RU2776152C2 - Dosing mode of s1p receptor modulator - Google Patents

Abstract

FIELD: medicine; neurology; immunology.

SUBSTANCE: invention relates to the field of medicine, namely to neurology and immunology; it is intended for the treatment of multiple sclerosis. A method for the treatment of multiple sclerosis in a patient who needs it includes oral administration to the specified patient of a daily dose of 0.5 mg of a drug selected from fingolimod (hereinafter – FTY720), its phosphate derivative or its pharmaceutically acceptable salt. In addition, the method includes identification of the medical history of eyes of the patient subjected to the treatment before the treatment with fingolimod (FTY720), its phosphate derivative or its pharmaceutically acceptable salt, as well as conduction of ophthalmological examinations performed 3-4 months after the treatment with FTY720, its phosphate derivative or its pharmaceutically acceptable salt, preferably by an ophthalmologist, wherein the specified examinations include checking and/or monitoring the appearance of macular edema.

EFFECT: use of the invention allows for increasing the efficiency and safety of the treatment of multiple sclerosis in a patient.

2 cl, 2 ex

Description

The present invention relates to a dosing regimen for an S1P receptor modulator or agonist in the treatment of patients with an inflammatory or autoimmune disease or disorder, such as multiple sclerosis (MS).

Multiple sclerosis is the leading cause of neurological disability in young adults and is the most common demyelinating disorder of the central nervous system. The types of treatment available, such as interferon-β and glatiramer acetate, show moderate efficacy and little effect on the progression of helplessness. These biological agents are administered parenterally and are associated, for example, with injection site reactions and febrile symptoms, such as flu-like symptoms. Thus, there is an urgent need in medicine for safe and effective oral treatment of multiple sclerosis.

Among MS patients undergoing treatment, a significant number continue to experience active disease or side effects, including flu-like symptoms, immediate post-injection reactions, and reactions at the injection site. As a result, a substantial portion of the patient population remains untreated, including many patients with active disease. These MS patients either received modern treatment but discontinued it due to intolerance, side effects, or a perceived lack of efficacy, or did not start any therapy due to associated side effects, fear of self-injection, fear of needles, or believe that the current available treatment options are not effective enough to carry them out. Thus, there is an unmet need for effective new therapies for MS that limit or reduce the possibility of unwanted manifestations or side effects.

S1P receptor modulators are compounds that signal as agonists at one or more sphingosine-1-phosphate receptors, for example from the S1P1 receptor to the S1P5 receptor. Binding of an agonist to the S1P receptor can result, for example, in the dissociation of intracellular heterotrimeric G proteins into Gα-GTP and Gβγ-GTP, and/or increased phosphorylation of the agonist-occupied receptor and activation of downstream signaling metabolic chains/kinases.

S1P receptor modulators are useful compounds for drug discovery in the treatment of various conditions in mammals, especially humans. For example, transplantation efficacy has been shown in rat (skin, heart, liver, small intestine), dog (kidney) and monkey (kidney) models. Because of their inherent immunomodulatory ability, S1P receptor modulators are also useful in the treatment of inflammatory and autoimmune diseases. The treatment of such diseases usually requires long-term use of the drug and maintaining an appropriate regimen of its use throughout treatment.

Oral fingolimod is the first compound in a new class of therapeutics called sphingosine-1-phosphate receptor modulators. It is believed that fingolimod reduces the number of lymphocytes circulating in the bloodstream by partially reversible capture in the lymph nodes. Accordingly, the number of activated lymphocytes reaching the brain is reduced, resulting in reduced inflammatory destruction. This is a new mechanism of action in the case of MS.

The efficacy of FTY720 in the treatment of multiple sclerosis has been demonstrated in humans (e.g., Mehling M. et al., Neurology, 71(16), 2008, pp. 1261-1267; Kappos L, Antel J, Comi G, Montalban X, O' Connor P, Polman CH, Haas T, Korn AA, Karlsson G, Radue EW, N Engl J Med, 355(11), 2006, pp. 1124-1140).

Administration of an S1P receptor modulator, such as fingolimod, may induce side effects, such as transient decreases in heart rate and cardiac conduction at the start of treatment. In particular, it has been described that administration of 1.25 mg FTY720 can induce a decrease in heart rate of about 8 beats/min (Robert Schmouder, Denise Serra, Yibin Wang, John M. Kovarik, John DiMarco, Thomas L. Hunt and Marie-Claude Bastien J Clin Pharmacol 46 (2006) 895).

In view of this possible side effect, the administration of the compound to patients should be carried out under full and constant medical supervision to confirm that the heart rate is maintained at an acceptable level and there is no high level of atrioventricular blocking. Patients may have to stay in the hospital, which complicates treatment and increases the cost of treatment. The presence of side effects during drug treatment may lead to hospitalization of the patient or prolongation of the existing hospitalization.

Such possible manifestations may cause patients to interrupt treatment, independently change the recommended dosing regimen, or use the drug irregularly, without any medical support or recommendation for such actions. Although of paramount importance in the treatment of an inflammatory or autoimmune disease such as multiple sclerosis is the fact that the drug is taken over a long period of time, sometimes throughout the life of the patient, an adequate drug regimen is maintained over such a long period of time.

Thus, there is a need to reduce or control the possible side effects that can be obtained by administering such an S1P receptor modulator while administering a dosage sufficient to treat or prevent the disease for which the compound is administered over the desired treatment period.

More specifically, there is a need to develop an effective treatment for an inflammatory or autoimmune disease or disorder, such as multiple sclerosis, for a large population of patients with multiple sclerosis, including patients who may be more vulnerable or more susceptible to these possible side effects, for a large population of patients with multiple sclerosis, including patients who may be more vulnerable or more sensitive to these possible side effects, patients who have never been treated or who have never been diagnosed with an inflammatory or autoimmune disease or disorder.

In addition, it is necessary to facilitate compliance with the regimen for patients.

Brief description of the invention

Surprisingly, it has been found that by administering an S1P receptor modulator or an agonist, such as fingolimod, according to a specific dosage regimen or method of treatment according to the present invention, it is possible to effectively treat a patient during control, reduce the manifestation of the disease or alleviate possible side effects, for example, side effects, which may be associated with the administration of such a compound.

An additional benefit is that the dosage regimen and methods of treatment of the present invention allow the administration of an S1P receptor modulator or agonist, such as fingolimod, to patients who may otherwise refuse to use or who may not have been instructed to use such a drug. In particular, they allow for the treatment of patients with an inflammatory or autoimmune disease or disorder, such as multiple sclerosis, for whom the risk/benefit ratio may otherwise be less favorable. Such patients are, for example, patients susceptible to or having one or more diseases or disorders affecting the heart or heart rhythm, respiratory function, eyes, liver function, or those diseases or disorders. This also applies to patients who have undergone a treatment interruption or switch to a maintenance dosing regimen due to a non-working day, such as a holiday lasting more than 10 days.

In addition, the dosage regimen and methods of treatment of the present invention are applicable to patients who have already been treated for an inflammatory or autoimmune disease, such as in the treatment of multiple sclerosis, as well as patients who have never been treated or who have not been diagnosed with an inflammatory or autoimmune disease. , in which case a modulator or agonist of the S1P receptor was previously consumed.

The dosing regimen of the present invention is an S1P receptor modulator or agonist treatment regimen that allows for the management of a therapeutic S1P receptor dosing regimen achieved with controlled or minimal side effects that may otherwise be associated with S1P receptor modulator therapy.

