How to Treat Hair Loss Disorders

Abstract

The present disclosure relates to the treatment of alopecia areata comprising the administration of Compound (I) or a pharmaceutically acceptable salt thereof.

Description

[Background technology]

[0001] Alopecia areata (AA) is an immune-mediated disease of hair follicles, resulting in non-scarring hair loss. Individuals with alopecia areata often experience chronic or recurrent disease, with severe psychological consequences. AA patients have limited treatment options, and there remains a significant clinical need for appropriate treatment. The present invention addresses this need by providing a therapeutic approach for the management and treatment of hair loss disorders, including alopecia areata. Summary of the Invention

[0002] The present invention relates to a method for treating alopecia areata.

[0003] In a first embodiment, the present invention relates to a method of treating alopecia areata in a subject in need thereof, the method comprising determining the subject's estimated glomerular filtration rate, and if the subject has an estimated glomerular filtration rate (eGFR) of ≧30 mL / min, MDRD, orally administering 16 mg / day or 24 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof to the subject, wherein Compound (I) is represented by the following structural formula: [ka] Each position specifically designated as deuterium has at least 95% incorporation of deuterium.

[0004] In a first aspect of the first embodiment, the subject has moderate renal impairment (eGFR of 30-59 mL / min, MDRD).

[0005] In a second aspect of the first embodiment, the subject has mild renal impairment (eGFR of 60-89 mL / min, MDRD).

[0006] In a third aspect of the first embodiment, the subject's eGFR is between ≧30 mL / min MDRD and <60 mL / min MDRD.

[0007] In a fourth aspect of the first embodiment, the subject's eGFR is between ≧60 mL / min MDRD and <90 mL / min MDRD.

[0008] In the fifth aspect of the first embodiment or any one of the first through fourth aspects thereof, the subject has an absolute SALT score of ≧50 at the start of treatment.

[0009] In the sixth aspect of the first embodiment or any one of the first through fourth aspects thereof, the subject has moderate to severe alopecia areata at the start of treatment.

[0010] In the seventh aspect of the first embodiment or any of the first through fourth aspects thereof, the subject has severe alopecia areata at the start of treatment.

[0011] In the eighth aspect of the first embodiment or any one of the first through seventh aspects thereof, after 8 weeks of treatment the subject has an absolute SALT score of ≦20.

[0012] In the ninth aspect of the first embodiment or any one of the first through seventh aspects thereof, after 12 weeks of treatment the subject has an absolute SALT score of ≦20.

[0013] In a tenth aspect of the first embodiment or any one of the first through seventh aspects thereof, after 16 weeks of treatment the subject has an absolute SALT score of ≦20.

[0014] In an eleventh aspect of the first embodiment or any one of the first through seventh aspects thereof, after 20 weeks of treatment the subject has an absolute SALT score of ≦20.

[0015] In a twelfth aspect of the first embodiment or any one of the first through seventh aspects thereof, after 24 weeks of treatment the subject has an absolute SALT score of ≦20.

[0016] In a thirteenth aspect of the first embodiment or any one of the first through seventh aspects thereof, after 24 weeks of treatment the subject has an absolute SALT score of ≦10.

[0017] In a fourteenth aspect of the first embodiment or any one of the first through seventh aspects thereof, after 52 weeks of treatment the subject has an absolute SALT score of ≦20.

[0018] In a fifteenth aspect of the first embodiment or any one of the first through seventh aspects thereof, after 24 weeks of treatment the subject has at least a 75% relative reduction in SALT score.

[0019] In a sixteenth aspect of the first embodiment or any one of the first through seventh aspects thereof, after 8 weeks of treatment the subject has at least a 75% relative reduction in SALT score.

[0020] In a seventeenth aspect of the first embodiment or any one of the first through seventh aspects thereof, after 12 weeks of treatment the subject has at least a 75% relative reduction in SALT score.

[0021] In an eighteenth aspect of the first embodiment or any one of the first through seventh aspects thereof, after 24 weeks of treatment the subject has at least a 90% relative reduction in SALT score.

[0022] In a nineteenth aspect of the first embodiment or any one of the first through seventh aspects thereof, after 12 weeks of treatment the subject has at least a 90% relative reduction in SALT score.

[0023] In a twentieth aspect of the first embodiment or any one of the first through seventh aspects thereof, after 24 weeks of treatment the subject reports a response of "satisfied" or "very satisfied" on the Hair Satisfaction Patient-Reported Outcome (SPRO) scale.

[0024] In a twenty-first aspect of the first embodiment or any one of the first through seventh aspects thereof, after 8 weeks of treatment the subject reports a response of "satisfied" or "very satisfied" on the Hair Satisfaction Patient-Reported Outcome (SPRO) scale.

[0025] In a twenty-second aspect of the first embodiment or any one of the first through seventh aspects thereof, after 12 weeks of treatment the subject reports a response of "satisfied" or "very satisfied" on the Hair Satisfaction Patient-Reported Outcome (SPRO) scale.

[0026] In a twenty-third aspect of the first embodiment or any one of the first through seventh aspects thereof, after 12 weeks of treatment, the subject reports a reduction in score of at least 1.5 points from baseline on the Satisfaction with Hair Patient-Reported Outcome (SPRO) scale, for example, the reduction in score is ≧2 points.

[0027] In a twenty-fourth aspect of the first embodiment or any one of the first through seventh aspects thereof, after 24 weeks of treatment, the subject reports a response of "much improved" or "very much improved" using the Patient Global Impression of Improvement (PGI-I).

[0028] In a twenty-fifth aspect of the first embodiment or any one of the first through seventh aspects thereof, after 12 weeks of treatment the subject reports a response of "much improved" or "very much improved" using the Patient Global Impression of Improvement (PGI-I).

[0029] In a twenty-sixth aspect of the first embodiment or any one of the first through seventh aspects thereof, after 16 weeks of treatment the subject reports a response of "much improved" or "very much improved" using the Patient Global Impression of Improvement (PGI-I).

[0030] In a twenty-seventh aspect of the first embodiment or any one of the first through seventh aspects thereof, after 20 weeks of treatment the subject reports a response of "much improved" or "very much improved" using the Patient Global Impression of Improvement (PGI-I).

[0031] In a twenty-eighth aspect of the first embodiment or any one of the first through seventh aspects thereof, after 12 weeks of treatment, a reduction in score from baseline of at least 1.5 points is reported by the subject on the Patient Global Impression of Improvement (PGI-I).

[0032] In a twenty-ninth aspect of the first embodiment or any one of the first through seventh aspects thereof, after 16 weeks of treatment, a reduction in score from baseline of at least 1.7 points is reported by the subject on the Patient Global Impression of Improvement (PGI-I).

[0033] In a thirty-first aspect of the first embodiment or any one of the first through seventh aspects thereof, after 24 weeks of treatment, a reduction in score from baseline of at least 2.1 points is reported by the subject on the Patient Global Impression of Improvement (PGI-I).

[0034] In a thirty-first aspect of the first embodiment or any one of the first through seventh aspects thereof, after 24 weeks of treatment the subject reports a response of "much improved" or "very much improved" using the Clinical Global Impression of Improvement (CGI-I).

[0035] In a thirty-second aspect of the first embodiment or any one of the first to seventh aspects thereof, after 12 weeks of treatment the subject reports a response of "much improved" or "very much improved" using the Clinical Global Impression of Improvement (CGI-I).

[0036] In a thirty-third aspect of the first embodiment or any one of the first through seventh aspects thereof, after 16 weeks of treatment the subject reports a response of "much improved" or "very much improved" using the Clinical Global Impression of Improvement (CGI-I).

[0037] In the thirty-fourth aspect of the first embodiment or any one of the first to seventh aspects thereof, after 20 weeks of treatment the subject reports a response of "much improved" or "very much improved" using the Clinical Global Impression of Improvement (CGI-I).

[0038] In a thirty-fifth aspect of the first embodiment or any one of the first through seventh aspects thereof, after 12 weeks of treatment, the subject reports a reduction in score from baseline of at least 1.0 on the Clinical Global Impression of Severity (CGI-S).

[0039] In a thirty-sixth aspect of the first embodiment or any one of the first through seventh aspects thereof, after 16 weeks of treatment, the subject reports a reduction in score from baseline of at least 1.5 points on the Clinical Global Impression of Severity (CGI-S).

[0040] In a thirty-seventh aspect of the first embodiment or any one of the first through seventh aspects thereof, after 24 weeks of treatment, a reduction in score from baseline of at least 2.0 is reported by the subject on the Clinical Global Impression of Severity (CGI-S).

[0041] In a thirty-eighth aspect of the first embodiment or any one of the first through seventh aspects thereof, after 24 weeks of treatment, an increase in score from baseline of at least 1.0 is achieved by the subject on the Brigham Eyelash Tool for Alopecia (BELA) or the Brigham Eyebrow Tool for Alopecia (BETA).

[0042] In a thirty-ninth aspect of the first embodiment or any one of the first through seventh aspects thereof, after 12 weeks of treatment, an increase in score from baseline of at least 0.5 points is achieved by the subject on the Brigham Eyelash Tool for Alopecia (BELA) or the Brigham Eyebrow Tool for Alopecia (BETA).

[0043] In the fortieth aspect of the first embodiment or any one of the first through thirty-ninth aspects thereof, the subject is a human. For example, the subject is an adult human. For example, the subject is an adolescent human (12 to less than 18 years old). For example, the subject is a pediatric human (6 to less than 12 years old).

[0044] In the forty-first aspect of the first embodiment or any one of the first through thirty-ninth aspects thereof, 16 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof is administered. For example, 16 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof is administered as 8 mg twice daily.

[0045] In the forty-second aspect of the first embodiment or any one of the first through seventh aspects thereof, after 68 weeks of treatment the subject has an absolute SALT score of ≦20.

[0046] In a second embodiment, the present invention relates to a method of treating alopecia areata in a subject in need thereof, the method comprising determining the subject's complete blood count; if the subject's complete blood count indicates an ALC of ≧500 cells / μl, an ANC of ≧1000 cells / μl, and / or a hemoglobin level of ≧8 g / dl, orally administering 16 mg / day or 24 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof to the subject, wherein Compound (I) is represented by the following structural formula: [ka] each position specifically designated as deuterium has at least 95% incorporation of deuterium, and monitoring ALC, ANC, and hemoglobin levels at 4, 8, 16, 20, and 24 weeks; and Discontinuing treatment of a subject if the subject's ALC is <500 cells / μl, ANC is <1000 cells / μl, and / or hemoglobin level is <8 g / dl.

[0047] In a first aspect of the second embodiment, the method further includes resuming treating the subject if the subject's ALC is determined to be ≧500 cells / μl, if the subject's ANC is determined to be ≧1000 cells / μl, and / or if the subject's hemoglobin level is determined to be ≧8 g / dl.

[0048] In a second aspect of the second embodiment, the method further comprises determining the subject's estimated glomerular filtration rate; and, if the subject has an estimated glomerular filtration rate (eGFR) of ≥ 30 mL / min, MDRD, orally administering 16 mg / day or 24 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof to the subject. For example, the subject has moderate renal impairment (eGFR of 30-59 mL / min, MDRD), or the subject's eGFR is between ≥ 30 mL / min, MDRD and < 60 mL / min, MDRD, or the subject has mild renal impairment (eGFR of 60-89 mL / min, MDRD), or the subject's eGFR is between ≥ 60 mL / min, MDRD and < 90 mL / min, MDRD.

[0049] In a third aspect of the second embodiment or the first or second aspect thereof, the subject has an absolute SALT score of ≧50 at the start of treatment.

[0050] In a fourth aspect of the second embodiment or the first or second aspect thereof, the subject has moderate to severe alopecia areata at the start of treatment.

[0051] In a fifth aspect of the second embodiment or the first or second aspect thereof, the subject has severe alopecia areata at the start of treatment.

[0052] In the sixth aspect of the second embodiment or any one of the first through fifth aspects thereof, after 8 weeks of treatment the subject has an absolute SALT score of ≦20.

[0053] In the seventh aspect of the second embodiment or any one of the first through fifth aspects thereof, after 12 weeks of treatment the subject has an absolute SALT score of ≦20.

[0054] In the eighth aspect of the second embodiment or any one of the first through fifth aspects thereof, after 16 weeks of treatment the subject has an absolute SALT score of ≦20.

[0055] In the ninth aspect of the second embodiment or any one of the first through fifth aspects thereof, after 20 weeks of treatment the subject has an absolute SALT score of ≦20.

[0056] In a tenth aspect of the second embodiment or any one of the first through fifth aspects thereof, after 24 weeks of treatment, the subject has an absolute SALT score of ≦20. For example, the subject has an absolute SALT score of ≦10.

[0057] In an eleventh aspect of the second embodiment or any one of the first through fifth aspects thereof, after 52 weeks of treatment the subject has an absolute SALT score of ≦20.

[0058] In the twelfth aspect of the second embodiment or any one of the first through fifth aspects thereof, after 24 weeks of treatment the subject has at least a 75% relative reduction in SALT score.

[0059] In the thirteenth aspect of the second embodiment or any one of the first through fifth aspects thereof, after 8 weeks of treatment the subject has at least a 75% relative reduction in SALT score.

[0060] In a fourteenth aspect of the second embodiment or any one of the first through fifth aspects thereof, after 12 weeks of treatment the subject has at least a 75% relative reduction in SALT score.

[0061] In a fifteenth aspect of the second embodiment or any one of the first through fifth aspects thereof, after 24 weeks of treatment the subject has at least a 90% relative reduction in SALT score.

[0062] In a sixteenth aspect of the second embodiment or any one of the first through fifth aspects thereof, after 12 weeks of treatment the subject has at least a 90% relative reduction in SALT score.

[0063] In the seventeenth aspect of the second embodiment or any one of the first through fifth aspects thereof, after 24 weeks of treatment the subject reports a response of "satisfied" or "very satisfied" on the Hair Satisfaction Patient-Reported Outcome (SPRO) scale.

[0064] In an eighteenth aspect of the second embodiment or any one of the first through fifth aspects thereof, after 8 weeks of treatment the subject reports a response of "satisfied" or "very satisfied" on the Hair Satisfaction Patient-Reported Outcome (SPRO) scale.

[0065] In a nineteenth aspect of the second embodiment or any one of the first through fifth aspects thereof, after 12 weeks of treatment the subject reports a response of "satisfied" or "very satisfied" on the Hair Satisfaction Patient-Reported Outcome (SPRO) scale.

[0066] In the twentieth aspect of the second embodiment or any one of the first through fifth aspects thereof, after 12 weeks of treatment, the subject reports a reduction in score of at least 1.5 points from baseline on the Satisfaction with Hair Patient-Reported Outcome (SPRO) scale, for example, the reduction in score is ≧2 points.

[0067] In a twenty-first aspect of the second embodiment or any one of the first through fifth aspects thereof, after 24 weeks of treatment, the subject reports a response of "much improved" or "very much improved" using the Patient Global Impression of Improvement (PGI-I).

[0068] In the twenty-second aspect of the second embodiment or any one of the first through fifth aspects thereof, after 12 weeks of treatment, the subject reports a response of "much improved" or "very much improved" using the Patient Global Impression of Improvement (PGI-I).

[0069] In the twenty-third aspect of the second embodiment or any one of the first through fifth aspects thereof, after 16 weeks of treatment, the subject reports a response of "much improved" or "very much improved" using the Patient Global Impression of Improvement (PGI-I).

[0070] In the twenty-fourth aspect of the second embodiment or any one of the first through fifth aspects thereof, after 20 weeks of treatment, the subject reports a response of "much improved" or "very much improved" using the Patient Global Impression of Improvement (PGI-I).

[0071] In a twenty-fifth aspect of the second embodiment or any one of the first through fifth aspects thereof, after 12 weeks of treatment, a reduction in score from baseline of at least 1.5 points is reported by the subject on the Patient Global Impression of Improvement (PGI-I).

[0072] In a twenty-sixth aspect of the second embodiment or any one of the first through fifth aspects thereof, after 16 weeks of treatment, a reduction in score from baseline of at least 1.7 points is reported by the subject on the Patient Global Impression of Improvement (PGI-I).

[0073] In a twenty-seventh aspect of the second embodiment or any one of the first through fifth aspects thereof, after 24 weeks of treatment, a reduction in score from baseline of at least 2.1 points is reported by the subject on the Patient Global Impression of Improvement (PGI-I).

[0074] In the twenty-eighth aspect of the second embodiment or any one of the first through fifth aspects thereof, after 24 weeks of treatment the subject reports a response of "much improved" or "very much improved" using the Clinical Global Impression of Improvement (CGI-I).

[0075] In the twenty-ninth aspect of the second embodiment or any one of the first through fifth aspects thereof, after 12 weeks of treatment the subject reports a response of "much improved" or "very much improved" using the Clinical Global Impression of Improvement (CGI-I).

[0076] In a thirtieth aspect of the second embodiment or any one of the first through fifth aspects thereof, after 16 weeks of treatment the subject reports a response of "much improved" or "very much improved" using the Clinical Global Impression of Improvement (CGI-I).

[0077] In the thirty-first aspect of the second embodiment or any one of the first through fifth aspects thereof, after 20 weeks of treatment the subject reports a response of "much improved" or "very much improved" using the Clinical Global Impression of Improvement (CGI-I).

[0078] In a thirty-second aspect of the second embodiment or any one of the first through fifth aspects thereof, after 12 weeks of treatment, a reduction in score from baseline of at least 1.0 is reported by the subject on the Clinical Global Impression of Severity (CGI-S).

[0079] In a thirty-third aspect of the second embodiment or any one of the first through fifth aspects thereof, after 16 weeks of treatment, a reduction in score from baseline of at least 1.5 points is reported by the subject on the Clinical Global Impression of Severity (CGI-S).

[0080] In a thirty-fourth aspect of the second embodiment or any one of the first through fifth aspects thereof, after 24 weeks of treatment, a reduction in score from baseline of at least 2.0 points is reported by the subject on the Clinical Global Impression of Severity (CGI-S).

[0081] In a thirty-fifth aspect of the second embodiment or any one of the first through fifth aspects thereof, after 24 weeks of treatment, an increase in score from baseline of at least 1.0 is achieved by the subject on the Brigham Eyelash Tool for Alopecia (BELA) or the Brigham Eyebrow Tool for Alopecia (BETA).

[0082] In a thirty-sixth aspect of the second embodiment or any one of the first through fifth aspects thereof, after 12 weeks of treatment, an increase in score from baseline of at least 0.5 points is achieved by the subject on the Brigham Eyelash Tool for Alopecia (BELA) or the Brigham Eyebrow Tool for Alopecia (BETA).

[0083] In the thirty-seventh aspect of the second embodiment or any one of the first through thirty-sixth aspects thereof, the subject is a human. For example, an adult human. For example, the subject is an adolescent human (12 to less than 18 years old). For example, the subject is a pediatric human (6 to less than 12 years old).

[0084] In a thirty-eighth aspect of the second embodiment or any one of the first through thirty-seventh aspects thereof, about 16 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof is administered. For example, 16 mg / day is administered as 8 mg twice daily.

[0085] In a thirty-ninth aspect of the second embodiment or any one of the first through fifth aspects thereof, after 68 weeks of treatment the subject has an absolute SALT score of ≦20.

[0086] In a third embodiment, the present invention relates to a method of treating alopecia areata, the method comprising determining the estimated glomerular filtration rate (eGFR) of a population of subjects suffering from alopecia areata, and orally administering 16 mg / day or 24 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof to a subgroup of the population of subjects having an eGFR of ≧30 mL / min and MDRD, wherein Compound (I) is represented by the following structural formula: [ka] Each position specifically designated as deuterium has at least 95% incorporation of deuterium.

[0087] In a first aspect of the third embodiment, a subgroup of the subject population has moderate renal impairment (eGFR of 30-59 mL / min, MDRD).

[0088] In a second aspect of the third embodiment, a subgroup of the subject population has mild renal impairment (eGFR of 30-59 mL / min, MDRD).

[0089] In a third aspect of the third embodiment, the eGFR of a subgroup of the subject population is between ≧30 mL / min MDRD and <60 mL / min MDRD.

[0090] In a fourth aspect of the third embodiment, the eGFR of a subgroup of the subject population is between ≧60 mL / min MDRD and <90 mL / min MDRD.

[0091] In a fifth aspect of the third embodiment or any one of the first through fourth embodiments thereof, a subgroup of the population of subjects has an absolute SALT score of ≧50 at the start of treatment.

[0092] In a sixth aspect of the third embodiment or any one of the first through fourth embodiments thereof, a subgroup of the subject population has moderate to severe alopecia areata at the start of treatment.

[0093] In a seventh aspect of the third embodiment or any one of the first through fourth embodiments thereof, a subgroup of the subject population has severe alopecia areata at the start of treatment.

[0094] In the eighth aspect of the third embodiment or any one of the first through seventh aspects thereof, after 12 weeks of treatment, at least 5% of a subgroup of the subject population has an absolute SALT score of ≦20.

[0095] In the ninth aspect of the third embodiment or any one of the first through seventh aspects thereof, after 16 weeks of treatment, at least 10% of a subgroup of the subject population has an absolute SALT score of ≦20.

[0096] In a tenth aspect of the third embodiment or any one of the first through seventh aspects thereof, after 20 weeks of treatment, at least 20% of a subgroup of the subject population has an absolute SALT score of ≦20.

[0097] In an eleventh aspect of the third embodiment or any one of the first through seventh aspects thereof, after 24 weeks of treatment, at least 25% of a subgroup of the subject population has an absolute SALT score of ≦20.

[0098] In a twelfth aspect of the third embodiment or any one of the first through seventh aspects thereof, after 24 weeks of treatment, at least 15% of a subgroup of the subject population has an absolute SALT score of ≦10.

[0099] In a thirteenth aspect of the third embodiment or any one of the first through seventh aspects thereof, after 52 weeks of treatment, at least 50% of a subgroup of the subject population has an absolute SALT score of ≦20.

[0100] In a fourteenth aspect of the third embodiment or any one of the first through seventh aspects thereof, after 24 weeks of treatment, at least 30% of a subgroup of the subject population has at least a 75% relative reduction in SALT score.

[0101] In a fifteenth aspect of the third embodiment or any one of the first through seventh aspects thereof, after 12 weeks of treatment, at least 7% of a subgroup of the subject population has at least a 75% relative reduction in SALT score.

[0102] In a sixteenth aspect of the third embodiment or any one of the first through seventh aspects thereof, after 24 weeks of treatment, at least 20% of a subgroup of the subject population has at least a 90% relative reduction in SALT score.

[0103] In a seventeenth aspect of the third embodiment or any one of the first through seventh aspects thereof, after 12 weeks of treatment, at least 1.5% of a subgroup of the subject population has at least a 90% relative reduction in SALT score.

