PLATELET COUNT-AGNOSTIC METHODS OF TREATING MYELOFIBROSIS
Reanalysis of the SIMPLIFY 1 and 2 trials data indicates MMB is effective in JAKi-naïve patients and in second line therapy to RUX, providing benefits of reducing enlarged spleens, improving myelofibrosis-related symptoms, and increasing transfusion independence in patient at risk for thrombocytopenia from the underlying disease and RUX therapy. Accordingly, methods of treating myeloproliferative neoplasms (MPN) such as myelofibrosis are described. The methods can include administering a therapeutically effective amount of momelotinib or a pharmaceutically acceptable salt thereof to a subject identified as having (i) myelofibrosis and (ii) a platelet count of less than 150×10 9 /L. Also described are methods including administering to a subject with myelofibrosis a therapeutically effective stable dose of momelotinib or a pharmaceutically acceptable salt thereof, for a period of a plurality of weeks, where the subject is assessed as maintaining a platelet count above a predetermined threshold platelet count during the period.
1 . A method of treating myelofibrosis in a subject, the method comprising:
administering to a subject with myelofibrosis a therapeutically effective stable dose of momelotinib or a pharmaceutically acceptable salt thereof, for a treatment period of a plurality of weeks,
wherein the subject is assessed as maintaining a platelet count above a predetermined threshold platelet count during the treatment period,
wherein the subject has a baseline platelet count of less than 150×10 9 /L, and
wherein the subject has previously been treated with a JAK inhibitor.
2 . The method according to claim 1 , wherein the predetermined threshold platelet count is at most 25% below the baseline platelet count of the subject.
3 . The method according to claim 1 , wherein the predetermined threshold platelet count is at least 25×10 9 /L.
4 . The method according to claim 1 , wherein the platelet count is a baseline platelet count determined within one week prior to initiation of momelotinib therapy, wherein the subject had not been treated with previous JAK inhibitor therapy for at least 2 weeks prior to momelotinib therapy.
5 . The method according to claim 1 , further comprising determining the level of platelets in a sample of a subject having myelofibrosis, prior to administering the momelotinib or pharmaceutically acceptable salt thereof.
6 . The method according to claim 1 , wherein the subject has previously been treated with at least one JAK inhibitor selected from the group consisting of ruxolitinib and fedratinib.
7 . The method according to claim 6 , wherein the subject has previously been treated with ruxolitinib.
8 . The method according to claim 7 , wherein the subject is an adult human who has had an inadequate response to or is intolerant of ruxolitinib.
9 . The method according to claim 7 , wherein the subject failed to respond or ceased to respond to previous ruxolitinib therapy.
10 . The method according to claim 6 , wherein the subject has previously been treated with fedratinib.
11 . The method according to claim 10 , wherein the subject is an adult human who has had an inadequate response to or is intolerant of fedratinib.
12 . The method according to claim 10 , wherein the subject failed to respond or ceased to respond to previous fedratinib therapy.
13 . The method according to claim 6 , wherein the previous treatment with at least one JAK inhibitor comprised a dose reduction of the at least one JAK inhibitor.
14 . The method according to claim 1 , wherein the myelofibrosis is intermediate or high-risk myelofibrosis.
15 . The method according to claim 14 , wherein the myelofibrosis is intermediate-2 or high-risk myelofibrosis.
16 . The method according to claim 1 , wherein the myelofibrosis is primary myelofibrosis (PMF).
17 . The method according to claim 1 , wherein the myelofibrosis is post-polycythemia vera or post-essential thrombocythemia myelofibrosis (Post-PV/ET MF).
18 . The method according to claim 1 , wherein the momelotinib or a pharmaceutically acceptable salt thereof is momelotinib dihydrochloride salt.
19 . The method according to claim 18 , wherein the momelotinib or a pharmaceutically acceptable salt thereof is momelotinib dihydrochloride monohydrate.
20 . The method according to claim 19 , wherein the momelotinib or a pharmaceutically acceptable salt thereof is momelotinib dihydrochloride monohydrate Form II.
21 . The method according to claim 20 , wherein the momelotinib dihydrochloride monohydrate Form II is a crystalline form comprising crystals having unit cell parameters at T=100° K of:
a=10.2837(6) Å, b=10.4981(6) Å, c=11.5143(7) Å, a=83.297(2)°, β=87.649(2)°, y=67.445(2)°, and a triclinic P−1 space group.
22 . The method according to claim 20 , wherein the momelotinib dihydrochloride monohydrate Form II is characterized by an X-ray powder diffraction (XRPD) pattern substantially as set forth in FIG. 19 .
23 . The method according to claim 20 , wherein the momelotinib dihydrochloride monohydrate Form II is characterized by an x-ray powder diffraction (XRPD) pattern as having peaks at about 7.7°, 19.3°, 24.0°, 25.7°, and 29.6° 2-θ±0.2° 2-θ.
24 . The method according to claim 20 , wherein the momelotinib dihydrochloride monohydrate Form II is characterized by differential scanning calorimetry (DSC) pattern substantially as set forth in FIG. 22 .
25 . The method according to claim 20 , wherein the momelotinib dihydrochloride monohydrate Form II is characterized by a dynamic vapor sorption (DVS) pattern substantially as set forth in FIG. 28 .
26 . The method according to claim 1 , wherein the momelotinib or a pharmaceutically acceptable salt thereof is administered orally.
27 . The method according to claim 1 , wherein the momelotinib or a pharmaceutically acceptable salt thereof is administered daily.
28 . The method according to claim 27 , wherein the momelotinib or a pharmaceutically acceptable salt thereof is administered once daily.
29 . The method according to claim 1 , wherein the therapeutically effective amount is between 50 mg/day and 200 mg/day.
30 . The method according to claim 29 , wherein the therapeutically effective amount is 200 mg/day.
31 . The method according to claim 29 , wherein the therapeutically effective amount is 150 mg/day.
32 . The method according to claim 29 , wherein the therapeutically effective amount is 100 mg/day.
33 . The method according to claim 29 , wherein the therapeutically effective amount is 50 mg/day.
34 . The method according to claim 1 , wherein the subject has at least a 35% reduction in spleen volume at 24 weeks of treatment, compared with a baseline spleen volume.
35 . The method according to claim 1 , wherein the subject has a baseline platelet count of from 50×10 9 /L to less than 100×10 9 /L.