DOSAGE REGIMEN OF AN S1P RECEPTOR MODULATOR

Abstract

S1P receptor modulators are administered following a dosage regimen providing a positive benefit-risk profile.

Claims

1. 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 receptor modulator or agonist, in such as way that the adverse events possibly associated with administering said S1P receptor modulator or agonist are controlled, limited, reduced or abolished, wherein said method comprises the steps of i) monitoring the patient during a specific period of time after the first administration of said S1P receptor modulator or agonist, wherein said patient monitoring comprises one or more steps of a) monitoring infections or infestations, e.g. viral infections, throughout administering said S1P receptor modulator or agonist, b) performing an ophthalmologic examination, ii) optionally interrupting the administration of said S1P receptor modulator or agonist and/or modifying the treatment regimen thereof.

2. 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 S1P receptor modulator or agonist, comprising administering to said patient a therapeutically effective amount of said S1P receptor modulator or agonist, wherein said method comprises one or more steps of a) monitoring infections or infestations, e.g. viral infections, and b) performing an ophthalmologic examination, ii) optionally interrupting the administration of said S1P receptor modulator or agonist and/or modifying the treatment regimen thereof.

3. Method according to claim 1 or 2 wherein the patient monitoring further comprises a step of c) monitoring the heart rate of the patient at least during the first hours after the first administration of said S1P receptor modulator or agonist, e.g. the 1 to 10 hours after the first administration of said S1P receptor modulator or agonist.

4. Method according to any preceding claim further comprises a step of d) observing the patient for the 1 to 10 hours after the first administration of said S1P receptor modulator or agonist to monitor the heart rate of the patient, e.g. during the first 6 hours.

5. Method according to any preceding claim wherein the ophthalmologic examination is performed at least 3 to 4 months after starting administration.

6. Method according to any preceding claim wherein the patient monitoring further comprises one or more of steps of performing liver function tests, performing dermatological examinations, performing pulmonary functions tests.

7. 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 SIP receptor modulator or agonist in such as way that the adverse events possibly associated with said S1P receptor modulator or agonist are controlled, limited, reduced or abolished, wherein said method comprises i) checking specific parameters of the patient before initiating and/or during administration of said S1P receptor modulator or agonist, wherein said parameters comprise one or more of a) signs of infections or infestations, e.g. viral infections, b) visual acuity c) liver enzymes d) blood pressure and ii) as necessary, interrupting the administration of said S1P receptor modulator or agonist and/or modifying the treatment regimen thereof.

8. Method of claim 7 wherein signs of infections or infestations are monitored throughout administering said S1P receptor modulator or agonist.

9. Method of claim 7 or 8 wherein visual acuity is monitored at initiating administration of said S1P receptor modulator or agonist or within the months preceding the first administration of said S1P receptor modulator or agonist, e.g. within the 6 months preceding the first administration of said S1P receptor modulator or agonist.

10. Method of claims 7 to 9 wherein visual acuity is monitored within the next months following the first administration of said S1P receptor modulator or agonist, e.g. within the 1 to 12 months following the first administration of said S1P receptor modulator or agonist.

11. Method of claims 7 to 10 wherein liver enzymes are monitored at initiating administration of said SIP receptor modulator or agonist, and optionally throughout administering said S1P receptor modulator or agonist.

12. Method of claims 7 to 11 further comprising checking the heart rate of the patient at initiating administration of said S1P receptor modulator or agonist and optionally within the 1 to 10 hours following the first administration of said S1 P receptor modulator or agonist.

13. Method of claims 7 to 12 further comprising checking the respiratory function of the patient at initiating administration of said S1P receptor modulator or agonist and/or throughout administering said S1P receptor modulator or agonist.

14. Method of claims 7 to 13 further comprising checking the presence of dermatological disorders or skin cancer.

15. Method according to any preceding claim wherein modifying the treatment regimen thereof consists of increasing or decreasing the daily dosage and/or increasing the period of time between two consecutives administrations.

