Acoramidis for use in the treatment of renal dysfunction

Abstract

Described herein are methods for treating subjects with impaired renal (e.g., kidney) function using Compound 1, or a pharmaceutically acceptable salt thereof. Also disclosed herein are methods of stabilizing renal function in subjects in need thereof using Compound 1, or a pharmaceutically acceptable salt thereof.

Description

ACORAMIDIS FOR USE IN THE TREATMENT OF RENAL DYSFUNCTIONCROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority under 35 U.S.C § 119(e) to U.S. Provisional Application Serial Nos. 63 / 645,694 filed May 10, 2024, and 63 / 738,088 filed December 23, 2024, the disclosures of each are incorporated herein by reference in their entirety.STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0002] NOT APPLICABLEREFERENCE TO A "SEQUENCE LISTING”

[0003] This application hereby incorporates by reference, in its entirety, the sequence listing created April 14, 2025, 2,092 bytes, submitted in computer readable form with this application, entitled: 2025-04-14 Sequence_Listing_ST26 Eidos-8.WO1 051418- 512001WO.xml.BACKGROUND

[0004] Aberrant protein interaction and aggregation, either through protein misfolding or over activation of a signaling pathway is the underlying cause of a large number of human degenerative diseases. As such, targeting protein protein interactions (PPIs) is of therapeutic interest.

[0005] One such example of aberrant protein aggregation is the soluble protein transthyretin (TTR or prealbumin). TTR is a 55 kDa homotetrameric protein present in blood and cerebrospinal fluid. When dissociated from its homotetrameric form, TTR dimers can misfold into amyloidogenic monomers. This has been observed with the wild type TTR as well as more than 100 different mutated variants. Research has shown that stabilizing the tetrameric form of TTR inhibits the misfolding of amyloidogenic monomers and subsequent TTR amyloid formation and deposition.

[0006] 3-(3-(3,5-dimethyl-lH-pyrazol-4-yl)propoxy)-4-fluorobenzoic acid (also known asAGIO or acoramidis) has been investigated for use in the treatment of TTR amyloid relateddiseases such as TTR amyloid cardiomyopathy (ATTR-CM). A Phase 2 open-label extension study of acoramidis in patients with symptomatic ATTR-CM demonstrated that acoramidis was generally well-tolerated and resulted in sustained, near-complete TTR stabilization. A subsequent Phase 3 clinical trial in ATTR-CM patients, ATTRibute-CM, demonstrated that acoramidis significantly reduced all-cause mortality in 611 participants with a baseline estimated glomerular filtration rate (eGFR) > 30 ml / min / 1.73 m2. Despite these impressive results, the effects of acoramidis in patients with impaired renal function are not known.

[0007] Intraglomerular hypertension provoking hyperfiltration is considered a risk factor for progression of chronic kidney disease (CKD). Lowering of intraglomerular pressure is the therapeutic goal of treatment of proteinuria, diabetic nephropathy, and other forms of chronic kidney disease (Anderson and Brenner 1986). Lowering of intraglomerular pressure is most often achieved with angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), sodium-glucose cotransporter 2 (SGLT2) inhibitors, and mineralocorticoid antagonists, which are known to be renally protective, reducing the risk of progression to end-stage renal disease in patients with CKD (Gansevoort et al. 1993, Brenner et al. 2001, Jafar et al. 2001, Lewis et al. 2001, Holtkamp et al. 201 1, Bakris et al. 2020). In general, a relative dilation of the efferent versus afferent renal arterioles lowers intraglomerular pressure, which, in turn, lowers filtration (i.e., GFR); this initial reduction in eGFR stabilizes after several months. Such renal hemodynamic effects are typically associated with acute, modest, non-progressive increases in serum creatinine that reverse with removal of the factor(s) affecting renal hemodynamics. Such effects are not structural; rather, they are physiological, driven by the pharmacology of a number of drug classes that are believed to alter renal hemodynamics. In the long-term, ACE inhibitors and ARBs have been shown to improve kidney outcomes such as time to development of end-stage kidney disease or doubling of serum creatinine (Gansevoort et al. 1993, Brenner et al. 2001, Jafar et al. 2001, Holtkamp et al. 2011). SGLT2 inhibitors are associated with early, modest creatinine elevations and improved long-term cardiac and renal outcomes (Neuen et al. 2022). Finally, mineralocorticoid antagonists also cause early decreases in intraglomerular pressure, GFR and proteinuria and slow the progression of CKD. Proteinuria is also a manifestation of and contributes to CKD progression.