Another benefit contemplated by the present invention is to provide a therapeutic regimen for an inflammatory or autoimmune disease, such as multiple sclerosis, which can be personalized, such as adapted to the specific profile of the patient being treated and/or the disease state of those patients, in such a way that it the disease is treated (or the severity of the disease is relieved) while side effects that may otherwise be associated with the administration of said S1P receptor modulator or agonist are controlled, reduced or eliminated. For example, the therapeutic regimen of the present invention may be personalized with respect to another disease or disorder to which the patient may be subject, with other medications that he may receive, for example, depending on the presence of a heart disease or disorder.

S1P receptor modulators or agonists

According to the present invention, the specific S1P receptor modulators of the present invention are 2-amino-2-tetradecyl-1,3-propanediols. An example of an S1P receptor modulator is fingolimod (FTY720), i.e. 2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in free form or in the form of a pharmaceutically acceptable salt, e.g. hydrochloride:

Another specific S1P receptor modulator of the present invention is a phosphorylated derivative of FTY720, also called fingolimod phosphate:

Preferably, the S1P receptor modulator or agonist of the present invention, eg free form fingolimod, pharmaceutically acceptable salt form or fingolimod phosphate, is administered orally.

Dosing regimen

It has previously been stated that the present invention provides a novel dosing regimen and method of treating an inflammatory or autoimmune disease or disorder for a patient in need thereof, comprising administering to said patient an S1P receptor modulator or agonist, for example, fingolimod (FTY720), a phosphate derivative thereof, or a pharmaceutically thereof. an acceptable salt, such that the disease is treated or the severity of the disease is reduced, while side effects that may be associated with the administration of said S1P receptor modulator or agonist are controlled, limited, reduced or abolished. For example, provided is a method of treating an inflammatory or autoimmune disease or disorder in a patient in need thereof, comprising administering to said patient an S1P receptor modulator or agonist, such as fingolimod (FTY720), a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, such that the symptoms of the disease are reduced or abolished, while side effects that may be associated with the administration of said S1P receptor modulator or agonist are controlled, limited, reduced or abolished.

As described herein, there is provided a method of administering FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof to a patient in need thereof, for treating an inflammatory or autoimmune disease or disorder, limiting associated symptoms, or progression of a disease, such as multiple sclerosis, in a patient who needs it. In particular, the present invention relates to a method for treating RRMS, limiting symptoms associated therewith, or disease progression in a patient in need thereof.

According to the present invention, the term "treatment" refers to both prophylactic and preventive treatment, as well as radical or disease-modifying treatment, including the treatment of patients at risk of contracting this disease or disorder or suspected of developing this disease or disorder, as well as patients who have fallen ill or have been diagnosed with a disease or disorder.

The autoimmune diseases or disorders of the present invention are preferably chronic long-term diseases such as multiple sclerosis (MS) such as relapsing-remitting multiple sclerosis (RRMS) or primary progressive multiple sclerosis (PPMS) such as RRMS. MS can come in several forms, with new symptoms occurring either as isolated attacks (relapsing forms) or as a gradual accumulation over time (progressive forms).

The dosage regimens and methods of treatment of the present invention are especially adapted for multiple sclerosis, such as RRMS.

As described herein, the treatment of multiple sclerosis refers to, but is not limited to, reducing the incidence of clinical manifestations or delaying the accumulation of physical impotence induced by multiple sclerosis. Treatment of multiple sclerosis can also refer to limiting the symptoms of the disease.

As described herein, symptoms or disorders associated with multiple sclerosis include neurological symptoms, physical and cognitive helplessness, and neuropsychiatric disorders.

As described herein, adverse events refer to any detrimental change in health that occurs in a patient being treated or over a period of time after completion of treatment. Controlling adverse events refers to limiting the occurrence, outcome, consequences, or impact of such events so that the health of the patient is not at risk, or treatment can be continued without compromising the general health of the patient. Adverse events are not necessarily related to the drug itself, they can also be associated with an inflammatory or autoimmune disease or disorder for which the patient is being treated, or due to another disease or disorder that the patient additionally has.

According to the present invention, the reduction of adverse events refers to the reduction of manifestations, for example, side effects, to a level that provides the patient with safety, for example, does not require specific treatment and/or specific medical care, hospitalization or medical monitoring. For example, the reduction of adverse events refers to the reduction of manifestations to a level acceptable for patient compliance with the regimen and treatment regimen.

According to the present invention, limiting adverse events refers to limiting the number or distribution of adverse events, e.g., side effects, in a patient to the number or prevalence of adverse events that are acceptable to the patient, e.g., which do not require specific treatment and/or specific medical care, hospitalization, or medical monitoring. For example, limiting adverse events refers to limiting the number or presence of adverse events to a number or presence acceptable to the patient's safety and/or compliance with the regimen.

Monitoring of possible side effects can be carried out as described in the present invention above. For example, it may be performed by ophthalmic examination, dermatological examination, pulmonary function tests, chest x-ray and/or CT scan, ambulatory monitoring, and/or echocardiography. In one of the embodiments of the present invention, monitoring and describing adverse events includes monitoring and describing bradycardia, syncope or pre-syncope, severe infections, liver toxicity, and macular edema.

As described herein, a patient treated with fingolimod (FTY720) is a patient receiving fingolimod (FTY720), its phosphate derivative (i.e., fingolimod phosphate), or a pharmaceutically acceptable salt thereof, for the treatment of an inflammatory or autoimmune disease or disorder. according to the present invention, for example, RS, for example, PPRS.

As described herein, a patient in need of fingolimod administration is a patient with an inflammatory or autoimmune disease or disorder of the present invention, such as a patient with MS.

Patients treated with fingolimod (FTY720) and patients in need of fingolimod may include patients who have never been treated for an inflammatory or autoimmune disease or disorder, such as patients who have never been treated for the treatment or prevention of MS, and patients who have previously undergone one or more treatments for an inflammatory or autoimmune disease or disorder, such as patients who have been treated one or more times for MS.

The effectiveness of the S1P modulator of the present invention for the treatment of multiple sclerosis can be evaluated by medical standards and criteria known to those skilled in the art. For example, it can be estimated by the frequency of relapses of multiple sclerosis per year.

For example, a dose of an S1P modulator or agonist of the present invention may be considered effective in treating a disease or ameliorating the symptoms associated therewith, such as in the treatment of multiple sclerosis, if the recurrence rate is reduced by more than 45%, such as by more than 50%. , for example, more than 60%.

In another embodiment of the present invention, the effectiveness of the S1P modulator or agonist of the present invention for the treatment of multiple sclerosis is assessed by the progression of disability, using, for example, the extended Kurtzke Disability Rating Scale (ECRS). The Extended Kurtzke Disability Rating Scale (ECRS) is a way to quantify disability in multiple sclerosis. RSSI quantifies disability in eight functional systems (FS) and allows neurologists to assess the functional system (FS) in each of them. For example, dosing of an S1P receptor modulator or agonist of the present invention may be considered effective in treating a disease or reducing symptoms associated therewith, such as in the treatment of multiple sclerosis, if the progression of the patient's disability is delayed by at least 25%, such as by at least at least 30%, for example at least 32%.

The effectiveness of the dosing regimen of the present invention can also be assessed by measuring brain damage, such as by scanning with magnetic resonance imaging.

Monitoring

The present invention provides a dosage regimen and method for treating an inflammatory or autoimmune disease or disorder in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of an S1P receptor modulator or agonist, said method comprising the steps of:

i) monitoring the patient for a specified period of time following the first administration of said S1P receptor modulator or agonist, and

ii) optionally interrupting the administration of said S1P receptor modulator or agonist and/or modifying the treatment regimen and/or administering a second drug that alleviates said possible side effects.

