WO2013055833A1 - Régime posologique pour un agoniste de récepteur de s1p - Google Patents

Régime posologique pour un agoniste de récepteur de s1p Download PDF

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Publication number
WO2013055833A1
WO2013055833A1 PCT/US2012/059619 US2012059619W WO2013055833A1 WO 2013055833 A1 WO2013055833 A1 WO 2013055833A1 US 2012059619 W US2012059619 W US 2012059619W WO 2013055833 A1 WO2013055833 A1 WO 2013055833A1
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dosage
receptor modulator
during
administered
agonist
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PCT/US2012/059619
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English (en)
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Robert Schmouder
Olivier David
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Novartis Ag
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Publication of WO2013055833A1 publication Critical patent/WO2013055833A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Definitions

  • the present invention relates to a dosage regimen of the S1P receptor modulator or agonist, such as fingolimod (FTY720), for example for the treatment of patients suffering from autoimmune diseases or disorders, such as multiple sclerosis (MS).
  • fingolimod fingolimod
  • Fingolimod (FTY720; GilenyaTM; Novartis Pharma AG, Basel, Switzerland) is a sphingosine 1 -phosphate receptor modulator. Fingolimod 0.5 mg once-daily is the first oral therapy approved for relapsing multiple sclerosis in many countries and for highly active relapsing- remitting MS (RRMS) in the European Union.
  • Multiple sclerosis is the chief cause of neurological disability in young adults and the most common demyelinating disorder of the central nervous system.
  • therapies such as interferon- ⁇ and glatiramer acetate, only have modest efficacy and therefore demonstrate only marginal effects on the progression of the disease.
  • these biological agents are administered parenterally and are associated with some adverse effects such as, for example, localized reactions at the injection site and pyretic symptoms. Therefore, there is a strong medical need for an effective oral treatment for multiple sclerosis.
  • fingolimod When administered for the first time, fingolimod may produce a negative chronotropic effect, i.e. may reduce the cardiac rhythm, as described e.g. in "FTY720: Placebo-Controlled Study of the Effect on Cardiac Rate and Rhythm in Healthy Subjects", Robert Schmouder, Denise Serra, Yibin Wang, John M. Kovarik, John DiMarco, Thomas L. Hunt and Marie-Claude Bastien. J. Clin. Pharmacol. 2006; 46; 895.
  • administration of 1.25 mg of FTY720 may induce a decrease in heart rate of approximately 8 beats/min (BPM).
  • BPM beats/min
  • fingolimod therapy is preferably to be initiated under close medical supervision for several hours in order to check that the cardiac rhythm of the patient who has taken fingolimod is maintained at an acceptable level. This may involve hospitalization of the patients, which makes the treatment more expensive and complicated. There is a need to reduce the time of medical supervision required after first dose administration of fingolimod, even preferably to avoid that supervision or limit it to specific categories of patients.
  • a specific dosing regimen will provide further unexpected benefits, when using the S1 P receptor modulator or agonist of the invention for the treatment of patients suffering from autoimmune diseases or disorders, such as for example multiple sclerosis.
  • the dosing regimen of the invention permits to significantly reduce or even completely eliminate the negative chronotropic effect associated with the first administration of fingolimod, e.g. to reduce or eliminate the need of several hours monitoring after the first drug administration or in case the drug treatment is been reinitiated after an interruption of several days or more.
  • Administering a fingolimod according to the specific dosage regimen of the present invention may also significantly reduce or even completely eliminate the risks that the patients taken this compound suffer from atrio-ventricular (AV) blocks or heart pause.
  • AV atrio-ventricular
  • the specific dosage regimen of the present invention permits to administer a fingolimod to categories of patients for which the ratio risk/benefit may otherwise be less favorable.
  • the titration regime is administered to patients susceptible to or suffering from heart failure or arrythmias, patients with high grade atrio-ventricular blocks or sick sinus syndrome, patients with a history of syncopal episodes, or patients under beta blockers or anti-arrhythmic treatment, such as patients under antiarrhythmic drugs.
  • the titration regime of the invention may also administered in patients who had an interruption or treatment holiday in the maintenance dosage regime e.g. a holiday of greater than 4 days, greater than 6, 7, 8, 10, 12 or 14 days, e.g. an interruption of a period of at least 4 days, e.g. at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 10 days, at least 12 days or at least 14 days..