16. Method according to any preceding claim wherein the step ii) comprises administering a second drug which mitigates said possible adverse events, for example administering a second drug which is an anti-infection drug.

17. Method according to any preceding claim wherein step ii) is performed in case the monitoring reveals infections or an eyes disease.

18. Method according to any preceding claim wherein specific parameters of the patient are checked before initiating said SIP receptor modulator or agonist, said parameters being selected from blood analysis (e.g. complete blood count), liver enzymes, ophthalmologic examination, electrocardiogram (ECG), pulmonary functions tests, dermatological examination, and liver function tests.

19. A method according to any preceding claim wherein step i) comprises one or more steps of determining whether the patient is under beta blockers, shows resting bradycardia, high grade AV block or sick-sinus symptom.

20. A method according to any preceding claim wherein the S1P receptor modulator or agonist is fingolimod (FTY720), a phosphate derivative thereof or a pharmaceutically acceptable salt thereof.

21. A method according to claim 20 wherein the S1P receptor modulator or agonist is administered at a daily dosage not exceeding about 0.5 mg to the patient, e.g. of about 0.5 mg.

22. A method according to claim 20 wherein the S1P receptor modulator or agonist is administered at a daily dosage exceeding 0.5 mg to the patient, e.g. of 1.25 mg.

23. A method of controlling, reducing, limiting or abolishing the possible adverse events associated with a treatment of a patient suffering from an inflammatory or autoimmune disease or disorder, wherein said treatment comprises administering a daily dosage of a drug selected from fingolimod (FTY720), a phosphate derivative thereof or a pharmaceutically acceptable salt thereof, not exceeding about 0.5 mg to the patient, such a method comprising monitoring the patient during a specific period of time after the first administration of said drug, and if necessary either interrupting the administration of said drug, either modifying the treatment regimen thereof and/or administering a second drug which mitigates said possible adverse events, wherein said monitoring comprises one or more steps of a) monitoring infections or infestations, e.g. viral infections, throughout drug administration, and b) performing an ophthalmologic examination after starting administration.

24. Method according to any one of claims 20 to 23 wherein modifying the treatment regimen consists of administering a daily dosage of fingolimod, a phosphate derivative thereof or a pharmaceutically acceptable salt thereof, that is lower than 0.5 mg and then increasing the dosage up to a daily dosage of about 0.5 mg, or increasing the period of time between two consecutive administrations thereof.

25. Method according to any one of claims 20 to 23 wherein fingolimod, a phosphate derivative thereof or a pharmaceutically acceptable salt thereof is co-administered with a second drug which mitigates said possible adverse events, for example with a second drug which is selected from the group consisting of anti-cancer agents, anti-infection agents and anti-hypertensive drugs.

26. 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 thereof or a pharmaceutically acceptable salt thereof in a patient in need thereof, (b) monitoring adverse events occurring in said patient, (c) monitoring reduction or abolition of symptoms associated with multiple sclerosis, and (d) determining optimal dose for said patient, wherein the daily dose of the drug does not exceed 0.5 mg.

27. 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 thereof or a pharmaceutically acceptable salt thereof in a patient in need thereof, (b) monitoring adverse events occurring in said patient, (c) monitoring reduction or abolition of symptoms associated with multiple sclerosis, and (d) determining optimal dose for said patient, wherein the daily dosage of the drug exceeds 0.5 mg, e.g. is about 1.25 mg.

28. 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, wherein said method comprises (a) administering a varied dose of said drug to the patient, (b) monitoring adverse events occurring in said patient, (c) monitoring reduction or abolition of symptoms associated with multiple sclerosis, and (d) determining optimal dose for said patient, wherein said regimen is adapted for treating said disease or disorder and controlling, reducing, or abolishing the possible adverse events associated with administering said S1P receptor modulator or agonist.

29. A method of any one of claims 26 to 28, wherein step (b) comprises one or more steps of i) monitoring infections or infestations, e.g. viral infections, ii) performing an ophthalmologic examination, e.g. 3 to 4 months after starting drug administration.

