CN117396205A

CN117396205A - Method for titrating Mitapilar

Info

Publication number: CN117396205A
Application number: CN202280038169.9A
Authority: CN
Inventors: A·巴比尔; C·鲍登; P·霍金斯; V·V·伊耶; M-H·朱文
Original assignee: Agios Pharmaceuticals Inc
Current assignee: Agios Pharmaceuticals Inc
Priority date: 2021-04-30
Filing date: 2022-04-28
Publication date: 2024-01-12
Also published as: WO2023154036A1

Abstract

Provided herein are safe and effective dosing regimens for mitsubvalvular and/or pharmaceutically acceptable salts thereof.

Description

Method for titrating Mitapilar

RELATED APPLICATIONS

The present application claims the priority benefits of PCT/US2021/030312 filed on month 4, 30 of 2021 and PCT/US2022/015684 filed on month 2, 8 of 2022, each of which is incorporated herein by reference in its entirety.

Background

Pyruvate Kinase Deficiency (PKD) is a red blood cell disorder caused by a deficiency of the enzyme Pyruvate Kinase R (PKR) due to a recessive mutation in the PKLR gene. PKR activators may be beneficial in the treatment of PKD, thalassemia (e.g., beta-thalassemia), non-beta lipoproteinemia or Bassen-Kornzweig syndrome, sickle cell disease, paroxysmal sleep-induced hemoglobinuria, anemias (e.g., congenital anemias (e.g., enzymopathies), hemolytic anemias (e.g., hereditary and/or congenital hemolytic anemias, acquired hemolytic anemias, chronic hemolytic anemias caused by phosphoglycerate kinase deficiency, chronic disease anemia, non-spherical erythrocyte hemolytic anemia, or hereditary spherical erythrocyte hyperplasia), treatment of PKD is supportive, including transfusion, splenectomy, chelation therapy to address iron overload, and/or intervention for other PKD-related conditions.

Mitapitava, also known as AG-348 or its chemical name N- (4- (4- (cyclopropylmethyl) piperazine-1-carbonyl) phenyl) quinoline-8-sulfonamide, is represented by the following structural formula:

and it is the first, orally bioavailable potent allosteric activator of wild-type RBC-specific forms of Pyruvate Kinase (PKR) and a range of PKR mutant enzymes. See, for example, WO 2011/002817, WO 2016/201227, and Kung et al blood.,2017, volume 130, 11: pages 1347-1356. RBC-specific forms of pyruvate kinase are 1 of 4 pyruvate kinase isozymes expressed in human tissue, expressed by 2 separate genes, namely liver-specific forms of Pyruvate Kinase (PKL) and pyruvate kinase muscle isozymes (PKM). Both PKR and PKL are splice isoforms of the PKLR gene, while both PKM1 and PKM2 are expressed by the PKM gene. Mitapravastatin is an allosteric activator of PKR, PKL and PKM2 isozymes with similar potency for each isozyme.

The sesquisulfate salt of betapravastatin (commonly known as betapravastatin sulfate) shows positive therapeutic effects in the treatment of PKD, thalassemia and Sickle Cell Disease (SCD). In view of its therapeutic potential, there is a current need for methods that provide safe and optimized doses of mitsui.

Disclosure of Invention

Clinical studies have shown that mitsubvalvular is effective in increasing hemoglobin levels. However, the extent to which the melagatran causes the haemoglobin change may vary from subject to subject. That is, the amount of mitsui needed to bring the subject's hemoglobin level within the desired target range may be lower for one subject but may be higher for another subject, or vice versa. Hemoglobin below normal levels may lead to anemia, while above normal levels may lead to stroke, heart attacks, and thrombosis. It is therefore important to provide the optimal dose of mitsui in order to achieve the optimal hemoglobin level, i.e. not too high nor too low.

Accordingly, provided herein are safe and effective methods for increasing hemoglobin levels in a subject who may benefit from treatment with Mitapilar, particularly subjects suffering from a pyruvate kinase-related disorder, including, for example, PKD, thalassemia, and SCD. In one aspect, the disclosed methods comprise a) administering to a subject in need of treatment an initial amount of mitsubpitava or a pharmaceutically acceptable salt thereof; b) Assessing whether the hemoglobin level of the subject is within a target level; c) Depending on whether the subject's hemoglobin level is at or within the target level, the amount of mitepiva or a pharmaceutically acceptable salt thereof is adjusted until, for example, the subject's hemoglobin level is within the target level. The process of assessing and adjusting the amount of mitsubvalvular or a pharmaceutically acceptable salt thereof (i.e., steps b and c) may occur multiple times during the course of treatment. However, in some cases, if the initial amount of the mitsubpitava or pharmaceutically acceptable salt thereof or the adjusted amount of the mitsubpitava or pharmaceutically acceptable salt thereof results in an excessive hemoglobin level, or the subject's hemoglobin level increases too rapidly, or the subject experiences an adverse event, the dose of the mitsubpitava or pharmaceutically acceptable salt thereof may be adjusted downward.

In one aspect, the methods described herein comprise a method of treating a disorder selected from PKD, thalassemia, or sickle cell disease in a subject in need thereof, the method comprising a) administering to the subject an initial amount of mitsubpitava or a pharmaceutically acceptable salt for a period of time, wherein the initial amount increases the hemoglobin level of the subject; b) Assessing the subject's hemoglobin level after the period of time to determine if the subject is within the target hemoglobin level; and c) continuing to administer the initial amount of mitsubvalvular or a pharmaceutically acceptable salt thereof if the subject's hemoglobin level is within the target hemoglobin level, or administering the first adjusted amount of mitsubvalvular or a pharmaceutically acceptable salt thereof if the subject's hemoglobin level is not within the target hemoglobin level.

In some aspects, the disclosed methods further comprise continuing to evaluate the subject's hemoglobin level, and then readjusting the amount of the mitrapiva or pharmaceutically acceptable salt thereof until the subject's hemoglobin level is within the target hemoglobin level, i.e., steps b and c.

In some aspects, the condition to be treated is selected from thalassemia and sickle cell disease.

In some aspects, the period of time between the administration of the initial and/or adjusted amount of mitsubpitava or pharmaceutically acceptable salt thereof to the subject and the assessment of the hemoglobin level of the subject ranges from about 1 week to about 15 weeks.

In some aspects, the amount of the mitsui cut administered to the subject as an initial or adjusted amount ranges from about 1mg to about 125mg once daily (QD), twice daily (BID), or three times daily (TID). In some aspects, the amount of the pharmaceutically acceptable salt of the mitsui-va administered to the subject as an initial or adjusted amount ranges from about 1mg of mitsui-va to about 125mg of mitsui-va once daily (QD), twice daily (BID), or three times daily (TID).

In some aspects, the target hemoglobin level is characterized by a normal level of hemoglobin in a male or female subject greater than or equal to about 16 years old, or a combination thereof. In some aspects, the target hemoglobin level is characterized by a baseline hemoglobin level of the subject that increases by greater than or equal to about 1.0g/dL to about 2.5g/dL over a defined period of time.

Clinical studies have also shown that acute hemolysis and subsequent anemia may occur after abrupt interruption or cessation of the mitsubnatal. However, the outcome may also vary from subject to subject, and thus there is no reliable way to predict whether a subject will have such a response. For example, in a phase 2 study with 300mg of mitsubvalvular twice daily, 3.8% of subjects presented with hemolysis after sudden withdrawal of mitsubvalvular, including 1 severe adverse event of acute hemolysis. In contrast, patients who missed only a few doses of mitsui at the end of the course of treatment did not have an acute haemolytic event. Although the exact risk factor for someone to be prone to acute hemolysis cannot be determined, the rapid loss of hemoglobin seems to be a problem in these cases. In view of the uncertainty of who may develop signs or symptoms of acute hemolysis (or subsequent anemia), it is important to develop methods to alleviate such events.

Thus, also provided herein are methods for stopping administration of, or for reducing the given daily amount of, betapirtine or a pharmaceutically acceptable salt thereof, wherein the methods comprise gradually reducing the amount of betapirtine or a pharmaceutically acceptable salt thereof, and monitoring the subject for an indication of acute hemolysis or anemia or both, until betapirtine or a pharmaceutically acceptable salt thereof is no longer administered. In some aspects, it may be desirable to reduce the dose from a given daily amount of mitsubvalvular or a pharmaceutically acceptable salt thereof only once before terminating the treatment. In other aspects, for example in the presence of signs and symptoms of acute hemolysis and/or anemia, or in the case where the subject is found to be excessively susceptible to acute hemolysis and/or anemia, it is contemplated to reduce the amount of administration of the mitsubpitaler or a pharmaceutically acceptable salt thereof a plurality of times. In some cases, such as in cases where a subject experiences clinically significant adverse effects, it may be desirable to immediately discontinue treatment and subsequently monitor for acute hemolysis or anemia, or both.

In one aspect, the methods described herein include a method of stopping treatment with mitsui or a pharmaceutically acceptable salt thereof, and a method of reducing the dose of mitsui or a pharmaceutically acceptable salt thereof to a subject administered a given daily amount of mitsui or a pharmaceutically acceptable salt thereof, the method comprising a) administering to the subject an adjusted amount of mitsui or a pharmaceutically acceptable salt thereof for a period of time, wherein the first adjusted amount is less than the given daily amount; and b) monitoring the subject for acute hemolysis or anemia or both during the period of time.

In one aspect, the methods described herein comprise a method of reducing the dose of mitsui or a pharmaceutically acceptable salt thereof to a subject administered a given daily amount of mitsui or a pharmaceutically acceptable salt thereof, the method comprising a) administering to the subject an adjusted amount of mitsui or a pharmaceutically acceptable salt thereof for a period of time, wherein the adjusted amount is less than the given daily amount; and b) monitoring the subject for acute hemolysis or anemia or both during the period of time.

In some aspects, the disclosed methods further comprise continuing to monitor the subject for acute hemolysis or anemia or both, and the subject's hemoglobin level, and then readjusting the amount of the mitsubpitava or a pharmaceutically acceptable salt thereof until administration of the mitsubpitava or a pharmaceutically acceptable salt thereof is terminated. In some aspects, the disclosed methods further comprise continuing to monitor the subject for acute hemolysis or anemia, or both, after terminating administration of the mitsui or a pharmaceutically acceptable salt thereof.

In some aspects, the period of time between the administration of the initial and/or adjusted amount of mitsubvalvular or a pharmaceutically acceptable salt thereof to the subject and monitoring the subject for acute hemolysis and/or anemia ranges from about 1 day to about 20 days.

In some aspects, the amount of mitsubnatal or pharmaceutically acceptable salt thereof administered to the subject in an adjusted amount ranges from about 30% to about 90% of a given daily amount, or in the case of multiple adjusted amounts, from about 30% to about 90% of the previous adjusted amount.

In some aspects, the amount of mitsui or pharmaceutically acceptable salt thereof administered to the subject in a given daily amount or in a regulated amount ranges from about 1mg to about 125mg once daily (QD), twice daily (BID), three times daily (TID), or once every two days (QOD).

In some aspects, a subject who is discontinued treatment with Mitapravastatin or a pharmaceutically acceptable salt thereof is receiving treatment for a disorder selected from PKD, thalassemia and sickle cell disease.

In some aspects, administration of the mitsui or a pharmaceutically acceptable salt thereof is immediately terminated (e.g., in the event that the subject experiences a clinically significant adverse effect), and the subject is monitored for acute hemolysis or anemia, or both, over a period of time.

Detailed Description

Dose escalation

As part of a first embodiment, provided herein is a method of treating a disorder selected from PKD, thalassemia, and sickle cell disease in a subject in need thereof, the method comprising a) administering to the subject an initial amount of mitsubpitaled or a pharmaceutically acceptable salt for a first period of time, wherein the amount increases the hemoglobin level of the subject; b) Assessing the subject's hemoglobin level after the first period of time to determine if the subject is within a target hemoglobin level; and c) continuing to administer the initial amount of mitsubvalvular or a pharmaceutically acceptable salt thereof if the subject's hemoglobin level is within the target hemoglobin level, or administering the first adjusted amount of mitsubvalvular or a pharmaceutically acceptable salt thereof if the subject's hemoglobin level is not within the target hemoglobin level. Alternatively, as part of the first embodiment, provided herein is a method of treating a disorder selected from thalassemia and sickle cell disease in a subject in need thereof, the method comprising a) administering to the subject an initial amount of mitsubpitava or a pharmaceutically acceptable salt for a first period of time, wherein the amount increases the hemoglobin level of the subject; b) Assessing the subject's hemoglobin level after the first period of time to determine if the subject is within a target hemoglobin level; and c) continuing to administer the initial amount of mitsubvalvular or a pharmaceutically acceptable salt thereof if the subject's hemoglobin level is within the target hemoglobin level, or administering the first adjusted amount of mitsubvalvular or a pharmaceutically acceptable salt thereof if the subject's hemoglobin level is not within the target hemoglobin level.

As part of the second embodiment, the disclosed methods (such as those in the first embodiment) further comprise administering a first adjusted amount of mitsubvalvular or a pharmaceutically acceptable salt thereof for a second period of time; assessing the subject's hemoglobin level after the second period of time to determine if the subject is within the target hemoglobin level; and continuing to administer the first adjusted amount if the subject's hemoglobin level is within the target hemoglobin level after the second period of time, or administering a second adjusted amount of mitepiva or a pharmaceutically acceptable salt thereof if the subject's hemoglobin level is not within the target hemoglobin level.

