DOSAGE REGIMEN FOR A S1P RECEPTOR AGONIST

Abstract

S1P receptor modulators or agonists are administered following a dosage regimen whereby during the initial days of treatment the daily dosage is lower than the standard daily dosage.

Claims

1-15. (canceled)

16. A method for the treatment of an autoimmune disease, wherein the method comprises administering to a patient in need thereof a medicament comprising an S1P1 selective receptor modulator, wherein the S1P1 selective receptor modulator causes negative chronotropic effects, and wherein the negative chronotropic effects are reduced or eliminated by administering the S1P1 selective receptor modulator during an initial treatment period, wherein the S1P1 selective receptor modulator is administered at an initial daily dosage which is about 4-fold less than a standard daily dosage, and, following the initial treatment period, the dosage comprises the standard daily dosage.

17. The method according to claim 16, wherein the initial treatment period comprises a second dosage that is 2-fold less than the standard daily dosage, and wherein the second dosage is administered after administration of the initial daily dosage.

18. The method according to claim 17, wherein the initial daily dosage is between 0.1-0.5 mg, the second dosage is between 0.2-0.5 mg, the standard daily dosage is between 0.5 mg and 2 mg, or a combination thereof.

19. The method according to claim 18, wherein the initial daily dosage is about 0.23 mg/day, the second dosage is about 0.46 mg/day, and the standard daily dosage is about 0.92 mg/day.

20. The method according to claim 16, wherein the initial daily dosage is between 0.1-0.5 mg, the standard daily dosage is between 0.5 mg and 2 mg, or a combination thereof.

21. The method according to claim 20, wherein the initial daily dosage is about 0.23 mg/day and the standard daily dosage is about 0.92 mg/day.

22. The method according to claim 16, wherein the initial treatment period comprises at least 4 days and up to 14 days.

23. The method according to claim 17, wherein the initial treatment period comprises 7 days and the second dosage begins on day 5 of the initial period and continues for the remainder of the initial period.

24. The method according to claim 16, wherein the autoimmune disease comprises multiple sclerosis, polymyositis, lupus nephritis, rheumatoid arthritis, inflammatory bowel disease, psoriasis, or a combination thereof.

25. The method according to claim 17, wherein the autoimmune disease comprises multiple sclerosis, polymyositis, lupus nephritis, rheumatoid arthritis, inflammatory bowel disease, psoriasis, or a combination thereof.

26. The method according to claim 16, wherein the patient suffers from or is susceptible to cardiac side effects or heart failure.

27. The method according to claim 16, wherein the method limits, reduces or prevents the occurrence of dizziness, fatigue, heart palpitations, or a combination thereof, in the patient.

28. A method for the treatment of multiple sclerosis in a patient, wherein the method comprises administering to a patient in need thereof a medicament comprising an S1P1 selective receptor modulator according to a dosage regimen, the dosage regimen comprising: an initial treatment period that begins upon a first administration of the S1P1 selective receptor modulation and continues for a total of 7 days, the initial treatment period comprising: administering the S1P1 selective receptor modulator at an initial daily dosage for the first 4 consecutive days and then increasing the S1P1 selective receptor modulator to a second daily dosage for 3 consecutive days, wherein the initial daily dosage is about 4-fold less than a standard daily dosage and the second dosage is about 2-fold less than the standard daily dosage; and after the initial period, administering the S1P1 receptor at the standard daily dosage.

29. The method of claim 28, wherein the dosage regimen limits, reduces or prevents the occurrence of dizziness, fatigue, heart palpitations, or a combination thereof, in the patient.

30. The method according to claim 28, wherein the initial daily dosage is between 0.1-0.5 mg, the second dosage is between 0.2-0.5 mg, and the standard daily dosage is between 0.5 mg and 2 mg.

31. The method according to claim 30, wherein the initial daily dosage is about 0.23 mg/day, the second dosage is about 0.46 mg/day, and the standard daily dosage is about 0.92 mg/day.

32. A method of ameliorating, decreasing or limiting a negative chronotropic side effect of a medicament for the treatment of an autoimmune disease in a patient, wherein the medicament comprises an S1P1 selective receptor modulator, the method comprising: administering to the patient the medicament at a daily oral dosage which is at least 2 fold lower than a standard daily oral dosage during an initial treatment period and, thereafter, raising the daily oral dosage to the standard daily oral dosage, wherein the initial treatment period is 7 consecutive days.

33. The method according to claim 32, wherein the initial treatment period comprises a first oral daily dosage that is about 4-fold less than a standard daily dosage and a second oral daily dosage that is about 2-fold less than the standard daily dosage, wherein the first oral daily dosage is administered during the first 4 days of the initial treatment period and the second oral daily dosage is administered during the final 3 days of the initial treatment period.

34. The method according to claim 33, wherein the first daily oral dosage is between 0.1-0.5 mg, the second daily oral dosage is between 0.2-0.5 mg, and the standard daily dosage is between 0.5 mg and 2 mg.

35. The method according to claim 34, wherein the first daily oral dosage is 0.23 mg/day, the second dosage is 0.46 mg/day, and the standard daily dosage is 0.92 mg/day.