30. Method according to any one of claims 20 to 29 wherein the adverse events are selected from bradycardia, atrioventricular conduction abnormalities, macular edema, skin cancer, altered liver functions, infections and hypertension.

31. A method for treating an inflammatory or autoimmune disease in a patient in need thereof and further suffering from bradyarrythmia or at risk thereof, said method comprising administering a therapeutically effective amount of a S1P receptor modulator or agonist, and comprising the steps of i) monitoring the patient during a specific period of time after the first administration of said SIP receptor modulator or agonist, and ii) optionally interrupting the administration of said S1 P receptor modulator or agonist and/or modifying the treatment regimen thereof, wherein said patient monitoring comprises the steps of a) monitoring infections or infestations, e.g. viral infections, throughout administering said S1P receptor modulator or agonist, b) performing an ophthalmologic examination, c) monitoring the heart rate of the patient at least during the first hours after the first administration of said S1P receptor modulator or agonist, e.g. the 1 to 10 hours after the first administration of said S1P receptor modulator or agonist, and optionally d) observing the patient for the 1 to 10 hours after the first administration of said S1P receptor modulator or agonist to monitor the heart rate of the patient, e.g. during the first 6 hours.

32. Method of according to any preceding claim wherein the patient is vaccinated before initiating administration of said S1P receptor modulator or agonist, e.g. vaccinated against viral infection.

33. A combination containing a first drug which is selected from the group consisting of fingolimod (FTY720), a phosphate derivative thereof and a pharmaceutically acceptable salt thereof, and a second drug which is selected from the group consisting of drugs which treat or prevent macular edema, anti-cancer agent, anti infection agents and anti-hypertensive drugs, whereby the daily dosage of the first drug is not exceeding about 0.5 mg.

34. A kit containing daily units of medication of a first drug which is selected from the group consisting of fingolimod (FTY720), a phosphate derivative thereof or a pharmaceutically acceptable salt thereof, and a second drug which is selected from the group consisting of anti-cancer agent, anti-infection agents and anti-hypertensive drugs, whereby the daily dosage of the first drug is above 0.5 mg.

35. A method, combination, or kit according to any preceding claim wherein the treatment is for a chronic long term disease, e.g. for multiple sclerosis.

36. S1 P 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 according to any one of claims 1 to 32.

37. FTY720, a phosphate derivative thereof or a pharmaceutically acceptable salt thereof, for use in a method for treating an inflammatory or autoimmune disease according to any one of claims 1 to 32, wherein said disease is multiple sclerosis, e.g. RRMS.

Description

EXAMPLE 1

[0312] Study: Two different daily dosages of fingolimod (0.5 mg and 1.25 mg) have been orally administered to patients with Relapsing-remitting Multiple Sclerosis during 24-month 1292 patients with RRMS from 172 centers 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 pg intramuscularly once a week. Patients randomized to fingolimod receive placebo injections once a week, and those randomized to interferon beta1-a receive a placebo pill once a day.

[0313] 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 MRI annually. Monitoring by ophthalmic examination, dermatologic examination, pulmonary function tests, chest X-ray and/or CT, Holter monitoring, and echocardiography are performed.

[0314] Participants who completed 1 year on treatment are offered an optional extension phase. Those randomized to fingolimod continue on their assigned dose, and those in the interferon beta1-a group are randomized to the 2 fingolimod doses.

[0315] Results:

[0316] There are reduced relapses in both fingolimod groups compared with interferon beta1-a. For the lower dose, there is a 52% reduction in relapses vs interferon beta1-a, and a 38% reduction with the higher dose. Results in both fingolimod groups are highly statistically significant vs interferon beta1-a, but not statistically different from each other.

TABLE-US-00001 Interferon Fingolimod Fingolimod End Point beta1-a 0.5 mg/day P 1.25 mg/day P Annualized 0.33 0.16 <.0001 0.20 <.0001 relapse rate

[0317] The proportion of relapse-free patients is 83% with fingolimod vs 69% in the interferon beta1-a group.

[0318] 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 lesions at month 12.

