Methods of treating TTR amyloidosis using AG10
Described herein are methods for treating transthyretin (TTR) amyloidosis in a subject. The methods include specific dosing regimens that have great efficacy in treating the subjects and that are well tolerated in subjects
1. A method of treating transthyretin amyloidosis (ATTR) cardiomyopathy in a subject in need thereof, the method comprising orally administering to a subject in need thereof a total daily dosage of about 1,600 milligrams (mg) of Compound 1 in HCl salt form or an equivalent amount of Compound 1 in freebase or in a different salt form, wherein Compound 1 has the Formula:
wherein Compound 1 in HCl salt form or an equivalent amount of Compound 1 in freebase or in a different salt form is administered twice daily.
2. The method of claim 1 , wherein administration of Compound 1 in HCl salt form or an equivalent amount of Compound 1 in freebase or in a different salt form improves and/or reduces the decline in a six-minute walk test compared to subjects who did not receive treatment with Compound 1 in HCl salt form or an equivalent amount of Compound 1 in freebase or in a different salt form.
3. The method of claim 1 , wherein the subject maintains about the same six minute walking distance as prior to treatment with Compound 1 in HCl salt form or an equivalent amount of Compound 1 in freebase or in a different salt form.
4. The method of claim 1 , wherein the ATTR cardiomyopathy is wild-type ATTR cardiomyopathy (ATTRwt-CM).
5. The method of claim 1 , wherein the ATTR cardiomyopathy is variant ATTR cardiomyopathy (ATTRv-CM).
6. The method of claim 5 , wherein the ATTRv-CM is characterized by a transthyretin (TTR) protein that comprises a valine to isoleucine mutation at position 122 (V122I).
7. The method of claim 5 , wherein the ATTRv-CM is characterized by a transthyretin (TTR) protein that comprises a threonine to proline mutation at position 49 (T49P) ), a valine to methionine mutation at position 30 (V30M), a threonine to alanine mutation at position 60 (T60A), a proline to serine mutation at position 24 (P24S), an aspartic acid to alanine mutation at position 38 (D38A), or a leucine to histidine mutation at position 58 (L58H).
8. A method of slowing the progression of transthyretin amyloidosis (ATTR) cardiomyopathy in a subject in need thereof, the method comprising orally administering to a subject in need thereof a total daily dosage of about 1,600 milligrams (mg) of Compound 1 in HCl salt form or an equivalent amount of Compound 1 in freebase or in a different salt form, wherein Compound 1 has the Formula:
wherein Compound 1 in HCl salt form or an equivalent amount of Compound 1 in freebase or in a different salt form is administered twice daily.
9. The method of claim 1 , wherein the administration of Compound 1 in HCl salt form or an equivalent amount of Compound 1 in freebase or in a different salt form decreases the frequency of cardiovascular-related hospitalizations as compared to subjects who did not receive treatment with Compound 1 in HCl salt form or an equivalent amount of Compound 1 in freebase or in a different salt form.
10. The method of claim 1 , wherein the administration of Compound 1 in HCl salt form or an equivalent amount of Compound 1 in freebase or in a different salt form decreases mortality as compared to subjects who did not receive treatment with Compound 1 in HCl salt form or an equivalent amount of Compound 1 in freebase or in a different salt form.
11. The method of claim 10 , wherein mortality is reduced by about 6% as compared to subjects who did not receive treatment with Compound 1 in HCl salt form or an equivalent amount of Compound 1 in freebase or in a different salt form after 30 months of administration.
12. The method of claim 10 , wherein mortality is reduced by about 10% as compared to subjects who did not receive treatment with Compound 1 in HCl salt form or an equivalent amount of Compound 1 in freebase or in a different salt form after 30 months of administration.
13. The method of claim 10 , wherein mortality is reduced by about 24% as compared to subjects who did not receive treatment with Compound 1 in HCl salt form or an equivalent amount of Compound 1 in freebase or in a different salt form after 30 months of administration.
14. The method of claim 10 , wherein Compound 1 in HCl salt form or an equivalent amount of Compound 1 in freebase or in a different salt form is in HCl salt form.
15. The method of claim 1 , wherein the administration of Compound 1 in HCl salt form or an equivalent amount of Compound 1 in freebase or in a different salt form increases transthyretin (TTR) blood serum concentration relative to a baseline level.
16. The method of claim 1 , wherein the administration of Compound 1 in HCl salt form or an equivalent amount of Compound 1 in freebase or in a different salt form increases transthyretin (TTR) blood serum concentration by at least 10% relative to a baseline level after 28 days of treatment.
17. The method of claim 1 , wherein the administration of Compound 1 in HCl salt form or an equivalent amount of Compound 1 in freebase or in a different salt form decreases serum blood levels of N-terminal pro-brain natriuretic peptide (N-terminal pro-BNP).
18. The method of claim 17 , wherein serum blood levels of N-terminal pro-BNP of the subject decreases at least 10% after 30 months of administration as compared to a baseline level of N-terminal pro-BNP in the subject prior to treatment with Compound 1 in HCl salt form or an equivalent amount of Compound 1 in freebase or in a different salt form.
19. The method of claim 1 , wherein the administration of Compound 1 in HCl salt form or an equivalent amount of Compound 1 in freebase or in a different salt form improves, stabilizes or delays worsening in the Kansas City Cardiomyopathy Questionnaire (KCCQ) classification of subjects.
20. The method of claim 19 , wherein subjects have an average improvement of at least one level in the Kansas City Cardiomyopathy Questionnaire (KCCQ) classification of subjects.