Methods for administering myosin inhibitors

Abstract

Described herein are methods for administering myosin inhibitors to patients and associated methods for mitigating risk, including controlling distribution. The methods disclosed herein provide for the safe administration of mavacamten and other myosin inhibitors, mitigating the risk of heart failure due to systolic dysfunction.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 335,028, filed April 26, 2022, No. 63 / 335,209, filed April 26, 2022, and No. 63 / 336,254, filed April 28, 2022, the entire contents of each of which are incorporated herein by reference.

[0002] The present disclosure relates to methods of administering myosin inhibitors to patients and related methods of mitigating risks, including control over distribution. [Background technology]

[0003] Hypertrophic cardiomyopathy (HCM) is a cardiac disease caused by an excessive number of myosin-actin crossbridges, leading to excessive contraction and impaired relaxation and compliance. Myosin inhibitors, such as mavacamten, are understood to reduce myocardial contractility by inhibiting the formation of excess myosin-actin crossbridges. Myosin inhibitors have been investigated for the treatment of cardiac diseases including obstructive hypertrophic cardiomyopathy (oHCM), nonobstructive hypertrophic cardiomyopathy (nHCM), and heart failure with preserved ejection fraction (HFpEF). Recently, the myosin inhibitor mavacamten has been shown to provide clinical benefit in a phase 3 clinical trial. Specifically, in the phase 3 EXPLORER-HCM clinical trial, treatment with mavacamten was effective in reducing the LVOT gradient and improving symptoms, exercise performance, and health status in a representative oHCM patient population. (Olivotto et al., 2020, The Lancet, 396(10253), 759-769). If approved, mavacamten would be the first myosin inhibitor approved by the FDA. However, due to the mechanism of action of myosin inhibitors, these drugs must be administered in a manner that mitigates the risk of excessive reduction in contractility, which can lead to contractile dysfunction and heart failure. Thus, there is a need for a method of administration of myosin inhibitors that maximizes clinical benefit while minimizing the risk of adverse events, patient burden, cost, and administration complexity. Summary of the Invention

[0004] The present disclosure relates to a method for safely administering a myosin inhibitor to a patient. Various aspects and embodiments of such a method are described herein. In some embodiments, the method includes multiple treatment periods during which the myosin inhibitor is administered to the patient, or, optionally, during which administration is temporarily discontinued. In some cases, administration may be discontinued permanently. An evaluation may be performed at or near the end of the treatment period, and the evaluation may be used to determine whether the dose administered during that treatment period should be increased, maintained, reduced, or discontinued during a subsequent treatment period. The evaluation and corresponding dose adjustments result in a safe and effective administration of the myosin inhibitor. Other aspects of the present disclosure include methods of co-administration of the myosin inhibitor with other drugs, and methods of administering the myosin inhibitor in a manner that avoids drug-drug interactions. Further aspects of the present disclosure include methods of controlling the distribution of the myosin inhibitor to mitigate risks. [Brief description of the drawings]

[0005] [Figure 1] 1 is a schematic of the beginning phase of an administration scheme for administering a myosin inhibitor. [Diagram 2] 1 is a schematic of the maintenance phase of an administration scheme for administering a myosin inhibitor. [Diagram 3] 1 is an outline of treatment interruption (temporary cessation) as part of a dosing scheme for administering a myosin inhibitor. [Figure 4] 1 is a schematic of the beginning phase of an exemplary dosing scheme for administering mavacamten. [Diagram 5] 1 is a schematic of the maintenance phase of an exemplary dosing scheme for administering mavacamten. [Figure 6] 1 is a schematic diagram of treatment interruption (temporary cessation) as part of an exemplary dosing scheme for administering mavacamten. [Figure 7] Graph of mean change from baseline over time in KCCQ-23 clinical summary scores. [Figure 8] Graph of the cumulative distribution of the change from baseline to week 30 in KCCQ-23 clinical summary scores. [Figure 9]Graph of mean change from baseline over time in the HCMSQ shortness of breath domain. [Figure 10] Graph of cumulative distribution of change from baseline to week 30 in the HMCSQ shortness of breath domain. [Figure 11] FIG. 1 is an exemplary schedule of echocardiogram evaluations, PSF submissions, and medications for the first 14 weeks after initiation of myosin inhibitor treatment. [Figure 12] FIG. 1 is an exemplary schedule of echocardiogram evaluations and medications during the first year after initiation of myosin inhibitor treatment. [Figure 13A] 1 is a graph of the percentage of patients with an LVEF below 50% over time among patients simulated with Regimen #1 according to Example 2, separated by patient phenotype. [Figure 13B] 1 is a graph of the percentage of patients with a VLVOT of 30 mmHg or less over time among patients simulated on Regimen No. 1 according to Example 2, separated by patient phenotype. [Figure 13C] 1 is a graph of the percentage of patients with mavacamten plasma concentrations greater than 700 ng / mL over time among patients simulated on Regimen #1 according to Example 2, separated by patient phenotype. [Figure 13D] 1 is a graph of the percentage of patients with mavacamten plasma concentrations greater than 1000 ng / mL over time among patients simulated on Regimen No. 1 according to Example 2, separated by patient phenotype. [Figure 14A] 1 is a graph of the percentage of patients with an LVEF of 50% or less over time among patients simulated with Regimen No. 2 according to Example 2, separated by patient phenotype. [Figure 14B] 1 is a graph of the percentage of patients with a VLVOT of 30 mmHg or less over time among patients simulated on Regimen No. 2 according to Example 2, separated by patient phenotype. [Figure 14C]1 is a graph of the percentage of patients with mavacamten plasma concentrations greater than 700 ng / mL over time among patients simulated on Regimen No. 2 according to Example 2, separated by patient phenotype. [Figure 14D] 1 is a graph of the percentage of patients with mavacamten plasma concentrations greater than 1000 ng / mL over time among patients simulated on Regimen No. 2 according to Example 2, separated by patient phenotype. [Figure 15A] 1 is a graph of the percentage of patients with an LVEF below 50% over time among patients simulated with Regimen No. 3 according to Example 2, separated by patient phenotype. [Figure 15B] 1 is a graph of the percentage of patients with a VLVOT of 30 mmHg or less over time among patients simulated on Regimen No. 3 according to Example 2, separated by patient phenotype. [Figure 15C] 1 is a graph of the percentage of patients with mavacamten plasma concentrations greater than 700 ng / mL over time among patients simulated on Regimen No. 3 according to Example 2, separated by patient phenotype. [Figure 15D] 1 is a graph of the percentage of patients with mavacamten plasma concentrations greater than 1000 ng / mL over time among patients simulated on Regimen No. 2 according to Example 2, separated by patient phenotype. [Figure 16] A is a graph of the percentage of patients with an LVEF <50% over time among patients simulated with Regimen No. 1 according to Example 2, separated by PM and non-PM phenotypes. B is a graph of the percentage of patients with an LVEF <50% over time among patients simulated with Regimen No. 2 according to Example 2, separated by PM and non-PM phenotypes. [Figure 17] 1 shows the results of subgroup analyses of the primary composite functional endpoint of the clinical trial described in Example 1. [Figure 18]1 shows the cumulative distribution of the change from baseline to week 30 in LVOT peak slope from the clinical trial described in Example 1. [Figure 19] 1 shows the cumulative distribution of change from baseline to week 30 in pVO2 from the clinical trial described in Example 1. [Figure 20A] Steady-state mavacamten profile from simulations of strong, moderate and weak inhibition of CYP2C19 and CYP3A4. Summary of geometric mean ratios of AUC. [Figure 20B] Steady-state mavacamten profile from simulations of strong, moderate and weak inhibition of CYP2C19 and CYP3A4. Summary of geometric mean ratios of Cmax. [Figure 21] 1 is a schematic diagram of an example system for authorizing the dispensing of a pharmaceutical prescription. [Figure 22] 1 is a flow chart of an example sequence of operations for a method of authorizing the dispensing of a pharmaceutical prescription. [Figure 23] 1 is a schematic diagram of an example computing device that may be used to implement the systems and methods described herein. [Figure 24] 4 is a flow chart of another example sequence of operations of a method for authorizing the dispensing of a pharmaceutical prescription. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0006] definition While various embodiments and aspects of the invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments and aspects are provided by way of example only. Numerous variations, modifications, and substitutions will occur to those skilled in the art without departing from the invention. It is understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention.

[0007] The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described. All documents or portions of documents cited in this application (including, but not limited to, patents, patent applications, articles, books, manuals, and treatises) are expressly incorporated herein by reference in their entirety for all purposes.

[0008] The following documents are incorporated by reference in their entirety: ·The American Society of Echocardiography,Recommendations for Cardiac Chamber Quantification in Adults:A Quick Reference Guide from the ASE Workflow and Lab Management Task Force,July 2018 ·Lang et al., Recommendations for Cardiac Chamber Quantification by Echocardiography in Adults: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging, Journal of the American Society of Echocardiography, January 2015 ·Nagueh et al.,Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography:An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging,Journal of the American Society of Echocardiography,2016;29:277-314 ·Caballero et al.,Echocardiographic reference ranges for normal cardiac Doppler data:results from the NORRE Study,European Heart Journal-Cardiovascular Imaging(2015)16,1031-1041 ·Jozine M.ter Maaten et al.,Connectin heart failure with preserved ejection fraction and renal dysfunction:the role of endothelial dysfunction and inflammation,European Journal of Heart Failure(2016)18,588-598 ·ATS / ACCP Statement on Cardiopulmonary Exercise Testing,American Thoracic Society / American College of Chest Physicians,November 1,2001 · Zaid et al., Pre- and Post-Operative Diastolic Dysfunction in Patients with Valvular Heart Disease, Journal of the American College of Cardiology, 2013, 62(21), 1922-1930 · Gupta et al., Racial differences in circulating natriuretic peptide levels: the atherosclerosis risk in communities study, Journal of the American Heart Association, 2015; 4: e001831 · Eugene Braunwald, Cardiomyopathies: An Overview, Circ Res. 2017; 121: 711-721 · Towbin and Jefferies, Cardiomyopathies Due to Left Ventricular Noncompaction, Mitochondrial and Storage Diseases and Inborn Errors of Metabolism, Circ Res. 2017; 121: 838-854 · Cirino and Ho, Hypertrophic Cardiomyopathy Overview. 2008. In: Adam et al., eds., GeneReviews (registered trademark), Seattle (WA): University of Washington, Seattle; 1993-2020.

[0009] Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. In carrying out the present invention, any method, device, and material similar or equivalent to the method, device, and material described herein can be used. The following definitions are provided to facilitate understanding of certain terms frequently used herein and are not intended to limit the scope of the present disclosure.

[0010] The terms "a" or "an" as used herein mean one or more.

[0011] The terms "comprise," "include," and "having," as well as their derivatives, are used interchangeably herein as inclusive, open-ended terms. For example, the use of "comprising," "including," or "having" means that none of the comprised, included, or included elements are the only elements included in the subject of the clause containing the verb.

[0012] As used herein, the term "about" refers to a range of values ​​that one of ordinary skill in the art would reasonably consider similar to the specified value, including the specified value. In some embodiments, the term "about" refers to within a standard deviation using measurements generally accepted in the art. In some embodiments, "about" refers to a range covering ±10% of the specified value. In some embodiments, "about" refers to the specified value.

[0013] As used herein, "treatment", "treat" or "ameliorate" are used interchangeably herein. These terms refer to an approach to obtain a beneficial or desired result, including, but not limited to, a therapeutic effect. A therapeutic effect refers to eradication or amelioration of the underlying disorder being treated, and / or eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder, such that an improvement is observed in the subject (even though the subject may still be afflicted with the underlying disorder). Treatment includes delaying the onset of clinical symptoms of the disease by administration of a composition, suppressing the disease, i.e., reducing the clinical symptoms of the disease, inhibiting the disease, i.e., arresting the onset of clinical symptoms by administration of a composition after symptoms first appear, and / or relieving the disease, i.e., reducing the clinical symptoms by administration of a composition after symptoms first appear. For example, certain methods described herein treat hypertrophic cardiomyopathy (HCM) by reducing or reducing the onset or progression of HCM, or treat HCM by reducing the symptoms of HCM. Symptoms of HCM or test results indicative of HCM will be known or determinable by one of skill in the art and may include, but are not limited to, shortness of breath (especially during exercise), chest pain (especially during exercise), fainting (especially during or immediately after exercise), fast heartbeat, fast irregular or throbbing heartbeat, atrial and ventricular arrhythmias, heart murmurs, left ventricular hypertrophy and diastolic dysfunction, thickening of the myocardium, thickening of the left ventricular wall, elevated pressure gradient across the left ventricular outflow tract (LVOT), and elevated LVOT gradient or Valsalva LVOT gradient after exercise.

[0014] "Patient" or "subject" refers to an organism suffering from or susceptible to a disease or condition that can be treated by using the methods provided herein. The term does not necessarily indicate that the subject has been diagnosed with a particular disease, but typically refers to an individual under the care of a physician. Non-limiting examples include humans, other mammals, cows, rats, mice, dogs, cats, monkeys, goats, sheep, cows, deer, and other non-mammals. In some embodiments, the patient or subject is a human. In some embodiments, the patient is suffering from obstructive HCM.

[0015] As used herein, "administration" of a compound of the present disclosure includes delivery of a compound as described herein, or a prodrug or other pharma- ceutically acceptable derivative thereof, to a subject using any suitable formulation or route of administration, e.g., as described herein. In some embodiments, administration is oral administration.

[0016] As used herein, "near the end of" refers to a portion of a treatment period that is more than halfway through the treatment period and within about 2 weeks of the end of the treatment period. In some embodiments, near the end of a treatment period is more than halfway through the treatment period and within about 1 week (e.g., within about 3 days, within about 1 day) of the end of the treatment period. In some embodiments, near the end of a treatment period is within ± about 2 weeks of the end of the treatment period. In some embodiments, near the end of a treatment period is within ± about 1 week of the end of the treatment period. In some embodiments, near the end of a treatment period is more than halfway through the treatment period and within the last 2 weeks of the treatment period. In some embodiments, near the end of a treatment period is the last week of the treatment period, e.g., the 4th week of a 4-week treatment period.

[0017] The phrase "pharmacologically acceptable" is used herein to refer to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response and / or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0018] As used herein, "pharmaceutically acceptable salt" refers to a derivative of the disclosed compound, in which the parent compound is modified by producing its acid salt or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral salts or organic acid salts of basic groups, such as amines, and alkali salts or organic salts of acidic groups, such as carboxylic acids. Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example, formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, as well as those prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and isethionic acid.

[0019] Myosin inhibitors have been investigated for the treatment of cardiac diseases including obstructive hypertrophic cardiomyopathy (oHCM), non-obstructive hypertrophic cardiomyopathy (nHCM), and heart failure with preserved ejection fraction (HFpEF). Myosin inhibitors have been shown to provide clinical benefits, for example, by reducing left ventricular outflow tract obstruction, but due to their mechanism of action, they also pose the risk of excessively reducing left ventricular (LV) contractility. Excessively reducing LV contractility generally results in contractile dysfunction, for example, a left ventricular ejection fraction (LVEF) less than 50%, which can lead to heart failure and death. When the plasma concentration of myosin inhibitors exceeds the therapeutic range, a reduction in LVEF can be attributed to myosin inhibitors. Many pharmacokinetic factors contribute to the plasma concentration of a drug, including dosage and rate of metabolism. As an example, mavacamten is primarily metabolized by the enzyme CYP2C19. Some individuals have mutations in the enzyme CYP2C19, which causes the enzyme to metabolize mavacamten at different rates, thereby affecting its plasma concentration. Individuals can be classified as poor, intermediate, normal, extensive and very extensive metabolizers based on mutations in CYP2C19. As an example, a poor CYP2C19 metabolizer receiving mavacamten at a daily dose of 5 mg for a period of several weeks may experience higher blood plasma concentrations of mavacamten above the therapeutic range and at a higher risk of adverse events due to the slower rate of metabolism of mavacamten. As another example, a very extensive CYP2C19 metabolizer receiving mavacamten at a daily dose of 5 mg for a period of several weeks may experience lower blood plasma concentrations of mavacamten below the therapeutic range and at a lower risk of therapeutic benefit (e.g., lowering the LVOT slope). Thus, the metabolism of mavacamten, and other myosin inhibitors, may vary with the intended patient population. A need exists for a method of administration of myosin inhibitors that maximizes clinical benefit while minimizing the risk of adverse events, patient burden, cost, and administration complexity.

[0020] Disclosed herein are methods of treating cardiac disease. Certain methods disclosed herein mitigate the risk of heart failure and systolic dysfunction during such treatment. In some embodiments, the risk is reduced, e.g., by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or more, compared to other administration methods. The methods may include a specific method of administering the myosin inhibitor, including dose adjustment (reduction and / or increase), and a specific evaluation method, e.g., echocardiography, evaluation of left ventricular outflow tract obstruction, and evaluation of LVEF, which can be used to guide administration of the myosin inhibitor. In some embodiments, the disclosed methods mitigate, manage, reduce, or lower the risk of such adverse events.

[0021] In some embodiments, aspects of the method of the present invention include determining the LVOT gradient, or another measure of left ventricular outflow tract obstruction, at one or more assessments after initiation of treatment with a myosin inhibitor, and adjusting the dose as necessary based on such assessment. For the treatment of oHCM and related heart diseases characterized by left ventricular outflow tract obstruction, the LVOT gradient is used as a measure of therapeutic efficacy. Once myosin inhibitor therapy is initiated, a rapid drop in LVOT gradient can be inferred to indicate high patient exposure to the myosin inhibitor. High levels of exposure to the myosin inhibitor pose a risk of systolic dysfunction and heart failure. According to aspects of the present disclosure, the LVOT gradient (or another measure of left ventricular outflow tract obstruction) is assessed at or near the end of two or more separate treatment periods during the initiation phase, and the risk of systolic dysfunction and heart failure is mitigated by reducing the dosage of the myosin inhibitor based on low LVOT gradient at those assessments. As a specific example, the risk of systolic dysfunction and heart failure can be mitigated by assessing the Valsalva LVOT slope at 4 and 8 weeks after the first dose of a myosin inhibitor (e.g., mavacamten) and reducing the dose of the myosin inhibitor (e.g., mavacamten) after 4 and 8 weeks when the Valsalva LVOT slope falls below a threshold (e.g., 20 mmHg). This criterion takes advantage of the excessive pharmacological effect early in treatment to prospectively reduce the dose in patients likely to experience later LVEF decline, prior to episodes of LVEF decline.

[0022] Dose adjustment based on two or more LVOT assessments can be further combined with a method involving determining LVEF at one or more assessments after (optionally before) initiation of myosin inhibitor treatment and modifying treatment (e.g., by temporary discontinuation) based on LVEF. Including LVEF assessment can further mitigate risk with myosin inhibitor treatment. LVEF is a direct measure of contractile dysfunction that can lead to heart failure. Using both LVEF and LVOT gradient provides two measurements during initiation of myosin inhibitor therapy and mitigates the risk of contractile dysfunction and heart failure. Both LVOT gradient and LVEF can be determined using non-invasive techniques, such as non-invasive imaging techniques (e.g., echocardiography, cardiac magnetic resonance imaging). When using non-invasive techniques (e.g., imaging techniques, echocardiography) to determine LVOT gradient and LVEF, the need for other procedures, including invasive procedures, can be eliminated. For example, the need for blood plasma concentrations (e.g., "trough" measurements) can be eliminated.

[0023] The use of one or more assessments may also allow for dosing across a broad patient population, for example by allowing the use of a "uniform dose" regardless of the patient's genotype. Different patients respond differently to myosin inhibitors, resulting in some at greater risk of adverse events. For example, different patients may have different levels of exposure that put some patients at greater risk of adverse events. Specifically, a given dose may be an ideal starting dose for a large patient population, for example intermediate, normal, extensive and / or extreme metabolizers, but patients who are poor metabolizers of the myosin inhibitor (e.g., due to a poor metabolizer phenotype of CYP2C19 (for mavacamten) or CYP2D6 (for aficamten)) may have high and potentially dangerous levels of exposure at that given dose. By providing the possibility of dose reduction and temporary discontinuation, especially during initial treatment ("initiation phase"), based on the results of the relevant assessments, all patients may begin treatment at the same starting dose and without the need for costly or time-consuming genotyping assays. Patients whose risk would be mitigated by dose reduction or temporary discontinuation can be identified in time by initiation assessment (e.g., LVOT and / or LVEF) and dose reduction or temporary discontinuation can occur before exposure becomes too great. Patients at low risk of adverse events can be maintained on a higher dose during initiation under the same dosing scheme, rather than receiving a potentially less effective lower dose.

[0024] In some embodiments, methods of the invention include methods of mitigating, managing, reducing, or lowering the risk of adverse events to myosin inhibitor therapy.

[0025] In some embodiments, the methods of the present invention include methods of mitigating, managing, reducing, or lowering the risk of adverse events from myosin inhibitor therapy.

[0026] In some embodiments, methods of the invention include methods of mitigating, managing, reducing, or lowering the risk of heart failure during myosin inhibitor therapy.

[0027] In some embodiments, the methods of the present invention relate to methods of mitigating, managing, reducing or lowering the risk of contractile dysfunction during myosin inhibitor therapy.

[0028] In some embodiments, the methods of the present invention relate to methods of mitigating, managing, reducing or lowering the risk of heart failure due to systolic dysfunction during myosin inhibitor therapy.

[0029] In some embodiments, the risk is mitigated, managed, reduced, or decreased during the initiation phase by dose reduction and / or treatment interruption (temporary cessation) during the initiation phase, the terms temporary cessation and treatment interruption being used interchangeably herein.

[0030] In some embodiments, the risk is mitigated, managed, reduced, or decreased during the maintenance phase by dose adjustments and / or treatment interruptions (temporary cessation) during the maintenance phase.

[0031] In some embodiments, the initiation period is about 2 weeks to about 36 weeks. In some embodiments, the initiation period is about 4 weeks to about 24 weeks. In some embodiments, the initiation period is about 4 weeks to about 16 weeks (e.g., 12 weeks). In some embodiments, the initiation period is about 8 weeks to about 24 weeks. In some embodiments, the initiation period is about 8 weeks to about 16 weeks. In some embodiments, the initiation period is about 4 weeks to about 12 weeks. In some embodiments, the initiation period is about 12 weeks. In some embodiments, the initiation period is about 8 weeks. In some embodiments, the initiation period is about 6 weeks. In some embodiments, the initiation period is about 4 weeks. In some embodiments, the initiation period is about 16 weeks.

[0032] In some embodiments, the methods of the invention include methods of treating a disease or administering a myosin inhibitor while mitigating, managing, reducing, or lowering the risk of an adverse event to myosin inhibitor therapy (e.g., heart failure, systolic dysfunction, or heart failure due to systolic dysfunction).

[0033] The methods of the invention are useful for treating patients with cardiac disease, heart disease, cardiovascular disease or symptom(s) thereof with myosin inhibitors, and are useful across a variety of cardiac diseases and diverse patient populations with different traits, genotypes and phenotypes.

[0034] In some embodiments, the patient is a poor metabolizer of the myosin inhibitor (e.g., mavacamten). In some embodiments, the patient is a normal metabolizer of the myosin inhibitor (e.g., mavacamten). In other embodiments, the patient is an intermediate, extensive or extremely extensive metabolizer of the myosin inhibitor (e.g., mavacamten). The disclosed method may provide for administration of the myosin inhibitor to the patient regardless of the patient's relative ability to metabolize the myosin inhibitor, e.g., mavacamten. The administration approach and evaluation provides for safe administration of the myosin inhibitor (e.g., mavacamten) across a diverse patient population, including poor, intermediate, normal, extensive and extremely extensive metabolizers. The administration approach also provides for initiation of administration without the need to perform genotyping assays to determine the patient's metabolic genotype, which can be costly and time consuming. This uniform dosing allows for timely evaluation of patient response in the clinic, reducing costs and complexity of administration. For example, physicians, pharmacists, and other personnel do not need to be trained or certified in genotyping protocols since genotyping is not required, nor do they need to be trained or certified in multiple genotype-specific dosing techniques (which may add additional complexity and risk leading to medication errors).The disclosed methods may provide for administration of a myosin inhibitor to a patient regardless of the patient's weight.

[0035] Poor metabolizers of myosin inhibitors (e.g., mavacamten) can include individuals with CYP2C19 polymorphisms. In some embodiments, poor metabolizers of myosin inhibitors (e.g., mavacamten) are of Asian descent. In some such cases, the poor metabolizers are of South Asian descent. In some embodiments, Asian descent includes, but is not limited to, Japanese populations, Chinese populations, Thai populations, Korean populations, Filipino populations, Indonesian populations, and Vietnamese populations. In some embodiments, poor metabolizers of myosin inhibitors (e.g., mavacamten) are not of Asian descent.

[0036] In some embodiments, a poor metabolizer of a myosin inhibitor (e.g., mavacamten) has a CYP2C19 genotype that is a poor metabolizer. * 2 / * 2. * 2 / * 3 or * 3 / * It has genotype 3.

[0037] In some embodiments, poor metabolizers of myosin inhibitors (e.g., mavacamten) are of Asian descent. In some embodiments, poor metabolizers of myosin inhibitors (e.g., mavacamten) are of Japanese descent.

[0038] Poor metabolizers of myosin inhibitors (e.g., aficamten) can include individuals with CYP2D6 polymorphisms. In some embodiments, poor metabolizers of myosin inhibitors (e.g., aficamten) have a CYP2D6 genotype that is a poor metabolizer.

[0039] In some embodiments, the patient treated by the methods described herein has been diagnosed with and / or suffers from a cardiac condition selected from the group consisting of hypertrophic cardiomyopathy (HCM), diastolic dysfunction, left ventricular hypertrophy, severe left ventricular hypertrophy, angina pectoris, ischemia, restrictive cardiomyopathy (RCM), heart failure with preserved ejection fraction (HFpEF), and combinations thereof. In some cases, the patient treated by the methods described herein has been diagnosed with and / or suffers from HCM and / or HFpEF.

[0040] In some embodiments, the patient treated by the methods described herein has been diagnosed with and / or is suffering from obstructive HCM (oHCM). In some such cases, the patient has been diagnosed with and / or is suffering from NYHA class II-III symptomatic obstructive HCM. In some such cases, the patient is an adult. In other cases, the patient is a pediatric patient.

[0041] The NYHA functional classification grades the severity of heart failure symptoms into one of four functional classes. The NYHA functional classification is widely used in clinical practice and research because it provides a standard description of severity that can be used to assess response to treatment and to guide management. Based on symptom severity and physical activity, the NYHA functional classification is as follows: Class I: No limitation of physical activity. Ordinary physical activity does not cause undue shortness of breath, fatigue or palpitations. Class II: Mild limitation of physical activity. No pain at rest, but ordinary physical activity causes excessive shortness of breath, fatigue or palpitations. Class III: Severe limitation of physical activity. No pain at rest, but less than normal physical activity causes excessive shortness of breath, fatigue or palpitations. Class IV: Any physical activity cannot be continued without pain. Rest symptoms may be present. Any physical activity increases pain.

[0042] In some embodiments, the patient has been diagnosed with and / or is afflicted with HFpEF.

[0043] In some embodiments, the patient is experiencing symptoms of cardiovascular disease, such as shortness of breath, dizziness, chest pain, fainting, or has limitations in activities of daily living (e.g., limitations in personal care, exercise, or diet).

[0044] In some embodiments, the patient has been diagnosed with and / or is suffering from a condition (e.g., a heart disease) selected from valvular aortic stenosis, mixed LV systolic and diastolic dysfunction, idiopathic RV hypertrophy, chronic kidney disease, aortic regurgitation, tetralogy of Fallot, mitral stenosis, Noonan syndrome, or acute coronary syndrome.

[0045] In some embodiments, the patient exhibits normal systolic contractility or systolic hypercontractility and the patient has a left ventricular ejection fraction of greater than 50%.

[0046] In some embodiments, the patient exhibits any one or combination of myocardial diastolic dysfunction, elevated left ventricular filling pressure, left ventricular hypertrophy, and left atrial enlargement (LAE).

[0047] Diastolic dysfunction is present or is a key feature of a range of diseases, including, but not limited to, hypertrophic cardiomyopathy (HCM), heart failure with preserved ejection fraction (HFpEF), and left ventricular hypertrophy (LVH), which includes both impaired active relaxation and impaired ventricular stiffness (diabetic HFpEF). Diastolic dysfunction may be diagnosed using one or more techniques and measurements, including catheterization, E / e', left atrial size, and BNP or NT-proBNP.

[0048] Individuals with HCM can be subdivided based on the presence or absence of left ventricular outflow tract obstruction (LVOT). The presence of LVOT obstruction, i.e., obstructive HCM (oHCM), is associated with more severe symptoms and an increased risk of heart failure and cardiovascular death. There are limited data to support medical treatment (beta-blockers, calcium channel blockers, disopyramide) in this subset of patients, and persistently symptomatic patients may be referred for invasive septal reduction therapy.

[0049] The ejection fraction is an indicator of normal or hypercontractile systolic function, i.e., the ejection fraction is greater than about 52% in patients with normal systolic function and about 50% in patients with hypercontractile systolic function.

[0050] LVH, which is characterized by wall thickness, may be diagnosed using one or more techniques and measurements, including echocardiogram, cardiac MRI, non-invasive imaging techniques (eg, tissue Doppler imaging), and E / e'.

[0051] Patients in need of treatment for diastolic dysfunction include patients in patient populations characterized by oHCM, nHCM, LVH, or HFpEF. Patients in need of treatment for diastolic dysfunction include patients with left ventricular stiffness as measured by echocardiography or left ventricular stiffness as measured by cardiac magnetic resonance.

[0052] In some embodiments, a patient in need of such treatment exhibits left ventricular stiffening as measured by echocardiography.

[0053] Further determinants for diagnosing diastolic dysfunction using echocardiography are described in J Am Soc Echocardiogr. 29(4):277-314 (2016), the entire contents of which are incorporated by reference herein for all purposes.

