PHARMACEUTICAL AGENT FOR TREATING AMYOTROPHIC LATERAL SCLEROSIS OR SUPPRESSING DISEASE PROGRESS THEREOF

Abstract

The invention provides a method for treating ALS or suppressing the disease progress thereof, or treating symptoms caused by ALS or suppressing the disease progress thereof by administering an agent containing, as an active ingredient, 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof, to a patient that complies with specific criteria. The agent is administered by repeating a 14-day administration period and a 14-day drug holiday period, or by establishing an initial 14-day administration period and an initial 14-day drug holiday period and then repeating an administration period for 10 out of 14 days and a 14-day drug holiday period.

Claims

1. A method for treating amyotrophic lateral sclerosis or suppressing progress of amyotrophic lateral sclerosis, comprising: administering an effective amount of 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof to a patient in need thereof if the patient is in a specific patient group in which each patient scores two or more points from each of all items constituting ALSFRS-R in combination with % FVC of 80% or more, wherein the administering comprises administering the effective amount to the patient for a plurality of administration periods establishing an initial administration period and an initial drug holiday period, and repeating an administration period and a drug holiday period such that the patient undergoes at least three administration periods including the initial administration period such that the specific patient group scores 2.5 points or better than a placebo administration group with respect to ALSFRS-R when the plurality of administration periods is six administration periods establishing an initial 14-day administration period and an initial 14-day drug holiday period, and thereafter, repeating the administration period of 10 out of 14 days and the drug holiday period of 14 days.

2. The method according to claim 1, wherein the administering comprises the plurality of administration periods establishing an initial 14-day administration period and an initial 14-day drug holiday period, and thereafter, repeating the administration period of 10 out of 14 days and the drug holiday period of 14 days.

3. The method according to claim 1, wherein the administering of the effective amount of 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof treats a symptom or suppresses progress of the symptom by amyotrophic lateral sclerosis including at least one of a decrease in respiratory function, a spoken language disorder, dysphagia and a limb movement disorder.

4. The method according to claim 2, wherein the administering of the effective amount of 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof treats a symptom or suppresses progress of the symptom by amyotrophic lateral sclerosis including at least one of a decrease in respiratory function, a spoken language disorder, dysphagia and a limb movement disorder.

5. The method according to claim 1, wherein the patient is determined to be Probable ALS according to the revised El Escorial diagnostic criteria.

6. The method according to claim 1, further comprising: evaluating the patient for efficacy of 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof based on ALSFRS-R and % FVC; and selecting the patient for treating amyotrophic lateral sclerosis or suppressing progress of amyotrophic lateral sclerosis with 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof if the patient is a specific patient group in which each patient scores two or more points from each of all items constituting ALSFRS-R in combination with % FVC of 80% or more.

7. The method according to claim 1, wherein the administering comprises administering the effective amount to the patient such that the specific patient group has a difference of 3.4 between an ALSFRS-R score before the initial 14-day administration period and an ALSFRS-R score upon termination of the six administration periods.

8. The method according to claim 1, wherein the administering comprises administering the effective amount to the patient such that a risk of death or tracheostomy by amyotrophic lateral sclerosis is reduced by 3.5% or more than a risk of death or tracheostomy by amyotrophic lateral sclerosis to a patient outside the specific patient group when administered with the same amount of 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof.

9. The method according to claim 1, wherein the patient is determined to be Definite ALS or Probable ALS according to the revised El Escorial diagnostic criteria.

10. The method according to claim 9, wherein the administering comprises establishing an initial 14-day administration period and an initial 14-day drug holiday period, and thereafter, repeating the administration period of 10 out of 14 days and the drug holiday period of 14 days.

11. The method according to claim 9, wherein the administering of the effective amount of 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof treats a symptom or suppresses progress of the symptom by amyotrophic lateral sclerosis including at least one of a decrease in respiratory function, a spoken language disorder, dysphagia and a limb movement disorder.

12. The method according to claim 10, wherein the administering of the effective amount of 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof treats a symptom or suppresses progress of the symptom by amyotrophic lateral sclerosis including at least one of a decrease in respiratory function, a spoken language disorder, dysphagia and a limb movement disorder.