[0008] As such, there exists a need in the art to provide methods for treating transthyretin (TTR) amyloidosis in subjects with impaired renal function, and to stabilize renal (e.g.,kidney) function generally. The present disclosure addresses these needs and provides related advantages as well.SUMMARY

[0009] The present disclosure provides methods of treating subjects (e.g., humans) with impaired renal function. Subjects may have a transthyretin (TTR) amyloid-related disease (such as transthyretin (TTR) amyloidosis), chronic kidney disease (CKD), proteinuria, or another condition impacting renal (e.g., kidney) function. The methods provided herein may treat one or more symptoms of TTR amyloidosis, CKD, proteinuria, or another condition impacting renal function. The methods provided herein may improve, delay progression of, ameliorate, eliminate, or prevent development of one or more symptoms of impaired renal function, such as a function of CKD or proteinuria.

[0010] In some embodiments, provided herein are methods of treating transthyretin (TTR) amyloidosis, the method comprising administering to a subject (e.g., a human) in need thereof a therapeutically effective amount of Compound 1 , having the formula:(Compound 1) or a pharmaceutically acceptable salt thereof, wherein the subject has impaired renal function.

[0011] In some embodiments, impaired renal function is determined by the calculation of eGFR in a subject, and the subject is considered to have impaired renal function if they have an eGFR as described herein. In some embodiments, impaired renal function is determined by a patient’s diagnosis with Stage 4 or Stage 5 chronic kidney disease (CKD). In some embodiments, the subject is diagnosed with Stage 4 CKD. In some embodiments, the subject is diagnosed with Stage 5 CKD. In some embodiments, the subject has an eGFR of < 30 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of < 25 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of < 20 mL / min / 1.73 m2.

[0012] In some embodiments, the therapeutically effective amount is a total daily dosage of about 10 mg to 2,500 mg of the HC1 salt form of Compound 1 or an equivalent amount of Compound 1 in free base form or in a different salt form. In some embodiments, the therapeutically effective amount is a total daily dosage of about 800 mg to 1,600 mg of the HC1 salt form of Compound 1 or an equivalent amount of Compound 1 in free base form orin a different salt form. In some embodiments, the therapeutically effective amount is a total daily dosage of about 1,600 mg of the HC1 salt form of Compound 1 or an equivalent amount of Compound 1 in free base form or in a different salt form.

[0013] In some embodiments, the therapeutically effective amount is a total daily dosage of about 10 mg to 2,500 mg of the HC1 salt form of Compound 1. In some embodiments, the therapeutically effective amount is a total daily dosage of about 800 mg to 1,600 mg of the HC1 salt form of Compound 1. In some embodiments, the therapeutically effective amount is a total daily dosage of about 1,600 mg of the HC1 salt form of Compound 1.

[0014] In some embodiments, the HC1 salt form of Compound 1 is administered. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is the HC1 salt form of Compound 1 , having the structure:(Compound 1»HC1).

[0015] In some embodiments, Compound 1 has the structure:

[0016] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, the HC1 salt form of Compound 1 is administered orally.

[0017] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered once daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily. In some embodiments, the HC1 salt form of Compound 1 is administered once daily. In some embodiments, the HC1 salt form of Compound 1 is administered twice daily. In some embodiments, the HC1 salt form of Compound 1 is administered three times daily. In some embodiments, Compound 1 in free base form is administered once daily. In some embodiments, Compound 1 in free base formis administered twice daily. In some embodiments, Compound 1 in free base form is administered three times daily.

[0018] In some embodiments, the TTR amyloidosis is a disease or condition selected from the group consisting of familial amyloid polyneuropathy, familial amyloid cardiomyopathy, senile systemic amyloidosis, central amyloidosis, ocular amyloidosis, Leptomeningeal amyloidosis, oculoleptomeningeal amyloidosis, vitreous amyloidosis, gastrointestinal amyloidosis, neuropathic amyloidosis, non-neuropathic amyloidosis, non-hereditary amyloidosis, reactive / secondary amyloidosis, and cerebral amyloidosis.

[0019] In some embodiments, the TTR amyloidosis is transthyretin amyloidosis (ATTR) cardiomyopathy (ATTR-CM). In some embodiments, the ATTR cardiomyopathy is wildtype ATTR cardiomyopathy (ATTRwt-CM). In some embodiments, ATTR cardiomyopathy is familial ATTR cardiomyopathy (ATTRm-CM).

[0020] In some embodiments, administration of a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof in a subject with ATTR cardiomyopathy decreases the frequency of cardiovascular-related hospitalizations as compared to subjects not receiving treatment.