[0054] In some embodiments, a patient in need of the treatment has left ventricular stiffness as measured by cardiac magnetic resonance, which is used to determine peak filling rate, time to peak filling rate, and peak diastolic strain rate. Thus, in some embodiments, a patient has left ventricular stiffness as measured by cardiac magnetic resonance when at least one of the following characteristics is present: abnormal peak filling rate, abnormal time to peak filling rate, or abnormal peak diastolic strain rate.

[0055] In some embodiments, the patient in need of treatment suffers from diastolic dysfunction, left ventricular hypertrophy, left ventricular outflow tract obstruction, increased left ventricular wall thickness (or mass index), increased interventricular septal (IVS) wall thickness, poor or decreased cardiac elasticity, poor or decreased left ventricular diastolic relaxation, abnormally high left atrial pressure, decreased E / e' ratio, decreased exercise capacity or exercise tolerance, decreased maximum oxygen consumption (VO2), elevated left ventricular diastolic pressure, or any combination thereof.

[0056] In some embodiments, the patient in need of such treatment is suffering from hypertrophic cardiomyopathy (HCM) characterized by at least one biomarker selected from elevated levels of NT-pro B-type natriuretic peptide (NT-proBNP), elevated levels of cardiac troponin I. In another embodiment, the HCM patient in need of such treatment is predisposed to developing HCM.

[0057] In some embodiments, the patient in need of treatment is suffering from chest pain, shortness of breath, angina, fainting or dizziness.

[0058] In some cases, patients may be at risk of high exposure levels to myosin inhibitors when co-administered with a compound that alters the activity of one or more cytochrome P450 (CYP) enzymes (e.g., CYP inducers, CYP inhibitors). For example, a patient receiving a myosin inhibitor that is primarily metabolized by CYP2C19 may have a very high and unsafe exposure level to the myosin inhibitor when co-administered with a strong CYP2C19 inhibitor. In some cases, patients may be at risk of low effective exposure levels to the myosin inhibitor when co-administered with a compound that alters the activity of one or more CYP enzymes (e.g., CYP inducers, CYP inhibitors). For example, a patient receiving a myosin inhibitor that is primarily metabolized by CYP2D6 may have a low effective exposure level to the myosin inhibitor when co-administered with a strong CYP2D6 inducer. In some cases, in patients receiving a myosin inhibitor in combination with a compound that alters the activity of one or more CYP enzymes, changing the dose of the compound (e.g., discontinuing administration of the compound) may pose a risk of excessively high or low exposure to the myosin inhibitor. The present disclosure includes methods of co-administering a myosin inhibitor with other drugs that mitigate, manage, reduce, and / or decrease the above risks.

[0059] In some embodiments, the patient is co-administered with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor during myosin inhibitor therapy (e.g., therapy with mavacamten). For example, in some embodiments, the patient is not administered a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor during myosin inhibitor therapy, but later begins to administer a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor. In some embodiments, the weak CYP2C19 inhibitor or the moderate CYP3A4 inhibitor is selected from the group consisting of cimetidine, ciprofloxacin, diltiazem, felbamate, omeprazole, isoniazid, fluconazole, and verapamil at a dose of 20 mg once daily.

[0060] In some embodiments, the patient is co-administered a weak CYP2D6 inhibitor or inducer in combination with myosin inhibitor therapy (eg, aficamten therapy).

[0061] Mavacamten is primarily metabolized by the enzyme CYP2C19 and secondarily metabolized by the enzyme CYP3A4. Thus, co-administration of a drug that inhibits CYP2C19 and / or CYP3A4 can affect the metabolism of mavacamten and, as a result, affect the patient's exposure to mavacamten. The inventors have determined that co-administration of mavacamten with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor can be safely performed under certain conditions. Example 5 and Figure 17 show the extent of exposure change expected when co-administering a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor under the conditions described herein. Methods of co-administration are described later in this specification.

[0062] The methods described herein include administration of a myosin inhibitor. In some embodiments, the myosin inhibitor is mavacamten or a pharma- ceutically acceptable salt thereof. In some embodiments, the myosin inhibitor is mavacamten. Mavacamten has the following structure: [ka]

[0063] Mavacamten is also known as MYK-461. Its chemical name is (S)-3-isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione or 3-(1-methylethyl)-6-[[(1S)-1-phenylethyl]amino]-2,4(1H,3H)-pyrimidinedione.

[0064] Mavacamten can be obtained according to the preparation methods described in US Pat. No. 9,181,200, which is incorporated by reference in its entirety for all purposes.

[0065] In some embodiments, the myosin inhibitor is a compound represented by the following formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 is C 1-8 Alkyl, C 3-8 cycloalkyl or phenyl; R 1 is optionally substituted with one or two halo; R 2 is phenyl optionally substituted with one or two halo; R 3 is C 1-8 Alkyl or C 3-8 cycloalkyl, and each R 3 is halo, hydroxyl or C 1-2 is optionally substituted with alkoxy; R 4 is H, X is H.

[0066] In some embodiments, the myosin inhibitor of formula (I) or a pharma- ceutical acceptable salt thereof is [ka] [ka] is selected from the group (I) consisting of:

[0067] In some embodiments, the myosin inhibitor of Formula (I) is MYK-581, having the following structure, or a pharma- ceutically acceptable salt thereof: [ka]

[0068] The chemical name of MYK-581 is (S)-6-((1-(3-fluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione.

[0069] The myosin inhibitors of formula (I), including the compounds of group (I), mavacamten or MYK-581, or pharma- ceutically acceptable salts thereof, can be obtained according to the preparation methods described in U.S. Pat. No. 9,181,200, which is incorporated by reference in its entirety for all purposes.

[0070] In some embodiments, the myosin inhibitor is represented by the following formula (II): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 Fluoro, chloro, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy or C 2-4 alkynyl and at least one R 1 is fluoro and R 2a and R 2b is fluoro and R 2a and R 2b the other is H and n is 1 or 2.

[0071] In some embodiments, the myosin inhibitor of formula (II) or a pharma- ceutical acceptable salt thereof is [ka] is selected from the group (II) consisting of:

[0072] The myosin inhibitors of formula (II), including the compounds of group (II) or pharma- ceutically acceptable salts thereof, can be obtained according to the production methods described in International Application PCT / US2019 / 058297, filed October 29, 2019, which is incorporated herein by reference in its entirety and for all purposes.

[0073] In some embodiments, the myosin inhibitor is represented by the following formula (III): [ka] or a pharma- ceutically acceptable salt thereof, wherein G1 -CR 4 R 5 - or -O-, G2 is a bond or -CR 6 R 7 - and G3 -CR 8 -or-N-, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently H, C1-C6 alkyl, halo, or hydroxyl; R 2 is H, C2-C6 alkyl, halo, or hydroxyl; Z is a bond, C1-C6 alkyl, -O-, -N(R 9 )-, -R X O-, -OR Y or -R Z S-, R 9 is H, C1-C6 alkyl or cycloalkyl; A is selected from the group consisting of C2 substituted alkynyl, unsubstituted C2 alkynyl, substituted phenyl, unsubstituted phenyl, and 5- or 6-membered heteroaryl containing at least one ring N atom, wherein the 5- or 6-membered heteroaryl is unsubstituted or is selected from the group consisting of one or more R10 is substituted with a substituent, Each R 10 are independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or -C(O)OR a and B is selected from the group consisting of H, C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, and the C1-C6 alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl of B is unsubstituted or is selected from the group consisting of one or more R 11 is substituted with a substituent, Each R 11 are independently substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, unsubstituted C1-C6 alkyl, one or more R 12 Substituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, halo, -OR b , -C(O)R c , -C(O)OR d , oxo and -NR e R f is selected from the group consisting of Each R 12 are independently halo, -OR b , -C(O)R g , -C(O)OR h and -C(O)NR i R j is selected from the group consisting of Each R a , R b , R c , R d , R e , R f , R g , R h , R i and R jare independently H or C1-C6 alkyl; R X , R Y and R Z are each C1-C6 alkyl.

[0074] In some embodiments, the myosin inhibitor of formula (III) or a pharma- ceutical acceptable salt thereof is [ka] is selected from the group (III) consisting of:

[0075] The myosin inhibitors of formula (III), including the compounds of group (III) or pharma- ceutically acceptable salts thereof, can be obtained according to the production methods described in International Publication No. WO2019 / 144041, published July 25, 2019, which is incorporated herein by reference in its entirety and for all purposes.

[0076] In some embodiments, the myosin inhibitor is aficamten or a pharma- ceutically acceptable salt thereof. Aficamten is [ka] It has the structure:

[0077] In some embodiments, myosin inhibitors include compounds disclosed in international publications published as WO2020 / 005887, WO2020 / 005888, and WO2020 / 047447, which are incorporated by reference in their entireties for all purposes.

[0078] The myosin inhibitor of the present invention is generally administered in a pharmaceutical composition. The pharmaceutical composition for administering the compound of formula (I), (II), (III), the compound of group (I), (II), (III), and / or mavacamten and / or MYK-581, or a pharma-ceutically acceptable salt thereof, may be conveniently provided in dosage unit form and may be prepared by any of the methods known in the pharmaceutical and drug delivery arts. Such methods include the step of bringing into association the active ingredient with the carrier, which may include one or more accessory ingredients. Generally, the pharmaceutical composition is prepared by uniformly and intimately bringing into association the active ingredient with a liquid carrier or finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired formulation. The pharmaceutical composition generally contains the active agent in an amount sufficient to exert the desired effect on myocardial contractility (i.e., to reduce systolic contractility, which is often supernormal in HCM), while improving diastolic left ventricular relaxation. Such improved relaxation can alleviate symptoms in hypertrophic cardiomyopathy and other causes of diastolic dysfunction. The pharmaceutical composition can also be used as an adjunct in angina pectoris and ischemic heart disease to improve the effects of diastolic dysfunction causing coronary flow impairment, improving coronary flow impairment. The pharmaceutical composition can also have an effect on adverse left ventricular remodeling in HCM and other causes of left ventricular hypertrophy due to chronic volume or pressure overload, for example, due to valvular heart disease or systemic hypertension.

[0079] The pharmaceutical compositions comprising the compounds of formula (I), (II), (III) and / or the compounds of group (I), (II), (III) and / or mavacamten and / or MYK-581, or pharma- ceutically acceptable salts thereof, may be in a form suitable for oral use, such as tablets, troches, lozenges, aqueous suspensions, oily suspensions, dispersible powders, dispersible granules, emulsions, hard capsules, soft capsules, syrups, elixirs, solutions, buccal patches, buccal gels, chewing gums, chewable tablets, effervescent powders and effervescent tablets. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, antioxidants and preservatives, in order to provide pharma- ceutically elegant and palatable preparations. The tablets contain the active ingredient in admixture with pharma- ceutically acceptable non-toxic excipients suitable for tablet manufacture. These excipients may be, for example, inert diluents such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium or sodium phosphate, granulating and disintegrating agents such as corn starch or alginic acid, binders such as PVP, cellulose, PEG, starch, gelatin or acacia, and lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or may be enteric-coated or otherwise coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period of time. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used. The tablets may be coated to form osmotically therapeutic tablets for controlled release.

[0080] The preparation for oral use may be provided as a hard gelatin capsule, in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin, or as a soft gelatin capsule, in which the active ingredient is mixed with water or oil medium, such as peanut oil, liquid paraffin or olive oil.In addition, emulsions can be prepared with water-immiscible ingredients, such as oils, and stabilized with surfactants, such as mono / diglycerides, PEG esters, etc.

[0081] In some embodiments, the compounds of formula (I), (II), (III) and / or the compounds of group (I), (II), (III) and / or mavacamten and / or MYK-581 can be used in the form of a pharmaceutically acceptable salt. Examples of the pharmaceutically acceptable salt include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids. In other embodiments, the compounds of formula (I), (II), (III) and / or the compounds of group (I), (II), (III) and / or mavacamten and / or MYK-581 can be used in the form of a free base.

[0082] The present disclosure includes novel pharmaceutical dosage forms of mavacamten or a pharma- ceutically acceptable salt thereof. The dosage forms described herein are suitable for oral administration to a patient. The dosage form may be in any form suitable for oral administration, including, but not limited to, a capsule or tablet. In some embodiments, the present disclosure provides a single dose unit capsule or tablet containing 1 to 25 mg (e.g., 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 6 mg, 7 mg, 7.5 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 12.5 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, or 25 mg) of mavacamten or a pharma- ceutically acceptable salt thereof. In some embodiments, the amount of mavacamten in a dose unit is about 2-5 mg, about 5-10 mg, about 2.5 mg, or about 5 mg. In some embodiments, the dose unit form is a capsule. In some embodiments, the dose unit form is a tablet. In some embodiments, the pharmaceutical composition is a capsule filled with mavacamten, silicon dioxide, mannitol, hypromellose, croscarmellose sodium, and magnesium stearate. In some embodiments, the capsule shell comprises gelatin and, optionally, titanium dioxide, black iron oxide, red iron oxide, and / or yellow iron oxide.

[0083] Described herein are methods for safely administering myosin inhibitors. Various aspects of these methods include methods that include adjusting the dose of myosin inhibitor administered to the patient over time based on evaluation of the patient over time, particularly evaluation of left ventricular outflow tract obstruction and / or left ventricular ejection fraction, and discontinuing administration if certain conditions apply, methods of administering myosin inhibitors to patients when the patient is receiving concomitant administration of certain other drug(s), methods of administering myosin inhibitors in a manner that avoids adverse drug-drug interactions, and methods of controlling distribution of myosin inhibitors to mitigate risks.

[0084] The myosin inhibitor may be administered by suitable means as known and described in the art. In some embodiments, the myosin inhibitor is administered orally. In some embodiments, the myosin inhibitor is administered in a pharmaceutical composition. In some embodiments, the pharmaceutical composition is in an oral dosage form.

[0085] Examples of oral dosage forms include tablets, troches, lozenges, aqueous suspensions, oily suspensions, dispersible powders, dispersible granules, emulsions, hard capsules, soft capsules, syrups, elixirs, solutions, oral patches, oral gels, chewing gums, chewable tablets, effervescent powders, and effervescent tablets. In some embodiments, the oral dosage form is a capsule. In other embodiments, the oral dosage form is a tablet.

[0086] According to the present disclosure, the dosage of the myosin inhibitor may be adjusted over time, i.e., by increasing the dose, decreasing the dose, maintaining the dose, or interrupting (temporarily ceasing) administration. In some embodiments, the dose is adjusted in a stepwise manner. FIG. 1 shows an initiation phase of the myosin inhibitor administration scheme, during which the dose may be adjusted from one treatment period to the next. In the initiation phase, an initial dose is administered and then maintained or reduced. FIG. 2 shows a maintenance phase, during which the dose may be adjusted by interrupting treatment, maintaining the dose, or increasing the dose. FIG. 3 shows a treatment interruption phase of the administration scheme, during which treatment may be interrupted and then resumed at a lower dose than before. For example, the daily dose of mavacamten may be adjusted between some or all of the following daily doses: 0 mg, 2.5 mg, 5 mg, 10 mg, and 15 mg. For example, a dose of 5 mg QD may be administered and then either increased to 10 mg QD, decreased to 2.5 mg QD, or maintained at 5 mg QD. In some embodiments, the escalating dose may include 1 mg as an additional dose. In some embodiments, the escalating dose may include 7.5 mg as an additional dose. In embodiments described herein, 7.5 mg may be included as an additional dose level, or in embodiments describing an increase from 5 mg QD to 10 mg QD, an increase from 5 mg QD to 7.5 mg QD may be used instead, with further increases from 7.5 mg QD to 10 mg QD and from 10 mg QD to 15 mg QD possible in subsequent treatment periods based on relevant evaluation results.

[0087] In some embodiments, the dose is a total daily dose administered once daily (QD). In other embodiments, the dose is a total daily dose administered two separate times per day (twice daily, BID).

[0088] The present disclosure relates to a method for safely administering a myosin inhibitor to a patient. Various aspects and embodiments of such methods are described herein. In some embodiments, the method includes multiple treatment periods during which the myosin inhibitor is administered to the patient, or, optionally, during which administration is temporarily suspended. An evaluation may be performed at or near the end of the treatment period, and the evaluation may be used to determine whether the dose administered during that treatment period should be increased, maintained, reduced, or discontinued during a subsequent treatment period. The evaluation and corresponding dose adjustments result in the safe and effective administration of the myosin inhibitor.

[0089] The evaluation, which is described in more detail below, may include an evaluation of left ventricular outflow tract obstruction (e.g., Valsalva LVOT gradient) and / or an evaluation of left ventricular ejection fraction (LVEF). The evaluation may be performed during the treatment period or at or near the end of the treatment period, e.g., the last week of a multi-week treatment period. The dosage of the myosin inhibitor may be adjusted from one treatment period to the next based on the evaluation results. In some embodiments, a treatment period (e.g., a first treatment period) may be immediately followed by a next treatment period (e.g., a second treatment period). For example, a first treatment period on days 1-28 may be immediately followed by a second treatment period on days 29-56, with the myosin inhibitor being administered once a day on each of days 1-56. When there are multiple treatment periods, each treatment period may immediately follow the previous treatment period, with the myosin inhibitor being administered from one treatment period to the next without interruption. In other embodiments, administration of the myosin inhibitor may be interrupted between treatment periods.

[0090] In some embodiments, a starting dose of the myosin inhibitor is administered in the first treatment period. With reference to FIG. 1, a starting dose is administered in the first treatment period, and an evaluation to determine the dose to be administered in the second treatment period is performed at or near the end of the first treatment period. In some embodiments, the first treatment period is part of an initiation phase, during which the dose of the myosin inhibitor is not increased and may be decreased. As shown in FIG. 1, the dose may be decreased or maintained, but not increased, from the first treatment period to the second treatment period and from the second treatment period to the third treatment period. For example, as shown in FIG. 4, the initiation phase of mavacamten may have a starting dose of 5 mg QD of mavacamten. In some embodiments, the first treatment period is about 1 to about 12 weeks in duration. In some embodiments, the first treatment period is about 2 to about 12 weeks in duration. In some embodiments, the first treatment period is about 2 to about 8 weeks in duration. In some embodiments, the first treatment period is about 2 to about 6 weeks in duration. In some embodiments, the first treatment period is about 3 to about 4 weeks in duration. In some embodiments, the first treatment period is about 4 weeks in duration. In some embodiments, the first treatment period is about 20 to about 35 days in duration. In some embodiments, the first treatment period is about 22 to about 28 days in duration.

[0091] In some embodiments, a second dose of the myosin inhibitor is administered during the second treatment period (i.e., after the first treatment period). As shown in FIG. 1, the second dose is determined based on the results of the first assessment and administered during the second treatment period. Assessment is also performed at or near the end of the second treatment period to determine the dose to be administered during the third treatment period. In some embodiments, the second treatment period is part of an initiation phase during which the dose of the myosin inhibitor is not increased and may be decreased. In some embodiments, the second dose is equal to or less than the initiation dose. In some embodiments, the second dose is less than the initiation dose. In some embodiments, the second dose is the same as the initiation dose. For example, as shown in FIG. 4, the second dose of mavacamten may be 2.5 mg QD of mavacamten. As another example, as shown in FIG. 4, the second dose of mavacamten may be 5 mg QD of mavacamten. In some embodiments, the second treatment period is about 1 to about 12 weeks in duration. In some embodiments, the second treatment period is about 2 to about 12 weeks in duration. In some embodiments, the second treatment period is about 2 to about 8 weeks in duration. In some embodiments, the second treatment period is about 2 to about 6 weeks in duration. In some embodiments, the second treatment period is about 3 to about 4 weeks in duration. In some embodiments, the second treatment period is about 4 weeks in duration. In some embodiments, the second treatment period is about 20 to about 35 days in duration. In some embodiments, the second treatment period is about 22 to about 28 days in duration.

[0092] In some embodiments, a third dose of the myosin inhibitor is administered in the third treatment period (i.e., after the second treatment period). As shown in FIG. 1, the third dose is determined based on the second assessment and administered in the third treatment period. Assessment is also performed at or near the end of the third treatment period to determine the dose to be administered in the fourth treatment period. In some embodiments, the third treatment period is part of an initiation phase, during which the dose of the myosin inhibitor is not increased and may be decreased. In some embodiments, the third dose is equal to or less than the initiation dose. In some embodiments, the third dose is less than the initiation dose. In some embodiments, the third dose is equal to or less than the second dose. In some embodiments, the third dose is less than the second dose. In some embodiments, the third dose is equal to the second dose. In some embodiments, the third dose is 2.5 mg QD of mavacamten. For example, the third dose of mavacamten may be 5 mg QD of mavacamten. As another example, the third dose may be 1 mg QD of mavacamten. In some cases, the third dose of mavacamten is 0 mg QD of mavacamten. Figure 4 shows examples of various doses that may be administered as the third dose in the third treatment period. Administering 0 mg of a myosin inhibitor (e.g., mavacamten) in a treatment period refers to a period in which the myosin inhibitor (e.g., mavacamten) is discontinued from being administered to the patient. In some embodiments, the third dose is 0 mg QD or 1 mg QD of mavacamten, and the patient is a poor metabolizer. In some embodiments, the third dose is 0 mg QD or 1 mg QD of mavacamten and the patient is concomitantly administered a CYP2C19 inhibitor or inducer (e.g., a weak CYP2C19 inhibitor or inducer) or a CYP3A4 inhibitor or inducer (e.g., a weak or moderate CYP3A4 inhibitor or inducer). In some embodiments, no myosin inhibitor is administered during the third treatment period.In some embodiments, the third treatment period is about 1 to about 12 weeks in duration. In some embodiments, the third treatment period is about 2 to about 12 weeks in duration. In some embodiments, the third treatment period is about 2 to about 8 weeks in duration. In some embodiments, the third treatment period is about 2 to about 6 weeks in duration. In some embodiments, the third treatment period is about 3 to about 4 weeks in duration. In some embodiments, the third treatment period is about 4 weeks in duration. In some embodiments, the third treatment period is about 20 to about 35 days in duration. In some embodiments, the third treatment period is about 22 to about 28 days in duration.

[0093] In some embodiments, a fourth dose of the myosin inhibitor is administered in the fourth treatment period (i.e., after the third treatment period). As shown in FIG. 1, the fourth treatment period may be considered the beginning of a maintenance period following an initiation period. As shown in FIG. 2, the maintenance period uses criteria to increase the dose, maintain the same dose, or discontinue (temporarily discontinue) treatment based on the evaluation results (e.g., evaluation results of LVEF and LVOT slope). In some embodiments, the fourth treatment period is part of a maintenance period, during which the dose of the myosin inhibitor may be increased. In some embodiments, the fourth dose is greater than the third dose. In some embodiments, in which the fourth dose is greater than the third dose, this represents an increase in the first dose in treatment. That is, the fourth dose may be the first increased dose, and the fourth treatment period may be the first treatment period in which an increased dose is administered. In some embodiments, the fourth dose is the same as the third dose. In some embodiments, the fourth dose is 0 mg QD, 1 mg QD, 2.5 mg QD, 5 mg QD, or 10 mg QD of mavacamten. FIG. 5 shows examples of criteria for determining the fourth dose. In some embodiments, the fourth treatment period is about 2 to about 26 weeks (or 6 months) in duration. In some embodiments, the fourth treatment period is about 4 to about 24 weeks in duration. In some embodiments, the fourth treatment period is about 4 to about 16 weeks in duration. In some embodiments, the fourth treatment period is about 8 to about 24 weeks in duration. In some embodiments, the fourth treatment period is about 8 to about 16 weeks in duration. In some embodiments, the fourth treatment period is about 12 weeks (or about 3 months) in duration. In some embodiments, the fourth treatment period is about 80 to about 100 days in duration. In some embodiments, the fourth treatment period is about 84 to about 90 days in duration.

[0094] In some embodiments, a fifth dose of the myosin inhibitor is administered in the fifth treatment period (i.e., after the fourth treatment period). In some embodiments, the fifth treatment period is part of a maintenance phase, during which the dose of the myosin inhibitor may be increased. The fifth dose may be determined according to FIG. 2. In some embodiments, the fifth dose is greater than the fourth dose. In some embodiments, the fifth dose is the same as the fourth dose. In some embodiments, the fifth dose is 2.5 mg QD, 5 mg QD, 10 mg QD, or 15 mg QD of mavacamten. FIG. 5 shows examples of criteria for determining the fifth dose in the maintenance phase. In some embodiments, the fifth treatment period is about 2 to about 26 weeks (or 6 months) in duration. In some embodiments, the fifth treatment period is about 4 to about 24 weeks in duration. In some embodiments, the fifth treatment period is about 4 to about 16 weeks in duration. In some embodiments, the fifth treatment period is about 8 to about 24 weeks in duration. In some embodiments, the fifth treatment period is about 8 to about 16 weeks in duration. In some embodiments, the fifth treatment period is about 12 weeks (or about 3 months) in duration. In some embodiments, the fifth treatment period is about 80 to about 100 days in duration. In some embodiments, the fifth treatment period is about 84 to about 90 days in duration.

[0095] In some embodiments, the method further comprises additional treatment periods (i.e., a sixth treatment period, a seventh treatment period, etc.) after the fifth treatment period. These additional treatment periods may be part of a maintenance phase, during which the dose of the myosin inhibitor may be increased. In some embodiments, the dose administered during the additional treatment periods is determined according to Figure 2. In some embodiments, the additional treatment periods are equal in duration to the fourth and / or fifth treatment periods.

[0096] In some embodiments, administration of the myosin inhibitor is temporarily suspended, for example, during the first, second, third, fourth, or fifth treatment period. As shown in FIG. 3, the temporary suspension (treatment interruption) may be indicated based on the evaluation results, for example, based on LVEF. In some embodiments, the temporary suspension is for a period of about 1 to about 12 weeks, for example, about 2 to 8 weeks, about 3 to 4 weeks, or about 4 weeks. In some embodiments, the temporary suspension is performed in patients whose LVEF is lower than a safety threshold, for example, as described herein. In some embodiments, the temporary suspension is performed in patients whose LVOT gradient is lower than a threshold, for example, as described herein. For example, as shown in FIG. 6, the threshold may be 50%. That is, during treatment with a myosin inhibitor over multiple treatment periods, administration of the myosin inhibitor may be temporarily suspended when, during evaluation during the treatment period, the LVEF and / or LVOT gradient falls below a threshold, and the temporary suspension may be performed by not administering the myosin inhibitor during the treatment period immediately following the treatment period during which the evaluation was performed.

[0097] In some embodiments, administration of the myosin inhibitor is permanently discontinued. For example, it may be permanently discontinued after the second, third, fourth or fifth treatment period. In some embodiments, administration is permanently discontinued after a temporary discontinuation of treatment during a previous treatment period. In some embodiments, administration is permanently discontinued after a temporary discontinuation of treatment during a previous treatment period and resumption of treatment after the temporary discontinuation. As shown in FIG. 3, administration may be permanently discontinued if the LVEF is below the safety threshold for the second time when administered at the lowest dose (both times). Permanent discontinuation may be determined based on an evaluation, for example, an evaluation of the LVEF, resulting in an LVEF below the safety threshold. Specifically, in some embodiments, when administration was previously interrupted due to an LVEF below 50%, administration is permanently discontinued if the LVEF is below 50% upon evaluation after administration is resumed. For example, as shown in Figure 6, if administration of 2.5 mg QD mavacamten was previously discontinued due to an LVEF of <50%, administration will be permanently discontinued if the LVEF is <50% upon evaluation after resumption of administration with 2.5 mg QD mavacamten. In some embodiments, treatment may be resumed despite meeting the criteria for permanent discontinuation if the discontinuation was due to a transient cause.

[0098] Certain methods described herein include an initiation phase. In some embodiments, the initiation phase includes a first and a second treatment period. In some embodiments, the initiation phase includes a first, a second and a third treatment period. In some embodiments, the initiation phase includes a first, a second, a third and a fourth treatment period. In some embodiments, the initiation phase includes the first, a second and a third treatment period and a portion of the fourth treatment period. In some embodiments, the dose of the myosin inhibitor is not increased during the initiation phase. In some embodiments, the myosin inhibitor does not reach steady-state pharmacokinetics in certain patients (e.g., poor metabolizers) during the initiation phase or does not reach steady-state pharmacokinetics until at or near the end of the initiation phase. In some embodiments, the myosin inhibitor is mavacamten, and reaches steady-state pharmacokinetics in certain patients (e.g., poor metabolizers) after about 10 weeks of once-daily administration. In some embodiments, the myosin inhibitor is mavacamten, and reaches steady-state pharmacokinetics in certain patients (e.g., poor metabolizers) after about 12 weeks of once-daily administration.

[0099] Certain methods described herein include a maintenance phase. In some embodiments, the maintenance phase includes a fourth treatment period. In some embodiments, the maintenance phase includes a fifth treatment period. In some embodiments, the maintenance phase includes additional treatment periods after the fourth and fifth treatment periods. In some embodiments, the myosin inhibitor is at steady state during the maintenance phase or reaches steady state at or near the start of the maintenance phase.

[0100] In some embodiments, the myosin inhibitor is co-administered with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor. In some embodiments, the myosin inhibitor is co-administered with a weak CYP2D6 inhibitor (e.g., aficamten). When co-administered with such agents, additional steps may be required to ensure safe administration of the myosin inhibitor. As described above, mavacamten is primarily metabolized by CYP2C19 and secondarily metabolized by CYP3A4. Thus, agents that inhibit these enzymes may reduce mavacamten metabolism and increase exposure, especially in patients with poor metabolizer genotypes. In some embodiments, co-administration of a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor is initiated when the patient is receiving myosin inhibitor therapy. In some embodiments, co-administration is initiated when the patient is receiving a stable dose of the myosin inhibitor, for example, during the third, fourth, or fifth treatment period, or after the third, fourth, or fifth treatment period. In some embodiments, the weak CYP2C19 inhibitor or moderate CYP3A4 inhibitor is selected from the group consisting of cimetidine, ciprofloxacin, diltiazem, felbamate, omeprazole, isoniazid, fluconazole, and verapamil at a dose of 20 mg once daily.