Description

BRIEF DESCRIPTION OF THE FIGURE

[0151] FIG. 1 shows the mean (+/−standard error) daily average heart rate on days 1 to 9 for the treatment regimen groups described in the Example below. The x-axis is shows the study days and the Y-axis shows the mean (+/−SE) daily average heart rate (beats per minute (BPM)).

EXAMPLE

[0152] A single-center, double-blind, placebo-controlled, dose titration, once-daily, multiple-oral-dose clinical study in healthy subjects was conducted to evaluate the effect of a dosage regimen of FTY720 according to the present invention.

[0153] A total of 36 subjects were randomly assigned to one of the three groups.

[0154] Each subject participated in a screening period of maximal 21 days, a baseline period (Day −1), a 9-day dose-administration period, and clinical study completion assessments on Day 10. Subjects were assigned to one of the three groups (dose titration regimen group, placebo control group, or active control group) and received the once daily dose in a double-blinded manner (Table 1).

[0155] In the dose titration group, increasing once daily doses of Compound A (FTY720), starting at 0.125 mg o.d. and ending at the maximal therapeutic dose of 1.25 mg o.d. were administered on days 1 to 9 of the study according to the schedule shown in Table 1 below. The placebo control group received placebo through out the duration of the study and the active control group received a once daily dose of 1.25 mg of FTY720 on days 1 to 9.

TABLE-US-00001 TABLE 1 Study group/ Baseline Administration period Number of Day subjects Day −1 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Dose titration Placebo 0.125 mg 0.125 mg 0.125 mg 0.25 mg 0.25 mg 0.5 mg 0.5 mg 1.25 mg 1.25 mg regimen group/ N = 15 Placebo Placebo Placebo, once daily over 9 days control group/ N = 9 Active Placebo 1.25 mg, once daily over 9 days control group/ N = 12

[0156] On Day −1 (baseline), subjects will undergo baseline assessments including 24 hour holter monitoring and telemetry assessments.

[0157] Pharmacodynamic and safety assessments are performed up to 24 hours post last dose. Heart rate is monitored via telemetry on Day −1 through Day 10, 24 hour after the last dosing. Heart rhythm is assessed via 24 hr continuous holter monitoring on Day −1, Day 1, and Day 9. For each dosing for each subject, the drug is administered as closely as practically possible to the time administered on Day −1. Safety assessments includes physical examinations, vital signs and body measurements, 12-lead ECG evaluations, standard clinical laboratory evaluations hematology, blood chemistry, urinalysis, adverse event and serious adverse event monitoring. Systolic and diastolic blood pressure and pulse are measured after the subject has rested quietly in the sifting position for at least 3 minutes. Blood pressure is measured at the same arm on each occasion. Standard 12-lead ECGs are recorded at Screening, baseline, 4 hours post-dose on Day 1 and Day 8, and at Study Completion. The variables recorded are: date and time of ECG, heart rate, PR interval, QT interval (uncorrected), QTcB, QRS duration. The overall interpretation is collected with a Yes/No statement to confirm if any clinically relevant abnormalities are present, which needs to be specified further.

[0158] Subjects remain on continuous telemetry, starting before breakfast on Day −1 and proceeding throughout the administration period up to Day 10 (24 hour after the last dose). Over this ten day duration of continuous heart rate collection for each subject, one heart rate value is obtained every minute (‘minute unit heart rate’), representing the average heart rate value over that minute. The heart rate database for each subject contains approximately 14,400 data points (10 days×24 hr×60 min).

[0159] 24-hour continuous Holter-ECG data are captured via a digital Holter monitor (12-lead, on Days −1, 1, 6, and 8), and transferred for interpretation and reporting. Holter monitoring starts approximately at 7:00 and the time of dose administration is regarded as the time “0 hours”. Holter “cuts” are derived from the dataset at 1 hour intervals starting from Day −1 and continuing for 24 hours or the end of the cleaned Holter monitoring dataset.

[0160] Cardiac conduction intervals: arrhythmia monitoring includes the frequency and duration of sinus pauses (>2 sec and >3 sec) and atrio-ventricular blocks. Frequency and duration of atrial and ventricular ectopy and sinus rhythm are also recorded.

[0161] The daily chronotropic effect is defined as the percent decrease in HR.sub.min (minimum heart rate) between two consecutive days. It is calculated on days 1 to 9.

Results:

[0162] The results are shown in FIG. 1. In the placebo group, daily average heart rate varies by approximately 5 BPM (beats per min) over the course of the study with a trend for heart rate to increase approximately 3-4 BPM from Day −1 to Day 2. The FTY720 1.25 mg treatment group manifests a significant decrease in heart rate of approximately 8 BPM from Day −1 to Day 1 and an additional decrease in heart rate approximately 3 BPM from Day 1 to Day 2. The FTY720 titration group manifests a gradual decrease in heart rate of approximately 1-2 BPM per day over the course of eight day course of the dose titration. The initiation of the 1.25 mg FTY720 on Day 8 does not result in dip in heart rate compared to the preceding days.

[0163] These results indicate that the use of a dose titration regimen according to the invention attenuates the negative chronotropic effect seen on Day 1 of FTY720 treatment initiation. Furthermore multiple analyses have been conducted to compare minimum heart rates between the two FTY720 treatment group. These analysis show that the FTY720 dose titration regimen provides improved daily minimum heart rates during the course of the study.