13. The method according to claim 9, wherein the patient is determined to be Probable ALS according to the revised El Escorial diagnostic criteria.

14. The method according to claim 9, further comprising: evaluating the patient for efficacy of 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof based on ALSFRS-R, % FVC, and revised El Escorial diagnostic criteria; and selecting the patient for treating amyotrophic lateral sclerosis or suppressing progress of amyotrophic lateral sclerosis with 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof if the patient scores two or more points from each of all items constituting ALSFRS-R in combination with % FVC of 80% or more and is determined to be Definite ALS or Probable ALS according to the revised El Escorial diagnostic criteria.

15. The method according to claim 1, wherein the patient is determined to be Definite ALS according to the revised El Escorial diagnostic criteria.

16. The method according to claim 15, wherein the administering comprises establishing an initial 14-day administration period and an initial 14-day drug holiday period, and thereafter, repeating the administration period of 10 out of 14 days and the drug holiday period of 14 days.

17. The method according to claim 15, wherein the administering of the effective amount of 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof treats a symptom or suppresses progress of the symptom by amyotrophic lateral sclerosis including at least one of a decrease in respiratory function, a spoken language disorder, dysphagia and a limb movement disorder.

18. The method according to claim 16, wherein the administering of the effective amount of 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof treats a symptom or suppresses progress of the symptom by amyotrophic lateral sclerosis including at least one of a decrease in respiratory function, a spoken language disorder, dysphagia and a limb movement disorder.

19. The method according to claim 15, wherein the patient is determined to be Probable ALS according to the revised El Escorial diagnostic criteria.

20. The method according to claim 15, further comprising: evaluating the patient for efficacy of 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof based on ALSFRS-R, % FVC, and revised El Escorial diagnostic criteria; and selecting the patient for treating amyotrophic lateral sclerosis or suppressing progress of amyotrophic lateral sclerosis with 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof if the patient scores two or more points from each of all items constituting ALSFRS-R in combination with % FVC of 80% or more and is determined to be Definite ALS according to the revised El Escorial diagnostic criteria.

Description

EXAMPLES

[0133] (Test Method)

[0134] 199 patients with amyotrophic lateral sclerosis who complied with the following selection standards were divided into an actual drug administration group consisting of 100 patients and a placebo administration group of 99 patients:

1) patients who comply with any one of “Definite ALS” “Probable ALS,” “Probable ALS-test positive,” and “ALS possible” according to the revised El Escorial (Airlie House) diagnostic criteria;
2) patients who are able to have a meal, excrete and move by themselves, and do not need assistance in a daily life;
3) patients who are within 3 years after the onset of ALS;
4) patients who are between the age of 20 (inclusive) and 75 (inclusive); 5) patients who have a change in the ALSFRS-R scores of −1 to −4 points for 12 weeks before initiation of the administration;
6) patients who do not have respiratory difficulty due to a decrease in respiratory function; and
7) patients who do not have complications such as Parkinson's disease, schizophrenia or dementia, which may have influence on evaluation of drug effects.

[0135] With regard to the actual drug administration group, two ampules of “Radicut (registered trademark), Injection 30 mg” (containing 30 mg of 3-methyl-1-phenyl-2-pyrazolin-5-one; manufactured and distributed by Mitsubishi Tanabe Pharma Corporation) were diluted with a suitable amount of normal saline before the use, and the thus prepared solution was intravenously administered to the patients by drops over 60 minutes once a day. On the other hand, with regard to the placebo administration group, only normal saline was administered to the patients in the same manner as for the actual drug administration group.

[0136] The administration period was divided into first to sixth courses. The first course consisted of a continuous 14-day administration period and the subsequent drug holiday period for 14 days in which drug administration was not carried out. In the second to sixth courses, 1 set consisting of an administration period for a total of 10 out of 14 days and the subsequent 14-day drug holiday period was repeated 5 times. Drug administration is shown in the following table.