[0101] Disclosed herein is a specific method for safely co-administering a myosin inhibitor with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor.In some embodiments, a first daily dose of a myosin inhibitor is administered during a first treatment period before starting combination therapy with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor, and a second daily dose of a myosin inhibitor is administered during a second treatment period, the second daily dose being less than the first daily dose, during which the patient receives combination therapy with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor. In some embodiments, disclosed are methods of treating HCM in a patient receiving a first daily dose of mavacamten, said patient requiring co-treatment with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor in addition to mavacamten, comprising administering to the patient a second daily dose of mavacamten that is less than the first daily dose in addition to the administration of the weak CYP2C19 inhibitor or moderate CYP3A4 inhibitor. In some embodiments, the myosin inhibitor is mavacamten, the first daily dose is 5 mg QD, 10 mg QD or 15 mg QD of mavacamten, and the second daily dose is 2.5 mg QD, 5 mg QD or 10 mg QD of mavacamten.

[0102] When a patient is on stable treatment with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor, administration of mavacamten may be initiated at an initial dose of 5 mg. Disclosed herein is a method of administering mavacamten to a patient receiving a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor, the method comprising: (a) determining that the patient is on stable treatment with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor; and (b) initiating administration of mavacamten to the patient at a daily dose of 5 mg per day.

[0103] Also disclosed herein is a method of administering a myosin inhibitor (e.g., mavacamten) to a patient undergoing myosin inhibitor therapy while initiating or increasing the dose of a negative inotropic combination therapy, comprising: (a) administering a therapeutically effective amount of the myosin inhibitor during a first treatment period; (b) continuing to administer the myosin inhibitor during a second treatment period, wherein the patient initiates or increases the dose of a negative inotropic combination therapy during the second treatment period; and (c) monitoring LVEF by echocardiography during the second treatment period. In some embodiments, monitoring LVEF by echocardiography is performed until a stable dose and clinical response is achieved. In some embodiments, the second treatment period is supervised by a physician.

[0104] Example 4 describes a study using drug interaction simulation based on the presentation that mavacamten is contraindicated with both strong and moderate inducers of CYP2C19 and CYP3A4.

[0105] Disclosed herein is a method for treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need of such treatment, comprising administering to the subject a therapeutically effective amount of mavacamten, wherein the patient is not also receiving concomitant administration of a strong or moderate CYP2C19 inducer or a strong or moderate CYP3A4 inducer.

[0106] Also disclosed in the present invention is a method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, the patient being treated with a strong or moderate CYP2C19 inducer, or a strong or moderate CYP3A4 inducer, the method comprising discontinuing administration of the strong or moderate CYP2C19 inducer, or the strong or moderate CYP3A4 inducer to the patient; and avoiding concomitant use of the strong or moderate CYP2C19 inducer, or mavacamten with the strong or moderate CYP3A4 inducer by administering a therapeutically effective amount of mavacamten to the subject.

[0107] In some embodiments, the disclosed methods include one or more evaluations of the patient. Exemplary schematics of the evaluations and corresponding dose adjustments are shown in Figures 1-3. The one or more evaluations can be used to determine the dose of myosin inhibitor to be administered to the patient. For example, the evaluation(s) during or at the end of the treatment period can be used to determine the dose of myosin inhibitor to be administered in the next treatment period, e.g., to increase, maintain, reduce, or discontinue the dose in the next treatment period. For example, Figure 1 shows an LVOT gradient assessment performed or obtained at the end of a treatment period, which is used to guide the dosage for the subsequent treatment period. In some embodiments, the evaluation(s) is performed at or near the end of the treatment period, e.g., in the last week of a multi-week treatment period.

[0108] In some embodiments, the patient is assessed for left ventricular outflow tract obstruction. In some embodiments, the patient is assessed for LVOT gradient. In some embodiments, the LVOT pressure gradient is measured at rest. In some embodiments, the LVOT pressure gradient in an individual is measured during or immediately after performing a Valsalva maneuver ("Valsalva LVOT gradient"). In some embodiments, the LVOT pressure gradient in an individual is measured after exercise. In some embodiments, the patient is assessed for LVEF.

[0109] In some embodiments, the assessment is performed using a non-invasive technique. In some embodiments, the non-invasive technique is an imaging technique (e.g., a cardiac imaging technique). In some embodiments, the non-invasive technique is echocardiography. In some embodiments, the non-invasive technique is two-dimensional echocardiography. In some embodiments, the two-dimensional echocardiography is used to determine LVEF. In some embodiments, the non-invasive technique is Doppler echocardiography. In some embodiments, Doppler echocardiography is used to determine LVOT gradient. In some embodiments, the non-invasive technique is transthoracic echocardiography. In alternative embodiments, the non-invasive technique is transesophageal echocardiography. A cardiac imaging technique may be used as the non-invasive technique. For example, cardiac magnetic resonance imaging may be used. Cardiac magnetic resonance imaging may be used to measure LVEF. An alternative technique for measuring LVEF and / or LVOT gradient is cardiac catheterization.

[0110] In some embodiments, the patient is evaluated for left ventricular outflow tract obstruction (e.g., LVOT gradient) at the end of each of two or more treatment periods, e.g., during the initiation phase, as shown in FIG. 1. Based on these evaluations, the patient may be administered a reduced dose to mitigate the risk of systolic dysfunction and heart failure. Multiple (i.e., more than one) evaluations of left ventricular outflow tract obstruction and corresponding dose adjustments have several advantages. First, by performing more than one evaluation during the initiation phase that can reduce the dose, the risk of adverse events for patients can be mitigated by identifying who would benefit from a dose reduction and who was not identified in the first evaluation (e.g., due to a dangerous exposure level not found in that first evaluation) in a second (or subsequent) evaluation. At the same time, because there are multiple opportunities to reduce the dose based on the evaluation of left ventricular outflow tract obstruction, a higher starting dose can be used, i.e., it is safe to start with a higher dose across the patient population. This benefits the majority of the patient population at low risk for adverse events by allowing them to receive a higher therapeutic dose during the initiation phase. Also, by performing more than one evaluation, additional patients who would benefit from a dose reduction can be identified at the second (or subsequent) evaluation, eliminating the need to be overly cautious in reducing the dose after the first evaluation. This results in more patients being able to maintain their starting dose throughout the initiation phase without dose reduction and potentially increase the dose at a later time point. Additionally, by performing more than one evaluation during the initiation phase that allows for dose reduction, patients who still have excessive drug exposure after a single dose reduction can have their dose further reduced or the drug temporarily discontinued. Example 2 describes an exemplary dosing scheme for mavacamten and provides data showing the advantage of performing two assessments of LVOT slope during the initiation phase to allow for corresponding dose reductions.

[0111] In some embodiments, the patient is evaluated for both LVOT gradient and LVEF during multiple treatment periods. In addition to evaluating the LVOT gradient, further risk mitigation may be achieved by using evaluation of LVEF. In some embodiments, the dose administered during a treatment period is determined based on evaluation of the LVOT gradient and LVEF during the previous treatment period (e.g., the last week of the previous treatment period). In some embodiments, and during some treatment periods, the results of the LVOT gradient and LVEF are used together to determine the dose adjustment, i.e., the dose for the next treatment period. For example, as shown in FIG. 2, if the LVEF is below a safety threshold, administration is discontinued during the next treatment period regardless of the result of the LVOT gradient, and if the LVOT gradient is below the threshold, a reduced dose (or an increased dose) is administered during the next treatment period regardless of the result of the LVEF, unless the result of the LVEF dictates that administration should be discontinued. In some embodiments, the results of the LVOT gradient and LVEF are used together to determine the dose for the next treatment period. For example, referring again to Figure 2, if the LVEF is above a threshold and the LVOT gradient is above a threshold, the dose is increased, but if either the LVEF falls below the threshold or the LVOT gradient falls below the threshold, the dose is maintained. In some embodiments, administration is discontinued (temporarily or permanently) when the LVEF falls below a safety threshold (e.g., 50%), regardless of the LVOT gradient measured at the same evaluation.

[0112] In some embodiments, the method does not include assessment of the pharmacokinetics of the myosin inhibitor in the patient during treatment, e.g., the method does not include assessment of blood plasma concentrations of the myosin inhibitor (e.g., mavacamten) during treatment.

[0113] In some embodiments, a pre-treatment assessment (or "baseline" assessment) is performed. In some embodiments, the pre-treatment assessment is performed up to about 12 weeks prior to the start of administration of the myosin inhibitor (e.g., up to about 8 weeks, up to about 4 weeks, about 8-12 weeks, about 6-10 weeks, about 4-8 weeks, about 2-6 weeks, or about 1-4 weeks prior to the start of administration). The pre-treatment assessment may include an assessment of LVEF, e.g., LVEF by echocardiography. A pre-treatment assessment result may be obtained from the pre-treatment assessment. Some methods may further include determining whether the pre-treatment assessment result is above or below a threshold. Some methods may further include determining whether the patient's LVEF is below a pre-treatment LVEF threshold. In some embodiments, the pre-treatment LVEF threshold is a percentage value between 40% and 65%, e.g., about 60%, about 55%, about 52%, or about 50%. In some embodiments, the pre-treatment LVEF threshold is about 55%. In some embodiments, the pre-treatment LVEF threshold is about 50%. In some embodiments, when the LVEF from the pre-treatment assessment is below the pre-treatment LVEF threshold, the patient is not administered a myosin inhibitor, and when the LVEF from the pre-treatment assessment is above the pre-treatment LVEF threshold, the patient is administered a starting dose of a myosin inhibitor during the first treatment period.

[0114] In some embodiments, a first evaluation is performed or obtained. With reference to FIG. 1, as a non-limiting example, the first evaluation is performed at or near the end of the first treatment period. In some embodiments, the first evaluation is performed during the last week of the first treatment period (e.g., days as described herein). For example, the first treatment period may be 28 days in duration, and the first evaluation results may be obtained on days 22 and 28 of the first treatment period. In some embodiments, the evaluation is performed during the last week of the treatment period. In some embodiments, the first evaluation includes evaluating left ventricular outflow tract obstruction by a non-invasive technique to obtain a first evaluation result. The method may further include determining whether the first evaluation result is above or below a threshold value. As shown in FIG. 1, the first evaluation may include evaluating the LVOT gradient. In some embodiments, the first evaluation includes evaluating the LVOT gradient with a Valsalva maneuver to obtain a first Valsalva LVOT gradient. In some embodiments, the non-invasive technique is an echocardiogram. In some embodiments, the non-invasive technique is an imaging technique. The method may further include determining whether the first Valsalva LVOT gradient is less than a Valsalva LVOT gradient threshold. The Valsalva LVOT gradient threshold may be a value between 20 mmHg and 30 mmHg, e.g., 20 mmHg, 25 mmHg, or 30 mmHg. In some embodiments, the Valsalva LVOT gradient threshold is about 20 mmHg.

[0115] In some embodiments, the first assessment includes (e.g., further includes) assessing the LVEF to obtain a first LVEF. The method may also include determining whether the first LVEF is above or below an LVEF threshold. The LVEF threshold may be a percentage value between 40% and 65%, e.g., about 60%, about 55%, about 52%, or about 50%. In some embodiments, the LVEF threshold is about 55%. In some embodiments, the LVEF threshold is about 50%. The first LVEF may be assessed using echocardiography. The first LVEF may be assessed using an imaging technique.

[0116] In some embodiments, a second assessment is performed or obtained. With reference to FIG. 1, the second assessment may be performed at or near the end of the second treatment period. In some embodiments, the second assessment is performed during the last week (e.g., a day as described herein) of the second treatment period. In some embodiments, the second assessment includes evaluating the left ventricular outflow tract obstruction by a non-invasive technique to obtain a second assessment result. The method may further include determining whether the second assessment result is above or below a threshold value. As shown in FIG. 1, the second assessment may include evaluating the LVOT gradient. In some embodiments, the second assessment includes evaluating the LVOT gradient with a Valsalva maneuver to obtain a second Valsalva LVOT gradient. In some embodiments, the non-invasive technique is an echocardiogram. In some embodiments, the non-invasive technique is an imaging technique. The method may further include determining whether the second Valsalva LVOT gradient is below a Valsalva LVOT gradient threshold value. The Valsalva LVOT gradient threshold may be between 20 mmHg and 30 mmHg, for example, a value of 20 mmHg, 25 mmHg, or 30 mmHg, hi some embodiments, the Valsalva LVOT gradient threshold is about 20 mmHg.

[0117] In some embodiments, the second assessment includes (e.g., further includes) assessing the LVEF to obtain a second LVEF. The method may also include determining whether the second LVEF is above or below an LVEF threshold. The LVEF threshold may be a percentage value between 40% and 65%, e.g., about 60%, about 55%, about 52%, or about 50%. In some embodiments, the LVEF threshold is about 55%. In some embodiments, the LVEF threshold is about 50%. The second LVEF may be assessed using echocardiography. The second LVEF may be assessed using an imaging technique.

[0118] Additional assessments similar to the first and second assessments may also be performed or obtained, for example during the initiation phase.

[0119] In some embodiments, a third assessment is performed or obtained. In some embodiments, the third assessment is performed at or near the end of the third treatment period (e.g., a date as described herein). For example, the third assessment may be performed in the last week of the third treatment period. In some embodiments, the third assessment may be considered a transition point from the initiation phase to the maintenance phase. In some embodiments, the third assessment includes evaluating left ventricular outflow tract obstruction by a non-invasive technique to obtain a third assessment result. The method may further include determining whether the third assessment result is above or below a threshold value. In some embodiments, the third assessment includes evaluating the LVOT gradient with a Valsalva maneuver to obtain a third Valsalva LVOT gradient. In some embodiments, the non-invasive technique is an echocardiogram. In some embodiments, the non-invasive technique is an imaging technique. The method may further include determining whether the third Valsalva LVOT gradient is greater than a Valsalva LVOT gradient threshold value. The threshold for the Valsalva LVOT gradient may be between 20 mmHg and 35 mmHg, for example, a value of 20 mmHg, 25 mmHg, 30 mmHg or 35 mmHg.

[0120] In some embodiments, the third assessment includes assessing the LVEF to obtain a third LVEF. The method may also include determining whether the third LVEF is above or below an LVEF threshold. The LVEF threshold may be a percentage value between 40% and 65%, e.g., about 60%, about 55%, about 52%, or about 50%. In some embodiments, the LVEF threshold is about 55%. In some embodiments, the LVEF threshold is about 50%. The third LVEF may be assessed using echocardiography. The third LVEF may be assessed using an imaging technique.

[0121] Additional assessments similar to the third assessment may be performed or obtained, for example, at or near the end of the fourth or fifth treatment period (eg, on dates as described herein).

[0122] The various assessments described herein may further include assessing other symptoms of the patient, e.g., other oHCM symptoms (e.g., new dyspnea, worsening dyspnea, chest pain, fatigue, palpitations, leg edema, or elevated N-terminal (NT) prohormone b-type natriuretic peptide (NT proBNP)).

[0123] The dosage of the myosin inhibitor may be adjusted based on one or more assessments, such as LVOT gradient(s) and / or LVEF(s) as described herein. In some embodiments, when the first assessment is below the LVOT gradient threshold, the starting dose is reduced, for example to the second dose. With reference to FIG. 1, when the LVOT gradient is below the threshold, the dose is reduced, and when the LVOT gradient is equal to or above the threshold, the dose is maintained. With reference to FIG. 4, as an example, when the first Valsalva LVOT gradient is less than 20 mmHg, the starting dose of 5 mg QD mavacamten is reduced to 2.5 mg QD. The second dose (e.g., 2.5 mg QD mavacamten) is administered until another assessment is performed. With reference again to FIG. 1, in some embodiments, when the first assessment is equal to or above the LVOT gradient threshold, the starting dose is maintained, for example, the second dose is the same as the starting dose. Referring again to FIG. 4, by way of example, if the first Valsalva LVOT gradient is ≧20 mmHg, mavacamten is continued at 5 mg QD until another evaluation is performed.

[0124] In some embodiments, when the second evaluation result is below the LVOT gradient threshold, the second dose is reduced, for example, to the third dose. With reference to FIG. 1, when the LVOT gradient is below the threshold, the dose is reduced or discontinued, and when the LVOT gradient is equal to or above the threshold, the dose is maintained. With reference to FIG. 4, for example, at week 8, when the Valsalva LVOT gradient is less than 20 mmHg, the dose is reduced, and when the Valsalva LVOT gradient is equal to or above 20 mmHg, the dose is maintained. In some embodiments, when the second Valsalva LVOT gradient is less than 20 mmHg, the dose of 2.5 mg QD mavacamten is reduced to 1 mg QD or reduced to 0 mg (or the dose of 5 mg QD mavacamten is reduced to 2.5 mg QD). The third dose (for example, 0 mg QD or 1 mg QD mavacamten, or 2.5 mg QD) is administered until another evaluation is performed. In some embodiments, if the second assessment is above the LVOT gradient threshold, the second dose is maintained, e.g., the third dose is the same as the second dose. In some embodiments, if the second Valsalva LVOT gradient is above 20 mmHg, administration of the second dose (e.g., 2.55 mg QD or 5 mg QD of mavacamten) is continued (as the third dose) until another assessment is performed.

[0125] In some embodiments, when the third evaluation result is above the LVOT gradient threshold, the third dose is increased, for example, to the fourth dose. Figure 1 shows the administration scheme before the maintenance phase. Figure 2 shows the criteria for the maintenance phase, in which the LVOT gradient is combined with, for example, the evaluation of LVEF to guide the dose adjustment. When the LVOT gradient is above the threshold, the dose may be increased if the LVEF is greater than the LVEF threshold. With reference to Figure 5, as an example, when the third Valsalva LVOT gradient is above 30mmHg, the third dose (for example, 0mg QD or 1mg QD of mavacamten) is increased to 2.5mg (or the 2.5mg dose is increased to 5mg QD, or the 5mg dose is increased to 10mg QD or 7.5mg QD). The fourth dose (for example, 2.5mg QD of mavacamten, or 5mg QD, 7.5mg QD, or 10mg QD) is administered until another evaluation is performed. In some embodiments, if the third assessment is below the LVOT gradient threshold, the third dose is maintained, e.g., the fourth dose is the same as the third dose. In some embodiments, if the third Valsalva LVOT gradient is less than 30 mmHg, administration of the third dose (e.g., 0 mg QD, 1 mg QD, 2.5 mg QD or 5 mg QD of mavacamten) is continued (as the fourth dose) until another assessment is performed.

[0126] In some embodiments, the third assessment includes assessing LVEF. In some embodiments, LVEF is compared to an LVEF threshold (e.g., about 50%, about 52%, about 55%, or about 60%). In some embodiments, when the LVEF at the third assessment is less than the LVEF threshold (e.g., 55%), the dose is not increased even if the Valsalva LVOT gradient is equal to or greater than the Valsalva LVOT gradient threshold (e.g., even if the Valsalva LVOT gradient is equal to or greater than 30 mmHg). In order to increase the dose, both the LVEF and the LVOT gradient must be equal to or greater than their respective thresholds, as shown in FIG. 2. Referring to FIG. 5, as an example, at week 12, if the Valsalva LVOT gradient is equal to or greater than 30 mmHg and the LVEF is equal to or greater than 55%, the dose is increased, otherwise the dose is maintained (assuming that the criteria for temporary discontinuation (interruption of administration) are not met).

[0127] In some embodiments, if the fourth assessment is above the LVOT gradient threshold, the fourth dose is increased, for example to the fifth dose. The criteria for this assessment and dose adjustment may follow the maintenance criteria as shown in FIG. 2. In some embodiments, if the fourth Valsalva LVOT gradient is above 30 mmHg, the dose of the myosin inhibitor is increased (e.g., 0 mg QD or 1-2.5 mg QD mavacamten, 2.5-5 mg QD mavacamten, 5-10 mg QD mavacamten or 10-15 mg QD mavacamten, or 5-7.5 mg QD or 7.5-10 mg QD mavacamten). The fifth dose is then administered until another assessment is performed. In some embodiments, if the fourth assessment is below the LVOT gradient threshold, the fourth dose is maintained, for example, the fifth dose is the same as the fourth dose. In some embodiments, if the fourth Valsalva LVOT gradient is less than 30 mmHg, administration of the fourth dose (e.g., 0 mg QD, 1 mg QD, 2.5 mg QD, 5 mg QD, 7.5 mg QD or 10 mg QD of mavacamten) is continued (as a fifth dose) until another evaluation is performed.

[0128] In some embodiments, the fourth assessment includes assessing LVEF. In some embodiments, the LVEF is compared to an LVEF threshold (e.g., about 50%, about 52%, about 55%, or about 60%), for example as shown in Figure 2. In some embodiments, if the LVEF at the fourth assessment is less than the LVEF threshold (e.g., 55%), the dose is not increased even if the Valsalva LVOT gradient is equal to or greater than the LVOT gradient threshold (e.g., even if the Valsalva LVOT gradient is 30 mmHg or greater).

[0129] In some embodiments, when the dose of the myosin inhibitor is increased, for example, during the maintenance phase, an additional assessment is made. In some embodiments, the additional assessment is an assessment of LVEF. For example, when the dose of the myosin inhibitor is increased, following the third assessment at the end of the third treatment period (e.g., the beginning of the maintenance phase), an additional assessment of LVEF is made during the fourth treatment period. In some embodiments, an additional assessment of LVEF is made about 4 weeks after the dose increase.

[0130] 3, in some embodiments, when the evaluation results include LVEF and LVEF being below a safety threshold (e.g., below 50%), administration of the myosin inhibitor is interrupted (temporarily discontinued). In some embodiments, when the evaluation results include LVEF and LVEF being equal to or above a safety threshold (e.g., below 50%), administration of the myosin inhibitor is continued (e.g., at the same dose or a different dose). The evaluation of LVEF may be determined at or near the end of the first, second, third, fourth, or fifth treatment period. In some embodiments, the evaluation of LVEF is performed at or near the end of a treatment period (e.g., the first treatment period), and the temporary discontinuation includes not administering the myosin inhibitor in the next treatment period (e.g., the second treatment period).

[0131] With further reference to FIG. 3, in some embodiments, after temporary discontinuation, administration of the myosin inhibitor is resumed after a subsequent assessment of LVEF indicates that the LVEF is equal to or above a safety threshold (e.g., 50%). In some embodiments, administration is resumed at a lower dose than that taken immediately prior to temporary discontinuation. In some embodiments, administration is resumed at the same dose taken immediately prior to temporary discontinuation, for example, when it is determined that the discontinuation was due to a temporary cause (e.g., atrial fibrillation or other uncontrolled tachyarrhythmia or severe infection). In some embodiments, administration is resumed at the lowest dose of the myosin inhibitor that is the lowest dose approved for administration to the patient by a government regulatory agency. In some embodiments, the government regulatory agency is an agency in the United States, the European Union, Switzerland, Japan, China, South Korea, Canada, Mexico, Australia, New Zealand, Brazil, Russia, Ukraine, Georgia, Vietnam, Singapore, Malaysia, Philippines, India, Indonesia, Hong Kong, Israel, South Africa, Colombia, Costa Rica, Dominican Republic, Ecuador, Guatemala, El Salvador, Honduras, Egypt, Syria, Algeria, Kenya, Morocco, or Nigeria.

[0132] In some embodiments, the evaluation results include LVEF and LVEF below a safety threshold (e.g., below 50%), and permanently discontinuing administration of the myosin inhibitor when administration of the myosin inhibitor is resumed after previously being temporarily discontinued.

[0133] Referring again to FIG. 3, in some embodiments, the assessment results include LVEF and LVEF being below a safety threshold (e.g., below 50%), where administration of the myosin inhibitor is permanently discontinued when administration of the myosin inhibitor was previously resumed after previously being temporarily discontinued due to a previous assessment of LVEF below 50%.

[0134] Referring to FIG. 6, by way of example, in some embodiments, the assessment results include LVEF and LVEF less than 50%, and the patient is receiving 2.5 mg QD of mavacamten and the administration of the myosin inhibitor is permanently discontinued when the patient has previously been resumed at a dose of 2.5 mg QD of mavacamten after previously temporarily discontinuing the administration of the myosin inhibitor due to a LVEF less than 50% in a previous assessment where the patient was receiving 2.5 mg QD of mavacamten.

[0135] Methods involving the co-administration of a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor may also be evaluated. In some embodiments, the evaluation includes evaluating the patient's LVEF during the treatment period in which the co-administration is initiated, and the administration of the myosin inhibitor is temporarily suspended if the LVEF falls below a safety threshold. In some embodiments, the safety threshold is 50%. In some embodiments, the evaluation includes evaluating the patient's LVEF and LVOT gradient after the administration is discontinued, and administration is resumed when the LVOT gradient exceeds the LVOT gradient threshold and the LVEF is equal to or greater than the LVEF threshold. In some embodiments, the LVOT gradient threshold is 30 mmHg and the LVEF threshold is 55%. In some embodiments, the evaluation of the patient's LVEF includes evaluating the patient's LVEF about 4 weeks after the start of the combination therapy or during the 4th week after the start of the combination therapy.

[0136] In some embodiments, the methods of the invention include establishing, adhering to, and / or enforcing protocols and restrictions for pharmacies and patients regarding dispensing of the myosin inhibitor or pharmaceutical composition thereof. The protocols and restrictions may be part of a Risk Evaluation and Risk Mitigation Strategy (REMS) program. In some embodiments, the objective of the REMS program is to mitigate the risk of heart failure due to systolic dysfunction. In some embodiments, the REMS educates prescribers, patients, and pharmacies about the risk of heart failure due to systolic dysfunction, certifies prescribers and pharmacies in the REMS, enrolls patients in the REMS, and restricts certified pharmacies to dispensing mavacamten to enrolled patients only with prescriptions written by certified prescribers and for patients with a current Patient Status Form (PSF), which indicates echocardiograms performed at the required frequency (e.g., as described herein for echocardiographic assessment of Valsalva LVOT gradient and LVEF). In some embodiments, the certified pharmacies distribute mavacamten in accordance with the requirements of the REMS.

[0137] In some embodiments, the risk mitigation methods of the invention include submitting a Patient Status Form (PSF) following the assessment as described herein. For example, the PSF is completed following an echocardiogram assessing the LVOT gradient and / or LVEF and submitted to a risk management manager. In some embodiments, the PSF is completed and submitted within 1, 2, or 3 days (e.g., within 2 days) of the echocardiogram assessment. In some embodiments, the PSF includes a physician's statement regarding the assessment results, e.g., whether the LVOT gradient is above or below a threshold and / or the LVEF is above or below a threshold.

[0138] In some embodiments, the risk mitigation methods of the invention include a dispensing limit, where a certain number of days of medication is requested, administered, and / or received. In some embodiments, the dispensing limit amount of the myosin inhibitor (or pharmaceutical composition thereof) is a 28-90 day supply, a 28-56 day supply, or a 30-40 day supply, e.g., a 35 day supply. For example, in some embodiments, the method includes requesting a pharmacy, hospital, physician, or patient to dispense the myosin inhibitor (or pharmaceutical composition thereof), where the requested amount is equal to the dispensing limit amount (e.g., a 35 day supply).

[0139] Figure 8 shows the timeline for echocardiogram evaluation, PSF submission, and dispensing for the first 14 weeks from initiation of myosin inhibitor therapy. Implementation rules are defined as follows: Every "X week echo" must occur within that week (e.g., week 4 echo must occur between days 22-28). Prescribers are educated to schedule the patient's week 4, 8, and 12 echoes at the start of therapy to accommodate scheduling approximately 4 weeks apart. Prescribers are educated to submit the PSF within 2 days of the echo. There is a deadline programmed into the REMS admin portal for PSF submission within 3 days of the echo deadline (e.g., for week 4, the deadline is day 31). Dispensing is withheld until the PSF is received. Once the PSF is received, pharmacy authorization and dispensing is performed (e.g., for week 4, this can occur anywhere between days 22-31). The pharmacy must verify the PSF submission and authorize the dispensing by the PSF submission deadline (e.g., in week 4, the pharmacy must authorize the dispensing by day 31). Based on this rule, the patient will receive a new dispensing from the day of the echo to 4 days after the PSF submission deadline (based on the typical time range between pharmacy authorization and patient receipt of the drug being 0-4 days with an average of 2 days). The 35-day dispensing limit ensures that drug availability is not hindered while the prescriber is interpreting the first echo, submitting the PSF, and the dispensing is authorized by the pharmacy and shipped to the patient. Figure 9 shows the echocardiogram evaluation and dispensing schedule for the first year from the initiation of myosin inhibitor therapy. From year 2 onwards, dispensing will increase to a 90-day limit while the patient is on a stable dose (i.e., no dose change within 12 weeks), and if the patient requires a dose change, there will be a 35-day limit on the dispensing. Once the patient is back on a stable dose, dispensing will return to the 90 day limit.

[0140] In some embodiments, the present invention discloses a method of controlling the distribution of a myosin inhibitor, the method comprising accrediting healthcare providers and pharmacies in a risk mitigation program, enrolling patients in the risk mitigation program, receiving a patient status form containing information regarding one or more echocardiogram evaluations of a patient being treated with a myosin inhibitor, receiving confirmation that a drug interaction screen has been performed, processing the patient status form, and authorizing the pharmacy to dispense the myosin inhibitor, wherein the certification is subject to dispensing restrictions.