As part of the third embodiment, the disclosed methods (such as those in the first and second embodiments) further comprise administering a third adjusted amount of mitsubvalvular or a pharmaceutically acceptable salt thereof for a third period of time; or if the subject's hemoglobin level is within the target hemoglobin level, continuing to administer the second adjustment amount.

As part of the fourth embodiment, the disclosed methods (such as any of those of the first to third embodiments) further comprise continuing to evaluate the subject's hemoglobin level and readjusting the amount of the mitsui or a pharmaceutically acceptable salt thereof until the subject's hemoglobin level is within the target hemoglobin level, or continuing to administer the mitsui or a pharmaceutically acceptable salt thereof to the subject without further adjustment.

As part of the fifth embodiment, the disclosed methods (such as any of those of the first to fourth embodiments) administer an initial and/or adjusted amount of mitsubpitant or a pharmaceutically acceptable salt thereof to the subject for a period of time ranging from about 1 week to about 12 weeks, and up to about 1 week to about 12 weeks, between assessing the subject's hemoglobin level. For example, as part of the fifth embodiment, the first, second, and third time periods described herein (such as any of those of the first to fourth embodiments) are each independently selected from about 1 to about 12 weeks, about 1 to about 11 weeks, about 1 to about 10 weeks, about 1 to about 9 weeks, about 1 to about 8 weeks, about 1 to about 7 weeks, about 1 to about 6 weeks, about 1 to about 5 weeks, about 1 to about 4 weeks, about 1 to about 3 weeks, about 1 to about 2 weeks, about 2 to about 12 weeks, about 2 to about 11 weeks, about 2 to about 10 weeks, about 2 to about 9 weeks, about 2 to about 8 weeks, about 2 to about 7 weeks, about 2 to about 6 weeks, about 2 to about 5 weeks, about 2 to about 4 weeks, about 2 to about 3 weeks from about 3 weeks to about 12 weeks, from about 3 weeks to about 11 weeks, from about 3 weeks to about 10 weeks, from about 3 weeks to about 9 weeks, from about 3 weeks to about 8 weeks, from about 3 weeks to about 7 weeks, from about 3 weeks to about 6 weeks, from about 3 weeks to about 5 weeks, from about 3 weeks to about 4 weeks, from about 4 weeks to about 12 weeks, from about 4 weeks to about 11 weeks, from about 4 weeks to about 10 weeks, from about 4 weeks to about 9 weeks, from about 4 weeks to about 8 weeks, from about 4 weeks to about 7 weeks, from about 4 weeks to about 6 weeks, from about 4 weeks to about 5 weeks, from about 5 weeks to about 12 weeks, from about 5 weeks to about 11 weeks, from about 5 weeks to about 10 weeks, from about 5 weeks to about 9 weeks, from about 5 weeks to about 8 weeks, from about 5 weeks to about 7 weeks, from about 5 weeks to about 6 weeks, from about 6 weeks to about 12 weeks, from about 6 weeks to about 11 weeks, from about 6 weeks to about 10 weeks, from about 6 weeks to about 9 weeks, from about 6 weeks to about 8 weeks, and from about 6 weeks to about 7 weeks. Alternatively, as part of the fifth embodiment, the first, second, and third time periods described herein (such as any of those of the first to fourth embodiments) are each independently selected from at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, and at least about 12 weeks. In another alternative, as part of the fifth embodiment, the first, second, and third time periods described herein (such as any of those of the first to fourth embodiments) are each independently selected from at most 1 week, at most 2 weeks, at most 3 weeks, at most 4 weeks, at most 5 weeks, at most 6 weeks, at most 7 weeks, at most 8 weeks, at most 9 weeks, at most 10 weeks, at most 11 weeks, and at most 12 weeks. In another alternative, as part of the fifth embodiment, the first, second, and third time periods described herein (such as any of those of the first to fourth embodiments) are each independently selected from about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, and about 12 weeks.

As part of the sixth embodiment, some or all of the time periods between administration of the initial and/or adjusted amount of the mitsubnatal or pharmaceutically acceptable salt thereof to the subject in the disclosed methods (such as any of those of the first to fifth embodiments) are of the same duration of time between evaluation of the hemoglobin level of the subject. For example, as part of the sixth embodiment, the first and second time periods described herein (such as any of those of the first to fifth embodiments) are the same duration; the first and third time periods described herein (such as any of those of the first to fifth embodiments) are the same duration; the second and third time periods described herein (such as any of those of the first to fifth embodiments) are the same duration; or the first, second, third time periods described herein (such as any of those of the first through fifth embodiments) are all the same duration.

Also described herein are amounts of the mitsui or pharmaceutically acceptable salt thereof used in the disclosed methods, and can vary depending on the nature of the method (e.g., dose or dose escalation versus dose or dose decrementing). As part of the seventh embodiment herein, and with reference to any one of the first to sixth embodiments, for example, the initial amount of mitsui, the first adjusted amount of mitsui, the second adjusted amount of mitsui, and the third adjusted amount of mitsui are each independently selected from about 5mg, about 20mg, about 50mg, and about 100mg; and the initial amount of the pharmaceutically acceptable salt of the mibeframate, the first adjusted amount of the pharmaceutically acceptable amount of the mibeframate, the second adjusted amount of the pharmaceutically acceptable amount of the mibeframate, and the third adjusted amount of the pharmaceutically acceptable amount of the mibeframate are each independently selected from amounts equal to about 5mg of mibeframate, about 20mg of mibeframate, about 50mg of mibeframate, and about 100mg of mibeframate. As part of the eighth embodiment, the initial amount of the mitsui or pharmaceutically acceptable salt thereof, the first adjusted amount, the second adjusted amount, and the third adjusted amount are each administered once daily (QD), twice daily (BID), or three times daily (TID).

As used herein, the term "target hemoglobin level" refers to a normal hemoglobin level based on the age and sex of a human or a rate of increase in hemoglobin value sufficient to bring the subject's hemoglobin level to a normal range over a period of time. In one aspect, as part of the ninth embodiment, the target hemoglobin level in the disclosed methods (e.g., as set forth in any one of the first to eighth embodiments) is characterized by a baseline hemoglobin level of the subject that is increased by about 1.0g/dL to about 2.0g/dL, individually or collectively, during any one of the first, second, or third time periods. Alternatively, as part of the ninth embodiment, the target hemoglobin level in the disclosed methods (e.g., as set forth in any one of the first to eighth embodiments) is characterized by a baseline hemoglobin level of the subject that is increased by about 1.0g/dL, about 1.5g/dL, or about 2.0g/dL, individually or collectively, during any one of the first, second, or third time periods. In another alternative, the target hemoglobin level in the disclosed method (e.g., as set forth in any one of the first through eighth embodiments) is between about 12.0g/dL and about 17.5g/dL as part of the ninth embodiment. In another alternative, the target hemoglobin level in the disclosed methods (e.g., as described in any one of the first to eighth embodiments) is between about 12.0g/dL and about 17.5g/dL for subjects aged greater than or equal to 16 years as part of the ninth embodiment. In another alternative, the target hemoglobin level in the disclosed methods (e.g., as in any one of the first through eighth embodiments) is between about 13.5g/dL and about 17.5g/dL for adult males (age. Gtoreq.18 years) and between about 12.0g/dL and about 15.5g/dL for adult females (age. Gtoreq.18 years) as part of the ninth embodiment. In another alternative, the target hemoglobin level in the disclosed methods (e.g., as described in any one of the first to eighth embodiments) is between about 13.5g/dL and about 17.5g/dL for men aged no less than 16 years, and between about 12.0g/dL and about 15.5g/dL for women aged no less than 16 years, as part of the ninth embodiment. In another alternative, the target hemoglobin level in the disclosed methods (e.g., as described in any one of the first to eighth embodiments) is between about 11.9g/dL and about 15.0g/dL for female subjects aged 11 to 18 years as part of the ninth embodiment. In another alternative, the target hemoglobin level in the disclosed methods (e.g., as described in any one of the first to eighth embodiments) is between about 12.7g/dL and about 17.7g/dL for a male subject aged 11 to 18 years old as part of the ninth embodiment. In another alternative, as part of the ninth embodiment, the target hemoglobin level in the disclosed methods (e.g., as set forth in any one of the first to eighth embodiments) is between about 10.7g/dL and about 19.9g/dL for subjects less than 18 years old (i.e., non-adult subjects).

As used herein, "baseline hemoglobin level of a subject" refers to the hemoglobin level of the subject prior to administration of the mitsubpitant or pharmaceutically acceptable salt thereof (e.g., prior to administration of an initial amount of mitsubpitant or pharmaceutically acceptable salt thereof in the foregoing embodiments). In some aspects, the subject's baseline hemoglobin level is less than about 14.0g/dL, such as less than about 13.5g/dL for adult males and less than about 12.0g/dL for adult females. In other aspects, the subject's baseline hemoglobin level is between about 5.5g/dL and about 10.5 g/dL.

Dose decrementing

As part of a tenth embodiment, provided herein is a method of stopping treatment with mitsui or a pharmaceutically acceptable salt thereof for a subject administered a given daily amount of mitsui or a pharmaceutically acceptable salt thereof, the method comprising a) administering to the subject a first adjusted amount of mitsui or a pharmaceutically acceptable salt thereof for a first period of time, wherein the first adjusted amount is less than the given daily amount; and b) monitoring the subject for acute hemolysis or anemia or both during the first period of time. Alternatively, as part of the tenth embodiment, provided herein is a method for reducing a given daily amount of mitsui or a pharmaceutically acceptable salt thereof administered to a subject, the method comprising a) administering to the subject a first adjusted amount of mitsui or a pharmaceutically acceptable salt thereof for a first period of time, wherein the first adjusted amount is less than the given daily amount; and b) monitoring the subject for acute hemolysis or anemia or both during the first period of time.

As used herein, a "given daily amount" of mitsui or a pharmaceutically acceptable salt thereof is synonymous with a "given daily dose" of mitsui or a pharmaceutically acceptable salt thereof and refers to the amount of mitsui or a pharmaceutically acceptable salt administered to a subject prior to administration of a first adjusted amount of mitsui or a pharmaceutically acceptable salt thereof to the subject. As further described herein, the predetermined daily amount may be an amount of the pharmaceutically acceptable salt of mitsui ranging from about 1mg to about 300mg of mitsui, or equal to about 1mg to about 300mg of mitsui. In some embodiments, the given daily amount may be an amount of the pharmaceutically acceptable salt of the mitsui ranging from about 1mg to about 200mg of mitsui, or equal to about 1mg to about 200mg of mitsui.

As part of the eleventh embodiment, the disclosed method (e.g., as described in the tenth embodiment) further comprises the steps of: c) If the subject exhibits symptoms of acute hemolysis or anemia, the subject is treated for acute hemolysis or anemia or both.

As part of the twelfth embodiment, the disclosed method (e.g., as described in the eleventh embodiment) comprises repeating steps a) and b) for a second period of time using a second adjustment amount, and continuing to monitor the subject for symptoms of acute hemolysis or anemia, or both, wherein the second adjustment amount is less than the first adjustment amount.

As part of the thirteenth embodiment, the disclosed method (e.g., as in any one of the tenth to eleventh embodiments and the thirty-fourth and thirty-sixth embodiments) further comprises the steps of: if the subject exhibits symptoms of acute hemolysis or anemia or both, the subject is treated for acute hemolysis or anemia or both.

As part of the fourteenth embodiment, the administration of the first adjusted amount in the disclosed methods (e.g., as described in any one of the tenth to thirteenth embodiments) is continued until symptoms of acute hemolysis or anemia or both are ameliorated.

As part of the fifteenth embodiment, administration of the second adjustment amount in the disclosed method (e.g., as set forth in any one of the twelfth to fourteenth embodiments) begins immediately after the first time period is completed.

As part of the sixteenth embodiment, the disclosed method (e.g., as set forth in any one of the twelfth to fifteenth embodiments) further comprises repeating steps a) and b), using a third adjustment amount for a third period of time, and continuing to monitor the subject for symptoms of acute hemolysis or anemia, or both, wherein the third adjustment amount is less than the adjustment amount administered in prior step a). Alternatively, as part of the sixteenth embodiment, the disclosed method (e.g., as set forth in any one of the twelfth to fifteenth embodiments) further comprises repeating steps a) and b), using a third adjustment amount for a third period of time, and continuing to monitor the subject for symptoms of acute hemolysis or anemia or both, wherein the third adjustment amount is less than the adjustment amount administered in the previous step a), and wherein administration of the third adjustment amount begins immediately after completion of the second period of time.

As part of the seventeenth embodiment, steps a) and b) of the disclosed method (e.g., as described in any of the tenth to sixteenth embodiments) are repeated until the subject is no longer administered the mitsubpitant or pharmaceutically acceptable salt thereof.

As part of the eighteenth embodiment, the disclosed method (e.g., as set forth in any one of the tenth to seventeenth embodiments and the thirty-fourth and thirty-sixth embodiments) further comprises the steps of: if the subject exhibits symptoms of acute hemolysis and/or anemia, the subject is treated for acute hemolysis and/or anemia. Alternatively, as part of the eighteenth embodiment, the disclosed method (e.g., as set forth in any one of the tenth to seventeenth embodiments and the thirty-fourth and thirty-sixth embodiments) further comprises the steps of: treating acute hemolysis and/or anemia in a subject if the subject exhibits symptoms of acute hemolysis and/or anemia; and continuing to treat the subject until symptoms of acute hemolysis or anemia or both improve.