[0104] In an eighteenth aspect of the third embodiment or any one of the first through seventh aspects thereof, after 24 weeks of treatment, at least 35% of a subgroup of the subject population reports a response of "satisfied" or "very satisfied" on the Hair Satisfaction Patient-Reported Outcome (SPRO) scale.

[0105] In a nineteenth aspect of the third embodiment or any one of the first through seventh aspects thereof, after 12 weeks of treatment, at least 35% of a subgroup of the subject population reports a response of "satisfied" or "very satisfied" on the Hair Satisfaction Patient-Reported Outcome (SPRO) scale.

[0106] In the twentieth aspect of the third embodiment or any one of the first through seventh aspects thereof, after 20 weeks of treatment, at least 35% of a subgroup of the subject population reports a response of "satisfied" or "very satisfied" on the Hair Satisfaction Patient-Reported Outcome (SPRO) scale.

[0107] In a twenty-first aspect of the third embodiment or any one of the first through seventh aspects thereof, after 24 weeks of treatment, at least 50% of a subgroup of the subject population reports a response of "satisfied" or "very satisfied" on the Hair Satisfaction Patient-Reported Outcome (SPRO) scale.

[0108] In the twenty-second aspect of the third embodiment or any one of the first through seventh aspects thereof, after 12 weeks of treatment, at least 50% of a subgroup of the subject population reports a response of "satisfied" or "very satisfied" on the Hair Satisfaction Patient-Reported Outcome (SPRO) scale.

[0109] In a twenty-third aspect of the third embodiment or any one of the first through seventh aspects thereof, after 20 weeks of treatment, at least 50% of a subgroup of the subject population reports a response of "satisfied" or "very satisfied" on the Hair Satisfaction Patient-Reported Outcome (SPRO) scale.

[0110] In a twenty-fourth aspect of the third embodiment or any one of the first through seventh aspects thereof, after 12 weeks of treatment, a reduction in score from baseline of at least 1.5 points is reported by a subgroup of the subject population on the Satisfaction with Hair Patient-Reported Outcome (SPRO) scale.

[0111] In a twenty-fifth aspect of the third embodiment or any one of the first through seventh aspects thereof, after 12 weeks of treatment, a reduction in score of ≧2 from baseline is reported by at least 45% of a subgroup of the subject population on the Satisfaction with Hair Patient-Reported Outcome (SPRO) scale.

[0112] In a twenty-sixth aspect of the third embodiment or any one of the first through seventh aspects thereof, after 24 weeks of treatment, at least 50% of a subgroup of the subject population reports a response of "much improved" or "very much improved" using the Patient Global Impression of Improvement (PGI-I).

[0113] In a twenty-seventh aspect of the third embodiment or any one of the first through seventh aspects thereof, after 12 weeks of treatment, at least 30% of a subgroup of the subject population reports a response of "much improved" or "very much improved" using the Patient Global Impression of Improvement (PGI-I).

[0114] In a twenty-eighth aspect of the third embodiment or any one of the first through seventh aspects thereof, after 16 weeks of treatment, at least 40% of a subgroup of the subject population reports a response of "much improved" or "very much improved" using the Patient Global Impression of Improvement (PGI-I).

[0115] In the twenty-ninth aspect of the third embodiment or any one of the first through seventh aspects thereof, after 20 weeks of treatment, at least 45% of a subgroup of the subject population reports a response of "much improved" or "very much improved" using the Patient Global Impression of Improvement (PGI-I).

[0116] In a thirty-first aspect of the third embodiment or any one of the first through seventh aspects thereof, after 12 weeks of treatment, a reduction in score from baseline of at least 1.5 points is reported on the Patient Global Impression of Improvement (PGI-I) by a subgroup of the subject population.

[0117] In a thirty-first aspect of the third embodiment or any one of the first through seventh aspects thereof, after 16 weeks of treatment, a reduction in score from baseline of at least 1.7 points is reported by a subgroup of the subject population on the Patient Global Impression of Improvement (PGI-I).

[0118] In a thirty-second aspect of the third embodiment or any one of the first through seventh aspects thereof, after 24 weeks of treatment, a reduction in score from baseline of at least 2.1 points is reported by a subgroup of the subject population on the Patient Global Impression of Improvement (PGI-I).

[0119] In the thirty-third aspect of the third embodiment or any one of the first through seventh aspects thereof, after 24 weeks of treatment, at least 50% of a subgroup of the subject population reports a response of "much improved" or "very much improved" using the Clinical Global Impression of Improvement (CGI-I).

[0120] In the thirty-fourth aspect of the third embodiment or any one of the first through seventh aspects thereof, after 12 weeks of treatment, at least 30% of a subgroup of the subject population reports a response of "much improved" or "very much improved" using the Clinical Global Impression of Improvement (CGI-I).

[0121] In the thirty-fifth aspect of the third embodiment or any one of the first through seventh aspects thereof, after 16 weeks of treatment, at least 40% of a subgroup of the subject population reports a response of "much improved" or "very much improved" using the Clinical Global Impression of Improvement (CGI-I).

[0122] In a thirty-sixth aspect of the third embodiment or any one of the first through seventh aspects thereof, after 20 weeks of treatment, at least 45% of a subgroup of the subject population reports a response of "much improved" or "very much improved" using the Clinical Global Impression of Improvement (CGI-I).

[0123] In a thirty-seventh aspect of the third embodiment or any one of the first through seventh aspects thereof, after 12 weeks of treatment, a reduction in score from baseline of at least 1.0 is reported by a subgroup of the subject population on the Clinical Global Impression of Severity (CGI-S).

[0124] In a thirty-eighth aspect of the third embodiment or any one of the first through seventh aspects thereof, after 16 weeks of treatment, a reduction in score from baseline of at least 1.5 points is reported on the Clinical Global Impression of Severity (CGI-S) by a subgroup of the subject population.

[0125] In a thirty-ninth aspect of the third embodiment or any one of the first through seventh aspects thereof, after 24 weeks of treatment, a reduction in score from baseline of at least 2.0 points is reported by a subgroup of the subject population on the Clinical Global Impression of Severity (CGI-S).

[0126] In the fortieth aspect of the third embodiment or any one of the first through seventh aspects thereof, after 24 weeks of treatment, an increase in score from baseline of at least 1.0 is achieved on the Brigham Eyelash Tool for Alopecia (BELA) or the Brigham Eyebrow Tool for Alopecia (BETA) by a subgroup of the subject population.

[0127] In the forty-first aspect of the third embodiment or any one of the first through seventh aspects thereof, after 12 weeks of treatment, an increase in score from baseline of at least 0.5 points is achieved on the Brigham Eyelash Tool for Alopecia (BELA) or the Brigham Eyebrow Tool for Alopecia (BETA) by a subgroup of the subject population.

[0128] In the forty-second aspect of the third embodiment or any one of the first through fourteenth aspects thereof, the population of subjects is humans. For example, adult humans. For example, the subjects are adolescent humans (12 to under 18 years old). For example, the subjects are pediatric humans (6 to under 12 years old).

[0129] In the forty-third aspect of the third embodiment or any one of the first through fourteenth aspects thereof, 16 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof is administered. For example, 16 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof is administered as 8 mg twice daily.

[0130] In the forty-fourth aspect of the third embodiment or any one of the first through seventh aspects thereof, after 52 weeks of treatment, at least 50% of a subgroup of the subject population has an absolute SALT score of ≦20.

[0131] In a fourth embodiment, the present invention relates to a method of treating alopecia areata, the method comprising orally administering 16 mg / day or 24 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof to a population of subjects for a first period of 24 weeks of treatment, wherein after the first period, at least 30% of the population of subjects have a SALT score of ≦20; and continuing to orally administer 16 mg / day or 24 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof to the population of subjects after completion of the first period of 24 weeks of treatment, for a second period of treatment of at least an additional 52 weeks, wherein after the second period of treatment, at least 50% of the population of subjects have a SALT score of ≦20, wherein Compound (I) is represented by the following structural formula: [ka] Each position specifically designated as deuterium has at least 95% incorporation of deuterium.

[0132] In a first aspect of the fourth embodiment, the subject has an absolute SALT score of ≧50 at the start of treatment.

[0133] In a second aspect of the fourth embodiment, the subject has moderate to severe alopecia areata at the start of treatment.

[0134] In a third aspect of the fourth embodiment, the subject has severe alopecia areata at the start of treatment.

[0135] In the fourth aspect of the fourth embodiment or the first or second aspects thereof, the first period and the second period are consecutive.

[0136] In a fifth aspect of the fourth embodiment or any one of the first through fourth aspects thereof, the second period of time is at least 60 weeks.

[0137] In a sixth aspect of the fourth embodiment or any one of the first through fifth aspects thereof, the second period of time is at least 65 weeks. For example, the second period of time is at least 70 weeks. For example, the second period of time is at least 75 weeks. For example, the second period of time is at least 80 weeks. For example, the second period of time is at least 85 weeks. For example, the second period of time is at least 90 weeks. For example, the second period of time is at least 95 weeks. For example, the second period of time is at least 100 weeks.

[0138] In the seventh aspect of the fourth embodiment or any one of the first through fifth aspects thereof, after the second period of treatment, at least 60% of the population of subjects have a SALT score of ≦20.

[0139] In the eighth aspect of the fourth embodiment or any one of the first through fifth aspects thereof, after the second period of treatment, at least 70% of the population of subjects have a SALT score of ≦20.

[0140] In the ninth aspect of the fourth embodiment or any one of the first through fifth aspects thereof, after the second period of treatment, at least 74% of the population of subjects have a SALT score of ≦20.

[0141] In a tenth aspect of the fourth embodiment or any one of the first through fifth aspects thereof, after the second period of treatment, at least 80% of the population of subjects have a SALT score of ≦20.

[0142] In an eleventh aspect of the fourth embodiment or any one of the first through fifth aspects thereof, after the second period of treatment, at least 85% of the population of subjects have a SALT score of ≦20.

[0143] In a twelfth aspect of the fourth embodiment or any one of the first through fifth aspects thereof, after the second period of treatment, at least 90% of the population of subjects have a SALT score of ≦20.

[0144] In a thirteenth aspect of the fourth embodiment or any one of the first through twelfth aspects thereof, the population of subjects is humans. For example, adult humans. For example, the subjects are adolescent humans (12 to under 18 years old). For example, the subjects are pediatric humans (6 to under 12 years old).

[0145] In a fourteenth aspect of the fourth embodiment or any one of the first through thirteenth embodiments thereof, 16 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof is administered. For example, 16 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof is administered as 8 mg twice daily.

[0146] In a fifth embodiment, the present invention relates to a method of treating alopecia areata in a subject in need thereof, the method comprising orally administering 16 mg / day or 24 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof to the subject for a first period of 24 weeks, and then determining whether the subject has a reduction in SALT score to ≦20, and if not, continuing the administration of Compound (I) for a second period of 52 weeks, such that after 52 weeks of treatment, the subject achieves a SALT score of ≦20; [ka] Each position specifically designated as deuterium has at least 95% incorporation of deuterium.

[0147] In a sixth embodiment, the present invention relates to a method of treating alopecia areata, comprising orally administering 16 mg / day or 24 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof to a population of subjects for a first period of 24 weeks of treatment, wherein after the first period, at least 30% of the population of subjects have a SALT score of ≦20; and continuing to orally administer 16 mg / day or 24 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof to a population of subjects after completion of the first period of 24 weeks of treatment for a second period of treatment of at least an additional 44 weeks, wherein after the second period of treatment, at least 50% of the population of subjects have a SALT score of ≦20; Compound (I) is represented by the following structural formula: [ka] Each position specifically designated as deuterium has at least 95% incorporation of deuterium.

[0148] In a first aspect of the sixth embodiment, the subject has an absolute SALT score of ≧50 at the start of treatment.

[0149] In a second aspect of the sixth embodiment, the subject has moderate to severe alopecia areata at the start of treatment.

[0150] In a third aspect of the fourth embodiment, the subject has severe alopecia areata at the start of treatment.

[0151] In the fourth aspect of the sixth embodiment or the first or second aspects thereof, the first period and the second period are consecutive.

[0152] In the fifth aspect of the sixth embodiment or any one of the first through fourth aspects thereof, the second period of time is at least 84 weeks. For example, the second period of time is at least 92 weeks. For example, the second period of time is at least 108 weeks. For example, the second period of time is at least 140 weeks. For example, the second period of time is at least 156 weeks. For example, the second period of time is at least 188 weeks. For example, the second period of time is at least 220 weeks. For example, the second period of time is at least 252 weeks.

[0153] In the sixth aspect of the sixth embodiment or any one of the first through fifth aspects thereof, after the second period of treatment, at least 60% of the population of subjects have a SALT score of ≦20.

[0154] In the seventh aspect of the sixth embodiment or any one of the first through fifth aspects thereof, after the second period of treatment, at least 70% of the population of subjects have a SALT score of ≦20.

[0155] In the eighth aspect of the sixth embodiment or any one of the first through fifth aspects thereof, after the second period of treatment, at least 74% of the population of subjects have a SALT score of ≦20.

[0156] In the ninth aspect of the sixth embodiment or any one of the first through fifth aspects thereof, after the second period of treatment, at least 80% of the population of subjects have a SALT score of ≦20.

[0157] In a tenth aspect of the sixth embodiment or any one of the first through fifth aspects thereof, after the second period of treatment, at least 85% of the population of subjects have a SALT score of ≦20.

[0158] In an eleventh aspect of the sixth embodiment or any one of the first through fifth aspects thereof, after the second period of treatment, at least 90% of the population of subjects have a SALT score of ≦20.

[0159] In a twelfth aspect of the sixth embodiment or any one of the first through eleventh aspects thereof, the population of subjects is humans. For example, adult humans. For example, the subjects are adolescent humans (12 to less than 18 years old). For example, the subjects are pediatric humans (6 to less than 12 years old).

[0160] In a thirteenth aspect of the fourth embodiment or any one of the first through twelfth embodiments thereof, 16 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof is administered. For example, 16 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof is administered as 8 mg twice daily.

[0161] In a seventh embodiment, the present invention relates to a method of treating alopecia areata in a subject in need thereof, the method comprising orally administering 16 mg / day or 24 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof to the subject for a first period of 24 weeks, and then determining whether the subject has a reduction in SALT score to ≦20, and if not, continuing the administration of Compound (I) for a second period of 44 weeks, such that after 44 weeks of treatment, the subject achieves a SALT score of ≦20; [ka] Each position specifically designated as deuterium has at least 95% incorporation of deuterium.

[0162] In an eighth embodiment, the present disclosure provides a method of treating alopecia areata in a subject in need thereof, the method comprising orally administering 16 mg / day or 24 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof to the subject, wherein Compound (I) is represented by the following structural formula: [ka] Each position specifically designated as deuterium has at least 95% deuterium incorporation and the subject has anxiety and / or depression.

[0163] In a first aspect of the eighth embodiment, the presence of symptoms of anxiety and depression is determined based on the subject's completion of the Hospital Anxiety and Depression Scale (HADS) patient outcome test.

[0164] In a second aspect of the eighth embodiment or the first aspect thereof, the subject has a baseline score of >7 on the anxiety or depression subscale of the Hospital Anxiety and Depression Scale (HADS).

[0165] In the third aspect of the eighth embodiment or any one of the first to second aspects thereof, the subject has a moderate presence of symptoms of anxiety and depression as indicated by a score of between 8 and 10 on the anxiety or depression subscale of the Hospital Anxiety and Depression Scale (HADS) prior to administration of Compound (I).

[0166] In the fourth aspect of the eighth embodiment or any one of the first through third aspects thereof, the subject has severe presence of anxiety and depression symptoms as indicated by a score of greater than 11 on the anxiety and depression subscales of the Hospital Anxiety and Depression Scale (HADS) prior to administration of Compound (I).

[0167] In the fifth aspect of the eighth embodiment or any one of the first through fourth aspects thereof, the subject has a reduction in global score from baseline of at least 1.0 point as reported by the subject on the Hospital Anxiety and Depression Scale (HADS) after 12 weeks of treatment.

[0168] In the sixth aspect of the eighth embodiment or any one of the first through fifth aspects thereof, the subject has a reduction in global score from baseline of at least 3.0 points as reported by the subject on the Hospital Anxiety and Depression Scale (HADS) after 12 weeks of treatment.

[0169] In the seventh aspect of the eighth embodiment or any one of the first through sixth aspects thereof, the subject has a reduction in global score from baseline of at least 2.0 points as reported by the subject on the Hospital Anxiety and Depression Scale (HADS) after 16 weeks of treatment.

[0170] In the eighth aspect of the eighth embodiment or any one of the first through seventh aspects thereof, the subject has a reduction in global score from baseline of at least 4.0 points as reported by the subject on the Hospital Anxiety and Depression Scale (HADS) after 16 weeks of treatment.

[0171] In a ninth aspect of the eighth embodiment or any one of the first through eighth aspects thereof, the subject has a reduction in global score from baseline of at least 6.0 points as reported by the subject on the Hospital Anxiety and Depression Scale (HADS) after 24 weeks of treatment.

[0172] In a tenth aspect of the eighth embodiment or any one of the first through ninth aspects thereof, the subject has a reduction in global score from baseline of at least 10.0 points as reported by the subject on the Hospital Anxiety and Depression Scale (HADS) after 24 weeks of treatment.

[0173] In an eleventh aspect of the eighth embodiment or any one of the first through tenth aspects thereof, the subject has a reduction in Hospital Anxiety and Depression Scale-Anxiety (HADS-A) subscale score of at least 1.0 point from baseline as reported by the subject on the Hospital Anxiety and Depression Scale (HADS) after 12 weeks of treatment.

[0174] In a twelfth aspect of the eighth embodiment or any one of the first through eleventh aspects thereof, the subject has a reduction in Hospital Anxiety and Depression Scale-Anxiety (HADS-A) subscale score of at least 2.0 points from baseline as reported by the subject on the Hospital Anxiety and Depression Scale (HADS) after 12 weeks of treatment.

[0175] In a thirteenth aspect of the eighth embodiment or any one of the first through twelfth aspects thereof, the subject has a reduction in Hospital Anxiety and Depression Scale-Anxiety (HADS-A) subscale score of at least 2.0 points from baseline as reported by the subject on the Hospital Anxiety and Depression Scale (HADS) after 16 weeks of treatment.

[0176] In a fourteenth aspect of the eighth embodiment or any one of the first through thirteenth aspects thereof, the subject has a reduction in Hospital Anxiety and Depression Scale-Anxiety (HADS-A) subscale score of at least 3.0 points from baseline as reported by the subject on the Hospital Anxiety and Depression Scale (HADS) after 16 weeks of treatment.

[0177] In a fifteenth aspect of the eighth embodiment or any one of the first through fourteenth aspects thereof, the subject has a reduction in Hospital Anxiety and Depression Scale-Anxiety (HADS-A) subscale score of at least 4.0 points from baseline as reported by the subject on the Hospital Anxiety and Depression Scale (HADS) after 24 weeks of treatment.

[0178] In a sixteenth aspect of the eighth embodiment or any one of the first through fifteenth aspects thereof, the subject has a reduction in Hospital Anxiety and Depression Scale-Anxiety (HADS-A) subscale score of at least 6.0 points from baseline as reported by the subject on the Hospital Anxiety and Depression Scale (HADS) after 24 weeks of treatment.

[0179] In a seventeenth aspect of the eighth embodiment or any one of the first through fifteenth aspects thereof, the subject has a reduction in Hospital Anxiety and Depression Scale-Depression (HADS-D) subscale score of at least 1.0 point from baseline as reported by the subject on the Hospital Anxiety and Depression Scale (HADS) after 12 weeks of treatment.

[0180] In an eighteenth aspect of the eighth embodiment or any one of the first through seventeenth aspects thereof, the subject has a reduction in Hospital Anxiety and Depression Scale-Depression (HADS-D) subscale score of at least 2.0 points from baseline as reported by the subject on the Hospital Anxiety and Depression Scale (HADS) after 12 weeks of treatment.

[0181] In a nineteenth aspect of the eighth embodiment or any one of the first through eighteenth aspects thereof, the subject has a reduction in Hospital Anxiety and Depression Scale-Depression (HADS-D) subscale score of at least 2.0 points from baseline as reported by the subject on the Hospital Anxiety and Depression Scale (HADS) after 16 weeks of treatment.

[0182] In a twentieth aspect of the eighth embodiment or any one of the first through nineteenth aspects thereof, the subject has a reduction in Hospital Anxiety and Depression Scale-Depression (HADS-D) subscale score of at least 3.0 points from baseline as reported by the subject on the Hospital Anxiety and Depression Scale (HADS) after 16 weeks of treatment.

[0183] In a twenty-first aspect of the eighth embodiment or any one of the first through twentieth aspects thereof, the subject has a reduction in the Hospital Anxiety and Depression Scale-Depression (HADS-D) subscale score of at least 3.0 points from baseline as reported by the subject on the Hospital Anxiety and Depression Scale (HADS) after 24 weeks of treatment.

[0184] In a twenty-second aspect of the eighth embodiment or any one of the first through twenty-first aspects thereof, the subject has a reduction in Hospital Anxiety and Depression Scale-Depression (HADS-D) subscale score of at least 5.0 points from baseline as reported by the subject on the Hospital Anxiety and Depression Scale (HADS) after 24 weeks of treatment.

[0185] In the twenty-third aspect of the eighth embodiment or any one of the first through twenty-second aspects thereof, the subject has completed an additional primary diagnostic test used to diagnose anxiety and / or depression prior to treatment for alopecia areata.

[0186] In a twenty-fourth aspect of the eighth embodiment or a twenty-third aspect thereof, the additional test is the Generalized Anxiety Disorder Questionnaire (GAD-7), the Hamilton Anxiety Rating Scale (HAM-A), the Patient Health Questionnaire (PHQ), the Beck Depression Inventory (BDI), the Center for Epidemiologic Studies Depression Scale (CES-D), EQ-5D, the Hamilton Depression Rating Scale (HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), or a combination thereof.

[0187] In the twenty-fifth aspect of the eighth embodiment or any one of the first through twenty-fourth aspects thereof, the subject is a human, e.g., the subject is an adult human. In another example, the subject is an adolescent human (12 to less than 18 years of age). In another example, the subject is a pediatric human (6 to less than 12 years of age).

[0188] In the twenty-sixth aspect of the eighth embodiment or any one of the first through twenty-fourth aspects thereof, the subject has moderate to severe alopecia areata at the start of treatment.

[0189] In the twenty-seventh aspect of the eighth embodiment or any one of the first through twenty-fourth aspects thereof, the subject has severe alopecia areata at the start of treatment.

[0190] In a ninth embodiment, the present disclosure provides a method of treating alopecia areata in a population of subjects in need thereof, the method comprising: The method comprises orally administering 16 mg / day or 24 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof to a population of subjects, wherein Compound (I) is represented by the following structural formula: [ka] Each position specifically designated as deuterium has at least 95% incorporation of deuterium, and Compound (I) is administered to a population of subjects for at least 52 weeks, and administration of Compound (I) results in maintaining a SALT score of ≦20 in at least 50% of the population of subjects.