[0141] In some embodiments, the information regarding one or more echocardiogram assessments in the patient status report includes (i) information regarding the Valsalva LVOT gradient of the patient being treated with a myosin inhibitor, and (ii) information regarding the LVEF of the patient being treated with a myosin inhibitor. In some embodiments, the information regarding the Valsalva LVOT gradient is information regarding whether a Valsalva LVOT gradient was determined. In some embodiments, the information regarding the Valsalva LVOT gradient is information regarding whether a Valsalva LVOT gradient is above or below one or more threshold(s). In some embodiments, the information regarding the LVEF is information regarding whether a LVEF was determined. In some embodiments, the information regarding the LVEF is information regarding whether the LVEF is above or below one or more threshold(s). In some embodiments, the method further includes providing information regarding drug interactions. In some embodiments, the dispensing limit is a 28-90 day supply, a 28-56 day supply, or a 30-40 day supply, e.g., a 35 day supply, of a myosin inhibitor to the pharmacy. In some embodiments, the patient status report must be submitted within a predetermined time frame, e.g., at or near the end of a treatment period, as described herein. In some embodiments, the method includes verifying that an echocardiogram was performed within the predetermined time frame and / or that a patient status report containing echocardiogram information was submitted within the predetermined time frame. In some embodiments, if the patient status report is not received within the predetermined time frame and / or if the echocardiogram is not performed within the predetermined time frame, dispensing will not be allowed.

[0142] In some embodiments, the method further includes withholding dispensing of the drug until the patient status is received. In some embodiments, the method further includes withholding dispensing of the drug until a complete patient status is received and continuing to withhold dispensing of the drug when an incomplete patient status is received. In some embodiments, the method further includes withholding dispensing of the drug when the patient status indicates that the patient's LVEF is less than 50%. In some embodiments, the information regarding the one or more echocardiogram evaluations in the patient status is received via a web-based portal. In some embodiments, receiving confirmation that a drug interaction screen has been performed includes receiving confirmation from a pharmacy and / or a healthcare provider. In some embodiments, receiving confirmation that a drug interaction screen has been performed includes receiving confirmation from both a pharmacy and a healthcare provider. In some embodiments, receiving confirmation that a drug interaction screen has been performed further includes receiving confirmation from a healthcare provider that no drug interactions are present. In some embodiments, receiving confirmation that a drug interaction screen has been performed further includes receiving confirmation from a pharmacy that no drug interactions are present.

[0143] In some embodiments, the patient status report is received via a data storage facility. The data storage facility may include a database of patient records, each patient record having a dispensing authorization field for entering a first prescription for mavacamten. The REMS system may further include a central controller having one or more processors connected to a communications network, the central controller connected to the data storage facility and reading and writing data to the data storage facility via the network. The REMS system may further include a drug storage facility where the mavacamten is stored. The central controller of the system may be programmed to monitor drug inventory in the drug storage facility and may be further programmed to control dispensing of the mavacamten from the drug storage facility.

[0144] The central controller may control the transmission and reception of data from the data storage facility via the network. The central controller may be programmed to output, via the network, a first dispensing authorization for a first prescription of mavacamten to a given patient who has previously been evaluated (e.g., as described herein). In some embodiments, the output of the dispensing authorization depends on the results of the evaluation, e.g., echocardiogram, LVOT gradient, LVEF. The central controller may be further programmed to output a time period during which the patient is authorized to use mavacamten, and to schedule a subsequent evaluation for the patient that requires receipt of subsequent test results for the patient before the patient is authorized to receive additional mavacamten. The central controller may be programmed to take an action selected from the output of authorization for additional prescriptions, modifications to the prescription, and a suggestion to discontinue the prescription, depending on the subsequent test results.

[0145] 21, in some embodiments, the exemplary drug dispensing authorization system 100 includes a remote system 140 that communicates with one or more user devices 10, e.g., via one or more networks. The remote system 140 may be a single computer, multiple computers, or a distributed system (e.g., a cloud environment) having scalable / elastic resources 142 including computing resources 144 (e.g., data processing hardware) and / or storage resources 146 (e.g., memory hardware). A data store 148 (i.e., a remote storage device) may be overlaid on top of the storage resources 146 to enable scalable use of the storage resources 146 by one or more clients (e.g., user devices 10) or computing resources 144. Additionally or alternatively, the data store 148 may be separate from the remote system 140, which communicates with the data store, e.g., via a network.

[0146] The remote system 140 executes a dispensing authorization controller 150. The dispensing authorization controller 150 obtains or receives a healthcare professional (HCP) assessment record 20 associated with the patient 14. The HCP assessment record 20 includes a treatment outcome 22 or an assessment as described herein. In some embodiments, the treatment outcome 22 includes an echocardiogram result. For example, the echocardiogram result may include a left ventricular ejection fraction (LVEF), a left ventricular outflow tract (LVOT) gradient, etc. derived from processing of the echocardiogram. In some examples, the HCP assessment record 20 includes a risk of a risk event (e.g., one or more clinical heart failure events) and / or a risk of a potential drug-drug interaction. The dispensing authorization controller 150 may receive the HCP assessment record 20 from a healthcare provider 12 via a user device 10 (e.g., at a doctor's office, hospital, or other facility of the healthcare provider).

[0147] The dispensing authorization controller 150 also obtains a pharmacy assessment record 30 associated with the patient 14. The pharmacy assessment record 30 includes the medical condition 32 of the patient 14 (e.g., cardiac conditions, allergies, etc.). Additionally or alternatively, the pharmacy assessment record 30 includes concomitant medications, concomitant supplements, and / or potential drug-drug interactions. The dispensing authorization controller 150 may obtain or receive the pharmacy assessment record 30 from the pharmacy 34 or other entity on behalf of the pharmacy 34. The HCP assessment record 20 and / or the pharmacy assessment record 30 may be stored in the data store 148 along with any other number of other records 20, 30 for any number of patients 14. The healthcare provider 12, the pharmacy 34, and any other entity may automatically upload the records 20, 30 to the data store 148 as they become available. Alternatively, the dispensing authorization controller 150 may request the records 20, 30 (e.g., periodically or on-demand) and store the received records 20, 30 in the data store 148.

[0148] The dispensing authorization controller 150 may use the HCP evaluation record 20 to determine whether the patient 14 is authorized to receive a prescription authorization 152 that authorizes the patient 14 to use the prescription drug 36. In some examples, the prescription drug includes a myosin inhibitor, such as mavacamten. In some embodiments, the dispensing authorization controller 150 determines whether the patient 14 is authorized to take the prescription drug 36 in response to a prescription request (e.g., from the patient 14, the healthcare provider 12, and / or the pharmacy 34). In some examples, a healthcare provider (e.g., a healthcare provider at the pharmacy 34, such as a pharmacist) determines whether the prescription authorization 152 is valid (e.g., by querying the dispensing authorization controller 150 and / or the data store 148). When the healthcare provider determines that the patient 14 has prescription authorization 152, the healthcare provider may provide the pharmacy evaluation record 30 to the dispensing authorization controller 150. That is, in some examples, a healthcare provider (eg, a pharmacist) provides the pharmacy evaluation record 30 to the dispensing authorization controller 150 and / or data store 148 upon receipt or verification of a prescription authorization 152 .

[0149] When the patient 14 is authorized to receive a prescription authorization 152 (e.g., when the treatment outcome 22 indicates that the patient 14 is a sufficient candidate for the prescription drug 36), the dispensing authorization controller 150 uses the pharmacy evaluation record 30 to determine whether the pharmacy 34 is authorized to dispense the prescription drug 36 to the patient 14. For example, the dispensing authorization controller 150 may determine whether the pharmacy evaluation record 30 contains sufficient pharmacy information (e.g., regarding the patient's medical condition 32), concomitant medications and supplements, and / or potential drug-drug interactions (e.g., with other medications that the patient 14 is taking).

[0150] When the pharmacy 34 is authorized to dispense the prescription to the patient 14 , the dispensing authorization controller 150 creates a dispensing authorization 154 and transmits the prescription authorization 152 and / or the dispensing authorization 154 to the pharmacy 34 .

[0151] The pharmacy 34 may dispense or distribute the prescription drug 36 to the patient 14 as authorized by the dispensing authorization 154. For example, the dispensing authorization 154 may include the amount of the prescription drug 36 that the patient 14 is authorized to take and / or the period of time that the patient 14 is authorized to take the prescription drug 36 (e.g., a dosing schedule indicating the time and / or frequency to take the prescription drug 36). The dispensing authorization controller 150 may use the HCP evaluation record 20 and / or the pharmacy evaluation record 30 to determine that the dispensing authorization 154 indicates a non-standard delivery amount of the prescription drug 36 (e.g., an amount and / or frequency that is greater than or less than a standard delivery amount or dosage).

[0152] The pharmacy 34 may request an updated or new dispensing authorization 154 before adjusting the quantity, duration, or any other parameters in distributing the prescription drug 36 to the patient 14. In some embodiments, the dispensing authorization controller 150 determines whether an updated dispensing result 22 associated with the patient 14 is available (e.g., after the period of time has passed).

[0153] For example, the dispensing authorization controller 150 determines whether a new or updated dispensing result 22 is available from the healthcare provider 12 or the data store 148 (e.g., the patient 14 has undergone a second procedure to obtain an updated dispensing result 22). When an updated dispensing result 22 is not available, the dispensing authorization controller 150 may decline to update the dispensing authorization 154, i.e., prevent the pharmacy from adjusting the amount or duration of the prescription 36 (e.g., not allow any refills). When an updated dispensing result 22 is available, the dispensing authorization controller 150 may update with the updated dispensing authorization 154. For example, the updated dispensing authorization may adjust the amount of the prescription 36 that the patient 14 is authorized to take and / or adjust the duration (e.g., the dosing schedule) that the patient 14 is authorized to take the prescription 36.

[0154] In some embodiments, the dispensing authorization controller 150 creates a record when the patient 14 is not authorized to take the prescription medication 36 and / or the pharmacy 34 is not authorized to dispense the prescription medication 36 to the patient 14. For example, when the HCP assessment record 20 and / or the pharmacy assessment record 30 contain insufficient reported information (e.g., regarding a history of clinical heart failure), the dispensing authorization controller 150 automatically creates a record that contains or references the insufficient information and transmits the record to one or more regulatory authorities.

[0155] 22 is a flowchart of an exemplary sequence of operations of a computer implemented method 2200 that, when executed by the data processing hardware 144, causes the data processing hardware 144 to perform the operations. The method 2200 includes, in operation 2202, obtaining an HCP assessment record 20 associated with the patient 14. The HCP assessment record includes a treatment outcome 22. The method 2200 includes, in operation 2204, using the HCP assessment record 20 to determine whether the patient 14 is authorized to receive a prescription authorization 152 authorizing use of a prescription drug 36. When the patient 14 is authorized to take the prescription drug 36, the method 2200 includes, in operation 2206, obtaining a pharmacy assessment record 30 associated with the patient 14. The pharmacy assessment record 30 includes a medical condition 32 of the patient 14. The method 2200 includes, in operation 2208, using the pharmacy assessment record 30 to determine whether the pharmacy 34 is authorized to dispense the prescription drug 36 to the patient 14. When the pharmacy 34 is authorized to dispense the prescription 36 to the patient 14 , the method 2200 also includes generating a dispensing authorization 154 at operation 2210 and transmitting the dispensing authorization 154 to the pharmacy 34 at operation 2212 .

[0156] 24 is a flowchart of an example of an alternative arrangement of operations of a computer-implemented method 200 that, when executed by the data processing hardware 144, causes the data processing hardware 144 to perform the operations. The method 200 includes, in operation 202, obtaining an HCP assessment record 20 associated with the patient 14. The HCP assessment record includes treatment outcomes 22. The method 200 includes, in operation 204, obtaining a pharmacy assessment record 30 associated with the patient 14. The pharmacy assessment record 30 includes medical conditions 32 of the patient 14. The method 200 includes, in operation 206, using the HCP assessment record 20 to determine whether the patient 14 is authorized to receive a prescription authorization 152 authorizing use of a prescription drug 36. When the patient 14 is authorized to take the prescription drug 36, the method 200 includes, in operation 208, determining using the pharmacy evaluation record 30 whether the pharmacy 34 is authorized to dispense the prescription drug 36 to the patient 14; and, when the pharmacy 34 is authorized to dispense the prescription drug 36 to the patient 14, creating a dispensing authorization 154 in operation 210 and transmitting the dispensing authorization 154 to the pharmacy 34 in operation 212.

[0157] 23 is a schematic diagram of an exemplary computing device 2300 that may be used to implement the systems and methods described herein. The computing device 2300 is intended to represent various forms of digital computers, such as laptops, desktops, workstations, personal digital assistants, servers, blade servers, mainframes, and other suitable computers. The components, their connections and relationships, and their functions shown herein are intended to be exemplary only and are not intended to limit the embodiments of the invention described and / or claimed herein.

[0158] Computing device 2300 includes processor 2310, memory 2320, storage device 2330, high-speed interface / controller 2340 connected to memory 2320 and high-speed expansion port 2350, and low-speed interface / controller 2360 connected to low-speed bus 2370 and storage device 2330. Each of components 2310, 2320, 2330, 2340, 2350, and 2360 are interconnected using various buses and may be mounted on a common motherboard or otherwise, as appropriate. Processor 2310 processes instructions for execution within computing device 2300, including instructions stored in memory 2320 or on storage device 2330, to display graphical information for a graphical user interface (GUI) on an external I / O device, such as display 2380, connected to high-speed interface 2340. In other embodiments, multiple processors and / or multiple buses may be used, along with multiple memories and multiple types of memories, as appropriate. Additionally, multiple computing devices 2300 may be connected (eg, as a server bank, a group of blade servers, or a multi-processor system) with each device providing a portion of the required work.

[0159] The memory 2320 stores information non-transiently within the computing device 2300. The memory 2320 may be a computer readable medium, a volatile memory unit(s) or a non-volatile memory unit(s). The non-transient memory 2320 may be a physical device used to store programs (e.g., instruction sequences) or data (e.g., program state information) on a temporary or permanent basis for use by the computing device 2300. Examples of non-volatile memory include, but are not limited to, flash memory, read-only memory (ROM) / programmable read-only memory (PROM) / erasable programmable read-only memory (EPROM) / electrically erasable programmable read-only memory (EEPROM) (e.g., typically used for firmware such as boot programs). Examples of volatile memory include, but are not limited to, random access memory (RAM), dynamic random access memory (DRAM), static random access memory (SRAM), phase change memory (PCM), and disk or tape.

[0160] The storage device 2330 can provide mass storage for the computing device 2300. In some implementations, the storage device 2330 is a computer-readable medium. In various different implementations, the storage device 2330 can be a floppy disk device, a hard disk device, an optical disk device, a tape device, a flash memory or other similar solid-state memory device, or an array of devices including devices in a storage area network or other configuration. In additional implementations, a computer program product is tangibly embodied in an information carrier. The computer program product includes instructions that, when executed, perform one or more methods as described above. The information carrier is a computer-readable medium or a machine-readable medium, such as the memory 2320, the storage device 2330, or memory on the processor 2310.

[0161] The high-speed controller 2340 manages bandwidth-intensive tasks for the computing device 2300, while the low-speed controller 2360 manages less bandwidth-intensive tasks. Such duty allocation is merely exemplary. In some implementations, the high-speed controller 2340 is connected to the memory 2320, the display 2380 (e.g., through a graphics processor or accelerator), and the high-speed expansion port 2350 (which can accept various expansion cards (not shown)). In some implementations, the low-speed controller 2360 is connected to the storage device 2330 and the low-speed expansion port 2390. The low-speed expansion port 2390 may include various communication ports (e.g., USB, Bluetooth, Ethernet, wireless Ethernet), but may also be connected to one or more input / output devices, such as a keyboard, pointing device, scanner, or networking devices, such as a switch or router, for example, through a network adapter.

[0162] The computing device 2300 may be implemented in a variety of different forms, as shown in the figure, such as a standard server 2300a, or multiple such servers 2300a, as a laptop computer 2300b, or as part of a rack server system 2300c.

[0163] Various implementations of the systems and techniques described herein may be realized in digital electronic and / or optical circuitry, integrated circuits, specially designed ASICs (application specific integrated circuits), computer hardware, firmware, software, and / or combinations thereof. These various implementations may include implementation in one or more computer programs executable and / or interpretable on a programmable system including at least one programmable processor, which may be special purpose or general purpose, and which may be coupled to receive data and instructions from and transmit data and instructions to a storage system, at least one input device, and at least one output device.

[0164] A software application (i.e., a software resource) may refer to computer software that causes a computing device to perform tasks. In some examples, a software application may be referred to as an "application," "app," or "program." Exemplary applications include, but are not limited to, system diagnostic applications, system management applications, system maintenance applications, word processing applications, spreadsheet applications, messaging applications, media streaming applications, social networking applications, and gaming applications.

[0165] These computer programs (also known as programs, software, software applications or codes) contain machine instructions for a programmable processor and may be implemented in high level procedural and / or object-oriented programming languages, and / or assembly / machine languages. As used herein, the terms "machine-readable medium" and "computer-readable media" refer to any computer program product, non-transitory computer-readable medium, apparatus and / or device (e.g., magnetic disk, optical disk, memory, programmable logic device (PLD)) used to provide machine instructions and / or machine data to a programmable processor (including machine-readable media that receive machine instructions as machine-readable signals). The term "machine-readable signal" refers to any signal used to provide machine instructions and / or machine data to a programmable processor.

[0166] The processes and logic flows described herein can be executed by one or more programmable processors, which may also be referred to as data processing hardware, and function by executing one or more computer programs to operate on input data and generate output. The processes and logic flows can be executed by dedicated logic circuitry, such as an FPGA (field programmable gate array) or an ASIC (application specific integrated circuit). Processors suitable for executing computer programs include, by way of example, both general purpose and dedicated microprocessors, and any one or more processors of any type of digital computer. Generally, a processor receives instructions and data from a read-only memory or a random access memory, or both. The essential elements of a computer are a processor for executing instructions and one or more memory devices for storing instructions and data. Generally, a computer will include or be operatively connected to one or more mass storage devices for storing data, such as magnetic disks, magneto-optical disks, or optical disks, to receive data from, transmit data to, or both. However, a computer need not have such devices. Computer-readable media suitable for storing computer program instructions and data include all forms of non-volatile memory, media and memory devices, including, for example, semiconductor memory devices, such as EPROM, EEPROM and flash memory devices, magnetic disks, such as internal hard disks or removable disks, magneto-optical disks, and CD ROM and DVD-ROM disks. The processor and the memory can be supplemented by, or incorporated in, dedicated logic circuitry.

[0167] One or more of the aspects of the present disclosure can be implemented on a computer having a display device, such as a CRT (cathode ray tube), LCD (liquid crystal display) monitor or touch screen, for displaying information to a user, and optionally a keyboard and a pointing device, such as a mouse or trackball, for allowing the user to provide input to the computer. Other types of devices can also be used to interact with the user, for example, the feedback provided to the user can be any form of sensory feedback, such as visual feedback, auditory feedback or tactile feedback, and the input from the user can be received in any form, including acoustic input, speech input or tactile input. In addition, the computer can interact with the user by sending documents to or receiving documents from a device that the user is using, for example, by sending a web page to a web browser on the user's client device in response to a request from the web browser.

[0168] Further aspects and embodiments of the invention are described below.

[0169] In one aspect, described herein is a method of treating with a myosin inhibitor in a patient in need of treatment, comprising: administering to the patient a starting dose of a myosin inhibitor during the first treatment period; administering to the patient a first reduced dose of a myosin inhibitor during a second treatment period when the patient's first measurement of left ventricular outflow tract obstruction at or near the end of the first treatment period falls below a threshold, the first reduced dose being less than the starting dose; and administering to the patient a second reduced dose of a myosin inhibitor during a third treatment period when the patient's second measurement of left ventricular outflow tract obstruction at or near the end of the second treatment period falls below a threshold value, the second reduced dose being less than the dose of the myosin inhibitor administered immediately prior to the second reduced dose; The method includes:

[0170] In some embodiments, the method comprises: Obtaining the patient's first measurement of left ventricular outflow tract obstruction at or near the end of the first treatment period; and obtaining a second measurement of the patient's left ventricular outflow tract obstruction at or near the end of the second treatment period; Further includes:

[0171] In some embodiments, the second treatment period immediately follows the first treatment period.

[0172] In some embodiments, the third treatment period immediately follows the second treatment period.

[0173] In some embodiments, the dose of myosin inhibitor administered to the patient is not increased until after the third treatment period.

[0174] In some embodiments, the first and second measurements are performed using echocardiography.

[0175] In some embodiments, the first measurement of left ventricular outflow tract obstruction is a measurement of the Valsalva LVOT gradient.

[0176] In some embodiments, the second measurement of left ventricular outflow tract obstruction is a measurement of the Valsalva LVOT gradient.

[0177] In some embodiments, the threshold is a Valsalva LVOT gradient of 20 mmHg.

[0178] In some embodiments, the patient's risk of an adverse event is reduced compared to continuing administration of the starting dose of the myosin inhibitor.

[0179] In some embodiments, the first treatment period is about 4 weeks.

[0180] In some embodiments, the second treatment period is about 4 weeks.

[0181] In some embodiments, the first, second and third treatment periods are each about 4 weeks.

[0182] In some embodiments, the patient is suffering from symptomatic obstructive hypertrophic cardiomyopathy.

[0183] In some embodiments, the patient suffers from symptomatic New York Heart Association (NYHA) Class II-III hypertrophic obstructive cardiomyopathy.

[0184] In some embodiments, the myosin inhibitor is selected from the group consisting of compounds of group (I), compounds of group (II), compounds of group (III), mavacamten, MYK-581, aficamten, and pharmaceutically acceptable salts thereof.

[0185] In some embodiments, the myosin inhibitor is mavacamten or a pharma- ceutically acceptable salt thereof.

[0186] In some embodiments, the myosin inhibitor is mavacamten.

[0187] In some embodiments, the starting dose is about 5 mg of mavacamten per day.

[0188] In some embodiments, the first reduced dose is less than about 5 mg of mavacamten per day.

[0189] In some embodiments, the first reduced dose is selected from the group consisting of about 2.5 mg of mavacamten per day, about 1 mg of mavacamten per day, or 0 mg of mavacamten per day.

[0190] In some embodiments, the second reduced dose is about 1 mg of mavacamten per day or 0 mg of mavacamten per day.

[0191] In some embodiments, the first reduced dose is about 2.5 mg of mavacamten per day and the second reduced dose is 0 mg of mavacamten per day.

[0192] In some embodiments, the patient's left ventricular ejection fraction at or near the end of the first and second treatment periods is about 50% or greater.

[0193] Another aspect of the present disclosure is a method of treating symptomatic hypertrophic obstructive cardiomyopathy in a patient in need thereof, comprising: administering to the patient a starting dose of 5 mg of mavacamten per day during the first treatment period (which first treatment period will be approximately 4 weeks); administering to the patient 2.5 mg of mavacamten per day during a second treatment period (which second treatment period is approximately 4 weeks) when the patient's Valsalva left ventricular outflow tract (LVOT) gradient obtained at or near the end of the first treatment period is below 20 mmHg; and administering 0 mg of mavacamten per day to the patient during a third treatment period (which third treatment period is approximately 4 weeks) when the patient's Valsalva left ventricular outflow tract (LVOT) gradient is below 20 mmHg, which was obtained at or near the end of the second treatment period; The method includes:

[0194] In some embodiments, the second treatment period immediately follows the first treatment period.

[0195] In some embodiments, the third treatment period immediately follows the second treatment period.

[0196] In some embodiments, the method further comprises administering to the patient 2.5 mg of mavacamten per day during a fourth treatment period (wherein the fourth treatment period is about 4 weeks) when the patient's measurement of left ventricular ejection fraction taken at or near the end of the third treatment period is greater than or equal to about 50%.

[0197] In some embodiments, the fourth treatment period immediately follows the third treatment period.

[0198] In some embodiments, the patient has an LVEF of about 50% or greater.

[0199] Another aspect described herein is a method of treating a patient in need thereof with a myosin inhibitor, comprising: (a) administering a starting dose of a myosin inhibitor during a first treatment period; (b) assessing the patient for left ventricular outflow tract obstruction to obtain a first assessment and determining whether the first assessment is below a first threshold; (c) administering a second dose during a second treatment period if the first assessment is below the first threshold, the second dose being less than the starting dose; (d) assessing the patient for left ventricular outflow tract obstruction to obtain a second assessment and determining whether the second assessment is below a second threshold; (e) administering a third dose in a third treatment period when the second assessment is below a second threshold, the third dose being less than the second dose; The method includes:

[0200] In some embodiments, the method comprises: (f) assessing the patient for left ventricular outflow tract obstruction at or near the end of the third treatment period to obtain a third assessment and determining whether the third assessment is equal to or greater than a third threshold to assess a left ventricular ejection fraction (LVEF) of the patient. (g) if the third assessment is equal to or greater than the third threshold and the patient's LVEF is equal to or greater than the LVEF threshold, administering a fourth dose in a fourth treatment period, the fourth dose being greater than the third dose; Further includes:

[0201] In some embodiments, the method comprises: (f) assessing the patient's left ventricular ejection fraction (LVEF) at or near the end of the third treatment period. (g) administering a fourth dose during a fourth treatment period when the patient's LVEF is equal to or greater than a safety threshold, the fourth dose being greater than the third dose; Further includes:

[0202] In some embodiments, the method comprises: (h) assessing the patient for left ventricular outflow tract obstruction at or near the end of a fourth treatment period to obtain a fourth assessment and determining whether the fourth assessment is equal to or greater than a fourth threshold to assess a left ventricular ejection fraction (LVEF) of the patient; (i) if the fourth assessment is equal to or greater than a fourth threshold and the patient's LVEF is equal to or greater than the LVEF threshold, administering a fifth dose in a fifth treatment period, the fifth dose being greater than the fourth dose; Further includes:

[0203] In some embodiments, the first and second assessments are performed by non-invasive techniques.

[0204] In some embodiments, the third assessment is performed by a non-invasive technique.

[0205] In some embodiments, the non-invasive technique includes echocardiography.

[0206] In some embodiments, the non-invasive technique includes a cardiac imaging technique.

[0207] In some embodiments, the non-invasive technique involves measurement of the LVOT gradient by Valsalva maneuver.

[0208] In some embodiments, the first assessment is a first Valsalva LVOT slope and the second assessment is a second Valsalva LVOT slope.

[0209] In some embodiments, the first and second thresholds are each a Valsalva LVOT slope.

[0210] In some embodiments, the first and second thresholds are each a Valsalva LVOT gradient of 20 mmHg.

[0211] In some embodiments, the method mitigates the risk of an adverse event.

[0212] In some embodiments, the adverse event is contractile dysfunction.

[0213] In some embodiments, the adverse event is heart failure.

[0214] In some embodiments, the patient's risk of an adverse event is reduced compared to continuing administration of the starting dose of the myosin inhibitor.

[0215] In some embodiments, the myosin inhibitor is selected from the group consisting of compounds of group (I), compounds of group (II), compounds of group (III), mavacamten, MYK-581, and aficamten, and pharmaceutically acceptable salts thereof.

[0216] In some embodiments, the myosin inhibitor is mavacamten or a pharma- ceutically acceptable salt thereof.

[0217] In some embodiments, the myosin inhibitor is mavacamten.

[0218] In some embodiments, the starting dose is 5 mg of mavacamten per day.

[0219] In some embodiments, the second dose is less than 5 mg of mavacamten per day.

[0220] In some embodiments, the second dose is 2.5 mg of mavacamten per day.

[0221] In some embodiments, the third dose is less than 2.5 mg of mavacamten per day.

[0222] In some embodiments, the third dose is 0 mg of mavacamten per day or 1 mg of mavacamten per day.

[0223] In some embodiments, the patient is suffering from obstructive hypertrophic cardiomyopathy (oHCM).

[0224] In some embodiments, the patient has symptomatic oHCM in New York Heart Association (NYHA) class II-III.

[0225] In some embodiments, 0 mg of mavacamten is administered per day during the third treatment period.

[0226] In some embodiments, the dose of myosin inhibitor administered to the patient is not increased until after the third treatment period.

[0227] In some embodiments, the LVEF threshold is 55%.

[0228] In some embodiments, the safety threshold is 50%.

[0229] In some embodiments, the method further includes assessing the patient's left ventricular ejection fraction (LVEF) at or near the end of the first treatment period and at or near the end of the second treatment period.

[0230] In some embodiments, the method further comprises temporarily discontinuing treatment when the LVEF is assessed to be less than 50% at or near the end of the first or second treatment period.

[0231] In some embodiments, the first treatment period is about 4 weeks and the second treatment period is about 4 weeks.

[0232] In some embodiments, the first treatment period is about 4 weeks, the second treatment period is about 4 weeks, and the third treatment period is about 4 weeks.

