Methods for treating hypertrophic cardiomyopathy
Inventors
Malik, Fady • Kupfer, Stuart • Heitner, Stephen B. • Robertson, Laura Ann • Meng, Lixin • Osmukhina, Anna • Wohltman, Qi
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12370179-B1
Publication Date
2025-07-29
Expiration Date
Abstract
Methods for treating obstructive hypertrophic cardiomyopathy are described herein. The treatment methods include the administration of a cardiac myosin inhibitor (CK-3773274, also referred to as CK-274 or aficamten) and may include titrating an administrated daily dose based on one or more components of an echocardiogram. The daily dose may be increased, maintained, decreased, or terminated, based on the echocardiogram.
Core Innovation
The invention provides a method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof by administering Compound 1, or a pharmaceutically acceptable salt thereof, in daily doses over multiple time periods. Compound 1 is identified as the cardiac myosin inhibitor CK-3773274/CK-274/aficamten.
A first daily dose is administered for a first time period, and after the first time period the treatment is adjusted based on one or more components of a first echocardiogram acquired for the patient. The echocardiogram components include LVEF and post-Valsalva LVOT-G, and the second daily dose is selected according to predetermined threshold relationships of LVEF and post-Valsalva LVOT-G.
In additional embodiments, the method further administers additional daily doses over further time periods, with dose selection guided by one or more components of subsequent echocardiograms acquired after earlier time periods. The dosing logic can include escalating the dose, decreasing the dose, keeping the dose the same, or terminating therapy based on the measured LVEF and post-Valsalva LVOT-G relationships, and the method can include co-administration of disopyramide or other antiarrhythmic medication and patient selection such as CYP2D6 poor metabolizer status.
Claims Coverage
The independent claim is clm-00001. It covers echocardiogram component-guided adjustment of Compound 1 dosing for oHCM using LVEF and post-Valsalva LVOT-G to select the second daily dose according to threshold-based criteria, with a defined first dosing period and second dosing period. Dependent claims further refine the method by adding co-administration, patient-selection criteria, additional dose periods, and quantitative outcome-related constraints.
Echocardiogram-guided dose adjustment using LVEF and post-Valsalva LVOT-G
Administering Compound 1 (or a pharmaceutically acceptable salt thereof) as a first daily dose for about 2 weeks, then administering a second daily dose for about 2 weeks based on one or more components of a first echocardiogram acquired after the first time period, where the one or more components comprise LVEF and a post-Valsalva LVOT-G and the second daily dose is selected according to predetermined threshold relationships of LVEF and post-Valsalva LVOT-G.
Threshold-based rule selecting the second daily dose
Selecting the second daily dose as about 10 mg when the LVEF is at or above 55% and the post-Valsalva LVOT-G is at or above 30 mmHg, and otherwise selecting the second daily dose to be the same as the first daily dose when either the LVEF is at or above 50% and below 55% or the LVEF is at or above 55% and the post-Valsalva LVOT-G is below 30 mmHg.
Optional co-administration with disopyramide or other antiarrhythmics
Administering disopyramide or another antiarrhythmic medication to the patient during treatment with Compound 1 (or a pharmaceutically acceptable salt thereof).
Pre-treatment exclusion of negative inotropic antiarrhythmic exposure
Applying the method so that the patient has not received disopyramide or an antiarrhythmic drug with negative inotropic activity within 4 weeks before treatment with Compound 1 (or a pharmaceutically acceptable salt thereof).
Patient selection for CYP2D6 poor metabolizer
Applying the method to a patient who is a CYP2D6 poor metabolizer.
Echocardiogram-guided extension to a third dosing period
Administering a third daily dose of Compound 1 (or a pharmaceutically acceptable salt) for a third time period where the dose is selected based on components of a second echocardiogram after the second time period using LVEF and post-Valsalva LVOT-G to determine whether the third dose is increased, decreased or therapy terminated, or kept the same.
Clinical outcome thresholds including pVO2, NYHA, KCCQ and LVOT-G response
Characterizing achievement of one or more specified clinical outcome thresholds involving pVO2 change, NYHA Functional Class, KCCQ-OSS/KCCQ-CSS score improvements, and LVOT-G measures before and after Valsalva along with NYHA class improvement.
Claim coverage centers on an echocardiogram component-guided dosing regimen for oHCM in which Compound 1 dosing is adjusted after an initial treatment period using LVEF and post-Valsalva LVOT-G thresholds to determine the second daily dose, including cases where the dose is increased to about 10 mg or kept the same as the first dose under specified LVEF and post-Valsalva LVOT-G conditions. Dependent claims add refinement through optional disopyramide or antiarrhythmic co-administration, a pre-treatment washout constraint for negative inotropic antiarrhythmic exposure, a CYP2D6 poor metabolizer patient subgroup, extension to additional dosing periods with termination or adjustment rules, and explicit clinical outcome threshold characterization.
Stated Advantages
Statistically significant reductions in resting and post-Valsalva LVOT-G/gradients within weeks.
High rates of reaching LVOT-G targets by Week 10.
Generally well-tolerated safety.
Reversible LVEF changes.
Documented Applications
Treatment of obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof using the cardiac myosin inhibitor Compound 1 (aficamten/CK-3773274/CK-274).
Dose-ranging clinical evaluation in a phase 1 clinical trial for Compound 1 in oHCM, with reported echocardiographic and clinical outcomes.
Interested in licensing this patent?