Methods of treating skeletal dysplasias

Abstract

Provided herein are methods of treating a skeletal dysplasia such as hypochondroplasia or achondroplasia in a subject in need thereof. The methods generally comprise administering to the subject an effective amount of infigratinib, or a pharmaceutically acceptable salt thereof. Also provided herein are minitablets comprising infigratinib monophosphate and a pharmaceutically acceptable excipient for use in treating a skeletal dysplasia, such as hypochondroplasia or achondroplasia, in a subject in need thereof.

Description

This article provides methods for treating skeletal dysplasia (such as achondroplasia or chondrodysplasia) in patients of need. These methods typically involve administering an effective amount of infraglatinib or a pharmaceutically acceptable salt thereof to the patient. This article also provides microtablets containing infraglatinib monophosphate and pharmaceutically acceptable excipients for the treatment of skeletal dysplasia (such as achondroplasia or chondrodysplasia). Abstract

Claims

CLAIMSWe claim:

1. A method of treating achondroplasia or hypochondroplasia in a subject in need thereof, comprising orally administering daily to the subject about 0.250 milligrams per kilogram (mg / kg) of infigratinib, or a pharmaceutically acceptable salt thereof.

2. A method of treating achondroplasia or hypochondroplasia in a subject in need thereof, comprising orally administering daily to the subject about 2.5 milligrams (mg) to about 20.0 mg of infigratinib, or a pharmaceutically acceptable salt thereof.

3. The method of claim 2, wherein about 2.5 mg of infigratinib, or a pharmaceutically acceptable salt thereof, is administered daily to the subject.

4. The method of claim 3, wherein the subject’s weight is less than about 12 kilograms (kg).

5. The method of claim 2, wherein about 3.5 mg of infigratinib, or a pharmaceutically acceptable salt thereof, is administered daily to the subject.

6. The method of claim 5, wherein the subject’s weight is between about 12 kg to about 15 kg.

7. The method of claim 2, wherein about 5.0 mg of infigratinib, or a pharmaceutically acceptable salt thereof, is administered daily to the subject.

8. The method of claim 7, wherein the subject’s weight is between about 16 kg and about 22 kg.

9. The method of claim 2, wherein about 7.0 mg of infigratinib, or a pharmaceutically acceptable salt thereof, is administered daily to the subject.

10. The method of claim 9, wherein the subject’s weight is between about 23 kg and about11. The method of claim 2, wherein about 10.0 mg of infigratinib, or a pharmaceutically acceptable salt thereof, is administered daily to the subject.

12. The method of claim 11, wherein the subject’s weight is between about 32 kg and about 43 kg.

13. The method of claim 2, wherein about 14.0 mg of infigratinib, or a pharmaceutically acceptable salt thereof, is administered daily to the subject.

14. The method of claim 13, wherein the subject’s weight is between about 44 kg and about 70 kg.

15. The method of claim 2, wherein about 20.0 mg of infigratinib, or a pharmaceutically acceptable salt thereof, is administered daily to the subject.

16. The method of claim 15, wherein the subject’s weight is at least about 70 kg.

17. The method of any one of claims 1-16, wherein the subject has achondroplasia.

18. The method of any one of claims 1-17, wherein the subject has hypochondroplasia.

19. The method of any one of claims 1-18, wherein the subject has an FGFR3 mutation.

20. The method of claim 19, wherein the FGFR3 mutation is a G380R mutation or N540K mutation.

21. The method of any one of claims 1-20, wherein the infigratinib, or a pharmaceutically acceptable salt thereof, is administered as minitablets, and wherein each minitablet comprises about 0. 1 mg or about 1 mg of infigratinib, or a pharmaceutically acceptable salt thereof.

22. The method of any one of claims 1-21, wherein the pharmaceutically acceptable salt of infigratinib is infigratinib monophosphate.

23. The method of claim 22, wherein the infigratinib monophosphate is present as an anhydrous crystalline form.

24. The method of claim 23, wherein the anhydrous crystalline form of infigratinib monophosphate is characterized by an XRPD peak (2 theta) at 15.0° ± 0.2°.

25. The method of any one of claims 1-24, wherein, after daily administration of the infigratinib, or a pharmaceutically acceptable salt thereof, the subject exhibits increased height velocity relative to baseline.

26. The method of any one of claims 1-25, wherein, after daily administration of the infigratinib, or a pharmaceutically acceptable salt thereof, the subject exhibits an increase in absolute height velocity.

27. The method of any one of claims 1-26, wherein during or after the treating, the subject has a mean change from baseline in annualized height velocity (AHV) of at least about 2.0 centimeters per year (cm / yr).