[0233] Yet another aspect of the present disclosure is a method of treating a patient in need thereof with mavacamten, comprising: (a) administering to the patient 5 mg of mavacamten per day during a first treatment period; (b) assessing the patient's LVOT gradient using a Valsalva maneuver to determine a first Valsalva LVOT gradient; (c) administering to the patient 2.5 mg of mavacamten per day during a second treatment period when the first Valsalva LVOT gradient falls below 20 mmHg; (d) assessing the patient's LVOT gradient using a Valsalva maneuver to determine a second Valsalva LVOT gradient; (e) administering to the patient 0 mg or 1 mg of mavacamten per day during a third treatment period when the second Valsalva LVOT gradient falls below 20 mmHg; The method includes:

[0234] In some embodiments, the method comprises: (f) assessing the patient's LVOT gradient with a Valsalva maneuver at or near the end of the third treatment period to determine a third Valsalva LVOT gradient and assess the patient's left ventricular ejection fraction (LVEF); (g) administering 2.5 mg of mavacamten per day to the patient during a fourth treatment period when the third Valsalva LVOT gradient is 30 mmHg or greater and the patient's LVEF is 55% or greater; Further includes:

[0235] In some embodiments, the method comprises: (f) assessing the patient's left ventricular ejection fraction (LVEF) at or near the end of the third treatment period. (g) administering to the patient 2.5 mg of mavacamten per day during a fourth treatment period when the patient's LVEF is greater than or equal to 50%; Further includes:

[0236] In some embodiments, the method comprises: (h) assessing the LVOT gradient of the patient using a Valsalva maneuver at or near the end of the fourth treatment period to determine a fourth Valsalva LVOT gradient and assess the left ventricular ejection fraction (LVEF) of the patient; (i) administering 5 mg of mavacamten per day to the patient during a fifth treatment period when the fourth Valsalva LVOT gradient is 30 mmHg or greater and the patient's LVEF is 55% or greater; Further includes:

[0237] Another aspect disclosed herein is a method of administering mavacamten to a patient suffering from oHCM, the method comprising: (a) administering to the patient an initial dose of mavacamten of 5 mg per day during a first treatment period; (b) assessing the patient's LVOT gradient using a Valsalva maneuver to determine a first Valsalva LVOT gradient; (c) administering to the patient 2.5 mg of mavacamten per day during a second treatment period when the first Valsalva LVOT gradient is less than 20 mmHg; (d) assessing the patient's LVOT gradient using a Valsalva maneuver to determine a second Valsalva LVOT gradient; (e) administering 0 mg of mavacamten per day to the patient during a third treatment period when the second Valsalva LVOT gradient falls below 20 mmHg; (f) evaluating the patient to determine a first left ventricular ejection fraction (LVEF); (g) administering to the patient 2.5 mg of mavacamten per day during a fourth treatment period when the first LVEF is greater than or equal to 50%; The method includes:

[0238] In some embodiments, the method comprises: (h) assessing the patient's LVOT gradient with a Valsalva maneuver to determine a third Valsalva LVOT gradient and evaluating the patient to determine a second left ventricular ejection fraction (LVEF); (i) administering to the patient 5 mg of mavacamten per day during a fifth treatment period when the third Valsalva LVOT gradient is 30 mmHg or greater and the second LVEF is 55% or greater; Further includes:

[0239] In some embodiments, the patient's risk of contractile dysfunction and / or heart failure is reduced compared to continuing administration of the starting dose of the myosin inhibitor.

[0240] In some embodiments, the first treatment period is about 4 weeks and the second treatment period is about 4 weeks.

[0241] In some embodiments, the third treatment period is about 4 weeks.

[0242] In some embodiments, the fourth treatment period is about 12 weeks.

[0243] In some embodiments, the patient has symptomatic oHCM in New York Heart Association (NYHA) class II-III.

[0244] Yet another aspect of the present disclosure is a method of administering mavacamten to a patient suffering from oHCM, the method comprising: administering to the patient an initial dose of 5 mg of mavacamten per day during a first treatment period; assessing the patient's LVOT gradient using a Valsalva maneuver to determine a first Valsalva LVOT gradient; administering a second dose of mavacamten during a second treatment period, the second dose being 2.5 mg per day if the first Valsalva LVOT gradient is less than 20 mmHg and the second dose being 5 mg per day if the first Valsalva LVOT gradient is 20 mmHg or greater; assessing the patient's LVOT gradient with a Valsalva maneuver to determine a second Valsalva LVOT gradient; administering a third dose of mavacamten during a third treatment period, where if the second Valsalva LVOT gradient is less than 20 mmHg, the third dose is less than the second dose and the third dose is 2.5 mg, 1 mg, or 0 mg per day, and if the first Valsalva LVOT gradient is 20 mmHg or greater, the third dose is the same as the second dose and the third dose is 5 mg or 2.5 mg per day; The method includes:

[0245] In some embodiments, the patient receives a third dose of 0 mg per day during a third treatment period, the method comprising: evaluating the patient to determine a first left ventricular ejection fraction (LVEF); administering a fourth dose of mavacamten during a fourth treatment period, the fourth dose being 2.5 mg per day if the first LVEF is 50% or greater and the fourth dose being 0 mg per day if the first LVEF is less than 50%; Further includes:

[0246] In some embodiments, the patient receives a third dose of 1 mg per day, 2.5 mg per day, or 5 mg per day during a third treatment period, the method comprising: assessing the patient's LVOT gradient with a Valsalva maneuver to determine a third Valsalva LVOT gradient and assessing the patient to determine a first left ventricular ejection fraction (LVEF); administering a fourth dose of mavacamten during a fourth treatment period, the fourth dose being greater than the third dose and being 2.5 mg, 5 mg, or 10 mg per day when the third Valsalva LVOT gradient is 30 mmHg or greater and the first LVEF is 55% or greater, and the fourth dose being the same as the third dose and being 1 mg, 2.5 mg, or 5 mg per day when the third Valsalva LVOT gradient is less than 30 mmHg or the first LVEF is less than 55%; Further includes:

[0247] In some embodiments, the risk of systolic dysfunction and / or heart failure in the patient is reduced compared to if the patient continued to receive the starting dose of mavacamten.

[0248] In some embodiments, the first treatment period is about 4 weeks and the second treatment period is about 4 weeks.

[0249] In some embodiments, the third treatment period is about 4 weeks.

[0250] In some embodiments, the fourth treatment period is about 12 weeks.

[0251] In some embodiments, the patient has symptomatic oHCM in New York Heart Association (NYHA) class II-III.

[0252] Yet another aspect of the present disclosure is a method of treating a patient in need thereof with a myosin inhibitor, comprising: administering to the patient a starting dose of a myosin inhibitor during the first treatment period; during a second treatment period, a second dose of a myosin inhibitor is administered to the patient; the second dose is less than the starting dose if the patient's LVOT gradient is below a threshold obtained at or near the end of the first treatment period; If the patient's LVOT gradient is equal to or greater than the threshold obtained at or near the end of the first treatment period, the second dose is the same as the starting dose; and during a third treatment period, a third dose of a myosin inhibitor is administered to the patient; the third dose is less than the second dose if the patient's LVOT gradient is below a threshold obtained at or near the end of the second treatment period; that the third dose is the same as the second dose if the patient's LVOT gradient is equal to or greater than the threshold, obtained at or near the end of the second treatment period; The method includes:

[0253] In some embodiments, the second treatment period immediately follows the third treatment period.

[0254] In some embodiments, the third treatment period immediately follows the second treatment period.

[0255] In some embodiments, the method further comprises administering to the patient a fourth dose of a myosin inhibitor during a fourth treatment period; the third dose is less than the second dose and the second dose is less than the starting dose, and the fourth dose is equal to the lowest dose previously administered during the fourth treatment period, if the patient has a measurement of left ventricular ejection fraction at or near the end of the third treatment period that is greater than or equal to about 50%; if the third dose is equal to the second dose and / or the second dose is equal to the starting dose, the fourth treatment period is longer than the third treatment period; Further includes:

[0256] In some embodiments, the fourth treatment period immediately follows the third treatment period.

[0257] In some embodiments, the first, second and third treatment periods are about 4 weeks.

[0258] In some embodiments, the threshold is 20 mmHg.

[0259] In some embodiments, the fourth treatment period is about 4 weeks, when the third dose is less than the second dose, the second dose is less than the starting dose, and the patient's LVEF measurement taken at or near the end of the third treatment period is greater than or equal to about 50%.

[0260] In some embodiments, when the third dose is equal to the second dose and / or the second dose is equal to the starting dose, the fourth treatment period is about 12 weeks.

[0261] In some embodiments, the patient has an LVEF of about 50% or greater.

[0262] In some embodiments, the LVOT gradient is a Valsalva LVOT gradient.

[0263] In some embodiments, the patient's risk of an adverse event is reduced compared to continuing administration of the starting dose of the myosin inhibitor.

[0264] In some embodiments, the first, second and third treatment periods are each about 4 weeks.

[0265] In some embodiments, the patient is suffering from symptomatic obstructive hypertrophic cardiomyopathy.

[0266] In some embodiments, the patient suffers from New York Heart Association (NYHA) Class II-III symptomatic hypertrophic obstructive cardiomyopathy.

[0267] In some embodiments, the myosin inhibitor is selected from the group consisting of compounds of group (I), compounds of group (II), compounds of group (III), mavacamten, MYK-581, aficamten, and pharmaceutically acceptable salts thereof.

[0268] In some embodiments, the myosin inhibitor is mavacamten or a pharma- ceutically acceptable salt thereof.

[0269] In some embodiments, the myosin inhibitor is mavacamten.

[0270] In some embodiments, the starting dose is about 5 mg of mavacamten per day.

[0271] In some embodiments, the second dose is less than about 5 mg of mavacamten per day.

[0272] In some embodiments, the third dose is less than about 2.5 mg of mavacamten per day.

[0273] In some embodiments, the second dose is selected from the group consisting of about 2.5 mg of mavacamten per day, about 1 mg of mavacamten per day, or about 0 mg of mavacamten per day.

[0274] In some embodiments, the third dose is about 1 mg of mavacamten per day or 0 mg of mavacamten per day.

[0275] In some embodiments, the second dose is about 2.5 mg of mavacamten per day and the third dose is about 0 mg of mavacamten per day.

[0276] In some embodiments, the fourth dose is selected from the group consisting of 2.5 mg, 5 mg, and 10 mg of mavacamten per day.

[0277] Disclosed herein is a method of treating a patient in need thereof with a myosin inhibitor, comprising: Administer an initiation dose of a myosin inhibitor at least once daily at the beginning of the initiation phase; During the initiation phase, the patient is assessed for left ventricular outflow tract obstruction at least once and has at least one outcome; and Discontinuing administration of myosin inhibitors based on one or more of the outcomes of these assessments; The method also includes the steps of:

[0278] In some embodiments, the method further comprises resuming administration of the myosin inhibitor after discontinuation thereof.

[0279] In some embodiments, administration is resumed following assessment of the patient's LVEF, and administration is resumed when the LVEF is equal to or greater than a safety threshold.

[0280] In some embodiments, the one or more assessments are performed by non-invasive techniques.

[0281] In some embodiments, the non-invasive technique includes echocardiography.

[0282] In some embodiments, the non-invasive technique includes a cardiac imaging technique.

[0283] In some embodiments, the non-invasive technique includes measuring a Valsalva LVOT gradient, and the one or more assessments are one or more Valsalva LVOT gradients.

[0284] In some embodiments, the method includes discontinuing administration of the myosin inhibitor when the Valsalva LVOT gradient falls below 20 mmHg.

[0285] In some embodiments, the method includes, at the onset, assessing the patient for left ventricular outflow tract obstruction by non-invasive techniques two or more times to obtain two or more assessments.

[0286] In some embodiments, the non-invasive technique includes measuring a Valsalva LVOT gradient, and the two or more assessments are two or more Valsalva LVOT gradients.

[0287] In some embodiments, the method includes discontinuing administration of the myosin inhibitor when at least two of the two or more Valsalva LVOT gradients fall below 20 mmHg.

[0288] In some embodiments, the method mitigates the patient's risk of an adverse event.

[0289] In some embodiments, the adverse event is contractile dysfunction.

[0290] In some embodiments, the adverse event is heart failure.

[0291] In some embodiments, the patient's risk of an adverse event is reduced compared to continuing administration of the myosin inhibitor.

[0292] In some embodiments, the myosin inhibitor is selected from the group consisting of compounds of group (I), compounds of group (II), compounds of group (III), mavacamten, MYK-581, and aficamten, optionally as a pharma- ceutically acceptable salt thereof.

[0293] In some embodiments, the myosin inhibitor is mavacamten or a pharma- ceutically acceptable salt thereof.

[0294] In some embodiments, the myosin inhibitor is mavacamten.

[0295] In some embodiments, the starting dose is 5 mg of mavacamten per day.

[0296] In some embodiments, the patient is suffering from oHCM.

[0297] In some embodiments, the initiation phase is a period of about 4 weeks to about 6 months.

[0298] In some embodiments, the initiation phase is a period of about 8 weeks to about 16 weeks.

[0299] In some embodiments, the safety threshold is 50%.

[0300] Disclosed herein is a method of treating a patient in need thereof with mavacamten, comprising the steps of: (a) administering to the patient at the beginning of a start-up period an initial dose of 5 mg of mavacamten per day; (b) during the initiation phase, assessing the LVOT gradient of the patient at two or more separate time points using a Valsalva maneuver to obtain two or more Valsalva LVOT gradients; (c) discontinuing administration of mavacamten when each of the two or more Valsalva LVOT gradients falls below 20 mmHg; The method also includes the steps of:

[0301] Another aspect of the present disclosure is a method of treating a patient in need thereof with a myosin inhibitor, comprising: administering to the patient a starting dose of a myosin inhibitor; Evaluating the patient for left ventricular outflow tract obstruction at or near the end of two or more separate treatment periods to obtain two or more assessments; and administering a first reduced dose and subsequently administering a second reduced dose based on the two or more evaluation results, where the evaluation results are below a threshold, the first reduced dose is less than the starting dose, and the second reduced dose is less than the first reduced dose; The method includes:

[0302] In some embodiments, the dose of myosin inhibitor administered to the patient is not increased until two or more assessments are obtained at or near the end of two or more separate treatment periods.

[0303] In some embodiments, the two or more assessments are performed by non-invasive techniques.

[0304] In some embodiments, the non-invasive technique includes echocardiography.

[0305] In some embodiments, the non-invasive technique includes a cardiac imaging technique.

[0306] In some embodiments, the non-invasive technique involves measurement of the LVOT gradient by Valsalva maneuver.

[0307] In some embodiments, the assessment is a Valsalva LVOT gradient.

[0308] In some embodiments, the threshold is the Valsalva LVOT slope.

[0309] In some embodiments, the threshold is a Valsalva LVOT gradient of 20 mmHg.

[0310] In some embodiments, the method mitigates the risk of an adverse event.

[0311] In some embodiments, the adverse event is contractile dysfunction.

[0312] In some embodiments, the adverse event is heart failure.

[0313] In some embodiments, the patient's risk of an adverse event is reduced compared to continuing administration of the starting dose of the myosin inhibitor.

[0314] In some embodiments, the myosin inhibitor is selected from the group consisting of compounds of group (I), compounds of group (II), compounds of group (III), mavacamten, MYK-581, aficamten, and pharmaceutically acceptable salts thereof.

[0315] In some embodiments, the myosin inhibitor is mavacamten or a pharma- ceutically acceptable salt thereof.

[0316] In some embodiments, the myosin inhibitor is mavacamten.

[0317] In some embodiments, the starting dose is 5 mg of mavacamten per day.

[0318] In some embodiments, the first reduced dose is less than 5 mg per day.

[0319] In some embodiments, the second reduced dose is less than 2.5 mg per day.

[0320] In some embodiments, the first reduced dose is 2.5 mg of mavacamten per day.

[0321] In some embodiments, the second reduced dose is 1 mg per day or 0 mg per day of mavacamten.

[0322] In some embodiments, the patient is suffering from obstructive hypertrophic cardiomyopathy (oHCM).

[0323] In some embodiments, the patient has symptomatic oHCM in New York Heart Association (NYHA) class II-III.

[0324] In some embodiments, the two or more separate treatment periods include a first treatment period and a second treatment period, and the two or more assessment results include a first assessment result at or near the end of the first treatment period and a second assessment result at or near the end of the second treatment period.

[0325] In some embodiments, the method further comprises administering a myosin inhibitor for a third treatment period after the second assessment.

[0326] In some embodiments, the dose of myosin inhibitor administered to the patient is not increased until after the third treatment period.

[0327] In some embodiments, the first treatment period is about 4 weeks and the second treatment period is about 4 weeks.

[0328] In some embodiments, the third treatment period is about 4 weeks.

[0329] In some embodiments, the methods include assessing the patient's left ventricular ejection fraction (LVEF) at or near the end of two or more separate treatment periods.

[0330] Yet another aspect of the present disclosure is a method of reducing the risk of heart failure by administering a myosin inhibitor to a patient to reduce ejection fraction, comprising the steps of: administering a myosin inhibitor to the patient; temporarily discontinuing administration of the myosin inhibitor when the patient's LVEF is less than 50%; resuming administration of a myosin inhibitor to the patient when the patient's LVEF is greater than or equal to 50%; permanently discontinuing administration of the myosin inhibitor if, after resumption of administration, the patient's LVEF is less than 50%; The method includes:

[0331] In some embodiments, the LVEF is determined by a non-invasive technique.

[0332] In some embodiments, the non-invasive technique is echocardiography.

[0333] In some embodiments, the non-invasive technique includes a cardiac imaging technique.

[0334] In some embodiments, resumption of administration involves administering the same dose that the patient was taking before the temporary discontinuation.

[0335] In some embodiments, resumption of administration comprises administering a dose that is lower than the dose the patient received before the temporary cessation.

[0336] In some embodiments, resumption of administration comprises administering a minimum dose of the myosin inhibitor to the patient, which is the minimum dose of the myosin inhibitor approved for administration to the patient by a government regulatory agency.

[0337] In some embodiments, the government regulatory agency is an agency in the United States, the European Union, Switzerland, Japan, China, South Korea, Canada, Mexico, Australia, New Zealand, Brazil, Russia, Ukraine, Georgia, Vietnam, Singapore, Malaysia, Philippines, India, Indonesia, Hong Kong, Israel, South Africa, Colombia, Costa Rica, Dominican Republic, Ecuador, Guatemala, El Salvador, Honduras, Egypt, Syria, Algeria, Kenya, Morocco, or Nigeria.

[0338] In some embodiments, the myosin inhibitor is selected from the group consisting of compounds of group (I), compounds of group (II), compounds of group (III), mavacamten, MYK-581, and aficamten, and pharmaceutically acceptable salts thereof.

[0339] In some embodiments, the myosin inhibitor is mavacamten or a pharma- ceutically acceptable salt thereof.

[0340] In some embodiments, the myosin inhibitor is mavacamten. In some embodiments, the patient is suffering from obstructive hypertrophic cardiomyopathy (oHCM).

[0341] In some embodiments, the patient has symptomatic oHCM in New York Heart Association (NYHA) class II-III.

[0342] Disclosed herein is a method for mitigating the risk of heart failure by reducing ejection fraction in a patient by administering mavacamten to the patient, the method comprising the steps of: administering mavacamten to the patient at a dose of 2.5 mg per day; temporarily discontinuing administration of mavacamten when the patient's LVEF is less than 50%; resuming administration of mavacamten to the patient at a dose of 2.5 mg per day when the patient's LVEF is equal to or greater than 50%; permanently discontinuing administration of mavacamten if, after resumption of administration, the patient's LVEF is less than 50%; The method also includes the steps of:

[0343] Disclosed herein is a method for treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, comprising administering a therapeutically effective amount of mavacamten to the patient, wherein the patient is not receiving concomitant administration of a strong or moderate CYP2C19 inducer or a strong or moderate CYP3A4 inducer.

[0344] Disclosed herein is a method of treating obstructive hypertrophic cardiomyopathy (oHCM) in a patient in need thereof, the patient being treated with a strong or moderate CYP2C19 inducer, or a strong or moderate CYP3A4 inducer, Discontinuing administration of strong or moderate CYP2C19 inducers or strong or moderate CYP3A4 inducers to the patient; and avoiding concomitant use of mavacamten with strong or moderate CYP2C19 inducers or strong or moderate CYP3A4 inducers by administering mavacamten to the patient in a therapeutically effective amount; The method also includes the steps of:

[0345] Another aspect disclosed herein is a method of administering a myosin inhibitor to a patient receiving myosin inhibitor therapy and initiating concomitant therapy with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor, comprising: administering a 1 daily dose of a myosin inhibitor during a 1 treatment period prior to initiating concomitant therapy with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor; and administering a second daily dose of a myosin inhibitor during a second treatment period that is less than the first daily dose, and the patient is receiving concomitant therapy with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor during the second treatment period; The method includes:

[0346] In some embodiments, the method further comprises assessing the patient's LVEF during the second treatment period; and temporarily discontinuing administration of the myosin inhibitor if the LVEF falls below a safety threshold.

[0347] In some embodiments, the safety threshold is 50%.

[0348] In some embodiments, the method further comprises assessing the patient's LVEF and LVOT gradient after cessation of administration; and resuming administration of the first daily dose when the LVOT gradient is above a threshold and the LVEF is above an LVEF threshold.

[0349] In some embodiments, the threshold is 30 mmHg and the LVEF threshold is 55%.

[0350] In some embodiments, the myosin inhibitor is selected from the group consisting of compounds of group (I), compounds of group (II), compounds of group (III), mavacamten, MYK-581, and aficamten, and pharmaceutically acceptable salts thereof.

[0351] In some embodiments, the myosin inhibitor is mavacamten or a pharma- ceutically acceptable salt thereof.

[0352] In some embodiments, the myosin inhibitor is mavacamten.

[0353] In some embodiments, the first daily dose is 5 mg, 10 mg or 15 mg of mavacamten and the second daily dose is 2.5 mg, 5 mg or 10 mg of mavacamten.

[0354] In some embodiments, the weak CYP2C19 inhibitor or moderate CYP3A4 inhibitor is selected from the group consisting of cimetidine, ciprofloxacin, diltiazem, felbamate, omeprazole, isoniazid, fluconazole, and verapamil at a dose of 20 mg once daily.

[0355] In some embodiments, the patient is suffering from obstructive hypertrophic cardiomyopathy (oHCM).

[0356] In some embodiments, the patient has symptomatic oHCM in New York Heart Association (NYHA) class II-III.

[0357] In some embodiments, assessing the patient's LVEF during the second treatment period comprises assessing the patient's LVEF about 4 weeks after initiation of the combination therapy.

[0358] In some embodiments, the second treatment period is at least 12 weeks, and the second daily dose is not escalated to a higher dose during at least the first 12 weeks of the second treatment period.

[0359] Yet another aspect of the present disclosure is a method of treating HCM in a patient receiving a first daily dose of mavacamten, wherein the patient requires co-treatment with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor in addition to mavacamten, administering to the patient a second daily dose of mavacamten that is less than the first daily dose in addition to administering the weak CYP2C19 inhibitor or moderate CYP3A4 inhibitor; The method includes:

[0360] In some embodiments, the first daily dose is 5 mg, 10 mg, or 15 mg per day and the second daily dose is 2.5 mg, 5 mg, or 10 mg per day.

[0361] Yet another aspect of the present disclosure is a method of initiating co-administration of mavacamten to a patient receiving a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor, the patient requiring co-administration of mavacamten with the weak CYP2C19 inhibitor or the moderate CYP3A4 inhibitor, the patient receiving stable therapy with the weak CYP2C19 inhibitor or the moderate CYP3A4 inhibitor, the method comprising the steps of: administering to the patient a daily dose of 5 mg per day of mavacamten in combination with stable therapy of a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor.

[0362] Yet another aspect of the present disclosure is a method of administering a myosin inhibitor to a patient who is undergoing myosin inhibitor therapy and is initiating or increasing the dose of a negative inotropic combination therapy, comprising: (a) administering a therapeutically effective amount of a myosin inhibitor during a first treatment period; (b) continuing to administer the myosin inhibitor during a second treatment period, and the patient initiates or increases the dose of a negative inotropic concomitant therapy during the second treatment period; and (c) echocardiographic monitoring of LVEF during the second treatment period; The method includes:

[0363] In some embodiments, echocardiographic monitoring of LVEF is performed until a stable dose and clinical response is achieved.

[0364] In some embodiments, the method further comprises close medical supervision during the second treatment period.

[0365] In some embodiments, the myosin inhibitor is mavacamten.

[0366] Another aspect of the present disclosure is a computer-implemented method that, when executed by data processing hardware, causes the data processing hardware to perform operations, comprising: Obtaining a Health Care Professional (HCP) assessment record relevant to the patient, which HCP assessment record includes treatment outcomes; Using the HCP evaluation record to determine whether the patient should be granted a prescribing authorization to use the prescribed drug; Once the patient is approved to take the prescribed medication, Obtain a pharmacy evaluation record relating to that patient, which pharmacy evaluation record includes the patient's medical condition; Using the pharmacy evaluation record to determine whether the pharmacy is authorized to dispense the prescription drug to the patient; Once the pharmacy is authorized to dispense the prescription to the patient, Creating a dispensing permit; and Transmitting the dispensing authorization to the pharmacy; The method includes:

[0367] In some embodiments, the treatment results include echocardiogram results.

[0368] In some embodiments, at least one of the HCP assessment record and the pharmacy assessment record includes a potential drug interaction.

[0369] In some embodiments, obtaining the HCP assessment record includes retrieving the HCP assessment record from a database remote to the data processing hardware.

[0370] In some embodiments, determining whether the patient is authorized to receive the prescription is responsive to receiving a prescription request.

[0371] In some embodiments, the dispensing authorization includes: The amount of prescription medication the patient is authorized to take; The period for which the patient will be permitted to take the prescribed drug; and Includes.

[0372] In some embodiments, the task, after the period has elapsed, Determine whether updated treatment results relevant to the patient are available; renewing the license to dispense using the renewal action results, when such renewal action results are available; and Refusing to renew a license to dispense medicines when the results of such renewal action are not available; Further includes:

[0373] In some embodiments, updating the dispensing authorization comprises: Adjusting the amount of prescription medication the patient is permitted to take; and Adjusting the length of time that the patient is permitted to take the prescribed drug; Includes at least one of the following.

[0374] In some embodiments, the operations further include creating a record for a regulatory agency when a patient is not authorized to take the prescription drug or when a pharmacy is not authorized to dispense the prescription drug to a patient.

[0375] In some embodiments, the prescription drug comprises mavacamten.

[0376] The present invention discloses Data processing hardware; memory hardware in communication with the data processing hardware storing instructions that, when executed on the data processing hardware, cause the data processing hardware to perform the operations described above; It is also a system that includes

[0377] Disclosed herein is a method for mitigating the risk of heart failure due to systolic dysfunction in a patient receiving a myosin inhibitor, comprising: providing a data storage facility including a database including a patient HCP assessment record and a patient pharmacy assessment record, each of the patient's HCP assessment records including information regarding the date of the patient's echocardiogram, the LVEF determined from the echocardiogram, the VLVOT determined from the echocardiogram, a history of clinical heart failure events, and a risk of potential drug interactions, and each of the patient's pharmacy assessment records including information regarding the patient's medical condition, concomitant medications and supplements, and potential drug interactions; and providing a central controller having one or more processors connected to a communications network, the central controller being connected to a data storage facility for reading and writing data to the data storage facility via the network; Including, The central controller controls the transmission and reception of data through the network to data storage facilities, the central controller being programmed to output, via the network, an HCP authorization for prescription of the myosin inhibitor to the patient, the output of the HCP authorization being contingent on sufficient HCP information regarding the date of the echocardiogram, the results of the echocardiogram, the history of clinical heart failure events, and risk of drug-drug interactions, as entered into each of the patient's HCP assessment records, and the central controller preventing the output of the HCP authorization in the event of insufficient HCP information; the central controller is further programmed to output, via the network, an authorization to dispense the myosin inhibitor to the patient, the output of the pharmacy authorization being dependent on the output of the HCP authorization and sufficient pharmacy information regarding the patient's medical condition, concomitant medications and supplements, and potential drug interactions, each of which has been entered into the patient's pharmacy assessment record, and the central controller prevents output of the authorization in the event of insufficient pharmacy information and / or absence of HCP authorization; It is also a method by which the central controller manages one or more aspects of reporting to a regulatory agency or other oversight body insufficient information regarding clinical heart failure event history.

[0378] Disclosed herein is a computer-implemented method that, when executed by data processing hardware, causes the data processing hardware to perform operations, Obtaining a Health Care Professional (HCP) assessment record relevant to the patient, which HCP assessment record includes treatment outcomes; Obtain a pharmacy evaluation record relating to that patient, which pharmacy evaluation record includes the patient's medical condition; Using the HCP evaluation record to determine whether the patient should be granted a prescribing authorization to use the prescribed drug; Once the patient is approved to take the prescribed medication, Using the pharmacy evaluation record to determine whether the pharmacy should be permitted to dispense the prescription drug to the patient; Once the pharmacy is authorized to dispense the prescription to the patient, Creating a dispensing permit; and Transmitting the dispensing authorization to the pharmacy; The method also includes the steps of:

[0379] In some embodiments, the treatment results include echocardiogram results.

[0380] In some embodiments, at least one of the HCP assessment record and the pharmacy assessment record includes a potential drug interaction.

[0381] In some embodiments, obtaining the HCP assessment record includes retrieving the HCP assessment record from a database remote to the data processing hardware.

[0382] In some embodiments, determining whether the patient is authorized to receive the prescription is responsive to receiving a prescription request.

[0383] In some embodiments, the dispensing authorization includes: The amount of prescription medication the patient is authorized to take; The period for which the patient will be permitted to take the prescribed drug; and Includes.

[0384] In some embodiments, the task, after the period has elapsed, Determine whether updated treatment results relevant to the patient are available; renewing the license to dispense using the renewal action results, when such renewal action results are available; and Refusing to renew a license to dispense medicines when the results of such renewal action are not available; Further includes:

[0385] In some embodiments, updating the dispensing authorization comprises: Adjusting the amount of prescription medication the patient is permitted to take; and Adjusting the length of time that the patient is permitted to take the prescribed drug; Includes at least one of the following.

[0386] In some embodiments, the operations further include creating a record for a regulatory authority when a patient is not authorized to receive the prescription drug or when a pharmacy is not authorized to dispense the prescription drug to the patient.

[0387] In some embodiments, the prescription drug comprises mavacamten.

[0388] The present invention discloses Data processing hardware; memory hardware in communication with the data processing hardware storing instructions that, when executed on the data processing hardware, cause the data processing hardware to perform the operations set forth in any of the methods described above; It is also a system that includes EXAMPLES

[0389] Example 1. Dose and Administration of Mavacamten 4-6 show the dosing scheme of an embodiment of the present invention. In the initiation phase (FIG. 4), a patient with obstructive HCM is orally administered a starting dose of 5 mg mavacamten once a day (QD) for 1-4 weeks. During the 4 weeks, the patient is evaluated by echocardiography. Specifically, the patient's Valsalva LVOT gradient and LVEF are obtained. As shown in FIG. 5, if the echocardiogram at this visit or any other visit reveals a LVEF of less than 50%, treatment is suspended (i.e., temporarily discontinued) for 4 weeks. After the 4-week treatment interruption, another echocardiogram is taken, and if the LVEF is 50% or greater, treatment is resumed at one dose level below the previous dose level. Referring again to FIG. 4, at the 4-week visit, the Valsalva LVOT gradient (VLVOT) is obtained, and if the VLVOT is less than 20 mmHg, the dose is reduced to 2.5 mg QD. At the week 4 visit, if VLVOT is ≥ 20 mmHg, the dose will be maintained at 5 mg QD.