This dosing regimen is partly adapted for the administration of fingolimod, for example, to a patient with multiple sclerosis.

In addition, the present invention provides an S1P receptor modulator or agonist, such as FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of an inflammatory or autoimmune disease or disorder, such as multiple sclerosis, said treatment comprising the steps of:

i) monitoring the patient for a specified period following the first administration of said S1P receptor modulator or agonist, and

ii) optionally interrupting the administration of said S1P receptor modulator or agonist and/or modifying the treatment regimen and/or administering a second drug that alleviates said possible side effects.

In one embodiment, the present invention provides FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, such as the hydrochloride salt of FTY720, for use in the treatment of multiple sclerosis, said treatment comprising the steps of:

i) monitoring the patient for a specified period after the first administration of FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, and

ii) optionally interrupting the administration of FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, and/or modifying the treatment regimen, and/or administering a second drug that alleviates these possible side effects.

The present invention further provides an S1P receptor modulator or agonist, such as FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, for use in a method for treating an inflammatory or autoimmune disease or disorder, such as multiple sclerosis, said method comprising the steps of:

i) monitoring the patient for a specified period following the first administration of said S1P receptor modulator or agonist, and

ii) optionally interrupting the administration of said S1P receptor modulator or agonist and/or modifying the treatment regimen and/or administering a second drug that alleviates said possible side effects.

In one embodiment, the present invention provides FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, for use in a method of treating multiple sclerosis, said treatment comprising the steps of:

i) monitoring the patient for a specified period following the first administration of said S1P receptor modulator or agonist, and

ii) optionally interrupting the administration of said S1P receptor modulator or agonist and/or modifying the treatment regimen and/or administering a second drug that alleviates said possible side effects.

According to the present invention, the action taken in step ii) depends on the results obtained in step i).

If the S1P receptor modulator or agonist is selected from fingolimod (FTY720), a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, the step of modifying the treatment regimen may consist of administering a daily dosage of the drug that is below about 0.5 mg and then increasing the dosage to the daily dosage about 0.5 mg. The daily dosage of the drug can then be increased step by step, for example by titration. It may also consist of administering a daily dosage of the drug in excess of 0.5 mg, eg a daily dosage of about 1.0 mg or about 1.25 mg.

In one embodiment of the present invention, for example, if the S1P receptor modulator or agonist is selected from fingolimod (FTY720), a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, the step of modifying the treatment regimen may consist of lengthening the period between successive drug administrations.

The present invention provides for patient monitoring, i.e. specific monitoring of patients treated with an S1P receptor modulator or agonist, such as fingolimod (FTY720), its phosphate derivative, or a pharmaceutically acceptable salt thereof, to control, limit or eliminate possible adverse events, said monitoring being carried out before and/or during drug administration .

Patient monitoring according to the present invention includes:

a) monitoring infections or infestations, e.g. viral infections, during administration of said S1P receptor modulator or agonist, and/or

b) conducting an ophthalmological examination.

Patient monitoring may additionally include one or more of the following steps:

c) monitoring the patient's heart rate for at least the first hours after the first administration of said S1P receptor modulator or agonist,

d) monitoring the patient during the first hours after the first administration of said S1P receptor modulator or agonist, monitoring the patient's heart rate,

e) carrying out tests for the functioning of the liver,

e) conducting dermatological examinations,

g) conducting pulmonary functional tests.

Patient monitoring may additionally include one or more of the following steps:

h) conducting a clinical blood test,

i) counting lymphocytes and/or recording key blood parameters,

k) monitoring and/or recording vital signs, such as heart rate, blood pressure, such as arterial blood pressure,

k) monitoring and / or registration of a heart disorder,

l) monitoring and / or recording other adverse events or side effects.

The present invention also provides a dosage regimen and method for controlling, reducing or eliminating possible side effects associated with treatment of a patient with an inflammatory or autoimmune disease or disorder with an S1P receptor modulator or agonist, comprising administering to said patient a therapeutically effective amount of said S1P receptor modulator or agonist, wherein said method includes

i) patient monitoring as described in the present invention above, and

ii) optionally interrupting the administration of said S1P receptor modulator or agonist and/or modifying the treatment regimen.

In one embodiment of the present invention, patient monitoring of the present invention may include one or more of the following steps, optionally all of the following steps:

- clinical blood test,

- count of lymphocytes,

- analysis of liver enzymes,

- monitoring and/or recording of vital signs, e.g. heart rate, blood pressure, e.g. arterial blood pressure,

- a history of viral infection analysis or viral serology, such as chicken pox,

- monitoring and/or recording infections or infestations, e.g. viral infections,

- dermatological examinations,

- ophthalmological examinations,

- performing pulmonary function tests,

- monitoring and/or registration of cardiac disorders,

- monitoring and/or registration of key blood parameters,

- monitoring and/or recording tests for liver function,

- monitoring and / or registration of other adverse events or side effects.

Preferably, patient monitoring of the present invention comprises one or more of the following steps, optionally all steps:

- clinical blood test,

- analysis of liver enzymes,

- ophthalmic examinations and

- a history of viral infection analysis or viral serology, such as chicken pox,

— monitoring and/or recording of infections or infestations, such as a viral infection.

Patient monitoring may additionally include:

- setting up an electrocardiogram (ECG), for example, at the beginning of drug administration, and / or

- vaccinating the patient prior to administration, for example, against the varicella zoster virus (VZV).

As described in the present invention, the monitoring of a patient according to the present invention may include the monitoring steps described above, or additional steps as well.

In one embodiment of the present invention, patient monitoring includes the steps of:

- monitoring and/or recording infections or infestations, e.g. viral infections,

- carrying out ophthalmological examinations,

and optionally further includes the steps of:

- monitoring and / or registration of cardiac disorders for a certain category of patients, and / or

- Carrying out dermatological examinations.

In another embodiment of the present invention, patient monitoring includes the steps of:

- monitoring and/or recording infections or infestations, e.g. viral infections,

- ophthalmological examinations,

- monitoring and/or registration of cardiac disorders, for example, for a certain category of patients,

- tests for liver function,

and optionally further includes the steps of:

- dermatological examinations.

In yet another embodiment of the present invention, patient monitoring includes the steps of:

- monitoring the patient's heart rate,

- monitoring and/or recording infections or infestations, e.g. viral infections,

- carrying out ophthalmological examinations,

and optionally further includes the steps of:

- Carrying out dermatological examinations.

In yet another embodiment of the present invention, patient monitoring includes the steps of:

- monitoring and/or recording infections or infestations, e.g. viral infections,

- conducting an ophthalmological examination in the first 1-10 days after the start of administration,

- observation of patients for at least 6 hours after the first dose,

and optionally further includes the steps of:

- Carrying out dermatological examinations.

Patient monitoring may further include the step of monitoring and/or recording liver function tests when the patient's symptoms are indicative of liver dysfunction.

In a preferred embodiment of the present invention, a method is provided for administering fingolimod (FTY720), a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof to a patient in need thereof, in such a manner as to limit possible adverse events prior to or during administration of fingolimod, said method comprising monitoring the patient , as described in the present invention above.

For example, the method of prescribing fingolimod may include one or more of the following steps:

- counting lymphocytes,

- monitoring and/or recording vital signs, such as blood pressure, such as arterial blood pressure,

- monitoring and/or recording infections or infestations, e.g. viral infections,

- performing dermatological examinations,

- carrying out ophthalmological examinations,

- performing lung function tests,

- monitoring and/or registration of cardiac disorders,

- monitoring and/or recording key blood parameters, such as serum ALT levels,

- performing liver function tests,

- monitoring and / or registration of other adverse events or side effects,

wherein each said step is carried out for a certain period of time prior to and/or during the period of drug administration.