  • the dosage regimen of the present invention is a regimen for the initiation of fingolimod therapy, which enables the standard daily therapeutic dosage range of fingolimod to be achieved with minimal negative chronotropic effects and/or the AV block effects possibly associated with fingolimod therapy.
  • Preferred S1P receptor agonists or modulators are fingolimod (FTY720), La, 2-amino-2-[2- (4-octyl phenyl) ethyl]propane-1 ,3-diol in free form or in a pharmaceutically acceptable salt form, or a phosphate derivative thereof.
  • the S1P receptor modulator is FTY720 hydrochloride, as shown below:
  • the S1 P receptor modulator is a phosphate derivative of fingolimod, e.g. FTY720-phosphate, as shown below:
  • the present invention provides a novel dosage regimen which is adapted to minimize the negative chronotropic effects and/or the AV block effects possibly associated with S1P receptor modulator or agonist therapy.
  • Heart effects include AV blocks, which include first degree AV blocks (e.g. PR intervals greater then 0.2 seconds) and second degree AV blocks e.g. first degree AV blocks.
  • Heart effects include heart pauses e.g. heart pauses greater than 2 seconds.
  • a S1 P receptor modulator or agonist in the manufacture of a medication, whereby said medication is administered in such a way that during the initial period of treatment the dosage is lower than the therapeutic daily dosage and the dosage is increased, optionally stepwise, or only once, until the standard daily dosage dose is reached, wherein the initial period of treatment is at least 2 weeks, e.g. at least 4 weeks, e.g. 4 weeks. Thereafter the treatment is preferably continued with the standard daily dosage of said S1 P receptor modulator or agonist.
  • the medication is administered in a dosage regimen such that daily decrease in heart rate (e.g. average or minimum daily heart rate) is acceptable or clinically not significant, or that the sinus rhythm of the patient is normal.
  • the daily decrease in heart rate e.g. average or minimum daily heart rate
  • the titration regime of the invetion are administeed in such as way that the daily decrease in heart rate may be of 2-7 bpm, e.g. 2-6bpm, e.g. 3-5 bpm.
  • normal sinus rhythm refers to the sinus rhythm of the patient when not undergoing treatment. The evaluation of normal sinus rhythm is within the ability of a physician. A normal sinus rhythm will generally give rise to a heart rate in the range from 60- 100 bpm.
  • the "initial period of treatment” refers to the period during which the S1 P receptor modulator or agonist is administered at a dosage lower than the
  • the "initial period of treatment” starts with the first administration of the S1P receptor modulator or agonist.
  • the duration of the initial period of treatment is at least of 2 weeks, e.g. at least of 4 weeks.
  • the initial period of treatment is up to 30 days, e.g. 28 days, e.g. 29 days.
  • the duration of the initial period of treatment may also be e.g. about four weeks, e.g. about a month, e.g., 5 weeks, e.g. more than one months, e.g. 2 months.
  • the initial period of treatment is 7 to 30 days, e.g. 7 to 28 days, e.g. 1 to 2 weeks or 7 to 14 days.
  • the initial period of treatment may also be of 2 to 3 weeks, or 3 to 4 weeks. It can also be e.g. 1 to 4 weeks or 2 to 4 weeks.
  • therapeutic daily dosage refers to the required daily maintenance dose of the drug which is given to the patients for treating or preventing the disease to be treated or prevented.
  • therapeutic daily dosage corresponds to the therapeutically effective dosage.
  • the therapeutically effective dosage refers to the dosage of the S1 P receptor modulator or agonist which is necessary to effectively treat the intended disease or condition (i.e. so that the subject shows reduced signs or symptoms of rebound of the disease to be treated or prevented, and preferably no signs and symptoms at all).
  • the S1 P receptor modulator or agonist of the invention may be administered at a dosage e.g. up to 10-fold less, e.g. up to 9-fold less, e.g. up to 8- fold less, e.g. between 8- and 9-fold less, e.g. up to 4-fold less, e.g. 4-fold less, e.g. 2-fold less, than the standard daily maintenance dose, e.g. than the therapeutic dose.
  • the dosage of the S P receptor modulator or agonist of the invention during the initial period of treatment is increased stepwise in defined increments up to the standard daily dosage of the S1 P receptor modulator or agonist.
  • the dosage of said S1 P receptor modulator or agonist during the initial period of treatment as hereinabove defined, e.g. during the initial 2 weeks or 4 weeks or more, is increased at least once.