[0191] In a second aspect of the ninth embodiment, Compound (I) is administered to the subject for at least 68 weeks.

[0192] In a third aspect of the ninth embodiment, Compound (I) is administered to the subject for at least 76 weeks.

[0193] In a tenth embodiment, the present disclosure provides a method of treating alopecia areata in a subject in need thereof, the method comprising: The method comprises orally administering 16 mg / day or 24 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof to a subject, wherein Compound (I) is represented by the following structural formula: [ka] Each position specifically designated as deuterium has at least 95% incorporation of deuterium, and Compound (I) is administered to the subject for at least 52 weeks, and administration of Compound (I) results in a sustained relative reduction in SALT score of at least 50%.

[0194] In a second aspect of the tenth embodiment, Compound (I) is administered to the subject for at least 68 weeks.

[0195] In a second aspect of the tenth embodiment, Compound (I) is administered to the subject for at least 76 weeks.

[0196] In an eleventh embodiment, the present disclosure provides a method of treating alopecia areata in a population of subjects in need thereof who have previously been administered and discontinued a Janus kinase (JAK) inhibitor that does not include Compound (I), the method comprising: The method comprises orally administering 16 mg / day or 24 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof to a population of subjects, wherein Compound (I) is represented by the following structural formula: [ka] Each position specifically designated as deuterium has at least 95% incorporation of deuterium, and Compound (I) is administered to a population of subjects for at least 8 weeks, and administration of Compound (I) results in a SALT score of ≦20 in at least 50% of the population of subjects.

[0197] In a first aspect of the eleventh embodiment, JAK inhibitors include, but are not limited to, baricitinib, ritrecitinib, and ruxolitinib.

[0198] In the second aspect of the eleventh embodiment or the first aspect thereof, Compound (I) is administered to the subject for at least 12 weeks.

[0199] In the third aspect of the eleventh embodiment or the first aspect thereof, Compound (I) is administered to the subject for at least 16 weeks.

[0200] In the fourth aspect of the eleventh embodiment or the first aspect thereof, Compound (I) is administered to the subject for at least 20 weeks.

[0201] In the fifth aspect of the eleventh embodiment or the first aspect thereof, Compound (I) is administered to the subject for at least 24 weeks.

[0202] In a sixth aspect of the eleventh embodiment or the first aspect thereof, Compound (I) is administered to the subject for at least 52 weeks.

[0203] In the seventh aspect of the eleventh embodiment or any one of the first through sixth aspects thereof, the subject has an absolute SALT score of ≧50 at the start of treatment.

[0204] In the eighth aspect of the eleventh embodiment or any one of the first through sixth aspects thereof, the subject has moderate to severe alopecia areata at the start of treatment.

[0205] In the ninth aspect of the eleventh embodiment or any of the first through sixth aspects thereof, the subject has severe alopecia areata at the start of treatment.

[0206] In the tenth aspect of the eleventh embodiment or any one of the first through ninth aspects thereof, after 8 weeks of treatment the subject has an absolute SALT score of ≦20.

[0207] In the eleventh aspect of the eleventh embodiment or any one of the first through ninth aspects thereof, after 12 weeks of treatment the subject has an absolute SALT score of ≦20.

[0208] In the twelfth aspect of the eleventh embodiment or any one of the first through ninth aspects thereof, after 16 weeks of treatment the subject has an absolute SALT score of ≦20.

[0209] In the thirteenth aspect of the eleventh embodiment or any one of the first through ninth aspects thereof, after 20 weeks of treatment the subject has an absolute SALT score of ≦20.

[0210] In the fourteenth aspect of the eleventh embodiment or any one of the first through ninth aspects thereof, after 24 weeks of treatment the subject has an absolute SALT score of ≦20.

[0211] In the fifteenth aspect of the eleventh embodiment or any one of the first through ninth aspects thereof, after 24 weeks of treatment the subject has an absolute SALT score of ≦10.

[0212] In the sixteenth aspect of the eleventh embodiment or any one of the first through ninth aspects thereof, after 52 weeks of treatment the subject has an absolute SALT score of ≦20.

[0213] In the seventeenth aspect of the eleventh embodiment or any one of the first through ninth aspects thereof, after 24 weeks of treatment the subject has at least a 75% relative reduction in SALT score.

[0214] In the eighteenth aspect of the eleventh embodiment or any one of the first through ninth aspects thereof, after 8 weeks of treatment the subject has at least a 75% relative reduction in SALT score.

[0215] In the nineteenth aspect of the eleventh embodiment or any one of the first through ninth aspects thereof, after 12 weeks of treatment the subject has at least a 75% relative reduction in SALT score.

[0216] In the twentieth aspect of the eleventh embodiment or any one of the first through ninth aspects thereof, after 24 weeks of treatment the subject has at least a 90% relative reduction in SALT score.

[0217] In a twenty-first aspect of the eleventh embodiment or any one of the first through ninth aspects thereof, after 12 weeks of treatment the subject has at least a 90% relative reduction in SALT score.

[0218] In the twenty-second aspect of the eleventh embodiment or any one of the first through ninth aspects thereof, after 24 weeks of treatment, the subject reports a response of "satisfied" or "very satisfied" on the Hair Satisfaction Patient-Reported Outcome (SPRO) scale.

[0219] In the twenty-third aspect of the eleventh embodiment or any one of the first through ninth aspects thereof, after 8 weeks of treatment the subject reports a response of "satisfied" or "very satisfied" on the Hair Satisfaction Patient-Reported Outcome (SPRO) scale.

[0220] In the twenty-fourth aspect of the eleventh embodiment or any one of the first through ninth aspects thereof, after 12 weeks of treatment the subject reports a response of "satisfied" or "very satisfied" on the Hair Satisfaction Patient-Reported Outcome (SPRO) scale.

[0221] In the twenty-fifth aspect of the eleventh embodiment or any one of the first through ninth aspects thereof, after 12 weeks of treatment, the subject reports a reduction in score of at least 1.5 points from baseline on the Hair Satisfaction Patient-Reported Outcome (SPRO) scale, for example, the reduction in score is ≧2 points.

[0222] In the twenty-sixth aspect of the eleventh embodiment or any one of the first through ninth aspects thereof, after 24 weeks of treatment, the subject reports a response of "much improved" or "very much improved" using the Patient Global Impression of Improvement (PGI-I).

[0223] In the twenty-seventh aspect of the eleventh embodiment or any one of the first through ninth aspects thereof, after 12 weeks of treatment, the subject reports a response of "much improved" or "very much improved" using the Patient Global Impression of Improvement (PGI-I).

[0224] In the twenty-eighth aspect of the eleventh embodiment or any one of the first through ninth aspects thereof, after 16 weeks of treatment, the subject reports a response of "much improved" or "very much improved" using the Patient Global Impression of Improvement (PGI-I).

[0225] In the twenty-ninth aspect of the eleventh embodiment or any one of the first through ninth aspects thereof, after 20 weeks of treatment, the subject reports a response of "much improved" or "very much improved" using the Patient Global Impression of Improvement (PGI-I).

[0226] In the thirty-first aspect of the eleventh embodiment or any one of the first through ninth aspects thereof, after 12 weeks of treatment, a reduction in score from baseline of at least 1.5 points is reported by the subject on the Patient Global Impression of Improvement (PGI-I).

[0227] In the thirty-first aspect of the eleventh embodiment or any one of the first through ninth aspects thereof, after 16 weeks of treatment, a reduction in score from baseline of at least 1.7 points is reported by the subject on the Patient Global Impression of Improvement (PGI-I).

[0228] In the thirty-second aspect of the eleventh embodiment or any one of the first through ninth aspects thereof, after 24 weeks of treatment, a reduction in score from baseline of at least 2.1 points is reported by the subject on the Patient Global Impression of Improvement (PGI-I).

[0229] In the thirty-third aspect of the eleventh embodiment or any one of the first through ninth aspects thereof, after 24 weeks of treatment, the subject reports a response of "much improved" or "very much improved" using the Clinical Global Impression of Improvement (CGI-I).

[0230] In the thirty-fourth aspect of the eleventh embodiment or any one of the first through ninth aspects thereof, after 12 weeks of treatment the subject reports a response of "much improved" or "very much improved" using the Clinical Global Impression of Improvement (CGI-I).

[0231] In the thirty-fifth aspect of the eleventh embodiment or any one of the first through ninth aspects thereof, after 16 weeks of treatment, the subject reports a response of "much improved" or "very much improved" using the Clinical Global Impression of Improvement (CGI-I).

[0232] In the thirty-sixth aspect of the eleventh embodiment or any one of the first through ninth aspects thereof, after 20 weeks of treatment, the subject reports a response of "much improved" or "very much improved" using the Clinical Global Impression of Improvement (CGI-I).

[0233] In the thirty-seventh aspect of the eleventh embodiment or any one of the first through ninth aspects thereof, after 12 weeks of treatment, a reduction in score from baseline of at least 1.0 is reported by the subject on the Clinical Global Impression of Severity (CGI-S).

[0234] In the thirty-eighth aspect of the eleventh embodiment or any one of the first through ninth aspects thereof, after 16 weeks of treatment, a reduction in score from baseline of at least 1.5 points is reported by the subject on the Clinical Global Impression of Severity (CGI-S).

[0235] In the thirty-ninth aspect of the eleventh embodiment or any one of the first through ninth aspects thereof, after 24 weeks of treatment, a reduction in score from baseline of at least 2.0 points is reported by the subject on the Clinical Global Impression of Severity (CGI-S).

[0236] In the fortieth aspect of the eleventh embodiment or any one of the first through ninth aspects thereof, after 24 weeks of treatment, an increase in score from baseline of at least 1.0 is achieved by the subject on the Brigham Eyelash Tool for Alopecia (BELA) or the Brigham Eyebrow Tool for Alopecia (BETA).

[0237] In the forty-first aspect of the eleventh embodiment or any one of the first through ninth aspects thereof, after 12 weeks of treatment, an increase in score from baseline of at least 0.5 points is achieved by the subject on the Brigham Eyelash Tool for Alopecia (BELA) or the Brigham Eyebrow Tool for Alopecia (BETA).

[0238] In the forty-second aspect of the eleventh embodiment or any one of the first through forty-first aspects thereof, the subject is a human. For example, the subject is an adult human. For example, the subject is an adolescent human (12 to less than 18 years old). For example, the subject is a pediatric human (6 to less than 12 years old).

[0239] In the forty-third aspect of the eleventh embodiment or any one of the first through forty-second aspects thereof, about 16 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof is administered. For example, 16 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof is administered as 8 mg twice daily. [Brief explanation of the drawings]

[0240] The foregoing will become apparent from the following more particular description of exemplary embodiments of the invention, as illustrated in the accompanying drawings, in which like reference characters refer to the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating embodiments of the invention.

[0241] [Figure 1] FIG. 1 is a graph showing the percentage of subjects with a SALT score ≦20 after 24 weeks of treatment with either 8 mg BID or 12 mg BID CTP-543. [Figure 2] FIG. 2 is a graph of the percentage of subjects receiving either 8 mg BID or 12 mg BID CTP-543 with a SALT score of ≦20 versus week of treatment. [Figure 3] Figure 3 is a diagram of patient / subject flow from the qualifying trial to the open-label extension. [Figure 4] FIG. 4 is a chart showing patient / subject demographics. [Figure 5] FIG. 5 is a graph showing the percentage of responders (subjects with a SALT score of ≦20) over time treated with any dose of durxolitinib. [Figure 6]FIG. 6 is a graph showing the percentage of responders (subjects with a SALT score of ≦20) over time treated with 8 mg durxolitinib twice daily. [Figure 7] FIG. 7 is a graph showing the percentage of responders (subjects with a SALT score of ≦20) over time treated with 12 mg durxolitinib twice daily. [Figure 8] FIG. 8 shows the mean SALT scores over time for all treatment groups in the OLE study. [Figure 9] FIG. 9 shows the mean SALT scores over time for the group of subjects treated with 8 mg BID durxolitinib in the OLE study. [Figure 10] FIG. 10 shows the mean SALT scores over time for the group of subjects treated with 12 mg BID durxolitinib in the OLE study. [Figure 11] FIG. 11 is a graph showing the percentage of responders (subjects with a SALT score of ≦20) over time treated with 8 mg of durxolitinib twice daily (censored population and LOCF (last observation carried forward) analysis). [Figure 12] FIG. 12 is a graph showing the percentage of responders (subjects with a SALT score of ≦20) over time treated with 12 mg durxolitinib twice daily (censored population and LOCF analysis). [Figure 13A] FIG. 13A shows the percentage of responders (subjects with a SALT score of ≦20) for durxolitinib (8 mg twice daily) up to 68 weeks. [Figure 13B] Figure 13B shows the percentage of responders (subjects with a SALT score of ≦20) for baricitinib (4 mg) up to 52 weeks. [Figure 13C] FIG. 13C shows the percentage of responders (subjects with a SALT score of ≦20) for ritrecitinib (50 mg) up to 48 weeks. [Figure 14A] FIG. 14A is a graph showing the percentage of responders with a "very satisfied" or "satisfied" response at 24 weeks of treatment with placebo, 8 mg BID, or 12 mg BID. [Figure 14B] Figure 14B is a graph showing the percentage of subjects achieving a SALT score < 10 at week 12. Subjects were treated with placebo, 8 mg BID, or 12 mg BID. DETAILED DESCRIPTION OF THE INVENTION

[0242] A description of exemplary embodiments of the present invention follows.

[0243] The teachings of all patents, published applications, and references cited herein are incorporated by reference in their entirety.

[0244] Hair loss disorder "Hair loss disorder" means any condition or disorder that results in the loss of hair on one or more areas of the body. Hair loss disorders include, without limitation, androgenetic alopecia, alopecia areata, telogen effluvium, alopecia totalis, and alopecia universalis. In a specific embodiment, the hair loss disorder is alopecia areata.

[0245] Alopecia areata is an autoimmune disease that can affect up to 650,000 Americans at any given time, resulting in partial or complete loss of scalp and body hair.Scalp is the most commonly affected area, but any hairy area can be affected alone or together with scalp.Disease development can occur throughout life, but it affects both men and women.Alopecia areata can be associated with serious psychological consequences, including anxiety and depression.

[0246] In specific embodiments, the condition is alopecia areata in a subject in need thereof, such as a mammalian (e.g., human) subject (e.g., patient). In certain embodiments, the alopecia areata is moderate to severe alopecia areata (e.g., hair loss over at least 50% of the scalp). Other descriptions of the severity of hair loss relate to alopecia areata in the description provided by Wyrwich et al. (Wyrwich KW, et al. The alopecia areata investigator global assessment scale: a measure for evaluating clinically meaningful success in clinical trials. Br J Dermaol. 2020; 183: 702-9), in which the severity of hair loss is described as: no hair loss (0% hair loss); limited hair loss = 1-20% hair loss; moderate hair loss = 21-49% hair loss; severe hair loss = 50-94% hair loss; and very severe hair loss = 95-100% hair loss.

[0247] JAK inhibitors Janus kinase (JAK) inhibitors, also known as jakinibs, are a class of immunomodulatory drugs that inhibit the activity of one or more of the Janus kinase family of enzymes (JAK1, JAK2, JAK3, TYK2), thereby disrupting the JAK-STAT signaling pathway in lymphocytes.

[0248] In some embodiments, the present disclosure provides a method of treating alopecia areata in a subject in need thereof, the method comprising determining the subject's estimated glomerular filtration rate, and if the subject has an estimated glomerular filtration rate (eGFR) of ≧30 mL / min, MDRD, orally administering a Janus kinase (JAK) inhibitor to the subject.

[0249] In some embodiments, the present disclosure provides a method of treating alopecia areata in a subject in need thereof, the method comprising orally administering a Janus kinase (JAK) inhibitor to the subject when the subject has an estimated glomerular filtration rate (eGFR) of ≧30 mL / min, MDRD.

[0250] In some embodiments, the present disclosure provides a method for treating alopecia areata in a subject in need thereof, the method comprising: determining the subject's complete blood count; if the subject's complete blood count indicates that ALC is ≧500 cells / μL, ANC is ≧1000 cells / μL, and / or hemoglobin level is ≧8 g / dL, orally administering a Janus kinase (JAK) inhibitor to the subject; monitoring ALC, ANC, and hemoglobin level; and if the subject's ALC is <500 cells / μL, ANC is <1000 cells / μL, and / or hemoglobin level is <8 g / dL, discontinuing treatment of the subject. In some embodiments, the method further comprises the steps of resuming treatment of the subject if the subject's ALC is determined to be ≧500 cells / μL, if the subject's ANC is determined to be ≧1000 cells / μL, and / or if the subject's hemoglobin level is determined to be ≧8 g / dL. In some embodiments, the method further comprises determining an estimated glomerular filtration rate to the subject, and if the subject has an estimated glomerular filtration rate (eGFR) of ≧30 mL / min for MDRD, orally administering a JAK inhibitor to the subject. In some embodiments, the method further comprises orally administering a JAK inhibitor to the subject if the subject has an estimated glomerular filtration rate (eGFR) of ≧30 mL / min for MDRD.

[0251] In some embodiments, the present disclosure provides methods of treating alopecia areata, the method comprising determining an estimated glomerular filtration rate (eGFR) of a population of subjects suffering from alopecia areata, and orally administering a JAK inhibitor to a subgroup of the population of subjects having an eGFR of ≧30 mL / min, MDRD. In certain embodiments, the present disclosure provides methods of treating alopecia areata, the method comprising orally administering a JAK inhibitor to a subgroup of the population of subjects having an eGFR of ≧30 mL / min, MDRD.

[0252] In some embodiments, the present disclosure provides a method of treating alopecia areata, the method comprising orally administering a JAK inhibitor to a population of subjects for a first period of 24 weeks of treatment, wherein after the first period, at least 30% of the population of subjects have a SALT score of ≦20, and continuing to orally administer the JAK inhibitor to the population of subjects after completion of the first period of 24 weeks of treatment, for a second period of treatment of at least an additional 52 weeks, wherein after the second period of treatment, at least 50% of the population of subjects have a SALT score of ≦20.

[0253] In some embodiments, the present disclosure provides a method of treating alopecia areata in a subject in need thereof, comprising orally administering a JAK inhibitor to the subject for a first period of 24 weeks, and then determining whether the subject has a reduction in SALT score to ≦20, and if not, continuing administration of the JAK inhibitor for a second period of 52 weeks, such that after 52 weeks of treatment, the subject achieves a SALT score of ≦20.

[0254] In some embodiments, the present disclosure provides a method of treating alopecia areata in a subject in need thereof, the method comprising orally administering a JAK inhibitor to the subject, wherein the subject has anxiety and / or depression.

[0255] In some embodiments, the present disclosure provides a method of treating alopecia areata in a population of subjects in need thereof, the method comprising orally administering a JAK inhibitor to the population of subjects, wherein the JAK inhibitor is administered to the population of subjects for at least 52 weeks, and wherein administration of the JAK inhibitor results in maintaining a SALT score of ≦20 in at least 50% of the population of subjects.

[0256] In some embodiments, the present disclosure provides a method of treating alopecia areata in a subject in need thereof, the method comprising orally administering a JAK inhibitor or a pharmaceutically acceptable salt thereof to the subject, wherein the JAK inhibitor is administered to the subject for at least 52 weeks, and wherein administration of the JAK inhibitor results in a sustained relative reduction in SALT score of at least 50%.

[0257] In certain embodiments, the JAK inhibitor is a JAK1 inhibitor. In certain embodiments, the JAK inhibitor is a JAK2 inhibitor. In certain embodiments, the JAK inhibitor inhibits the activity of one or more JAK enzymes. For example, the JAK inhibitor inhibits the activity of JAK1, JAK2, and JAK3. In certain embodiments, the JAK inhibitor is a JAK1 / JAK2 inhibitor.

[0258] Compound (I) Compound I, as referred to herein, is (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(cyclopentyl-2,2,3,3,4,4,5,5-d8)propanenitrile. [ka]

[0259] Compound (I), also referred to herein as CTP-543 and duloxolitinib, and also referred to herein as LEQSELVI™, is a potent, selective inhibitor of the Janus kinases JAK1 and JAK2. This compound is disclosed in International Patent Applications WO2013 / 188783A1, WO2017 / 192905A1, and WO2020 / 163653. CTP-543, as described herein, is currently being investigated in human clinical trials and has been shown to stimulate hair growth in subjects with alopecia areata.

[0260] Synthesis of Compound (I), or a pharmaceutically acceptable salt thereof (e.g., phosphate salt, etc.), can be readily achieved by the methods described in U.S. Pat. No. 9,249,149, WO 2017 / 192905 A1, WO 2020 / 163653, and U.S. Pat. No. 10,561,659, the teachings of all of which are incorporated herein by reference, with appropriate modifications, if necessary.

[0261] Additional methods for preparing ruxolitinib (i.e., the non-deuterated analog compound (I)) are disclosed in U.S. Pat. No. 9,000,161 and can be used to prepare compound (I) using an appropriate deuterated reagent.

[0262] Such methods can be carried out utilizing corresponding deuterated, and optionally other isotopically-containing reagents and / or intermediates, to synthesize the compounds detailed herein, or by invoking standard synthetic protocols known in the art for introducing isotopic atoms into a chemical structure.

[0263] It will be recognized that some variation in natural isotope abundance will occur in synthesized compounds depending on the origin of the chemical materials used in synthesis. Thus, preparations of ruxolitinib inherently contain small amounts of deuterated isotope substitution. Despite this variation, the concentrations of naturally abundant stable hydrogen and carbon isotopes are small and immaterial compared to the degree of stable isotope substitution of the deuterated compounds of the present invention (e.g., Compound (I)). See, for example, Wada, E et al., Seikagaku, 1994, 66:15; Gannes, LZ et al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119:725.

[0264] In any of the compounds described herein, e.g., Compound (I), any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen," the position is understood to have hydrogen at its natural abundance isotopic composition. However, in certain described embodiments, when a position is specifically designated as "H" or "hydrogen," the position has at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% hydrogen. In some embodiments, when detailed, when a position is specifically designated as "H" or "hydrogen," the position incorporates ≦20% deuterium, ≦10% deuterium, ≦5% deuterium, ≦4% deuterium, ≦3% deuterium, ≦2% deuterium, or ≦1% deuterium. Also, unless otherwise stated, when a position is specifically designated as "D" or "deuterium," the position is understood to have deuterium at an abundance at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% deuterium incorporation). The amount of deuterium incorporation at a designated position may be measured by analytical methods known to those skilled in the art, for example, by proton NMR.

