable with the above, imatinib is administered to the patient before, simultaneously with or after thrombectomy.Thrombectomy is here understood as any surgical removal or breakdown of a clot, whatever the method used.

[0076] According to another embodiment, freely combinable with the above, imatinib is administered to the patient before, simultaneously with or after thrombolysis.Thrombolysis is here understood as the pharmacological breakdown of a blood clot, regardless of which specific drug or pharmacological treatment is used.

[0077] According to a preferred embodiment freely combinable with the above, imatinib is administered to a patient who is undergoing or has undergone thrombectomy and thrombolysis.

[0078] Most preferably, imatinib is administered to the patient as soon as possible, even before it is determined whether the patient has suffered an acute ischemic stroke or a hemorrhagic stroke.

[0079] According to another embodiment freely combinable with the above, wherein the thrombolysis comprises administering a tissue plasminogen activator (tPA) (selected from alteplase Reteplase Tenecteplase

[0080] According to a preferred embodiment that can be freely combined with the above, the imatinib is administered to the patient at a starting dose of 1000 mg / day or higher on the first day, and at a dose of 650 mg / day to about 1000 mg / day in the subsequent days. Although the starting dose should be higher than the subsequent dose, it is currently envisioned that imatinib should not be administered at a dose higher than 1600 mg / day as the starting dose. In addition, it is envisioned that imatinib should not be administered at a dose higher than 1200 mg / day on any of the consecutive days. Similarly, the exact dose can be adjusted by the treating physician and adapted to the severity of the disease, the age and sex of the patient, the weight, and other details of the patient.

[0081] According to another embodiment that can be freely combined with the above, imatinib is administered orally. Oral administration forms include, but are not limited to, tablets, capsules, caplets, suspensions and solutions. A person skilled in the art of galenic chemistry can prepare suitable oral administration forms without undue burden.

[0082] According to an alternative and currently preferred embodiment, freely combinable with the above, imatinib is administered intravenously. Intravenous administration forms include conventional intravenous solutions as exemplified above. A person skilled in the art of galenic chemistry can prepare suitable intravenous administration forms without undue burden.

[0083] It is also contemplated that at least a portion of an initial dose of imatinib is administered intravenously, while subsequent, continuous doses are administered orally.

[0084] The steps of any method disclosed herein do not have to be performed in the exact order disclosed, unless explicitly stated.

[0085] Specific embodiments include pharmaceutical compositions for intravenous administration, which include a 1000 mg dose of imatinib in 500 ml of a 0.9% NaCl solution. It is envisioned that for emergency room use, a ready-to-use intravenous solution containing a predetermined dose of imatinib in a suitable intravenous solution should be prepared for immediate use. Alternatively, an intravenous solution containing imatinib can be prepared by adding a concentrated imatinib solution to a conventional intravenous solution, such as saline, glucose or Ringer's solution.

[0086] Thus, one embodiment is a kit comprising imatinib, preferably in lyophilized form, and a solution suitable for reconstitution of lyophilized imatinib, and a solution suitable for intravenous administration, and optional adjuvants and excipients. In a specific embodiment, imatinib is provided in separate vials at doses of 400 mg and 800 mg, and the solution suitable for intravenous administration is a 0.9% NaCl solution, provided in a container, such as a flexible bag having a capacity of 50 ml, 100 ml, 250 ml, 500 ml or 1000 ml, preferably 500 ml.

[0087] It is currently preferred to administer imatinib intravenously, but when imatinib is available in tablet form, it is envisaged that the initial dose of imatinib is administered intravenously at least during the first day of treatment, while imatinib is administered orally during the remainder of the treatment. Therefore, another embodiment is a kit comprising a solution of 1000 mg imatinib in 500 ml of 0.9% NaCl and n*400 mg imatinib tablets, wherein n is an integer between 2 and 4.

