NZ726133B2 - Dosage regimen of an S1P receptor modulator - Google Patents

Abstract

Disclosed is a method for treating multiple sclerosis in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of fingolimod, wherein the adverse events possibly associated with administering fingolimod are controlled, limited or abolished, wherein the daily dosage of said S1P receptor modulator or agonist is of about 0.5 mg, and wherein the patient is monitored during a specific period of time after the first administration of said medicament wherein the monitoring comprises the steps of: a) monitoring and/or recording of infections or infestations; and b) performing an ophthalmologic examination at least 3 to 4 months after initiating administration wherein the monitoring and/or recording may indicate that the administration of the fingolimod to the patient should be interrupted and/or modified and/or a second drug should be administered which mitigates said adverse effects. e daily dosage of said S1P receptor modulator or agonist is of about 0.5 mg, and wherein the patient is monitored during a specific period of time after the first administration of said medicament wherein the monitoring comprises the steps of: a) monitoring and/or recording of infections or infestations; and b) performing an ophthalmologic examination at least 3 to 4 months after initiating administration wherein the monitoring and/or recording may indicate that the administration of the fingolimod to the patient should be interrupted and/or modified and/or a second drug should be administered which mitigates said adverse effects.

Description

PATENTS FORM NO. 5 Our ref: FIP237607NZPR Divisional application out of NZ 710791 In turn a divisional application out of NZ 621765 In turn a divisional application out of NZ 598534 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPEClFICATlON Dosage regimen of an S1P or modulator We, Novartis AG, of Lichtstrasse 35, CH-4056 Basel, Switzerland, hereby e the invention, for which we pray that a patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement: (followed by page 1a) Dosage Regimen of an S1P Receptor tor The present invention and the invention of NZ 598534, which is a related application to the present application, relate to a dosage regimen of an 81 P receptor tor or agonist in the course of the treatment of patients ing from an inflammatory or autoimmune disease or disorder, for e multiple sclerosis (MS). The complete ption of the present invention and the ion of NZ 598534 is retained herein for clarity and teness.

Multiple sclerosis is the chief cause of neurological disability in young adults and the most common demyelinating disorder of the central nervous . Available therapies such as interferon-[3’ and glatiramer acetate have modest efficacy and marginal effects on the progression of disability. These biological agents are administered parenterally and are associated, e.g., with injection site reactions and pyretic symptoms, such as flu-like symptoms.

Therefore, there is a strong medical need for a safe and effective oral treatment of multiple sclerosis.

Of those people with multiple sclerosis who receive treatment, a significant number continue to experience disease activity clinically or experience side s that include flu-like symptoms, immediate post-injection reactions and injection site ons. As a result, a substantial population of patients are untreated, including many with active disease. These MS patients have either tried an ng therapy but discontinued due to intolerance, adverse effects, or perceived lack of efficacy or have not started any therapy because of their n with adverse effects, fear of self-injection, fear of needles, or belief that currently ble options are not effective enough to warrant trial. Thus, there is a significant unmet need for effective new therapies in MS, which limit or reduce the possible adverse events or side effects. 81P receptor tors are compounds which signal as agonists at one or more sphingosinel-phosphate receptors, e.g. S1P1 to 81P5. Agonist binding to a SiP receptor may e.g. result in dissociation of intracellular heterotrimeric G—proteins into Ga—GTP and P, and/or increased phosphorylation of the agonist—occupied receptor and activation of downstream signaling pathways/kinases.

S1P receptor modulators are valuable compounds for the manufacture of medication for the treatment of various conditions in mammals, especially in human beings. For example, efficacy in transplantation has been demonstrated in rats (skin, heart, liver, small bowel), dogs (kidney), and monkeys (kidney) models. Due to their immune-modulating potency, SiP receptor modulators are also useful for the treatment of inflammatory and autoimmune diseases.

Treating such diseases y requires prolonged taking of medication, and ining the adequate drug regimen over time. (followed by page 2) PCT/U82010/049441 Oral imod is the first compound in the new class of therapeutics called sphingosine 1-phosphate receptor modulators. Fingolimod is believed to reduce the number of lymphocytes circulating in the blood stream by reversibly trapping a proportion of them in the lymph nodes. Consequently, the number of ted lymphocytes reaching the brain is sed, resulting in reduced inflammatory destruction. This is a new mechanism of action for MS.

FTY720 efficacy in the treatment of multiple sclerosis has been shown in humans (eg. as described in “FTY720 therapy exerts differential effects on T cell subsets in le sclerosis". Mehling M, et at... ogy. 2008 Oct i4;71(16):1261-7; and “Oral fingolimod (FTY720) for relapsing le sclerosis".Kappos L, Antel J, Comi G, Montalban X, O'Connor P, Polman CH, Haas T, Kom AA, Karlsson G, Radue EW; FTY720 D2201 Study Group. N Engl J Med. 2006 Sep 14355002112440).

Administration of a SiP receptor tor, such as fingolimod may induce adverse events, such as a transient reduction of the heart rate and cardiac conduction at treatment initiation. In particular it has been described that administration of 1.25 mg of FTY720 may induce a decrease in heart rate of approximately 8 beets/min ("FTY720z Placebo- Controlled Study of the Effect on Cardiac Rate and Rhythm in Healthy ts”, Robert Schmouder, Denise Serra, Yibin Wang, John M. Kovarik, John DiMarco, Thomas L. Hunt and Marie-Claude Bastien. J. Clin. Pharmacol. 2006; 46; 895.) .

Because of such a possible adverse event, administration of the compound to the patients may have to be made under full and constant medical control, in order to check that the c rhythm is maintained at an acceptable level and no high degree atrioventricular block occurs. Patients may have to stay in hospitals which complicate the treatment and increase the costs of treatment. Occurrence of adverse events during a drug treatment may induce patient hospitalization or prolongation of existing hospitalization.

Such possible events may also cause the ts to interrupt their treatment, change the recommended dosing n on their own or take the medication on an lar basis, without any medical support or recommendation for doing that. While it is paramount for treating inflammatory or autoimmune diseases, such as for example multiple sclerosis, that the adequate medication is taken over a long period of time, sometimes during the whole life of the patient, and the adequate drug regimen is kept over such a long period of time.

Therefore there is a need to reduce or manage the possible adverse events which may be generated by administration of such a StF’ receptor modulator, while stering a dosage which is te to treat or prevent the e for which the compound is administered during the required period of treatment.

More specifically, there is a need to provide an efficient treatment for treating an inflammatory or autoimmune disease or disorder, such as multiple sclerosis, for a large population of multiple sclerosis patients, ing patients who could be more exposed or more sensitive to said possible adverse events, patients who were never treated or diagnosed for an inflammatory or autoimmune disease or disorder There is furthermore a need to ameliorate patient compiiance.

Brief Disclosure of the invention Surprisingly it has been found that by administering a S‘lP receptor modulator or t, such as fingolimod, according to the specific dosage regimen or method of treatment of the invention, it is possible to treat the t efficiently while controlling, ng or abolishing the possible e , e.g. side effects, which may be associated with administration of such a nd.

A further benefit is that the dosing regimen and methods of treatment of the invention permit to administer a SiP or modulator or agonist, such as fingolimod, to patients who otherwise may have been reluctant or not could not have been instructed to take that medication. in particular they permit to treat patients suffering from an inflammatory or autoimmune disease or disorder, such as multiple sclerosis, for which the ratio risk/benefit may otherwise be less favourable. Such patients are for example patients susceptible to or suffering from one or more disease or disorders affecting the heart or heart rhythm, respiratory functions, eyes, hepatic functions. This also concerns patients that have undergone an interruption or treatment holiday in the maintenance dosage regime e.g. a hoiiday of greater than 10 days.

Furthermore the dosing regimen and methods of treatment of the invention is applicable for patients who were already under ent for an inflammatory or autoimmune or disease, for example under treatment for multiple sclerosis, as well as patients who were never treated or were not diagnosed for an matory or autoimmune or disease before taking a 81 P receptor modulator or agonist.

The dosage regimen of the t invention is a regimen for a SP receptor modulator or agonist therapy, which enables administration of a therapeutic dosage range of the SlP receptor to be achieved with controlled or minimal side effects, which could otherwise have been possibly ated with 81 P receptor modulatortherapy.

