Methods of treating TTR amyloidosis using AG10
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Publication Number
US-12070449-B2
Publication Date
2024-08-27
Expiration Date
Abstract
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
Core Innovation
The patent discloses orally administering Compound 1 (AG10) to treat transthyretin amyloidosis (ATTR) cardiomyopathy, including ATTR-CM, wild-type ATTR cardiomyopathy (ATTRwt-CM), and variant/familial ATTR cardiomyopathy (ATTRm-CM). The disclosed regimen uses Compound 1 in HCl salt form or an equivalent amount in freebase or in a different salt form, at a total daily dosage of about 1,600 milligrams administered twice daily.
The disclosure describes clinical and biomarker effects assessed using NYHA class, Kansas City Cardiomyopathy Questionnaire (KCCQ), EuroQoL-5 Dimensions (EQ-5D-5L), 6-minute walk test, troponins, BNP/N-terminal pro-BNP, hospitalization frequency, and mortality. It also ties pharmacodynamic outcomes to TTR target engagement and pharmacological action, including FPE (Fluorescent Probe Exclusion) occupancy and TTR tetramer stabilization, with prior or expected serum TTR concentration increases.
The invention further describes AG10 HCl pharmacodynamic target engagement and time-dependent, dose-responsive TTR tetramer stabilization in human cohorts, with stabilization observed up to 12 hr post-dose and sustained target engagement after 12 days. It also presents binding thermodynamics characterized by ITC-based binding thermodynamics, including enthalpy versus entropy, selectivity in serum proteins including albumin, mechanistic considerations using T4 binding site interactions, and mechanistic mimicry through hydrogen bonding to S117/S117′.
Claims Coverage
The provided independent claims cover orally administering Compound 1 to treat or slow progression of transthyretin amyloidosis (ATTR) cardiomyopathy at a specified total daily dose with a twice-daily regimen, using Compound 1 in HCl salt form or an equivalent amount in freebase or a different salt form. Across the claim sets, the core claim coverage centers on this oral dosing regimen, with dependent claim features adding measurable clinical and biomarker outcomes and patient subtype limitations.
Oral twice-daily dosing of Compound 1 HCl salt at about 1,600 mg total daily dose
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, and 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.
Treating or slowing progression of ATTR cardiomyopathy
Orally administering Compound 1 in HCl salt form or an equivalent amount of Compound 1 in freebase or in a different salt form to treat transthyretin amyloidosis (ATTR) cardiomyopathy or slow progression of transthyretin amyloidosis (ATTR) cardiomyopathy.
Reducing mortality using Compound 1 in HCl salt form or equivalent freebase/different salt
Administering Compound 1 in HCl salt form or an equivalent amount of Compound 1 in freebase or in a different salt form to reduce mortality compared with subjects who did not receive Compound 1 or did not receive the equivalent amount in freebase or a different salt form.
Increasing blood serum TTR concentration by at least 10% after 28 days
Administering Compound 1 as an HCl salt form or an equivalent amount as freebase or another salt increases transthyretin (TTR) blood serum concentration by at least 10% relative to baseline after 28 days of treatment.
Improving performance on a six-minute walk test
Administering Compound 1 in an HCl salt form or an equivalent amount in freebase or another salt form improves and/or reduces the decline in performance on a six-minute walk test compared with untreated subjects.
Using an ATTRv-CM with a V122I TTR mutation
Administering Compound 1 in a method characterized by using an ATTRv-CM having a transthyretin (TTR) protein with a V122I mutation at position 122.
Across the independent claims, the core claim coverage is the oral administration of Compound 1 at about 1,600 mg total daily dose, twice daily, with dosing provided as Compound 1 in HCl salt form or an equivalent amount in freebase or another salt form. Dependent claims further specify outcomes such as mortality reduction, TTR serum concentration increase, functional effects on a six-minute walk test, and a V122I mutation patient population.
Stated Advantages
Reducing mortality.
Increasing blood serum transthyretin (TTR) concentration by at least 10% after 28 days.
Improving and/or reducing the decline in performance on a six-minute walk test.
Slowing the progression of transthyretin amyloidosis (ATTR) cardiomyopathy.
Documented Applications
Treating transthyretin amyloidosis (ATTR) cardiomyopathy in a subject in need thereof.
Slowing the progression of transthyretin amyloidosis (ATTR) cardiomyopathy in a subject in need thereof.
Assessing clinical and biomarker effects in ATTR-CM including functional measures, biomarkers, hospitalization frequency, and mortality.
Studying pharmacokinetics/pharmacodynamics via first-in-human SAD/MAD in healthy volunteers and a planned Phase 2 in ATTR-CM.
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