[0088] It is envisioned that for emergency room use, different kits will be available, including imatinib in different concentrations as an intravenous solution, and optionally imatinib in an oral administration form at a prescribed dose, and instructions for use to allow rapid and safe administration to patients in need thereof.

[0089] Another aspect and embodiment of the present invention relates to a method for treating acute ischemic stroke, wherein nilotinib is administered to a patient at a dose of 200 to 600 mg / day or more for at least 3 consecutive days, preferably at least 4 consecutive days, and most preferably at least 5 consecutive days.

[0090] Furthermore, in an embodiment of the method, nilotinib is administered to the patient at a dose of 300 mg / day or higher, preferably 400 mg / day or higher, more preferably 600 mg / day or higher.

[0091] Preferably, nilotinib is administered to the patient before, simultaneously with, or after thrombectomy. More preferably, nilotinib is administered to the patient before, simultaneously with, or after thrombolysis. In a preferred embodiment of the method, nilotinib is administered to the patient as soon as possible, even before determining whether the patient has an ischemic stroke or a hemorrhagic stroke.

[0092] In an embodiment of the method, the thrombolysis comprises administering an agent selected from the group consisting of alteplase Reteplase Tenecteplase tissue plasminogen activator (tPA).

[0093] In another embodiment that can be freely combined with the above embodiment, the nilotinib is administered to the patient at a starting dose of 500 mg / day or higher on day 1, and at a dose ranging from 300 mg / day to 500 mg / day on the following days. The nilotinib is administered orally or intravenously, preferably intravenously. According to a specific embodiment, at least a portion of the starting dose is administered intravenously, and continuous doses are administered orally.

[0094] Example

[0095] The present inventors conducted a Phase II, dose-escalation, safety and tolerability, regional multicenter clinical trial with randomized treatment group assignment, open-label treatment, and blinded endpoint assessments in patients with acute ischemic stroke treated with intravenous thrombolysis.

[0096] In this study, oral administration as soon as possible on the day of arrival and oral doses of imatinib treatment for the next 5 days were compared with standard treatment. In the first phase of the study (n = 20), a daily dose of 400 mg imatinib was used, followed by 600 mg in the next phase (n = 20), and finally 800 mg (n = 20). Safety assessment and approval were performed by an independent safety committee before each dose increase. Randomization was 3: 1, creating four groups of equal size (n = 15), including a total of 60 patients in the control group. All patients received intravenous thrombolysis in accordance with recognized indications, and patients with large artery occlusion underwent mechanical thrombectomy in accordance with local intervention criteria.

[0097] 1. Materials and Methods

[0098] 1.1 Patients and participating centers

[0099] The study was conducted in 5 centers in Stockholm County. Patients considered for mechanical thrombectomy were started on intravenous thrombolysis at their local hospital and then transferred to Karolinska University Hospital at Solna (KS). Patients were 18-85 years old and had acute ischemic stroke onset resulting in a neurological deficit of 7 to 25 points on the National Institutes of Health Stroke Scale (NIHSS). All patients received 0.9 mg / kg of intravenous thrombolysis within 4.5 hours of stroke onset according to generally accepted criteria. After informed consent, all patients were randomized to active treatment or control within 1 hour of discontinuation of reperfusion therapy, either intravenous thrombolysis alone or followed by mechanical thrombectomy. If assigned to active treatment, it had to be started as soon as possible after randomization.

[0100] 1.2 Treatment

[0101] The first treatment was given as soon as possible after randomization (Day 0). Depending on the phase of the study, treatment was given orally as a 400 mg, 600 mg, or 800 mg tablet. If necessary, the tablet was crushed and administered via a nasogastric tube. From Day 1 to Day 5, one tablet was given daily in the morning, except for the highest dose level (800 mg) when the 400 mg tablet was given twice daily (morning and evening).