TABLE-US-00002 TABLE 3 Table 3 Drug administration First course Second course Third course Admini- Drug Admini- Drug Admini- Drug stration holiday stration holiday stration holiday period period period period period period 14 days 14 days Total of 14 days Total of 14 days 10 out of 10 out of 14 days 14 days Fourth course Fifth course Sixth course Admini- Drug Admini- Drug Admini- Drug stration holiday stration holiday stration holiday period period period Period period period Total of 14 days Total of 14 days Total of 14 days 10 out of 10 out of 10 out of 14 days 14 days 14 days

[0137] (Test Results)

[0138] Before initiation of the drug administration in the first course, and upon termination of the drug holiday periods in the first, second, third, fourth, fifth and sixth courses, the 199 patients were measured in terms of ALSFRS-R. Among the 199 patients, some patients were dropped out from the test during a period after initiation of the administration in the fourth course and before termination of the drug holiday period in the sixth course. In the case of these drop-out patients, the ALSFRS-R score measured immediately before dropping out from the test was considered to be the score upon termination of the drug holiday period in the sixth course, and it was used in the analysis.

[0139] A difference between the ALSFRS-R scores between before initiation of the administration in the first course and upon termination of the drug holiday period in the sixth course is shown below.

TABLE-US-00003 TABLE 4 Table 4 Number Before- Between- of and-after group patients difference difference S. D. t-test Actual drug 100 −5.3 0.7 5.4 p > 0.05 administration group Placebo  99 −6.0 6.0 administration group

[0140] Subsequently, the 199 patients were divided into the following (1) to (7):

(1) patients who were determined to be “Definite ALS” or “Probable ALS” according to the revised El Escorial (Airlie House) diagnostic criteria;
(2) patient who were determined to be “Definite ALS” according to the revised El Escorial (Airlie House) diagnostic criteria;
(3) patients who scored two or more points from all items constituting the ALSFRS-R;
(4) patients whose % FVC was 80% or more;
(5) patients who scored two or more points from all items constituting the ALSFRS-R and whose % FVC was 80% or more;
(6) patients who were determined to be “Definite ALS” or “Probable ALS” according to the revised El Escorial (Airlie House) diagnostic criteria, scored two or more points from all items constituting the ALSFRS-R, and whose % FVC was 80% or more; and
(7) patients who were determined to be “Definite ALS” according to the revised El Escorial (Airlie House) diagnostic criteria, scored two or more points from all items constituting the ALSFRS-R, and whose % FVC was 80% or more. With regard to the thus specified patients (1) to (7), differences in the ALSFRS-R scores between before the administration in the first course and upon termination of the drug holiday period in the sixth course are shown below.

TABLE-US-00004 TABLE 5 Table 5 Number Before- Between- of and-after group patients difference difference S. D. t-test (1) Definite ALS or Probable ALS Actual drug 80  −5.7 1.2 5.7 p > 0.05 administration group Placebo 71  −6.9 6.4 administration group (2) Definite ALS Actual drug 28  −6.7 2.0 6.7 p > 0.05 administration group Placebo 21  −8.7 7.8 administration group (3) Two or more points from all items constituting ALSFRS-R Actual drug 64  −4.7 1.6 5.6 p > 0.05 administration group Placebo 65  −6.3 6.4 administration group (4) 80% or more % FVC Actual drug 79  −3.9 1.3 3.6 p > 0.05 administration group Placebo 74  −5.2 5.9 administration group (5) Two or more points from all items constituting ALSFRS-R and 80 % or more % FVC Actual drug 53  −3.4 2.5 3.4 p > 0.0184 administration group Placebo 46  −5.9 6.8 administration group (6) Definite ALS or Probable ALS, two or more points from all items constituting ALSFRS-R, and 80% or more % FVC Actual drug 45  −3.8 3.7 3.4 p > 0.0038 administration group Placebo 32  −7.5 7.3 administration group (7) Definite ALS, two or more points from all items constituting ALSFRS-R, and 80% or more % FVC Actual drug 18  −4.6 6.4 4.2 p > 0.0126 administration group Placebo 10 −11.0 8.6 administration group