[0265] As used herein, the term "isotopic enrichment factor" means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[0266] In other embodiments, deuterated compounds of the invention have an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), at least 6533.3 (98% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0267] In some embodiments, in the compounds of the present invention, each designated deuterium position (or atom) has at least 52.5% deuterium incorporation. In some embodiments, in the compounds of the present invention, each designated deuterium position has at least 60% deuterium incorporation. In some embodiments, in the compounds of the present invention, each designated deuterium position has at least 67.5% deuterium incorporation. In some embodiments, in the compounds of the present invention, each designated deuterium position has at least 75% deuterium incorporation. In some embodiments, in the compounds of the present invention, each designated deuterium position has at least 80% deuterium incorporation. In some embodiments, in the compounds of the present invention, each designated deuterium position has at least 85% deuterium incorporation. In some embodiments, in the compounds of the present invention, each designated deuterium position has at least 90% deuterium incorporation. In some embodiments, in the compounds of the present invention, each designated deuterium position has at least 95% deuterium incorporation. In some embodiments, in the compounds of the present invention, each designated deuterium position has at least 97% deuterium incorporation. In some embodiments, in the compounds of the present invention, each designated deuterium position has at least 98% deuterium incorporation. In some embodiments, in the compounds of the present invention, each designated deuterium position has at least 99% deuterium incorporation. In some embodiments, in the compounds of the present invention, each designated deuterium position has at least 99.5% deuterium incorporation.

[0268] The term "isotopomer" refers to a species whose chemical structure differs from any of the compounds described herein only in its isotopic composition.

[0269] The term "compound," when referring to a deuterated compound of the invention, e.g., Compound I, refers to a collection of molecules having the same chemical structure, except that there may be isotopic variations among the constituent atoms of the molecule. Thus, it will be apparent to one of skill in the art that a compound represented by a particular chemical structure containing a deuterium atom as shown also includes isotopic substitutions having a hydrogen atom at one or more of the designated deuterium positions in that structure. The relative amount of such isotopic substitutions in a compound of the invention will depend on a number of factors, including the isotopic purity of the deuteration reagent used to make the compound and the efficiency of deuterium incorporation in the various synthetic steps used to prepare the compound. In certain embodiments, the relative amount of such isotopic substitutions, overall, is less than 49.9% of the compound. In other embodiments, the relative amount of such isotopic substitutions, overall, is less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound.

[0270] The term "stable compound," as used herein, refers to a compound that is sufficiently stable to permit its manufacture and maintains its compound integrity for a sufficient period of time to be useful for the purposes detailed herein (e.g., formulation into a therapeutic product, an intermediate for use in the production of a therapeutic compound, an isolatable or storable intermediate compound, treating a disease or condition responsive to a therapeutic agent).

[0271] "D" and "d" both refer to deuterium. "Stereoisomer" refers to both enantiomers and diastereomers. "Tert" and "t-" each refer to tertiary. "US" refers to the United States of America.

[0272] "Substituted with deuterium" refers to the replacement of one or more hydrogen atoms with a corresponding number of deuterium atoms.

[0273] As depicted above, Compound (I) is shown as the “free base.” In some embodiments, a pharmaceutically acceptable salt of Compound (I) is used.

[0274] The term "pharmaceutically acceptable," as used herein, refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio. A "pharmaceutically acceptable salt" means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of the invention. A "pharmaceutically acceptable counterion" is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient.

[0275] Pharmaceutically acceptable salts of Compound (I) include acid addition salts formed with inorganic or organic acids. Suitable inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid. Suitable organic acids include paratoluenesulfonic acid, salicylic acid, tartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, succinic acid, citric acid, benzoic acid, and acetic acid. In certain embodiments, the pharmaceutically acceptable salt of Compound (I) is selected from sulfate, phosphate, paratoluenesulfonate, and methanesulfonate (mesylate).

[0276] In certain embodiments, the pharmaceutically acceptable salt of Compound (I) is a phosphate salt. In certain embodiments, a phosphate salt of Compound (I) (in a molar ratio of 1:1) is used. The phosphate salt of Compound (I) is depicted below. [ka]

[0277] The molecular weight of Compound (I) is 314.2 g / mol. The molecular weight of the 1:1 phosphate salt of Compound (I) is 412.2 g / mol.

[0278] In one embodiment, the ratio of Compound I to the salt form of phosphate is about 1:1.

[0279] In one embodiment, any atom not designated as deuterium is present at its natural isotopic abundance in Compound (I), or a pharmaceutically acceptable salt thereof.

[0280] The pharmaceutically acceptable salt of Compound (I) may exist as a hydrate, a solvate, or in anhydrous form. In certain embodiments, the pharmaceutically acceptable salt is anhydrous. In more specific embodiments, the phosphate salt is anhydrous.

[0281] Throughout this specification, unless otherwise specified, references to the amount of Compound (I) will be understood to refer to the amount of the parent compound on a free base basis, even when the compound is present as a salt of Compound I.

[0282] Purely by way of example, a reference to 12 mg of Compound (I) or a salt thereof will be understood to refer to 12 mg of free base, or a salt of Compound (I) with 12 mg of free base equivalent. In the context of the anhydrous monophosphate salt of Compound (I), approximately 15.7 mg of salt delivers 12 mg of Compound (I) (free base equivalent).

[0283] In certain embodiments, the amount of Compound (I), or a pharmaceutically acceptable salt thereof, administered in the method for inducing hair growth is about 8 mg (such as 8 mg) twice a day or 16 mg / day. In a specific embodiment, Compound (I) is administered as about 10.5 mg (such as 10.5 mg) of the phosphate salt of Compound (I) twice a day.

[0284] In certain embodiments, the amount of Compound (I), or a pharmaceutically acceptable salt thereof, administered in the method for inducing hair growth is about 12 mg (e.g., 12 mg) twice daily or 24 mg per day. In a specific embodiment, Compound (I) is administered as about 15.7 mg (e.g., 15.7 mg) of the phosphate salt of Compound (I) twice daily.

[0285] Dosage and Administration of JAK Inhibitors and Compound (I) The term "treating" refers to reducing, inhibiting, attenuating, diminishing, arresting, or stabilizing the onset or progression of a disease (e.g., a disease or disorder detailed herein), reducing the severity of a disease, or ameliorating symptoms associated with a disease. For example, treating a hair loss disorder includes regrowing hair, preventing further hair loss, or reducing the rate of hair loss.

[0286] As used herein, the term "subject" refers to a mammal, preferably a human, but can also refer to animals requiring veterinary treatment, such as companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like), and laboratory animals (e.g., rats, mice, guinea pigs, and the like). The terms subject and patient are used interchangeably herein. In certain embodiments, the subject or patient is a human. In even more particular embodiments, the subject or patient is an adult human. In another even more particular embodiment, the subject is an adolescent human (12 to under 18 years of age). In another even more particular embodiment, the subject is a pediatric human (6 to under 12 years of age).

[0287] As used herein, a "patient population" or "population of subjects" refers to a predetermined group of subjects. For example, a patient population or a population of subjects can be subjects who are receiving treatment at or near the same time and who are being monitored and evaluated together. For example, a patient population or a population of subjects can be members of a clinical trial.

[0288] As used herein, a "therapeutically effective amount" is an amount sufficient to treat a target condition or disorder. If the drug is approved by the U.S. Food and Drug Administration (FDA), the "therapeutically effective amount" can be the dosage approved by the FDA.

[0289] In certain embodiments, the amount of Compound (I), or a pharmaceutically acceptable salt thereof, administered in the method for treating hair loss disorders is about 8 mg / day (such as 8 mg / day), about 16 mg / day (such as 16 mg / day), about 24 mg / day (such as 24 mg / day), or about 32 mg / day (such as 32 mg / day). In more specific embodiments, the amount of Compound (I), or a pharmaceutically acceptable salt thereof, administered in the method for treating hair loss disorders is about 8 mg / day (such as 8 mg / day), about 16 mg / day (such as 16 mg / day), or about 24 mg / day (such as 24 mg / day).

[0290] In certain embodiments, the amount of Compound (I), or a pharmaceutically acceptable salt thereof, administered in the method for treating hair loss disorders is about 4 mg (such as 4 mg) twice daily. In a specific embodiment, Compound (I) is administered as about 5.3 mg (such as 5.3 mg) of the phosphate salt of Compound (I) twice daily.

[0291] In another embodiment, the amount of Compound (I), or a pharmaceutically acceptable salt thereof, administered in the method of treating hair loss disorders is about 8 mg (e.g., 8 mg) twice daily. In a specific embodiment, Compound (I) is administered as about 10.5 mg (e.g., 10.5 mg) of the phosphate salt of Compound (I) twice daily.

[0292] In certain embodiments, the amount of Compound (I), or a pharmaceutically acceptable salt thereof, administered in the method for treating hair loss disorders is about 12 mg (such as 12 mg) twice daily. In a specific embodiment, Compound (I) is administered as about 15.8 mg (such as 15.8 mg) of the phosphate salt of Compound (I) twice daily.

[0293] In certain embodiments, the amount of Compound (I), or a pharmaceutically acceptable salt thereof, administered in the method for treating hair loss disorders is about 16 mg (such as 16 mg) twice daily. In a specific embodiment, Compound (I) is administered as about 21.1 mg (such as 21.1 mg) of the phosphate salt of Compound (I) twice daily.

[0294] In certain embodiments, the hair loss disorder is alopecia areata.

[0295] In certain embodiments, the subject is a human. In a specific embodiment, the subject is an adult human (e.g., a human who is 18 years of age or older). In another specific embodiment, the subject is an adolescent human (e.g., a human who is 12 years of age but less than 18 years of age). In another specific embodiment, the subject is a pediatric human (e.g., a human who is 6 years of age but less than 12 years of age).

[0296] In specific embodiments, Compound (I), or a pharmaceutically acceptable salt thereof (e.g., phosphate salt, etc.), is administered orally in any of the dosage amounts described herein. In even more specific embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, is administered orally in any of the dosage amounts described herein in a pharmaceutical formulation that is a tablet.

[0297] In certain embodiments, a therapeutically effective amount of the JAK inhibitor is administered once or twice daily, and the amount of the JAK inhibitor is in the range of about 4 mg / day to about 50 mg / day, for example, about 5 mg / day, about 10 mg / day, about 20 mg / day, about 30 mg / day, about 40 mg / day, or about 50 mg / day. In certain embodiments, the amount of the JAK inhibitor is about 4 mg / day, 8 mg / day, 16 mg / day, 32 mg / day, or 48 mg / day. In certain embodiments, the JAK inhibitor is administered orally at any of the aforementioned dosages. In another specific embodiment, the JAK inhibitor is administered orally at any of the aforementioned dosages in a pharmaceutical formulation that is a tablet.

[0298] In yet another specific embodiment, the tablet is a coated tablet comprising the following ingredients found in Table 1: [Table 1]

[0299] In such embodiments, the total weight of the tablet core is about 120 mg, and the dose of durxolitinib phosphate is the equivalent of 8 mg of free base. In some embodiments, the tablet is coated with, for example, 3.60 mg of Opadry® amb II coating. In some embodiments, the tablet film coating includes the following excipients: carmine, FD&C Blue #2 aluminum lake, glyceryl mono- and dicapryl caprate, polyvinyl alcohol, sodium lauryl sulfate, talc, and titanium dioxide.

[0300] Tablets can be prepared by various techniques, some of which are known in the art. In some embodiments, the described tablet oral dosage form can be prepared by: (a) combining durxolitinib phosphate, microcrystalline cellulose, lactose monohydrate, hydroxypropyl cellulose, and polyvinylpyrrolidone; (b) wet granulating the combination of (a) to form particles; (c) blending the formed particles with microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate to form a blend; and (d) compressing the blend into a tablet. In some embodiments, the tablet is coated to provide a coated tablet comprising a tablet core and an outer coating layer.

[0301] Patient evaluation i. ALC, ANC, and hemoglobin levels from a complete blood count A complete blood count (CBC) is a blood test. It is used to look at overall health and detect a wide range of conditions, including anemia, infection, and leukemia. A CBC measures: red blood cells, which carry oxygen; white blood cells, which fight infection; hemoglobin, the oxygen-carrying protein in red blood cells; hematocrit, which is the amount of red blood cells in the blood; and platelets, which help blood clot.

[0302] The absolute lymphocyte count (ALC) represents the number of lymphocytes in a given volume of blood and is part of the complete blood count.

[0303] The absolute neutrophil count (ANC) is an estimate of the body's ability to fight infection, especially bacterial infections. These test results are often referred to as a patient's "count." The ANC measures the number of neutrophils in the blood. Neutrophils are a type of white blood cell that kills bacteria.

[0304] A hemoglobin test measures the amount of hemoglobin in your blood, a protein in your red blood cells that carries oxygen to the body's organs and tissues and transports carbon dioxide back to your lungs.

[0305] In a specific embodiment, the patient / subject being treated has a complete blood count that shows an ALC of ≧500 cells / μl, an ANC of ≧1000 cells / μl, and / or a hemoglobin level of ≧8 g / dl. In a further embodiment, the patient / subject's ALC, ANC, and hemoglobin level are monitored at 4, 8, 12, 16, 20, and 24 weeks after initiation of treatment. In yet another embodiment, the patient / subject's treatment is discontinued if the ALC is <500 cells / μl, the ANC is <1000 cells / μl, and / or the hemoglobin level is <8 g / dl.

[0306] ii. SALT score The effectiveness of the treatment of hair loss disorder, such as alopecia areata, can be measured in various ways, some of which are known in the art.For example, " severity of alopecia tool " known as SALT is a validated rating scale developed by the National Alopecia Areata Foundation Working Group to evaluate the degree of hair loss.For example, Olsen EA, Hordinsky MK, Price VH, et al.Alopecia areata investigational assessment guidelines-Part II.J Am Acad Dermatol 2004:51:440-447 and King BA, et al.Defining Severity in Alopecia Areata: Current Perspective and Multidimensional Framework (the content of which is incorporated herein by reference).

[0307] SALT score is calculated for each patient / subject by measuring the percentage of hair loss in each of the four scalp regions, and adding up the total to achieve a composite score (referred to herein as absolute SALT score).Hair regrowth is reflected by a decrease in SALT score.For example, no hair on scalp will have a SALT score of 100 (i.e., absolute SALT score), while complete hair regrowth will have a SALT score of 0 (i.e., absolute SALT score).

[0308] In one embodiment, the patient / subject has an absolute SALT score greater than or equal to 50 at the start of treatment (i.e., an absolute SALT score of ≧50). The absolute SALT score at the start of treatment is referred to as the baseline SALT score.

[0309] In one specific embodiment, the patient / subject's SALT score at the start of treatment is an absolute SALT score of ≧50.

[0310] In another embodiment, the patient / subject has, at the start of treatment, an absolute SALT score of greater than or equal to 60 (i.e., an absolute SALT score of ≧60), greater than or equal to 70 (i.e., an absolute SALT score of ≧70), greater than or equal to 80 (i.e., an absolute SALT score of ≧80), greater than or equal to 90 (i.e., an absolute SALT score of ≧90), or greater than or equal to 95 (i.e., an absolute SALT score of ≧95).

[0311] In some embodiments, absolute SALT score can be used to define the category of hair loss.For example, Wyrwich et al. (Wyrwich KW, et al. The alopecia areata investigator global assessment scale: a measure for evaluating clinically meaningful success in clinical trials. Br J Dermaol. 2020;183:702-9) describes the severity of hair loss as follows: no hair loss, 0% hair loss; limited hair loss = 1-20% hair loss; moderate hair loss = 21-49% hair loss; severe hair loss = 50-94% hair loss; and very severe hair loss = 95-100% hair loss.

[0312] In certain embodiments, the methods of treatment described herein can provide a reduction in absolute SALT score of at least 10 points after treatment (e.g., from a pre-treatment SALT score of 100 to a post-treatment SALT score of 90). In further embodiments, the methods of treatment described herein can provide a reduction in SALT score of at least 20 points, 30 points, 40 points, 50 points, 60 points, 70 points, 80 points, 90 points, or 100 points.

[0313] In other embodiments, the methods of treatment described herein can provide a subject / patient with an absolute SALT score of ≦20 (i.e., scalp hair loss of less than or equal to 20%) after treatment. For example, after 12 weeks of treatment described herein, the subject has an absolute SALT score of ≦20, or after 16 weeks of treatment described herein, the subject has an absolute SALT score of ≦20, or after 20 weeks of treatment described herein, the subject has an absolute SALT score of ≦20, or after 24 weeks of treatment described herein, the subject has an absolute SALT score of ≦20, or after 52 weeks of treatment described herein, the subject has an absolute SALT score of ≦20.

[0314] In further embodiments, the methods of treatment described herein can provide a subject / patient with an absolute SALT score of ≦10 (i.e., scalp hair loss of less than or equal to 10%) after treatment. For example, after 12 weeks of treatment described herein, the subject has an absolute SALT score of ≦10, or after 16 weeks of treatment described herein, the subject has an absolute SALT score of ≦10, or after 20 weeks of treatment described herein, the subject has an absolute SALT score of ≦10, or after 24 weeks of treatment described herein, the subject has an absolute SALT score of ≦10, or after 52 weeks of treatment described herein, the subject has an absolute SALT score of ≦10.

[0315] In certain embodiments, the methods of treatment described herein can provide, after treatment, at least a 20% reduction in the patient's / subject's SALT score from baseline (pre-treatment), or at least a 30% reduction in the patient's / subject's SALT score from baseline, or at least a 40% reduction in the patient's / subject's SALT score from baseline, or at least a 50% reduction in the patient's / subject's SALT score from baseline, or at least a 60% reduction in the patient's / subject's SALT score from baseline, or at least a 70% reduction (e.g., a 75% reduction) in the patient's / subject's SALT score from baseline, or at least an 80% reduction in the patient's / subject's SALT score from baseline, or at least a 90% reduction in the patient's / subject's SALT score from baseline. Such a % reduction in SALT score is referred to herein as a % relative reduction in SALT score.

[0316] In a specific embodiment, after 12 weeks of treatment, the subject has at least a 75% relative reduction in SALT score.

[0317] In certain embodiments, treatment continues for a period of at least 4 weeks, or at least 8 weeks, or at least 12 weeks, or at least 16 weeks, or at least 20 weeks, or at least 24 weeks, or at least 28 weeks, or at least 32 weeks, or at least 36 weeks, or at least 40 weeks, or at least 44 weeks, or at least 48 weeks, or at least 52 weeks.

[0318] In some embodiments, the present disclosure provides a method of treating alopecia areata in a subject in need thereof, wherein the proportion of participants achieving a SALT < 20 continues to increase for at least 54 weeks, at least 68 weeks, or at least 76 weeks when administered Compound (I) as described herein. In some embodiments, the present disclosure provides a method of treating alopecia areata in a subject in need thereof, wherein the rate of increase in the proportion of participants achieving a SALT < 20 does not decrease by more than 30%, more than 40%, more than 50%, or more than 60% during a 4-week period for at least 48 weeks, at least 54 weeks, at least 68 weeks, or at least 76 weeks.

[0319] iii. Hospital Anxiety and Depression Scale The Hospital Anxiety and Depression Scale (HADS) is used to measure anxiety and depression in general medical populations. The HADS consists of 14 items (7 items each for anxiety and depression), with scores ranging from 0 to 21 for the anxiety and depression subscales. A score between 8 and 10 indicates a moderate presence of anxiety and depression symptoms, while a score above 11 indicates a significant number of anxiety and depression symptoms, likely corresponding to a clinical diagnosis. The total HADS score can be considered as a global measure of psychological distress (Roberts et al., 2001; Johnston et al., 2000). A negative change in a subject's HADS score from the start time point to the end point during treatment, for example, from baseline to 24 weeks of treatment, indicates an improvement in anxiety and depression symptoms. HADS questionnaires were completed by subjects at baseline and 24 weeks. As used herein, the term "baseline" refers to the HADS score (or HADS-A or HADS-D score) determined before administration of Compound (I).

[0320] In yet another embodiment, the patient / subject reports a change (decrease) of at least 1.0 point in the global score from baseline on the HADS scale after 12 weeks of treatment with 8 mg twice daily. In a specific embodiment, the point change (decrease) in the global score is 3.0 points after 12 weeks of treatment with 8 mg twice daily. In yet another embodiment, the patient / subject reports a change (decrease) of at least 2.0 points in the global score from baseline on the HADS scale after 16 weeks of treatment with 8 mg twice daily. In a specific embodiment, the point change (decrease) in the global score is 4.0 points after 16 weeks of treatment with 8 mg twice daily. In yet another embodiment, the patient / subject reports a change (decrease) of at least 6.0 points in the global score from baseline on the HADS scale after 24 weeks of treatment with 8 mg twice daily. In a specific embodiment, the point change (decrease) in the global score is 10.0 points after 24 weeks of treatment with 8 mg twice daily.

[0321] In yet another embodiment, the patient / subject reports a point change (decrease) of at least 1.0 point from baseline in the Hospital Anxiety and Depression Scale-Anxiety (HADS-A) subscale score on the HADS scale after 12 weeks of treatment with 8 mg twice daily. In a specific embodiment, the point change (decrease) in the HADS-A subscale is 2.0 points after 12 weeks of treatment with 8 mg twice daily. In yet another embodiment, the patient / subject reports a point change (decrease) of at least 2.0 points in the global score on the HADS-A subscale after 16 weeks of treatment with 8 mg twice daily. In a specific embodiment, the point change (decrease) in the HADS-A subscale is 3.0 points after 16 weeks of treatment with 8 mg twice daily. In yet another embodiment, the patient / subject reports a point change (decrease) in the HADS-A subscale of at least 4.0 points in the global score on the HADS scale after 24 weeks of treatment with 8 mg twice daily. In a specific embodiment, the point change (decrease) in the HADS-A subscale is 6.0 points after 24 weeks of treatment with 8 mg twice daily.

[0322] In yet another embodiment, the patient / subject reports a point change (decrease) of at least 1.0 point from baseline in the Hospital Anxiety and Depression Scale-Depression (HADS-D) subscale score on the HADS scale after 12 weeks of treatment with 8 mg twice daily. In a specific embodiment, the point change (decrease) in the HADS-D subscale is 2.0 points after 12 weeks of treatment with 8 mg twice daily. In yet another embodiment, the patient / subject reports a point change (decrease) of at least 2.0 points in the global score on the HADS-D subscale after 16 weeks of treatment with 8 mg twice daily. In a specific embodiment, the point change (decrease) in the HADS-D subscale is 3.0 points after 16 weeks of treatment with 8 mg twice daily. In yet another embodiment, the patient / subject reports a point change (decrease) in the HADS-D subscale of at least 3.0 points in the global score from baseline on the HADS scale after 24 weeks of treatment with 8 mg twice daily. In a specific embodiment, the point change (decrease) in the HADS-D subscale is 5.0 points after 24 weeks of treatment with 8 mg twice daily.