[0102] Imatinib plasma concentrations were examined in one patient in period 1 and in all patients in periods 2 and 3 at the following three time points: 1) 3 hours after the first tablet dose, 2) before the morning dose on day 1, and 3) before the morning dose on day 2. Plasma concentrations were also examined before the morning dose on days 3-5 in two patients, one on 600 mg / day and one on 800 mg daily.

[0103] 1.3 Result Measurement

[0104] 1.3.1 Main Results

[0105] The primary outcome of the study was any serious or non-serious adverse event. A serious adverse event was defined as any untoward medical event that resulted in death, was life-threatening, required hospitalization or prolonged existing hospitalization, caused persistent or significant disability / incapacity, or was a congenital anomaly / birth defect. A non-serious adverse event was defined as any other unfavorable, unexpected sign (including, for example, abnormal laboratory findings), symptom, or illness temporally associated with the use of the drug product, whether or not considered to be related to the drug product. These measures included mortality and any adverse deviations in test values ​​as part of the safety evaluation.

[0106] 1.3.2 Secondary Results

[0107] The occurrence and severity of hemorrhagic transformation, intracerebral hemorrhage, and cerebral edema on computed tomography (CT) or magnetic resonance imaging (MR) after treatment were secondary outcomes. Others were neurological function at 2 hours, 24 hours, and day 7 after the start of intravenous thrombolysis, functional outcome at month 3, and infarct volume at day 7. The evaluation of infarct volume will be discussed in the following publication.

[0108] 1.4 Clinical and radiological evaluation

[0109] Before intravenous thrombolysis and start of study treatment (baseline), 2 hours (Day 0), Day 1 and then daily until Day 7, clinical assessments including determination of NIHSS scores were performed. Final NIHSS scores were included in 3-month follow-up examinations. From Day 0 to Day 7, daily, and finally at 3 months, assessments of any adverse events were performed. CT scans were performed at baseline, 24 hours (intervals 22-36 hours accepted) and on the optional Day 7, MRI was performed at 24 hours (intervals accepted for CT) and on the Day 7. The definitions of hemorrhagic transformation, substantial hemorrhage and edema are described in early publication R1 and are also listed in Table 1. At the 3rd month, functional status was assessed using modified Rankin Scale (mRS) scoring. Three months of follow-up examinations were performed blindly in different hospitals, rather than in the hospital responsible for acute treatment.

[0110] Table 1: Definitions of hemorrhagic transformation, parenchymal hemorrhage, and cerebral edema

[0111] Definition of hemorrhagic transformation

[0112] HI1: Type 1 hemorrhagic infarction with small hemorrhages along the infarct margins

[0113] HI2: Type 2 hemorrhagic infarction, with more confluent hemorrhages within the infarct area but no mass effect PH1: Type 1 parenchymal hemorrhage, with clot not exceeding 30% of the infarct area, with some mild mass effect

[0114] PH2: Type 2 parenchymal hemorrhage, blood clot exceeds 30% of the infarct area, with significant mass effect

[0115] PHr1: Type 1 distal parenchymal hemorrhage, small or medium-sized clot distal to the actual infarct; mild mass effect may be present

[0116] PHr2: Type 2 distal parenchymal hemorrhage, a large confluent dense clot distal to the actual infarct area; significant mass effect may be present

[0117] Definition of edema

[0118] CED 1: Type 1 cerebral edema, focal brain swelling up to one-third of a hemisphere CED 2: Type 2 cerebral edema, focal brain swelling exceeding one-third of a hemisphere CED 3: Type 3 cerebral edema, brain swelling with midline shift

[0119] 1.5 Statistical analysis

[0120] To analyze whether imatinib had any effect on NIHSS, imatinib doses were divided into absolute and continuous for treatment. When looking at individual time points, linear regression with robust standard errors was used while adjusting for thrombectomy. When looking at the average effect over the entire time course, we used a linear mixed model with random cutoffs and adjustment for thrombectomy, which used robust standard errors and allowed residuals to have autoregressive 1 (AR1) correlation within individuals. The use of AR1 correlation was chosen by comparing the Akaike information criterion with a model without AR1 correlation. Due to some missing NIHSS values, multiple imputation R2 was used. The association between treatment group and functional independence was analyzed using odds ratios. The statistical software Stata v.13 was used.