  • the same dosage is administered during the first week or the first 2 weeks of treatment, and then an increased dosage is administered during the following weeks, e.g. the following 2 weeks.
  • a first dosage that is at least 4-time lower than the therapeutic dosage is administered during 2 weeks and a second dosage at least 2-time lower than the therapeutic dosage is administered during the following two weeks.
  • the dosages may be increased by multiplying each preceding dosage by about 1.5 or more, e.g. by 2 or more, e.g. by 2.
  • the first administered dosage can be 4-time lower than the therapeutic dosage, and then the administered dosage can 2-time lower than the therapeutic dosage, and then the therapeutic dosage is administered.
  • the same dosage may be administered for e.g. one week, e.g. at least one week, e.g. 2 weeks, e.g. at least 2 weeks before increasing the dosage further.
  • the dose may be about 10-fold less, about 9-fold or between 9- and 8-fold less than the standard daily dosage, e.g. than the therapeutic dose, during e.g. one week or two weeks.
  • the dosage may be increased to a daily dosage which is about 4-fold less than the standard daily dosage, during e.g. one week or two weeks.
  • the dosage may be further increased to a daily dosage which is about 2-fold less than the standard daily dosage, during e.g. one week or two weeks.
  • treatment can be continued at the standard daily dosage.
  • the daily dosage is further increased to a daily dosage which is about 1.5-fold less than the standard daily dosage, during e.g. one week or two weeks.
  • a dosage about 4-fold less than the standard daily dosage e.g. than the therapeutic dose, is administered, e.g. during one, 2 or 4 weeks, and then an increased dosage of about 2-fold less than the standard daily dosage is
  • each subsequent incremental dosage increase is administered during 1 , 2, 3 or 4 weeks, preferably during 2 or 4 weeks.
  • each subsequent incremental dosage is administered after one week.
  • One or more dosage increases may be performed until the standard daily dosage is given.
  • the S1 P receptor agonist is fingolimod (FTY720); a pharmaceutically acceptable salt thereof, e.g. the hydrochloride salt thereof; or a phosphate derivative thereof, e.g. FTY720-phosphate.
  • an example of standard daily dosage may be a daily dosage of up to 0.5mg, for example the dosage may be 0.5 mg, e.g. 0.25mg.
  • the highest dose of the S1P receptor modulator or agonist of the invention given during the period before administering the therapeutic dosage may be up to 0.4 mg, e.g. up to 0.35mg or up to 0.25mg, e.g. about 0.310mg, e.g. about 0.325mg, e.g. about 0.355mg, e.g. about 0.375mg.
  • the highest first administered dosage may be comprised between 0.01 mg and 0.30 mg, e.g. between 0.01 mg and 0.15 mg, e.g. between 0.050 mg and 0.125mg, e.g. between 0.050 mg and 0.125mg.
  • the highest first administered dosage may be about 0.1mg, e.g. about 0.125mg, e.g. about 0.06mg.
  • a particularly preferred dosage range of the S1P receptor modulator or agonist of the invention during the initial period of treatment as hereinabove defined is e.g. 0.1-0.5 mg, or 0.125-0.250 mg, or 0.125-0.375 mg, or 0.125-0.500 mg, or 0.25-0.50 mg, or 0.06-0.50 mg, or 0.125-0.250 mg, or 0.060-0.125 mg, or 0.060-0.250 mg or 0.060-0.375 mg.
  • it may be a regimen of 0.125mg/0.25mg, respectively, during the initial period of 2 weeks, during when the same dosage is given for one week, or during the initial period of one month during when the same dosage is given for 2 weeks. Thereafter the treatment is continued with the standard daily dosage, e.g. a dosage of 0.5 mg.
  • the standard daily dosage e.g. a dosage of 0.5 mg.
  • it may be a regimen of 0.125mg/0.25mg/0.375mg, respectively, e.g. during the initial period of 3 weeks or more, e.g. the same dosage being administered one or two weeks. Thereafter the treatment is continued with the standard daily dosage, e.g. a dosage of 0.5 mg.
  • it may be a regimen of 0.06mg/0.125mg/0.25mg/0.375mg, respectively, e.g. during the initial period of 4 weeks or more, e.g. the same dosage being administered one or two weeks. Thereafter the treatment is continued with the standard daily dosage, e.g. 0.5mg.