Another benefit of the present invention is to provide an therapeutic regimen for an inflammatory or autoimmune or disease, such as multiple sclerosis, which can be personalized, e.g. adapted to the specific profile of the patient to be treated and/or to the state of the disease in this patient, in such as way that that the disease is treated (or the disease ty is reduced), while the adverse events which could othenlvise have been associated with administering said SlP or modulator or agonist are controlled. reduced, or hed. For example, therapeutic regimen of the present invention may be personalized in view of the other diseases or disorders the patient could be affected with, the other medication he could be taken, eg. depending of whether he is suffering from a heart disease or disorder. 81 P receptor modulators or agonists According to the invention, specific 81 P receptor modulators of the invention are 2-amino- 2-tetradecyl-1,3—propanediol. An example of S1P or modulator is fingolimod (FTY720), Le; 2-amino-Z-[Z-(4-octylphenyl) ethyl]propane-1,3-diol in free form or in a pharmaceutically acceptable salt form, eg. the hydrochloride, as shown: HO OH Another specific S1P receptor modulator of the invention is the orylated derivative of , also referred to as fingolimod-phosphate, as shown: o: P—OH PCT/U52010/049441 Preferably, the S1? receptor modulator or agonist of the invention, e.g. fingolimod in free form, in a ceutically able salt form or fingolimod-phosphate, is administered orally.

Dosage Regimen As previously stated, the present invention provides a new dosage regimen and method for ng an inflammatory or autoimmune disease or disorder in a patient in need thereof, comprising administering to said patient a S1P receptor modulator or agonist, such as fingolimod (FTY720), a phosphate derivative thereof or a pharmaceutically acceptable salt thereof, in such a way that the e is treated or the disease ty is reduced, while the adverse events possibly associated with administration of said S1P receptor modulator or t are controlled, limited, reduced or abolished. For example there is ed a method for treating an inflammatory or autoimmune disease or disorder in a patient in need thereof, comprising administering to said patient a StP receptor modulator or agonist, such fingolimod (FTY720), a phosphate derivative thereof or a pharmaceutically acceptable sait thereof, in such as way that the symptoms of the disease are reduced or abolished while the adverse events possibly associated with administration of said S‘IP receptor modulator or agonist are controlled, limited, reduced or abolished.

According to the invention there is ed a method for administering FTY720, a phosphate derivative thereof or a phannaceutically able salt thereof, to a patient in need thereof preferably refers to a method for ng an inflammatory or autoimmune disease or disorder, limiting the ms associated thereof or the progression thereof, e.g. multiple sclerosis, in a patient in need thereof. in particular it refers to a method for treating RRMS, limiting the symptoms associated thereof or the progression f in a patient in need thereof.

According to the present invention the terms “treatment” or " refer to both prophylactic or preventive treatment as well as curative or disease-modifying treatment, ing ent of patients at risk of contracting the e or disorder, or suspected to have contracted the disease or disorder, as well as patients who are ill or have been diagnosed as suffering from the disease or disorder.

Autoimmune diseases or disorders according to the invention are preferably chronic long term diseases, e.g. multiple sclerosis (MS), for example relapsing ing multiple PCT/U82010/049441 sclerosis (RRMS) or primary progressive multiple sclerosis (PPMS), e.g. RRMS. MS takes several forms, with new symptoms occurring either in discrete attacks (relapsing forms) or slowly accumulating over time (progressive forms).

The dosing regimens and methods of ent according to the present invention are particulariy adapted for multiple sclerosis, e.g. RRMS.

{As herein defined, treating le sclerosis refers to, but is not limited to, reducing the frequency of clinical bations or delaying the accumulation of physical lity induced by multipie sclerosis. lt may also refer to limiting the symptoms of the disease.

As herein defined, symptoms or disorders associated with multiple sclerosis encompass neurological symptoms, physical and cognitive disability and neuropsychiatric ers.

As herein defined, adverse event refers to any adverse change in health that occurs to a patient receiving a ent or within a specified period of time after the treatment has been completed. Controlling the adverse events refers to limiting the extension, outcome, consequences or impact of such events in such a way that the patient's health is not a risk, or the treatment can be continued without worsening the overall health of the t.

The adverse events are not arily related to the medication itself, they may also be related to the inflammatory or autoimmune disease or er for which the patient is d or another disease or disorder that the patient is further affected with.

According to the invention reduction of the adverse events refers to the reduction of the events, e.g. of side-effects, to a levei that is acceptable to the patient safety, e.g. which does not require specific treatment and/or specific medical care, alization or medical ring. For example reduction of the e events refers to the reduction of the events to a levet that is acceptable for the patient compliance.

According to the invention limitation of the adverse events refers to limitation of the number or occurrence of adverse events, e.g. of side-effects, in a patient, to a number or occurrence which is acceptable to the t, e.g. which does not require ic treatment and/or specific medical care, hospitalization or medical monitoring. For example limitation of the adverse events refers to limitation of the number or occurrence of adverse events to a number or occurrence that is acceptable for the patient safety and/or compliance.

PCT/USZOIO/049441 The monitoring of possible adverse events may be done as bed herein above. For example it may be done by lmic examination, dermatologic examination, pulmonary function tests, chest X-ray and/or CT, Holter monitoring, and/or echocardiography. in a specific embodiment of the invention, the monitoring and reporting of e events comprises the monitoring and reporting of bradycardia, syncope or pre-syncope, serious infectious, liver toxicity, and macuiar edema.

As herein defined, a patient treated with fingolimod (FTY720) refers to a t receiving mod (FTY720), a phosphate derivative thereof (Le. fingolimod-phosphate) or a pharmaceutically acceptable salt thereof, for treating an inflammatory or autoimmune disease or disorder according to the invention, e.g. MS, e.g. RRMS.

As herein defined, a patient in need of prescribing fingolimod refers to a patient suffering from an inflammatory or autoimmune disease or disorder ing to the invention, e.g. a MS patient.

Patients treated with fingoiimod (FTY720) and the patients in need of prescribing fingolimod may be ts who have never received treatment for an inflammatory or mune disease or er, such as patients who have never received a treatment for treating or preventing MS, as well as patients who previously received one or more treatment for an inflammatory or autoimmune disease or disorder, for example who previously received one or more treatment for MS.

The effectiveness of the SiP modulator of the invention in treating multiple sis may be ted by medical standards and criteria known to the skilled person. For example, it can be evaluated through annual relapse rate of multiple scierosis.

For example, the dosage of the 31 P receptor modulator or agonist of the invention can be considered as efficient for treating the disease or reducing the symptoms associated thereof, e.g. for treating muitiple sclerosis, when the reiapse rate is decreased by more than 45%, e.g. more than 50%, e.g. more than 60%. in another embodiment effectiveness of the SiP receptor modulator or agonist of the invention in treating multiple sclerosis is ted h the disability ssion, e.g. according to the e Expanded Disability Status Scale (EDSS). The Kurtzke PCT/U52010/049441 ed Disability Status Scale (EDSS) is a method of quantifying disability in multiple sclerosis. The EDSS quantifies disability in eight Functional Systems (F8) and allows neurologists to assign a Functional System Score (FSS) in each of these. For example, the dosage of the 81 P receptor modulator or agonist of the invention can be considered as efficient for treating the disease or reducing the symptoms associated thereof, eg. for treating multiple sis, when progression of the patient disability is delayed by at least %, e.g. by at least 30%, e.g. by at least 32%.

The effectiveness of the dosing regimen of the invention may also be evaluated by measuring brain lesions, eg, by Magnetic Resonance imaging (RMI) scans.

Monitoring The present invention es a dosing regimen and 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 a S1P or modulator or t, wherein said method ses the steps of i) monitoring the t during a specific period of time after the first administration of said 81 P receptor modulator or agonist, and ii) optionally interrupting the administration of said S1P receptor modulator or agonist and/or modifying the treatment regimen thereof and/or administering a second drug which mitigates said possible adverse events.

Such a dosing regimen is particularly d for administering fingolimod, eg in patient ing from multiple sclerosis.