[0121] 2. Results

[0122] 2.1 Patients’ characteristics

[0123] A total of 60 patients were enrolled between February 2011 and November 2014, with 20 patients per dose level. At the first dose level, 15 patients were randomized to 400 mg daily (low dose) and 5 patients were included in the control group. The second dose level included 14 patients assigned to 600 mg daily (medium dose) and 6 patients were included in the control group. At the final dose level, 14 patients were randomized to 800 mg daily (high dose) and 6 patients were included in the control group. Baseline characteristics are provided in Table 2 and logistic properties are provided in Figure 1 Available in.

[0124] Table 2. Demographic data and baseline data according to ITT

[0125] Control group Low dose Medium dose High dose Number of patients 17 15 14 14 Age (median) 70 76 73 72 NS male% 65 53 79 43 NS hypertension% 76 73 64 50 NS Atrial fibrillation % 29 33 43 36 NS diabetes% 18 20 7 7 NS Hyperlipidemia% 35 20 29 36 NS Smokers (current) % 18 7 29 0 NS Smokers (former) % 35 40 50 29 NS Previous stroke (>3M)% 12 7 0 7 NS Previous TIA% 12 13 7 0 NS Baseline NIHSS 13 12 11 13 NS IVT% 100 100 100 100 NS IAT% 0 7 0 0 NS MT% 29 47 21 71 NS Bracket % 6 13 0 7 NS aspirin% 31 47 36 21 NS Warfarin % 6 0 8 7 NS Oral antidiabetic drugs% 7 7 0 7 NS insulin% 6 0 8 0 NS Statins % 50 20 21 21 NS

[0126] All patients were included in the safety analyses according to intention to treat. Other analyses were performed consistent with their actual treatment. Therefore, 3 patients at the first dose level were removed from each protocol analysis because they received some but incomplete doses. One patient who was intended to receive 400 mg daily did not receive any treatment and was analyzed as a control. One patient who was intended to receive 600 mg daily instead received 400 mg daily and was included in the corresponding dose group. Therefore, for each protocol analysis, the control group included 18 patients, the low-dose group 12 patients, the medium-dose group 13 patients, and the high-dose group 14 patients.

[0127] 2.2 Plasma Concentration of Imatinib

[0128] The mean plasma concentration of imatinib from day 0 to day 6 was 530 ng / ml (95% CI 74-987) for 400 mg daily, 1094 ng / ml (797-1391) for 600 mg daily, and 2054 ng / ml (1642-2465) for 800 mg daily (Figure F2). Within 3 hours of the first dose, the plasma concentration was 996 ng / ml for 400 mg, 1572 ng / ml for 600 mg, and 1727 ng / ml for 800 mg.

[0129] 2.3 Safety Analysis-Mortality

[0130] Three patients died during the study. One patient was assigned to the low-dose group but did not receive active treatment and died of intracerebral hemorrhage. One patient in the control group died of infection. The third patient received two doses of moderate-dose imatinib and died of recurrent ischemic stroke.

[0131] 2.4 Safety Analysis-Adverse Events

[0132] Four serious adverse events were reported, resulting in the deaths of the three patients mentioned above and one clinical deterioration. One patient in the control group deteriorated with fever and infection. The patient also had an increased femoral hematoma at the femoral artery puncture site. There were no serious adverse events in the high-dose group.

[0133] A total of 118 non-serious adverse events were reported in 41 patients (Table 3), including 25 in the control group, 19 in the low-dose group, 44 in the medium-dose group, and 30 in the high-dose group. The number of events reported per patient varied between 1 and 7.