  • Such regimens are particularly adapted for FTY720 or FTY720 hydrochloride.
  • Preferred medications comprise medication for patients suffering from chronic long term diseases, such as autoimmune diseases, e.g. multiple sclerosis, Polymyositis, lupus nephritis, rheumatoid arthritis, inflammatory bowel diseases or psoriasis.
  • medications are medications for patients suffering from multiple sclerosis, for example relapse remitting multiple sclerosis (RRMS) or primary progressive multiple sclerosis (PPMS), e.g. for patients suffering from RRMS.
  • RRMS relapse remitting multiple sclerosis
  • PPMS primary progressive multiple sclerosis
  • the dosage regimen of the present invention is particularly useful for treating patents at risk of cardiac side effects, for example patients at risk of heart failure, arrythmias, patients with high grade atrio-ventricular blocks or sick sinus syndrome, patients with a history of syncopal episodes, or patients requiring or under beta blockers, or patients requiring or under antiarrhythmic treatment, such as patients under treatment with Class la (e.g. quinidine, procainamide) or Class III anti-arrhythmic drugs (e.g., amiodarone, sotalol).
  • Class la e.g. quinidine, procainamide
  • Class III anti-arrhythmic drugs e.g., amiodarone, sotalol
  • the present invention also provides:
  • a S1 P receptor modulator or agonist of the invention preferably fingolimod in free form or in a pharmaceutically acceptable salt form, e.g the hydrochloride salt thereof, in the manufacture of a medication, whereby said medication is administered as hereian above defined.
  • a S1 P receptor modulator or agonist of the invention preferably fingolimod in free form or in a pharmaceutically acceptable salt form, e.g. the hydrochloride salt thereof, in the manufacture of a medication, whereby said medication is at a daily dosage lower than the therapeutic daily dosage during an initial period of at least 2 weeks, e.g. during 4 weeks, before administering the therapeutic daily dosage.
  • a S1 P receptor modulator or agonist of the invention preferably fingolimod in free form or in a pharmaceutically acceptable salt form, or a phosphate derivative thereof, e.g. the hydrochloride salt thereof, in the manufacture of a medication, whereby said medication is administered in such a way that before administering the therapeutic daily dosage, the administered dosage is escalated stepwise with at least one dose increment, and wherein the same dosage is administered during at least one week, e.g. during two weeks, before being increased.
  • a S1 P receptor modulator or agonist of the invention preferably fingolimod in free form or in a pharmaceutically acceptable salt form, or a phosphate derivative thereof, e.g. the hydrochloride salt thereof, in the manufacture of a medication, whereby said medication is administered in such a way that the first administered dosage is at least 4-time lower, e.g. at least 9-times, e.g. between 9- and 8-time lower than the therapeutic dosage and is administered for at least one week.
  • a S1 P receptor modulator or agonist of the invention preferably fingolimod in free form or in a pharmaceutically acceptable salt form, or a phosphate derivative thereof, e.g. the hydrochloride salt thereof, in the manufacture of a medication, whereby said medication is administered in such a way that before administering the therapeutic dosage a first dosage that is at least 4-time lower than the therapeutic dosage is administered during 2 weeks, a second dosage at least 2-time lower than the therapeutic dosage is administered during the following two weeks.
  • a S1 P receptor modulator or agonist of the invention preferably fingolimod in free form or in a pharmaceutically acceptable salt form, or a phosphate derivative thereof, e.g. the hydrochloride salt thereof, in the manufacture of a medication, whereby said medication is administered in such a way that during the initial 2 to 4 weeks of treatment the dosage of said S1P receptor modulator or agonist is not more than 10% or not more than 25% of the standard daily dose of the S1 P receptor modulator or agonist.
  • S P receptor modulator or agonist as defined under 1.1 to 1.6, in the manufacture of a medication, whereby said medication is administered in such a way to a subject that the possible risk of AV block is limited or reduced to a level clinically not significant.
  • S1 P receptor modulator or agonist as defined under 1.1 to 1.6, in the manufacture of a medication, whereby said medication is administered in such a way to a subject that the sinus rhythm of the patient is normal.
  • arrhythmias e.g. requiring or under treatment with Class la (e.g. quinidine, procainamide) or Class III anti-arrhythmic drugs (e.g. amiodarone, sotalol), or a patient requiring or under beta-blocker therapy.