[0323] iv. Hair satisfaction and hair quality patient-reported outcomes The SPRO is a single-item questionnaire completed by subjects and designed to measure how satisfied subjects with alopecia areata are with their hair at the time of evaluation. Subjects answer questions on a scale of 1 to 5, representing "very satisfied" to "very dissatisfied." The satisfaction categories 1 to 5 on the scale are defined as follows: 1 = "very satisfied"; 2 = "satisfied"; 3 = "neither satisfied nor dissatisfied"; 4 = "dissatisfied"; and 5 = "very dissatisfied."

[0324] SPRO results were analyzed in three different ways: 1) percentage of responders, 2) change from baseline, and 3) percentage of subjects achieving a ≧2.0 point change from baseline.

[0325] In certain embodiments, the patient / subject reports "satisfied" or "very satisfied" on the SPRO scale after 24 weeks of treatment. In further embodiments, the patient / subject reports "satisfied" or "very satisfied" on the SPRO scale after 12 weeks of treatment.

[0326] In certain embodiments, at least 30% of patients / subjects responded to SPRO after 24 weeks of treatment with 8 mg of Compound I administered twice daily. In certain embodiments, at least 40% of patients / subjects responded to SPRO after 24 weeks of treatment with 8 mg of Compound I administered twice daily. In certain embodiments, at least 40% of patients / subjects responded to SPRO after 24 weeks of treatment with 12 mg of Compound I administered twice daily. In certain embodiments, at least 50% of patients / subjects responded to SPRO after 24 weeks of treatment with 12 mg of Compound I administered twice daily. In certain embodiments, there is at least a 30% increase in patients / subjects responding to SPRO after 24 weeks of treatment with 8 mg of Compound I administered twice daily compared to patients / subjects treated with placebo. In certain embodiments, there is at least a 40% increase in patients / subjects who respond to SPRO after 24 weeks of treatment with 8 mg of Compound I administered twice daily compared to patients / subjects treated with a placebo. In certain embodiments, there is at least a 40% increase in patients / subjects who respond to SPRO after 24 weeks of treatment with 12 mg of Compound I administered twice daily compared to patients / subjects treated with a placebo. In certain embodiments, there is at least a 50% increase in patients / subjects who respond to SPRO after 24 weeks of treatment with 12 mg of Compound I administered twice daily compared to patients / subjects treated with a placebo.

[0327] In yet another embodiment, the patient / subject reports a point change (decrease) of at least 1.5 from baseline on the SPRO scale. In a specific embodiment, the point change (decrease) is greater than or equal to 2 (i.e., the point change (decrease) is ≧2).

[0328] v. General Impression Scale The global impression scale uses a 7-point Likert scale (1 being better and 7 being worse) that measures either the severity of the disease state or improvement after treatment.

[0329] a. Clinical Global Impression of Improvement (CGI-I) The CGI-I was assessed by the investigator. Compared with the subject's alopecia areata at baseline before treatment, the investigator assessed the current state of the subject's alopecia areata according to the investigator's perceived change. The investigator selected one of seven numerical options representing "very significantly worse" to "very significantly improved." To reduce variability, one assessor was to conduct the CGI-I assessment for each subject throughout the duration of the study. The definitions of the numerical options were as follows: 1 = very significantly improved since the start of treatment; 2 = significantly improved; 3 = minimally improved; 4 = no change from baseline (start of treatment); 5 = minimally worse; 6 = significantly worse; 7 = very significantly worse since the start of treatment.

[0330] In certain embodiments, the patient / subject reports "much improved" or "very much improved" on the CGI-I scale after 24 weeks of treatment. In further embodiments, the patient / subject reports "much improved" or "very much improved" on the CGI-I scale after 20 weeks of treatment. In yet another embodiment, the patient / subject reports "much improved" or "very much improved" on the CGI-I scale after 16 weeks of treatment. In yet another embodiment, the patient / subject reports "much improved" or "very much improved" on the CGI-I scale after 12 weeks of treatment.

[0331] b. Patient's overall impression of improvement The PGI-I was assessed by the subject. Compared to the subject's AA at baseline before treatment, the subject's current AA status was assessed according to his / her perceived change. The subject selected one of seven numerical options representing "very significantly worse" to "very significantly improved." If the subject was unable to attend an in-person visit due to COVID-19, the PGI-I was to be administered via a virtual visit with video capability. Numerical options were defined as follows: 1 = very significantly improved; 2 = significantly improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = significantly worse; and 7 = very significantly worse.

[0332] In certain embodiments, the patient / subject reports "much improved" or "very much improved" on the PGI-I scale after 24 weeks of treatment. In further embodiments, the patient / subject reports "much improved" or "very much improved" on the PGI-I scale after 20 weeks of treatment. In yet other embodiments, the patient / subject reports "much improved" or "very much improved" on the PGI-I scale after 16 weeks of treatment. In yet other embodiments, the patient / subject reports "much improved" or "very much improved" on the PGI-I scale after 12 weeks of treatment.

[0333] In yet another embodiment, the patient / subject reports a point change (decrease) of at least 1.5 from baseline on the PGI-I scale after 12 weeks of treatment. In a specific embodiment, the point change (decrease) is at least 1.7 after 16 weeks of treatment. In another specific embodiment, the point change (decrease) is at least 2.1 after 24 weeks of treatment.

[0334] c. Clinical Global Impression of Severity The CGI-S was assessed by the investigator and took into account the severity of the subject's alopecia at the time of assessment. The investigator selected one of seven numerical options representing "normal, no hair loss" to "between the most extreme hair loss." To reduce variability, one assessor was to perform the CGI-S assessment for each subject. The numerical options were defined as follows: 1 = normal, no hair loss; 2 = marginal hair loss; 3 = mild hair loss; 4 = moderate hair loss; 5 = significant hair loss; 6 = severe hair loss; 7 = between the most extreme hair loss.

[0335] In certain embodiments, patients / subjects report a point change (decrease) of at least 1.0 from baseline on the CGI-S scale after 12 weeks of treatment. In a specific embodiment, the point change (decrease) is at least 1.5 after 16 weeks of treatment. In another specific embodiment, the point change (decrease) is at least 2.0 after 24 weeks of treatment. d. Patient Global Impression of Severity The PGI-S was assessed by the subject, taking into account the severity of their alopecia areata at the time of assessment. The subject selected one of seven numerical options representing "normal, no hair loss" to "between the most extreme hair loss." Numerical options were defined as follows: 1 = normal, no hair loss; 2 = marginal hair loss; 3 = mild hair loss; 4 = moderate hair loss; 5 = significant hair loss; 6 = severe hair loss; 7 = between the most extreme hair loss.

[0336] In certain embodiments, patients / subjects report a point change (decrease) of at least 1.5 from baseline on the PGI-S scale after 12 weeks of treatment. In a specific embodiment, the point change (decrease) is at least 1.7 after 16 weeks of treatment. In another specific embodiment, the point change (decrease) is at least 2.1 after 24 weeks of treatment.

[0337] vi. Brigham Eyebrow Tool for Alopecia (BETA) The BETA is a clinician-rated scale developed by dermatologists at Brigham and Women's Hospital to assess all present eyebrow hairs (Tkachenko, E, et al., Brigham Eyebrow Tool for Alopecia: A Reliable Assessment of Eyebrow Alopecia Areata, Journal of Investigative Dermatology Symposium Proceedings (2020) 20, S41-S44). BETA is calculated based on hair density (range 0-3) and the surface area of ​​each individual eyebrow. The BETA score is the sum of the right and left eyebrow scores (range 0 (absent) to 6). A panel of certified raters at Brigham and Women's Hospital performed a central reading based on eyebrow photographs provided by the study site and determined a score for each subject with eyebrow involvement after each visit where assessment of eyebrow hair presence was assessed. BETA was administered at baseline, week 12, and week 24. If the subject was unable to attend the in-person clinic visit due to COVID-19, the BETA would not have been performed due to the inability to take photographs of the eyebrows.

[0338] In certain embodiments, a point change (increase) from baseline of at least 1.0 is achieved by the patient / subject in BETA after 24 weeks of treatment.

[0339] In another embodiment, a point change (increase) from baseline of at least 0.5 is achieved by patients / subjects being treated with BETA after 12 weeks of treatment. vii. Brigham Eyelash Tool for Alopecia (BELA) The BELA is a clinician-rated scale developed by dermatologists at Brigham and Women's Hospital to assess the presence of all eyebrow hairs. Manjaly, P. et al., Development and validation of the Brigham Eyelash Tool for Alopecia (BELA): A measure of eyelash alopecia areata, J Am Acad Dermatol (2021) 1-2. BELA is calculated based on grade values ​​(range 0-3) and distribution. The BELA score is the sum of individual scores for the left and right eyes (range 0 (absent) to 6). The same expert panel of certified raters at Brigham and Women's Hospital who performed the BELA assessment also performed a central reading based on eyelash photographs and determined a score for each subject with eyelash involvement after each visit where assessment of eyelash hair presence was assessed. BELA was performed at baseline, week 12, and week 24. If subjects were unable to attend the in-person clinic visit due to COVID-19, the BELA would not have been performed due to the inability to take photographs of the eyebrows.

[0340] In certain embodiments, a point change (increase) from baseline of at least 1.0 is achieved by the patient / subject on the BELA after 24 weeks of treatment.

[0341] In another embodiment, a point change (increase) from baseline of at least 0.5 is achieved by patients / subjects being treated with BELA after 12 weeks of treatment.

[0342] viii. eGFR level Glomeruli are tiny filters in your kidneys that help remove toxins from your blood. Estimated glomerular filtration rate (eGFR) measures how much blood these filters purify each minute based on your body size. eGFR is used to monitor subjects for the development of kidney disease.

[0343] Tests to accurately measure GFR are highly complex. For this reason, such tests are typically performed only for research or transplant purposes. Instead, formulas to derive estimated GFR (eGFR) are used in clinical practice. The formula combines results from serum creatinine blood tests with other information.

[0344] A serum creatinine blood test measures your creatinine levels. Your body makes and uses creatine to provide energy to your muscles. When your muscles use this energy, muscle tissue breaks down and releases creatinine (a toxin) into your blood. Healthy kidneys filter this toxin out of the blood, and your body removes it when you urinate. However, if you have kidney disease, creatinine stays in your blood and gradually builds up.

[0345] The eGFR level can be determined using the following equation:

[0346] MDRD equation: GFR(ml / min / 1.73m 2 )=186×(SCR) -1.154 ×(age) -1.154 × coefficient The coefficients are 0.742 (female) and 1.210 (African-American). S cr (normalized serum creatinine) = mg / dL Age = years old

[0347] Renal function classification based on FDA and EMA guidance 8,9 [Table 2] References 8. Food and Drug Administration, Center for Drug Evaluation and Research. Pharmacokinetics in Patients with Impaired Renal Function - Implications for Study Design, Data Analysis, and Dosing. https: / / www.fda.gov / media / 78573 / download Cited (2020). Accessed November 4, 2020. 9. European Medicines Agency. Guideline for the evaluation of the pharmacokinetics of medicinal products in patients with reduced renal function. https: / / www.ema.europa.eu / en / documents / scientific-guideline / guideline-evaluation-pharmacokinetics-medicinalproducts-patients-decreased-renal-function_en.pdf Cited (2015). Accessed August 27, 2020.

[0348] Based on the above table, a subject with moderate renal impairment is one with an eGFR of 30-59 mL / min. Similarly, a subject with normal renal function is one with an eGFR of ≥ 90 mL / min. All other categories of renal disease (impairment) can be determined with reference to the above table.

[0349] For all embodiments described herein, where eGFR is expressed as mL / min MDRD, there are corresponding embodiments where eGFR is expressed as mL / min / 1.73m 2 or expressed as mL / min.

[0350] Example Example 1 - Renal Damage Test A study was conducted to determine the effect of moderate renal impairment on the PK of CTP-543 and its two most abundant metabolites (C-21714 and C-21717) in humans after administration of a single 12 mg oral dose of CTP-543. A secondary objective of this study was to evaluate the safety and tolerability of a single 12 mg oral dose of CTP-543 in subjects with moderate renal impairment and subjects with normal renal function. The study enrolled eight subjects in a normal renal function cohort and eight subjects in a moderately impaired renal function cohort.

[0351] The primary endpoints of this study were single-dose PK exposure parameters: Cmax, AUC (0-Tlast) , and AUC (0-∞) .

[0352] The secondary endpoints of this study were: Adverse events, laboratory findings, physical examination, ECG, and vital signs. Other PK parameters include, but are not limited to: max , λ z , t 1 / 2 , CL / F, and V z / F.

[0353] All subjects had samples collected for PK. Blood samples were collected pre-dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 18, 24, 36, and 48 hours after CTP-543 dosing. All subjects had a sample collected 2 hours post-dose to assess plasma protein binding of CTP-543.

[0354] All plasma PK parameter calculations for CTP-543, C-21714, and C-21717 were performed over several hours using real-time PK parameters determined using non-compartmental analysis (NCA) methods based on individual plasma concentration-time data for all PK analytes.

[0355] A summary of the CTP-543 PK parameters of the PK population excluding outliers after a single oral dose of 12 mg CTP-543 is presented in Table 2. Geometric mean C max , AUC 0-Tlast , and AUC 0-inf were 199 ng / mL, 836 h ng / mL, and 843 h ng / mL, respectively, in subjects with normal renal function. max , AUC 0-Tlast , and AUC 0-inf were 207 ng / mL, 1040 h·ng / mL, and 1050 h·ng / mL, respectively, in subjects with moderate renal impairment (Table 2 ). [Table 3]

[0356] PK exposure parameters of CTP-543 in subjects with normal renal function were compared with those in the moderate renal impairment cohort, and the GMRs are presented in Table 3 along with 90% confidence intervals (CI). [Table 4]

[0357] A summary of the PK parameters of C-21714 and C-21717 in the outlier-excluded PK populations following a single oral dose of 12 mg CTP-543 is presented in Tables 4 and 5, respectively.

[0358] After a single oral dose of 12 mg of CTP-543, C-21714 max The geometric means of metabolite-to-parent ratios for C-21714 were 0.0362 and 0.0212, and the AUC 0-Tlast The C of C-21717 was 0.157 and 0.0842 for the normal renal function cohort and the moderate renal impairment cohort, respectively. (Table 4) max The geometric means of metabolite-to-parent ratios for C-21717 were 0.0433 and 0.0265, and the AUC 0-Tlast were 0.133 and 0.0859 for the normal renal function cohort and the moderate renal impairment cohort, respectively (Table 5). [Table 5] [Table 6]

[0359] PK exposure parameters of C-21714 and C-21717 in subjects with normal renal function were compared with those in the moderate renal impairment cohort, and the GMRs are presented in Table 6 along with 90% CIs. [Table 7]

[0360] Moderate renal impairment is max The metabolite-to-parent ratios of C-21714 and C-21717 were significantly higher than those of C-21714 for both cohorts. max and AUC were ≦0.2. Healthy control subjects had higher metabolite-to-parent ratios compared with subjects with moderate renal impairment. No meaningful differences in plasma protein binding of CTP-543 were detected between the cohort of subjects with moderate renal impairment and the cohort of matched control subjects with normal renal function.

[0361] Based on these results, no dose adjustment is required in subjects with moderate renal impairment.

[0362] Subjects with moderate renal impairment are those with an eGFR in the range of 30-59 mL / min. Subjects with normal renal function are those with an eGFR in the range of 90 mL / min.

[0363] Example 2 Phase III clinical trial A Phase III clinical trial was conducted to evaluate the efficacy and safety of CTP-543 in adult subjects with moderate to severe AA. Approximately 440 adult male and female subjects, aged 18 to 65 years, with moderate to severe AA were enrolled in the study. Subjects with a confirmed diagnosis of AA and at least 50% hair loss as defined by a SALT score of ≥ 50, who met all inclusion criteria and none of the exclusion criteria, were enrolled in the study.

[0364] The screening period lasted up to 28 days before the start of study drug. The treatment period was a 24-week double-blind, placebo-controlled period to define the efficacy and safety of CTP-543. Subjects were randomized in a 1:2:1 ratio (CTP-543 12 mg BID:CTP-543 8 mg BID:placebo). Randomization was stratified by scalp hair loss into one of two categories: 1) partial scalp hair loss (SALT ≥ 50 and < 95), or 2) complete or near-total scalp hair loss (SALT ≥ 95).

[0365] Assessment of treatment response using SALT for efficacy will occur at weeks 4, 8, 12, 16, 20, and 24.

[0366] Efficacy was determined based on the following primary and secondary endpoints:

[0367] Primary efficacy endpoint The primary efficacy endpoint was the percentage of subjects achieving an absolute SALT score of ≦20.

[0368] Key secondary endpoints The key secondary efficacy endpoint was the percentage of responders (defined as "satisfied" or "very satisfied") on the Hair Satisfaction Patient-Reported Outcome (SPRO) scale at 24, 20, 16, 12, and 8 weeks.

[0369] Secondary efficacy endpoints Additional secondary efficacy endpoints included: Relative change in SALT score from baseline at weeks 4, 8, 12, 16, 20, and 24. Percentage of responders (defined as "much improved" or "very much improved") using the Clinical Global Impression of Improvement (CGI-I) at weeks 12, 16, 20, and 24. Percentage of responders (defined as "much improved" or "very much improved") using the Patient Global Impression of Improvement (PGI-I) at weeks 12, 16, 20, and 24. Change from baseline in Clinical Global Impression of Severity (CGI-S) at weeks 12, 16, 20, and 24. Change from baseline in Patient Global Impression of Severity (PGI-S) at weeks 12, 16, 20, and 24. Change from baseline in Brigham Eyebrow Tool (BETA) score for alopecia at 12 and 24 weeks. Change from baseline in Brigham Eyelash Tool (BELA) score for alopecia at 12 and 24 weeks. Percentage of subjects achieving at least a 75% relative reduction in SALT score from baseline at weeks 12 and 24. Percentage of subjects achieving at least a 90% relative reduction in SALT score from baseline at weeks 12 and 24. Percentage of responders (defined as "satisfied" or "very satisfied") on the SPRO scale at weeks 12, 16, and 20. Change from baseline in the SPRO scale at weeks 12, 16, 20, and 24. Percentage of subjects achieving a ≥ 2-point change from baseline on the SPRO scale at weeks 12, 16, 20, and 24. Changes from baseline in individual items of the Hair Quality Patient-Reported Outcome (QPRO) scale at weeks 12, 16, 20, and 24. Change from baseline in the Hospital Anxiety and Depression Scale (HADS) depression scale at 24 weeks. Change from baseline in the HADS anxiety scale at 24 weeks. Percentage of subjects achieving an absolute SALT score ≤ 20 at week 4. Percentage of subjects achieving an absolute SALT score ≤ 10 at week 24.

[0370] Selection criteria: Clinical findings compatible with alopecia areata, with the current episode lasting at least 6 months at screening and not exceeding 10 years. Total disease duration greater than 10 years is acceptable. At least 50% scalp hair loss as defined by a Severity of Alopecia Tool (SALT) score ≥ 50 at screening and baseline. · Willingness to comply with study visit and study protocol requirements.

[0371] Exclusion criteria: Treatment with other medicines or agents within 1 month of baseline or during the study that may affect hair regrowth or immune response. Active scalp inflammation, psoriasis, or seborrheic dermatitis requiring topical treatment of the scalp, significant trauma to the scalp, or other scalp conditions that may interfere with SALT assessment, or untreated actinic keratosis anywhere on the body at screening and / or baseline. Treatment with systemic immunosuppressive medications within 3 months of screening or during the study, or with biologics within 6 months of screening or during the study. Screening labs outside the normal range for parameters associated with potential risk for the treatment under investigation, including but not limited to: a. Platelets ≤ 100 x 109 / L or ≥ 600 x 109 / L b. Absolute neutrophil count ≤ 1.5 × 109 / L c. Hemoglobin level ≤ 10.5 g / dL for women or ≤ 12.0 g / dL for men · Screening blood levels of hemoglobin A1c ≥ 7.5% (58mmol / mol, 9.3mmol / L). Abnormal renal function (estimated glomerular filtration rate <60 mL / min / 1.73 m2 using the CKD-EPI 2009 equation at screening) An example of the CKD-EPI 2009 equation can be: GFR = 141 × min(Scr / κ, 1)α ×max(Scr / κ, 1) -1.209 ×0.993 年齢 × 1.018[for women]_1.159[for blacks], where Scr is serum creatinine, κ is 0.7 for women and 0.9 for men, α is −0.329 for women and −0.411 for men, min indicates the minimum value of Scr / κ or 1, and max indicates the maximum value of Scr / κ or 1. Women who are nursing, pregnant, or planning to become pregnant during the study and for 30 days after the last dose of study medication. Clinically significant medical, psychiatric, or social conditions that, as determined by the investigator, may adversely alter the risk-benefit of study participation, affect study compliance, or confound interpretation of study results.

[0372] result: Durxolitinib (a compound represented by Compound (I) described herein) has demonstrated significant improvement in hair regrowth versus placebo in two Phase 3 clinical trials, THRIVE-AA1 and THRIVE-AA2.

[0373] The primary efficacy endpoint was the percentage of subjects achieving an absolute SALT score of ≦20 at Week 24. At Week 24, 33% of subjects in the CTP-543 8 mg BID group, 38.3% of subjects in the CTP-543 12 mg BID group, and 0.8% of subjects in the placebo group achieved a SALT score of ≦20. The percentage of subjects with an absolute SALT score of ≦20 at Week 24 is presented graphically in Figure 1.

[0374] When stratified by baseline scalp hair loss, 57 / 134 (42.5%), 50 / 88 (56.8%), and 1 / 55 (1.8%) of subjects with partial scalp hair loss in the 8 mg BID, 12 mg BID, and placebo groups, respectively, achieved a SALT score ≦20 at week 24 compared with 37 / 184 (20.1%), 33 / 112 (29.5), and 0 / 73 (0%) in subjects with complete or near-complete scalp hair loss.

[0375] When stratified by baseline scalp hair loss, 46 / 93 (54.1%), 27 / 48 (57.4%), and 1 / 48 (2.2%) of subjects with partial scalp hair loss in the 8 mg BID, 12 mg BID, and placebo groups, respectively, achieved a SALT score ≦20 at week 24 compared with 31 / 156 (20.9%), 19 / 79 (26.0), and 0 / 79 (0%) in subjects with complete or near-complete scalp hair loss.

[0376] When stratified by duration of current AA episode at screening, the percentages of participants with a duration of ≤4 years at week 24 were 38.3% (57 / 157), 44.0% (33 / 77), and 0% (0 / 80) for the 8 mg BID, 12 mg BID, and placebo groups, respectively, and the values ​​for participants with a duration of >4 years were 23.8% (20 / 92), 28.9% (13 / 50), and 2.4% (1 / 47), respectively.