[0021] In some embodiments, administration of a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof in a subject with ATTR cardiomyopathy decreases mortality as compared to subjects not receiving treatment.

[0022] In some embodiments, the TTR amyloidosis is transthyretin amyloidosis (ATTR) polyneuropathy (ATTR-PN). In some embodiments, the ATTR polyneuropathy is wild-type ATTR polyneuropathy (ATTRwt-PN). In some embodiments, ATTR polyneuropathy is familial ATTR polyneuropathy (ATTRm-PN).

[0023] In an embodiment, provided herein are methods of preventing renal (e.g., kidney) disease, the method comprising administering a therapeutically effective amount of acoramidis, or a pharmaceutically acceptable salt thereof, to a subject (e.g., a human) in need thereof. In some embodiments, the subject does not have ATTR, ATTR-CM, or ATTR-PN.

[0024] In another embodiment, provided herein are methods of slowing the progression of renal (e.g., kidney) disease, the method comprising administering a therapeutically effective amount of acoramidis, or a pharmaceutically acceptable salt thereof, to a subject (e.g., ahuman) in need thereof. In some embodiments, the subject does not have ATTR, ATTR-CM, or ATTR-PN.

[0025] In another embodiment, provided herein are methods of treating or preventing impaired renal (e.g., kidney) function, the method comprising administering a therapeutically effective amount of acoramidis, or a pharmaceutically acceptable salt thereof, to a subject (e.g., a human) in need thereof. In some embodiments, the subject does not have ATTR, ATTR-CM, or ATTR-PN.

[0026] In another embodiment, provided herein are methods of stabilizing renal (e.g., kidney) function, the method comprising administering a therapeutically effective amount of acoramidis, a pharmaceutically acceptable salt thereof, to a subject (e.g., a human) in need thereof. In some embodiments, the subject does not have ATTR, ATTR-CM, or ATTR-PN.

[0027] In another embodiment, provided herein are methods of treating proteinuria, the method comprising administering a therapeutically effective amount of acoramidis, or a pharmaceutically acceptable salt thereof, to a subject (e.g., a human) in need thereof. In some embodiments, the subject does not have ATTR, ATTR-CM, or ATTR-PN.

[0028] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered chronically.

[0029] In some embodiments, the methods described herein further comprise administering to the subject a diuretic therapy agent.

[0030] Other objects, features, and advantages of the present invention will be apparent to one of skill in the art from the following detailed description and figures.BRIEF DESCRIPTION OF THE DRAWINGS

[0031] FIG. 1 displays a summary of the trial design for the Phase 3 clinical study in subjects with ATTR-CM, ATTRibute-CM.

[0032] FIG. 2 displays the composition of the Stage 4 CKD participants in ATTRibute- CM.

[0033] FIG. 3 displays the change from baseline in serum creatinine over time in ATTR patients treated with acoramidis or placebo in ATTRibute-CM. Abbreviations: CFB = change from baseline; SD = standard deviation.DETAILED DESCRIPTION OF THE INVENTIONI. General

[0034] Described herein are methods for treating impaired renal function in a subject, such as a subject having transthyretin (TTR) amyloidosis, chronic kidney disease (CKD), proteinuria, or another condition characterized by impaired renal function, with 3-(3-(3,5- dimethyl-lH-pyrazol-4-yl)propoxy)-4-fluorobenzoic acid (“Compound 1”), or a pharmaceutically acceptable salt thereof. Compound 1 is primarily metabolized in the liver to acoramidis P-D-glucuronide, which is cleared by the kidney. As such, it is not known if Compound 1 or a pharmaceutically acceptable salt thereof can be used for the treatment of transthyretin (TTR) amyloidosis in subjects with impaired renal function. More specifically, it is not known how reduced renal function in a subject will impact the rate of excretion of Compound 1 or if it will impact the activity and efficacy of Compound 1 in the treatment of transthyretin (TTR) amyloidosis. The present disclosure demonstrates that Compound 1 can be used to treat transthyretin (TTR) amyloidosis in subjects with impaired renal function. As detailed in the examples herein, in high-risk participants with Stage 4 CKD, treatment with Compound 1 was associated with 25% fewer observed deaths at Month 30 versus placebo.

[0035] It has also been observed that patients with transthyretin (TTR) amyloidosis (e.g., ATTR-CM) experience a decline in their renal function over time without intervention due to progressive heart failure and impaired renal perfusion from chronically and progressively reduced cardiac output. Administration of Compound 1 was associated with a reduction in the decline of renal impairment, and provided greater odds of improving renal function over 30 months.