Specific and routine monitoring of treated patients may consist of one or more of the following steps:

- counting lymphocytes,

- monitoring and/or recording vital signs, such as blood pressure, such as arterial blood pressure,

- monitoring and/or recording infections or infestations, e.g. viral infections,

- performing dermatological examinations,

- carrying out ophthalmological examinations,

- performing lung function tests,

- monitoring and/or registration of cardiac disorders,

- monitoring and/or recording key blood parameters, such as serum ALT levels,

- performing liver function tests,

- monitoring and / or registration of other adverse events or side effects,

wherein each said step is carried out for a certain period of time prior to and/or during the period of drug administration.

Each step may be performed as described below.

Preferably, patient monitoring may include one or more of the following steps:

- monitoring and/or recording infections or infestations, e.g. viral infections, during FTY720 therapy,

- ophthalmic examinations as described in the present invention,

- monitoring and / or registration of cardiac disorders for a certain category of patients,

- performing liver function tests if patients develop symptoms suggestive of liver dysfunction,

and optionally further includes the steps

- dermatological examinations.

Various stages of patient monitoring according to the present invention are carried out in a certain period of time after the administration of the first dose.

These steps can be performed as described in the present invention.

In one of the embodiments of the present invention, patients being treated are subjected to monitoring under medical supervision for a certain period after the first dose, during the first 1-10 hours after the first administration of an S1P receptor modulator or agonist, for example, fingolimod, its phosphate derivative, or its pharmaceutical acceptable salt, for at least 6 hours after the first dose.

According to the present invention, one or more steps, such as monitoring and/or recording a heart disorder, is carried out at least 4 hours after the first dose, for example, at least 6 hours after the first dose, or at least 8 hours after administration of the first dose, eg 3 to 8 hours after the first dose, eg 4 to 6 hours after the first dose, eg 4 to 6 hours after the first dose. Preferably, the monitoring and/or recording of the cardiac disorder is carried out approximately 6 hours after the first dose. The step of monitoring and/or reporting a cardiac disorder may consist of observing patients for a period after the first dose, for example, for at least 4 hours after the first dose, for example, for at least 6 hours after the first dose, or for at least 8 hours after the first dose.

According to the present invention, cardiac disorders that are monitored and/or recorded include, but are not limited to, bradycardia and high levels of atrioventricular block.

In the present invention, infections that are recorded and monitored include, for example, viral infections, such as varicella zoster virus (VZV) infection, influenza virus infection, herpes virus infection, lower respiratory tract infection, such as bronchitis and pneumonia.

In one of the embodiments of the present invention, monitoring of infections or infestations is carried out during the first three months after the first dose, for example, during the first two months after the first dose. In another embodiment of the present invention, monitoring of infections or invasions is carried out during the period of drug administration.

Before initiating administration of an S1P receptor modulator or agonist, the patient may be checked for a history of infections, such as a viral infection, such as chickenpox. If the serological test is negative, the patient may be vaccinated, for example, against the varicella zoster virus or the influenza virus.

Monitoring or recording of infections or infestations, such as viral infections, can be carried out by medical methods available, for example, through a clinical blood test and/or lymphocyte count.

According to the present invention, the ophthalmic examination preferably includes comparison and/or monitoring of visual acuity disturbances, such as the appearance of macular edema.

In one embodiment of the present invention, eye examinations include at least one of the following: eye history, visual acuity, dilated ophthalmoscopy, optical coherence tomography (OCT), fundus examination. Such examinations are preferably carried out by an ophthalmologist.

According to the present invention, an ophthalmic examination may be performed after initiation of administration of an S1P receptor modulator or agonist, e.g. , 2-5 months, such as 3-4 months. Additional ophthalmic examinations may be performed as needed based on the patient's symptoms, for example at intervals determined by the ophthalmologist.

According to the present invention, an ophthalmic examination may include the steps of:

1) ascertaining the medical history of the eye of the patient being treated before starting treatment with FTY720,

2) conducting ophthalmic examinations performed as described above, for example, 3-4 months after the start of treatment with FTY720, preferably performed by an ophthalmologist, and optionally

3) conducting additional ophthalmic examinations based on the patient's symptoms, for example, at intervals determined by the ophthalmologist.

An ophthalmic examination may also be performed prior to initiation of administration of an S1P receptor modulator or agonist, for example, prior to initiation of FTY720 therapy. This embodiment of the present invention is partly adapted to specific categories of patients, for example in the case of patients with eye diseases or disorders and/or a history of diabetes or uveitis.

According to the present invention, a dermatological examination may include an analysis of the appearance of, for example, neoplasms, malignant skin lesions, melanoma, squamous cell carcinoma, basal cell carcinoma. Dermatological screening may be performed before or shortly after initiation of therapy. In one embodiment of the present invention, dermatological screenings are performed annually on a patient receiving an S1P receptor modulator or agonist, such as FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof.

Dermatological screening may be performed by a physician, such as a dermatologist. In another embodiment of the present invention, such screening is performed more frequently, for example, by the patient himself.

According to the present invention, lung function tests can be performed spirometrically using lung function tests such as FEV1, FVC, FEF25-75%, DLCO, carbon monoxide diffusivity, or high resolution computed tomography (HRCT) of the chest.

In one of the embodiments of the present invention, the pulmonary function test (LPT) is carried out from several hours to several days after the first administration, for example, on the day of the first administration, for example, from 2 to 12 hours after the first administration of the drug, for example, from 2 to 8 hours after the first administration of the drug, for example, from 2 to 6 hours after the first administration of the drug, for example, 6 hours after the first administration of the drug. The second LFP can be performed several days after the first drug administration, for example, from 2 to 10 days after the first drug administration, for example, from 3 to 8 days after the first drug administration, for example, about a week after the first drug administration .

In one of the embodiments of the present invention, the level of liver enzymes, for example, serum ALT, is assessed during the initiation of therapy and optionally periodically thereafter. The continuous assessment is especially adapted in the case of patients who have developed symptoms indicative of liver dysfunction.

According to the present invention, liver function tests can be performed on a certain category of patients, for example, patients who have developed symptoms indicative of liver dysfunction, such as nausea, vomiting, abdominal pain, anorexia or jaundice.

According to the present invention, monitoring and/or recording tests for liver function may include any one of the steps:

1) detecting the level of a liver enzyme, for example, serum ALT, in the patient being treated before the first administration of an S1P receptor modulator or agonist, for example, FTY720, its phosphate derivative, or its pharmaceutically acceptable salt, and administering the first dose only if the level of alanine aminotransferase (alanine aminotransferase - ALT) exceeds no more than twice the upper limit of the normal range (ULN),

2) identification of a liver enzyme level, eg, serum ALT, in a treated patient and interruption of therapy in patients with jaundice or an increase in the liver enzyme level of more than 5 times the upper limit of the normal range (ULN).

Patient monitoring according to the present invention may include the step of examining the patient during the first 1-10 hours after the first administration of an S1P receptor modulator or agonist, for example, fingolimod, its phosphate derivative, or a pharmaceutically acceptable salt thereof, for example, the first 2-8 hours after the first administration, e.g. the first 3-9 hours after the first injection, e.g. the first 2-8 hours after the first injection, e.g. the first 4-7 hours after the first injection, e.g. the first 6 hours, e.g. the first 5 hours, e.g. the first 4 hours after the first administration of said S1P receptor modulator or agonist, for example fingolimod, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof. For example, monitoring a patient of the present invention may include the step of seeing the patient at least 2 hours after the first administration of said S1P receptor modulator or agonist, e.g., fingolimod, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, e.g., at least 4 hours after the first injection, for example, at least 6 hours after the first injection.