[0134] Table 3. Adverse events

[0135]

[0136]

[0137] As can be seen in the table, the most common adverse events were fever and infection (21), cerebral hemorrhage (15), nausea and vomiting (12), arrhythmias including tachycardia and bradycardia (10), and pruritus and skin reactions (10). Pruritus / skin reactions and nausea / vomiting were slightly more common in the higher dose groups. Most cerebral hemorrhages were found in the medium dose group.

[0138] Most non-serious adverse events were mild (74), of which 42 were considered unrelated or unlikely related, 25 possibly or probably related, and 7 unclassified. Of all mild events, 73 recovered, and 1 was unclassified. For 29 patients, adverse events were reported of moderate severity, 16 unrelated or unlikely related, and 13 possibly or probably related. Most of these recovered (21), 4 recovered with sequelae, and 1 was in the control group. 3 patients were unclassified. Severe non-serious adverse events occurred in 3 patients, 2 in the control group, and 1 patient was judged unlikely to be related, in the medium-dose group. Although 1 control patient recovered with sequelae and 1 control patient had persistent symptoms, the latter recovered. In 14 patients, the severity was unclassified; of these 9 were unrelated or unlikely related, and 1 was possibly related. 4 recovered, 4 control patients, and 6 additional patients had no classification of the outcome of the event.

[0139] 2.5 Hemorrhagic transformation

[0140] A total of 22 cases of hemorrhagic transformation were reported (3 HI1 and 16 HI2), 6 in the control group and low-dose group, 7 in the medium-dose group, and 3 in the high-dose group. Three cases of parenchymal hemorrhage were reported. One case of PH1 occurred in the control group, one in the high-dose group, and one in the medium-dose group.

[0141] In addition, 5 cases of milder distal parenchymal hemorrhage (PHr1) were reported, 1 case each in the low-dose and medium-dose groups and 3 cases in the high-dose group.

[0142] For patients who started treatment with imatinib within 5 hours of stroke onset, no bleeding was reported in the 5 patients treated in the high-dose group, while bleeding occurred in 5 of 10 patients treated in the medium-dose group and in 4 of 8 patients treated in the low-dose group.

[0143] For patients who completed reperfusion therapy (intravenous thrombolysis alone or combined with thrombectomy) within 4.5 hours, no bleeding was reported in the 7 patients treated in the high-dose group, whereas within the same time period, bleeding was found in 6 of 11 patients treated in the medium-dose group, 5 of 9 patients treated in the low-dose group, and 6 of 16 patients in the control group.

[0144] 2.6 Brain edema

[0145] There were 33 cases of cerebral edema in the study (28 CED 1, 3 CED-2 and 2 CED-3), 9 in the control group, 6 in the low-dose group, 8 in the medium-dose group and 10 in the high-dose group. The mildest form, CED 1, was found in 7 patients in the control group, 4 patients in the low-dose group, 7 patients in the medium-dose group and all 10 patients in the high-dose group. Two cases of moderately severe edema (CED-2) were found in the low-dose group and one case of moderately severe edema (CED-2) was found in the medium-dose group. Two cases of severe edema (CED-3) were found in the control group.

[0146] For patients who started imatinib within 5 hours of stroke onset, 2 of 5 patients in the high-dose group had CED 1 at follow-up, whereas 5 of 10 patients in the medium-dose group and 4 of 8 patients in the low-dose group had CED 1 or 2.

[0147] For patients who completed reperfusion therapy within 4.5 hours (intravenous thrombolysis alone or with thrombectomy), 4 of 7 patients in the high-dose group had CED 1, 6 of 11 in the medium-dose group, 4 of 9 in the low-dose group, and 8 of 16 in the control group had CED 1 or 2; the control group also included 1 patient with CED 3.

[0148] Above the invention has mainly been described with reference to a few embodiments. However, as is readily appreciated by a person skilled in the art, other embodiments than the ones disclosed above are equally possible within the scope of the invention, as defined by the appended claims.