Furthermore there is provided a S1P receptor modulator or agonist , e.g. FTY720, a phosphate derivative thereof or a pharmaceuticaiiy able salt thereof, for use in the treatment of an inflammatory or an autoimmune disease or disorder, e.g. multiple sclerosis, wherein said treatment comprises the steps of i) monitoring the patient during a specific period of time after the first administration of said S‘iP receptor tor or agonist, and ii) ally interrupting the administration of said SiP receptor modulator or agonist and/or modifying the treatment regimen f and/or administering a second drug which mitigates said possible adverse events.

In a specific ment, the present invention provides FTY720, a phosphate derivative thereof or a pharmaceutically acceptable salt thereof, e.g. the hydrochloride salt of , for use in the treatment of multiple sis, wherein said treatment comprises the steps of i) ring the patient during a specific period of time after the first administration of FTY720, a phosphate derivative thereof or a pharmaceutically acceptable salt thereof, ii) optionally interrupting the administration of FTY720, a phosphate derivative thereof or a pharmaceutically acceptable salt thereof, and/or modifying the treatment regimen thereof, and/or administering a second drug which mitigates said possible adverse events.

The present ions further pertains to a 81 P receptor modulator or agonist, e.g.

FTY720, a phosphate derivative f or a pharmaceutically acceptable salt thereof, for use in a method for treating an inflammatory or an autoimmune disease or disorder, e.g. multiple sclerosis, wherein said method comprises the steps of i) monitoring the patient during a specific period of time after the first stration of said 81 P receptor tor or agonist, and ii) optionally interrupting the administration of said StP receptor modulator or agonist and/or modifying the treatment regimen thereof and/or administering a second drug which tes said possible adverse events. in a specific embodiment, the present invention pertains to FTY720, a ate derivative thereof or a pharmaceutically acceptable salt thereof for use in a method for the treatment of multiple sclerosis, wherein said treatment comprises the steps of i) monitoring the patient during a specific period of time after the first administration of said 81 P receptor modulator or t, and ii) ally interrupting the administration of said 81P receptor modulator or agonist and/or modifying the treatment regimen thereof and/or administering a second drug which mitigates said possible adverse events. ing to the invention, the action taken on step ii) depends on the results obtained under step i).

When the S1P receptor modulator or agonist is ed from fingolimod (FTY720), a phosphate derivative f 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 lower than about 0.5 mg and then increasing the dosage up to a daily dosage of about 0.5mg. The daily dosage of the drug may then be increased stepwise, eg. by ion. It may also t of administering a daily dosage of the drug higher than 0.5 eg. a daily dosage of about 1.0 mg or about 1.25mg. in a specific embodiment of the invention, eg. when the SiP receptor tor or agonist is selected from fingolimod (FTY720), a phosphate tive f or a pharmaceutically acceptable salt thereof, the step of modifying the treatment regimen may consist of increasing the period of time between two consecutive administrations of the medication. ing to the invention, there is provided a patient monitoring, Le. a specific monitoring of patients treated with a 81 P receptor tor or agonist, such as fingolimod (FTY720), a phosphate derivative thereof or a pharmaceutically acceptable salt thereof, in order to control, limit or abolish the possible adverse events, wherein said monitoring is med before and/or during administration of the medication.

The patient monitoring of the invention comprises a) monitoring infections or infestations, e.g. viral infections, throughout administering said 81 P receptor modulator or agonist, and/or b) performing an ophthalmologic examination.

The patient monitoring may further comprise one or more steps of c) ring the heart rate of the patient at least during the first hours after the first administration of said 81 P receptor modulator or agonist, d) observing the patient during the first hours after the first administration of said 81 P receptor modulator or agonist, to monitor the heart rate of the patient, e) performing liver function tests, f) performing ological examinations, g) performing pulmonary functions tests.

The patient monitoring may further comprise one or more steps of h) determining complete blood counting (CBC), i) lymphocytes counting and/or ing of blood key parameters, j) monitoring and/or recording of vital signs, e.g. heart rate, blood re, e.g. arterial blood re, k) monitoring and/or recording of cardiac disorders, l) monitoring and/or recording of other adverse events or side-effects.

The invention also provides a closing regimen and a method of controlling, reducing, or abolishing the possible adverse events associated with treating a patient suffering from an inflammatory or autoimmune disease or disorder with a S‘lP or modulator or agonist, comprising administering to said t a eutically effective amount of said 81 P receptor modulator or agonist, wherein said method comprises i) a patient monitoring as defined herein above, and ii) ally interrupting the administration of said SiP receptor modulator or agonist and/or modifying the treatment regimen thereof.

In one embodiment of the invention, the patient monitoring of the invention may comprise one or more of the following steps, optionally all the steps of, — complete blood counting (CBC), - lymphocytes counting, - analysis of liver enzymes, - monitoring and/or recording of vital signs, e.g. heart rate, blood pressure, e.g. arterial blood pressure, - testing history of viral infection or viral serology, e.g. regarding chickenpox, — monitoring and/or recording of infections or infestations, e.g. viral infections, - dem'tatological examinations, - lmologic examinations, - examinations of pulmonary on, - monitoring and/or recording of c ers, - monitoring and/or recording of blood key parameters, - monitoring and/or recording of liver function tests, - monitoring and/or recording of other adverse events or side—effects.

Preferably, the patient monitoring of the invention comprises one or more of the following steps, optionally all the steps of: WO 41146 PCT/U82010/049441 complete btood counting (CBC), analysis of liver enzymes, ophthalmologic examinations, and testing y of virai infection or viral serology, e.g. regarding chickenpox, monitoring and/or recording of infections or infestations, e.g. viral ion.

The patient monitoring of the invention may further se establishing an electrocardiogram (ECG), e.g. at starting administration with the medication, and/or vaccinate the patient before starting administration, e.g. t, varicelia zoster virus (VZV).

As herein defined, the patient monitoring of the invention may comprise or more of the above described monitoring steps.

In one ment of the invention, the t monitoring comprises the steps of - monitoring andlor recording of infections or infestations, e.g. viral infections, — performing ophthalmologic examinations, and ally further comprises the steps of - monitoring and/or recording of cardiac disorders for specific category of patients, and/or - performing dermatologicat examinations. in another embodiment of the invention, the patient monitoring comprises the steps of — monitoring and/or recording of infections or infestations, e.g. viral infections, - ophthalmologic examinations, - monitoring and/or recording of cardiac disorders. e.g. for ic category of patients, - liver function tests; and optionally further comprises the steps of - dermatological ations. in yet a further embodiment of the invention, the patient monitoring comprises the steps of - monitoring the heart rate of the patient, — monitoring and/or recording of infections or infestations, e.g. viral infections, - ming ophthalmologic examinations, and optionally r comprises the steps of - ming dermatological examinations.

In yet another embodiment of the invention, the t monitoring comprises the steps of — monitoring and/or recording of infections or infestations, e.g. viral infections, - performing an ophthalmologic examination within the first 1 to 10 after starting administration, ~ observing patients for at least 6 hours after the first dose administration, and optionally further ses the steps of - dermatological examinations.

The patient monitoring may further comprise a step of monitoring and/or recording of liver function tests in case patients develop ms suggestive of hepatic dysfunction. in a red embodiment of the invention, there is provided a method of prescribing fingolimod (FTY720), a phosphate derivative thereof or a pharmaceutically acceptable salt thereof, to a patient in need thereof, in such a way as to limit the possible adverse events before of during administration of fingolimod, n said method comprises the patient monitoring as herein above described.

For example the method of prescribing fingolimod may comprise one or more of the following steps : ~ performing lymphocyte counting, - monitoring and/or recording of vital signs, e.g. blood pressure, e.g. arterial blood pressure, - monitoring and/or recording of infections or infestations, e.g. viral infections, - performing dermatological examinations, - performing lmologic examinations, - performing examinations of pulmonary function, - monitoring and/or ing of cardiac ers, - monitoring and/or recording of blood key parameters, eg. level of serum ALT, - performing iiver function tests, PCT/U82010/049441 - monitoring and/or recording of other adverse events or side-effects, and wherein each of said steps is performed for a specific period of time before and/or during the period of administering the drug.