[0377] Hair Satisfaction Patient-Reported Outcome Responder at Week 24 Responders were subjects with a response of "very satisfied" or "satisfied." At week 24, the rates of SPRO responders, based on subjects with non-missing data, were 46.5% for CTP-543 8 mg BID subjects, 51.7% for CTP-543 12 mg BID subjects, and 1.7% for placebo subjects (Table 7 and Figure 14A). [Table 8]

[0378] Hair satisfaction patient-reported outcome (SPRO) was also determined based on the 5-point SPRO scale from baseline to week 24 among primary endpoint responders. In the THRIVE-AA1 and THRIVE-AA2 trials, subjects who received a SALT score ≤20 at week 24 were included in the analysis. A shift analysis excluded subjects who reported a score of 3 (neither satisfied nor dissatisfied) at baseline and after baseline and determined the percentage of subjects who shifted from "dissatisfied" (including very dissatisfied / dissatisfied) at baseline to "satisfied" (including satisfied / very satisfied) during treatment. Among week 24 SALT ≤20 responders to durxolitinib 8 mg who were dissatisfied with their hair at baseline, 79.6% were satisfied at week 12, 86.8% were satisfied at week 16, 93.8% were satisfied at week 20, and 95.7% were satisfied at week 24. These results demonstrate that subjects who achieved clinically meaningful hair regrowth (SALT score ≦20) during 24 weeks of durxolitinib 8 mg BID treatment were satisfied at 24 weeks.

[0379] Absolute SALT score ≤ 20 at weeks 20, 16, 12, and 8 Statistically significant differences in outcomes supporting activity over placebo were observed at each of these time points, except at week 8 (Figure 2). Absolute SALT scores of ≤20 were achieved by 24.8% of CTP-543 8 mg BID subjects, 28.8% of CTP-543 12 mg BID subjects, and 0.8% of placebo subjects at week 20. Absolute SALT scores of ≤20 were achieved by 20.2% of CTP-543 8 mg BID subjects, 21.1% of CTP-543 12 mg BID subjects, and 0.8% of placebo subjects at week 16. Absolute SALT scores of ≤20 were achieved by 10.5% of CTP-543 8 mg BID subjects, 12.3% of CTP-543 12 mg BID subjects, and 0.8% of placebo subjects at week 12. An absolute SALT score of ≦20 was achieved by 2.9% of CTP-543 8 mg BID subjects, 2.4% of CTP-543 12 mg BID subjects, and 0.8% of placebo subjects at week 8.

[0380] Relative change in Alopecia Tool severity score from baseline at weeks 4, 8, 12, 16, 20, and 24 A decrease in SALT score indicates increased hair growth. A decrease in the LS mean SALT score was first observed at Week 4. At each subsequent assessment, the size of the observed decrease increased until Week 24, and at each time point, the LS mean difference versus placebo was greater for the CTP-543 8 mg BID and CTP-543 12 mg BID groups. At Week 8, the LS mean change from baseline SALT score was higher in subjects treated with durxolitinib 8 mg BID (8.6%) than in subjects treated with 16 mg once daily (QD) (2.7%).

[0381] At week 4, the LS mean change from baseline was -2.5 (95% CI, -3.7, -1.4) for the CTP-543 8 mg BID group, -3.1 (95% CI, -4.6, -1.5) for the CTP-543 12 mg BID group, and -0.3 (95% CI, -1.3, 1.8) for the placebo group.

[0382] At week 8, the LS mean change from baseline was -11.5 (95% CI -13.9, -9.0) for the CTP-543 8 mg BID group, -16.3 (95% CI -19.7, -12.8) for the CTP-543 12 mg BID group, and -2.1 (95% CI -5.5, 1.3) for the placebo group.

[0383] At week 12, the LS mean change from baseline was -23.8 (95% CI -27.1, -20.4) for the CTP-543 8 mg BID group, -30.1 (95% CI -34.7, -25.4) for the CTP-543 12 mg BID group, and -0.8 (95% CI -5.4, 3.9) for the placebo group.

[0384] At week 16, the LS mean change from baseline was -34.1 (95% CI -38.0, -30.2) for the CTP-543 8 mg BID group, -39.5 (95% CI -44.9, -34.2) for the CTP-543 12 mg BID group, and -0.7 (95% CI -4.7, 6.1) for the placebo group.

[0385] At week 20, the LS mean change from baseline was -38.4 (95% CI -42.6, -34.3) for the CTP-543 8 mg BID group, -46.3 (95% CI -52.1, -40.5) for the CTP-543 12 mg BID group, and 0.3 (95% CI -5.5, 6.1) for the placebo group.

[0386] At week 24, the LS mean change from baseline was -44.4 (95% CI -48.8, -40.0) for the CTP-543 8 mg BID group, -51.3 (95% CI -57.4, -45.2) for the CTP-543 12 mg BID group, and 1.5 (95% CI -4.5, 7.6) for the placebo group.

[0387] Percentage of Responders Using Clinical Global Impression of Improvement at Weeks 12, 16, 20, and 24 Subjects with a response of "very substantially improved" or "much improved" were considered CGI-I responders. The percentage of responders was higher in each CTP-543 group than in the placebo group at all time points evaluated; the CTP-543 12 mg BID group was numerically superior to that of the CTP-543 8 mg BID group at all time points evaluated. Detailed data are provided below. At each visit, the percentage of CGI-I responders (non-missing data) was as follows:

[0388] At week 12, CGI-I responders were 38.0% in the CTP-543 8 mg BID group (CMH P<0.0001), 44.3% in the CTP-543 12 mg BID group (CMH P<0.0001), and 3.3% in the placebo group.

[0389] At week 16, CGI-I responders were 45.0% in the CTP-543 8 mg BID group (CMH P<0.0001), 52.0% in the CTP-543 12 mg BID group (CMH P<0.0001), and 3.2% in the placebo group.

[0390] At week 20, CGI-I responders were 50.0% in the CTP-543 8 mg BID group (CMH P<0.0001), 9.0% in the CTP-543 12 mg BID group (CMH P<0.0001), and 1.7% in the placebo group.

[0391] At week 24, CGI-I responders were 54.1% in the CTP-543 8 mg BID group (CMH P<0.0001), 61.7% in the CTP-543 12 mg BID group (CMH P<0.0001), and 2.5% in the placebo group.

[0392] Percentage of responders using Patient Global Impression of Improvement at 12, 16, 20, and 24 weeks PGI-I responders were subjects with a response of "very significantly improved" or "much improved." The CTP-543 group had a higher percentage of PGI-I responders compared to the placebo group at all time points evaluated. The percentage of PGI-I responders in the CTP-543 12 mg BID group was numerically superior to that in the CTP-543 8 mg BID group at all time points evaluated. Detailed data are provided below.

[0393] At each visit, the percentage of PGI-I responders (non-missing data) was as follows: At week 12, PGI-I responders were 43.3% in the CTP-543 8 mg BID group (CMH P<0.0001), 49.2% in the CTP-543 12 mg BID group (CMH P<0.0001), and 3.3% in the placebo group. At week 16, PGI-I responders were 46.2% (CMH P<0.0001) in the CTP-543 8 mg BID group, 59.8% (CMH P<0.0001) in the CTP-543 12 mg BID group, and 4.0% in the placebo group. At week 20, PGI-I responders were 48.7% in the CTP-543 8 mg BID group (CMH P<0.0001), 64.4% in the CTP-543 12 mg BID group (CMH P<0.0001), and 5.8% in the placebo group. At week 24, PGI-I responders were 50.9% in the CTP-543 8 mg BID group (CMH P < 0.0001), 68.3% in the CTP-543 12 mg BID group (CMH P < 0.0001), and 1.7% in the placebo group.

[0394] Change from baseline in Clinical Global Impression of Severity at Weeks 12, 16, 20, and 24 A decrease in CGI-I score indicates improvement (impression is decreased severity). As with other endpoints, a decrease in favor of the active group over placebo was observed beginning at week 12 and continuing through week 24, with the magnitude of the difference increasing at each subsequent time point. In addition, and consistent with other endpoints, the CTP-543 12 mg BID group experienced a greater LS mean decrease in CGI-S than the CTP-543 8 mg BID group at each time point evaluated. Detailed data for each time point are provided below.

[0395] At week 12, the LS mean change from baseline was -1.3 (95% CI -1.4, -1.1) for the CTP-543 8 mg BID group, -1.4 (95% CI -1.7, -1.2) for the CTP-543 12 mg BID group, and -0.0 (95% CI -0.3, 0.2) for the placebo group. At week 16, the LS mean change from baseline was -1.6 (95% CI -1.8, -1.4) for the CTP-543 8 mg BID group, -1.8 (95% CI -2.1, -1.6) for the CTP-543 12 mg BID group, and -0.0 (95% CI -0.2, 0.2) for the placebo group. At week 20, the LS mean change from baseline was -1.8 (95% CI -2.0, -1.6) for the CTP-543 8 mg BID group, -2.1 (95% CI -2.4, -1.9) for the CTP-543 12 mg BID group, and -0.1 (95% CI -0.4, 0.2) for the placebo group. At week 24, the LS mean change from baseline was -2.1 (95% CI -2.3, -1.9) for the CTP-543 8 mg BID group, -2.4 (95% CI -2.6, -2.1) for the CTP-543 12 mg BID group, and 0.0 (95% CI -0.3, 0.3) for the placebo group.

[0396] Change from baseline in Patient Global Impression of Severity at Weeks 12, 16, 20, and 24 A reduction from baseline indicates improvement (impression is decreased severity). The LS mean treatment group difference favored the CTP-543 group over the placebo group at all time points evaluated. At each visit, the LS mean treatment group difference was more favorable (more negatives) for the CTP-543 12 mg BID group than for the CTP-543 8 mg BID group. Detailed data for each time point are provided below.

[0397] At week 12, the LS mean change from baseline was -1.6 (95% CI -1.8, -1.4) for the CTP-543 8 mg BID group, -1.8 (95% CI -2.1, -1.4) for the CTP-543 12 mg BID group, and -0.2 (95% CI -0.5, 0.1) for the placebo group. At week 16, the LS mean change from baseline was -1.8 (95% CI -2.0, -1.6) for the CTP-543 8 mg BID group, -2.0 (95% CI -2.3, -1.7) for the CTP-543 12 mg BID group, and -0.2 (95% CI -0.5, 0.1) for the placebo group. At week 20, the LS mean change from baseline was -2.0 (95% CI -2.2, -1.8) for the CTP-543 8 mg BID group, -2.2 (95% CI -2.5, -1.9) for the CTP-543 12 mg BID group, and -0.3 (95% CI -0.6, 0.1) for the placebo group. At week 24, the LS mean change from baseline was -2.2 (95% CI -2.5, -2.0) for the CTP-543 8 mg BID group, -2.5 (95% CI -2.8, -2.1) for the CTP-543 12 mg BID group, and -0.1 (95% CI -0.5, 0.2) for the placebo group.

[0398] Percentage of subjects achieving at least a 75% relative reduction in SALT score from baseline at weeks 8, 12, and 24 At week 8, 3.4% of CTP-543 8 mg BID subjects, 3.5% of CTP 16 mg BID subjects, and 0 placebo subjects had a relative reduction in SALT score from baseline that was ≥ 75%. At week 12, 8.9% of CTP-543 8 mg BID subjects, 11.5% of CTP 12 mg BID subjects, and 0 placebo subjects had a relative reduction in SALT score from baseline that was ≥ 75%. At week 24, 33.5% of CTP-543 8 mg BID subjects, 38.3% of CTP 12 mg BID subjects, and 0 placebo subjects achieved a relative reduction in SALT score from baseline that was ≥ 75%.

[0399] Percentage of subjects achieving at least a 90% relative reduction in Alopecia Tool score severity from baseline at Weeks 12 and 24 The percentage of subjects with a 90% relative reduction in SALT score from baseline at Week 12 was 1.7% of CTP-543 8 mg BID subjects, 4.9% of CTP 12 mg BID subjects, and 0 placebo subjects. At Week 24, 21.9% of CTP-543 8 mg BID subjects, 25.0% of CTP 12 mg BID subjects, and 0 placebo subjects achieved a ≥ 90% relative reduction in SALT score from baseline.

[0400] Percentage of responders, change from baseline, and percentage of subjects achieving a ≥ 2.0 point change from baseline on the Hair Satisfaction Patient-Reported Outcome Scale. SPRO was assessed in three different ways: percentage of responders, change from baseline, and percentage of subjects achieving a ≥ 2.0 point change from baseline.

[0401] At week 12, the percentage of responders (based on non-missing data) was 43.2% in the CTP-543 8 mg BID group, 41.0% in the CTP-543 12 mg BID group, and 4.9% in the placebo group.

[0402] At week 16, the percentage of responders (based on non-missing data) was 41.0% in the CTP-543 8 mg BID group, 45.1% in the CTP-543 12 mg BID group, and 4.9% in the placebo group.

[0403] At week 20, the percentage of responders (based on no missing data) was 40.1% in the CTP-543 8 mg BID group, 52.5% in the CTP-543 12 mg BID group, and 1.7% in the placebo group.

[0404] A decrease in SPRO scores indicates a higher degree of satisfaction. The LS mean change from baseline at week 12 was -1.6 (95% CI -1.8, -1.5) for the CTP-543 8 mg BID group, -1.7 (95% CI -1.9, -1.5) for the CTP-543 12 mg BID group, and -0.4 (95% CI -0.7, -0.2) for the placebo group.

[0405] At week 16, the LS mean change from baseline was -1.6 (95% CI -1.7, -1.4) for the CTP-543 8 mg BID group, -1.7 (95% CI -1.9, -1.5) for the CTP-543 12 mg BID group, and -0.2 (95% CI -0.4, 0.0) for the placebo group.

[0406] The LS mean change from baseline at week 20 was -1.5 (95% CI -1.7, -1.4) for the CTP-543 8 mg BID group, -1.8 (95% CI -2.1, -1.6) for the CTP-543 12 mg BID group, and -0.1 (95% CI -0.3, 0.1) for the placebo group.

[0407] At week 24, the LS mean change from baseline was -1.6 (95% CI -1.8, -1.5) for the CTP-543 8 mg BID group, -1.8 (95% CI -2.1, -1.6) for the CTP-543 12 mg BID group, and -0.1 (95% CI -0.3, 0.1) for the placebo group.

[0408] The percentage of subjects with non-missing data with a change of ≥ 2 points at Week 12 was 50.4% for CTP-543 8 mg BID subjects, 59.0% for CTP-543 12 mg BID subjects, and 15.6% for placebo subjects.

[0409] The percentage of subjects with non-missing data with a change of ≥ 2 points at Week 16 was 52.6% for CTP-543 8 mg BID subjects, 57.4% for CTP-543 12 mg BID subjects, and 9.8% for placebo subjects.

[0410] The percentage of subjects with non-missing data with a change of ≥ 2 points at Week 20 was 50.4% for CTP-543 8 mg BID subjects, 63.6% for CTP-543 12 mg BID subjects, and 9.2% for placebo subjects.

[0411] The percentage of subjects with non-missing data with a change of ≥ 2 points at Week 24 was 52.6% for CTP-543 8 mg BID subjects, 61.7% for CTP-543 12 mg BID subjects, and 8.5% for placebo subjects.

[0412] Percentage of subjects achieving an absolute severity of Alopecia Tool score ≤ 10 at Week 24 At week 24, 24.9% of CTP-543 8 mg BID subjects, 26.7% of CTP-543 12 mg BID subjects, and 0 placebo subjects had an absolute SALT score ≦10 (FIG. 14B).

[0413] Change from baseline in Brigham Eyebrow tool for alopecia score at 12 and 24 weeks An increase in BETA score indicates an increase in hair growth. At week 12, the LS mean change from baseline was 0.8 (95% CI 0.5, 1.0) for the CTP-543 8 mg BID group, 0.8 (95% CI 0.5, 1.0) for the CTP-543 12 mg BID group, and -0.3 (95% CI 0.5, 0.0) for the placebo group.

[0414] At week 24, the LS mean change from baseline was 1.1 (95% CI 0.9, 1.3) for the CTP-543 8 mg BID group, 1.4 (95% CI 1.1, 1.7) for the CTP-543 12 mg BID group, and -0.4 (95% CI -0.7, -0.0) for the placebo group.

[0415] Change from baseline in Brigham Eyelash tool alopecia score at 12 and 24 weeks An increase in BELA score indicates an increase in hair growth. The LS mean change from baseline at week 12 was 0.9 (95% CI 0.7, 1.2) for the CTP-543 8 mg BID group, 1.0 (95% CI 0.7, 1.4) for the CTP-543 12 mg BID group, and -0.1 (95% CI -0.5, 0.2) for the placebo group.

[0416] The LS mean change from baseline at week 24 was 1.4 (95% CI 1.1, 1.7) for the CTP-543 8 mg BID group, 1.5 (95% CI 1.1, 1.9) for the CTP-543 12 mg BID group, and -0.1 (95% CI -0.5, 0.3) for the placebo group.

[0417] Changes from baseline in individual items of the Hair Quality Patient-Reported Outcome Scale at weeks 12, 16, 20, and 24 The individual items of satisfaction with hair coverage thickness, satisfaction with hair coverage evenness, satisfaction with eyebrows, and satisfaction with eyelashes are rated on a scale of 1 to 5. A decrease from baseline in the QPRO score represents improvement. For each item and time point, the treatment group difference favored CTP-543 over placebo.

[0418] For satisfaction with hair coverage, both CTP-543 groups demonstrated improvement over placebo at weeks 12, 16, 20, and 24, with placebo generally consistent but showing a more negative trend. For the CTP-543 8 mg BID group, treatment differences from placebo ranged from -1.3 to -1.0. For the CTP-543 12 mg BID group, treatment differences from placebo ranged from -1.6 to -1.1.

[0419] For satisfaction with evenness of hair coverage, the CTP-543 groups showed a trend toward more negativity, while placebo was generally consistent. For the CTP-543 8 mg BID group, treatment differences from placebo ranged from -1.3 to -0.9. For the CTP-543 12 mg BID group, treatment differences from placebo ranged from -1.5 to -1.0.

[0420] For eyebrow satisfaction, the CTP-543 group showed a trend toward more negative responses, while placebo was generally consistent. For the CTP-543 8 mg BID group, treatment differences from placebo ranged from -1.2 to -1.0. For the CTP-543 12 mg BID group, treatment differences from placebo ranged from -1.5 to -1.1.

[0421] For satisfaction with eyelashes, the CTP-543 groups showed a trend toward more negativity, while placebo was generally consistent. For the CTP-543 8 mg BID group, treatment differences from placebo ranged from -1.2 to -0.9. For the CTP-543 12 mg BID group, treatment differences from placebo ranged from -1.4 to -0.9.

[0422] Subjects who completed 24 weeks of treatment with LEQSELVI 8 mg twice daily in the Phase 3 trial were eligible to continue treatment in an open-label extension study. After 52 additional weeks of treatment with LEQSELVI™ 8 mg twice daily, the clinical response rate continued to increase, with approximately 74% of 80 subjects achieving a SALT of ≦20 over 76 weeks at 8 mg twice daily.

[0423] Change from baseline in patient response on the Hospital Anxiety and Depression Scale (HADS) at 24 weeks Changes from baseline to week 24 in depression scores were measured in subjects randomized to treatment with durxolitinib 8 mg twice daily (BID), durxolitinib 12 mg BID, or placebo for 24 weeks. Subjects completed the 14-item HADS questionnaire, with 7 items for anxiety (HADS-A) and 7 items for depression (HADS-D). Each item on the HADS was scored on a 4-point scale (0 to 3), with an overall score ranging from 0 to 42 (0 to 21 for HADS-A and 0 to 21 for HADS-D). Among subjects treated with durxolitinib 8 mg BID, 22.5% achieved a ≥6-point improvement in the overall HADS score from baseline to week 24, compared with 11.8% of placebo-treated subjects.

[0424] Change from baseline in anxiety scales 18.9% of subjects receiving durxolitinib 8 mg BID versus 10.2% of placebo-treated subjects achieved a ≥4-point improvement in HADS-A score. At week 24, the LS mean change from baseline was -1.1 (95% CI -1.5, -0.8) for CTP-543 8 mg BID, -0.9 (95% CI -1.3, -0.4) for CTP-543 12 mg BID, and -0.7 (-1.1, -0.2) for placebo. The LS mean treatment group difference from placebo was 0.5 (95% CI -0.1, 1.0; P = 0.1206) and 0.2 (95% CI -0.5, 0.9; P = 0.5367) for CTP-543 8 mg BID and CTP-543 12 mg BID, respectively.

[0425] Change from baseline in depression scales 26.2% of subjects treated with durxolitinib 8 mg BID versus 14.2% of subjects treated with placebo achieved a ≥ 3-point improvement in HADS-D score from baseline to week 24. At week 24, the LS mean change from baseline was -1.2 (95% CI -1.6, -0.9) for CTP-543 8 mg BID, -1.5 (95% CI -2.0, -1.1) for CTP-543 12 mg BID, and -0.4 (95% CI -0.9, 0.0) for placebo. The LS mean treatment group difference from placebo was 0.8 (95% CI 0.2, 1.3; P=0.0064) and 1.1 (95% CI 0.4, 1.7; P=0.0011) for CTP-543 8 mg BID and CTP-543 12 mg BID, respectively.

[0426] These results show that a significantly greater proportion of subjects treated with durxolitinib 8 mg BID reported clinically meaningful improvements in overall HADS score, and HADS-A and HADS-D subscales from baseline to week 24 compared to placebo.

[0427] Example 3: Open-Label Extension (OLE) Study background Durxolitinib (a compound represented by Compound (I) described herein) has demonstrated significant improvement in hair regrowth versus placebo in two Phase 3 clinical trials, THRIVE-AA1 and THRIVE-AA2: treatment of adult subjects with alopecia areata receiving doses of 8 mg twice daily (BID) and 12 mg BID for 24 weeks. The long-term efficacy of durxolitinib is being evaluated in two ongoing OLE studies in North America and the European Union. After analysis of long-term data up to 52 weeks of dosing, continued improvement in hair regrowth beyond that assessed in the initial 24-week controlled study was observed. Details and results of the OLE studies are described below.

[0428] After analysis of long-term data up to 68 weeks of treatment, improvements in hair regrowth continued to be observed beyond those assessed in the initial 24-week controlled study.

[0429] Exam details explanation Two separate OLE trials were conducted in North America (CP543.5001) and the European Union (CP543.5002). Subjects with AA who completed the 24-week treatment period from eligible Phase II and Phase III trials were eligible to enroll, regardless of whether they received active treatment or placebo. Eligible clinical trials included: 1. NCT03137381; 2. NCT03811912; 3. NCT03941548; 4. NCT04784533; 5. NCT04518995; and 6. NCT04797650 (all available at https: / / clinicaltrials.gov). Both OLE trials were similarly designed, with the following exceptions: Study CP543.5001 (North America) participants have the opportunity to continue in the study for up to 276 weeks; Study CP543.5002 (European Union) participants have the opportunity to continue in the study for up to 108 weeks.