[0390] After another 4 weeks, at the week 8 visit (week 8), the patient is re-evaluated by echocardiography. If LVEF is less than 50%, treatment is again interrupted (i.e., temporarily discontinued) for at least 4 weeks. If VLVOT is 20mmHg or greater, the dose is reduced, with patients taking 2.5mg QD reducing their dose to 0mg QD (i.e., stopping the drug) and patients taking 5mg QD reducing their dose to 2.5mg QD. If VLVOT is 20mmHg or less, the dose is maintained (i.e., maintained at 2.5mg QD or 5mg QD). That is, the dose is not increased at the week 4 or week 8 visits.

[0391] After another 4 weeks, patients are re-evaluated by echocardiography at the 12 week visit (Week 12). If LVEF is less than 50%, treatment is again interrupted. For patients taking 5 mg QD or 2.5 mg QD at the Week 12 visit, if LVEF is 55% or greater and VLVOT is 30 mmHg or greater, the dose is increased by one level. Dose levels are 0 mg, 2.5 mg, 5 mg, 10 mg, and 15 mg (QD). That is, for example, patients taking 5 mg QD before the Week 12 visit who have an LVEF 55% or greater and a VLVOT 30 mmHg or greater will increase to 10 mg QD after the Week 12 visit. For patients who were discontinued / withdrawn (0 mg) at the Week 12 visit, if LVEF is 50% or greater, they will resume at 2.5 mg QD.

[0392] If the dose is increased (including from 0 mg to 2.5 mg QD), the patient will have another visit 4 weeks after the dose increase to evaluate LVEF. The patient will continue on the same dose for the next 8 weeks if LVEF is not less than 50%. Starting at week 12, patients will have clinical visits every 12 weeks at which LVEF and VLVOT will be obtained and the dose may be increased one level if LVEF is 55% or greater and VLVOT is 30 mmHg or greater. The maximum dose of mavacamten is 15 mg QD. If LVEF is less than 50% on two occasions at 2.5 mg QD during treatment, treatment will be permanently discontinued.

[0393] Concomitant administration of mavacamten with moderate and strong CYP2C19 inhibitors is contraindicated. Concomitant administration of mavacamten with strong CYP3A4 inhibitors is contraindicated. Concomitant administration of mavacamten with moderate and strong inducers of CYP3A4 or CYP2C19 is contraindicated.

[0394] Mavacamten capsules for oral use

[0395] WARNING: Risk of heart failure Mavacamten may cause heart failure due to systolic dysfunction. Echocardiogram assessment of left ventricular ejection fraction (LVEF) is required prior to and during use of mavacamten. Not recommended to be initiated in patients with LVEF <55%. Discontinue if LVEF <50% or clinical deterioration. Certain CYP450 inhibitors / inducers are contraindicated in patients taking mavacamten due to an increased risk of heart failure. Mavacamten is only available through a restricted program called the Mavacamten REMS program.

[0396] Indications and Use

[0397] Mavacamten is a cardiac myosin inhibitor indicated for the treatment of adults with symptomatic New York Heart Association (NYHA) class II-III obstructive hypertrophic cardiomyopathy (HCM) to improve functional capacity and symptoms.

[0398] Dosage and Administration

[0399] Dosing must be individualized based on the clinical status and echocardiographic assessment of the patient's response. See full prescribing information for instructions.

[0400] Dosage form and strength

[0401] Capsules: 2.5 mg, 5 mg, 10 mg, and 15 mg

[0402] contraindications Moderate to strong CYP2C19 inhibitor or strong CYP3A4 inhibitor Moderate to strong CYP2C19 inducer or moderate to strong CYP3A4 inducer

[0403] Warnings and Cautions Heart failure: Consider discontinuing mavacamten in patients with concomitant disease. Drug-drug interactions leading to heart failure or loss of efficacy: Inform patients of possible drug-drug interactions, including those with over-the-counter medications. Embryo-fetal toxicity: May cause harm to the fetus. Advise females of childbearing potential to use effective contraception until 4 months after the last dose. Use a method not affected by induction of the enzyme CYP450 or an additional non-hormonal method of contraception.

[0404] Adverse Reactions

[0405] Adverse reactions occurring in 5% or more patients and more common with mavacamten than with placebo were dizziness (27%) and syncope (6%).

[0406] Drug-drug interactions Weak CYP2C19 inhibitors and moderate CYP3A4 inhibitors: The risk of heart failure may be increased. A mavacamten dose reduction and additional monitoring may be required if an inhibitor is initiated. Negative inotropes: Close medical supervision and LVEF monitoring is recommended when initiating negative inotropes or increasing the dose of negative inotropes. Avoid certain combinations of negative inotropes.

[0407] Full prescribing information

[0408] WARNING: Risk of heart failure

[0409] Mavacamten may reduce left ventricular ejection fraction (LVEF) and lead to heart failure due to systolic dysfunction.

[0410] Echocardiographic assessment of LVEF is required before and during treatment with mavacamten. Initiation of mavacamten is not recommended in patients with LVEF <55%. Interrupt mavacamten if LVEF <50% at any visit or if the patient has symptoms of heart failure or clinical deterioration.

[0411] Concomitant use of mavacamten with certain cytochrome P450 inhibitors, or withdrawal of certain cytochrome P450 inducers, may increase the risk of heart failure due to systolic dysfunction; therefore, use of mavacamten is contraindicated with the following: Moderate to strong CYP2C19 inhibitor or strong CYP3A4 inhibitor Moderate to strong CYP2C19 inducer or moderate to strong CYP3A4 inducer

[0412] Mavacamten is available only through a restricted program under a Risk Evaluation and Risk Mitigation Strategy (REMS), known as the Mavacamten REMS program, due to the risk of heart failure due to systolic dysfunction.

[0413] 1. Indications and Use

[0414] Mavacamten is indicated for the treatment of adults with symptomatic New York Heart Association (NYHA) class II-III hypertrophic obstructive cardiomyopathy (HCM) to improve functional capacity and symptoms.

[0415] 2. Dosage and Administration

[0416] 2.1. Initiation, maintenance and discontinuation of treatment

[0417] In women of childbearing potential, ensure that they are not pregnant and are using effective contraception.

[0418] Initiation or titration of mavacamten is not recommended in patients with LVEF <55%.

[0419] The recommended starting dose is 5 mg once daily, with or without food, with permitted subsequent titrations of 2.5 mg, 5 mg, 10 mg, or 15 mg once daily.

[0420] Patients may develop heart failure while taking mavacamten. Regular assessment of LVEF and Valsalva left ventricular outflow tract (LVOT) gradient is required for careful titration to achieve appropriate targets for the LVOT gradient while maintaining LVEF above 50% and avoiding heart failure symptoms (see Figures 4 and 5).

[0421] With once-daily dosing, it can take several weeks for steady-state levels of drug and therapeutic effect to be reached, and genetic variability in metabolism and drug-drug interactions can result in wide variations in exposure.

[0422] When initiating or titrating mavacamten, first consider LVEF, then Valsalva LVOT gradient and the patient's clinical condition to guide the appropriate mavacamten dose. The appropriate mavacamten dose and monitoring schedule should follow the initiation (Figure 4) and maintenance (Figure 5) algorithms.

[0423] If LVEF is <50% while taking mavacamten, treatment should be interrupted. Guidelines for interrupting, resuming, or discontinuing mavacamten should follow the algorithm for interruption (Figure 6). If interrupted at 2.5 mg, either resume at 2.5 mg or discontinue permanently.

[0424] The initiation phase is shown in Figure 4. The maintenance phase is shown in Figure 5. Figure 6 shows that treatment was discontinued if LVEF was <50% at any outpatient visit.

[0425] Dose escalation should be delayed in the presence of intercurrent illness (e.g., severe infection) or arrhythmias that may compromise systolic function (e.g., atrial fibrillation or other uncontrolled tachyarrhythmias). Consider discontinuing mavacamten in patients with intercurrent illness.

[0426] Missed or late doses

[0427] If a dose is missed, it should be taken as soon as possible and the next dose should be taken at the usual time the following day. The exact timing of doses within a day is not essential, but two doses should not be taken on the same day.

[0428] Swallow the capsule whole. Do not crush, open or chew the capsule.

[0429] 2.2. Concomitant use of a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor

[0430] In patients receiving stable therapy with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor, initiate mavacamten orally at the recommended starting dose of 5 mg once daily.

[0431] In patients initiating a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor, reduce the mavacamten dose by one level (i.e., from 15 mg to 10 mg, 10 mg to 5 mg, or 5 mg to 2.5 mg). Schedule clinical and echocardiographic evaluation 4 weeks after initiating inhibitor use and do not titrate mavacamten until 12 weeks after inhibitor initiation. Avoid initiating a concomitant weak CYP2C19 inhibitor and a moderate CYP3A4 inhibitor in patients stable on 2.5 mg mavacamten because smaller once-daily doses of mavacamten are not available.

[0432] 3. Dosage form and strength

[0433] Mavacamten is available in the following strengths as capsules imprinted with the strength and "Mava": 2.5mg - Light purple cap 5mg - Yellow Cap 10mg - pink cap 15mg - Grey Cap

[0434] 4.Contraindications

[0435] Mavacamten is contraindicated for use in combination with: Moderate to strong CYP2C19 inhibitor or strong CYP3A4 inhibitor Moderate to strong CYP2C19 inducer or moderate to strong CYP3A4 inducer

[0436] 5. Warnings and Cautions

[0437] Heart failure

[0438] Mavacamten can reduce premature beats, cause heart failure, or completely block ventricular function. Patients with a history of serious intercurrent illness (e.g., severe infection) or arrhythmias (e.g., atrial fibrillation or other uncontrolled tachyarrhythmias) are at increased risk of developing systolic dysfunction and heart failure.

[0439] Assess the patient's clinical status and LVEF prior to and periodically during treatment and adjust the mavacamten dose accordingly. New or worsening arrhythmias, dyspnea, chest pain, fatigue, palpitations, leg edema, or elevated N-terminal pro-b-type natriuretic peptide (NT-proBNP) may be signs and symptoms of heart failure and should also prompt evaluation of cardiac function.

[0440] Asymptomatic decline in LVEF, intercurrent illness, and arrhythmias warrant consideration of additional dosing.

[0441] Initiation of mavacamten is not recommended in patients with LVEF <55%. Avoid concomitant use of mavacamten in patients taking a beta-blocker and disopyramide, ranolazine, or verapamil, or a beta-blocker and diltiazem, as these doses and combinations were excluded from the clinical trial of mavacamten in obstructive HCM (EXPLORER-HCM). Concomitant use of mavacamten with disopyramide, in combination with verapamil or diltiazem, has been associated with left ventricular systolic dysfunction and heart failure symptoms in patients with obstructive HCM.

[0442] 5.2. Drug-drug interactions with CYP450 leading to heart failure or loss of efficacy

[0443] Mavacamten is primarily metabolized by the enzymes CYP2C19 and CYP3A4. Concomitant use of mavacamten with drugs that interact with these enzymes can lead to life-threatening drug-drug interactions, such as heart failure, or loss of efficacy.

[0444] Inform patients of the potential for drug-drug interactions, including with over-the-counter medications (e.g., omeprazole, esomeprazole, or cimetidine). Encourage patients to inform their health care providers of all concomitant medications before or during treatment with mavacamten.

[0445] 5.3.Mavacamten REMS Program

[0446] Mavacamten is available only through a restricted program, the Mavacamten REMS program, due to the risk of heart failure due to systolic dysfunction.

[0447] Notable requirements for the mavacamten REMS program include: Prescribers must be certified by enrolling in the mavacamten REMS program. Patients must be enrolled in the mavacamten REMS program and comply with ongoing monitoring requirements. ·Pharmacies must be certified by enrolling in the mavacamten REMS program and must dispense only to patients authorized to take mavacamten. · Wholesalers and distributors must distribute only to authorized pharmacies.

[0448] Embryo-fetal toxicity

[0449] Mavacamten may cause fetal toxicity when administered to pregnant women based on findings from animal studies. In females of childbearing potential, determine pregnancy status prior to treatment and advise patients to use effective contraception during treatment with mavacamten and for 4 months after the last dose. Mavacamten may reduce the effectiveness of combined hormonal contraceptives (CHCs). Advise patients using CHCs to use an alternative contraceptive method not affected by induction of the enzyme CYP450 or to add a non-hormonal method of contraception.

[0450] Inform women of childbearing potential of the potential risk to the fetus from maternal exposure to mavacamten during pregnancy.

[0451] 6. Adverse Reactions

[0452] Other sections of the label discuss the following adverse reactions: ·heart failure

[0453] 6.1 Clinical Trial History

[0454] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug may not be directly comparable to rates in clinical trials of another drug and may not reflect rates observed in practice.

[0455] The safety of mavacamten was evaluated in EXPLORER-HCM, a phase 3, double-blind, randomized, placebo-controlled trial. Among 251 adults with obstructive HCM, 123 patients were treated with mavacamten 2.5 to 15 mg daily and 128 patients were treated with placebo. Patients treated with mavacamten had a median exposure duration of 30 weeks (range: 2 to 40 weeks).

[0456] Syncope (0.8%) was the only adverse drug reaction leading to discontinuation in patients taking mavacamten.

[0457] Adverse reactions occurring in ≥5% of patients and more common with mavacamten than with placebo were dizziness (18% vs. 27%) and syncope (2% vs. 6%).

[0458] Effects on contractile function

[0459] In the EXPLORER-HCM study, the mean (SD) resting LVEF was 74% (6) at baseline in both treatment groups. Consistent with mavacamten's mechanism of action, the mean (SD) absolute change from baseline in LVEF was -4% (8) in the mavacamten group and 0% (7) in the placebo group over the 30-week treatment period. At week 38, after 8 weeks of discontinuation of study drug, the mean LVEF was similar to baseline in both treatment groups. In the EXPLORER-HCM study, seven (6%) patients in the mavacamten group and two (2%) patients in the placebo group experienced a reversible decline in LVEF to less than 50% during treatment (median 48%, range 35-49%). In three of the seven mavacamten patients and one of the two placebo patients, these declines were asymptomatic. In all seven patients treated with mavacamten, LVEF returned after discontinuation of mavacamten.

[0460] 7. Drug-Drug Interactions

[0461] 7.1. Other drugs may affect plasma concentrations of mavacamten

[0462] Mavacamten is primarily metabolized by CYP2C19 and, to a lesser extent, by CYP3A4 and CYP2C9. Inducers and inhibitors of CYP2C19 and moderate to strong inhibitors or inducers of CYP3A4 may affect exposure to mavacamten. (See Table 1.)

[0463] Table 1: Proven and potentially significant pharmacokinetic drug-drug interactions with mavacamten

[0464] [Table 1]

[0465] 7.2. Potential for mavacamten to affect plasma concentrations of other drugs

[0466] Mavacamten is an inducer of CYP3A4, CYP2C9, and CYP2C19. Coadministration with substrates of CYP3A4, CYP2C19, or CYP2C9 may decrease the plasma concentrations of these drugs. Monitor closely when mavacamten is coadministered with substrates of CYP3A4, CYP2C19, or CYP2C9, as decreased plasma concentrations of these drugs may decrease the activity of these drugs.

[0467] Hormonal contraception: Progestins and ethinyl estradiol are CYP3A4 substrates. Concomitant use of mavacamten may decrease the exposure of ethinyl estradiol and progestins, which may result in contraceptive failure or increased breakthrough bleeding. Advise patients to use a method of contraception not affected by induction of the enzyme CYP450 (e.g., intrauterine system) or an additional non-hormonal method of contraception (e.g., condoms) during concomitant use and for 4 months after the last dose of mavacamten.

[0468] 7.3. Drugs that reduce cardiac contractility

[0469] Expect an additive negative inotropic effect of mavacamten and other drugs that reduce cardiac contractility. In the EXPLORER-HCM study, 119 of 123 patients receiving mavacamten were given concomitant therapy with a beta-blocker (n=94), verapamil (n=19), or diltiazem (n=6).

[0470] Avoid concomitant use of mavacamten with disopyramide in combination with verapamil or diltiazem, as such use has been associated with left ventricular systolic dysfunction and heart failure symptoms.

[0471] If combination therapy with a negative inotropic agent is initiated or the dose of the negative inotropic agent is increased, LVEF is closely monitored until a stable dose and clinical response is achieved.

[0472] 8. Use in Specific Populations

[0473] 8.1. Pregnancy

[0474] Risk Overview

[0475] Mavacamten may cause adverse fetal effects when administered to pregnant women based on animal data. There are no human data from the use of mavacamten during pregnancy to assess the drug-associated risk of major congenital anomalies, miscarriage, or other adverse maternal or fetal outcomes. Underlying maternal conditions during pregnancy pose risks to the mother and fetus. Inform pregnant women of the possible risks to the fetus from maternal exposure to mavacamten during pregnancy.

[0476] In animal studies of embryo-fetal development, mavacamten-associated decreases in mean fetal body weight, decreases in fetal ossification, and increases in post-implantation embryonic losses (early and / or late resorptions) were observed in rats, and increases in visceral and skeletal malformations were observed in both rabbits and rats at exposures similar to those achieved at the maximum recommended dose (MRHD) in humans.

[0477] The estimated background risks of major birth defects and miscarriage for the populations indicated are unknown. Every pregnancy has a background risk of birth defects, death, or other adverse outcomes. In the general U.S. population, the estimated background risk of major birth defects in clinically recognized pregnancies is 2% to 4%, and the estimated background risk of miscarriage is 15% to 20%.

[0478] Pregnancy safety studies exist for mavacamten. Healthcare providers should report exposure to mavacamten if it is administered during pregnancy or if a patient who is taking mavacamten or has been taking mavacamten within 4 months of her last dose becomes pregnant.

[0479] Clinical considerations

[0480] Maternal and embryo-fetal disease-related risks

[0481] Obstructive HCM during pregnancy is associated with an increased risk of preterm birth.

[0482] data

[0483] Animal data

[0484] When pregnant rats were administered mavacamten orally (0.3-1.5 mg / kg / day) during the period of organogenesis, increased post-implantation losses, decreased mean fetal body weights, decreased fetal ossification, and fetal malformations (visceral and skeletal) were observed in the high-dose group (1.5 mg / kg / day). Increased incidences of visceral malformations (including fetal cardiac malformations and one case of complete situs inversus) and skeletal malformations (mainly sternoclasmia) were observed at exposures equivalent to those observed in humans at the MRHD. In rats, the plasma exposure (based on the area under the concentration-time curve, or AUC) at the no-effect dose for embryo-fetal development is 0.3-fold that observed in humans at the MRHD.

[0485] When pregnant rabbits were administered mavacamten orally (0.6-2.0 mg / kg / day) during the period of organogenesis, fetal malformations (visceral and skeletal) were increased at doses of 1.2 mg / kg / day or more, and plasma exposures at 1.2 mg / kg / day were similar to those in humans at the MRHD. Visceral findings consisted of malformations of the great vessels (dilation of the pulmonary trunk and / or aortic arch). Skeletal malformations consisted of an increased incidence of sternoclasm at doses of 1.2 mg / kg / day or more. In rabbits, the plasma exposure (AUC) at the no-effect dose for embryo-fetal development was 0.4-fold that in humans at the MRHD.

[0486] In a pre- / post-natal development study, mavacamten was administered orally (0.3-1.5 mg / kg / day) to pregnant rats from gestation day 6 through lactation / post-partum day 20. No adverse effects were observed in dams or pups exposed daily from prenatal (in utero) through lactation. The no observed adverse effect level (NOAEL) was 1.5 mg / kg / day (the highest dose level tested) and the area under exposure (AUC) was similar to that in humans at the MRHD.

[0487] 8.2. Breastfeeding

[0488] Risk Overview

[0489] The presence of mavacamten in human or animal milk, the effect of the drug on the breast-fed infant, and the effect on milk production are unknown. The developmental and health effects of breast-feeding must be considered along with the maternal clinical need for mavacamten and the potential for adverse effects on the breast-fed child, either from mavacamten or from underlying maternal conditions.

[0490] 8.3. Women and Men of Reproductive Potential

[0491] Mavacamten may cause adverse fetal effects when administered to pregnant women based on animal data.

[0492] Pregnancy test

[0493] In women of childbearing potential, ensure that they are not pregnant before initiating mavacamten.

[0494] contraception

[0495] woman

[0496] Advise females of childbearing potential to use effective contraception during treatment with mavacamten and for 4 months after the last dose. Use of mavacamten may decrease the effectiveness of CHCs. Advise patients using CHCs to use an alternative or additional non-hormonal method of contraception.

[0497] 8.4. Pediatric Use

[0498] The safety and effectiveness of mavacamten have not been established in pediatric patients.

[0499] 8.5. Use by Elderly People

[0500] Clinical trials included 263 patients who received mavacamten, of whom 95 were aged 65 years or older (36.1%) and 17 (6.5%) were aged 75 years or older. Safety, efficacy, and pharmacokinetics were similar between patients aged 65 years or older and younger patients.

[0501] Liver disorders

[0502] No dose adjustment is required in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. Mavacamten exposure (AUC) was increased by up to 220% in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment compared to patients with normal hepatic function. However, in patients with mild to moderate hepatic impairment, no further dose adjustment is required, and a dose titration algorithm and monitoring plan is recommended. The effect of severe (Child-Pugh C) hepatic impairment is unknown.

[0503] 10. Overdose

[0504] There is limited history of overdose of mavacamten in humans. Mavacamten has been administered in single doses of up to 144 mg in patients with HCM. One subject receiving a single dose of 144 mg experienced serious adverse events (including vasovagal reactions, hypotension, and asystole), but the subject recovered. Doses up to 25 mg have been administered in healthy subjects for up to 25 days, with 3 of 8 participants treated at the 25 mg dose level experiencing a decline in LVEF of 20% or more. An infant death was reported after accidentally ingesting 3 15 mg capsules.

[0505] Systolic dysfunction is the most likely consequence of mavacamten overdose. Treatment of mavacamten overdose consists of discontinuing mavacamten therapy and medical supportive measures to maintain hemodynamic stability, including close monitoring of vital signs and LVEF, and management of the patient's clinical status. Overdose in humans is life-threatening and may result in asystole refractory to any medical intervention.

[0506] 11. Details

[0507] Mavacamten capsules for oral use contain mavacamten, a cardiac myosin inhibitor.

[0508] The chemical name of mavacamten is 3-(1-methylethyl)-6-[[(1S)-1-phenylethyl]amino]-2,4(1H,3H)-pyrimidinedione. Its molecular formula is C 15 H 19 It is N3O2 and has a molecular weight of 273.33 g / mol.

[0509] The structural formula of mavacamten is: [ka] It is.

[0510] Mavacamten is a white to off-white powder that is practically insoluble in water and aqueous buffers at pH 2-10, sparingly soluble in methanol and ethanol, and freely soluble in DMSO and NMP.

[0511] Mavacamten is supplied in size 2 immediate release hard gelatin capsules containing 2.5 mg, 5 mg, 10 mg or 15 mg of mavacamten as the active ingredient per capsule, and the following inactive ingredients: croscarmellose sodium, hypromellose, magnesium stearate (non-bovine origin), mannitol and silicon dioxide. The capsule shell contains edible black ink, black iron oxide, gelatin, red iron oxide, titanium dioxide and yellow iron oxide.

[0512] 12. Clinical Pharmacology

[0513] 12.1. Mechanism of action

[0514] Mavacamten is a selective, allosteric, and reversible inhibitor of cardiac myosin. Mavacamten regulates the number of myosin heads that can be in the "on actin" (force-generating) state, thus decreasing the likelihood of force-generating crossbridges (systole) and remaining crossbridges (diastole). Excessive myosin-actin crossbridge formation and dysregulation of the super-relaxed state are mechanistic hallmarks of HCM. Mavacamten shifts the entire myosin population into an energy-suppressing, mobilizable super-relaxed state. In patients with HCM, myosin inhibition with mavacamten reduces dynamic LVOT obstruction and improves cardiac filling pressures.

[0515] 12.2. Drug potency

[0516] Left ventricular ejection fraction and left ventricular outflow tract obstruction

[0517] In the EXPLORER-HCM study, patients experienced a decline in mean resting LVOT gradient and mean evoked (Valsalva) LVOT gradient by week 4, which persisted throughout the 30-week study. At week 30, the mean (SD) change from baseline in resting LVOT gradient was -39 (29) mmHg and the mean (SD) change from baseline in Valsalva LVOT gradient was -49 (34) mmHg in the mavacamten group, and the mean (SD) change from baseline in resting LVOT gradient was -6 (28) mmHg and the mean (SD) change from baseline in Valsalva LVOT gradient was -12 (31) mmHg in the placebo group. The decline in Valsalva LVOT gradient was accompanied by a decline in LVEF, which was generally within the normal range. Eight weeks after cessation of mavacamten, the mean LVEF and Valsalva LVOT gradient were similar to baseline.

[0518] Structure of the Heart

[0519] In EXPLORER-HCM, echocardiographic measurements of cardiac structure demonstrated a mean (SD) reduction in left ventricular mass index (LVMI) from baseline to week 30 in the mavacamten group (-7.4 [17.8] g / m 2 ) compared with an increase in LVMI (8.9 [15.3] g / m 2 The mavacamten group also showed a reduction in mean (SD) from baseline in left atrial volume index (LAVI) (-7.5 [7.8] mL / m 2 ) versus no change in the placebo group (-0.1 [8.7] mL / m 2 ). The clinical significance of these findings is unclear.

[0520] Cardiac Biomarkers

[0521] In the EXPLORER-HCM study, reductions in NT-proBNP, a biomarker of cardiac wall stress, were observed by week 4 and sustained until the end of treatment. At week 30, compared with baseline, NT-proBNP reductions after treatment with mavacamten were 80% greater than with placebo (geometric mean ratio between the two groups was 0.20 [95% CI: 0.17, 0.24]). The clinical significance of these findings is unknown.

[0522] Cardiac Electrophysiology

[0523] In healthy volunteers receiving multiple doses of mavacamten, a concentration-dependent prolongation of the QTc interval was observed at doses up to 25 mg once daily. No acute changes in QTc were observed at comparable exposures during single-dose studies. The mechanism of QT prolongation is unknown.

[0524] Meta-analyses across clinical trials in patients with HCM have not suggested a clinically meaningful prolongation of the QTc interval over the therapeutic exposure range. The primary disease in HCM can result in intrinsic prolongation of the QT interval in association with ventricular pacing or with drugs that may prolong the QT interval and are commonly used in the HCM population. The effect of coadministration of mavacamten with drugs that prolong the QT interval or in patients with potassium channel variants that prolong the QT interval is not well characterized.

[0525] Pharmacokinetics

[0526] Mavacamten exposure increases approximately dose-proportionally after multiple dosing of 1 mg to 15 mg once daily. At the same dose level of mavacamten, mavacamten exposure was observed to be 170% greater in patients with HCM compared to healthy subjects.

[0527] absorption

[0528] Mavacamten has an estimated oral bioavailability of at least 85% and an estimated time to maximum plasma concentration (Tmax) of 1 hour.

[0529] Effects of food

[0530] No clinically significant differences were observed in the pharmacokinetics of mavacamten following administration with a high-fat meal. Tmax increased by 4 hours.

[0531] distribution

[0532] The plasma protein binding of mavacamten is 97-98%.

[0533] Disappearance

[0534] For mavacamten, the variable terminal t1 / 2 depends on the metabolic state of CYP2C19. The terminal half-life of mavacamten is 6-9 days in normal metabolizers (NM) of CYP2C19 and extends to 23 days in poor metabolizers (PM) of CYP2C19. In NM of CYP2C19, the drug accumulates with an accumulation rate of approximately 2-fold in Cmax and approximately 7-fold in AUC. This accumulation depends on the metabolic state of CYP2C19, with the greatest accumulation observed in PM of CYP2C19. At steady state, the peak-to-trough ratio of plasma concentrations with once-daily dosing is approximately 1.5.

[0535] metabolism

[0536] Mavacamten is metabolized primarily through CYP2C19 (74%), CYP3A4 (18%), and CYP2C9 (8%).

[0537] excretion

[0538] After a single 25 mg dose of radiolabeled mavacamten, 7% of the dose was recovered in the feces (1% was unchanged) and 85% was recovered in the urine (3% was unchanged).

[0539] Specific populations

[0540] Age (range: 18–82 years), sex, race or ethnicity, or mild renal impairment (eGFR: 60–89 mL / min / 1.73 m 2 ) to moderate renal impairment (eGFR: 30-59 mL / min / 1.73 m 2 No clinically significant differences were observed in the pharmacokinetics of mavacamten based on the eGFR of 15-30 mL / min / 1.73 m. 2 ) and renal failure (eGFR: <15 mL / min / 1.73 m 2 The effects of schizophrenia on patients with schizophrenia (including dialysis patients) are unknown.

[0541] Liver damage

[0542] Mavacamten exposure (AUC) was increased by up to 220% in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. The effect of severe (Child-Pugh C) hepatic impairment is unknown.

[0543] Drug-drug interactions

[0544] Clinical trials and model-based approaches

[0545] Weak CYP2C19 inhibitors: Healthy NMs and extensive metabolizers (RMs, e.g. * 1 / * 17) In a study in which coadministration of mavacamten (15 mg) and omeprazole (20 mg) once daily increased the AUCinf of mavacamten by 48% without affecting Cmax.

[0546] Moderate CYP3A4 inhibitors: moderate metabolizers of CYP2C19 (IMs, e.g. * 1 / * 2. * 1 / * 3. * 2 / * 17, * 3 / *17) and NM, coadministration of mavacamten (25 mg) and verapamil extended-release (240 mg) increased the AUCinf of mavacamten by 15% and the Cmax by 52%. Coadministration of mavacamten and diltiazem in PMs with CYP2C19 is predicted to increase the AUC0-24h of mavacamten by up to 55% and the Cmax by up to 42%.