As part of the nineteenth embodiment, prior to the first adjustment amount, the established daily amount of the mitsui that is administered to the subject prior to the first adjustment amount in the disclosed methods (e.g., as set forth in any one of the tenth to eighteenth embodiments) is selected from the group consisting of about 10 mg/day, about 40 mg/day, about 100 mg/day, and about 200 mg/day; and the given daily amount of the pharmaceutically acceptable salt is selected from an amount equal to about 10mg of mitsunobu, about 40mg of mitsunobu, about 100mg of mitsunobu, and about 200mg of mitsunobu. Alternatively, as part of the nineteenth embodiment, prior to the first adjustment amount, the given daily amount of the mitsui-va administered to the subject prior to the first adjustment amount in the disclosed methods (e.g., as set forth in any one of the tenth to eighteenth embodiments) is selected from about 5mg BID, about 20mg BID, about 50mg BID, or about 100mg BID; and prior to the first adjustment amount, the given daily amount of the pharmaceutically acceptable salt administered to the subject is equal to about 5mg BID of mitsubvalvular, about 20mg BID of mitsubvalvular, about 50mg BID of mitsubvalvular, or about 100mg BID of mitsubvalvular.

As part of the twentieth embodiment, the first adjusted amount of the mitsubpint or pharmaceutically acceptable salt in the disclosed method (e.g., as set forth in any one of the tenth to nineteenth embodiments) is an amount selected from the group consisting of: from about 40% to about 80%, from about 40% to about 60%, from about 45% to about 55%, and from about 49% to about 51% less than the given daily amount of the mitsubvalvular or pharmaceutically acceptable salt. Alternatively, as part of the twentieth embodiment, the first adjusted amount of the mitsui or pharmaceutically acceptable salt in the disclosed method (e.g., as set forth in any one of the tenth to nineteenth embodiments) is about 50% less than the given daily amount of the mitsui or pharmaceutically acceptable salt. In another alternative, as part of the twentieth embodiment, the first adjusted amount of the mitsubnatal or pharmaceutically acceptable salt in the disclosed method (e.g., as set forth in any of the tenth to nineteenth embodiments) is selected from about 5mg, about 20mg, about 50mg, about 100mg; and the first adjusted amount of the pharmaceutically acceptable salt is equal to about 5mg of mitsunobu, about 20mg of mitsunobu, about 50mg of mitsunobu, and about 100mg of mitsunobu. In another alternative, as part of the twentieth embodiment, the first adjusted amount of the mitsui or pharmaceutically acceptable salt in the disclosed method (e.g., as set forth in any one of the tenth to nineteenth embodiments) is selected from the group consisting of about 5mg QD, about 20mg QD, about 50mg QD, and about 100mg QD; and the first adjusted amount of the pharmaceutically acceptable salt is equal to about 5mg of the QD's mitsunobu, about 20mg of the QD's mitsunobu, about 50mg of the QD's mitsunobu, and about 100mg of the QD's mitsunobu.

As part of the twenty-first embodiment, the second adjusted amount of the mitsui or pharmaceutically acceptable salt in the disclosed method (e.g., as set forth in any one of the tenth to twentieth embodiments) reduces the first adjusted amount of the mitsui or pharmaceutically acceptable salt by an amount selected from the group consisting of: about 60% to about 80%, about 70% to about 80%, about 45% to about 85%, about 55% to about 65% less than the given daily amount of the mitsubvalvular or pharmaceutically acceptable salt. Alternatively, as part of the twenty-first embodiment, the second adjusted amount of the mitsui or pharmaceutically acceptable salt in the disclosed methods (e.g., as set forth in any one of the tenth to twentieth embodiments) is about 60% or about 75% less than the given daily amount of the mitsui or pharmaceutically acceptable salt thereof. In another alternative, as part of the twentieth embodiment, the second adjusted amount of the mitsubnatal or pharmaceutically acceptable salt in the disclosed method (e.g., as set forth in any of the tenth to twentieth embodiments) is about 50mg, about 20mg, or about 5mg; and the second adjusted amount of the pharmaceutically acceptable salt of the mitsui is equal to about 50mg of mitsui, about 20mg of mitsui or about 5mg of mitsui.

As part of the twenty-second embodiment, the second adjusted amount of the mitsubvalvular or pharmaceutically acceptable salt thereof in the disclosed methods (e.g., as set forth in any of the tenth to twenty-first embodiments) is equal to the amount of the first adjusted amount of mitsubvalvular or pharmaceutically acceptable salt administered once every two days (QOD). Alternatively, as part of the twenty-second embodiment, in the disclosed method (e.g., as in any one of the tenth to twenty-first embodiments), the second adjusted amount of the mitsubpitava or pharmaceutically acceptable salt thereof is about 5mg QOD, about 20mg QD, or about 50mg QD; and the second adjusted amount of the pharmaceutically acceptable salt is equal to about 5mg of QOD of mitsubpitava, about 20mg of QD of mitsubpitava, or about 50mg of QD of mitsubpitava.

As part of the twenty-third embodiment, the third adjusted amount of the mitsubnatal or pharmaceutically acceptable salt in the disclosed methods (e.g., as described in any of the sixteenth to twenty-first embodiments) is equal to the amount of the second adjusted amount of mitsubnatal or pharmaceutically acceptable salt administered once every two days (QOD). Alternatively, as part of the twenty-third embodiment, the third adjusted amount of the melagatran in the disclosed methods (e.g., as set forth in any one of the sixteenth to twenty-first embodiments) is about 20mg QOD or about 50mg QOD; and the third adjusted amount of the pharmaceutically acceptable salt is equal to about 20mg of QOD of Mitapravastatin, or about 50mg of QOD of Mitapravastatin.

As part of the twenty-fourth embodiment, the time period between administration and monitoring (such as any of those of the tenth to twenty-third embodiments) is each independently selected from about 1 day to about 16 days. Alternatively, for example, as part of the twenty-fourth embodiment, the first and second time periods in the disclosed methods (such as any of those of the tenth to twenty-third embodiments) are each independently selected from about 1 to about 14 days, about 1 to about 12 days, about 1 to about 10 days, about 2 to about 14 days, about 2 to about 12 days, about 2 to about 10 days, about 2 to about 9 days, about 2 to about 5 days, about 2 to about 4 days, about 5 to about 9 days, about 5 to about 8 days, and about 6 to about 8 days. In another alternative, as part of the twenty-fourth embodiment, the first and second time periods in the disclosed methods (such as any of those of the tenth to twenty-third embodiments) are each independently selected from about 2 days to about 5 days, about 2 days to about 4 days, about 5 days to about 8 days, and about 6 days to about 8 days. In another alternative, as part of the twenty-fourth embodiment, the first time period and the second time period in the disclosed method (such as any of those of the tenth embodiment through the twenty-third embodiment) are each independently selected from about 3 days and about 7 days.

As part of the twenty-fifth embodiment, both the first and second time periods (such as any of those of the tenth to twenty-fourth embodiments) in the disclosed methods are the same.

As part of the twenty-sixth embodiment, the third time period in the disclosed methods (such as any of those of the sixteenth to twenty-fifth embodiments) is selected from about 1 to about 14 days, about 1 to about 12 days, about 1 to about 10 days, about 2 to about 14 days, about 2 to about 12 days, about 2 to about 10 days, about 2 to about 9 days, about 2 to about 5 days, about 2 to about 4 days, about 5 to about 9 days, about 5 to about 8 days, and about 6 to about 8 days. Alternatively, as part of the twenty-sixth embodiment, the third time period in the disclosed method (such as any of those of the sixteenth to twenty-fifth embodiments) is selected from about 2 to about 5 days, about 2 to about 4 days, about 5 to about 8 days, and about 6 to about 8 days. In another alternative, the third time period in the disclosed methods (such as any of those of the sixteenth to twenty-fifth embodiments) is about 7 days as part of the twenty-sixth embodiment.

As part of the twenty-seventh embodiment, the first, second, and third time periods in the disclosed method (such as any of those of the tenth to twenty-sixth embodiments) are each the same duration.

As part of the twenty-eighth embodiment, the disclosed method (such as any one of the tenth to twenty-seventh embodiments and thirty-fourth and thirty-sixth embodiments) further comprises monitoring the subject for acute hemolysis or anemia or both after terminating administration of the mitsui-pravastatin or a pharmaceutically acceptable salt thereof. Alternatively, as part of the twenty-eighth embodiment, the disclosed methods (such as any of the tenth to twenty-seventh embodiments and thirty-fourth and thirty-sixth embodiments) further comprise monitoring the subject for acute hemolysis or anemia or both after terminating administration of the mitsui or a pharmaceutically acceptable salt thereof, wherein monitoring comprises testing the subject for acute hemolysis or anemia or both.

As part of the twenty-ninth embodiment, there is provided a method for stopping administration of a given daily amount of mitsui or a pharmaceutically acceptable salt thereof to a subject in need thereof, the method comprising a) immediately terminating all administration of mitsui or a pharmaceutically acceptable salt thereof; and b) monitoring the subject for acute hemolysis or anemia or both over a period of time (e.g., from about 1 day to about 14 days, from about 1 day to about 12 days, from about 1 day to about 10 days, from about 2 days to about 14 days, from about 2 days to about 12 days, from about 2 days to about 10 days, from about 2 days to about 9 days, from about 2 days to about 5 days, from about 2 days to about 4 days, from about 5 days to about 9 days, from about 5 days to about 8 days, from about 6 days to about 8 days, about 14 days or less, or about 7 days or less).

As part of the thirty-first embodiment, there is provided a method for stopping administration of a given daily dose of mitsui or a pharmaceutically acceptable salt thereof to a subject suffering from an adverse event, the method comprising a) immediately terminating all administration of mitsui or a pharmaceutically acceptable salt thereof; and b) monitoring the subject for acute hemolysis or anemia or both over a period of time (e.g., from about 1 day to about 14 days, from about 1 day to about 12 days, from about 1 day to about 10 days, from about 2 days to about 14 days, from about 2 days to about 12 days, from about 2 days to about 10 days, from about 2 days to about 9 days, from about 2 days to about 5 days, from about 2 days to about 4 days, from about 5 days to about 9 days, from about 5 days to about 8 days, from about 6 days to about 8 days, about 14 days or less, or about 7 days or less). Alternatively, as part of the thirty-first embodiment, there is provided a method for stopping administration of a given daily dose of mitsui or a pharmaceutically acceptable salt thereof to a subject suffering from a clinically significant adverse effect, the method comprising a) immediately stopping all administration of mitsui or a pharmaceutically acceptable salt thereof; and b) monitoring the subject for acute hemolysis or anemia or both over a period of time (e.g., from about 1 day to about 14 days, from about 1 day to about 12 days, from about 1 day to about 10 days, from about 2 days to about 14 days, from about 2 days to about 12 days, from about 2 days to about 10 days, from about 2 days to about 9 days, from about 2 days to about 5 days, from about 2 days to about 4 days, from about 5 days to about 9 days, from about 5 days to about 8 days, from about 6 days to about 8 days, about 14 days or less, or about 7 days or less).

Also provided herein is a method of administering to a subject, mitapilar or a pharmaceutically acceptable salt thereof, whereby abrupt cessation of Mitapilar or a pharmaceutically acceptable salt thereof is avoided to minimize the risk of acute hemolysis.

As used herein, "acute hemolysis" refers to the rupture of red blood cells that can lead to hemolytic anemia. Methods for determining whether a subject is acutely hemolyzed are known in the art and include physical and visual symptoms. In one aspect, for example, as part of the thirty-first embodiment, the acute hemolysis disclosed in the methods of the present invention (such as any one of the tenth to thirty-first embodiments and thirty-sixth embodiments) is characterized by a rapid loss of hemoglobin of greater than about 0.1 g/dL/day to about 0.2 g/dL/day. Alternatively, as part of the thirty-first embodiment, the acute hemolysis disclosed in the methods of the present invention (such as any one of those of the tenth to thirty-first embodiments and thirty-sixth embodiments) is characterized by a loss of hemoglobin of about 1.7 g/dL/day to about 2.5 g/dL/day. In another alternative, as part of the thirty-first embodiment, the acute hemolysis disclosed in the methods of the present invention (such as any one of the tenth to thirty-first embodiments and thirty-sixth embodiments) is characterized by the subject having one or more of jaundice, jaundice in the sclera, and reddish urine. In another alternative, as part of the thirty-first embodiment, the acute hemolysis disclosed in the methods of the present invention (such as any one of the tenth to thirty-first embodiments and thirty-sixth embodiments) is characterized by the subject suffering from one or more of reddish urine, yellowing of skin or eyes, dizziness, blurred consciousness, tiredness, dizziness, or shortness of breath. In another alternative, as part of the thirty-first embodiment, the acute hemolysis disclosed in the methods of the present invention (such as any one of the tenth to thirty-first embodiments and thirty-sixth embodiments) is characterized by the subject suffering from one or more of jaundice, jaundice in the sclera, reddish urine, dizziness, blurred consciousness, fatigue, or shortness of breath.