[0430] Treatment assignment and data analysis Subjects receiving any active dose of durxolitinib in the eligibility trial were initially assigned to receive either 8 mg BID or 12 mg BID in the OLE trial. Subjects receiving placebo in the eligibility trial were assigned to receive either 8 mg BID or 12 mg BID durxolitinib. Subjects were allowed to switch doses during the OLE after their initial treatment assignment at the investigator's discretion. Figure 3 shows a diagram of patient flow from the eligibility trial to the open-label extension.

[0431] The OLE efficacy population was defined as all subjects who received at least one dose of durxolitinib and had at least one post-baseline SALT assessment in the OLE. Data analysis included data from subjects from eligible trials. Missing SALT scores were not imputed. The number of subjects decreased over time due to missing data, patient withdrawals, or not yet being included at later time points. Any SALT data after an eligible dose change in the OLE was censored for all figures included herein, except those showing the overall treatment sequence. An "eligible dose change" referred to herein could be from placebo in any eligible trial to any dose of durxolitinib in the OLE (including subjects who switched doses), or from any dose of durxolitinib in an eligible trial to any dose of durxolitinib in the OLE. Various analyses using SALT scores were performed to best estimate the overall long-term effect of durxolitinib, taking into account issues with dose changes and the decreasing number of patients over time. The "Any Dose" analysis tracks all active subjects pooled across the two doses over time. The "As Observed" analysis censors subjects at the time of dose adjustment or study discontinuation. The "LOCF" (Last Observation Carried Forward) analysis utilizes the last SALT score before dose change and carries it forward to 52 weeks for all other time points. Patient demographics are shown in Figure 4.

[0432] In some embodiments, the LOCF analysis utilizes the last SALT score before the dose change and carries it forward to 68 weeks for all other time points. For example, the time point is at least 74 weeks. For example, the time point is at least 90 weeks. For example, the time point is at least 108 weeks. For example, the time point is at least 140 weeks. For example, the time point is at least 172 weeks. For example, the time point is at least 204 weeks. For example, the time point is at least 236 weeks. For example, the time point is at least 276 weeks.

[0433] result Percentage of responders over time Figures 5-7 show that, based on an interim analysis of pooled results from two OLE studies, the percentage of subjects with a SALT score of ≦20 increased over time through week 52. Specifically, Figure 5 is a graph showing the percentage of responders (subjects with a SALT score of ≦20) over time treated with any dose of durxolitinib. The graph shows that 57.1% of subjects receiving any dose of durxolitinib in the OLE (including the switch dose) achieved a SALT score of ≦20. Figure 6 is a graph showing the percentage of responders (subjects with a SALT score of ≦20) over time treated with 8 mg twice daily. The graph in Figure 6 shows that 63.6 percent of subjects receiving 8 mg twice daily of durxolitinib in the OLE achieved a SALT score of ≦20. Figure 7 is a graph showing the percentage of responders (subjects with a SALT score of ≦20) over time treated with 12 mg twice daily. The graph in Figure 7 shows that 62.1 percent of subjects receiving 12 mg twice daily of durxolitinib achieved a SALT score of ≦20 in OLE. Figure 11 is a graph showing the percentage of responders (subjects with a SALT score of ≦20) over time treated with 8 mg twice daily of durxolitinib (censored population and LOCF analysis).

[0434] Figure 12 is a graph showing the percentage of responders (subjects with a SALT score of ≦20) over time treated with 12 mg of durxolitinib twice daily (censored population and LOCF analysis). Figures 13A, 13B, and 13C show the percentage of responders (subjects with a SALT score of ≦20) over 68 weeks for durxolitinib (8 mg, twice daily), 52 weeks for baricitinib (4 mg), and 48 weeks for ritrecitinib (50 mg). Baricitinib data were taken from the BRAVE-AA1 and BRAVE-AA2 trials summarized in King et al., N. Engl. J. Med. (2022) 386:1687-1699. Ritrecitinib data was taken from the ALLEGOR trial summarized in Piliang et al, J. Cutaneous Med, (2024) 8:s394.

[0435] Pooled mean SALT scores over time Figures 8-10 show mean SALT scores over time by treatment group. Specifically, Figure 8 shows the pooled mean SALT scores over time for subjects receiving either 8 mg BID or 12 mg BID in the OLE. The graph in Figure 8 shows that subjects in the OLE study who were medicated with either 8 mg BID or 12 mg BID and who had been medicated with durxolitinib in the previous study had a mean SALT score of 31.7; and subjects in the OLE study who received a placebo in the previous study had a mean SALT score of 43.6 at 52 weeks. Figure 9 shows the pooled mean SALT scores over time for subjects who received 8 mg BID in the OLE. The graph in Figure 9 shows that subjects in the OLE study who were medicated with 8 mg durxolitinib in the previous study had a mean SALT score of 25.6 at 52 weeks; and subjects in the OLE study who received a placebo in the previous study had a mean SALT score of 30.4. Figure 10 shows the pooled mean SALT scores over time for subjects receiving 12 mg BID in the OLE. The graph in Figure 10 shows that subjects in the OLE study who were administered 12 mg of durxolitinib in the previous study had a mean SALT score of 27.7 at 52 weeks; and subjects in the OLE study who received a placebo in the previous study had a mean SALT score of 43.0.

[0436] Longitudinal results over 68 weeks and beyond The mean SALT score decreased from baseline 86.8 (SD 17.9; n=984) to 26.8 (SD 34.7; n=836) at 68 weeks in participants receiving durxolitinib (any dose) in the qualifying study (QS) and OLE. The proportion of participants achieving an established SALT score of ≤20 in QS increased from 34.9% to 62.6% in OLE at week 68. Both the 8 mg BID and 12 mg BID doses demonstrated continued efficacy using LOCF imputed analyses and as-observed (AO) analyses. For LOCF, the proportion of participants achieving a SALT score of ≤20 at week 68 was 48.8% for 8 mg BID and 60.9% for 12 mg BID. For AO, the proportion of participants achieving a SALT score of ≤20 at week 68 was 76.6% for 8 mg BID and 66.7% for 12 mg BID. The findings of treatment-emergent adverse events from the pooled analysis are consistent with the safety profiles observed for other JAK inhibitors indicated for chronic inflammatory conditions. Figure 13A demonstrates that the proportion of participants achieving SALT ≤ 20 continued to increase, reaching >80% for 8 mg BID at week 68. The data are unexpected because other JAK inhibitors used to treat AA, ritrecitinib and baricitinib, have not previously been shown to provide a proportion of participants achieving SALT ≤ 20 that is even greater than 50%, and the rate of increase in the proportion of participants achieving SALT ≤ 20 may taper off and plateau. See Figures 13B and 13C.

[0437] A total of 521 patients treated with durxolitinib 8 mg BID in the eligible trial received the same dose in the OLE (8 mg BID / 8 mg BID); 122 patients receiving placebo in the eligible trial received durxolitinib 8 mg BID in the OLE (placebo / 8 mg BID). As observed, 179 / 256 (69.9%) patients in the 8 mg BID / 8 mg BID group and 39 / 59 (66.1%) patients in the placebo / 8 mg BID group achieved SALT10 at Week 68. Using LOCF, 213 / 521 (40.9%) and 41 / 122 (33.6%) patients in the 8 mg BID / 8 mg BID and placebo / 8 mg BID groups, respectively, achieved SALT10 at Week 68. The proportion of patients achieving SALT10 in either group increased from Week 24 to Week 68 of the OLE. Of 373 patients who received durxolitinib 8 mg BID in an OLE without an eligible dose change, 283 were considered OLE responders, of whom 282 (99.6%) maintained their treatment response in the OLE.

[0438] conclusion Durxolitinib 8 mg BID and durxolitinib 12 mg BID demonstrated significant hair regrowth in Phase II and Phase III clinical trials. The long-term efficacy of durxolitinib is being evaluated in two ongoing OLE studies in North America and the European Union. After analysis of long-term data up to 52 weeks of treatment, continued improvement in hair regrowth beyond that assessed in the initial 24-week controlled study was observed.

[0439] After analysis of long-term data up to 68 weeks of treatment, continued improvement in hair regrowth was observed beyond that assessed in the initial 24-week controlled trial.

[0440] An interim analysis of pooled results from the two OLE studies showed that the percentage of subjects with a SALT score ≦20 increased over time through week 52. 57% of subjects receiving any dose of durxolitinib (including switch doses) in the OLE studies achieved a SALT score ≦20. 64% of subjects receiving durxolitinib 8 mg BID in the OLE studies achieved a SALT score ≦20. 62% of subjects receiving durxolitinib 12 mg BID in the OLE studies achieved a SALT score ≦20.

[0441] An interim analysis of pooled results from the two OLE studies showed that the percentage of subjects with a SALT score ≦20 increased over time through week 68. 63% of subjects receiving any dose of durxolitinib (including switch doses) in the OLE studies achieved a SALT score ≦20. 77% of subjects receiving durxolitinib 8 mg BID in the OLE studies achieved a SALT score ≦20. 67% of subjects receiving durxolitinib 12 mg BID in the OLE studies achieved a SALT score ≦20.

[0442] Durxolitinib was generally well tolerated in the OLE study. The most common adverse events were COVID-19, acne, nasopharyngitis, headache, asymptomatic COVID-19, increased creatinine phosphokinase, and upper respiratory tract infection. The number of serious treatment-related TEAEs remains low. To date, four subjects have reported related thrombotic events (all at the 12 mg BID dose) after ≥52 weeks of treatment.

[0443] While the present invention has been particularly shown and described with reference to illustrative embodiments thereof, it will be understood by those skilled in the art that various changes in form and details can be made therein without departing from the scope of the invention as encompassed by the appended claims.

Claims

1. 1. A method of treating alopecia areata in a subject in need thereof, said method comprising: determining an estimated glomerular filtration rate of the subject; and and orally administering to the subject 16 mg / day or 24 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof, if the subject has an estimated glomerular filtration rate (eGFR) of ≥ 30 mL / min for MDRD, wherein Compound (I) is represented by the following structural formula: 【Chemistry 1】 A method wherein each position specifically designated as deuterium has at least 95% incorporation of deuterium.

2. 1. A method of treating alopecia areata in a subject in need thereof, said method comprising orally administering 16 mg / day or 24 mg / day of compound (I) or a pharmaceutically acceptable salt thereof to said subject having an estimated glomerular filtration rate (eGFR) of ≧30 mL / min for MDRD, wherein compound (I) is represented by the following structural formula: 【Chemistry 2】 A method wherein each position specifically designated as deuterium has at least 95% incorporation of deuterium.

3. 3. The method of claim 1 or 2, wherein the subject has moderate renal impairment (eGFR of 30-59 mL / min, MDRD).

4. 3. The method of claim 1 or 2, wherein the subject's eGFR is ≧30 mL / min to <60 mL / min, MDRD.

5. 3. The method of claim 1 or 2, wherein the subject's eGFR is ≧60 mL / min to <90 mL / min, MDRD.

6. 6. The method of any one of claims 1 to 5, wherein the subject has an absolute SALT score of ≧50 at the start of treatment.

7. 6. The method of any one of claims 1 to 5, wherein the subject has moderate to severe alopecia areata at the start of treatment.

8. 6. The method of any one of claims 1 to 5, wherein the subject has severe alopecia areata at the start of treatment.

9. 9. The method of any one of claims 1 to 8, wherein after 8 weeks of treatment, the subject has an absolute SALT score of ≦20.

10. 9. The method of any one of claims 1 to 8, wherein after 12 weeks of treatment, the subject has an absolute SALT score of ≦20.

11. 9. The method of any one of claims 1-8, wherein after 16 weeks of treatment, the subject has an absolute SALT score of ≦20.

12. 9. The method of any one of claims 1-8, wherein after 20 weeks of treatment, the subject has an absolute SALT score of ≦20.

13. 9. The method of any one of claims 1-8, wherein after 24 weeks of treatment, the subject has an absolute SALT score of ≦20.

14. 14. The method of claim 13, wherein after 24 weeks of treatment, the subject has an absolute SALT score of ≦10.

15. 9. The method of any one of claims 1-8, wherein after 52 weeks of treatment, the subject has an absolute SALT score of ≦20.

16. 9. The method of any one of claims 1 to 8, wherein after 24 weeks of treatment, the subject has at least a 75% relative reduction in SALT score.

17. 9. The method of any one of claims 1 to 8, wherein after 12 weeks of treatment, the subject has at least a 75% relative reduction in SALT score.

18. 9. The method of any one of claims 1 to 8, wherein after 8 weeks of treatment, the subject has at least a 75% relative reduction in SALT score.

19. 9. The method of any one of claims 1 to 8, wherein after 24 weeks of treatment, the subject has at least a 90% relative reduction in SALT score.

20. 9. The method of any one of claims 1 to 8, wherein after 12 weeks of treatment, the subject has at least a 90% relative reduction in SALT score.

21. 9. The method of any one of claims 1 to 8, wherein after 24 weeks of treatment, the subject reports a response of "satisfied" or "very satisfied" on the Satisfaction with Hair Patient-Reported Outcomes (SPRO) scale.

22. 9. The method of any one of claims 1-8, wherein after 12 weeks of treatment, the subject reports a response of "satisfied" or "very satisfied" on the Hair Satisfaction Patient-Reported Outcome (SPRO) scale.

23. 9. The method of any one of claims 1-8, wherein after 8 weeks of treatment, the subject reports a response of "satisfied" or "very satisfied" on the Hair Satisfaction Patient-Reported Outcome (SPRO) scale.

24. 9. The method of any one of claims 1-8, wherein after 12 weeks of treatment, the subject reports a reduction in score from baseline of at least 1.5 points on the Satisfaction with Hair Patient-Reported Outcomes (SPRO) scale.

25. 25. The method of claim 24, wherein the decrease in score is ≧2 points.

26. 9. The method of any one of claims 1-8, wherein after 24 weeks of treatment, the subject reports a response of "much improved" or "very much improved" using the Patient Global Impression of Improvement (PGI-I).

27. 9. The method of any one of claims 1-8, wherein after 12 weeks of treatment, the subject reports a response of "much improved" or "very much improved" using the Patient Global Impression of Improvement (PGI-I).

28. 9. The method of any one of claims 1-8, wherein after 16 weeks of treatment, the subject reports a response of "much improved" or "very much improved" using the Patient Global Impression of Improvement (PGI-I).

29. 9. The method of any one of claims 1-8, wherein after 20 weeks of treatment, the subject reports a response of "much improved" or "very much improved" using the Patient Global Impression of Improvement (PGI-I).

30. 9. The method of any one of claims 1-8, wherein after 12 weeks of treatment, a reduction in score from baseline of at least 1.5 points is reported by the subject on the Patient Global Impression of Improvement (PGI-I).

31. 9. The method of any one of claims 1-8, wherein after 16 weeks of treatment, a reduction in score from baseline of at least 1.7 points is reported by the subject on the Patient Global Impression of Improvement (PGI-I).

32. 9. The method of any one of claims 1-8, wherein after 24 weeks of treatment, a reduction in score from baseline of at least 2.1 points is reported by the subject on the Patient Global Impression of Improvement (PGI-I).

33. 9. The method of any one of claims 1 to 8, wherein after 24 weeks of treatment, the subject reports a response of "much improved" or "very much improved" using the Clinical Global Impression of Improvement (CGI-I).

34. 9. The method of any one of claims 1 to 8, wherein after 12 weeks of treatment, the subject reports a response of "much improved" or "very much improved" using the Clinical Global Impression of Improvement (CGI-I).

35. 9. The method of any one of claims 1-8, wherein after 16 weeks of treatment, the subject reports a response of "much improved" or "very much improved" using the Clinical Global Impression of Improvement (CGI-I).

36. 9. The method of any one of claims 1-8, wherein after 20 weeks of treatment, the subject reports a response of "much improved" or "very much improved" using the Clinical Global Impression of Improvement (CGI-I).

37. 9. The method of any one of claims 1-8, wherein after 12 weeks of treatment, a reduction in score from baseline of at least 1.0 is reported by the subject on the Clinical Global Impression of Severity (CGI-S).

38. 9. The method of any one of claims 1-8, wherein after 16 weeks of treatment, a reduction in score from baseline of at least 1.5 points is reported by the subject on the Clinical Global Impression of Severity (CGI-S).

39. 9. The method of any one of claims 1-8, wherein after 24 weeks of treatment, a reduction in score from baseline of at least 2.0 is reported by the subject on the Clinical Global Impression of Severity (CGI-S).

40. 9. The method of any one of claims 1-8, wherein after 24 weeks of treatment, an increase in score from baseline of at least 1.0 is achieved by the subject on the Brigham Eyelash Tool for Alopecia (BELA) or the Brigham Eyebrow Tool for Alopecia (BETA).

41. 9. The method of any one of claims 1-8, wherein after 12 weeks of treatment, an increase in score from baseline of at least 0.5 points is achieved by the subject on the Brigham Eyelash Tool for Alopecia (BELA) or the Brigham Eyebrow Tool for Alopecia (BETA).

42. The method of any one of claims 1 to 41, wherein the subject is a human.

43. 43. The method of claim 42, wherein the subject is an adult human.

44. 1. A method of treating alopecia areata in a subject in need thereof, said method comprising: (a) determining the subject's complete blood count; (b) orally administering to the subject 16 mg / day or 24 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof, wherein Compound (I) is represented by the following structural formula: 【Transformation 3】 orally administering, wherein each position specifically designated as deuterium has at least 95% incorporation of deuterium; (c) monitoring the ALC, ANC, and hemoglobin levels; and (d) discontinuing treatment of the subject if the subject's ALC is <500 cells / μl, ANC is <1000 cells / μl, and / or hemoglobin level is <8 g / dl.

45. 45. The method of claim 44, wherein the ALC, ANC, and hemoglobin levels are monitored at 4, 8, 16, 20, and 24 weeks.

46. 452. The method of claim 44 or 452, further comprising resuming treating the subject if the subject's ALC is determined to be > 500 cells / μl, the subject's ANC is determined to be > 1000 cells / μl, and / or the subject's hemoglobin level is determined to be > 8 g / dl.

47. The method comprises: a) determining an estimated glomerular filtration rate of said subject; and 47. The method of any one of claims 44-46, further comprising: b) orally administering to the subject 16 mg / day or 24 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof if the subject has an estimated glomerular filtration rate (eGFR) of ≥ 30 mL / min for MDRD.

48. 47. The method of any one of claims 44-46, wherein the method further comprises orally administering to the subject 16 mg / day or 24 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof if the subject has an estimated glomerular filtration rate (eGFR) of ≥ 30 mL / min, MDRD.

49. 49. The method of claim 47 or 48, wherein the subject has moderate renal impairment (eGFR of 30-59 mL / min, MDRD).

50. 50. The method of any one of claims 47-49, wherein the subject's eGFR is ≧30 mL / min to <60 mL / min, MDRD.

51. 48. The method of claim 47, wherein the subject has an eGFR of >= 60 mL / min to < 90 mL / min, MDRD.

52. 51. The method of any one of claims 44 to 50, wherein the subject has an absolute SALT score of ≧50 at the start of treatment.

53. 51. The method of any one of claims 44 to 50, wherein the subject has moderate to severe alopecia areata at the start of treatment.

54. 51. The method of any one of claims 44 to 50, wherein the subject has severe alopecia areata at the start of treatment.

55. 55. The method of any one of claims 44-54, wherein after 8 weeks of treatment, the subject has an absolute SALT score of ≦20.

56. 55. The method of any one of claims 44-54, wherein after 12 weeks of treatment, the subject has an absolute SALT score of ≦20.

57. 55. The method of any one of claims 44-54, wherein after 8 weeks of treatment, the subject has an absolute SALT score of ≦20.

58. 55. The method of any one of claims 44-54, wherein after 16 weeks of treatment, the subject has an absolute SALT score of ≦20.

59. 55. The method of any one of claims 44-54, wherein after 20 weeks of treatment, the subject has an absolute SALT score of ≦20.

60. 55. The method of any one of claims 44-54, wherein after 24 weeks of treatment, the subject has an absolute SALT score of ≦20.

61. 61. The method of claim 60, wherein after 24 weeks of treatment, the subject has an absolute SALT score of ≦10.

62. 55. The method of any one of claims 44-54, wherein after 52 weeks of treatment, the subject has an absolute SALT score of ≦20.

63. 55. The method of any one of claims 44-54, wherein after 24 weeks of treatment, the subject has at least a 75% relative reduction in SALT score.

64. 55. The method of any one of claims 44-54, wherein after 12 weeks of treatment, the subject has at least a 75% relative reduction in SALT score.

65. 55. The method of any one of claims 44-54, wherein after 8 weeks of treatment, the subject has at least a 75% relative reduction in SALT score.

66. 55. The method of any one of claims 44-54, wherein after 24 weeks of treatment, the subject has at least a 90% relative reduction in SALT score.

67. 55. The method of any one of claims 44-54, wherein after 12 weeks of treatment, the subject has at least a 90% relative reduction in SALT score.

68. 55. The method of any one of claims 44-54, wherein after 24 weeks of treatment, the subject reports a response of "satisfied" or "very satisfied" on the Hair Satisfaction Patient-Reported Outcome (SPRO) scale.

69. 55. The method of any one of claims 44-54, wherein after 12 weeks of treatment, the subject reports a response of "satisfied" or "very satisfied" on the Hair Satisfaction Patient-Reported Outcome (SPRO) scale.

70. 55. The method of any one of claims 44-54, wherein after 8 weeks of treatment the subject reports a response of "satisfied" or "very satisfied" on the Hair Satisfaction Patient-Reported Outcome (SPRO) scale.

71. 55. The method of any one of claims 44-54, wherein after 12 weeks of treatment, the subject reports a reduction in score from baseline of at least 1.5 points on the Satisfaction with Hair Patient-Reported Outcome (SPRO) scale.

72. 72. The method of claim 71, wherein the decrease in score is ≧2 points.

73. 55. The method of any one of claims 44-54, wherein after 24 weeks of treatment, the subject reports a response of "much improved" or "very much improved" using the Patient Global Impression of Improvement (PGI-I).

74. 55. The method of any one of claims 44-54, wherein after 12 weeks of treatment, the subject reports a response of "much improved" or "very much improved" using the Patient Global Impression of Improvement (PGI-I).

75. 55. The method of any one of claims 44-54, wherein after 16 weeks of treatment, the subject reports a response of "much improved" or "very much improved" using the Patient Global Impression of Improvement (PGI-I).

76. 55. The method of any one of claims 44-54, wherein after 20 weeks of treatment, the subject reports a response of "much improved" or "very much improved" using the Patient Global Impression of Improvement (PGI-I).

77. 55. The method of any one of claims 44-54, wherein after 12 weeks of treatment, a reduction in score from baseline of at least 1.5 points is reported by the subject on the Patient Global Impression of Improvement (PGI-I).