[0319] Observed adverse events include bradycardia and atrioventricular (AV) block, and infections, including 3 herpes viral infections.

TABLE-US-00002 Interferon Fingolimod beta1-a, n Fingolimod 0.5 1.25 mg/day, Type (%) mg/d, n (%) n (%) Basal-cell 1 (0.2) 3 (0.7) 2 (0.5) carcinoma Squamous-cell 1 (0.2) 0 0 carcinoma Malignant 0 3 (0.7) 0 melanoma Breast cancer 0 2 (0.5) 2 (0.5)

EXAMPLE 2

[0320] Study:

[0321] Patients with moderate asthma are divided into 3 dosing cohorts of 12 patients each. In each cohort, the 12 patients are randomized to FTY720 (0.5 mg, 1.25 mg, and 2.5 mg in cohorts 1, 2, and 3 respectively) or placebo in a 3:1 ratio resulting in 9 patients treated with FTY720 at each dose level and 9 patients treated with placebo.

[0322] The study consists of a screening period of between 12 and 26 days, baseline and a 10 day treatment period followed by a study completion evaluation (performed 1-7 days after the last dose).

[0323] Two screening visits are performed, the initial Screening visit and a second visit at Day-7 (+1-1 day). The initial screening visit (Visit 1) is used to start pulmonary function test (PFT) monitoring to assess eligibility 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 specified time. Short-acting β2agonist use prior to treatment with study medication is also recorded in this 14 day period.

[0324] Patients return to the clinic one or 2 days prior to dosing for baseline assessments. PFT profiling is assessed at 7 time points during the visit and routine 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 approximately 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 β2agonist use is also recorded throughout the treatment period up to and including Day 11 (24 hours post last dose).

[0325] Blood samples are collected on Day 1 at pre-dose and at 1, 2, 4, 6, 8, 12, 16, and 24h post-dose, 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.

[0326] Safety assessments include physical examinations, ECGs, vital signs, spirometry assessments, standard clinical laboratory evaluations (hematology, blood chemistry, urinalysis), adverse event and serious adverse event monitoring.

[0327] 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 initial 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).

[0328] The magnitude and time course of the effect of FTY720 on FEV1 and other pulmonary function tests (FVC, FEF25-75%, and FEV1/FVC) is measured.

[0329] Results:

[0330] The magnitude of the bronchoconstriction is primarily assessed by the baseline-adjusted FEV, AUC0-6h on Day 1. This primary PD variable is defined as the ratio of the AUEC FEV, over the 6-hour PFT profile on Day 1 divided by the same variable at baseline (Day-1).

[0331] This primary PD variable is analyzed on the log-scale by means of a linear model adjusted for the (log-transformed) baseline FEV, AUC0-6h and the treatment group as fixed effects. The geometric mean baseline-adjusted FEV.sub.1 AUC0-6h 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% Cl, and is back-transformed to obtain the geometric mean percent change from placebo and its 95% Cl.

[0332] Additional PD variables are calculated: baseline-adjusted FEV.sub.1 AUC0-6h on Day 10 and baseline-adjusted FEV.sub.1 Emax1-6h on Days 1 and 10. The Emax variables are defined as the ratio between Day 1 (or Day 10) and Day-1 regarding the minimum from 6 assessments scheduled at 1 to 6 hours post dose. Those variables are defined for FEV, as well as for the other PFT parameters (FVC, FEF.sub.25-75%, and FEV,/FVC) and are analyzed using the same model as for the primary PD endpoint.

[0333] 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 FEV.sub.1, FVC, FEF.sub.25-75%, and FEV.sub.1/FVC is summarized by means of descriptive statistics at each visit/time point. The log-transformed ratio from time-match baseline is analyzed, separately at each post-baseline visit/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% CI are obtained from the model and are back-transformed to obtain the geometric mean percent change from placebo and its 95% Cl. No adjustment was made to the P values for multiple testing.

[0334] The results show that at a daily dosage of 0.5 mg FTY720 is safe and well tolerated in patients with moderate asthma.