As part of the thirty-second embodiment, the subject in the disclosed method (e.g., as set forth in any one of the tenth to thirty-first embodiments and thirty-fourth and thirty-sixth embodiments) is receiving treatment for a disorder selected from the group consisting of Pyruvate Kinase Deficiency (PKD), thalassemia, and Sickle Cell Disease (SCD). Alternatively, as part of the thirty-second embodiment, the subject in the disclosed method (e.g., as set forth in any one of the tenth to thirty-first embodiments and thirty-fourth and thirty-sixth embodiments) is receiving treatment for PKD. In another alternative, as part of the thirty-second embodiment, the subject in the disclosed method (e.g., as set forth in any one of the tenth to thirty-first embodiments and thirty-fourth and thirty-sixth embodiments) is receiving treatment for hemolytic anemia or anemia arising from or associated with Pyruvate Kinase Deficiency (PKD). In another alternative, the subject in the disclosed method (e.g., as set forth in any one of the tenth to thirty-first embodiments and thirty-fourth and thirty-sixth embodiments) is receiving treatment for SCD as part of the thirty-second embodiment. In yet another alternative, the subject in the disclosed methods (e.g., as set forth in any one of the tenth to thirty-first embodiments and thirty-fourth and thirty-sixth embodiments) is receiving treatment for thalassemia. In another alternative, the subject in the disclosed methods (e.g., as in any one of the tenth to thirty-first embodiments and thirty-fourth and thirty-sixth embodiments) is receiving treatment for alpha thalassemia or beta thalassemia.

As part of the thirty-third embodiment, if the subject suffers from an adverse event or clinically significant adverse reaction, administration of the mitsui-va or pharmaceutically acceptable salt thereof disclosed herein is immediately terminated (e.g., as described in any one of the tenth to thirty-second embodiments) regardless of the time period or the intended daily dose.

In one aspect, thalassemia of the disclosed methods (e.g., as described in any one of the first to thirty-third embodiments) is non-transfusion dependent thalassemia or transfusion dependent thalassemia.

In one aspect, the thalassemia of the disclosed method (e.g., as set forth in any one of the first through thirty-third embodiments) is alpha thalassemia or beta thalassemia.

As part of the thirty-fourth embodiment, provided herein is a method of stopping treatment with betapravastatin or a pharmaceutically acceptable salt thereof (e.g., sulfate, hemisulfate or sesquisulfate salt) for a subject administered with betapravastatin twice daily (BID) in an amount of about 5mg or equal to about 5mg of betapravastatin BID, the method comprising administering betapravastatin or a pharmaceutically acceptable drug thereof (e.g., sulfate, hemisulfate or sesquisulfate salt) according to the following dose-decreasing schedule: day 1 to day 7: administering to the subject about 5mg of mitsuiva once per day (QD), or administering to the subject a pharmaceutically acceptable salt of mitsuiva (e.g., a sulfate, hemisulfate, or sesquisulfate salt of sesquihydrate) in an amount equal to about 5mg of mitsuiva QD; day 8: thereafter, the administration of the mitsubpitava or a pharmaceutically acceptable salt of mitsubpitava (e.g., a sulfate, hemisulfate, or sesquisulfate salt) is stopped. Alternatively, as part of the thirty-fourth embodiment, provided herein is a method of stopping treatment with the metaplava or a pharmaceutically acceptable salt thereof (e.g., sulfate, hemisulfate, or sesquisulfate salt) of metaplava for a subject administered an amount of about 5mg of metaplava twice daily (BID) or equal to about 5mg of metaplava BID, the method comprising administering the metaplava or a pharmaceutically acceptable drug thereof (e.g., sulfate, hemisulfate, or sesquisulfate salt of sesquisulfate) according to the following dose-decreasing schedule: day 1 to day 7: administering to the subject about 5mg of mitsuiva once per day (QD), or administering to the subject a pharmaceutically acceptable salt of mitsuiva (e.g., a sulfate, hemisulfate, or sesquisulfate salt of sesquihydrate) in an amount equal to about 5mg of mitsuiva QD; day 8 to day 14: administering to the subject about 5mg of mitsubpitava once every two days (QOD), or administering to the subject a pharmaceutically acceptable salt of mitsubpitava (e.g., a sulfate, hemisulfate, or sesquisulfate salt of sesquisulfate) in an amount equal to about 5mg of mitsubpitava QOD; day 15: the administration of the mitsubvalvular or a pharmaceutically acceptable salt thereof (e.g., a sulfate, a hemisulfate, or a sesquisulfate salt) is stopped. In another alternative, as part of the thirty-fourth embodiment, provided herein is a method of stopping treatment with the pharmaceutical acceptable salt of the mitsui or the pharmaceutical acceptable salt thereof (e.g., the sulfate, hemisulfate, or hemisulfate sesquihydrate salt) for a subject administered the pharmaceutical acceptable salt of the mitsui (e.g., the sulfate, hemisulfate, or hemisulfate sesquihydrate salt) in an amount of about 20mg of mitsui bitime per day (BID), the method comprising administering the pharmaceutical acceptable salt of the mitsui or the pharmaceutical acceptable salt thereof (e.g., the sulfate, hemisulfate, or hemisulfate sesquihydrate salt) according to the dose-decreasing schedule: day 1 to day 7: administering to the subject about 20mg of mitsuiva once per day (QD), or administering to the subject a pharmaceutically acceptable salt of mitsuiva (e.g., a sulfate, hemisulfate, or sesquisulfate salt of sesquihydrate) in an amount equal to about 20mg of mitsuiva QD; day 8 to day 14: administering to the subject about 5mg of mitsuiva once per day (QD), or administering to the subject a pharmaceutically acceptable salt of mitsuiva (e.g., a sulfate, hemisulfate, or sesquisulfate salt of sesquihydrate) in an amount equal to about 5mg of mitsuiva QD; day 15: the administration of the mitsubvalvular or a pharmaceutically acceptable salt thereof (e.g., a sulfate, a hemisulfate, or a sesquisulfate salt) is stopped. In another alternative, provided herein as part of the thirty-fourth embodiment is a method of stopping treatment with mitsui or a pharmaceutically acceptable salt thereof (e.g., a sulfate, a hemisulfate, or a sesquisulfate salt) of mitsui for a subject administered about 20mg of mitsui twice daily (BID) or an amount of a pharmaceutically acceptable salt of mitsui (e.g., a sulfate, a hemisulfate, or a sesquisulfate salt) of mitsui equal to about 20mg of mitsui BID administered to the subject, the method comprising administering mitsui or a pharmaceutically acceptable drug thereof (e.g., a sulfate, a hemisulfate, or a sesquisulfate salt) according to the dose-decreasing schedule: day 1 to day 7: administering to the subject about 20mg of mitsuiva once per day (QD), or administering to the subject a pharmaceutically acceptable salt of mitsuiva (e.g., a sulfate, hemisulfate, or sesquisulfate salt of sesquihydrate) in an amount equal to about 20mg of mitsuiva QD; day 8 to day 14: administering to the subject about 20mg of mitsubpitava once every two days (QOD), or administering to the subject a pharmaceutically acceptable salt of mitsubpitava (e.g., a sulfate, hemisulfate, or sesquisulfate salt of sesquisulfate) in an amount equal to about 20mg of mitsubpitava QOD; day 15: the administration of the mitsubvalvular or a pharmaceutically acceptable salt thereof (e.g., a sulfate, a hemisulfate, or a sesquisulfate salt) is stopped. In another alternative, provided herein as part of the thirty-fourth embodiment is a method of stopping treatment with the mizopravastatin or a pharmaceutically acceptable salt thereof (e.g., sulfate, hemisulfate, or sesquisulfate salt) of the mizoprava for a subject administered about 50mg of mizoprava twice daily (BID) or administered an amount of a pharmaceutically acceptable salt of the mizoprava (e.g., sulfate, hemisulfate, or sesquisulfate salt) equal to about 50mg of mizoprava BID administered to the subject, the method comprising administering the mizoprava or a pharmaceutically acceptable drug thereof (e.g., sulfate, hemisulfate, or sesquisulfate salt) according to the dose-decreasing schedule: day 1 to day 7: administering to the subject about 50mg of mitsuiva once per day (QD), or administering to the subject a pharmaceutically acceptable salt of mitsuiva (e.g., a sulfate, hemisulfate, or sesquisulfate salt of sesquihydrate) in an amount equal to about 50mg of mitsuiva QD; day 8 to day 14: administering to the subject about 20mg of mitsuiva once per day (QD), or administering to the subject a pharmaceutically acceptable salt of mitsuiva (e.g., a sulfate, hemisulfate, or sesquisulfate salt of sesquihydrate) in an amount equal to about 20mg of mitsuiva QD; day 15: the administration of the mitsubvalvular or a pharmaceutically acceptable salt thereof (e.g., a sulfate, a hemisulfate, or a sesquisulfate salt) is stopped. In another alternative, provided herein as part of the thirty-fourth embodiment is a method of stopping treatment with the mizopravastatin or a pharmaceutically acceptable salt thereof (e.g., sulfate, hemisulfate, or sesquisulfate salt) of the mizoprava for a subject administered about 50mg of mizoprava twice daily (BID) or administered an amount of a pharmaceutically acceptable salt of the mizoprava (e.g., sulfate, hemisulfate, or sesquisulfate salt) equal to about 50mg of mizoprava BID administered to the subject, the method comprising administering the mizoprava or a pharmaceutically acceptable drug thereof (e.g., sulfate, hemisulfate, or sesquisulfate salt) according to the dose-decreasing schedule: day 1 to day 7: administering to the subject about 50mg of mitsuiva once per day (QD), or administering to the subject a pharmaceutically acceptable salt of mitsuiva (e.g., a sulfate, hemisulfate, or sesquisulfate salt of sesquihydrate) in an amount equal to about 50mg of mitsuiva QD; day 8 to day 14: administering to the subject about 20mg of mitsuiva once per day (QD), or administering to the subject a pharmaceutically acceptable salt of mitsuiva (e.g., a sulfate, hemisulfate, or sesquisulfate salt of sesquihydrate) in an amount equal to about 20mg of mitsuiva QD; day 15 to day 21: about 20mg of mitsui is administered to the subject once every two days (QOD), or a pharmaceutically acceptable salt of mitsui (e.g., sulfate, hemisulfate, or sesquisulfate salt) is administered to the subject in an amount equal to about 20mg of mitsui QOD: day 22: the administration of the mitsubvalvular or a pharmaceutically acceptable salt thereof (e.g., a sulfate, a hemisulfate, or a sesquisulfate salt) is stopped.

In a thirty-fifth embodiment, the method described in the thirty-fourth embodiment further comprises monitoring the subject for acute hemolysis or anemia, or both.

In a thirty-sixth embodiment, the mitsubnatal or pharmaceutically acceptable salt thereof described in the above dose decrements can be crystalline or amorphous.

Throughout this application, brackets are used to further describe certain aspects of the present invention and should not be construed in a limiting sense. For example, with respect to salts, the terms "sulfate", "hemisulfate" and "sesquisulfate salt" mentioned in "or pharmaceutically acceptable salts of Mitapil (e.g., sulfate, hemisulfate or sesquisulfate salt)" are provided as alternative exemplary embodiments and should not be construed as limiting descriptions of the broader term "salt".

As used herein, the terms "treat (treatment, treat and treating)" refer to reversing, alleviating, reducing the likelihood of developing, or inhibiting the progression of, a disease or disorder or one or more of its effects or symptoms. In some embodiments, the treatment, i.e., therapeutic treatment, may be administered after one or more symptoms have occurred. In other embodiments, the treatment may be administered in the absence of symptoms. For example, treatment, i.e., prophylactic treatment, may be administered to a susceptible individual prior to onset of symptoms (e.g., based on a history of symptoms and/or based on genetic or other predisposing factors). Treatment may also be continued after the symptoms subside, for example, to reduce the likelihood of recurrence or to delay recurrence.

As used herein, the terms "subject" and "patient" are used interchangeably and refer to a mammal in need of or undergoing treatment. Typically, the subject is a human in need of treatment. In some aspects, the subject in the disclosed methods is an adult subject (i.e., male or female aged 18 years or older). In other aspects, the subject in the disclosed methods is a non-adult subject (i.e., male or female aged 17 years or less). In other aspects, the subject in the disclosed methods is a male or female aged 16 years or older.

The terms "dose" and "amount" are used interchangeably.

As used herein, the term "adverse reaction" refers to an adverse reaction that is reasonably associated with the use of a drug, which may occur as part of the pharmacological effect of the drug, or which may occur unpredictably.

The term "clinically significant adverse reaction" as used herein refers to any reaction that occurs in a patient or subject at any dose that results in any of the following outcomes: death, life threatening adverse events, a non-refractory hospitalization or prolonged existing hospitalization time, persistent or severe disability or incapacity, or congenital abnormalities or birth defects. Other medical events that may not lead to death or be life threatening or require hospitalization may be considered adverse reactions if, based on appropriate medical judgment, such events may endanger the patient or subject and medical or surgical intervention may be required to prevent any of the outcomes listed in the previous sentence.

As used herein, the term "adverse event" refers to any adverse medical event associated with the use of a drug by a human, whether or not the medical event is deemed to be associated with the drug.

In some aspects, the mitsubpitant or pharmaceutically acceptable salt thereof as disclosed in the methods of the invention (e.g., as set forth in any of the first through thirty-fourth embodiments) can be crystalline or amorphous.

The term "pharmaceutically acceptable salts" when referring to pharmaceutically acceptable salts of Mitazipras refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and lower animals without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art, for example, as described in detail in Berge et al, J.pharmaceutical Sciences,1977, volume 66, pages 1-19. Pharmaceutically acceptable salts of mitsubvalvular include salts derived from suitable inorganic and organic acids. Examples of pharmaceutically acceptable acid addition salts are salts of amino groups with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartate, benzenesulfonates, benzoates, benzenesulfonates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecylsulfate, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphate, gluconate, gentisates, hemisulfates, heptanates, caprates, hydroiodinates, 2-hydroxyethanesulfonates, lactonates, lactates, laurates, laurylsulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmates, pamonates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, tosylate, undecanoates, valerates, and the like.