The present invention provides a method for treating an inflammatory or autoimmune disease or disorder in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of an S1P receptor modulator or agonist, wherein specific parameters of the patient are checked prior to initiating said treatment and, if necessary, the treatment regimen is adjusted. and/or administering a second drug that alleviates possible side effects.

The present invention further relates to an S1P receptor modulator or agonist, such as FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, for use in a method of treating an inflammatory or autoimmune disease or disorder, such as multiple sclerosis, said method comprising the steps of verifying specific patient parameters prior to initiating said treatment, and, if necessary, adapting the treatment regimen and/or administering a second drug that alleviates possible side effects.

These parameters are selected from signs of infection or invasion (eg, viral infections), visual acuity, presence of eye disease, liver enzymes, blood pressure, blood test (eg, CBC), electrocardiogram (ECG), pulmonary function, presence of skin disease, or disorders and liver function.

In one embodiment of the present invention, these parameters are selected from signs of infections or infestations (eg, viral infections), visual acuity, liver enzymes, blood pressure, and optionally heart rate.

For example, an ECG is performed prior to initiating administration of said S1P receptor modulator or agonist.

These parameters can also be monitored during treatment with said S1P receptor modulator or agonist.

In another of the embodiments of the present invention provide:

1 shows a method of administering to a patient in need thereof an S1P receptor modulator or agonist, for example, fingolimod, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

a) ascertaining the history of ocular disease in the patient being treated prior to initiation of treatment with said S1P receptor modulator or agonist,

b) carrying out ophthalmological examinations performed according to the above description of the present invention, for example, 3-4 months after the start of treatment with said S1P receptor modulator or agonist, preferably performed by an ophthalmologist, and optionally

c) conducting ophthalmic examinations based on the patient's symptoms, for example at intervals set by the ophthalmologist.

2 shows a method for treating an inflammatory or autoimmune disease or disorder (e.g., multiple sclerosis) and limiting the symptoms associated therewith, or reducing the severity of the disease, in a patient in need thereof, comprising steps a.), b.) and c. ) as above.

3 is an S1P receptor modulator or agonist, such as FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, for use in a method of treating an inflammatory or autoimmune disease or disorder, such as multiple sclerosis, said method comprising steps a), b) and c ) as above.

4 is an S1P receptor modulator or agonist, such as FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of an inflammatory or autoimmune disease or disorder, such as multiple sclerosis, said treatment comprising steps a.), b.) and c. .) as above.

5 - FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, for example the hydrochloride salt of FTY720, for use in a method for the treatment of multiple sclerosis, said treatment comprising the steps of:

a') ascertaining the history of ocular disease in the patient being treated prior to treatment with FTY720, its phosphate derivative or its pharmaceutically acceptable salt,

a) carrying out ophthalmological examinations performed according to the above description of the present invention, for example, 3-4 months after the start of treatment with FTY720, its phosphate derivative or its pharmaceutically acceptable salt, preferably performed by an ophthalmologist, and optionally

b) conducting ophthalmic examinations based on the patient's symptoms, for example at intervals set by the ophthalmologist.

6 - FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, for example the hydrochloride salt of FTY720, for use in the treatment of multiple sclerosis, said treatment comprising steps a'), b') and c') as described above.

In one embodiment, the present invention provides

7 shows a method of administering an S1P receptor modulator or agonist, such as fingolimod, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, to a patient in need thereof, comprising the steps of:

d) identifying the level of a liver enzyme, e.g., serum ALT, in the patient being treated prior to the first administration of said S1P receptor modulator or agonist, and administering the first dose only if the ALT level does not exceed >2x ULN, and

e) identifying a liver enzyme level, eg, serum ALT, in a treated patient, and interrupting therapy in patients with jaundice or liver enzyme elevation >5x ULN.

8 - A method of treating an inflammatory or autoimmune disease or disorder (eg, multiple sclerosis) and limiting the symptoms associated with it, or reducing the severity of the disease in a patient in need of such treatment, including steps d) and e) as described above.

9 is an S1P receptor modulator or agonist, such as FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, for use in a method of treating an inflammatory or autoimmune disease or disorder, such as multiple sclerosis, said method comprising steps d) and e) as described above.

10 is an S1P receptor modulator or agonist, such as FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of an inflammatory or autoimmune disease or disorder, such as multiple sclerosis, said treatment comprising steps d) and e) as described above.

11 - FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, for example the hydrochloride salt of FTY720, for use in a method for the treatment of multiple sclerosis, said method comprising the steps of:

d) identifying the level of a liver enzyme, e.g., serum ALT, in the treated patient prior to the first administration of FTY720, its phosphate derivative, or a pharmaceutically acceptable salt thereof, and administering the first dose only if the ALT level does not exceed >2x ULN, and

e) identifying the level of a liver enzyme, eg, serum ALT, in the patient being treated, and interrupting therapy in patients with jaundice or liver enzyme elevation > 5x ULN.

12 - FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, for example the hydrochloride salt of FTY720, for use in the treatment of multiple sclerosis, said treatment comprising steps d) and e) as described above.

13 - In yet another embodiment, the present invention provides a method of administering an S1P receptor modulator or agonist, e.g., FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, to a patient in need thereof and receiving concomitant beta-blocker therapy, comprising the steps of:

f) measuring the heart rate and/or blood pressure of the patient being treated prior to treatment with said S1P receptor modulator or agonist,

g) or measuring the heart rate every 3-5 hours, for example, every 4 hours, for a subsequent at least 6 hours, and / or performing an ECG 3-6 hours, for example, 4-6 hours, after dosing, and

h) providing adequate treatment if symptoms associated with bradysystolic atrial fibrillation are observed at stage g), for example, the administration of atropine or isoprenaline.

In one embodiment of the present invention, this method relates to a method of administering FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, eg, FTY720 hydrochloride salt, to a patient with multiple sclerosis.

14 - A method of treating an inflammatory or autoimmune disease or disorder (e.g., multiple sclerosis) and limiting the symptoms associated with it, or reducing the severity of the disease, in a patient in need thereof, comprising steps f), g) and h) as described above.

15 - An S1P receptor modulator or agonist, for example FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, for use in a method for treating an inflammatory or autoimmune disease or disorder, for example multiple sclerosis, said method comprising steps f), g) and h ) as described above.

16 - An S1P receptor modulator or agonist, such as FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of an inflammatory or autoimmune disease or disorder, such as multiple sclerosis, said treatment comprising steps f.), g.) and h) as described above.

17 - FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, for example the hydrochloride salt of FTY720, for use in a method for the treatment of multiple sclerosis, said method comprising the steps of:

e') measuring the heart rate and/or blood pressure of the patient to be treated prior to treatment with FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof,

g') or measuring the heart rate every 3-5 hours, for example, every 4 hours, then for at least 6 hours, and / or performing an ECG from 3 to 6 hours, for example, from 4 to 6 hours after dosing, and

h') providing adequate treatment if symptoms associated with bradysystolic atrial fibrillation are observed at stage g), for example, the administration of atropine or isoprenaline.

18 - FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, for example the hydrochloride salt of FTY720, for use in the treatment of multiple sclerosis, said treatment comprising steps e'.), g'.) and h'.) as described above.