The specific and regular monitoring of the treated patients may t of one or more of the following steps - performing cyte counting, - monitoring and/or recording of vital signs, e.g. blood pressure, e.g. arterial blood pressure, - monitoring and/or recording of infections or infestations, e.g. viral infections, - ming dermatological ations, - performing ophthalmologic examinations, - performing ations of pulmonary function, - monitoring and/or recording of cardiac disorders, - ring and/or recording of blood key parameters, e.g. level of serum ALT, - performing liver function tests, - monitoring and/or recording of other e events or side—effects, and wherein said steps are performed for a specific period of time before and/or during the period of administering the drug.

Each step may be performed as further explained below.

Preferably, the patient monitoring may consist of one or more of the following steps : - monitoring and/or recording of infections or infestations, e.g. viral infections, during FTY720 therapy, - ophthalmologic examinations as herein defined, - monitoring and/or recording of cardiac disorders for specific ry of patients, - liver function tests in case patients develop symptoms suggestive of hepatic dysfunction, and Optionally further comprises the steps of - dermatological examinations. 2010/049441 The different steps the patient monitoring of the invention are performed at a specific period of time after administration of the first dose.

These steps can be performed as described herein.

In a specific embodiment of the invention, the treated patients are monitored under supervision of medical doctors for a specific period of time after the first dose administration, for the first 1 to 10 hours after the first administration of the S1P receptor modulator or agonist, e.g. imod ,a phosphate derivative thereof or a pharmaceutically acceptable salt thereof, for at least 6 hours after the first dose administration.

According to the invention, one or more of these steps, e.g. monitoring and/or recording of cardiac disorders, are performed at least 4 hours after the first dose administration, e.g. at least for 6 hours after the first dose administration, or at least 8 hours after the first dose administration, e.g. 3 to 8 hours after the first dose administration, e.g. 4 to 6 hours after the first dose administration, e.g. 4 to 6 hours after the first dose stration. Preferably monitoring and/or recording of cardiac disorders are performed about 6 hours after the first dose administration The step of monitoring and/or recording of cardiac disorders may t of observing ts during that period of time after the first dose administration, e.g. during at least 4 hours after the first dose administration, e.g. at least for 6 hours after the first dose stration, or at least 8 hours after the first dose administration.

According to the invention, the cardiac disorders which are monitored and/or recorded comprise but are not limited to ardia and high-grade AV block.

According to the invention, the infections which are recorded or monitored are for example viral infections, e.g. varicella zoster virus (VZV), influenza viral infection, herpes viral infection, lower respiratory tract infection, e.g. bronchitis and pneumonia. in an embodiment of the invention, the monitoring of infections or infestations is performed within the first three months after the first dose administration, e.g. within the first two months after the first dose administration. in another ment of the invention, the monitoring of infections or infestations is performed throughout administration of the medication.

PCT/U82010/049441 Prior to starting administering the S1P receptor modulator or t, the patient may be tested for history of infections, e.g. viral infection, in particular chickenpox. In case the searched serology is negative, the patient may be vaccinated, e.g. against lla zoster virus or influenza virus.

The monitoring or recording of infections or infestations, e.g. virai infections, may be performed with medical techniques available, for example through complete blood counting (CBC) and/or lymphocytes counting.

According to the invention, the ophthalmologic examination preferably comprises the checking and/or monitoring of disturbances in visual acuity, e.g. appearance of r edema. in a specific embodiment of the invention, eye examinations inciude at least one of eye history, visual acuity, dilated ophthaimoscopy, Optical Coherence Tomography (OCT), evaluation of the fundus. Such examinations are preferably performed by an lmoiogist.

According to the invention, ophthalmologic examination may be performed after initiating the administration with S1 P receptor modulator or agonist , e.g. after commencing FTY720 therapy, e.g. within the first i to 12 months, e.g. 2 to 10 months, e.g. 2 to 6 months, e.g. 2 to 5 , e.g. 3 to 4 . Additional ophthalmologic examinations may be performed as needed based on patient ms, e.g. at intervals determined by the ophthalmologist.

According to the invention, the lmologic examination may comprising the steps of 1) identifying the eye diseases history of the t to be treated before commencing the treatment with , 2) having ophthalmologic examinations performed as herein above mentioned, e.g. 3 to 4 months after commencing the treatment with FTY720, ably by an lmologist, and optionally 3) having additional ophthalmologic examinations performed based on patient symptoms, e.g. at intervals determined by the ophthalmologist.

Ophthalmologic examination may also be performed before starting the administration with S1 P receptor modulator or agonist, e.g. before starting FTY720 therapy. This embodiment is particularly adapted for specific patients categories, for example in case of ts who have an eyes disease or disorder, and/or history of diabetes or uveitis.

According to the invention, the dermatological examination may comprise the checking of appearance e.g. of neoplasms, skin malignancies, melanoma, squamous cell carcinoma, basal cell carcinoma. Dermatological screening may be performed prior to, or shortly after initiation of therapy. In a specific embodiment of the invention, dermatological screenings are performed annually in patient receiving the StP receptor modulator or agonist, e.g.

FTY720, a phosphate derivative thereof or a ceutically acceptable salt thereof.

Dermatological screening may be performed by a physician, e.g. a dermatologist. in another embodiments, such screening is performed more frequently, e.g. by the patient himself. ing to the invention, the examinations of ary function may be performed by spirometry, pulmonary function tests, e.g. FEV1, FVC, FEF25-75%, DLCO, diffusion ty for carbon monoxide, or chest high resolution ed tomography (HRCT). in a specific embodiment of the invention the pulmonary function test (PFT) is performed few hours to a few days after the first administration, for example at the day of the first administration, for example from 2 to 12 hours after the first drug administration, for example from 2 to 8 hours after the first drug administration, for example from 2 to 6 hours after the first stration, for example at 6-hour after the first administration. A second PFT may be performed a few days after the first administration, for e from 2 to 10 days after the first drug administration, for example from 3 to 8 days first drug administration, for example abut a week after the first drug administration. in a specific ment of the invention the level of liver enzyme, e.g. serum ALT, is evaluated at initiation of therapy and optionally periodically thereafter. Continuous evaluation is ularly adapted in case of patients who develop symptoms suggestive of hepatic dysfunction.

According to the invention, the liver function tests may be performed for ic category of ts, e.g. patients who develop symptoms suggestive of hepatic dysfunction, e.g. nausea, ng, nal pain, anorexia, orjaundice.

PCT/U82010/049441 According to the invention, monitoring and/or recording of liver function tests may comprise any one of the steps of 1) identifying the level of liver enzyme, e.g. semm ALT, in the patient to be treated before the first administration of the S‘iP receptor modulator or agonist , e.g. FTY720, a phosphate derivative thereof or a ceutically acceptable salt f, and administering the first dose only if alanine aminotransferase (ALT) level is not more than 2 times the upper limit of the normal range (ULN) 2) identifying the level of liver enzyme, e.g. serum ALT, in the patient under therapy, and discontinue the y in patients experiencing jaundice or ion of liver enzyme is more than 5 times the upper limit of the normal range (ULN).

The patient monitoring of the invention may comprise a step of observing the patient for the first 1 to 10 hours after the first administration of the 31 P receptor modulator or agonist , e.g. fingolimod , a phosphate derivative thereof or a pharmaceutically acceptable salt thereof, e.g. the first 2 to 8 hours after the first administration, e.g. the first 3 to 9 hours after the first administration, e.g. the first 2 to 8 hours after the first stration, e.g. the first 4 to 7 hours after the first administration, e.g. the first 6 hours, e.g. the first 5hours, e.g. the first 4 hours after the first administration of said 81 P receptor tor or agonist , e.g. fingolimod , a phosphate derivative thereof or a phannaoeutically acceptable salt thereof. For example, the patient monitoring of the invention may se a step of observing the patient at least 2 hours after the first administration of said StP receptor modulator or agonist , e.g. fingolimod , a phosphate derivative thereof or a ceutically acceptable salt thereof, e.g. at least 4 hours after the first stration, e.g. at least 6 hours after the first administration.