[0547] Strong CYP3A4 inhibitors: Coadministration of mavacamten (15 mg) with ketoconazole 400 mg once daily is predicted to increase the AUC0-24 of mavacamten by up to 130% and the Cmax by up to 90%.

[0548] Strong inducers of CYP2C19 and CYP3A4: Coadministration of mavacamten (15 mg single dose) with a strong inducer of CYP2C19 and CYP3A4 (rifampin at a daily dose of 600 mg) is predicted to decrease the AUC0-inf of mavacamten by 87% and the Cmax by 22% in CYP2C19 NMs and to decrease the AUC0-inf of mavacamten by 69% and the Cmax by 4% in CYP2C19 PMs.

[0549] CYP3A4 substrate: In healthy NM with CYP2C19, concomitant use of a 16-day course of mavacamten (25 mg on days 1 and 2 followed by 15 mg for 14 days) reduced midazolam AUCinf by 13% and Cmax by 7%. Following coadministration of mavacamten once daily in patients with HCM, midazolam AUCinf is predicted to be reduced by 21-64% and Cmax by 13-48%, depending on mavacamten dose and CYP2C19 phenotype.

[0550] CYP2C8 Substrates: Concomitant use of once-daily mavacamten in patients with HCM is predicted to decrease the AUC and Cmax of repaglinide, a CYP2C8 and CYP3A substrate, by 12% to 39%, depending on the mavacamten dose and CYP2C19 phenotype.

[0551] CYP2C9 Substrates: Concomitant use of mavacamten once daily in patients with HCM is predicted to decrease the AUC and Cmax of tolbutamide, a CYP2C9 substrate, by 33% to 65%, depending on the mavacamten dose and CYP2C19 phenotype.

[0552] CYP2C19 Substrates: Concomitant use of once-daily mavacamten in patients with HCM is predicted to decrease the AUC and Cmax of omeprazole, a CYP2C19 substrate, by 48% to 67%, depending on the mavacamten dose and CYP2C19 phenotype.

[0553] In vitro testing

[0554] CYP Enzymes: Mavacamten does not inhibit CYP1A2, CYP2B6, or CYP2C8. Mavacamten is not an inhibitor of CYP2D6, CYP2C9, CYP2C19, or CYP3A4 at clinically relevant concentrations. Mavacamten is a CYP2B6 inducer.

[0555] Transporter systems: Mavacamten does not inhibit P-gp, BCRP, BSEP, MATE1, MATE2-K, organic anion transporting polypeptides (OATPs), organic cation transporters (OCTs) or organic anion transporters (OATs).

[0556] 12.5 Pharmacogenomics

[0557] Following a single 15 mg dose of mavacamten, the AUCinf of mavacamten was increased by 241% and the Cmax was increased by 47% in poor metabolizers (PMs) of CYP2C19 compared with normal metabolizers (NMs). The mean half-life was prolonged in CYP2C19 PMs compared with NMs (23 days in PMs vs. 6-9 days in NMs).

[0558] The CYP2C19 polymorphism is the main enzyme involved in the metabolism of mavacamten. Individuals with two normally functioning alleles are classified as NM (e.g. * 1 / * 1). Individuals with two non-functional alleles are classified as PM (e.g.,* 2 / * 2. * 2 / * 3. * 3 / * 3).

[0559] The incidence of poor metabolizers of CYP2C19 varies by ancestry: approximately 2% of individuals of European descent and 4% of individuals of African descent are PMs, and the incidence of PMs is higher in Asian populations (e.g., approximately 13% of East Asians).

[0560] 13.Non-clinical Toxicity

[0561] 13.1. Carcinogenesis, Mutagenesis and Impairment of Fertility

[0562] Mavacamten was not genotoxic in a bacterial reverse mutation test (Ames test), an in vitro human lymphocyte clastogenicity assay, or an in vivo rat micronucleus assay.

[0563] A 6-month study in rasH2 transgenic mice administered mavacamten at doses up to 2.0 mg / kg / day in males and 3.0 mg / kg / day in females found no evidence of carcinogenicity, and exposures (AUC) were 1.8-fold and 3-fold higher in males and females, respectively, than the AUC for humans at the MRHD.

[0564] Reproductive toxicity studies showed no evidence of effects of mavacamten on mating and fertility in male or female rats at doses up to 1.2 mg / kg / day, or on the viability and fertility of offspring in dams treated with doses up to 1.5 mg / kg / day. Plasma exposure (AUC) of mavacamten at the highest dose tested was similar to that in humans at the MRHD.

[0565] 13.2. Animal Toxicity and / or Pharmacology

[0566] The safety of mavacamten has been evaluated orally in rats and dogs at multiple dose levels (0.06-10 mg / kg / day). It is noted that toxicity in rats (including echocardiographic findings, reduced systolic function, cardiac dilatation and death, and increased heart weight) was consistent with mavacamten's mechanism of action and primary pharmacological activity. Other findings included cardiac osseous metaplasia in rats and QTc prolongation in dogs. The plasma exposure (AUC) at the NOAEL in rats was 0.1-fold and in dogs 0.3-fold the human exposure (AUC) at the MRHD.

[0567] 14. Clinical Trials

[0568] Hypertrophic obstructive cardiomyopathy

[0569] The efficacy of mavacamten was evaluated in the international, phase 3, double-blind, randomized, placebo-controlled, multicenter, parallel-group study EXPLORER-HCM (NCT-03470545) in 251 adults with symptomatic obstructive HCM of NYHA class II and III, LVEF ≥ 55%, and Valsalva LVOT peak gradient ≥ 50 mmHg at rest or upon induction.

[0570] Patients receiving dual combination beta-blocker and calcium channel blocker therapy, or monotherapy with disopyramide or ranolazine, were excluded. Patients with known infiltrative or storage disorders causing cardiac hypertrophy that mimicked obstructive HCM (e.g., Fabry disease with left ventricular hypertrophy, amyloidosis, or Noonan syndrome) were also excluded.

[0571] Patients were randomized 1:1 to receive either mavacamten at a starting dose of 5 mg or placebo once daily for 30 weeks. Treatment allocation was stratified by baseline NYHA functional class, baseline beta-blocker use, and type of ergometer (treadmill or stationary bike).

[0572] The groups were divided into groups according to age (mean 59 years), BMI (mean 30 kg / m2 They were well matched for age, heart rate (mean 62 bpm), blood pressure (mean 128 / 76 mmHg), and race (90% Caucasian). Men made up 54% of the mavacamten group and 65% of the placebo group.

[0573] At baseline, approximately 73% of randomized patients were NYHA class II and 27% were NYHA class III. Mean LVEF was 74%, and mean Valsalva LVOT gradient was 73 mm Hg. Approximately 10% had received prior septal reduction therapy, 75% had received beta-blockers, 17% had received calcium channel blockers, and 14% had a history of atrial fibrillation.

[0574] All patients were initiated on mavacamten 5 mg (or matching placebo) once daily, with the dose adjusted periodically to optimize patient response (reduction in LVOT gradient by Valsalva maneuver) and maintain LVEF ≥ 50%, as determined by plasma concentrations of mavacamten.

[0575] In the mavacamten group, 49% of patients were receiving a dose of 5 mg, 33% a dose of 10 mg, and 11% a dose of 15 mg at the end of treatment. Three patients had their treatment temporarily interrupted due to an LVEF less than 50%, two of whom had treatment restarted at the same dose, and one had the dose reduced from 10 mg to 5 mg.

[0576] Primary Endpoint

[0577] The primary composite functional endpoint assessed at 30 weeks was defined as the proportion of patients with either an improvement in mixed venous oxygen tension (pVO2) of ≥1.5 mL / kg / min and an improvement in at least one NYHA class or an improvement in pVO2 of ≥3.0 mL / kg / min and no worsening of NYHA class.

[0578] At 30 weeks, a greater proportion of patients in the mavacamten group met this primary endpoint compared with the placebo group (37% vs. 17% in the placebo group; p=0.0005; see Table 2).

[0579] [Table 2]

[0580] The effects of demographic characteristics, baseline disease characteristics, and range of baseline concomitant medications on outcomes were examined.The results of the primary analysis consistently favored mavacamten across all subgroups analyzed (Figure 17).

[0581] Figure 17 shows the subgroup analysis results for the primary composite functional endpoint.

[0582] The dashed vertical line represents the overall treatment effect, and the solid vertical line (no effect) indicates the point where there is no difference between the treatment groups. Note: This figure shows the effect in various subgroups, all of which are baseline characteristics. The 95% confidence limits shown do not take into account the number of comparisons made and may not reflect the effect of a particular factor after adjusting for all other factors. Apparent homogeneity or heterogeneity between groups should not be overestimated.

[0583] The benefit of mavacamten was smaller (smaller improvement in pVO2) in patients receiving background beta-blocker therapy compared with those not, but analysis of other secondary endpoints (symptoms, LVOT gradient) suggests that patients may benefit from treatment with mavacamten regardless of beta-blocker use.

[0584] Secondary Endpoints

[0585] The treatment effect of mavacamten on LVOT obstruction, functional capacity, and health status was assessed by change from baseline to week 30 in LVOT peak slope after exercise, pVO2, percentage of patients with improvement in NYHA class, Kansas City Cardiomyopathy Questionnaire-23 (KCCQ-23) clinical summary score (CSS), and Hypertrophic Cardiomyopathy Symptom Questionnaire (HCMSQ) shortness of breath (SoB) domain score. At week 30, patients receiving mavacamten had greater improvements across all secondary endpoints compared to the placebo group (Table 3, Figure 18, Figure 19, Table 4, and Figures 7-10).

[0586] [Table 3]

[0587] FIG. 18 shows the cumulative distribution of the change from baseline to week 30 in LVOT peak slope.

[0588] FIG. 19 shows the cumulative distribution of change in pVO2 from baseline to week 30.

[0589] [Table 4]

[0590] †KCCQ-23 CSS is derived from the KCCQ-23 Total Symptom Score (TSS) and Physical Limitation (PL) scores. The CSS ranges from 0 to 100, with higher scores representing less severe symptoms and / or physical limitations.

[0591] ‡HCMSQ SoB domain scores measure the frequency and severity of shortness of breath. HCMSQ SoB domain scores range from 0 to 18, with lower scores representing less shortness of breath.

[0592] Missing data were not imputed to estimate values ​​for baseline and change from baseline to week 30. Mean differences in change from baseline between treatment groups were estimated using repeated measures mixed models.

[0593] The time course of change in KCCQ-23 CSS is shown in Figure 7. Figure 8 shows the distribution of change from baseline to week 30 for KCCQ-23 CSS.

[0594] The figure shows the cumulative percentage of patients who experienced a particular level of response.

[0595] The time course of change in HCMSQ SoB is shown in Figure 9. Figure 10 shows the distribution of change from baseline to week 30 for HCMSQ SoB.

[0596] 16. Supply / storage and handling methods

[0597] Mavacamten is supplied as size 2 immediate release hard gelatin capsules containing 2.5 mg, 5 mg, 10 mg or 15 mg of mavacamten. The capsules contain a white to off-white powder. Mavacamten capsules are available in bottles of 30 capsules as listed in the table below. [Table 5]

[0598] storage

[0599] Store at 20°C to 25°C (68°F to 77°F), with an acceptable variation of 15°C to 30°C (59°F to 86°F) [see USP room temperature control].

[0600] 17. Patient Counseling Information

[0601] Advise patients and / or caregivers to read the FDA-approved patient labeling (dosing instructions).

[0602] heart failure

[0603] Inform patients that they should be monitored for heart failure with cardiac function monitoring using echocardiography. Advise patients to immediately report any signs or symptoms of heart failure to their healthcare provider.

[0604] Drug-drug interactions

[0605] Advise patients to inform their healthcare providers of all concomitant medications and supplements, including over-the-counter medications (e.g., omeprazole, esomeprazole, or cimetidine), before and during treatment with mavacamten.

[0606] Mavacamten REMS program

[0607] Mavacamten is available only through a restricted program called the Mavacamten REMS program. Inform patients of the following notable requirements: · Patients must be enrolled in the program and comply with ongoing monitoring requirements.

[0608] Mavacamten must be prescribed only by certified health care providers and dispensed only by certified pharmacies participating in the program. Patients will be provided with a telephone number and website for information on how to obtain the product.

[0609] Embryo-fetal toxicity

[0610] Inform pregnant women and women of childbearing potential of the possible risks to the fetus. Advise women of childbearing potential to notify their health care providers of their known or suspected pregnancy.

[0611] Advise women of childbearing potential to use effective contraception during treatment with mavacamten and for 4 months after the last dose. Advise patients using CHCs to use an alternative or additional non-hormonal method of contraception, as mavacamten may reduce the effectiveness of CHCs.

[0612] Inform women exposed to mavacamten during pregnancy of the availability of pregnancy safety studies to monitor pregnancy outcomes.

[0613] Mavacamten dosage instructions

[0614] Mavacamten capsules should be swallowed whole. Advise patients that if a dose of mavacamten is missed, it should be taken as soon as possible on that day and the next dose should be taken at the usual time the following day. Patients should not take two doses on the same day.

[0615] Example 2. Simulation of dosing regimens for safety and efficacy Mavacamten has substantial pharmacokinetic (PK) variability, with the largest contributing factor being CYP2C19 phenotype. Moderate inter-individual variability remains after incorporating all PK covariates, in addition to phenotype. As a result of PK variability, the need to strike an ideal balance between preserving patients' left ventricular ejection fraction (LVEF) while decreasing the left ventricular outflow tract Valsalva gradient (VLVOT) led to the development of an echocardiogram (ECHO)-based titration-and-detaching regimen. Modeling and simulation analyses were performed to further evaluate dose titration by CYP2C19 phenotype.

[0616] In addition, an exposure-response simulation-based approach was utilized to examine multiple titration regimens with evenly distributed CYP2C19 phenotypes to provide additional sensitivity in evaluating the performance of titration regimens by phenotype. The evaluation included genotype-specific doses and titrations, an adjusted starting dose of 2.5 mg, and additional monitoring intervals. For each dosage examined, the key objective was to remain consistent, i.e., to limit the percentage of simulated patients with LVEF < 50%, while gradually titrating the dose to VLVOT < 30 mmHg. This example outlines the evaluation of three titration regimens, as described below.

[0617] The methodology used to perform these simulations is described as follows: To investigate the described regimens, 5000 hypothetical oHCM patients were simulated, with approximately 1000 patients simulated from each of the five CYP2C19 phenotypes: poor metabolizers (PM), intermediate metabolizers (IM), normal metabolizers (NM), extensive metabolizers (RM) and extremely extensive metabolizers (UM). To construct the covariate distribution for the simulated patients, a set of covariates was selected from the set of subjects in the active arms of the MYK-461-005 study (EXPLORER-HCM, NCT03470545) and MYK-461-007 study (MAVA-LTE, a study for subjects with oHCM, NCT03723655), stratified by phenotype.

[0618] The same 5000 simulated patients were used for each simulation of regimen, allowing for robust comparison of the simulated performance of each regimen across metabolic capacity states, while controlling for patient covariates or residual variability across weeks that may contribute to differences between regimens.

[0619] Each regimen was simulated for 104 weeks, and the simulation code was designed to mimic the regimens of interest as closely as possible. For any patient who required a dose interruption, a consultation was added after 4 weeks (if the visit was not part of the regimen) to evaluate whether the simulated patient met criteria for resumption of therapy. If criteria were not met, the therapy interruption was maintained for another 4 weeks, and after 4 weeks (8 weeks total), resumption was "forced" if no visit was scheduled (i.e., resumption was achieved without a 4-week visit in the simulation code, which is a simplification of the clinical implementation of titration-tapering regimens that state resumption 4–6 weeks after dose interruption). Patients were resumed at the next lowest available dose intensity, or at the same 2.5 mg dose if discontinued at 2.5 mg.

[0620] The simulations described below in each section provide the following key points: Table showing the percentage of patients with LVEF ≤ 50% stratified by CYP2C19 metabolic status / phenotype at selected time points over 104 weeks Table showing the percentage of patients with LVOT ≤ 30mmHg at the same time points over 104 weeks, stratified by CYP2C19 metabolic status / phenotype Table showing the percentage of patients with mavacamten plasma concentrations >1000 ng / mL at the same time points over 104 weeks, stratified by CYP2C19 metabolizer status / phenotype Diagram showing important safety and efficacy thresholds (percentage of patients with LVEF ≤ 50%, LVOT ≤ 30mmHg, mavacamten plasma concentration > 700ng / mL, and mavacamten plasma concentration > 1000ng / mL) stratified by CYP2C19 metabolic status / phenotype Number of dose distributions at week 104 for each CYP2C19 metabolizer status / phenotype stratified by CYP2C19 metabolizer status / phenotype

[0621] Regimen No. 1: First proposed titration-tapering regimen with uniform CYP2C19 stratification

[0622] In this scenario, the proposed ECHO-based dosing was as follows: Each patient will begin treatment with mavacamten at a dose of 5 mg once daily. All patients will return at week 4 to be assessed for criteria for treatment interruption (LVEF <50%) or tapering (VLVOT <20mmHg). · All patients will return at week 12 for an opportunity to titrate (patients with LVEF ≥ 55% and VLVOT ≥ 30mmHg). Patients who discontinue treatment at week 4 will return 4 weeks later to be assessed for meeting the LVEF criteria for resuming treatment at the next lower dose (recovery of LVEF ≥ 50%). This criterion will be applied at all visits. Patients who are titrated up at week 12 will return 4 weeks later to assess LVEF and LVOT gradient. After this 4-week follow-up, the next visit will be scheduled 12 weeks later (week 28) for the next opportunity to titrate, and every 12 weeks thereafter (unless there is a dose escalation or interruption that results in an additional 4-week follow-up visit). After the week 12 visit, patients with no change in dose will be evaluated at the 12-week visit, then every 12 weeks until week 52, and every 24 weeks from weeks 52-104. After week 40, all patients follow the same visit schedule with a 12-week visit at week 52 and every 24 weeks thereafter. To account for the clinically targeted 4-week follow-up visits only for patients who have titrated up or been interrupted, all simulated patients are evaluated 4 weeks after the quarterly (12-week) or semiannual (24-week) visits. · Titrations cannot occur within 12 weeks of another titration. For code abbreviation, a "forced resumption" was performed 8 weeks after discontinuation if the patient did not meet the LVEF ≥ 50% criterion at the coded 4-week follow-up visit. This abbreviation was performed 4 times (once at week 20 and three times between weeks 40 and 104).

[0623] Table 5 shows the number of percentages of patients with LVEF ≤ 50% across time points over a 104-week period stratified by phenotype. In general, the highest percentages of patients with LVEF ≤ 50% were based on phenotype status, highest in PM (10.2% at week 24) and lowest in UM (< 2% at all time points). This relationship was also seen for LVOT, with the highest percentages of patients meeting an LVOT ≤ 30 mmHg in PM and the lowest percentages in Um (Table 6). Across all phenotypes, more than 60% of patients met the LVOT ≤ 30 mmHg requirement after week 18.

[0624] Table 7 shows that the percentage of patients with mavacamten plasma concentrations >1000 ng / mL was generally low, with no more than 4% exceeding this threshold across phenotypes. Figure 13 shows important safety and efficacy thresholds including mavacamten plasma concentrations >700 ng / mL over the 104 week period. The dose distribution shown in Table 8 indicates that a wide range of doses were assigned across all phenotypes at week 104 in the simulated patients, indicating that no single dose intensity is appropriate for all patients with the proposed dosing. [Table 6] [Table 7] [Table 8]

[0625] Figure 13 (A-D) shows the percentage of patients (%) who had an LVEF ≤ 50%, a VLVOT ≤ 30 mmHg, a mavacamten plasma concentration > 700 ng / mL, and a mavacamten plasma concentration > 1000 ng / mL over time (over the 104-week treatment period) in Regimen No. 1. [Table 9]

[0626] Regimen No. 2: Second proposed dosage with additional ECHO monitoring

[0627] This dosing maintains some similarity to the originally proposed dosing in that it presents one "uniform" dosing for all patients with the same starting dose (5 mg), LVEF criteria for titration and tapering, and VLVOT criteria for titration and tapering. The dosing for regimen #2 is consistent with the dosing in Example 1 and Figures 4-6. Compared to regimen #1, important modifications to the dosing include an additional visit at week 8 for all patients with an opportunity for tapering, an opportunity for permanent discontinuation in patients who cannot tolerate the lowest dose of mavacamten (as defined by patients with LVEF < 50% twice during treatment with a dose of 2.5 mg), and the continuation of the monitoring interval every 3 months in the second year of treatment. An additional opportunity for tapering in patients maintained on 5 mg was realized at the week 8 visit for patients who did not taper at week 4 and met the criterion of VLVOT < 20 mmHg. The implementation of the simulation remained consistent with the methodology outlined above. In addition, after the first titration opportunity at week 12, all patients were scheduled for visits every 12 weeks rather than 12 weeks after their previous visit. In the second year, patients remained scheduled for visits every 12 weeks rather than every 24 weeks.

[0628] Table 9 shows the number of patients with LVEF 50% or less stratified by phenotype over the time points over the 104-week period. In general, the highest percentage of patients with LVEF 50% or less was based on phenotype status, highest in PM (4.2% at week 8) and lowest in UM (1% or less at all time points). This relationship was also seen for LVOT, with the highest percentage of patients meeting an LVOT 30mmHg or less in PM and the lowest percentage in Um (Table 10). In all phenotypes except UM, more than 60% of patients met the LVOT 30mmHg or less requirement after week 18.

[0629] Table 11 shows that the percentage of patients with mavacamten plasma concentrations >1000 ng / mL was generally low, with approximately 2% or less exceeding this threshold across phenotypes. Figure 14 shows important safety and efficacy thresholds including mavacamten plasma concentrations >700 ng / mL over the 104-week period. The dose distribution shown in Table 12 shows a continued broad range of doses across all phenotypes, with the final distribution being relatively consistent with the initial dose, except for approximately 10% of PMs who were permanently discontinued during the course of treatment. This criterion appears to have minimal impact on all other metabolic phenotypes, improving the overall benefit / risk ratio while appropriately identifying patients who may not be able to tolerate the lowest dose intensity available. According to the dose distribution simulation below, this reflects approximately 10% of the PM population and 0.3% of the IM population. Considering the CYP2C19 phenotype distribution in the EU population, this criterion would result in less than 0.5% of patients being excluded / permanently discontinued overall. [Table 10] [Table 11] [Table 12]

[0630] Figure 14 (A-D) shows the change over time in the percentage of patients (%) in Regimen No. 2 who (over the 104-week treatment period) had (A) LVEF ≤ 50%, (B) VLVOT ≤ 30 mmHg, (C) mavacamten plasma concentration > 700 ng / mL, and (D) mavacamten plasma concentration > 1000 ng / mL. [Table 13]

[0631] Regimen No. 3: Evaluation of a lower starting dose with additional ECHO monitoring

[0632] This regimen remains the same as the one defined above as "regimen no. 2," except with a lower starting dose of 2.5 mg. This regimen was evaluated to assess whether a simple recommendation could be made, e.g., a lower starting dose, for patients known to be CYP2C19 PMs. For the purposes of this simulation, all patients were started on a 2.5 mg starting dose, with the intention to evaluate whether a subgroup of phenotypes could benefit from a lower starting dose and no other modifications to the titration-tapering regimen.

[0633] Table 13 shows the number of patients with LVEF 50% or less stratified by phenotype over the time points over the 104-week period. In general, the highest percentage of patients with LVEF 50% or less was based on phenotype status, highest in PM (4.9% at week 24) and lowest in UM (1% or less at all time points). This relationship was also seen for LVOT, with the highest percentage of patients meeting LVOT 30mmHg or less in PM and the lowest percentage in Um (Table 14). In all phenotypes except UM, more than 60% of patients met LVOT 30mmHg or less after week 30.

[0634] Table 15 shows that the percentage of patients with mavacamten plasma concentrations >1000 ng / mL was generally low, but higher than in Regimen 2 above, with no more than 2.6% exceeding this threshold across phenotypes. Figure 15 shows important safety and efficacy thresholds, including mavacamten plasma concentrations >700 ng / mL over a 104-week period. The dose distribution shown in Table 16 is quite consistent with that obtained with Regimen 2 above, indicating that the same patients will end up with similar individualized optimal doses over time. This regimen has a delayed onset of efficacy in patients without improved safety compared to Regimen 2 above. The main reason for this is that Regimen 2 introduces an additional taper visit at week 8, increasing the opportunity for early taper in patients who may ultimately require a dose reduction. Starting patients, especially PMs, at a lower dose would eliminate the benefit of additional taper opportunities, and final titration after week 12 would result in a longer treatment period without ECHO visits compared to the first 12 weeks, resulting in a higher percentage of PMs overall with LVEF ≤ 50% later in treatment, i.e., at week 24, rather than at week 8. Table 16 shows that in simulated patients, a wide range of doses were assigned across all phenotypes at week 104, indicating that with the proposed dosing, no single dose intensity is appropriate for all patients. [Table 14] [Table 15] [Table 16]

[0635] Figure 15 (A-D) shows the change over time in the percentage of patients (%) in Regimen No. 3 who (over the 104-week treatment period) had (A) an LVEF of 50% or less, (B) a VLVOT of 30 mmHg or less, (C) a mavacamten plasma concentration of greater than 700 ng / mL, and (D) a mavacamten plasma concentration of greater than 1000 ng / mL. [Table 17]

[0636] overview In the overview, several titration / tapering regimens were evaluated to improve the proposed titration / tapering regimen. The regimens evaluated included monitoring frequency, phenotype-specific fixed doses, phenotype-specific starting doses, phenotype-specific titration / tapering rules, and permanent discontinuation criteria. A second dosing proposal (regimen no. 2) was considered to improve the safety profile, especially in PMs, while achieving the best benefit / risk ratio across the entire population. Regimen no. 3 was tested to evaluate whether simple modifications / recommendations could be made in patients with known CYP2C19 phenotypes. The benefit / risk ratio was improved by recommending a lower starting dose in PMs. There was a delay in achieving VLVOT below 30 mmHg and a higher proportion of patients with LVEF below 50% at any one visit. The safety profile appears to improve over the first 12 weeks, but the overall proportion of patients with LVEF below 50% was higher than with regimen no. 2. However, this phenomenon was observed later, as expected, once patients were titrated up at week 12. This makes it clear that simple modifications to the titration scheme, such as a lower starting dose, do not improve the safety profile of PMs. Additional modifications to the dosing regimen based on phenotype may provide some benefit to PMs, but may also create additional risks for the entire patient population in terms of label complexity, risk of medication errors, and impact on safety. Balancing all these components, it was assessed that this uniform dosing in regimen #2 allows for an improved benefit / risk ratio without the label introducing excessive complexity that could lead to unintended medication errors.

[0637] FIG. 16 (A and B) shows a comparison between Regimen No. 1 and Regimen No. 2 in terms of the percentage (%) of patients whose LVEF became less than 50%. As shown in the figure, the percentage (%) of patients, especially patients with low metabolic capacity, whose LVEF became less than 50% is low in Regimen No. 2. For example, in Regimen No. 1, about 10% of patients with low metabolic capacity (PM) and about 1.2% of non-PM patients have an LVEF of less than 50% at week 24, while in Regimen No. 2, about 3.8% of PM patients and about 0.85% of non-PM patients have an LVEF of less than 50% at week 24. In addition, in Regimen No. 1, about 7% of patients with low metabolic capacity (PM) and about 0.25% of non-PM patients have an LVEF of 50% or less at week 12, while in Regimen No. 2, about 2.2% of PM patients and about 0.025% of non-PM patients have an LVEF of 50% or less at week 12.

[0638] Example 3. Risk Evaluation and Mitigation Strategy (REMS)

[0639] I. REMS Goals

[0640] The goal of the mavacamten Risk Evaluation and Risk Mitigation Strategy (REMS) program is to reduce the risk of heart failure due to systolic dysfunction.

[0641] the goal: 1. Monitor with regular echocardiograms to detect heart failure due to systolic dysfunction. 2. Screen for drug interactions before each dispensing.

[0642] II. REMS Requirements

[0643] [Table 18-1] [Table 18-2] [Table 18-3] [Table 18-4]

[0644] REMS program administrators must provide training to health care providers who prescribe mavacamten.

[0645] The training will include the following materials: Program Outline Educational programs for healthcare providers and pharmacies Healthcare provider knowledge assessment

[0646] The training must be available online, via email, and in hard copy format via mail.

[0647] REMS program administrators must provide training to pharmacies that dispense mavacamten.

[0648] The training will include the following materials: Program Outline Educational programs for healthcare providers and pharmacies Pharmacy Certified Representative Knowledge Assessment

[0649] Training must be available online, via email, and in hard copy format via mail.