28. The method of any one of claims 1-26, wherein during or after the treating, the subject has a change from baseline in AHV of between about 1.0 cm / yr and about 14 cm / yr.

29. The method of claim 28, wherein during or after the treating, the subject has a change from baseline in AHV of between about 2.5 cm / yr and about 4.5 cm / yr.

30. The method of any one of claims 1-26, wherein during or after the treating, the subject has a change from baseline in AHV of about 1.0 cm / yr, about 1.1 cm / yr, about 1.2 cm / yr, about 1.3 cm / yr, about 1.4 cm / yr, about 1.5 cm / yr, about 1.6 cm / yr, about 1.7 cm / yr, about 1.8 cm / yr, about 1.9 cm / yr, about 2.0 cm / yr, about 2.1 cm / yr, about 2.2 cm / yr, about 2.3 cm / yr, about 2.4 cm / yr, about 2.5 cm / yr, about 2.6 cm / yr, about 2.7 cm / yr,about 2.8 cm / yr, about 2.9 cm / yr, about 3.0 cm / yr, about 3.1 cm / yr, about 3.2 cm / yr, about 3.3 cm / yr, about 3.4 cm / yr, about 3.5 cm / yr, about 3.6 cm / yr, about 3.7 cm / yr, about 3.8 cm / yr, about 3.9 cm / yr, about 4.0 cm / yr, about 4.1 cm / yr, about 4.2 cm / yr, about 4.3 cm / yr, about 4.4 cm / yr, about 4.5 cm / yr, about 4.6 cm / yr, about 4.7 cm / yr, about 4.8 cm / yr, about 4.9 cm / yr, about 5.0 cm / yr, about 5.1 cm / yr, about 5.2 cm / yr, about 5.3 cm / yr, about 5.4 cm / yr, about 5.5 cm / yr, about 5.6 cm / yr, about 5.7 cm / yr, about 5.8 cm / yr, about 5.9 cm / yr, about 6.0 cm / yr, about 6.1 cm / yr, about 6.2 cm / yr, about 6.3 cm / yr, about 6.4 cm / yr, about 6.5 cm / yr, about 6.6 cm / yr, about 6.7 cm / yr, about 6.8 cm / yr, about 6.9 cm / yr, about 7.0 cm / yr, about 7.1 cm / yr, about 7.2 cm / yr, about 7.3 cm / yr, about 7.4 cm / yr, about 7.5 cm / yr, about 7.6 cm / yr, about 7.7 cm / yr, about 7.8 cm / yr, about 7.9 cm / yr, about 8.0 cm / yr, about 8.1 cm / yr, about 8.2 cm / yr, about 8.3 cm / yr, about 8.4 cm / yr, about 8.5 cm / yr, about 8.6 cm / yr, about 8.7 cm / yr, about 8.8 cm / yr, about 8.9 cm / yr, about 9.0 cm / yr, about 9.1 cm / yr, about 9.2 cm / yr, about 9.3 cm / yr, about 9.4 cm / yr, about 9.5 cm / yr, about 9.6 cm / yr, about 9.7 cm / yr, about 9.8 cm / yr, about 9.9 cm / yr, about 10.0 cm / yr, about 10.1 cm / yr, about 10.2 cm / yr, about 10.3 cm / yr, about 10.4 cm / yr, about 10.5 cm / yr, about 10.6 cm / yr, about 10.7 cm / yr, about 10.8 cm / yr, about 10.9 cm / yr, about 11.0 cm / yr, about 11.1 cm / yr, about 11.2 cm / yr, about 11.3 cm / yr, about 11.4 cm / yr, about 11.5 cm / yr, about 11.6 cm / yr, about 11.7 cm / yr, about 11.8 cm / yr, about 11.9 cm / yr, about 12.0 cm / yr, about 12.1 cm / yr, about 12.2 cm / yr, about 12.3 cm / yr, about 12.4 cm / yr, about 12.5 cm / yr, about 12.6 cm / yr, about 12.7 cm / yr, about 12.8 cm / yr, about 12.9 cm / yr, about 13.0 cm / yr, about 13.1 cm / yr, about 13.2 cm / yr, about 13.3 cm / yr, about 13.4 cm / yr, about 13.5 cm / yr, about 13.6 cm / yr, about 13.7 cm / yr, about 13.8 cm / yr, about 13.9 cm / yr, or about 14.0 cm / yr.

31. The method of claim 30, wherein, during or after the treating, the subject has a change from baseline in AHV of about 3.0 cm / yr.

32. The method of claim 30, wherein, during or after the treating, the subject has a change from baseline in AHV of about 4.0 cm / yr.