[0036] Further described herein are methods of treating or preventing renal (e.g., kidney) disease, or stabilizing renal (e.g., kidney) function. As detailed in the examples herein, findings from the clinical use of acoramidis are consistent with a renal hemodynamic effect that would provide a protective benefit to the kidneys, and that could treat proteinuria.IL Definitions

[0037] While various embodiments of the present invention are shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood thatvarious alternatives to the embodiments of the invention described herein may be employed in practicing the invention.

[0038] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in the application including, without limitation, patents, patent applications, articles, books, manuals, and treatises are hereby expressly incorporated by reference in their entirety for any purpose.

[0039] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. See, e.g., Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY, 2nd ed., J. Wiley & Sons (New York, NY 1994); Sambrook et al., MOLECULAR CLONING, A LABORATORY MANUAL, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989). Any methods, devices and materials similar or equivalent to those described herein can be used in the practice of this invention. The following definitions are provided to facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the present disclosure.

[0040] “Compound 1” refers to the chemical 3-(3-(3,5-dimethyl-lH-pyrazol-4- yl)propoxy)-4-fluorobenzoic acid (also known as AGIO or acoramidis), having the formula:(Compound 1) or a pharmaceutically acceptable salt thereof. This compound is disclosed in International Patent Application No. PCT / US2013 / 076213, filed December 18, 2013. When referring to specific amounts of Compound 1 administered to patients, unless indicated otherwise, this disclosure refers to the amount of HC1 salt form of Compound 1 administered. A person of skill in the art would recognize that in order to administer the same amount of Compound 1 in freebase or in a different salt form, small adjustments in overall amount administered is necessary. For example, a person of ordinary skill in the art will recognize that 800 milligrams (mg) of the HC1 salt form of Compound 1 is equivalent to 712 mg of Compound 1 in free base form. Similarly, a person of ordinary skill in the art will recognize that 712 mg of free acoramidis is equivalent to 800 mg of acoramidis hydrochloride.

[0041] “Free acoramidis” as used herein refers to acoramidis that is not bound to any counter ion and is not in a salt form. Free acoramidis has the following chemical structure:

[0042] “Acoramidis hydrochloride” as used herein refers to the HC1 salt form of acoramidis, having the formula:(acoramidis hydrochloride).

[0043] The terms "a" or "an," as used in herein means one or more.

[0044] The term “administered chronically” as used herein refers to the treatment or a health condition that requires ongoing administration over a period of years, decades, or the lifetime of the subject receiving treatment.

[0045] The terms “comprise,” “include,” and “have,” and the derivatives thereof, are used herein interchangeably as comprehensive, open-ended terms. For example, use of “comprising,” “including,” or “having” means that whatever element is comprised, had, or included, is not the only element encompassed by the subject of the clause that contains the verb.

[0046] As used herein, the term "about" means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In some embodiments, the term "about" means within a standard deviation using measurements generally acceptable in the art. In some embodiments, about means a range extending to + / - 10% of the specified value. In some embodiments, about means the specified value.

[0047] As used herein, "treatment" or "treating," or "palliating" or "ameliorating" are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including but not limited to a therapeutic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeuticbenefit is achieved with the 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, notwithstanding that the subject may still be afflicted with the underlying disorder. Treatment includes causing the clinical symptoms of the disease to slow in development by administration of a composition; suppressing the disease, that is, causing a reduction in the clinical symptoms of the disease; inhibiting the disease, that is, arresting the development of clinical symptoms by administration of a composition after the initial appearance of symptoms; and / or relieving the disease, that is, causing the regression of clinical symptoms by administration of a composition after their initial appearance. For example, certain methods described herein treat transthyretin (TTR) amyloidosis by decreasing or reducing the occurrence, or progression of TTR fibril formation; or treat TTR amyloidosis by decreasing a symptom of TTR amyloidosis.

[0048] An "effective amount" or a "pharmaceutically effective amount" is an amount sufficient to accomplish a stated purpose (e.g., achieve the effect for which it is administered, treat a disease, reduce enzyme activity, reduce one or more symptoms of a disease or condition). An example of an "effective amount" is an amount sufficient to contribute to the treatment, or reduction of a symptom or symptoms of a disease, which could also be referred to as a "therapeutically effective amount." A "reduction" of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). Efficacy can also be expressed as "-fold" increase or decrease. For example, a therapeutically effective amount can have at least a 1.2- fold, 1.5-fold, 2-fold, 5-fold, or more effect over a control.

[0049] "Patient" or "subject" or "subject in need thereof" refers to a living organism suffering from or prone 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 medical supervision. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In some embodiments, a patient, subject, or subject in need thereof is a human.