  • Class la e.g. quinidine, procainamide
  • Class III anti-arrhythmic drugs e.g. amiodarone, sotalol
  • fingolimod in free form or as a pharmaceutically acceptable form, or the hydrochloride salt thereof, in the manufacture of a medication, whereby said medication is administered, after an initial regimen as hereinabove defined, at a daily dosage of about 0,5mg or less as herein above defined.
  • a chronic long term diseases such as an autoimmune disease, e.g. multiple sclerosis, e.g. RRMS.
  • an autoimmune disease e.g. multiple sclerosis, e.g. RRMS
  • fingolimod in free form or as a pharmaceutically acceptable form, e.g. the
  • a method of ameliorating or preventing a negative chronotrophic side effect associated with fingolimod treatment of a subject suffering from an autoimmune disease comprising administering fingolimod , in free form or as a pharmaceutically acceptable form, e.g. the hydrochloride salt thereof to the subject in need thereof, at a daily dosage which is lower than the standard daily dosage during an initial treatment period and raising the daily dosage stepwise up to the standard daily dosage, wherein said initial period is of at least 2 weeks, e.g. of one month or more.
  • a method as defined under 2.1 or 2.2 for treating multiple sclerosis is a method as defined under 2.1 or 2.2 for treating multiple sclerosis.
  • hydrochloride salt or FTY720 phosphate
  • a method of ameliorating or preventing a negative chronotrophic side effect associated with a treatment of an autoimmune disease using fingolimod comprising administering fingolimod in free form or a pharmaceutically acceptable salt thereof, e.g. hydrochloride salt, or FTY720 phosphate, at a daily dosage which is lower than the standard daily dosage during an initial treatment period of at least 2 weeks or one month, and raising the daily dosage, optionally stepwise, up to the standard daily dosage.
  • a pharmaceutically acceptable salt thereof e.g. hydrochloride salt, or FTY720 phosphate
  • a chronic long term diseases as herein above defined, e.g. an autoimmune disease, e.g. multiple sclerosis, e.g. RRMS, in a patient who is at risk of heart failure
  • the method comprising administering the S1 P receptor modulator or agonist of the invention according to the rdosing regime as defined herein.
  • a pharmaceutical composition comprising fingolimod in free form or a pharmaceutically acceptable salt thereof, e.g. hydrochloride salt, or FTY720 phosphate, for the treatment of a long chronic disease in a patient, whereby the composition comprises a daily dosage which is up to 10-fold lower than the standard daily therapeutic dosage and , whereby the composition is to be administered during about one month, e.g. 28 days, prior to commencing the administration of fingolimod at the standard daily therapeutic dosage.
  • a pharmaceutically acceptable salt thereof e.g. hydrochloride salt, or FTY720 phosphate
  • kits containing daily units of medication of the S1 P receptor modulator or agonist of the invention e.g. fingolimod in free form or a pharmaceutically acceptable salt thereof, e.g. hydrochloride salt, or FTY720 phosphate, of varying daily dosage, whereby said doses are lower than the standard daily dosage, and wherein each dosage is to be administered for one week or for two weeks.
  • the kit comprises unit doses of 0.125mg of fingolimod and unit doses of 0.25mg of fingolimod.
  • the kit may further comprise unit doses of 0.375mg of fingolimod.
  • the kit comprise usnit doses of 0.5mg of fingolimod.
  • kits comprising units of medication of a S1P receptor modulator or agonist as defined herein for administration according to the dosage regimen defined herein, whereby one or more low-dose units of a dose strength below the standard daily dose of the S1 receptor agonist of the invention are provided for the initial period of treatment as herein above defined, e.g. the first month of treatment.
  • kits containing units of medication of an S1 P receptor modulator or agonist as defined herein of varying daily dosage whereby said kit contains a) at least one of the following: about 1/8, about 1 ⁇ 4, about 1/2, about 1/1.5, of the standard dose of the S1 P receptor modulator or agonist, respectively, and b) optionally units for the standard daily dosage of the S1 P receptor modulator or agonist.
  • Each dosage may be provided for at least one week administration, e.g. for two weeks.
  • kits containing units of medication of an S1 P receptor modulator or agonist as defined herein of varying daily dosage whereby said kit contains a) about 1 ⁇ 4 and about 1/2, of the standard dose of the S1P receptor modulator or agonist, respectively, and b) optionally units for the standard daily dosage of the S1P receptor modulator or agonist, and wherein each dosage is provided for at least one week administration, e.g. for two weeks.