[0650] To support the work of the REMS, the REMS program manager must: 1. For each patient, based on receipt of the patient registration form and patient status form, and for pharmacies based on receipt of the drug interaction and counseling checklist, authorize dispensing according to the following schedule. At first dispensing: If the Patient Registration Form and Drug Interaction and Counseling Checklist for the Pharmacy have not been completed, the patient will not be allowed to take the medication until the completed forms have been received. Subsequent Dispensing: Prior to each dispense, if a Patient Status Form (as described in the Provider and Pharmacy Education Program) has not been received within 3 calendar days of the end of the week in which the echocardiogram is due and a completed Drug Interactions and Counseling Checklist for the Pharmacy has not been completed, the patient will not be allowed to receive the medication until the completed form has been received. 2. Establish and maintain a REMS website. The REMS website must include the ability for providers and pharmacies to complete certification and enrollment online; the ability for patients to enroll and manage online, including completing drug interaction and counseling checklists and patient status forms for pharmacies; the ability to review enrollment and certification status and provider certification status and to become certified to dispense; and the option to print prescribing information, medication guides, and REMS materials. All consumer- and provider-facing product websites must include a prominent REMS-specific link to the REMS program website. The REMS program website must not link externally to promotional product website(s). 3. When mavacamten is first commercially available, have the REMS website fully operational and make all REMS materials available via the website and the Mavacamten REMS call center. 4. Establish and maintain a REMS call center for REMS participants. 5. Establish and maintain a verified and secure database of all REMS participants enrolled and / or certified in the mavacamten REMS. 6. Allow healthcare providers and pharmacies to complete the certification process online and by fax. 7. Allow healthcare providers to complete the patient registration process online and by fax. 8. Allow healthcare providers to complete patient status forms online and by fax. 9. Allow pharmacies to document prescribed doses and complete pharmacy-specific drug interaction and counseling checklists online and by fax. 10. Allow pharmacies to obtain authorization to dispense medication online and over the phone. 11. Provide the program outline, educational programs for providers and pharmacies, and the provider registry or pharmacy registry to health care providers who (1) intend to prescribe or dispense mavacamten and are not yet certified, or (2) inquire about how to become certified. 12. When a REMS is approved, healthcare providers and pharmacies will be notified within one business day. 13. When patient enrollment is complete, notify the healthcare provider within one business day. 14. Provide authorized health care providers with access to their database of registered patients and authorized pharmacies. 15. Provide certified pharmacies with access to a database of certified healthcare providers and registered patients. 16. Provide authorized wholesalers and distributors with access to a database of authorized pharmacies.

[0651] To ensure that REMS participants comply with the REMS, the REMS program administrator must: 17. Certify annually that the name and contact information of the Certified Representative corresponds to that of the pharmacy's current designated Certified Representative. If different, the pharmacy must recertify the new Certified Representative. 18. Adequate records shall be maintained that demonstrate the requirements of the REMS are being met, including, but not limited to, records of distribution and dispensing of mavacamten, provider and pharmacy certification, patient enrollment, completed patient status forms and drug interaction and counseling checklists for pharmacies, and audits of certified pharmacies and authorized wholesalers and distributors. These records shall be readily available for inspection by FDA. 19. Establish and maintain a plan to address violations of the requirements of the REMS. 20.Continually monitor healthcare providers, pharmacies, and wholesalers / distributors to ensure that they comply with the requirements of the REMS, and take corrective action, up to and including revocation of accreditation, if violations are identified. 21. Audit the pharmacy and wholesaler / distributor once they are certified, and annually within 180 calendar days to ensure that all REMS processes and procedures are implemented and functional and support the requirements of the REMS. 22. Based on the monitoring and evaluation of the mavacamten REMS, take reasonable steps to improve the operation of and comply with the requirements of the REMS.

[0652] III. REMS Evaluation Timetable

[0653] The REMS program manager must submit a REMS evaluation annually from the date of initial approval of the REMS program. To allow reasonable time to prepare the submission while encouraging inclusion of as much information as possible, the end of the reporting interval applicable to each evaluation must be no less than 60 calendar days prior to the submission date of that evaluation. The REMS program manager must submit each evaluation so that FDA receives it on or before its due date.

[0654] IV.REMS materials

[0655] The following materials are part of the REMS for mavacamten: Registration Form Healthcare Providers: 1. Healthcare Provider Registration Form patient: 2. Patient Registration Form pharmacy: 3.Pharmacy registration form Training and Materials Healthcare Providers: 4. Educational Programs for Healthcare Providers and Pharmacies 5. Program Overview 6. Healthcare Provider Knowledge Assessment patient: 7. Patient Brochures pharmacy: 8. Educational Programs for Healthcare Providers and Pharmacies 9. Program Outline 10. Pharmacy Certified Representative Knowledge Assessment Patient Care Forms 11.Patient status report 12. Drug Interaction and Counseling Checklist for Pharmacies Other resources 13.REMS Website

[0656] Example 4. Simulation of drug interactions

[0657] Statement of Objective: Mavacamten is a first-in-class, selective, allosteric, reversible cardiac myosin inhibitor being developed for the treatment of adults with symptomatic obstructive hypertrophic cardiomyopathy. Mavacamten is primarily metabolized in the liver via CYP2C19 (74%), CYP3A4 (18%), and CYP2C9 (8%). A previously developed physiologically based, fit-for-purpose pharmacokinetic (PBPK) model was applied to explore the induction effects of rifampin, a strong CYP3A4 / CYP2C19 inducer, and carbamazepine, a strong CYP3A4 inducer, on mavacamten exposure.

[0658] Methods: Modeling and simulation analyses were performed using Simcyp v19 (Certara). The mavacamten compound file was further validated against additional mavacamten phase I clinical data in healthy volunteers. The study design for the DDI simulation included a lead-in inducer period (rifampin: 600 mg QD for 7 days, carbamazepine: 400 mg BID for 14 days) to maximize induction effect, followed by a single mavacamten dose (15 mg) and continued inducer administration for an additional 2 months until the end of the virtual study. Default compound files for rifampin and carbamazepine that were supplied to Simcyp Simulator (V19) were used in all simulations. Results of the simulation were stratified by three populations: healthy volunteers including all CYP2C19 phenotypes, healthy volunteers excluding CYP2C19 poor metabolizers (PMs), and healthy volunteers including only CYP2C19 PMs.

[0659] Data and Results: In the rifampin DDI simulations, the AUC of mavacamten was significantly higher in all hypothetical populations evaluated. 0-T Moderate decreases in AUC (geometric mean (GM) 60-69%) and minimal decreases in Cmax (GM 4-7%) were observed. Mavacamten clearance was increased 2.5-3.2-fold in the presence of induction with rifampin. DDI simulations with carbamazepine showed that the AUC 0-T There was a slight decrease in Cmax (GM13-30%) and a minimal decrease in Cmax (GM1%). Mavacamten clearance was increased 1.1-1.4-fold in the presence of induction by carbamazepine.

[0660] Conclusions: Using the Simcyp Simulator, we investigated the effect of strong inducers of CYP2C19 and / or CYP3A4 on mavacamten exposure based on CYP2C19 phenotype distribution in a virtual population. Application of the model to understand the effect of a strong CYP2C19 / CYP3A4 inducer (rifampin) revealed a moderate decrease in mavacamten exposure in all populations. A weak induction effect was observed in all populations when mavacamten was co-administered with carbamazepine, a strong CYP3A4 inducer with a lower intensity. We propose that mavacamten is contraindicated with both strong and moderate inducers of CYP2C19 and CYP3A4 due to the decrease in mavacamten exposure when co-administered with strong inducers of CYP2C19 and / or CYP3A4.

[0661] Example 5. Simulation of combined administration

[0662] Statement of Objective: Mavacamten is a first-in-class allosteric, selective, reversible cardiac myosin inhibitor currently in development for the treatment of adults with symptomatic obstructive hypertrophic cardiomyopathy. A physiologically based pharmacokinetic (PBPK) model was utilized to explore the drug-drug interaction (DDI) situations in which mavacamten becomes an interacting drug due to induction of CYP2C19 and CYP3A4. The PBPK model was further conducted to explore the possible effects of inhibitors of CYP2C19 and CYP3A4 on the pharmacokinetics of mavacamten.

[0663] Methods: All modeling was performed using the software Simcyp v19 (Certara). A previously developed fit-for-purpose PBPK model was validated with additional clinical data from a DDI study of mavacamten with the CYP3A4 inhibitor verapamil. Strong, moderate and weak inhibition of CYP2C19 and CYP3A4 were explored individually using Simcyp library compounds of ticlopidine, omeprazole, itraconazole, diltiazem and cimetidine to understand the possible effect on mavacamten exposure and to obtain the most recommended clinical dose (15mg QD). Simulations were performed at steady-state conditions for both mavacamten and the interacting drug, and potential DDIs were explored for each CYP2C19 phenotype.

[0664] Data and Results: Simulations of strong inhibition of CYP2C19 or CYP3A4 showed that the geometric mean AUC increased by up to 2.3-fold with CYP2C19 inhibition and by up to 1.8-fold with CYP3A4 inhibition, and the geometric mean Cmax increased by up to 1.6-fold with CYP2C19 inhibition and by up to 1.5-fold with CYP3A4 inhibition, with phenotype-specific trends observed for inhibition, e.g., strong CYP2C19 inhibition most affected very extensive metabolizers of CYP2C19, and strong CYP3A4 inhibition most affected poor metabolizers (Figures 20A and B). Moderate CYP2C19 or CYP3A4 inhibition predicted a maximum 1.6-fold increase in AUC and a maximum 1.4-fold increase in Cmax. Weak CYP2C19 inhibition was predicted to increase AUC by up to 1.4-fold and C by up to 1.2-fold, while weak CYP3A4 inhibition was predicted to increase mavacamten exposure by less than 1.1-fold. The results are shown in Figure 20 (A and B).

[0665] Conclusions: Because CYP2C19 is a highly polymorphic enzyme, the results of this simulation across CYP2C19 phenotypes were used to provide insight into dosing of mavacamten in the context of DDI inhibition of CYP2C19 and CYP3A4 in the patient population. Due to the increased exposure observed in the simulation, we suggest a contraindication to the coadministration of moderate to strong CYP2C19 inhibitors and strong CYP3A4 inhibitors. Additional suggestions for weak CYP2C19 or moderate CYP3A4 inhibitors are proposed, including initiating treatment with mavacamten at the accepted recommended dose in patients on a stable inhibitor regimen, and reducing the mavacamten dose by one level in patients intending to start treatment with a weak or moderate CYP2C19 inhibitor. In conclusion, PBPK modeling was performed to provide insight into DDI inhibition recommendations for mavacamten, taking into account differences in CYP2C19 phenotypes.

[0666] Example 6. Requirements for risk assessment and risk mitigation strategies The REMS must include the following:

[0667] Elements to ensure safe use: Elements to ensure safe use will be required as part of the REMS to mitigate the risk of heart failure due to systolic dysfunction (as listed in the drug labeling).

[0668] The REMS will include the following elements to mitigate this risk: Healthcare providers have specific backgrounds, training, or are specially certified The pharmacy, practitioner, or medical setting that dispenses the drug is specifically certified Dispensing the drug to patients who have a certificate or other documentation of safe use Each patient using the drug is subject to specific monitoring

[0669] Delivery System: A REMS must include a delivery system that monitors, evaluates, and works to improve the delivery of its components and ensure safe use (as outlined above), which requires that pharmacies that dispense the drug be specifically certified and that the drug be dispensed to patients with documentation of safe use conditions.

[0670] A REMS consists of elements that ensure safe use, an implementation system, and a timetable for the submission and evaluation of the REMS.

[0671] The REMS evaluation plan must include, but is not limited to, the following program outreach and communications (provide data at the 1-year evaluation only):

[0672] 1. REMS Program Website a) The date the REMS website was published b) Total and unique visitors to the REMS Program website c) The number and type of mavacamten REMS materials downloaded or accessed

[0673] Program implementation and operation

[0674] 2. REMS Call Center Records (providing data for the past two reporting periods, for the current reporting period, and cumulatively) a) Number of calls by type of stakeholder (patient, healthcare provider, contractor, pharmacy, wholesaler / distributor, other) b) Summary of reason for call (e.g., registration question) and type of stakeholder (patient, provider, contractor, pharmacy, other). Limit this summary to the top five reasons for call per stakeholder group. c) If the summary of the reason for the call(s) indicates a complaint, include details about the nature of the complaint(s) and whether the caller is indicating a possible REMS challenge or patient access issue. d) If the summary of the reason for the call(s) indicates an adverse event related to heart failure or a contraindicated medication or drug-drug interaction, include the details and outcome of the call(s). e) Percentage of calls to the REMS call center that were answered within 20 minutes f) The minimum waiting time for a call to be answered, the maximum waiting time for a call to be answered, and the median waiting time for a call to be answered g) The percentage of calls to the REMS call center in which the caller hung up before the phone was answered f) Minimum waiting time to hang up, maximum waiting time to hang up, median waiting time to hang up

[0675] 3. Program implementation (provide data only at the one-year evaluation) a) The date mavacamten was first marketed b) For each stakeholder (healthcare provider, contractor, pharmacy, patient), the date on which they became eligible to be certified. c) The date that the Mabacamteng REMS call centre was established and fully operational.

[0676] 4. REMS Certification and Registration (provide data for the past two reporting periods, for the current reporting period, and cumulatively) a) Healthcare Providers i. Number of newly admitted providers and number of active providers (i.e., providers who have prescribed at least one prescription during the reporting period) stratified by license (e.g., internist, osteopath, nurse practitioner, physician assistant, other), specialty (e.g., cardiology, electrophysiology, geneticist, other), and geographic region (as defined by the U.S. Census). If "other" represents more than 10% of respondents, provide the most common specialty identified. Specifically identify and categorize the specialty as within cardiology or not within cardiology. b) Number of recipients stratified by role (e.g., RPh / PharmD, RN, NP, or hPA) i. How to certify healthcare providers and contractors (online or fax) c) Pharmacy i. Number of newly certified pharmacies ii. Number of active pharmacies (i.e., pharmacies that have dispensed mavacamten) d) patient i. Number of newly enrolled patients and number of active patients (i.e., patients who have received at least one dosage of mavacamten), stratified by composite variables of age and sex and geographic region. The youngest and oldest enrolled patients are provided. For the sex / age variable, age of use ranges from <18, 18-40, 41-60, and ≥61 years. e) Wholesalers and distributors i. The number of newly contracted wholesalers / distributors and the number of active wholesalers / distributors (i.e., wholesalers / distributors that have shipped mavacamten);

[0677] 5. Compliance with REMS (provide data for the past two reporting periods, for the current reporting period, and cumulatively) a) Copies of violation plans (starting with the one-year evaluation and annually thereafter) for healthcare providers, pharmacies, and wholesalers / distributors, including the criteria for violations, the steps to be taken to address the violations in each case, and the events that would result in removal of certification from the mavacamten REMS. b) Audit i. Copy of Audit Plan for Pharmacies and Wholesalers / Distributors ii. Recording of audit findings for each stakeholder (pharmacy and wholesaler / distributor); iii. The number of audits anticipated and the number of audits to be conducted; iv. Documentation of training completion for relevant staff v. Documentation that processes and procedures are in place to comply with the mavacamten REMS vi. Verify that the designated Certified Representative remains the same for each stakeholder facility audited. If different, document that the pharmacy has been recertified with the name and contact information of the new Certified Representative. vii. The number and type of non-compliances observed in each stakeholder group audited (as a percentage of stakeholders audited). viii. For each pharmacy audited, the number of violations (numerator) divided by the number of prescriptions dispensed at that pharmacy audited (denominator): The provider was not certified and filled the prescription. The patient was not registered and the prescription was filled - Prescriptions were dispensed without completing the drug interaction and counseling checklist · Audit of drug interaction and counseling checklist forms that identified cases where medications were dispensed but the necessary steps were not taken Certification was denied and prescription was dispensed ix. For stakeholders where non-compliance was observed, the number of corrective and preventive action (CAPA) plans that were successfully completed and the percentage of stakeholders for which a CAPA plan was required; x. For any stakeholders who did not complete the CAPA plan, a description of the actions taken c) Provider Violations (for each non-compliant event, the source of the record, a description of the event, an analysis of the cause of the event, and any corrective actions taken) Number of providers who did not comply with the mavacamten REMS program requirements, provided as a percentage of active providers. ii. Provide the number of providers whose accreditation has been decertified and the reason for decertification as a percentage of active providers, including any provider who has been recertified. d) Pharmacy (for each non-compliance event, the source of the record, a description of the event, an analysis of the cause of the event, and any corrective actions taken). i. The number of pharmacies where a REMS violation for mavacamten was detected (numerator) divided by the total number of pharmacies that dispensed mavacamten (denominator). ii. The number of non-certified pharmacies dispensing mavacamten (numerator) divided by the total number of pharmacies dispensing mavacamten (denominator). Expected compliance rate is 99.9%. iii. The number of mavacamten prescriptions dispensed by non-certified pharmacies (numerator) divided by the total number of mavacamten prescriptions dispensed (denominator) and measures taken to prevent this from occurring in the future. Compliance rate of 99.9% is expected. iv. The number of dispensed mavacamten prescriptions written by non-certified medical providers (numerator) divided by the total number of dispensed prescriptions (denominator). For dispensed prescriptions written by non-certified medical providers, a cause analysis will be conducted and measures will be taken to prevent future occurrences. A compliance rate of 99.9% is expected. v. The number of mavacamten prescriptions dispensed to non-registered patients (numerator) divided by the total number of prescriptions dispensed (denominator). For mavacamten prescriptions dispensed to non-registered patients, a cause analysis will be conducted and measures will be taken to prevent future occurrences. A compliance rate of 99.9% is expected. vi. The number of prescriptions for mavacamten dispensed to non-registered patients based on prescriptions from non-certified medical providers (numerator) divided by the total number of prescriptions dispensed (denominator). For prescriptions dispensed to non-registered patients based on prescriptions from non-certified medical providers, a cause analysis will be conducted and measures will be taken to prevent future occurrences. A compliance rate of 99.9% is expected. vi. The number of times a certified pharmacy filled a mavacamten prescription due to a circumvention of the mavacamten REMS certification process (numerator) divided by the number of times filled by all certified pharmacies (denominator). A causal analysis will be performed that will include a description of how the event was identified and any corrective actions taken. A compliance rate of 99.9% is expected. vii. The number of pharmacies whose certification was revoked, the reason for revocation, and the actions taken to address the violations, provided as a ratio of the number of pharmacies whose certification was revoked (numerator) divided by the total number of certified pharmacies (denominator). e) Wholesalers and distributors (for each non-compliance incident, the source of the record, a description of the incident, an analysis of the cause of the incident, and any corrective actions taken) i. The number of contracted wholesalers / distributors in which a REMS violation for mavacamten was detected (numerator) divided by the number of contracted wholesalers / distributors (denominator) ii. The number of wholesalers and distributors that have been suspended, the reasons for suspension, and the measures taken to address violations; iii. The number of times mavacamten was distributed to non-certified pharmacies (numerator) divided by the number of times mavacamten was distributed (denominator)

[0678] 6. Usage Data (provide data for the past two reporting periods, for the current reporting period, and cumulatively) a) Number of prescriptions filled (new and refills) stratified by: i. Provider rank / qualification and geographic region ii. Patient demographics (age and sex and geographic region); b) Number of prescriptions filled and rejected (not accepted) stratified by: i. The reason for refusal and the number of refusals (numerator) divided by the total number of refusals (denominator) Non-certified medical providers Prescriptions written by a trustee Patients who are not registered Patient status reports documenting echocardiograms were not submitted on an appropriate schedule Drug interaction and counseling checklists not completed Drug-drug interactions or contraindications were not identified and appropriate measures were taken Other reasons for refusal not categorized above ii. Provider rank / qualifications and geographic region c) The actual number of providers who wrote prescriptions filled during the reporting period (active providers). d) Actual number of patients taking mavacamten, stratified by age, sex, and geographic region

[0679] 7. Healthcare system burden and / or barriers to patient access

[0680] Provide reports to the mavacamten REMS call center indicating burden on the health system or barriers to patient access. Evaluate whether burden is due to REMS, insurance, availability of care, or other factors.

[0681] Safe Use Behavior

[0682] 8. Patient Status Report (provide data for the past two reporting periods, for the current reporting period, and cumulatively) a) Number of Patient Status Forms Projected, Received, and Backlogged at the Time of REMS Evaluation Deadline b) The number of patients whose first shipment occurred before receipt of the patient registration form (numerator) divided by the total number of patients to whom mavacamten was dispensed (denominator), resulting in an expected compliance rate of 99.9%. c) The actual number of patients for whom a Patient Status Report was submitted and whose echocardiogram was reviewed by a healthcare provider (numerator) divided by the actual number of patients for whom a Patient Status Report was submitted (denominator). d) The actual number of patients for whom a Patient Status Report was submitted and for whom the provider approved treatment (numerator) divided by the actual number of patients for whom a Patient Status Report was submitted (denominator) e) The number of patient status forms that are outstanding from the prior reporting period and that are completed in the current reporting period (the numerator) divided by the number of patient status forms that are outstanding (if applicable) from the prior reporting period. f) Number of patients who completed an echocardiogram but were unable to take the medication due to denials and reasons (e.g., medication not dispensed due to lost patient status paperwork, insurance issues preventing medication from being dispensed, or transportation issues preventing the patient from obtaining an echocardiogram). g) Number of patient status notes in which the provider indicated the patient had a history of clinical heart failure events that required hospitalization h) Number of patient status papers in which the provider indicated the patient had a history of LVEF falling below 50% i) Number of patients who were not allowed to take mavacamten and had this documented in their patient status report

[0683] 9. Drug Interactions and Counseling Checklist for Pharmacies (provide data over the past two reporting periods, over the current reporting period, and cumulatively) a) The actual number of patients with a drug interaction and counseling checklist completed before first dispensing of mavacamten (numerator) divided by the number of patients who initiated treatment with mavacamten (denominator). Expected compliance rate is 99.9%. b) The number of filled prescriptions with a drug interaction and counseling checklist completed before dispensing (numerator) divided by the number of prescriptions filled with mavacamten (denominator). Expected compliance rate is 99.9%. c) The number of checklists for drug interactions and counseling that identified contraindicated drugs (numerator) divided by the total number of completed checklists for drug interactions and counseling (denominator). d) For drug interaction and counseling checklists that identify contraindicated medications, indicate the cause of the drug interaction and the actions taken after the health care provider contact, including the following: i.Cause 1. Interacting medications prescribed by a certified medical provider / contractor for mavacamten 2. Interacting medications prescribed by other healthcare providers 3. Interacting medications purchased by the patient over the counter ii. Actions taken 1. Discontinuation of mavacamten 2. Discontinuation of contraindicated medications e) The number of drug interaction and counseling checklists that identified concomitant medications requiring dose reduction (numerator) divided by the total number of completed drug interaction and counseling checklists (denominator). f) For drug interaction and counseling checklists that identify concomitant medications requiring dose reductions, after provider contact, indicate the cause of the drug interaction and the actions taken, including: i.Cause 1. Interacting medications prescribed by a certified medical provider / contractor for mavacamten 2. Interacting medications prescribed by other healthcare providers 3. Interacting medications purchased by the patient over the counter ii. Actions taken 1. Discontinuation of mavacamten 2. Reduction in the dose of mavacamten 3. Discontinuation of other medication(s) g) Any information obtained from audits or self-reported by pharmacies indicating that a patient took mavacamten while also taking a contraindicated medication, expressed as the number of patients taking concomitant contraindicated medications who also received at least one shipment of mavacamten (numerator) divided by the total number of patients who received at least one shipment of mavacamten (denominator). In either case, include the name of the contraindicated medication, the dose, and the duration of treatment.

[0684] 10. Knowledge Assessment (provide data for the 1st and 2nd year assessment reports only) a) Number of provider knowledge assessments completed (including method and number attempted) b) Summary of the most frequently omitted questions in the provider knowledge assessment c) A summary of any potential comprehension or cognitive problems identified in the provider knowledge assessment. d) Number of Pharmacy Certified Representative Knowledge Assessments completed (including method and number attempted) e) Summary of the most frequently omitted questions in the Pharmacy Certified Representative Knowledge Assessment f) A summary of any potential comprehension or cognitive problems identified during the Pharmacy Certified Representative Knowledge Assessment.

Claims

1. A pharmaceutical composition comprising a myosin inhibitor for use in the treatment of heart disease or disorder in patients requiring treatment, wherein the treatment is (a) The step of administering an initial dose of myosin inhibitor during the first treatment period, (b) A step of evaluating the left ventricular outflow tract obstruction of the patient, obtaining a first evaluation result, and determining whether the first evaluation result falls below the first threshold, (c) The step of determining that the result of the first evaluation is below the first threshold and administering a second dose during the second treatment period, wherein the second dose is less than the initial dose, (d) The process of evaluating the left ventricular outflow tract obstruction of the patient, obtaining a second evaluation result, and determining whether the second evaluation result falls below a second threshold, (e) The step of determining that the result of the second evaluation is below the second threshold, and administering a third dose during the third treatment period, wherein the third dose is less than the second dose. A pharmaceutical composition containing the above.

2. The treatment is (f) At the end of or near the end of the third treatment period, the left ventricular outflow tract obstruction of the patient is evaluated to obtain a third evaluation result, it is determined whether the third evaluation result is equal to or greater than the third threshold, and the left ventricular ejection fraction (LVEF) of the patient is evaluated. (g) The step of determining that the result of the third evaluation is above the third threshold and that the patient's LVEF is above the LVEF threshold, and administering a fourth dose during the fourth treatment period, wherein the fourth dose is greater than the third dose. The pharmaceutical composition according to claim 1, further comprising:

3. The treatment is (f) The step of evaluating the left ventricular ejection fraction (LVEF) of the patient at or near the end of the third treatment period, (g) When the patient's LVEF is above the safety threshold, the step of administering a fourth dose during the fourth treatment period, wherein the fourth dose is greater than the third dose. The pharmaceutical composition according to claim 1, further comprising:

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the first and second evaluations are performed by a non-invasive technique including echocardiography.

5. The pharmaceutical composition according to claim 4, wherein the echocardiography includes measurement of the LVOT gradient using the Valsalva maneuver.

6. The pharmaceutical composition according to claim 5, wherein the first evaluation result is the first Valsalva LVOT gradient, and the second evaluation result is the second Valsalva LVOT gradient.

7. The pharmaceutical composition according to claim 6, wherein the first threshold and the second threshold are each a Valsalva LVOT gradient of 20 mmHg.

8. A pharmaceutical composition according to any one of claims 1 to 3, used to mitigate the risk of systolic dysfunction or heart failure.

9. The pharmaceutical composition according to any one of claims 1 to 3, wherein the myosin inhibitor is mabacamten or a pharmaceutically acceptable salt thereof.

10. The pharmaceutical composition according to any one of claims 1 to 3, wherein the myosin inhibitor is mabacamten.

11. The pharmaceutical composition according to claim 10, wherein the initial dose is 5 mg of mabacamten per day.

12. The pharmaceutical composition according to claim 11, wherein the second dose is 2.5 mg of mabacamten per day.

13. The pharmaceutical composition according to claim 12, wherein the third dose is 0 mg of mabacamten per day or 1 mg of mabacamten per day.

14. The pharmaceutical composition according to any one of claims 1 to 3, wherein the patient is suffering from symptomatic oHCM of New York Heart Association (NYHA) class II to III.

15. The pharmaceutical composition according to any one of claims 1 to 3, wherein 0 mg of mabacamten is administered during the third treatment period.

16. The pharmaceutical composition according to any one of claims 1 to 3, wherein the dose of the myosin inhibitor administered to the patient is not increased until the third treatment period.

17. The pharmaceutical composition according to any one of claims 1 to 3, wherein the first treatment period is approximately 4 weeks, the second treatment period is approximately 4 weeks, and the third treatment period is approximately 4 weeks.

18. A pharmaceutical composition comprising mabacamten for use in the treatment of obstructive hypertrophic cardiomyopathy (HCM) in patients requiring treatment, wherein the treatment is (a) During the first treatment period, administer 5 mg of mabacamten per day to the patient, (b) A step of evaluating the patient's LVOT gradient using the Valsalva maneuver to obtain the first Valsalva LVOT gradient, (c) Based on the determination that the first Valsalva LVOT gradient is below 20 mmHg, the patient is administered 2.5 mg of mabacamten per day during the second treatment period. (d) A step of evaluating the patient's LVOT gradient using the Valsalva maneuver to obtain the second Valsalva LVOT gradient, (e) Based on the determination that the second Valsalva LVOT gradient is below 20 mmHg, the patient is administered 0 mg or 1 mg of mavacamten per day during the third treatment period. A pharmaceutical composition containing the above.

19. The treatment is (f) At the end of or near the end of the third treatment period, the LVOT gradient of the patient is evaluated using the Valsalva maneuver to obtain the third Valsalva LVOT gradient, and the left ventricular ejection fraction (LVEF) of the patient is evaluated. (g) Based on the determination that the third Valsalva LVOT gradient is 30 mmHg or higher and the patient's LVEF is 55% or higher, the patient is administered 2.5 mg of mabacamten per day during the fourth treatment period. The pharmaceutical composition according to claim 18, further comprising:

20. The treatment is (f) The step of evaluating the left ventricular ejection fraction (LVEF) of the patient at or near the end of the third treatment period, (g) Based on the determination that the patient's LVEF is 50% or more, the patient is administered 2.5 mg of mabacamten per day during the fourth treatment period. The pharmaceutical composition according to claim 18, further comprising:

21. A pharmaceutical composition comprising mabacamten for use in the treatment of oHCM in pediatric patients requiring treatment, wherein the treatment is (a) During the first treatment period, administer 5 mg of mabacamten per day to the pediatric patient, (b) A step of evaluating the LVOT gradient of the pediatric patient using the Valsalva method to obtain the first Valsalva LVOT gradient, (c) Based on the determination that the first Valsalva LVOT gradient is below 20 mmHg, the step of administering 2.5 mg of mabacamten per day to the pediatric patient during the second treatment period, (d) A step of evaluating the LVOT gradient of the pediatric patient using the Valsalva maneuver to obtain the second Valsalva LVOT gradient, (e) Based on the determination that the second Valsalva LVOT gradient is below 20 mmHg, the patient is administered 0 mg or 1 mg of mavacamten per day during the third treatment period. A pharmaceutical composition containing the above.

22. A pharmaceutical composition comprising mabacamten for use in the treatment of oHCM in pediatric patients requiring treatment, wherein the treatment is (a) During the treatment period, administer 2.5 mg of mabacamten per day to the pediatric patient, (b) A step of evaluating the LVOT gradient of the pediatric patient using the Valsalva method to obtain the first Valsalva LVOT gradient, (c) Based on the determination that the first Valsalva LVOT gradient is below 20 mmHg, the process of administering 1 mg of mavacamten per day to the pediatric patient during the subsequent treatment period. A pharmaceutical composition containing the above.

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