According to the present invention, there is provided a method for treating an matory or autoimmune disease or disorder in a patient in need thereof, comprising administering to said patient a therapeuticaily effective amount of S1P receptor modulator or agonist, wherein specific ters of the patient are checked before initiating said treatment, and if necessary, the treatment regimen is adapted and/or a second drug which mitigates the adverse events which could possibly occur.

The invention further pertains to a S1P receptor modulator or t, e.g. FTY720, a phosphate derivative thereof or a pharmaceutically acceptable salt thereof, for use in a method of treating an matory or an autoimmune disease or disorder, e.g. multiple 2010/049441 sclerosis, n said method comprises the steps of checking specific parameters of the patient before initiating said treatment, and if necessary adapting the ent regimen thereof and/or administering a second drug which mitigates the adverse events which could possibly occur.

Said parameters are selected from signs of infections or infestations (e.g. viral infections), visual acuity, presence of eye disease, liver enzymes, blood re, blood analysis (e.g. complete blood count), , electrocardiogram (ECG), pulmonary function, presence of skin disease or disorder, and liver function . in a specific embodiment, these parameters are selected from signs of infections or infestations (e.g. viral infections), visual acuity, liver enzymes and biood pressure, and optionally heart rate.

For exampie, a ECG is performed before initiating administration with said S1P or modulator or agonist.

These parameters may also be checked throughout the treatment with said 81P receptor modulator or agonist.

In a specific embodiment of the invention there is provided a method for administering a S1P receptor modulator or agonist, e.g. fingoiimod, a ate derivative thereof or a pharmaceutically able salt thereof, in a patient in need thereof, comprising the steps of ) identifying the eye diseases history of the patient to be treated before commencing the treatment with said 81 P receptor modulator or t, ) having ophthalmologic examinations performed as herein above mentioned, eg. 3 to 4 months after commencing the treatment with said SlP receptor moduiator or agonist, preferably by an ophthalmologist, and ally ) having additional ophthalmologic examinations performed based on patient symptoms, eg. at intervals determined by the ophthalmoiogist.

A method for treating an atory or autoimmune disease or disorder (for example multiple sis), and limiting the symptoms associated thereof or ng the severity of the disease, in a patient in need thereof, comprising the steps a.), b.) and c.) as defined above.

WO 41146 PCT/U52010/049441 3.. a S1P receptor modulator or agonist , e.g. FTY720, a phosphate derivative thereof or a pharmaceutically acceptable salt thereof, for use in a method for treating an inflammatory or an autoimmune disease or er, e.g. multiple sclerosis, wherein said method comprises the steps a), b.) and c.) as defined above. a S1P receptor modulator or agonist , e.g. FTY720, a phosphate derivative thereof or a pharmaceutically acceptable sait thereof, for use in the treatment of an inflammatory or an autoimmune disease or disorder, e.g. le sclerosis, wherein said treatment comprises the steps a.), b.) and c.) as defined above.

FTY720, a phosphate derivative thereof or a phannaceutically acceptable salt thereof, e.g. the hydrochloride salt of FTY720, for use in a method for the treatment of multiple sclerosis, wherein said treatment comprises the steps of a‘) identifying the eye diseases history of the t to be treated before commencing the ent with FTY720, phosphate derivative or pharmaceuticaliy acceptable salt thereof, ) having ophthalmologic examinations performed as herein above mentioned, e.g. 3 to 4 months after commencing the ent with , phosphate derivative or pharmaceutically able salt thereof, preferably by an ophthalmologist, and optionally ) having additional ophthalmologic examinations performed based on patient symptoms, e.g. at intervals determined by the ophthalmologist.

FTY720, a phosphate derivative thereof or a phannaceuticaily acceptable salt thereof, e.g. the hydrochloride salt of FTY720, for use in the treatment of multiple sclerosis, wherein said treatment comprises the steps a'.), b’.) and c’.) as d above. in a specific embodiment of the invention there is provided A method for stering a S1P receptor tor or agonist, e.g. fingolimod, a phosphate derivative thereof or a pharmaceutically acceptable salt thereof, in a patient in need thereof, comprising the steps of d) identifying the level of liver enzyme, e.g. serum ALT, in the patient to be treated before the first administration of said S1P receptor modulator or agonist and administering the first dose only if ALT level is not > 2x ULN, and e) fying the level of liver enzyme, e.g. serum ALT, in the patient under y, and discontinue the therapy in patients experiencing jaundice or elevation of liver enzyme >5x ULN. 8- A method for treating an inflammatory or autoimmune disease or disorder (for example multiple sclerosis), and limiting the ms associated thereof or reducing the severity PCT/U52010/049441 of the disease, in a patient in need thereof, comprising the steps d.), and e.) as defined above. 9- A S1P or modulator or agonist, e.g. FTY720, a phosphate tive thereof or a aceutically acceptable salt thereof, for use in a method for treating an inflammatory or an autoimmune disease or disorder, e.g. multiple sclerosis, wherein said method comprises the steps d.), and e.) as defined above.

- A S1P receptor modulator or t, e.g. FTY720, a phosphate derivative thereof or a ceutically acceptable salt thereof, for use in the treatment of an inflammatory or an autoimmune disease or disorder, e.g. multiple sclerosis, wherein said treatment comprises the steps d.), and e.) as defined above. 11- F‘lY'lZO, a phosphate derivative thereof or a pharmaceutically acceptable salt thereof, e.g. the hydrochloride salt of FTY720, for use in a method for the treatment of le sclerosis, wherein said method comprises the steps of d‘ ) identifying the level of liver enzyme, e.g. serum ALT, in the t to be treated before the first administration of F l Y720, a phosphate derivative thereof or a pharmaceutically acceptable salt thereof, and administering the first dose only if ALT level is not > 2x ULN. e’ ) identifying the level of liver enzyme, e.g. serum ALT, in the patient under y, and discontinue the therapy in patients experiencing jaundice or elevation of liver enzyme >5x 12- FTY720, a phosphate derivative thereof or a phannaceutically acceptable salt thereof, e.g. the hydrochloride salt of FTY720, for use in the ent of multiple sclerosis, wherein said treatment comprises the steps d’.), and e’.) as defined above. in yet another embodiment of the invention there is provided 13~A method for administering a S1P receptor modulator or agonist , e.g. , a phosphate tive f or a pharmaceutically acceptable salt thereof, in a patient in need thereof and receiving concomitant beta—blocker therapy, comprising the steps of f) measuring heart rate and/or blood pressure of the patient to be treated before commencing the treatment with said StP receptor modulator or agonist, 9) either measuring heart rate every 3 to 5 hour, e.g. every four hour, for at least 6 hour hereafter, and/or perform an ECG 3 to 6 hours, eg. 4 to 6 hours, post-dose, and h) administering an adequate treatment if bradyarrhythmia-related symptom is seen under step 9), e.g. atropine or isoprenaline.

PCT/U82010/049441 In one embodiment, that method refers to a method for administering FTY720, a phosphate derivative thereof or a pharmaceuticaliy acceptable salt thereof, e.g. the hydrochloride salt of FTY720, in a patient affected by multiple sclerosis. 14—A method for treating an inflammatory or autoimmune disease or disorder (for example multiple sclerosis), and limiting the ms associated thereof or reducing the severity of the disease, in a patient in need f, sing the steps f.), g. ) and h.) as defined above.

-A S‘lP receptor modulator or agonist, e.g. , a phosphate derivative thereof or a pharmaceutically acceptable salt thereof, for use in a method for ng an inflammatory or an autoimmune disease or disorder, e.g. multiple sclerosis, wherein said method comprises the steps f.), g. ) and h.) as defined above. 16- A S1P receptor modulator or agonist, e.g. , a phosphate derivative thereof or a ceutically acceptable salt f, for use in the treatment of an inflammatory or an autoimmune e or disorder, e.g. multiple sclerosis, wherein said treatment comprises the steps f.), g. ) and h.) as defined above. 17- FTY720, a phosphate derivative thereof or a pharmaceutically acceptable salt thereof, e.g. the hydrochloride salt of FTY720, for use in a method for the treatment of multiple sclerosis, wherein said method comprises the steps of f‘ ) measuring heart rate and/or blood pressure of the patient to be treated before commencing the treatment with FTY720, a phosphate derivative thereof or a pharmaceutically acceptable sait thereof, 9’ ) either measuring heart rate every 3 to 5 hour, e.g. every four hour, for at least 6 hour hereafter, and/or perform an ECG 3 to 6 hours, e.g. 4 to 6 hours, post-dose, and h’ ) administering an adequate ent if bradyarrhythmia-reiated m is seen under step 9), e.g. atropine or isoprenaline. 18- FTY720, a phosphate derivative thereof or a phannaceutically acceptable salt thereof, e.g. the hydrochloride salt of FTY720, for use in the treatment of multiple sclerosis, wherein said ent ses the steps of f’.), g’. ) and h'.) as defined above.