  • kits as defined above under 4.0 to 4.3 comprising fingolimod in free form or as a pharmaceutically acceptable salt, e.g. hydrochloride salt thereof, wherein said kit contains at least one unit dose of 0.4 mg, 0.35mg or 0.25mg fingolimod, e.g. comprise 7 to 14 unit doses of 0.4 mg, 0.35mg or 0.25mg fingolimod .
  • a kit as defined above under 4.0 to 4.3 comprising fingolimod in free form or as a pharmaceutically acceptable salt, e.g.
  • kits contains at least one unit dose of about 0.31 Omg, 0.325mg, 0.355mg or 0.375mg of fingolimod, e.g. comprise 7 to 14 unit doses of 0.310mg, 0.325mg, 0.355mg or 0.375mg of fingolimod.
  • kits contains at least one unit dose of 0.06mg of fingolimod, e.g. the kits contains 7 to 14 unist doseases of 0.06mg of fingolimod.
  • kits contains a) 7 to 14 dose units of 0.125mg of fingolimod, and b) 7 to 14 dose units of 0.25mg of fingolimod, and optionally dose units of 0.5 mg of fingolimod.
  • the kit comprises 14 dose units of 0.125mg of fingolimod, and 14 dose units of 0.25mg of fingolimod; or 7 dose units of each dose strength.
  • kits contains a) 7 to 14 dose units of 0.125mg of fingolimod, b) 7 to 14 dose units of 0.25mg of fingolimod, c) 7 to 14 dose units of 0.375mg of fingolimod, and optionally dose units of 0.5 mg of fingolimod.
  • the kit comprises 7 dose units of 0.125mg of fingolimod, 7 dose units of 0.25mg of fingolimod and 7 dose units of 0.325mg of fingolimd; or 14 dose units of each dose strength.
  • kits contains a) 7 to 14 dose units of 0.06mg of fingolimod, b) 7 to 14 dose units of 0.125mg of fingolimod, c) 7 to 14 dose units of 0.250mg of fingolimod, d) 0.375mg of fingolimod, and optionally dose units of 0.5 mg of fingolimod.
  • the kit comprises 7 dose units of 0.06mg of fingolimod, 7 dose units of 0.125mg of fingolimod, 7 dose units of 0.25mg of fingolimod and 7 dose units of 0.375mg of fingolimod; or 14 dose units of each dose strength.
  • the kit may comprise just one low dose unit of medication at a dosage strength corresponding to an initial dosage of the S1P receptor modulator or agonist of the invention.
  • a patient may then take one unit of the low dose medication for a specified number of days and then, optionally, two or more units per day on subsequent days until therapy is commenced with a unit of medication that comprises the standard daily dose of the S1 P receptor agonist.
  • the kit may comprise a number of low-dose units of medication with a range of dosage strengths so that the patient can be administered one dosage unit per day, but the amount of S1P receptor modulator or agonist administered can be titrated upwards until therapy commences at the standard daily dosage.
  • the daily units of said S1 P receptor modulator or agonist may be of about 1/8 or 1/9, about 1 ⁇ 4, about 1 ⁇ 2 and about 1/1.5, of the standard dose of said S1 P receptor modulator or agonist, respectively.
  • the daily units of said S1 P receptor modulator or agonist may be of about 1/8, about 1/4 and about 1 ⁇ 2; or about 1/4 and about 1 ⁇ 2, of the standard dose of said S1 P receptor modulator or agonist, respectively.
  • the kit may further comprise units for the standard daily dosage of the S1P receptor modulator or agonist of the invention, e.g. fingolimod, or the hydrochloride salt thereof.
  • the kit may also contain instructions for use.
  • a method for assessing the need or suitability of a patient for a treatment regimen as described above comprising the steps of:
  • the patient may be in the above category if he or she suffers from or is susceptible to heart failure, arrhythmias, high grade atrioventricular blocks or sick sinus syndrome or has a history of syncopal episodes; or is undergoing beta blocker or anti-arrhythmic treatment, e.g. is under treatment with anti-arrhythmic drugs; or has undergone an interruption or treatment holiday in the maintenance dosage regime e.g. a holiday of greater than 4 days, greater than 6, 8, 10, 12 or 14 days.