In some aspects, the pharmaceutically acceptable salt of mitsui as described in the methods of the invention (e.g., as described in any one of the first to thirty-fourth embodiments) is a sulfate salt. In some aspects, the pharmaceutically acceptable salt of mitsui as described in the methods of the invention (e.g., as described in any one of the first to thirty-fourth embodiments) is a hemisulfate. In some aspects, the pharmaceutically acceptable salt of mitsui as described in the methods of the invention (e.g., as described in any one of the first to thirty-fourth embodiments) is a hydrated hemi-sulfate salt. In some aspects, the pharmaceutically acceptable salt of mitsui as described in the methods of the invention (e.g., as described in any one of the first to thirty-fourth embodiments) is a sesquisulfate salt of sesquihydrate, also known as mitsui sulfate or a 1- (cyclopropylmethyl) -4- (4- (quinoline-8-sulfonylbenzoyl) piperazin-1-ium sesquisulfate salt having formula a:

alternatively, in some aspects, the pharmaceutically acceptable salt of mitsui as described in the methods of the invention (e.g., as described in any one of the first to thirty-fourth embodiments) is a sulfate trihydrate, also known as mitsui-va trihydrate or 1- (cyclopropylmethyl) -4- (4- (quinoline-8-sulfonylbenzoyl) piperazin-1-ium sulfate trihydrate having formula B:

The sesquisulfate salt of mitsubvalvular (i.e., mitsubvalvular sulfate) can be crystalline, for example, form a as disclosed in U.S. publication No. 20200277279. Form a is characterized by using one or more of the following x-ray powder diffraction patterns of Cu ka radiation at 2Θ angles (±0.2°): 9.9 °, 15.8 °, and 22.6 °;15.0 °, 17.1 °, 21.3 ° and 21.9 °;9.9 °, 15.0 °, 15.8 °, 17.1 °, 21.3 °, 21.9 °, and 22.6 °;9.9 °, 11.4 °, 15.0 °, 15.3 °, 15.8 °, 17.1 °, 17.7 °, 21.3 °, 21.9 °, 22.6 ° and 23.5 °; or 4.9 °, 9.9 °, 11.0 °, 11.4 °, 11.7 °, 12.3 °, 12.8 °, 13.6 °, 13.9 °, 14.2 °, 15.0 °, 15.3 °, 15.8 °, 17.1 °, 17.4 °, 17.7 °, 18.8 °, 19.1 °, 19.8 °, 21.3 °, 21.9 °, 22.6 °, 23.0 °, 23.2 °, 23.5 °, 23.8 °, 24.1 °, 24.5 °, 25.3 °, 25.6 °, 26.1 °, 27.1 °, 28.1 °, and 29.8 °. In some embodiments, form a is characterized by x-ray powder diffraction peaks at 9.9 °, 15.8 °, and 22.6 ° at 2Θ angles (±0.2°). In certain embodiments, form a is characterized by an x-ray powder diffraction peak at 9.9 °, 15.8 °, and 22.6 ° at 2Θ angle (±0.2°) and at least one additional x-ray powder diffraction peak selected from 15.0 °, 17.1 °, 21.3 °, and 21.9 ° at 2Θ angle (±0.2°). In certain embodiments, form a is characterized by an x-ray powder diffraction peak at 9.9 °, 15.8 °, and 22.6 ° at 2Θ angle (±0.2°) and at least two additional x-ray powder diffraction peaks selected from 15.0 °, 17.1 °, 21.3 °, and 21.9 ° at 2Θ angle (±0.2°). In yet another alternative, form a is characterized by x-ray powder diffraction peaks at 9.9 °, 15.8 °, and 22.6 ° at 2Θ angles (±0.2°) and at least three additional x-ray powder diffraction peaks selected from 15.0 °, 17.1 °, 21.3 °, and 21.9 ° at 2Θ angles (±0.2°). In certain embodiments, form a is characterized by x-ray powder diffraction peaks at 9.9 °, 15.0 °, 15.8 °, 17.1 °, 21.3 °, 21.9 °, and 22.6 ° at 2Θ angles (±0.2°). In certain embodiments, form a is characterized by x-ray powder diffraction peaks at 9.9 °, 11.4 °, 15.0 °, 15.3 °, 15.8 °, 17.1 °, 17.7 °, 21.3 °, 21.9 °, 22.6 °, and 23.5 ° at 2Θ angles (±0.2°). In certain embodiments, form a is characterized by X-ray powder diffraction peaks at 4.9 °, 9.9 °, 11.0 °, 11.4 °, 11.7 °, 12.3 °, 12.8 °, 13.6 °, 13.9 °, 14.2 °, 15.0 °, 15.3 °, 15.8 °, 17.1 °, 17.4 °, 17.7 °, 18.8 °, 19.1 °, 19.8 °, 21.3 °, 21.9 °, 22.6 °, 23.0 °, 23.2 °, 23.5 °, 23.8 °, 24.1 °, 24.5 °, 25.3 °, 25.6 °, 26.1 °, 27.1 °, 28.1 °, and 29.8 ° at 2Θ angles (±0.2°). In yet another alternative, form a is characterized by a Differential Scanning Calorimetry (DSC) thermogram comprising endothermic peaks at about 159 ℃ ± 5 ℃ and 199 ℃ ± 5 ℃. In yet another alternative, crystalline form a is characterized by a thermogram of thermogravimetric analysis (TGA) comprising a weight loss of about 4.5% ± 0.5% at up to 180 ℃ ± 2 ℃. In some embodiments, the sesquisulfate salt of mitsuiv is 1- (cyclopropylmethyl) -4- (4- (quinoline-8-sulfonylamino) benzoyl) piperazin-1-ium sesquisulfate salt form a.

As used herein, the dose of mitsubpitava or a pharmaceutically acceptable salt thereof (e.g., the sesquisulfate hydrate salt of mitsubpitava) is based on equivalents to the free base form of mitsubpitava. For example, in the disclosed methods, an amount of the sesquisulfate salt of mitsunobu equal to about 2.0mg of mitsunobu refers to about 2.0mg of the free base mitsunobu or about 2.33mg of the sesquisulfate salt of formula a.

The mitsubvalance or a pharmaceutically acceptable salt thereof (e.g., mitsubvalance sulfate) can be formulated as a pharmaceutical composition and administered. The pharmaceutical composition of the mitsubvalvular or a pharmaceutically acceptable salt thereof (e.g., mitsubvalvular sulfate) may be prepared by any method known in the pharmacological arts. Generally, such preparation methods comprise the step of combining the mitsubvalance or a pharmaceutically acceptable salt thereof (e.g., mitsubvalance sulfate) with a carrier and/or one or more other auxiliary ingredients, and then, if needed and/or desired, shaping and/or packaging the product into the required single-or multi-dose unit. In one aspect, the pharmaceutical composition is administered orally in an orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In one aspect, the mitsubishi or a pharmaceutically acceptable salt thereof (e.g., mitsubishi sulfate) is formulated into a tablet composition with a pharmaceutically acceptable carrier according to the disclosure of international patent application No. WO 2019/104134.

In some aspects, the mitsubvalance or a pharmaceutically acceptable salt thereof (e.g., mitsubvalance sulfate) is formulated in a cone pack. In some aspects, the mitsubvalance, or a pharmaceutically acceptable salt thereof (e.g., mitsubvalance sulfate) is formulated in a cone pack of about 5mg, about 20mg, about 50mg, or about 100 mg. In some aspects, the mitsubvalance or pharmaceutically acceptable salt thereof (e.g., mitsubvalance sulfate) is formulated as a cone pack of about 5mg, about 20mg, about 50mg, or about 100mg packaged in a carton. In other aspects, the mitsubvalance or pharmaceutically acceptable salt thereof (e.g., mitsubvalance sulfate) is formulated as a cone pack of about 5mg, about 20mg, about 50mg, or about 100mg packaged in cartons containing at least 1 blister card (or packet). In other aspects, the mitsubpitales or pharmaceutically acceptable salts thereof (e.g., mitsubpitales sulfate) are formulated as cone packs packaged in cartons containing at least 1 blister card (or packet) containing about 5 (five) to about 10 (ten) dosage forms of about 5mg, about 20mg, about 50mg, or about 100mg of mitsubpitales. In other aspects, about 5mg of the dosage form is a round blue film coated tablet with one side printed with "M5". In other aspects, about 20mg of the dosage form is a round blue film coated tablet with one side printed with "M20". In other aspects, about 50mg of the dosage form is a rectangular blue film coated tablet with one side printed with "M50". In other aspects, about 100mg of the dosage form is a film coated tablet with one side printed with "M100" or embossments. In some aspects, the mitsubpitava or a pharmaceutically acceptable salt thereof (e.g., mitsubpitava sulfate) is formulated as follows:

About 5mg cone pack packaged in cartons containing 1 blister card (or packet) containing 7 round blue film coated tablets with "M5" printed on one side.

About 5mg cone pack packaged in cartons containing 2 blister cards (or packets) containing 7 round blue film coated tablets with "M5" printed on one side.

About 20mg cone pack packaged in cartons containing 2 blister cards (or packets) containing 7 round blue film coated tablets with "M20" printed on one side.

About 50mg cone pack packaged in cartons containing 2 blister cards (or packets) containing 7 rectangular blue film coated tablets with "M50" printed on one side.

About 100mg cone pack packaged in cartons containing 2 blister cards (or packets) containing 7 film coated tablets printed on one side with "M100" or embossing.

As used herein, the terms "about" and "approximately" are used herein to mean within the tolerances typical in the art. In one embodiment, "about" means within 2 standard deviations of the mean. In one embodiment, "about" refers to ± 10%. In one embodiment, "about" refers to ± 5%. In another embodiment, "about" refers to ±2 days. When "about" occurs before a number of a range of numbers, it is to be understood that the term applies to any and each of the numbers and ranges recited in the range.

Example

Example 1: dose escalation and decrementation in subjects with Pyruvate Kinase Deficiency (PKD)

To gradually increase the hemoglobin (Hb) level and maximize the therapeutic effect, the mitepin should be titrated twice daily with consecutive doses of 5mg, 20mg and 50mg, with the dose increasing to the next dose level every 4 weeks (see table 1). Hb levels should be assessed before increasing to the next dose level, as some patients 5mg or 20mg twice daily may reach normal Hb levels. The maximum recommended dose is 50mg twice daily.

Table 1: dose titration schedule

In order to minimize the risk of acute hemolysis, abrupt interruptions or disabling of the mitsui-cut should be avoided. Instead, the dose of mitsui should be decremented, for example following the schedule in table 2 or table 2A. During the period of decrementing, the patient should also be monitored for signs of acute hemolysis and anemia, including jaundice, jaundice in the sclera, reddish urine, dizziness, blurred consciousness, fatigue, and/or shortness of breath.

Table 2 dose decrementing schedule

Abbreviations: n/a = inapplicable.

Table 2A dose decrementing schedule alternatives

Abbreviations: n/a = inapplicable.

Example 2-evaluation of therapeutic efficacy and safety of Mitaprava in adult subjects with non-transfusion dependent alpha-or beta-thalassemia stage 3, double blind, randomized, placebo controlled, multicenter study (ENERGIZE)

The main objective of this study was to compare the effects of mirtazapine with placebo on anemia (i.e. Hb response), which is supported by patient report outcome (facility-fatigue) and performance outcome (6 MWT) measurements that evaluate subject sensory and functional, hemolysis and erythropoiesis parameters, and iron metabolism. Other secondary objectives include evaluation of pharmacokinetic and pharmacodynamic parameters and safety. Safety will be assessed in terms of incidence, severity and type of AE, vital sign assessment, physical examination results, clinical laboratory results, and bone mineral density scan. Blood transfusion and other supportive care therapies (including iron chelation therapies) are allowed according to clinical instructions to control symptoms and prevent secondary complications. Dose adjustment is allowed in some cases, for example in case of an over-reaction of hemoglobin.

Inclusion criteria for the subjects included:

age at which informed consent was provided was ≡18 years old.

Diagnosis of thalassemia (β -thalassemia, hbE/β -thalassemia or α -thalassemia/HbH disease with or without a mutation in the α -globin gene) based on Hb electrophoresis, hb high performance liquid chromatography and/or DNA analysis in the medical records of the subject. If this information cannot be provided in the subject's medical record, testing can be performed by the local laboratory during the screening period. If the local laboratory is not able to detect, the results of the integrated α -and β -globin genotyping performed by the research center laboratory can be used.

Based on the average of at least 2 Hb concentration measurements (interval. Gtoreq.7 days) collected during the screening period, hb concentration. Ltoreq.10.0 g/dL.

Non-transfusion dependency, defined as ∈5 Red Blood Cell (RBC) units during the 24 week period prior to random grouping, and no Red Blood Cells (RBC) were infused for ∈8 weeks prior to providing informed consent or during the screening period.

If hydroxyurea is taken, the hydroxyurea dose must be stable for > 16 weeks prior to random grouping.

The primary endpoint of this study was the hemoglobin (Hb) reaction, which is defined as an increase in average Hb concentration from week 12 to week 24 of > 1.0g/dL compared to baseline.

The subjects will receive 100mg BID mitsubpital or matched placebo for oral administration. Subjects who stopped the study will experience dose escalation and be monitored for signs and symptoms of acute hemolysis and exacerbation of anemia. Exemplary dose decrementing schemes based on various starting doses of mitsubvalvular are described below.