[0149] 2.7 Neurological Function

[0150] Treatment with imatinib significantly improved neurological function. After adjusting for the effect of thrombectomy, each 100 mg of imatinib improved the National Institutes of Health Stroke Scale (NIHSS) by 0.6 points. After adjusting for thrombectomy, the mean reduction (improvement) in NIHSS score was 2 points with low dose (-2.30; 95% CI -6.30-1.70; p < 0.259), 3 points with medium dose (-3.05; 95% CI -6.75-0.64; p < 0.106), and 5 points with high dose (-4.94; -8.78, -1.11; p < 0.012). For all individual time points except baseline and 2 hours, the adjusted mean NIHSS scores of patients treated with high-dose imatinib were statistically significantly lower than those in the control group, at day 1 by 5 points (-5.28; -95% CI -9.60, -0.96; p < 0.018), at day 7 by 6 points (-5.68; 95% CI -10.38-0.98; p < 0.019), and at month 3 by 5 points (-4.81; 95% CI -10.39, -0.98; p < 0.019).

[0151] 2.8 Functional Results

[0152] Functional outcomes were measured on the modified Rankin score (mRS). Functional independence (mRS 0-2) was 61% in the control group, 72% in all imatinib-treated patients, and 79% in patients treated with the high dose. For the high dose, the proportion of functional independence had an absolute increase of 17% (OR 2.33; 95% CI 0.48-11.44; p<0.296).

[0153] Two patients in the control group developed severe disability (mRS score of 5) and two patients died (score of 6), whereas none of these occurred in any of the imatinib-treated patients.

Claims

1. Use of imatinib in the preparation of a medicament for treating stroke, characterized in that: The content of imatinib in the drug is 400, 600 or 800 mg / tablet, or 400-1200 mg imatinib in 0.8-1.0% NaCl solution.

2. The use of imatinib according to claim 1, wherein The imatinib is administered to the patient at a dose of 650 mg / day or higher for at least 3 consecutive days, preferably at least 4 consecutive days, and most preferably at least 5 consecutive days.

3. The use of imatinib according to claim 2, wherein: The imatinib is administered to the patient at a dose of 700 mg / day or more, preferably 750 mg / day or more, more preferably 800 mg / day or more.

4. The use of imatinib according to any one of claims 1 to 3, wherein The imatinib is administered to the patient before, simultaneously with, or after thrombectomy.

5. The use of imatinib according to any one of claims 1 to 4, wherein The imatinib is administered to the patient before, simultaneously with or after thrombolysis.

6. The use of imatinib according to any one of claims 1 to 5, wherein The imatinib is administered to patients who are undergoing or have undergone thrombectomy and thrombolysis.

7. The use of imatinib according to claim 5 or 6, wherein The thrombolysis comprises administering a tissue plasminogen activator (tPA) selected from the group consisting of alteplase, reteplase, and tenecteplase.

8. The use of imatinib according to any one of claims 1 to 7, wherein The drug is administered to the patient prior to determining whether the patient has suffered an acute ischemic stroke or a hemorrhagic stroke.

9. The use of imatinib according to any one of claims 1 to 8, wherein The imatinib is administered to patients at a starting dose of 1000 mg / day or higher on day 1, and at a dose ranging from 650 mg / day to 1000 mg / day on subsequent days.

10. The use of imatinib according to any one of claims 1 to 9, wherein The imatinib is administered orally or intravenously.

11. The use of imatinib as defined in claim 9, wherein: At least a portion of the initial dose is administered intravenously, and subsequent doses are administered orally.

12. The use of imatinib according to any one of claims 1 to 9, wherein The initial dose of imatinib was administered intravenously during at least the first day of treatment, while imatinib was administered orally for the remainder of treatment.

13. A method of treating stroke, wherein a dose of 650 mg / day or more is administered to a patient for at least 3 consecutive days, preferably at least 4 consecutive days, and most preferably at least 5 consecutive days.

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