  • the regimen of S1 P receptor modulator or agonist which is administered to the subject according to the invention may be given either during at the beginning of the disease therapy, e.g. during the initial 14 days, e.g. first month, e.g. first two months. It may also be given after an interruption of the therapy, for example an interruption of more than 10 days, more than 12 days, e.g. more than 14 days.
  • the utility of the dosage regimenof 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 methods described hereinafter.
  • the value of the titration may be demonstrated by checking any of the following parameters: avoiding an abrupt heart rate reductions after treatment initiation, minimizing the risk for AV conduction abnormalities or attenuation of persisting magnitude of heart rate reduction.
  • Two different dose titration regimens of fingolimod 0.125mg-0.25mg-0.5mg, and 0.06mg- 0.125mg-0.25mg-0.375mg-0.5mg are compared to a fixed fingolimod 0.5 mg dose over 30 days of daily dosing.
  • a total of 60 subjects are enrolled and randomly assigned to one the four groups (two dose titration groups, or placebo- or active- control group) and receive the once daily treatment in a blinded manner.
  • Each subject participates in a screening period of maximal 21 days, a baseline period (Day -1), and a 30-day active treatment period.
  • Heart rate (HR) (is monitored starting prior to breakfast on Day-1 through Day31 , 24hr after the last dosing. Heart rhythm is assessed via 24hr continuous Holter monitoring on Day-1 , Day1 and Day29. On Day 31 , subjects are discharged from the study following a study completion evaluation to rule out clinical signs of toxicities or infection.
  • the daily mean HR is assessed, as well as the daily minimum HR and the daily average minimum HR.
  • the daily average minimum HR is defined as the minimum of the hourly averages observed during one day.
  • minimum and minimum average HRs are compared between the last day of the lower dose and the first day of the higher dose within each titration cohort. This analysis is a Bayesian analysis using uninformative priors.
  • the hourly mean and minimum HR are also measured for Days 1 , 8, 15, 22 and 29.
  • the means +/- standard deviation are plotted by treatment group and hours post dose for the first 6 hours post-dose on Days 1 , 8, 15, 22 and 29.
  • the table below describes the treatment sequence for the study
  • Fingolimod 0.5 mg daily resulted in a mean decrease in HR of approximately 10 bpm on hour 6 of Day 1.
  • Titration group-1 slowly accumulated negative chronotropic effect over the first two weeks of the study of approximately 6-7 bpmcompared to baseline or the placebo group and then stabilized between weeks two and four.
  • Titration group-2 slowly accumulated negative chronotropic effect over the first three weeks of the study of approximately 5 bpm compared to baseline or the placebo group and then stabilized between weeks three and four.
  • both titration regimens were associated with a decrease in HR of 3-5 bpm during the first six hours.
  • both titration regimens did attenuate the first 6 hour effects of fingolimod treatment initiation on HR on Day 1.

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Abstract

L'invention concerne des modulateurs ou des agonistes d'un récepteur de S1P qui sont administrés suivant un régime posologique, le dosage quotidien étant inférieur au dosage quotidien standard au cours des premiers jours de traitement.
PCT/US2012/059619 2011-10-11 2012-10-10 Régime posologique pour un agoniste de récepteur de s1p WO2013055833A1 (fr)

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CN103724215A (zh) * 2013-11-28 2014-04-16 镇江圣安医药有限公司 2-氨基-2-[2-(4-辛基苯基)乙基]-1,3-丙二醇的新型衍生物及其应用
WO2021084068A1 (fr) 2019-10-31 2021-05-06 Idorsia Pharmaceuticals Ltd Combinaison d'un antagoniste de cxcr7 avec un modulateur du récepteur s1p1
US11944602B2 (en) 2015-02-26 2024-04-02 Novartis Ag Treatment of autoimmune disease in a patient receiving additionally a beta-blocker

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103724215A (zh) * 2013-11-28 2014-04-16 镇江圣安医药有限公司 2-氨基-2-[2-(4-辛基苯基)乙基]-1,3-丙二醇的新型衍生物及其应用
US11944602B2 (en) 2015-02-26 2024-04-02 Novartis Ag Treatment of autoimmune disease in a patient receiving additionally a beta-blocker
WO2021084068A1 (fr) 2019-10-31 2021-05-06 Idorsia Pharmaceuticals Ltd Combinaison d'un antagoniste de cxcr7 avec un modulateur du récepteur s1p1

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