Table 3: study 1 dose decrementing

Dosage of	Time schedule
		100mg	BID
100mg	QD was kept for 7 days, then the Mitapimavan was stopped

Table 4: rapid dose decrementing

Initial dose	First step for x 3 days	Second step for x 3 days	Third step x 3 days
				5mg BID	5mg QD	5mg QOD	-
20mg BID	20mg QD	20mg QOD	-
				50mg BID	50mg QD	20mg QD	20mg QOD

Table 5: progressive dose decrementing

Initial dose	First step x 7 days	Second step x 7 days	Third step x 7 days
				5mg BID	5mg QD	5mg QOD	-
20mg BID	20mg QD	20mg QOD	-
				50mg BID	50mg QD	20mg QD	20mg QOD

Table 6: study 2 dose decrementing

Initial dose	First step x 7 days	Second step x 7 days
			5mg BID	5mg QD	-
20mg BID	20mg QD	5mg QD
			50mg BID	50mg QD	20mg QD

Table 6A: study 2 dose escalation alternatives

For example, dose escalation as described in example 1 is optional for this study.

Example 3-evaluation of therapeutic efficacy and safety of Mitapravastatin in adult subjects with non-transfusion dependent alpha-or beta-thalassemia phase 3, double blind, randomized, placebo controlled, multicenter study (ENERGIZE-T)

The main objective of this study was to compare the effect of mitsui and placebo on the transfusion burden of subjects with-or-Transfusion Dependent Thalassemia (TDT). Other secondary objectives include assessment of iron overload markers, pharmacokinetic and pharmacodynamic parameters, and safety. Safety will be assessed in terms of incidence, severity and type of AE, vital sign assessment, physical examination results, clinical laboratory results, and bone mineral density scan. The subject will continue to receive appropriate supportive care in accordance with the clinical instructions and in accordance with applicable guidelines to control symptoms and prevent secondary complications. Dose adjustments are allowed for excessive hemoglobin response, study drug-related AEs, and special adverse events of transaminase increase.

Inclusion criteria for the subjects included:

age at which informed consent was provided was ≡18 years old.

Transfusion dependency, defined as the period of 6 to 20 RBC units infused in 24 weeks period prior to random grouping and no transfusion less than 6 weeks.

The primary endpoint of this study was the Transfusion Reduction Response (TRR), which is defined as a reduction of > 50% in infused Red Blood Cell (RBC) units and > 2 units in infused RBC units over the baseline period of any consecutive 12 weeks to 48 weeks.

The subjects will receive 100mg BID mitsubpital or matched placebo for oral administration. Subjects who stopped the study will experience dose escalation and be monitored for signs and symptoms of acute hemolysis and exacerbation of anemia. Exemplary dose-decreasing schedules for various starting doses based on mitsubvalvular are described in tables 3-6 above. For example, dose escalation as described in example 1 is optional for this study.

Numbered embodiments

Embodiment 1. A method of treating thalassemia or sickle cell disease in a subject in need thereof, the method comprising administering to the subject an initial amount of mitsubvalvular or a pharmaceutically acceptable salt for a first period of time, wherein the amount increases the hemoglobin level of the subject; assessing the subject's hemoglobin level after the first period of time to determine if the subject is within a target hemoglobin level; and continuing to administer the initial amount of mitsubvalvular or a pharmaceutically acceptable salt thereof if the subject's hemoglobin level is within the target hemoglobin level, or administering a first adjusted amount of mitsubvalvular or a pharmaceutically acceptable salt thereof if the subject's hemoglobin level is not within the target hemoglobin level.

Embodiment 2. The method of embodiment 1, wherein the method further comprises administering the first adjusted amount of mitsubvalvular or a pharmaceutically acceptable salt thereof for a second period of time; assessing the subject's hemoglobin level after the second period of time to determine if the subject is within the target hemoglobin level; and continuing to administer the first adjusted amount if the subject's hemoglobin level is within the target hemoglobin level after the second period of time, or administering the second adjusted amount of mitepiva or a pharmaceutically acceptable salt thereof if the subject's hemoglobin level is not within the target hemoglobin level.

Embodiment 3. The method according to embodiment 1 or 2, wherein the method further comprises administering a third adjusted amount of mitsubvalvular or a pharmaceutically acceptable salt thereof for a third period of time; or continuing to administer the second adjustment amount if the subject's hemoglobin level is within the target hemoglobin level.

Embodiment 4. The method of any one of embodiments 1 to 3, wherein the method further comprises continuing to evaluate the subject's hemoglobin level and readjusting the amount of the mitsubpitant or pharmaceutically acceptable salt thereof until the subject's hemoglobin level is within the target hemoglobin level, or continuing to administer the mitsubpitant or pharmaceutically acceptable salt thereof to the subject without further adjustment.

Embodiment 5. The method according to any one of embodiments 1 to 4, wherein the first time period, the second time period, and the third time period are each independently selected from about 1 week to about 12 weeks, about 1 week to about 11 weeks, about 1 week to about 10 weeks, about 1 week to about 9 weeks, about 1 week to about 8 weeks, about 1 week to about 7 weeks, about 1 week to about 6 weeks, about 1 week to about 5 weeks, about 1 week to about 4 weeks, about 1 week to about 3 weeks, about 1 week to about 2 weeks, about 2 weeks to about 12 weeks, about 2 weeks to about 11 weeks, about 2 weeks to about 10 weeks, about 2 weeks to about 9 weeks, about 2 weeks to about 8 weeks, about 2 weeks to about 7 weeks, about 2 weeks to about 6 weeks, about 2 weeks to about 5 weeks, about 2 weeks to about 4 weeks, about 2 weeks to about 3 weeks, about 3 weeks to about 12 weeks, about 3 weeks to about 11 weeks, about 2 weeks to about 8 weeks about 3 to about 10 weeks, about 3 to about 9 weeks, about 3 to about 8 weeks, about 3 to about 7 weeks, about 3 to about 6 weeks, about 3 to about 5 weeks, about 3 to about 4 weeks, about 4 to about 12 weeks, about 4 to about 11 weeks, about 4 to about 10 weeks, about 4 to about 9 weeks, about 4 to about 8 weeks, about 4 to about 7 weeks, about 4 to about 6 weeks, about 4 to about 5 weeks, about 5 to about 12 weeks, about 5 to about 11 weeks, about 5 to about 10 weeks, about 5 to about 9 weeks, about 5 to about 8 weeks, about 5 to about 7 weeks, about 5 to about 6 weeks, about 6 to about 12 weeks, about 6 to about 11 weeks, about 6 to about 10 weeks, about 6 to about 9 weeks, about 6 to about 8 weeks, and from about 6 weeks to about 7 weeks.

Embodiment 6. The method of any of embodiments 1 to 4, wherein the first time period, the second time period, and the third time period are each independently selected from at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, and at least about 12 weeks.

Embodiment 7. The method of any of embodiments 1 to 4, wherein the first time period, the second time period, and the third time period are each independently selected from at most about 1 week, at most about 2 weeks, at most about 3 weeks, at most about 4 weeks, at most about 5 weeks, at most about 6 weeks, at most about 7 weeks, at most about 8 weeks, at most about 9 weeks, at most about 10 weeks, at most about 11 weeks, and at most about 12 weeks.

Embodiment 8. The method of any of embodiments 1 to 4, wherein the first time period, the second time period, and the third time period are each independently selected from about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, and about 12 weeks.

Embodiment 9. The method of any one of embodiments 1 to 8, wherein the first time period and the second time period are the same duration; the first time period and the third time period are the same duration; the second time period and the third time period are the same duration; or the first time period, the second time period, and the third time period are all the same duration.

Embodiment 10 the method of any one of embodiments 1 to 9, wherein the initial amount of mitsui, the first adjusted amount of mitsui, the second adjusted amount of mitsui, and the third adjusted amount of mitsui are each independently selected from the group consisting of about 5mg, about 20mg, about 50mg, and about 100mg; and wherein said initial amount of said pharmaceutically acceptable salt of mitsui, said first adjusted amount of said pharmaceutically acceptable amount of mitsui, said second adjusted amount of said pharmaceutically acceptable amount of mitsui and said third adjusted amount of said pharmaceutically acceptable amount of mitsui are each independently selected from amounts equal to about 5mg of mitsui, about 20 mitsui, about 50mg of mitsui and about 100mg of mitsui.

Embodiment 11. The method of any one of embodiments 1 to 10, wherein the initial amount of the mitepin or the pharmaceutically acceptable salt thereof, the first adjustment amount, the second adjustment amount, and the third adjustment amount are each administered once daily (QD), twice daily (BID), or three times daily (TID).

Embodiment 12. The method of any one of embodiments 1 to 11, wherein the target hemoglobin level is characterized by an increase in baseline hemoglobin level of the subject of about 1.0g/dL to about 2.0g/dL, alone or together, during any one of the first time period, the second time period, or the third time period.

Embodiment 13. The method of any one of embodiments 1 to 12, wherein the target hemoglobin level is characterized by an increase in baseline hemoglobin level of the subject of about 1.0g/dL, about 1.5g/dL, or about 2.0g/dL, alone or together, during any one of the first time period, the second time period, or the third time period.

Embodiment 14. The method of any one of embodiments 1 to 11, wherein the target hemoglobin level is between about 12.0g/dL to about 17.5 g/dL.

Embodiment 15 the method of any one of embodiments 1 to 11 and 14, wherein the target hemoglobin level is between about 13.5g/dL and about 17.5g/dL for men aged ≡16 years old and between about 12.0g/dL and about 15.5g/dL for women aged ≡16 years old.

Embodiment 16. The method of any one of embodiments 1 to 15, wherein thalassemia is non-transfusion dependent thalassemia or transfusion dependent thalassemia.

Embodiment 17 the method of any one of embodiments 1 to 16, wherein the thalassemia is selected from the group consisting of non-transfusion dependent alpha thalassemia, non-transfusion dependent beta thalassemia, transfusion dependent alpha thalassemia, or transfusion dependent beta thalassemia.

Embodiment 18. A method of discontinuing treatment with mitsui or a pharmaceutically acceptable salt thereof in a subject administered a given daily amount of mitsui or a pharmaceutically acceptable salt thereof, the method comprising a) administering to the subject a first adjusted amount of mitsui or a pharmaceutically acceptable salt thereof for a first period of time, wherein the first adjusted amount is less than the given daily amount; and b) monitoring the subject for acute hemolysis or anemia or both during the first period of time.

Embodiment 19. A method for reducing a given daily amount of mitsui or a pharmaceutically acceptable salt thereof administered to a subject, the method comprising a) administering to the subject a first adjusted amount of mitsui or a pharmaceutically acceptable salt thereof for a first period of time, wherein the first adjusted amount is less than the given daily amount; and b) monitoring the subject for acute hemolysis or anemia or both during the first period of time.

Embodiment 20. The method of embodiment 18 or 19, further comprising the steps of: c) If the subject exhibits symptoms of acute hemolysis or anemia or both, the subject is treated for acute hemolysis or anemia or both.

Embodiment 21. The method of embodiment 20, comprising repeating steps a) and b), using a second adjustment amount of mitsubpitaled or a pharmaceutically acceptable salt thereof for a second period of time, and continuing to monitor the subject for symptoms of acute hemolysis or anemia or both, wherein the second adjustment amount is less than the first adjustment amount.

Embodiment 22. The method of embodiment 21, further comprising the steps of: if the subject exhibits symptoms of acute hemolysis or anemia or both, the subject is treated for acute hemolysis or anemia or both.

Embodiment 23 the method of any one of embodiments 20 to 22, wherein the administration of the first adjusted amount of mitsubvalvular or a pharmaceutically acceptable salt thereof is continued until the symptoms of acute hemolysis or anemia or both are ameliorated.

Embodiment 24. The method of any one of embodiments 21 to 23, wherein administering the second adjusted amount of mitsubvalvular or a pharmaceutically acceptable salt thereof begins immediately after the completion of the first period of time.

Embodiment 25 the method according to any one of embodiments 21 to 24, further comprising repeating steps a) and b), using a third adjustment amount of mitsubpitant or a pharmaceutically acceptable salt thereof for a third period of time, and continuing to monitor the subject for symptoms of acute hemolysis or anemia or both, wherein the third adjustment amount is less than the adjustment amount administered in previous step a).

Embodiment 26. The method of embodiment 25, wherein the administration of the third adjusted amount of mitsubnatal or a pharmaceutically acceptable salt thereof is started immediately after completion of the second time period.

Embodiment 27. The method of any one of embodiments 18 to 26, wherein steps a) and b) are repeated until the subject is no longer administered the mitepiva or a pharmaceutically acceptable salt thereof.

Embodiment 28. The method of any of embodiments 18 to 27, further comprising the steps of: if the subject exhibits symptoms of acute hemolysis or anemia or both, the subject is treated for acute hemolysis or anemia or both.

Embodiment 29. The method of embodiment 28, wherein treatment is continued until the symptoms of acute hemolysis or anemia or both are ameliorated.

Embodiment 30 the method of any one of embodiments 18 to 29, wherein the given daily amount of mitsubvalvular is selected from about 10 mg/day, about 40 mg/day, about 100 mg/day, and about 200 mg/day; and wherein said predetermined daily amount of said pharmaceutically acceptable salt is selected from an amount equal to about 10mg of mitsunobu, about 40mg of mitsunobu, about 100mg of mitsunobu, and about 200mg of mitsunobu.

Embodiment 31 the method of any one of embodiments 18 to 30, wherein the given daily amount of mitsubnatal administered to the subject prior to the first adjustment amount is selected from about 5mg BID, about 20mg BID, about 50mg BID or about 100mg BID; and wherein prior to said first adjustment amount, said predetermined daily amount of said pharmaceutically acceptable salt administered to said subject is equal to about 5mg BID of mitsubvalvular, about 20mg BID of mitsubvalvular, about 50mg BID of mitsubvalvular, or about 100mg BID of mitsubvalvular.