In yet another embodiment of the invention there is provided PCT/U82010/049441 19-A method for stering a S1P receptor modulator or agonist , e.g. FTY720 , a ate derivative thereof or a pharmaceutically acceptable salt thereof, in a patient in need thereof, comprising the steps of i) observing the patient after the first dose administration for an observing period as defined hereinabove, e.g. for at least 6 hours j) measuring heart rate of the patient his period, k) either releasing the patient if the if the is > 40 bpm, or of 40-60 bpm e.g. in case this value is not the lowest heart rate measured during the 6-hour observation period; or maintaining the patient in an appropriate setting.

Such a method is particularly adapted to patients with low g heart rate (e.g. lower than 50) or those taking beta blockers, or having high grade atrio-ventricular (AV) block sick-sinus syndrome. in a specific embodiment, that method refers to a method for administering , a phosphate derivative thereof or a phannaceutically acceptable salt thereof, e.g. the hydrochloride salt of FTY720, in a patient ed by multiple sclerosis.

The present invention also provides - FTY720, a phosphate derivative thereof or a pharrnaceutically acceptable salt thereof, e.g. the hydrochloride salt of FTY720, for use in the treatment of multiple sclerosis, wherein said treatment comprises the steps i.), j. ) and k.) as defined above. 21-FTY720, a phosphate derivative f or a pharmaceutically acceptable salt thereof, e.g. the hydrochloride salt of FTY720, for use in a method of treating multiple sclerosis, wherein said method comprises the steps i.), j. ) and k.) as defined above. in specific cases, e.g. when patients experiencing symptomatic events associated with arrythmia not resolved by the end of the 6 hour observation, day 2 dose may also be performed with an ation period like the first administration, e.g. as described above.

An observation period as defined hereinabove, e.g. 6 hour observation, may also be performed in case of a patient restarting the SP receptor modulator or agonist , e.g.

FTY720, a phosphate tive thereof or a pharrnaceutically able salt thereof, after a drug interruption of more than 4 days, e.g. more than 6 days, e.g. more than 8 days, e.g. more than 10 days, e.g. more than 12 days, e.g. more than 14 days, e.g. more than 18 days, e.g. more than 21 days.

In another embodiment of the invention, there is provided a method for administering FTY720, a phosphate derivative thereof or a pharmaceutically acceptable salt thereof, to a patient in need thereof while lling, limiting or abolishing the possible adverse events associated or in relation to such an administering, wherein the patients at possible risk of showing such events are identified before administering the drug and specific and regular monitoring of the d patients is performed, e.g. by an adequate physician.

The ts at possibly increased risk may be ts selected from patients who have eyes diseases or disorders; patients who show a high ALT level, patients who have hepatic ction, patients who have hypertension; and patients who have heart failure or arrhythmias. It may also concern patient affected by asthma, for example moderate asthma and/or diabetic patients. in another ment, it can be pregnant women.

As herein defined, an eyes e or disorder refers to a disease or disorder impacting eyes, e.g. uveitis, diabetes.

Patients who show a high ALT level refers to patients who show an ALT level of, or superiorto, 2 times than ULN, e.g. before initiating FTY720 treatment) Patients who have heart disorders refers to one or more disorders selected from highgrade AV block, sick sinus syndrome, ic heart disease, congestive heart failure, and arrhythmia. For example, this concerns patients suffering from or at risk of bradyarrhythmia, patients with high grade atrio-ventricular blocks or sick sinus syndrome, patients with a history of syncopal es, or patients under beta blockers or anti- arrhythmic treatment, such as patients under anti—arrhythmic drugs.

According to the invention, there is provided a ic monitoring of patients treated with a StP receptor modulator or agonist , e.g. FTY720, a ate derivative thereof or a pharmaceutically acceptable salt f, wherein said patients are suffering from an inflammatory or an autoimmune disease or disorder, e.g. multiple sis, comprising any one of the following steps of: i) observation , e.g. at least 6 hour, e.g. 4 to 6 hours, during which or at the end of which heart rate is checked, as defined herein, ii) annual skin examination after first dose administration, as defined herein, iii) regular review of liver enzyme, e.g. serum ALT, as defined herein, iv) ophthalmologic examinations 2 to 12 months, e.g. 3 to 4 months, after first dose stration, as defined , v) regular checking of patient visual function, as defined herein.

There is further provided method of administering a S‘lP receptor modulator or agonist, e.g. fingoiimod in the form of FTY720, a ate derivative f or a pharmaceutically acceptable salt thereof, to patients ing from an inflammatory or an autoimmune disease or disorder, e.g. multiple sclerosis, comprising a) ming any ones of the following steps of: i) observation period, e.g. at least 6 hour, e.g. 4 to 6 hours, during which or at the end of which heart rate is checked, as defined herein, ii) annual skin examination after first dose administration, as defined , iii) regular review of liver enzyme, e.g. serum ALT, as defined herein, iv) ophthalmologic examinations 3 to 4 months after first dose administration, as defined herein, v) regular checking of patient visual function, as defined herein; b) if required, interrupting fingoiimod administration based upon the results of one of more of the above steps or changing the treatment regimen and/or administering a second drug.

Step b) may correspond to appearance of adverse events. The second drug may be a drug which mitigates said possible adverse events.

Interrupting fingoiimod administration, changing the treatment regimen and/or administering a second drug, may occur in case of any of the following conditions: bradycardia or atrioventricuiar conduction alities, macular edema or other visual -26— disturbance, skin cancer, altered liver functions or liver injury, infections or hypertension. Duration of the interruption is defined by the physician. interrupting fingolimod administration, changing the ent regimen and/or administering a second drug, may also occur in case the lymphocyte count of the patient becomes abnormally low, or becomes lower than 200/mL.

For example, step a) may se one or more steps of i) monitoring the heart rate of the patient, ii) monitoring infections or ations, e.g. viral infections, and iii) performing ophthalmologic examination within the first 1 to 10 after starting administration.

Therapeutic dosages In a preferred embodiment of the invention the methods for administering FTY720, a ate derivative thereof or a pharmaceutically acceptable salt thereof as defined herein above, in particular the s for treating an inflammatory or autoimmune disease or disorder, limiting the ms associated thereof or the progression thereof, e.g. multiple sclerosis, in a patient in need thereof comprise administering a daily dosage of FTY720, a phosphate derivative thereof or a ceutically acceptable salt thereof, e.g. FTY720 hydrochloride, of not more than 0.5 mg, e.g. of about 0.5mg.

According to the invention there is provided a compound selected from fingolimod (FTY720), a phosphate derivative thereof or a pharmaceutically acceptable salt thereof, e.g. fingolimod hydrochloride, for use in treating or preventing an inflammatory or autoimmune e, whereby said compound is administered in such a way to a patient that the e events possibly associated with administration of said compound are controlled, limited, reduced or abolished. For example, the daily dosage of fingolimod (FTY720), a ate derivative thereof or a pharmaceutically acceptable salt thereof, e.g. fingolimod hydrochloride, does not exceed 0.5mg, e.g. is of about 0.5 mg.

In a specific embodiment of the invention there is provided a method for treating multiple sis, controlling or limiting the symptoms associated f 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 salt thereof, e.g. fingolimod hydrochloride, wherein said daily dosage does not exceed 0.5mg, e.g. is of about 0.5 mg, and wherein the patient is further affected by asthma (for example moderate asthma), by a disease or disorder ing eyes or has an history of eyes es or disorders (for example is affected by uveitis or diabetes), show high-grade AV block, sick sinus me, hepatic dysfunction or hypertension.