[0141] Even in a case in which patients with amyotrophic lateral sclerosis were not specified, while the ALSFRS-R score was decreased by 6.0 points in the placebo administration group, it was decreased by only 5.3 points in the actual drug administration group. Thus, it was found that 3-methyl-1-phenyl-2-pyrazolin-5-one exhibited effects on the treatment of amyotrophic lateral sclerosis or suppression of the disease progress thereof, or on the treatment of symptoms caused by amyotrophic lateral sclerosis or suppression of the disease progress thereof. However, it became clear that, even among such amyotrophic lateral sclerosis patients, the effects of 3-methyl-1-phenyl-2-pyrazolin-5-one were more clearly exhibited on the following ALS patients: (1) patients who are determined to be “Definite ALS” or “Probable ALS” according to the revised El Escorial (Airlie House) diagnostic criteria; (2) patient who are determined to be “Definite ALS” according to the revised El Escorial (Airlie House) diagnostic criteria; (3) patients who score two or more points from all items constituting the ALSFRS-R; (4) patients whose % FVC is 80% or more; (5) patients who score two or more points from all items constituting the ALSFRS-R and whose % FVC is 80% or more; (6) patients who are determined to be “Definite ALS” or “Probable ALS” according to the revised El Escorial (Airlie House) diagnostic criteria, score two or more points from all items constituting the ALSFRS-R, and whose % FVC is 80% or more; and (7) patients who are determined to be “Definite ALS” according to the revised El Escorial (Airlie House) diagnostic criteria, score two or more points from all items constituting the ALSFRS-R, and whose % FVC is 80% or more. That is to say, when patients with amyotrophic lateral sclerosis were not specified, a difference in the ALSFRS-R scores between before initiation of the administration in the first course and upon termination of the drug holiday period in the sixth course was −5.3 in the actual drug administration group, whereas the same difference in the ALSFRS-R scores was −6.0 in the placebo administration group. Thus, the between-group difference was 0.7. In contrast, in the case of (1) patients who are determined to be “Definite ALS” or “Probable ALS” according to the revised El Escorial (Airlie House) diagnostic criteria, the between-group difference was 1.2; in the case of (2) patient who are determined to be “Definite ALS” according to the revised El Escorial (Airlie House) diagnostic criteria, the between-group difference was 2.0; in the case of (3) patients who score two or more points from all items constituting the ALSFRS-R, the between-group difference was 1.6; in the case of (4) patients whose % FVC is 80% or more, the between-group difference was 1.3; in the case of (5) patients who score two or more points from all items constituting the ALSFRS-R and whose % FVC is 80% or more, the between-group difference was 2.5; in the case of (6) patients who are determined to be “Definite ALS” or “Probable ALS” according to the revised El Escorial (Airlie House) diagnostic criteria, score two or more points from all items constituting the ALSFRS-R, and whose % FVC is 80% or more, the between-group difference was 3.7; and in the case of (7) patients who are determined to be “Definite ALS” according to the revised El Escorial (Airlie House) diagnostic criteria, score two or more points from all items constituting the ALSFRS-R, and whose % FVC is 80% or more, the between-group difference was 6.4. Hence, all of the obtained values were greater than the aforementioned value 0.7. Even in the case of (1), which had the smallest between-group difference value among the aforementioned (1) to (7), the value is 1.2. This value has a difference of 0.5 from the value obtained in the case of not specifying patients with amyotrophic lateral sclerosis (0.7). It has been reported that a difference of 1 point in the ALSFRS-R score would increase the risk of death or tracheostomy for patients with amyotrophic lateral sclerosis by 7% (Neurology 2005; 64: 38-43). Accordingly, in the case of specific patients in the present invention, the risk of such death or tracheostomy can be reduced by 3.5% or more, and thus, this is greatly advantageous for patients with amyotrophic lateral sclerosis. Further, the between-group differences were 2.5, 3.7 and 6.4 in the patient groups (5) to (7) above, respectively. Thus, excellent results could be obtained, in which these values were 3 times or more greater than the between-group difference obtained in the case of not specifying patient groups (0.7). It was also found that these patient groups (5) to (7) each had a significant difference, in comparison with the placebo administration group.