In another embodiment, the present invention provides

19 shows a method of administering an S1P receptor modulator or agonist, such as FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, to a patient in need thereof, comprising the steps of:

i) monitoring the patient after the first dose for an observational period as described in the present invention above, for example for at least 6 hours,

j) measuring the patient's heart rate after the completion of this period,

k) or release the patient if the heart rate is > 40 beats per minute, or 40-60 beats per minute if this value is not the lowest heart rate measured during the observation period of 6 hours; or keeping the patient on an appropriate regimen.

This method is highly adapted for patients with persistently low heart rates (eg, below 50), or those taking beta-blockers, or those who have a high level of atrioventricular block or a symptom of sinus node dysfunction.

In one embodiment, the present invention relates to the administration of FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, eg FTY720 hydrochloride salt, to a patient with multiple sclerosis.

The present invention also provides:

20 - FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, for example the hydrochloride salt of FTY720, for use in the treatment of multiple sclerosis, said treatment comprising steps i), j) and k) as described above.

21 - FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, for example the FTY720 hydrochloride salt, for use in a method of treating multiple sclerosis, said treatment comprising steps i), j) and k) as described above.

In certain cases, for example, if patients exhibit symptoms associated with bradysystolic atrial fibrillation that do not end by the end of the 6-hour observation, the 2 daily dose may also be administered with the same observation period as the first administration as described above.

The observation period described in the present invention above, such as a 6-hour observation, can also be performed in the event that the patient resumes the use of an S1P receptor modulator or agonist, for example, FTY720, its phosphate derivative, or its pharmaceutically acceptable salt, after discontinuing the use medicinal product for more than 4 days, for example, for more than 6 days, for example, for more than 8 days, for example, for more than 10 days, for example, for more than 12 days, for example, for more than 14 days, for example, more than 18 days, for example, more than 21 days.

In another embodiment, the present invention provides a method of administering FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof to a patient in need thereof, while controlling, limiting, or eliminating possible adverse events associated with or associated with such administration, wherein patients with possible the risk of such manifestations is identified prior to administration of the drug, and specific and regular monitoring of treated patients is carried out, for example, by a qualified physician.

Patients at possibly increased risk may be patients selected from patients who have ocular diseases or disorders, patients exhibiting high ALT levels, patients with liver dysfunction, patients with hypertension, and patients with heart failure or arrhythmia. This may also apply to patients with asthma, eg mild asthma, and/or diabetic patients.

In another embodiment, the present invention may relate to pregnant women.

Eye diseases or disorders as described herein refer to diseases or disorders affecting the eye, such as uveitis and diabetes.

Patients with high ALT levels include patients who have an ALT level of two or more times the ULN, for example, prior to initiation of treatment with FTY720.

Patients with cardiac disorders include those patients who have one or more disorders selected from high levels of atrioventricular block, sinus node dysfunction syndrome, coronary heart disease, congestive heart failure, and arrhythmia. For example, this may include patients with or at risk of bradysystolic atrial fibrillation, patients with high levels of atrioventricular block or sinus node dysfunction syndrome, patients with a history of syncope, or patients being treated with beta-blockers or anti-arrhythmia agents. such as drugs for arrhythmias.

The present invention provides for specific monitoring of patients treated with an S1P receptor modulator or agonist, such as FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, said patients with an inflammatory or autoimmune disease or disorder, such as multiple sclerosis, comprising one or more of the following: stages:

i) an observation period, for example at least 6 hours, for example 4 to 6 hours, during or at the end of which the heart rate is checked, as described in the present invention,

ii) an annual skin examination, starting with the first dose, as described in the present invention,

iii) regular analysis of a liver enzyme, for example, serum ALT, as described in the present invention,

iv) ophthalmic examinations from 2 to 12 months, for example, from 3 to 4 months, starting from the administration of the first dose, as described in the present invention,

v) regular monitoring of the visual function of the patient, as described in the present invention.

The present invention also provides a method of administering an S1P receptor modulator or agonist, such as fingolimod in the form of FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, to patients with an inflammatory or an autoimmune disease or disorder, such as multiple sclerosis, comprising:

a) performing any one of the following steps:

i) an observation period, for example at least 6 hours, for example 4 to 6 hours, during or at the end of which the heart rate is checked, as described in the present invention,

ii) an annual skin examination, starting with the first dose, as described in the present invention,

iii) regular analysis of a liver enzyme, for example, serum ALT, as described in the present invention,

iv) ophthalmic examinations 3 to 4 months from the first dose, as described in the present invention,

v) regular monitoring of the visual function of the patient, as described in the present invention;

and

b) if necessary, interrupting the administration of fingolimod, based on the results of one or more of the above stages, or changing the treatment regimen and/or administering a second drug. Stage b) may correspond to the appearance of side effects. The second drug may be a drug that alleviates these possible side effects.

Interruption of fingolimod administration, change of treatment regimen and/or administration of a second drug may be in the case of any of the following conditions: bradycardia or atrioventricular conduction disorders, macular edema or other visual impairment, skin cancer, altered liver function or liver damage , infections or hypertension. The duration of the interruption is determined by the doctor.

Interrupting the administration of fingolimod, changing the treatment regimen and/or administering the second drug may also be the case if the patient's lymphocyte count becomes below normal or falls below 200/ml.

For example, step a) may include one or more steps:

i) monitoring the patient's heart rate,

ii) monitoring infections or infestations, such as viral infections, and

iii) conducting ophthalmic examinations in the first 1-10 days after the start of administration.

Therapeutic dosages

In a preferred embodiment of the present invention, methods of administering FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, as described above in the present invention, especially methods of treating an inflammatory or autoimmune disease or disorder limiting symptoms associated with or progressing in connection with them, for example , multiple sclerosis, in a patient in need thereof, include administering a daily dosage of FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, such as FTY720 hydrochloride, of not more than 0.5 mg, such as about 0.5 mg.

In one embodiment, the present invention provides a compound selected from fingolimod (FTY720), a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, e.g., fingolimod hydrochloride, for use in the treatment or prevention of an inflammatory or autoimmune disease, whereby said compound is administered to a patient such that the side effects associated with the administration of said compound are controlled, limited or eliminated. For example, a daily dosage of fingolimod (FTY720), a phosphate derivative thereof or a pharmaceutically acceptable salt thereof, eg fingolimod hydrochloride, does not exceed 0.5 mg, eg about 0.5 mg.

In one embodiment, the present invention provides a method for treating multiple sclerosis, controlling or limiting the symptoms associated therewith, or reducing the severity of said disease in a patient in need thereof, comprising administering a daily dosage of fingolimod (FTY720), a phosphate derivative thereof, or a pharmaceutically acceptable thereof a salt, e.g., fingolimod hydrochloride, wherein said daily dosage does not exceed 0.5 mg, e.g., about 0.5 mg, and in which the patient additionally has asthma (e.g., mild asthma), a disease or disorder affecting the eyes, or history of eye diseases or disorders (eg, those affected by uveitis or diabetes), high-level atrioventricular block, sinus node dysfunction syndrome, liver dysfunction, or hypertension.

In another embodiment, the present invention provides a method for treating multiple sclerosis, controlling or limiting the symptoms associated therewith, or reducing the severity of said disease to a patient in need thereof, including administering a daily dosage of fingolimod (FTY720), a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, for example, fingolimod hydrochloride, said daily dosage not exceeding 0.5 mg, eg about 0.5 mg, the patient being a pregnant woman.

In yet another embodiment, the present invention provides a method for treating multiple sclerosis, limiting the symptoms associated with it, or reducing the severity of the disease in a patient in need thereof, comprising administering a daily dosage of fingolimod (FTY720), its phosphate derivative, or a pharmaceutically acceptable salt thereof. , for example, fingolimod hydrochloride, and the specified daily dosage does not exceed 0.5 mg, for example, is about 0.5 mg, and the patients are patients with multiple sclerosis who have never been previously treated for this disease, i. de novo patients.