In a further embodiment of the invention there is provided a method for treating multiple sclerosis, lling or limiting the symptoms associated thereof or reducing the severity of said disease in a patient in need f, comprising administering a daily dosage of fingolimod (FTY720), a phosphate derivative thereof or a pharmaceutically acceptable salt thereof, e.g. fingolimod hydrochloride, wherein said daily dosage does not exceed 0.5mg, e.g. is of about 0.5 mg, and wherein the t is pregnant.

In yet a further embodiment of the ion there is provided a method for treating multiple sclerosis, limiting the symptoms associated thereof 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 salt thereof, e.g. fingolimod hloride, wherein said daily dosage does not exceed 0.5mg, e.g. is of about 0.5 mg, and wherein the patient is a MS patients who has never received treatment for MS, e.g. de novo patient.

According to the ion, adopting the ent regimen may consist of decreasing the dosage, or increasing the time between two consecutive strations of the 81P receptor modulator or agonist, e.g. fingolimod, a phosphate derivative f or a pharmaceutically acceptable salt thereof. For example it may consist of administering 0.25mg of fingolimod, a phosphate derivative thereof or a pharmaceutically acceptable salt thereof, two times a day. It may also consist of increasing se the dosage of the drug during the first period of administration up to a daily dosage of 0.5mg or 1.25 mg, e.g. adopting a stepwise administration, e.g. a titration.

The present invention pertains to a method for treating multiple sclerosis comprising (a) administering a varied dose of a drug selected from the group consisting of fingolimod (FTY720), a phosphate derivative f or a pharmaceutically acceptable salt thereof in a patient in need thereof, (b) monitoring adverse events occurring in said patient, 2010/049441 (o) ring reduction or abolition of symptoms ated with multiple sclerosis, and (d) determining optimal dose for said patient The daily dose of the drug may be not exceeding 0.5mg. in another embodiment, the daily dose of the drug is above 0.5mg, e.g. is about , e.g. about 1.25mg, e.g. about 1.5mg.

There is also provided a SlP receptor modulator or agonist, e.g. FTY720, a phosphate derivative thereof or a pharmaceutically acceptable salt thereof, for use in a method for treating an inflammatory or autoimmune disease, e.g. multiple sclerosis, wherein said method comprises (a) administering a varied dose of said S1P receptor modulator or agonist in a patient in need thereof, (b) monitoring adverse events occurring in said patient, (c) monitoring reduction or abolition of symptoms associated with said inflammatory or autoimmune disease, and (d) determining optimal dose for said patient .

This method is particularly adapted for , a phosphate derivative thereof or a pharmaceutically able salt thereof, e.g. FTY720 hloride, for treating multiple sclerosis.

When the S1P receptor modulator or agonist is selected from FTY720, a phosphate derivative thereof or a pharmaceutically acceptable salt thereof, e.g. is FTY720 hydrochloride, and the disease is multiple sclerosis, the daily dose of the drug may not be exceeding 0.5mg. in another embodiment, the 81 P receptor modulator or agonist is selected from FTY720, a phosphate derivative thereof or a pharmaceutically acceptable salt thereof, e.g. FTY720 hydrochloride, and the daily dose is exceeding 0.5mg, e.g. is about 1.00mg, e.g. about 1.25mg, e.g. about 1.5mg. in yet a further embodiment of the invention, there is provided a personalized method for treating an inflammatory or autoimmune e or disorder, e.g. multiple sis, in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a SP receptor tor or agonist, wherein said method comprises (a) administering a varied dose of said drug to the patient, (b) ring e events occurring in said patient, (c) monitoring reduction or abolition of symptoms associated with multiple sclerosis, and (d) determining l dose for said patient, wherein said regimen is adapted for treating said disease or disorder and controlling, ng, or abolishing the possible adverse events associated with administering said 81 P receptor modulator or agonist.

The steps(a) to (d) above may also be used in a method for determining a personalized therapeutic treatment regimen of a drug selected from the group consisting of fingolimod (FTY720), a phosphate derivative thereof or a pharmaceutically acceptable salt thereof , in a patient suffering from an inflammatory or autoimmune disease, e.g. multiple sis.

The present invention also pertains a compound selected from FTY720, a ate tive thereof or a pharmaceutically acceptable salt thereof, e.g. FTY720 hydrochloride, for use in a method for treating an inflammatory or autoimmune disease or disorder in a patient in need thereof, wherein said method is personalized, e.g. is adapted for treating said disease or disorder to the specific profile of the patient in such a way that the adverse events associated with stering said StP receptor modulator or agonist are controlled, reduced, or abolished. In such a case, the patient to be treated my be selected from patients who have never received treatment for that disease or disorder, patients suffering or at risk of heart failure or hmias, patients affected by asthma, ts who have eyes diseases or disorders, hepatic dysfunction or hypertension.

The present invention es for a compound selected from FTY720, a phosphate derivative thereof or a pharmaceuticaliy able salt thereof, e.g. FTY720 hydrochloride, for use in treating patients suffering from an inflammatory or an autoimmune disease or er, e.g. multiple sclerosis, wherein the compound is stered through the administration pattern defined above.

The present invention also provides for a compound selected from , a phosphate derivative thereof or a pharmaceutically acceptable salt f, e.g. FTY720 hydrochloride, for use in treating patients suffering from an inflammatory or an or disorder disease, e.g. multiple sis, wherein the compound is administered through the patient monitoring defined above.

Combination In another ment of the invention, the SiP or modulator, e.g. fingolimod (FTY720), a phosphate tive f or a pharmaceutically acceptable salt thereof, e.g. fingolimod hydrochloride, is administered together with a second drug which mitigates the le adverse event associated with administration of fingolimod.

Such a second drug may be administered only in the event that an adverse event, e.g. a side-effect, occurs or increases in intensity or frequency to a level which is not acceptable anymore, e.g. as hereinabove described.

The second drug may be selected from the group consisting of drugs which treat or prevent macular edema, anti-cancer agents (e.g. chemotherapeutic agents), anti—infection agents, anti-hypertensive drugs, anti-bradycardia agents, and mixture f.

Examples of second drug include, but are not limited to, calcium channel blocker (e.g. zem), atenolol, valsartan, When the S1P or modulator or agonist of the invention, 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 which mitigates the possible adverse event associated with administration of fingolimod, the daily dosage of said SiP receptor modulator or agonist may be above 0.5mg, e.g. may be about 1,00mg, e.g. about 1.25mg, e.g. about 1.5mg.

For example there is provided a combination, e.g. a kit, containing a S1P receptor modulator or agonist of the 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- infection agents, anti—microbial , anti—viral therapy, and anti—hypertensive drugs, whereby the dosage of said SiP receptor modulator or t is above 0.5 mg, e.g. is about .

The invention also provides a specific dosage regimen of FTY720 for treating an inflammatory or autoimmune disease or er, limiting the symptoms associated f or the progression thereof, e.g. multiple sis, in a patient in need thereof, comprising administering to said patient a daily dosage of fingolimod (FTY720), a phosphate PCT/USZOIO/049441 derivative thereof or a pharmaceutically acceptable salt thereof, which leads to a reduction of peripheral lymphocyte count of about 70 to 75%, e.g. of about 73%, 75% or 76%. in another embodiment the invention provides a specific dosage regimen of FTY720 for ng an inflammatory or mune disease or disorder, limiting the symptoms associated thereof or the progression thereof, e.g. multiple sclerosis, in 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 f, which leads to a reduction of peripheral lymphocyte count to a level low enough to obtain the therapeutic effect on the disease while controlling, limiting or abolishing the incidence of infections.

Preferably this daily dosage is not more than 0.5 mg of fingolimod 0), a phosphate derivative thereof or a pharmaceutically acceptable salt thereof, e.g. of the hydrochloride salt thereof Utility of the dosage regimen of the invention in treating diseases and conditions as hereinabove specified may be demonstrated in standard animal or clinical tests, e.g. in accordance with the s described hereinafter.