33. The method of any one of claims 1-26, wherein during or after the treating, the subject has an absolute AHV of at least about 2.0 centimeters per year (cm / yr).

34. The method of claim 33, wherein, during or after the treating, the subject has an absolute AHV of at least about 7.0 cm / yr.

35. The method of any one of claims 1-26, wherein, during or after the treating, the subject has an absolute AHV of between about 1.0 cm / yr and about 14 cm / yr.

36. The method of any one of claims 1-35, during or after the treating, the subject does not experience a treatment-related adverse event.

37. The method of claim 36, wherein, during or after the treating, the subject does not experience a serious adverse event.

38. The method of any one of claims 1-37, wherein, after daily administration of the infigratinib, or a pharmaceutically acceptable salt thereof, the subject exhibits an increase, relative to baseline, in an anthropometric measurement selected from the group consisting of standing height, sitting height, upper and lower arm length, thigh length, knee height, arm span, and combinations thereof.

39. The method of any one of claims 1-38, wherein, after daily administration of the infigratinib, or a pharmaceutically acceptable salt thereof, the subject exhibits an absolute increase in an anthropometric measurement selected from the group consisting of standing height, sitting height, upper and lower arm length, thigh length, knee height, arm span, and combinations thereof.

40. The method of any one of claims 1-39, wherein after daily administration of the infigratinib, or a pharmaceutically acceptable salt thereof, the subject exhibits a decrease, relative to baseline, in weight.

41. The method of any one of claims 1-40, wherein, after daily administration of the infigratinib, or a pharmaceutically acceptable salt thereof, the subject exhibits an absolute decrease in weight.

42. The method of any one of claims 1-41, wherein, after daily administration of the infigratinib, or a pharmaceutically acceptable salt thereof, the subject exhibits a proportional increase, relative to baseline, in head circumference.

43. The method of any one of claims 1-42, wherein, after daily administration of the infigratinib, or a pharmaceutically acceptable salt thereof, the subject exhibits an absolute proportional increase in head circumference.

44. The method of any one of claims 1-43, wherein, after daily administration of the infigratinib, or a pharmaceutically acceptable salt thereof, the subject exhibits a normalization, relative to baseline, of a body proportion measurement ratio.

45. The method of any one of claims 1-44, wherein, after daily administration of the infigratinib, or a pharmaceutically acceptable salt thereof, the subject exhibits an absolute normalization of a body proportion measurement ratio.

46. The method of claim 44 or 45, wherein the body proportion measurement ratio is selected from the group consisting of upper to lower body segment ratio, upper arm to forearm ratio, upper leg to lower leg length ratio, arm span to standing height ratio, head circumference to standing height ratio, and combinations thereof.

47. The method of any one of claims 1-46, wherein after daily administration of the infigratinib, or a pharmaceutically acceptable salt thereof, the pediatric patient exhibits an increase, relative to baseline, in a biomarker of bone turnover selected from the group consisting of type X collagen degradation fragment, collagen X marker, and combinations thereof.

48. The method of any one of claims 1-47, wherein, during or after the treating, the subject has a mean change in collagen X marker from baseline of at least about 5%.

49. The method of any one of claims 1-48, wherein, the subject has a mean change in collagen X marker from baseline of between about 10.0% and about 40.0%.

50. The method of any one of claims 1-49, wherein, after daily administration of the infigratinib, or a pharmaceutically acceptable salt thereof, the subject exhibits an increase, relative to baseline, in mobility.

51. The method of any one of claims 1-50, wherein after daily administration of the infigratinib, or a pharmaceutically acceptable salt thereof, the subject exhibits a decrease, relative to baseline, in the number of episodes of otitis media.

52. The method of any one of claims 1-51, wherein, after daily administration of the infigratinib, or a pharmaceutically acceptable salt thereof, the pediatric patient exhibits a decrease, relative to baseline, in the number of episodes and / or severity of sleep apnea.

53. The method of any one of claims 1-52, wherein, after daily administration of the infigratinib, or a pharmaceutically acceptable salt thereof, the pediatric patient exhibits an increase in quality of life, wherein quality of life is assessed using the Pediatric Quality of Life Inventory.

54. The method of any one of claims 1-53, wherein the subject is less than 18 years of age.

55. The method of claim 54, wherein the subject is 12 to 17 years of age.

56. The method of claim 54, wherein the subject is 3 to 11 years of age.

57. The method of claim 54, wherein the subject is 5 to 8 years of age.

58. The method of claim 54, wherein the subject is 8 to 11 years of age.

59. The method of claim 54, wherein the subject is less than 5 years of age.

60. The method of claim 54, wherein the subject is less than 12 years of age.

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