According to the present invention, the adaptation of the treatment regimen may include reducing the dosage or increasing the time between two successive administrations of an S1P receptor modulator or agonist, for example, fingolimod, its phosphate derivative, or its pharmaceutically acceptable salt. For example, the treatment regimen may include the administration of 0.25 mg of fingolimod, its phosphate derivative or its pharmaceutically acceptable salt twice a day. It may also consist of stepwise increasing the dosage of the drug during the first period of administration to a daily dosage of 0.5 mg or 1.25 mg, for example, adapting the stepwise administration, for example, titration.

The present invention relates to a method for the treatment of multiple sclerosis, including:

(a) administering a varying dose of a drug selected from the group consisting of fingolimod (FTY720), a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, to a patient in need thereof,

(b) monitoring adverse events occurring in said patient,

(c) monitoring the reduction or elimination of symptoms associated with multiple sclerosis, and

(d) determining the optimal dose for said patient.

The daily dose of the drug can be no more than 0.5 mg.

In another embodiment of the present invention, the daily dose of the drug is greater than 0.5 mg, such as greater than 1.00 mg, such as about 1.25 mg, such as about 1.5 mg.

The present invention also provides an S1P receptor modulator or agonist, such as FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, for use in a method of treating an inflammatory or autoimmune disease, such as multiple sclerosis, said method comprising:

(a) administering a varying dose of said S1P receptor modulator or agonist to a patient in need thereof,

(b) monitoring adverse events occurring in said patient,

(c) monitoring the reduction or elimination of symptoms associated with said inflammatory or autoimmune disease, and

(d) determining the optimal dose for said patient.

This method is highly adapted to FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, eg FTY720 hydrochloride salt, for the treatment of multiple sclerosis.

If the S1P receptor modulator or agonist is selected from FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, such as FTY720 hydrochloride, and the disease is multiple sclerosis, the daily dose of the drug may not exceed 0.5 mg.

In another embodiment of the present invention, the S1P receptor modulator or agonist is selected from FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, e.g., the hydrochloride salt of FTY720, and the daily dose is greater than 0.5 mg, e.g., is about 1.00 mg, e.g., about 1.25 mg, for example about 1.5 mg.

In yet another embodiment, the present invention provides a personalized method for treating an inflammatory or autoimmune disease or disorder, such as multiple sclerosis, for a patient in need thereof, comprising administering to said patient a therapeutically effective amount of an S1P receptor modulator or agonist,

wherein said method includes:

(a) administering a varying dose of said drug to a patient,

(b) monitoring adverse events present in said patient,

(c) monitoring the reduction or elimination of symptoms associated with multiple sclerosis, and

(d) determining the optimal dose for said patient,

wherein said regimen is adapted to treat said disease or disorder and control, reduce or eliminate potential side effects associated with administration of said S1P receptor modulator or agonist.

Steps (a) to (d) above can also be used in a method for determining a personalized therapeutic treatment regimen with a drug selected from the group consisting of fingolimod (FTY720), a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, for a patient with an inflammatory or autoimmune disease. disease, such as multiple sclerosis.

The present invention is also directed to a compound selected from FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, such as FTY720 hydrochloride, for use in a method of treating an inflammatory or autoimmune disease or disorder in a patient in need thereof, said method being personalized, for example, adapted for the treatment of said disease or disorder in a specific profile such that side effects associated with the administration of said S1P receptor modulator or agonist are controlled, reduced or abolished. In this case, the patient being treated may be selected from patients who have never been treated for such a disease or disorder, patients with heart failure or arrhythmias, or at risk of developing these disorders, patients with asthma, patients with eye diseases or disorders, dysfunction liver or hypertension.

The present invention provides a compound selected from FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, e.g., FTY720 hydrochloride, for use in the treatment of patients with an inflammatory or autoimmune disease or disorder, e.g., multiple sclerosis, the compound being administered by the type of administration described above. .

The present invention also provides a compound selected from FTY720, a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, such as FTY720 hydrochloride, for use in the treatment of patients with an inflammatory or autoimmune disease or disorder, such as multiple sclerosis, wherein the compound is administered during patient monitoring according to described above.

Combination

In another embodiment of the present invention, an S1P receptor modulator, e.g., fingolimod (FTY720), a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, e.g., fingolimod hydrochloride, is administered together with a second drug that reduces a possible side effect associated with the administration of fingolimod.

Such a second drug may only be administered if there is an adverse event, eg a side effect, or if its intensity or frequency increases to a level that is no longer tolerable, eg as described in the present invention above.

The second drug may be selected from the group consisting of drugs that treat or prevent macular edema, anti-cancer agents (eg, chemotherapeutic agents), anti-infective agents, antihypertensive drugs, anti-bradycardia agents, and mixtures thereof.

Examples of the second drug include, but are not limited to, a calcium channel blocker (eg, diltiazem), atenolol, valsartan.

If an S1P receptor modulator or agonist of the present invention, such as fingolimod (FTY720), a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, such as fingolimod hydrochloride, is administered together with a second drug that alleviates possible side effects associated with the administration of fingolimod, the daily dosage said S1P receptor modulator or agonist may be greater than 0.5 mg, such as may be greater than 1.00 mg, such as greater than 1.25 mg, such as about 1.5 mg.

For example, a combination is contemplated, e.g. a kit, containing an S1P receptor modulator or agonist of the present invention, e.g., fingolimod (FTY720), a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, e.g., fingolimod hydrochloride, and a second drug which is selected from the group, consisting of anti-cancer agents, anti-infective agents, anti-microbial agents, anti-viral drugs and anti-hypertensive drugs, whereby the dosage of said S1P receptor modulator or agonist is greater than 0.5 mg, such as about 1.25 mg.

The present invention also provides a specific dosage regimen of FTY720 for the treatment of an inflammatory or autoimmune disease or disorder, limitation of symptoms associated with said disease or disorder, or their progression, such as multiple sclerosis, for a patient in need thereof, comprising administering to said patient a daily dosage of fingolimod ( FTY720), a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, which results in a decrease in the number of lymphocytes in the peripheral blood by about 70-75%, for example, about 73%, 75% or 76%.

In another embodiment, the present invention provides a specific dosage regimen of FTY720 for the treatment of an inflammatory or autoimmune disease or disorder, limitation of symptoms associated with said disease or disorder, or their progression, such as multiple sclerosis, for a patient in need thereof, comprising administering to said patient a daily dosage of fingolimod (FTY720), its phosphate derivative, or a pharmaceutically acceptable salt thereof, which results in a reduction in the number of lymphocytes in the peripheral blood to a level low enough to obtain a therapeutic effect on the disease while controlling, limiting or eliminating the incidence of infections. Preferably, such a daily dosage does not exceed 0.5 mg of fingolimod (FTY720), its phosphate derivative, or a pharmaceutically acceptable salt thereof, eg the hydrochloride salt.

The use of the dosage regimen of the present invention in the treatment of diseases and conditions as described above can be demonstrated using standard animals and clinical tests, for example, in accordance with the methods described in the present invention.

Example 1

Study: Two different daily doses of fingolimod (0.5 mg and 1.25 mg) were administered orally to patients with relapsing-remitting multiple sclerosis (RRMS) for 24 months.

1292 RRMS patients from 172 centers in 18 countries are randomized to receive oral fingolimod 0.5 mg/day or 1.25 mg/day or 30 mcg interferon beta1-a intramuscularly once a week. Patients randomized to fingolimod receive placebo injections once a week, and patients randomized to interferon beta1-a receive a placebo tablet once daily.