Embodiment 32 the method of any one of embodiments 18 to 31, wherein the first adjusted amount of the mitepin or the pharmaceutically acceptable salt is an amount selected from the group consisting of: from about 40% to about 80%, from about 40% to about 60%, from about 45% to about 55%, and from about 49% to about 51% less than the given daily amount of mitsubvalvular or the pharmaceutically acceptable salt.

Embodiment 33 the method of any one of embodiments 18 to 32, wherein the first adjusted amount of mitsubpitaled or the pharmaceutically acceptable salt is about 50% less than the given daily amount of mitsubpinaled or the pharmaceutically acceptable salt.

Embodiment 34 the method of any one of embodiments 18 to 33, wherein the first adjusted amount of mitsubpint is selected from about 5mg, about 20mg, about 50mg, and about 100mg; and wherein said first adjusted amount of said pharmaceutically acceptable salt is equal to about 5mg of mitsui, about 20mg of mitsui, about 50mg of mitsui and about 100mg of mitsui.

Embodiment 35 the method of any one of embodiments 18 to 34, wherein the first adjusted amount of mitsui is selected from about 5mg QD, about 20mg QD, about 50mg QD, and about 100mg QD; and wherein said first adjusted amount of said pharmaceutically acceptable salt is equal to about 5mg QD mitsubpital, about 20mg QD mitsubpital, about 50mg QD mitsubpital, and about 100mg QD mitsubpital.

Embodiment 36 the method of any one of embodiments 21 to 35, wherein the second adjusted amount of mitsubpitaled or the pharmaceutically acceptable salt reduces the first adjusted amount of mitsubpitaled or the pharmaceutically acceptable salt by an amount selected from the group consisting of: about 60% to about 80%, about 70% to about 80%, about 45% to about 85%, about 55% to about 65% less than the given daily amount of the mitsubvalvular or the pharmaceutically acceptable salt.

Embodiment 37 the method of any one of embodiments 19 to 36, wherein the second adjusted amount of mitsubpitava or the pharmaceutically acceptable salt is about 60% or about 75% less than the given daily amount of mitsubpitava or the pharmaceutically acceptable salt thereof.

Embodiment 38 the method of any one of embodiments 19 to 37, wherein the second adjusted amount of mitsubpint is about 50mg, about 20mg, or about 5mg; and wherein said second adjusted amount of said pharmaceutically acceptable salt of Mitapilar is equal to about 50mg of Mitapilar, about 20mg of Mitapilar, or about 5mg of Mitapilar.

Embodiment 39 the method of any one of embodiments 19 to 38, wherein said second adjusted amount of mitsubnatal or said pharmaceutically acceptable salt is equal to said amount of said first adjusted amount of mitsubnatal or said pharmaceutically acceptable salt administered once daily (QD).

Embodiment 40. The method of embodiment 39, wherein the amount of the second adjusted amount of mitsui is about 5mg QOD, about 20mg QD, or about 50mg QD; and wherein said second adjusted amount of said pharmaceutically acceptable salt is equal to about 5mg of QOD of mitsubpitava, about 20mg of QOD of mitsubpitava, or about 50mg of QD of mitsubpitava.

Embodiment 41 the method of any one of embodiments 25 to 40, wherein the third adjusted amount of the mitsui or the pharmaceutically acceptable salt is equal to the amount of the second adjusted amount of the mitsui or the pharmaceutically acceptable salt administered once every two days (QOD).

Embodiment 42 the method of any one of embodiments 23 to 41, wherein the third adjusted amount of mitsubpitaled is about 20mg QOD or about 50mg QOD; and wherein said third adjusted amount of said pharmaceutically acceptable salt is equal to about 20mg QOD or about 50mg QOD of mitepiva.

Embodiment 43 the method of any one of embodiments 16 to 42, wherein the first time period and the second time period are each independently selected from about 1 day to about 14 days, about 1 day to about 12 days, about 1 day to about 10 days, about 2 days to about 14 days, about 2 days to about 12 days, about 2 days to about 10 days, about 2 days to about 9 days, about 2 days to about 5 days, about 2 days to about 4 days, about 5 days to about 9 days, about 5 days to about 8 days, and about 6 days to about 8 days.

Embodiment 44. The method of any of embodiments 18 to 43, wherein the first time period and the second time period are each independently selected from about 2 days to about 5 days, about 2 days to about 4 days, about 5 days to about 8 days, and about 6 days to about 8 days.

Embodiment 45. The method of any of embodiments 18 to 44, wherein the first period of time and the second period of time are each independently selected from about 3 days and about 7 days.

Embodiment 46. The method of any of embodiments 18 to 45, wherein the first time period and the second time period are both the same duration.

Embodiment 47. The method of any of embodiments 25 to 46, wherein the third time period is selected from the group consisting of about 1 day to about 14 days, about 1 day to about 12 days, about 1 day to about 10 days, about 2 days to about 14 days, about 2 days to about 12 days, about 2 days to about 10 days, about 2 days to about 9 days, about 2 days to about 5 days, about 2 days to about 4 days, about 5 days to about 9 days, about 5 days to about 8 days, and about 6 days to about 8 days.

Embodiment 48. The method of any of embodiments 25 to 47, wherein the third period of time is selected from about 2 days to about 5 days, about 2 days to about 4 days, about 5 days to about 8 days, and about 6 days to about 8 days.

Embodiment 49 the method of any one of embodiments 25 to 48, wherein the third period of time is about 7 days.

Embodiment 50. The method of any of embodiments 25 to 49, wherein the first time period, the second time period, and the third time period are each the same duration.

Embodiment 51 the method of any one of embodiments 18 to 50, further comprising monitoring the subject for acute hemolysis or anemia or both after terminating the administration of the mitepiva or pharmaceutically acceptable salt thereof.

Embodiment 52 the method of any one of embodiments 18 to 51, wherein monitoring comprises testing the subject for acute hemolysis or anemia, or both.

Embodiment 53 the method of any one of embodiments 18 to 52, wherein acute hemolysis is characterized by rapid loss of hemoglobin.

Embodiment 54 the method of any one of embodiments 18 to 53, wherein acute hemolysis is characterized by a hemoglobin loss of greater than about 0.1 g/dL/day to about 0.2 g/dL/day.

Embodiment 55 the method of any one of embodiments 18-54, wherein acute hemolysis is characterized by a hemoglobin loss of about 1.7 g/dL/day to about 2.5 g/dL/day.

Embodiment 56 the method of any one of embodiments 18 to 52, wherein acute hemolysis or anemia or both is characterized by the subject suffering from one or more of jaundice, jaundice scleral, reddish urine, dizziness, blurred consciousness, fatigue, or shortness of breath.

Embodiment 57 the method of any one of embodiments 18 to 56, wherein if the subject suffers from an adverse event, the administration of the mitsui or a pharmaceutically acceptable salt thereof is immediately terminated regardless of the period of time or the intended daily dose.

Embodiment 58 the method of embodiments 18 to 57, wherein the subject is receiving treatment for a disorder selected from the group consisting of Pyruvate Kinase Deficiency (PKD), thalassemia, and Sickle Cell Disease (SCD).

Embodiment 59. The method of embodiments 18 to 57, wherein the subject is receiving treatment for hemolytic anemia or anemia caused by or associated with Pyruvate Kinase Deficiency (PKD).

Embodiment 60. The method of embodiments 16 to 58, wherein the subject is receiving treatment for Sickle Cell Disease (SCD).

Embodiment 61. The method of embodiment 58, wherein the thalassemia is non-transfusion dependent thalassemia or transfusion dependent thalassemia.

Embodiment 62. The method of embodiment 58 or 61, wherein the thalassemia is alpha thalassemia or beta thalassemia.

Embodiment 63. A method for stopping administration of a given daily dose of mitsui or a pharmaceutically acceptable salt thereof to a subject in need thereof, said method comprising a) immediately terminating all administration of mitsui or a pharmaceutically acceptable salt thereof; b) Acute hemolysis or anemia or both of the subject are monitored over a period of time.

Embodiment 64. The method of embodiment 63, wherein the subject suffers from a clinically significant adverse reaction.

Embodiment 65 the method of embodiment 63 or 64, wherein the subject is monitored for acute hemolysis or anemia or both for a period of about 1 day to about 14 days, about 1 day to about 12 days, about 1 day to about 10 days, about 2 days to about 14 days, about 2 days to about 12 days, about 2 days to about 10 days, about 2 days to about 9 days, about 2 days to about 5 days, about 2 days to about 4 days, about 5 days to about 9 days, about 5 days to about 8 days, and about 6 days to about 8 days.

Embodiment 66. The method of embodiment 63 or 64, wherein the subject is monitored for about 14 days or less.

Embodiment 67 the method of embodiment 63 or 64, wherein the subject is monitored for about 7 days or less.

Embodiment 68 the method of any one of embodiments 1 to 67, wherein the mitsubpitava or pharmaceutically acceptable salt thereof is in crystalline form.

Embodiment 69 the method of any one of embodiments 1 to 68 wherein the mitsubpitava or pharmaceutically acceptable salt thereof is amorphous.

Embodiment 70 the method of any one of embodiments 1 to 69, wherein the subject is administered Mitapida.

Embodiment 71 the method of any one of embodiments 1 to 69, wherein the subject is administered a pharmaceutically acceptable salt of mitsubvalvular.

Embodiment 72 the method of any one of embodiments 1 to 69 and 71 wherein the subject is administered a hemisulfate salt of mitsuiva.

Embodiment 73 the method of any one of embodiments 1 to 69, 71 and 72 wherein the subject is administered a sesquisulfate salt of mitsui.

Embodiment 74. A method of discontinuing treatment with mitsunobu or a pharmaceutically acceptable drug thereof in a subject administered a quantity of mitsunobu of about 5mg twice daily (BID) or equal to about 5mg of mitsunobu BID, the method comprising administering mitsunobu or a pharmaceutically acceptable drug thereof according to the following dose-decreasing schedule: day 1 to day 7: administering to the subject about 5mg of mitsui once per day (QD), or administering to the subject a pharmaceutically acceptable salt of mitsui in an amount equal to about 5mg of mitsui QD; day 8: thereafter stopping said administration of the mitsui or the pharmaceutically acceptable salt of mitsui.

Embodiment 75. A method of stopping treatment with mitsunobu or a pharmaceutically acceptable salt thereof in a subject administered a quantity of mitsunobu of about 5mg twice daily (BID) or equal to about 5mg of mitsunobu BID, the method comprising administering mitsunobu or a pharmaceutically acceptable drug thereof according to the following dose-decreasing schedule: day 1 to day 7: administering to the subject about 5mg of mitsui once per day (QD), or administering to the subject a pharmaceutically acceptable salt of mitsui in an amount equal to about 5mg of mitsui QD; day 8 to day 14: administering to the subject about 5mg of mitsuiva once every two days (QOD), or administering to the subject a pharmaceutically acceptable salt of mitsuiva in an amount equal to about 5mg of mitsuiva QOD; day 15: stopping said administration of mitsubvalvular or said pharmaceutically acceptable salt thereof.

Embodiment 76. A method of discontinuing treatment with mitsunobu or a pharmaceutically acceptable salt thereof in a subject administered a quantity of mitsunobu BID of about 20mg twice daily (BID) or equal to about 20mg of mitsunobu BID, the method comprising administering mitsunobu or a pharmaceutically acceptable drug thereof according to the following dose-decreasing schedule: day 1 to day 7: administering to the subject about 20mg of mitsui once per day (QD), or administering to the subject a pharmaceutically acceptable salt of mitsui in an amount equal to about 20mg of mitsui QD; day 8 to day 14: administering to the subject about 5mg of mitsui once per day (QD), or administering to the subject a pharmaceutically acceptable salt of mitsui in an amount equal to about 5mg of mitsui QD; day 15: stopping said administration of mitsubvalvular or said pharmaceutically acceptable salt thereof.

Embodiment 77. A method of stopping treatment with mitsunobu or a pharmaceutically acceptable salt thereof in a subject administered about 20mg of mitsunobu twice daily (BID), or with a pharmaceutically acceptable salt of mitsunobu in an amount equal to about 20mg of mitsunobu BID, comprising administering mitsunobu or a pharmaceutically acceptable drug thereof according to the following dose-decreasing schedule: day 1 to day 7: administering to the subject about 20mg of mitsui once per day (QD), or administering to the subject a pharmaceutically acceptable salt of mitsui in an amount equal to about 20mg of mitsui QD; day 8 to day 14: administering to the subject about 20mg of mitsuiva once every two days (QOD), or administering to the subject a pharmaceutically acceptable salt of mitsuiva in an amount equal to about 20mg of mitsuiva QOD; day 15: stopping said administration of mitsubvalvular or said pharmaceutically acceptable salt thereof.

Embodiment 78. A method of stopping treatment with mitsunobu or a pharmaceutically acceptable salt thereof in a subject administered about 50mg of mitsunobu twice daily (BID), or with a pharmaceutically acceptable salt of mitsunobu in an amount equal to about 50mg of mitsunobu BID, comprising administering mitsunobu or a pharmaceutically acceptable drug thereof according to the following dose-decreasing schedule: day 1 to day 7: administering to the subject about 50mg of mitsui once per day (QD), or administering to the subject a pharmaceutically acceptable salt of mitsui in an amount equal to about 50mg of mitsui QD; day 8 to day 14: administering to the subject about 20mg of mitsui once per day (QD), or administering to the subject a pharmaceutically acceptable salt of mitsui in an amount equal to about 20mg of mitsui QD; day 15: stopping said administration of mitsubvalvular or said pharmaceutically acceptable salt thereof.