Example 1: Study: Two different daily dosages of fingolimod (0.5 mg and 1.25 mg) have been orally administered to patients with Relapsing-remitting le Sclerosis during 24-month 1292 patients with RRMS from 172 s in 18 countries are randomized to receive oral fingolimod, in a dose of 0.5 mg/day or 1.25 mg/day, or interferon beta1-a 30 ug intramuscularly once a week. Patients randomized to fingolimod e placebo injections once a week, and those randomized to interferon betel-a receive a o pill once a day.

The patients are seen clinically every month for 3 months and every 3 months thereafter.

The Expanded Disability Status Scale (EDSS) is performed every 3 months, the MS Functional Composite (MSFC) every 6 months, and MRl annually. Monitoring by lmic examination, dermatologic ation, ary function tests, chest X-ray and/or CT, Holter monitoring, and echocardiography are performed.

ZOIO/049441 Participants who completed 1 year on treatment are d an optional extension phase.

Those randomized to imod continue on their assigned dose, and those in the interferon beta1-a group are randomized to the 2 fingolimod doses.

There are reduced relapses in both fingolimod groups compared with interferon beta1-a.

For the lower dose, there is a 52% reduction in reiapses vs interferon beta1-a, and a 38% reduction with the higher dose. Results in both flngolimod groups are highly statistically significant vs interferon a, but not statistically different from each other.

End Fioint Interfero Fingolimod Fingolim‘od I P P n beta1-a 0.5 mglday 1.25 mglday 'Annualized‘ l ' _, {com 0.16 < 0.20' 0.33 _ relapse .0001 rate r , V V .1 . . r r The proportion of relapse-free patients is 83% with fingolimod vs 69% in the interferon beta1-a group.

MRI lesion activity shows a reduction in both fingolimod groups in the number of new or newly enlarging T2 lesions and the number of gadolinium-enhancing T1 s at month Observed adverse events include bradycardia and atrioventricular (AV) block, and infections, including 3 herpes viral infections.

. Type interferon Fingolimod 0.5 Fingolimod beta1-a, n mgld, n (%) 1.25 mglday, M) n (%) Basal-cell 1 (0.2) 3 (0.7) carcinoma Squamous-cell 1 (0.2) o carcinoma [Malignant ‘0 ‘3 (0.7) PCT/U$2010/049441 .33.. {melanoma 1 i I [Breast cancer ’0 ’2(0.5) '2 (0.5) Example 2: Study: Patients with moderate asthma are divided into 3 dosing cohorts of 12 patients each. in each cohort, the 12 patients are randomized to FTY720 (0.5mg, 1.25mg, and 2.5mg in cohorts 1, 2, and 3 respectively) or placebo in a 3:1 ratio resulting in 9 patients treated with FTY720 at each dose level and 9 patients d with placebo.

The study consists of a ing period of between 12 and 26 days, baseline and a 10 day treatment period followed by a study completion evaluation (performed 1-? days after the last dose).

Two screening visits are performed, the initial Screening visit and a second visit at Day -7 (+I- 1 day). The initial screening visit (Visit 1) is used to start ary function test (PFT) monitoring to assess ility for the study and to obtain relevant background information and informed consent. The PFT is performed at a clock time similar to the 6-hour post— dose timepoint on Day 1. On Day -7 a PFT is again performed at the ied time. Short- acting [32 agonist use prior to treatment with study medication is also recorded in this 14 day period.

Patients return to the clinic one or 2 days prior to dosing for baseline assessments. PFT ng is assessed at 7 time points during the visit and e baseline evaluations are performed. On Day 1, patients are randomized in a 3:1 ratio to FTY720 or placebo and PFT profiling is assessed at 8 time points (namely pre-dose, then at 1, 2, 3, 4, 5, 6 and 12 hours post-dose). PFT assessments are also performed on Days 2, 3, 7 (all single time points assessed at imately the same clock time as the 6 hours post—dose PFT on Day 1) and Day 10 (7 time points, namely pre-dose and then at 1, 2, 3, 4, 5 and 6 hours post-dose). On each of the days when PFT assessments are performed, a reversibility test follows the last PFT assessment of the day. Short-acting L32 agonist use is also recorded throughout the treatment period up to and including Day 11 (24hours post last dose). 2010/049441 Blood samples are collected on Day 1 at pre-dose and at 1, 2, 4, 6, 8, 12, 16, and 24h postodose, on Days 2, 3 and 7 at 6 hours post-dose and on Day 10 at pre-dose and at 1, 2, 4, and 6h post-dose.

Safety assessments include physical examinations, ECGs, vital signs, spirometry assessments, standard al laboratory evaluations ology, blood chemistry, urinalysis), adverse event and serious adverse event monitoring.

Only one half of each treatment cohort, a maximum of 6 patients, is allowed to start treatment on any given day for safety reasons. At least 1 day (24 hours) separates the l dosing of the first group of patients from the dosing of the second group (and at least 1 further day separates the second group from any subsequent groups required to complete each cohort).

The magnitude and time course of the effect of FTY720 on FEV1 and other pulmonary function tests (FVC, FEF25—75%, and FEV1IFVC) is measured. _R_es_u|t_s_: The magnitude of the bronchoconstriction is primarily assessed by the baseline-adjusted FEV1 AUCO-6h on Day 1. This primary PD variable is defined as the ratio of the AUEC FEV1 over the 6-hour PFT profile on Day 1 divided by the same variable at baseline (Day -1).

This primary PD variable is ed on the log-scale by means of a linear model adjusted for the (log-transformed) baseline FEV1 AUCD-Bh and the treatment group as fixed effects.

The geometric mean baseline-adjusted FEV1 AUCO-6h is obtained from the model for each treatment group; the geometric mean ratio between each FTY720 group and placebo is also obtained along with its 95% Ci, and is back—transformed to obtain the geometric mean percent change from placebo and its 95% Cl.

Additional PD les are calculated: baseline—adjusted FEV1 AUCO—6h on Day 10 and baseline-adjusted FEV1 Emax1-6h on Days 1 and 10. The Emax variables are d as the ratio n Day 1 (or Day 10) and Day -1 ing the minimum from 6 assessments scheduled at 1 to 6 hours post dose. Those variables are d for FEV, as well as for the other PFT parameters (FVC, FEF25.75%, and FEVJFVC) and are analyzed using the same model as forthe primary PD endpoint.

The time-course of the PFT parameters is explored on Day 1 over the 12-hour profile and on Day 10 over the 6-hour profile. The percent change from time-matched baseline in FEV1, FVC, FEF25,75%, and FEV1IFVC is summarized by means of descriptive statistics at ZOIO/049441 each visit/time point. The ansfonned ratio from time-match baseline is analyzed, separately at each post-baseline time point, by means of a linear model adjusted for the time-matched log-transformed baseline value and the treatment group as fixed effect.

For each FTY720 group, the estimate for the mean treatment difference versus placebo and its 95% Cl are obtained from the model and are back-transformed to obtain the geometric mean percent change from placebo and its 95% Ci. No adjustment was made to the P values for multiple testing.

The results show that at a daily dosage of 0.5mg FTY720 is safe and well tolerated in patients with moderate asthma. -36—

Claims (5)

What is claimed is:

1. Use of a therapeutically effective amount of a 81 P receptor modulator or agonist, which is fingolimod in free form, in pharmaceutically acceptable salt form or fingolimod ate, in the manufacture of a medicament for treating multiple sis in a patient in need thereof, n the adverse events possibly associated with administering said 81 P receptor modulator or agonist are controlled, limited or abolished, wherein the daily dosage of said 81 P or modulator or agonist is of about 0.5 mg, and said medicament is d for administration to a patient that is monitored during a specific period of time after the first administration of said medicament wherein the monitoring comprises the steps of a) ring and/or recording of infections or infestations; and b) ming an ophthalmologic examination at least 3 to 4 months after initiating administration of the medicament, wherein the monitoring and/or recording may indicate that the administration of the medication to the patient should be interrupted and/or modified and/or a second drug should be stered which mitigates said adverse effects.

2. The use according to claim 1, wherein the ophthalmologic examination comprises the checking and/or monitoring of appearance of macular edema.

3. The use according to claim 1 or 2 wherein the multiple sclerosis is relapsing remitting multiple sclerosis.

4. The use according to claim 1, substantially as herein described with nce to any one of the Examples thereof.

5. The use according to any one of claims 1 to 3, substantially as herein described.