The clinical condition of patients is assessed monthly for 3 months, and then every three months. The extended Kurtzke Disability Scale (ECS) is assessed every three months, the MS Functional Composite (MSFC) is assessed every 6 months, and magnetic resonance imaging (MRI) is performed annually. Monitoring is carried out by ophthalmological examination, dermatological examination, pulmonary function tests, X-ray and/or CT of the chest, outpatient monitoring and echocardiography.

Participants who complete a 1-year course of treatment are offered an optional extension phase. Those randomized to fingolimod continue to take the prescribed dose, and those in the interferon beta1-a group are randomized to 2 doses of fingolimod.

results

A decrease in relapses was observed in both fingolimod treatment groups compared to interferon beta1-a. For the lower dose, a 52% reduction in relapses was observed compared with interferon beta1-a and a 38% reduction at the higher dose. The results in both fingolimod treatment groups are highly statistically significant relative to interferon beta1-a, but are not statistically different from each other.

end point Interferon
beta1-a Fingolimod
0.5 mg/day P Fingolimod
1.25 mg/day P Frequency
relapses per year 0.33 0.16 < 0.001 0.20 < 0.001

The proportion of patients who did not show relapses is 83% with fingolimod versus 69% with interferon beta1-a.

MRI action lesion shows a reduction in both fingolimod treatment groups in the number of new or re-increasing T2 lesions and in the number of gadolinium-enhancing T1 lesions at 12 months.

Observed side effects include bradycardia and atrioventricular block, as well as infections, including 3 herpes virus infections.

Type of Interferon beta1-a, n (%) Fingolimod 0.5 mg/day, n (%) Fingolimod 1.25 mg/day, n (%) Localized skin cancer Basal cell carcinoma 1 (0.2) 3 (0.7) 2 (0.5) Squamous cell carcinoma 1 (0.2) 0 0 malignant melanoma 0 3 (0.7) 0 breast cancer 0 2 (0.5) 2 (0.5)

Example 2

Study: patients with moderate asthma are divided into 3 cohorts of 12 patients each. In each cohort, 12 patients are randomized to FTY720 (0.5 mg, 1.25 mg, and 2.5 mg in cohorts 1, 2, and 3, respectively) or placebo in a 3:1 ratio, resulting in 9 patients treated with FTY720 at each level dosing and 9 patients receive placebo.

The study consists of a screening period of 12 to 26 days, a baseline and a treatment period of 10 days, followed by a final study evaluation (performed 1 to 7 days after the last dose).

Conduct two screening visits, the initial screening visit and the second visit on day 7 (+/- 1 day). The initial screening visit (Visit 1) is used to initiate pulmonary function test (LPT) monitoring to assess eligibility for study and to obtain meaningful baseline information and informed consent. LFP is carried out according to the exact time signal close to the 6-hour time point after dosing for 1 day. On the -7th day, LFP is again carried out at the set time. A short-acting β2 agonist is used prior to study drug treatment and is also recorded over this 14-day period.

Patients return to the clinic one or two days prior to dosing for baseline evaluations. PAF profiling is assessed at 7 time points throughout the visit and baseline assessments are made. On day 1, patients are randomized 3:1 to FTY720 or placebo and the LFP profile is assessed at 8 time points (namely pre-dosing, then 1, 2, 3, 4, 5, 6 and 12 hours post-dosing). Pulmonary function test (LPT) assessments are also performed on days 2, 3, 7 (all individual time points are estimated at approximately the same exact time as the 6-hour LPT after day 1 dosing) and day 10 (7 time points, and just prior to dosing and then 1, 2, 3, 4, 5 and 6 hours after dosing). On each day of the LPP assessment, the last LPP assessment of the day is followed by a reversibility test. The use of a short-acting β2 agonist is also recorded during the treatment period up to 11 days inclusive (24 hours after the last dose).

Blood samples are taken 1 day before dosing and 1, 2, 4, 6, 8, 12, 16 and 24 hours after dosing, on days 2, 3 and 7 6 hours after dosing and 10 days before dosing and 1, 2, 4 and 6 hours after dosing.

Safety evaluations include physical examinations, ECG monitoring, vital signs, spirometry evaluations, standard clinical laboratory evaluations (hematology, blood chemistry, urinalysis), adverse events, and severe adverse events.

Only half of each treatment cohort, of a maximum of 6 patients, allows treatment to begin on any given day for safety reasons. At least 1 day (24 hours) separates the initial dosing of patients in the first group from the dosing of the second group (and at least 1 additional day separates the second group from any of the subsequent groups required to replenish each cohort).

Measure the magnitude and duration of exposure to FTY720 on FEV1 and other lung function tests (FVC, FEF25-75% and FEV1/FVC).

results

The magnitude of bronchoconstriction is initially assessed by the baseline FEV ₁ AUC0-6h on day 1. The main variable PD is expressed as the ratio of AUEC FEV ₁ on a 6-hour LFP profile on day 1, divided by the same variable at baseline (day -1).

The main variable PD is examined on a logarithmic scale with a linear model adjusted to the (log-transformed) baseline FEV ₁ AUC0-6h and treatment group as fixed effects. Baseline geometric mean FEV ₁ AUC0-6h is obtained from the model for each treatment group; the geometric mean ratio between each FTY720 group and placebo was also obtained along with their 95% CI, and converted back to obtain the geometric mean percent change from placebo and its 95% CI.

Additional PD variables are calculated: baseline-adjusted FEV ₁ AUC0-6h on day 10 and baseline-adjusted FEV ₁ Emax1-6h on days 1 and 10. Emax variables are expressed as the ratio between 1 day (or 10 days) and -1 day, relative to the minimum of 6 assessments provided from 1 to 6 hours post dosing. Such variables are defined for FEV ₁ as well as for other LFP parameters (FVC, FEF _25-75% and FEV ₁ /FVC) and analyzed using the same model as for the main PD endpoint.

Time-dependent LFP parameters are examined on day 1 using a 12-hour profile and on day 10 using a 6-hour profile. Percentage change from time-matched baseline for FEV ₁ , FVC, FEF _25-75% and FEV ₁ /FVC samples are summarized by means of descriptive statistics for each visit/time point. The log-transformed time-to-match baseline ratio is analyzed, separately for each post-baseline visit/time point, with a linear model adjusted for the time-consistent log-transformed baseline and treatment groups as a fixed effect. For each FTY720 group, an estimate of the mean treatment difference from placebo is obtained and its 95% CI is derived from the model and converted back to obtain the geometric mean percent change from placebo and its 95% CI. No agreement is made on P values for different tests.

The results show that a daily dosage of 0.5 mg FTY720 is safe and tolerable in patients with moderate asthma.

Claims (5)

1. A method of treating multiple sclerosis in a patient in need thereof, comprising orally administering to said patient a daily dose of 0.5 mg of a drug selected from fingolimod (FTY720), a phosphate derivative thereof, or a pharmaceutically acceptable salt thereof, said method comprising the steps of: a) identifying the medical history of the eye of the patient being treated prior to treatment with fingolimod (FTY720), its phosphate derivative or its pharmaceutically acceptable salt, b) conducting ophthalmic examinations performed 3-4 months after the start of treatment with FTY720, its phosphate derivative or its pharmaceutically acceptable salt, preferably by an ophthalmologist, which examinations include checking and/or monitoring the appearance of macular edema, and optionally, c) conducting additional ophthalmic examinations based on the patient's symptoms at intervals determined by the ophthalmologist. 2. The method of claim 1 wherein the multiple sclerosis is relapsing-remitting multiple sclerosis.