78. 55. The method of any one of claims 44-54, wherein after 16 weeks of treatment, a reduction in score from baseline of at least 1.7 points is reported by the subject on the Patient Global Impression of Improvement (PGI-I).

79. 55. The method of any one of claims 44-54, wherein after 24 weeks of treatment, a reduction in score from baseline of at least 2.1 points is reported by the subject on the Patient Global Impression of Improvement (PGI-I).

80. 55. The method of any one of claims 44-54, wherein after 24 weeks of treatment, the subject reports a response of "much improved" or "very much improved" using the Clinical Global Impression of Improvement (CGI-I).

81. 55. The method of any one of claims 44-54, wherein after 12 weeks of treatment, the subject reports a response of "much improved" or "very much improved" using the Clinical Global Impression of Improvement (CGI-I).

82. 55. The method of any one of claims 44-54, wherein after 16 weeks of treatment, the subject reports a response of "much improved" or "very much improved" using the Clinical Global Impression of Improvement (CGI-I).

83. 55. The method of any one of claims 44-54, wherein after 20 weeks of treatment, the subject reports a response of "much improved" or "very much improved" using the Clinical Global Impression of Improvement (CGI-I).

84. 55. The method of any one of claims 44-54, wherein after 12 weeks of treatment, a reduction in score from baseline of at least 1.0 is reported by the subject on the Clinical Global Impression of Severity (CGI-S).

85. 55. The method of any one of claims 44-54, wherein after 16 weeks of treatment, a reduction in score from baseline of at least 1.5 points is reported by the subject on the Clinical Global Impression of Severity (CGI-S).

86. 55. The method of any one of claims 44-54, wherein after 24 weeks of treatment, a reduction in score from baseline of at least 2.0 is reported by the subject on the Clinical Global Impression of Severity (CGI-S).

87. 55. The method of any one of claims 44-54, wherein after 24 weeks of treatment, an increase in score from baseline of at least 1.0 is achieved by the subject on the Brigham Eyelash Tool for Alopecia (BELA) or the Brigham Eyebrow Tool for Alopecia (BETA).

88. 55. The method of any one of claims 44-54, wherein after 12 weeks of treatment, an increase in score from baseline of at least 0.5 points is achieved by the subject on the Brigham Eyelash Tool for Alopecia (BELA) or the Brigham Eyebrow Tool for Alopecia (BETA).

89. The method of any one of claims 44 to 88, wherein the subject is a human.

90. 90. The method of claim 89, wherein the subject is an adult human.

91. 91. The method of any one of claims 1 to 90, wherein 16 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof is administered.

92. 92. The method of claim 91, wherein the 16 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof is administered as 8 mg twice per day.

93. 1. A method of treating alopecia areata, said method comprising: a) determining the estimated glomerular filtration rate (eGFR) of a population of subjects suffering from alopecia areata; and b) orally administering 16 mg / day or 24 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof at a flow rate of ≧30 mL / min to a subgroup of said population of subjects with eGFR for MDRD; Compound (I) is represented by the following structural formula: 【Chemistry 4】 A method wherein each position specifically designated as deuterium has at least 95% incorporation of deuterium.

94. A method of treating alopecia areata, comprising orally administering 16 mg / day or 24 mg / day of compound (I) or a pharmaceutically acceptable salt thereof at a flow rate of ≧30 mL / min to a subgroup of said population of subjects with eGFR for MDRD, wherein compound (I) is represented by the following structural formula: 【Transformation 5】 A method wherein each position specifically designated as deuterium has at least 95% incorporation of deuterium.

95. 95. The method of claim 93 or 94, wherein said subgroup of said population of subjects has moderate renal impairment (eGFR of 30-59 mL / min, MDRD).

96. 95. The method of claim 93 or 94, wherein the eGFR of the subgroup of the population of subjects is between > 30 mL / min MDRD and < 60 mL / min MDRD.

97. 95. The method of claim 93 or 94, wherein the eGFR of the subgroup of the population of subjects is between > 60 mL / min MDRD and < 90 mL / min MDRD.

98. 98. The method of any one of claims 93 to 97, wherein said subgroup of said population of subjects has an absolute SALT score of ≧50 at the start of treatment.

99. 98. The method of any one of claims 93 to 97, wherein said subgroup of said population of subjects has moderate to severe alopecia areata at the start of treatment.

100. 98. The method of any one of claims 93 to 97, wherein said subgroup of said population of subjects has severe alopecia areata at the start of treatment.

101. 101. The method of any one of claims 93-100, wherein after 12 weeks of treatment, at least 5% of said subgroup of said population of subjects has an absolute SALT score of ≦20.

102. 101. The method of any one of claims 93-100, wherein after 16 weeks of treatment, at least 10% of said subgroup of said population of subjects has an absolute SALT score of ≦20.

103. 101. The method of any one of claims 93-100, wherein after 20 weeks of treatment, at least 20% of said subgroup of said population of subjects has an absolute SALT score of ≦20.

104. 101. The method of any one of claims 93-100, wherein after 24 weeks of treatment, at least 25% of said subgroup of said population of subjects has an absolute SALT score of ≦20.

105. 101. The method of claims 93-100, wherein after 24 weeks of treatment, at least 15% of said subgroup of said population of subjects has an absolute SALT score of ≦10.

106. 101. The method of any one of claims 93-100, wherein after 52 weeks of treatment, at least 50% of said subgroup of said population of subjects has an absolute SALT score of ≦20.

107. 101. The method of any one of claims 93-100, wherein after 24 weeks of treatment, at least 30% of said subgroup of said population of subjects has a relative reduction in SALT score of at least 75%.

108. 101. The method of any one of claims 93-100, wherein after 12 weeks of treatment, at least 7% of said subgroup of said population of subjects has a relative reduction in SALT score of at least 75%.

109. 101. The method of any one of claims 93-100, wherein after 24 weeks of treatment, at least 20% of said subgroup of said population of subjects has a relative reduction in SALT score of at least 90%.

110. 101. The method of any one of claims 93-100, wherein after 12 weeks of treatment, at least 1.5% of said subgroup of said population of subjects has a relative reduction in SALT score of at least 90%.

111. 101. The method of any one of claims 93-100, wherein after 24 weeks of treatment, at least 35% of said subgroup of said population of subjects report a response of "satisfied" or "very satisfied" on the Hair Satisfaction Patient-Reported Outcome (SPRO) scale.

112. 101. The method of any one of claims 93-100, wherein after 12 weeks of treatment, at least 35% of said subgroup of said population of subjects report a response of "satisfied" or "very satisfied" on the Hair Satisfaction Patient-Reported Outcome (SPRO) scale.

113. 101. The method of any one of claims 93-100, wherein after 12 weeks of treatment, a reduction in score from baseline of at least 1.5 points is reported by said subgroup of said population of subjects on the Satisfaction with Hair Patient-Reported Outcome (SPRO) scale.

114. 101. The method of any one of claims 93-100, wherein after 12 weeks of treatment, a reduction in score from baseline of ≧2 points on the Satisfaction with Hair Patient-Reported Outcome (SPRO) scale is reported by at least 45% of said subgroup of said population of subjects.

115. 101. The method of any one of claims 93-100, wherein after 24 weeks of treatment, at least 50% of said subgroup of said population of subjects reports a response of "much improved" or "very much improved" using the Patient Global Impression of Improvement (PGI-I).

116. 101. The method of any one of claims 93-100, wherein after 12 weeks of treatment, at least 30% of said subgroup of said population of subjects reports a response of "much improved" or "very much improved" using the Patient Global Impression of Improvement (PGI-I).

117. 101. The method of any one of claims 93-100, wherein after 16 weeks of treatment, at least 40% of said subgroup of said population of subjects reports a response of "much improved" or "very much improved" using the Patient Global Impression of Improvement (PGI-I).

118. 101. The method of any one of claims 93-100, wherein after 20 weeks of treatment, at least 45% of said subgroup of said population of subjects reports a response of "much improved" or "very much improved" using the Patient Global Impression of Improvement (PGI-I).

119. 101. The method of any one of claims 93-100, wherein after 12 weeks of treatment, a reduction in score from baseline of at least 1.5 points is reported on the Patient Global Impression of Improvement (PGI-I) by said subgroup of said population of subjects.

120. 101. The method of any one of claims 93-100, wherein after 16 weeks of treatment, a reduction in score from baseline of at least 1.7 points is reported on the Patient Global Impression of Improvement (PGI-I) by said subgroup of said population of subjects.

121. 101. The method of any one of claims 93-100, wherein after 24 weeks of treatment, a reduction in score from baseline of at least 2.1 points from baseline is reported on the Patient Global Impression of Improvement (PGI-I) by said subgroup of said population of subjects.

122. 101. The method of any one of claims 93-100, wherein after 24 weeks of treatment, at least 50% of said subgroup of said population of subjects reports a response of "much improved" or "very much improved" using the Clinical Global Impression of Improvement (CGI-I).

123. 101. The method of any one of claims 93-100, wherein after 12 weeks of treatment, at least 30% of said subgroup of said population of subjects reports a response of "much improved" or "very much improved" using the Clinical Global Impression of Improvement (CGI-I).

124. 101. The method of any one of claims 93-100, wherein after 16 weeks of treatment, at least 40% of said subgroup of said population of subjects reports a response of "much improved" or "very much improved" using the Clinical Global Impression of Improvement (CGI-I).

125. 101. The method of any one of claims 93-100, wherein after 20 weeks of treatment, at least 45% of said subgroup of said population of subjects reports a response of "much improved" or "very much improved" using the Clinical Global Impression of Improvement (CGI-I).

126. 101. The method of any one of claims 93-100, wherein after 12 weeks of treatment, a reduction in score from baseline of at least 1.0 point is reported on the Clinical Global Impression of Severity (CGI-S) by said subgroup of said population of subjects.

127. 101. The method of any one of claims 93-100, wherein after 16 weeks of treatment, a reduction in score from baseline of at least 1.5 points is reported on the Clinical Global Impression of Severity (CGI-S) by said subgroup of said population of subjects.

128. 101. The method of any one of claims 93-100, wherein after 24 weeks of treatment, a reduction in score from baseline of at least 2.0 points is reported on the Clinical Global Impression of Severity (CGI-S) by said subgroup of said population of subjects.

129. 101. The method of any one of claims 93-100, wherein after 24 weeks of treatment an increase in score from baseline of at least 1.0 is achieved on the Brigham Eyelash Tool for Alopecia (BELA) or the Brigham Eyebrow Tool for Alopecia (BETA) by said subgroup of said population of subjects.

130. 101. The method of any one of claims 93 to 100, wherein after 12 weeks of treatment an increase in score from baseline of at least 0.5 points is achieved on the Brigham Eyelash Tool for Alopecia (BELA) or the Brigham Eyebrow Tool for Alopecia (BETA) by said subgroup of said population of subjects.

131. 131. The method of any one of claims 93 to 130, wherein said population of subjects is human.

132. 132. The method of claim 131, wherein the human is an adult.

133. 131. The method of any one of claims 93 to 130, wherein 16 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof is administered.

134. 134. The method of claim 133, wherein the 16 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof is administered as 8 mg twice per day.

135. 1. A method of treating alopecia areata, said method comprising: a) orally administering 16 mg / day or 24 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof to a population of subjects for a first period of 24 weeks of treatment, wherein after said first period at least 30% of said population of subjects has a SALT score of ≦20; b) continuing to orally administer 16 mg / day or 24 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof to the population of subjects after completion of the first period of 24 weeks of treatment for a second period of treatment of at least an additional 52 weeks, wherein after the second period of treatment at least 50% of the population of subjects have a SALT score of ≦20; Compound (I) is represented by the following structural formula: 【Transformation 6】 A method wherein each position specifically designated as deuterium has at least 95% incorporation of deuterium.

136. 136. The method of claim 135, wherein the subject has an absolute SALT score of ≧50 at the start of treatment.

137. 136. The method of claim 135, wherein the subject has moderate to severe alopecia areata at the start of treatment.

138. 136. The method of claim 135, wherein the subject has severe alopecia areata at the start of treatment.

139. 139. The method of any one of claims 135 to 138, wherein the administration during the first period and the second period is sequential.

140. 139. The method of any one of claims 135 to 138, wherein the second period of time is at least 60 weeks.

141. 139. The method of any one of claims 135 to 138, wherein the second period of time is at least 65 weeks.

142. 139. The method of any one of claims 135 to 138, wherein the second period of time is at least 70 weeks.

143. 139. The method of any one of claims 135 to 138, wherein the second period of time is at least 75 weeks.

144. 139. The method of any one of claims 135 to 138, wherein the second period of time is at least 80 weeks.

145. 139. The method of any one of claims 135 to 138, wherein the second period of time is at least 85 weeks.

146. 139. The method of any one of claims 135 to 138, wherein the second period of time is at least 90 weeks.

147. 139. The method of any one of claims 135 to 138, wherein the second period of time is at least 95 weeks.

148. 139. The method of any one of claims 135 to 138, wherein the second period of time is at least 100 weeks.

149. 139. The method of any one of claims 135-138, wherein after the second period of treatment, at least 60% of the population of subjects has a SALT score of ≦20.

150. 139. The method of any one of claims 135-138, wherein after the second period of treatment, at least 70% of the population of subjects has a SALT score of ≦20.

151. 139. The method of any one of claims 135-138, wherein after the second period of treatment, at least 74% of the population of subjects has a SALT score of ≦20.

152. 139. The method of any one of claims 135-138, wherein after the second period of treatment, at least 80% of the population of subjects has a SALT score of ≦20.

153. 139. The method of any one of claims 135-138, wherein after the second period of treatment, at least 85% of the population of subjects has a SALT score of ≦20.

154. 139. The method of any one of claims 135-138, wherein after said second period of treatment, at least 90% of said population of subjects has a SALT score of ≦20.

155. 139. The method of any one of claims 135 to 138, wherein said population of subjects is human.

156. 156. The method of claim 155, wherein the population of subjects is adult humans.

157. 157. The method of any one of claims 135 to 156, wherein 16 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof is administered.

158. 158. The method of claim 157, wherein the 16 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof is administered as 8 mg twice a day.

159. 1. A method of treating alopecia areata in a subject in need thereof, comprising orally administering 16 mg / day or 24 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof to the subject for a first period of 24 weeks, and then determining whether the subject's SALT score has decreased to ≦20, and if not, continuing the administration of Compound (I) for a second period of 52 weeks, such that after 52 weeks of treatment the subject achieves a SALT score of ≦20; 【Transformation 7】 A method wherein each position specifically designated as deuterium has at least 95% incorporation of deuterium.

160. 1. A method of treating alopecia areata in a subject in need thereof, the method comprising orally administering to the subject 16 mg / day or 24 mg / day of compound (I) or a pharmaceutically acceptable salt thereof, wherein compound (I) is represented by the following structural formula: 【Transformation 8】 each position specifically designated as deuterium has at least 95% incorporation of deuterium; and The method, wherein the subject has anxiety and / or depression.

161. 161. The method of claim 160, wherein the presence of symptoms of anxiety and depression is determined based on the subject's completion of a Hospital Anxiety and Depression Scale (HADS) patient outcome test.

162. 161. The method of claim 160, wherein the subject has a baseline score of >7 on the anxiety or depression subscale of the Hospital Anxiety and Depression Scale (HADS).

163. 163. The method of any one of claims 160 to 162, wherein the subject has a moderate presence of anxiety and depression symptoms as indicated by a score of between 8 and 10 on the anxiety or depression subscale of the Hospital Anxiety and Depression Scale (HADS) prior to administration of compound (I).

164. 163. The method of any one of claims 160 to 162, wherein the subject has, prior to administration of compound (I), the presence of severe symptoms of anxiety and depression as indicated by a score of greater than 11 on the anxiety and depression subscales of the Hospital Anxiety and Depression Scale (HADS).

165. 164. The method of any one of claims 160-163, wherein the subject has a reduction in global score from baseline of at least 1.0 point as reported by the subject on the Hospital Anxiety and Depression Scale (HADS) after 12 weeks of treatment.

166. 164. The method of any one of claims 160-163, wherein the subject has a reduction in global score from baseline of 3.0 points as reported by the subject on the Hospital Anxiety and Depression Scale (HADS) after 12 weeks of treatment.

167. 164. The method of any one of claims 160-163, wherein the subject has a reduction in global score from baseline of at least 2.0 points as reported by the subject on the Hospital Anxiety and Depression Scale (HADS) after 16 weeks of treatment.

168. 164. The method of any one of claims 160-163, wherein the subject has a reduction in global score from baseline of 4.0 points as reported by the subject on the Hospital Anxiety and Depression Scale (HADS) after 16 weeks of treatment.

169. 164. The method of any one of claims 160-163, wherein the subject has a reduction in global score from baseline as reported by the subject on the Hospital Anxiety and Depression Scale (HADS) of at least 6.0 points after 24 weeks of treatment.

170. 164. The method of any one of claims 160-163, wherein the subject has a reduction in global score from baseline as reported by the subject on the Hospital Anxiety and Depression Scale (HADS) of at least 10.0 points after 24 weeks of treatment.

171. 166. The method of any one of claims 160-165, wherein the subject has a reduction in Hospital Anxiety and Depression Scale-Anxiety (HADS-A) subscale score of at least 1.0 point from baseline as reported by the subject on the Hospital Anxiety and Depression Scale (HADS) after 12 weeks of treatment.

172. 166. The method of any one of claims 160-165, wherein the subject has a reduction in Hospital Anxiety and Depression Scale-Anxiety (HADS-A) subscale score of at least 2.0 points from baseline as reported by the subject on the Hospital Anxiety and Depression Scale (HADS) after 12 weeks of treatment.

173. 168. The method of any one of claims 160-167, wherein the subject has a reduction in Hospital Anxiety and Depression Scale-Anxiety (HADS-A) subscale score of at least 2.0 points from baseline as reported by the subject on the Hospital Anxiety and Depression Scale (HADS) after 16 weeks of treatment.

174. 168. The method of any one of claims 160-167, wherein the subject has a reduction in Hospital Anxiety and Depression Scale-Anxiety (HADS-A) subscale score of at least 3.0 points from baseline as reported by the subject on the Hospital Anxiety and Depression Scale (HADS) after 16 weeks of treatment.

175. 170. The method of any one of claims 160-169, wherein the subject has a reduction in Hospital Anxiety and Depression Scale-Anxiety (HADS-A) subscale score of at least 4.0 points from baseline as reported by the subject on the Hospital Anxiety and Depression Scale (HADS) after 24 weeks of treatment.

176. 170. The method of any one of claims 160-169, wherein the subject has a reduction in Hospital Anxiety and Depression Scale-Anxiety (HADS-A) subscale score of at least 6.0 points from baseline as reported by the subject on the Hospital Anxiety and Depression Scale (HADS) after 24 weeks of treatment.

177. 172. The method of any one of claims 160-171, wherein the subject has a reduction in the Hospital Anxiety and Depression Scale-Depression (HADS-D) subscale score of at least 1.0 point from baseline as reported by the subject on the Hospital Anxiety and Depression Scale (HADS) after 12 weeks of treatment.

178. 172. The method of any one of claims 160-171, wherein the subject has a reduction in the Hospital Anxiety and Depression Scale-Depression (HADS-D) subscale score of at least 2.0 points from baseline as reported by the subject on the Hospital Anxiety and Depression Scale (HADS) after 12 weeks of treatment.

179. 174. The method of any one of claims 160-173, wherein the subject has a reduction in Hospital Anxiety and Depression Scale-Depression (HADS-D) subscale score of at least 2.0 points from baseline as reported by the subject on the Hospital Anxiety and Depression Scale (HADS) after 16 weeks of treatment.

180. 174. The method of any one of claims 160-173, wherein the subject has a reduction in Hospital Anxiety and Depression Scale-Depression (HADS-D) subscale score of at least 3.0 points from baseline as reported by the subject on the Hospital Anxiety and Depression Scale (HADS) after 16 weeks of treatment.

181. 176. The method of any one of claims 160-175, wherein the subject has a reduction in Hospital Anxiety and Depression Scale-Depression (HADS-D) subscale score of at least 3.0 points from baseline as reported by the subject on the Hospital Anxiety and Depression Scale (HADS) after 24 weeks of treatment.

182. 176. The method of any one of claims 160-175, wherein the subject has a reduction in Hospital Anxiety and Depression Scale-Depression (HADS-D) subscale score of at least 5.0 points from baseline as reported by the subject on the Hospital Anxiety and Depression Scale (HADS) after 24 weeks of treatment.

183. 183. The method of any one of claims 160-182, wherein the subject has completed an additional primary diagnostic test used to diagnose anxiety and / or depression prior to treatment for alopecia areata.

184. 184. The method of claim 183, wherein the additional test is the Generalized Anxiety Disorder Questionnaire (GAD-7), the Hamilton Anxiety Rating Scale (HAM-A), the Patient Health Questionnaire (PHQ), the Beck Depression Inventory (BDI), the Center for Epidemiologic Studies Depression Scale (CES-D), the EQ-5D, the Hamilton Depression Rating Scale (HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), or a combination thereof.

185. The method of any one of claims 160 to 184, wherein the subject is a human.

186. 186. The method of claim 185, wherein the subject is an adult human.

187. 187. The method of any one of claims 160 to 186, wherein the subject has moderate to severe alopecia areata at the start of treatment.

188. 188. The method of any one of claims 160 to 187, wherein the subject has severe alopecia areata at the start of treatment.

189. 1. A method of treating alopecia areata in a population of subjects in need thereof, said method comprising: orally administering 16 mg / day or 24 mg / day of Compound (I) or a pharmaceutically acceptable salt thereof to said population of subjects, wherein Compound (I) is represented by the following structural formula: 【Chemistry 9】 wherein each position specifically designated as deuterium has at least 95% incorporation of deuterium, and wherein said compound (I) is administered to said population of subjects for at least 52 weeks, and wherein said administration of compound (I) results in maintaining a SALT score of ≦20 in at least 50% of said population of subjects.

190. 190. The method of treating alopecia areata according to claim 189, wherein compound (I) is administered to the subject for at least 68 weeks.

191. 190. The method of treating alopecia areata according to claim 189, wherein compound (I) is administered to the subject for at least 76 weeks.

192. 1. A method of treating alopecia areata in a subject in need thereof, said method comprising: The method comprises orally administering to the subject 16 mg / day or 24 mg / day of compound (I) or a pharmaceutically acceptable salt thereof, wherein compound (I) is represented by the following structural formula: 【Chemistry 10】 wherein each position specifically designated as deuterium has at least 95% incorporation of deuterium, and wherein said compound (I) is administered to said subject for at least 52 weeks, and wherein said administration of compound (I) results in a sustained relative reduction in SALT score of at least 50%.

193. 193. The method of treating alopecia areata according to claim 192, wherein compound (I) is administered to the subject for at least 68 weeks.

194. 193. The method of treating alopecia areata according to claim 192, wherein compound (I) is administered to the subject for at least 76 weeks.

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