Embodiment 79 a method of stopping treatment with mitsunobu or a pharmaceutically acceptable salt thereof in a subject administered about 50mg of mitsunobu twice daily (BID), or with a pharmaceutically acceptable salt of mitsunobu in an amount equal to about 50mg of mitsunobu BID, comprising administering mitsunobu or a pharmaceutically acceptable drug thereof according to the following dose-decreasing schedule: day 1 to day 7: administering to the subject about 50mg of mitsui once per day (QD), or administering to the subject a pharmaceutically acceptable salt of mitsui in an amount equal to about 50mg of mitsui QD; day 8 to day 14: administering to the subject about 20mg of mitsui once per day (QD), or administering to the subject a pharmaceutically acceptable salt of mitsui in an amount equal to about 20mg of mitsui QD; day 15 to day 21: administering to the subject about 20mg of mitsuiva once every two days (QOD), or administering to the subject a pharmaceutically acceptable salt of mitsuiva in an amount equal to about 20mg of mitsuiva QOD; day 22: stopping said administration of mitsubvalvular or said pharmaceutically acceptable salt thereof.

Embodiment 80 the method of any one of embodiments 74-79, further comprising monitoring the subject for acute hemolysis or anemia or both.

Embodiment 81 the method of any one of embodiments 74 to 80, further comprising the steps of: c) If the subject exhibits symptoms of acute hemolysis or anemia or both, the subject is treated for acute hemolysis or anemia or both.

Embodiment 82 the method of any one of embodiments 74 to 81, wherein the subject is receiving treatment for a disorder selected from the group consisting of Pyruvate Kinase Deficiency (PKD), thalassemia, and Sickle Cell Disease (SCD).

Embodiment 83 the method of any one of embodiments 74-82, wherein the subject is receiving treatment for hemolytic anemia or anemia arising from or associated with Pyruvate Kinase Deficiency (PKD).

Embodiment 84 the method of any one of embodiments 74-82, wherein said subject is receiving treatment for Sickle Cell Disease (SCD).

Embodiment 85. The method of embodiment 82, wherein the thalassemia is non-transfusion dependent thalassemia or transfusion dependent thalassemia.

Embodiment 86 the method of embodiment 82 or 85, wherein the thalassemia is alpha thalassemia or beta thalassemia.

Embodiment 87 the method of any of embodiments 74 to 86, wherein the mitsubpitava or pharmaceutically acceptable salt thereof is in crystalline form.

Embodiment 88 the method of any one of embodiments 74 to 86, wherein the mitsubpitava or pharmaceutically acceptable salt thereof is amorphous.

Embodiment 89 the method of any one of embodiments 74-88, wherein the subject is administered to the subject prior to the dose escalation schedule.

Embodiment 90 the method of any one of embodiments 74-89, wherein the subject is administered to the subject in an amount recited by the dose escalation schedule.

Embodiment 91 the method of any of embodiments 74-88, wherein a pharmaceutically acceptable salt of mitsubvalvular is administered to said subject prior to said dose escalation schedule.

Embodiment 92 the method of any one of embodiments 74 to 88 and 91, wherein the pharmaceutically acceptable salt of mitsui is administered to the subject in an amount recited in the dose escalation schedule.

Embodiment 93 the method of any one of embodiments 74 to 88, 91, and 92, wherein the subject is administered a hemisulfate salt of Mitaprava.

Embodiment 94 the method according to any one of embodiments 74 to 88 and 91 to 93, wherein the subject is administered a sesquisulfate salt of mitsubvalvular.

Embodiment 95. A kit comprising a cone pack comprising one or more oral dosage forms selected from about 5mg, about 20mg and about 50mg of mitsunobu or a pharmaceutically acceptable salt thereof in an amount equal to a dosage form of about 5mg of mitsunobu, about 20mg of mitsunobu and about 50mg of mitsunobu.

Embodiment 96 the kit of embodiment 95, wherein the mitsubpitaled or pharmaceutically acceptable salt thereof is administered according to the method of any of embodiments 1-94 to minimize the risk of acute hemolysis or anemia or both.

Embodiment 97 the kit of embodiments 95 or 96, wherein the cone pack comprises one to about seven oral doses selected from about 5mg, about 20mg, and about 50mg of mitepiva, or a pharmaceutically acceptable salt thereof, in an amount equal to a dose selected from about 5mg, about 20mg, and about 50mg of mitepiva.

Embodiment 98 the kit of any one of embodiments 95 to 97, wherein the cone pack comprises one to about seven oral doses of about 5mg of mitsubpitalea or a pharmaceutically acceptable salt thereof in an amount equal to about 5mg of mitsubpitalea.

Embodiment 99 the kit of any one of embodiments 95 to 97, wherein the cone pack comprises one to about seven oral doses of about 5mg of mitsubvala and one to about seven oral doses of about 20mg of mitsubvala or a pharmaceutically acceptable salt thereof in an amount equal to about 5mg and about 20mg of mitsubvala.

Embodiment 100 the kit of any one of embodiments 95 to 97, wherein the cone pack comprises one to about seven oral doses of about 20mg of mitsubvala and one to about seven oral doses of about 50mg of mitsubvala or a pharmaceutically acceptable salt thereof in an amount equal to about 20mg or about 50mg of mitsubvala.

Although a number of embodiments have been described, the scope of the disclosure will be defined by the appended claims rather than by the specific embodiments that have been presented by way of example. The entire contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated by reference. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly known to one of ordinary skill in the art.

Claims

1. A method of discontinuing treatment with mitsunobu or a pharmaceutically acceptable drug thereof in a subject administered with a pharmaceutically acceptable salt of mitsunobu in an amount of about 5mg twice daily (BID) or equal to about 5mg of mitsunobu BID, the method comprising administering mitsunobu or a pharmaceutically acceptable drug thereof according to the following dose-decreasing schedule:

day 1 to day 7: administering to the subject about 5mg of mitsui once per day (QD), or administering to the subject a pharmaceutically acceptable salt of mitsui in an amount equal to about 5mg of mitsui QD;

day 8: thereafter stopping said administration of the mitsui or the pharmaceutically acceptable salt of mitsui.

2. A method of discontinuing treatment with mitsui or a pharmaceutically acceptable salt thereof in a subject administered with about 5mg of mitsui twice daily (BID) or an amount of a pharmaceutically acceptable salt of mitsui equal to about 5mg of mitsui BID, the method comprising administering mitsui or a pharmaceutically acceptable drug thereof according to the following dose-decreasing schedule:

Day 8 to day 14: administering to the subject about 5mg of mitsuiva once every two days (QOD), or administering to the subject a pharmaceutically acceptable salt of mitsuiva in an amount equal to about 5mg of mitsuiva QOD;

day 15: stopping said administration of mitsubvalvular or said pharmaceutically acceptable salt thereof.

3. A method of discontinuing treatment with mitsui or a pharmaceutically acceptable salt thereof in a subject administered with about 20mg of mitsui twice daily (BID) or an amount of a pharmaceutically acceptable salt of mitsui equal to about 20mg of mitsui BID, the method comprising administering mitsui or a pharmaceutically acceptable drug thereof according to the following dose-decreasing schedule:

day 1 to day 7: administering to the subject about 20mg of mitsui once per day (QD), or administering to the subject a pharmaceutically acceptable salt of mitsui in an amount equal to about 20mg of mitsui QD;

day 8 to day 14: administering to the subject about 5mg of mitsui once per day (QD), or administering to the subject a pharmaceutically acceptable salt of mitsui in an amount equal to about 5mg of mitsui QD;

4. A method of discontinuing treatment with mitsui or a pharmaceutically acceptable salt thereof in a subject administered about 20mg of mitsui twice daily (BID), or in the subject administered a pharmaceutically acceptable salt of mitsui in an amount equal to about 20mg of mitsui BID, the method comprising administering mitsui or a pharmaceutically acceptable drug thereof according to the following dose-decreasing schedule:

day 8 to day 14: administering to the subject about 20mg of mitsuiva once every two days (QOD), or administering to the subject a pharmaceutically acceptable salt of mitsuiva in an amount equal to about 20mg of mitsuiva QOD;

5. A method of discontinuing treatment with mitsui or a pharmaceutically acceptable salt thereof for a subject administered about 50mg of mitsui twice daily (BID), or for the subject administered a pharmaceutically acceptable salt of mitsui in an amount equal to about 50mg of mitsui BID, the method comprising administering mitsui or a pharmaceutically acceptable drug thereof according to the following dose-decreasing schedule:

Day 1 to day 7: administering to the subject about 50mg of mitsui once per day (QD), or administering to the subject a pharmaceutically acceptable salt of mitsui in an amount equal to about 50mg of mitsui QD;

day 8 to day 14: administering to the subject about 20mg of mitsui once per day (QD), or administering to the subject a pharmaceutically acceptable salt of mitsui in an amount equal to about 20mg of mitsui QD;

6. A method of discontinuing treatment with mitsui or a pharmaceutically acceptable salt thereof for a subject administered about 50mg of mitsui twice daily (BID), or for the subject administered a pharmaceutically acceptable salt of mitsui in an amount equal to about 50mg of mitsui BID, the method comprising administering mitsui or a pharmaceutically acceptable drug thereof according to the following dose-decreasing schedule:

Day 15 to day 21: administering to the subject about 20mg of mitsuiva once every two days (QOD), or administering to the subject a pharmaceutically acceptable salt of mitsuiva in an amount equal to about 20mg of mitsuiva QOD;

day 22: stopping said administration of mitsubvalvular or said pharmaceutically acceptable salt thereof.

7. The method of any one of claims 1 to 6, further comprising monitoring the subject for acute hemolysis or anemia or both.

8. The method according to any one of claims 1 to 7, further comprising the step of: c) If the subject exhibits symptoms of acute hemolysis or anemia or both, the subject is treated for acute hemolysis or anemia or both.

9. The method of any one of claims 1 to 8, wherein the subject is receiving treatment for a disorder selected from the group consisting of Pyruvate Kinase Deficiency (PKD), thalassemia, and Sickle Cell Disease (SCD).

10. The method of any one of claims 1 to 9, wherein the subject is receiving treatment for hemolytic anemia or anemia caused by or associated with Pyruvate Kinase Deficiency (PKD).

11. The method of any one of claims 1 to 9, wherein the subject is receiving treatment for Sickle Cell Disease (SCD).

12. The method of any one of claims 1 to 9, wherein the subject is receiving treatment for thalassemia.

13. The method of claim 12, wherein the thalassemia is non-transfusion dependent thalassemia or transfusion dependent thalassemia.

14. The method of claim 12 or 13, wherein the thalassemia is alpha thalassemia or beta thalassemia.

15. The method of any one of claims 1 to 14, wherein the mitsubpitava or pharmaceutically acceptable salt thereof is in crystalline form.

16. The method of any one of claims 1 to 14, wherein the mitsubpitant or pharmaceutically acceptable salt thereof is amorphous.

17. The method of any one of claims 1 to 16, wherein the subject is administered to the subject prior to the dose escalation schedule.

18. The method of any one of claims 1 to 17, wherein the subject is administered to the subject melapidva in an amount recited by the dose-decrementing schedule.

19. The method of any one of claims 1 to 16, wherein the subject is administered a pharmaceutically acceptable salt of mitepiva prior to the dose escalation schedule.

20. The method of any one of claims 1 to 16 and 19, wherein the pharmaceutically acceptable salt of mitsubvalvular is administered to the subject in an amount recited by the dose-decrementing schedule.

21. The method of any one of claims 1 to 16, 19 and 20, wherein the subject is administered to the subject a hemisulfate salt of mitsuiva.

22. The method of any one of claims 1 to 16 and 19 to 21, wherein the subject is administered a sesquisulfate salt of mitsui.

23. A kit comprising a cone pack comprising one or more oral dosage forms selected from about 5mg, about 20mg and about 50mg of mitsui or a pharmaceutically acceptable salt thereof in an amount equal to a dosage form of about 5mg of mitsui, about 20mg of mitsui and about 50mg of mitsui.

24. The kit of claim 23, wherein the mitsui or pharmaceutically acceptable salt thereof is administered according to the method of any one of claims 1 to 22 to minimize the risk of acute hemolysis or anemia or both.

25. The kit of claim 23 or 24, wherein the cone pack comprises one to about seven oral doses selected from about 5mg, about 20mg, and about 50mg of mitepiva, or a pharmaceutically acceptable salt thereof, in an amount equal to a dose selected from about 5mg, about 20mg, and about 50mg of mitepiva.

26. The kit of any one of claims 23 to 25, wherein the cone pack comprises one to about seven oral doses of about 5mg of mitsubpitaled or a pharmaceutically acceptable salt thereof in an amount equal to about 5mg of mitsubpinaled.

27. The kit of any one of claims 23 to 26, wherein the cone pack comprises one to about seven oral doses of about 5mg of mitsubpinalli and one to about seven oral doses of about 20mg of mitsubpinalli or a pharmaceutically acceptable salt thereof in an amount equal to about 5mg and about 20mg of mitsubpinalli.

28. The kit of any one of claims 23 to 27, wherein the cone pack comprises one to about seven oral doses of about 20mg of mitsubpitalea and one to about seven oral doses of about 50mg of mitsubpinalea or a pharmaceutically acceptable salt thereof in an amount equal to about 20mg or about 50mg of mitsubpinalea.