[0050] As used herein, the term “CKD” means chronic kidney disease. Examples of diseases or conditions that can cause CKD include diabetic kidney disease, hypertensivekidney disease, glomerular disorders, hereditary nephropathies, chronic tubulointerstitial nephropathies, and obstructive uropathy.

[0051] As used herein, the term “eGFR” means estimated glomerular filtration rate, and is expressed as milliliters per minute per 1.73 square meters of body surface area (mL / min / 1.73m2).

[0052] As used herein, the term “UACR” means urine albumin-to-creatinine ratio, and is expressed as milligrams of albumin per gram of creatinine (mg / g) in one deciliter of urine, or as grams of albumin per mole of creatinine.

[0053] As used herein, the term “Stage 1 CKD” means the subject has an eGFR of 90 mL / min / 1.73 m2or higher, and / or a UACR of 30 or higher.

[0054] As used herein, the term “Stage 2 CKD” means the subject has an eGFR of 60 to <90 mL / min / 1.73 m2.

[0055] As used herein, the term “Stage 3 CKD” means Stage 3a CKD and / or Stage 3b CKD. As used herein, “Stage 3a CKD” means the subject has an eGFR of 45 to <60 mL / min / 1.73 m2. As used herein, “Stage 3b CKD” means the subject has an eGFR of 30 to <45 mL / min / 1.73 m2. Thus, “Stage 3 CKD” means the subject has an eGFR of 30 to <60 mL / min / 1.73 m2.

[0056] As used herein, the term “Stage 4 CKD” means the subject has an eGFR of 15 to < 30 mL / min / 1.73 m2.

[0057] As used herein, the term “Stage 5 CKD” means the subject has an eGFR of less than 15 mL / min / 1.73 m2(< 15 mL / min / 1.73 nr). Stage 5 CKD is also referred to as end stage renal disease (or “ESRD”) or end stage kidney disease (“ESKD”).

[0058] As used herein, the term “Stage of CKD” means Stage 1 CKD, Stage 2 CKD, Stage 3 CKD, Stage 3a CKD, Stage 3b CKD, Stage 4 CKD, and / or Stage 5 CKD.

[0059] As used herein, the term “higher Stage of CKD” means a higher numbered Stage of CKD than the referenced Stage of CKD. For example, Stage 5 CKD is a higher Stage of CKD than Stage 4 CKD.

[0060] As used herein, the term “lower Stage of CKD” means a lower numbered Stage of CKD than the referenced Stage of CKD. For example, Stage 1 CKD is a lower Stage of CKD than Stage 2 CKD.

[0061] As used herein, the term “baseline” refers to a measurement of a referenced metric in a subject prior to treatment (e.g., administration of Compound 1 or a pharmaceutically acceptable salt thereof).III. Detailed Description of the EmbodimentsAmyloidosis Methods

[0062] In one embodiment, provided herein are methods of treating transthyretin (TTR) amyloidosis, the method comprising administering to a subject (e.g., a human) in need thereof a therapeutically effective amount of Compound 1 , having the formula:(Compound 1) or a pharmaceutically acceptable salt thereof, wherein the subject has impaired renal function. In some embodiments, the subject is a human.

[0063] In some embodiments, impaired renal function is determined by the measurement of eGFR in a subject, and the subject is considered to have impaired renal function if they have an eGFR as described herein. In some embodiments, impaired renal function is determined by a patient’s diagnosis with chronic kidney disease, such as Stage 2, Stage 3a, Stage 3b, Stage 4, or Stage 5 chronic kidney disease (CKD). In some embodiments, impaired renal function is determined by a subject’s diagnosis with Stage 4 or Stage 5 chronic kidney disease (CKD). In some embodiments, impaired renal function is determined by a subject’s diagnosis with Stage 4 chronic kidney disease (CKD). In some embodiments, impaired renal function is determined by a subject’s diagnosis with Stage 5 chronic kidney disease (CKD). In some embodiments, impaired renal function is determined by a patient’s diagnosis with an acute kidney or renal issue, such as an acute kidney injury (AKI). In some embodiments, impaired renal function is associated with or caused, at least in part, by another condition, such as autoimmune and / or genetic condition. In some embodiments, the subject is a human.

[0064] In some embodiments, the subject is at least 18 years of age. In some embodiments, the subject is less than 18 years of age (e.g., a human child). In some embodiments, the subject is a pediatric human patient. In some embodiments, the subject is less than 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 years of age. In some embodiments, the subject is at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 25, 30, 35, 40,45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95 years of age. In some embodiments, the subject is between 0-18, 1-18, 2-18, 3-18, 4-18, 5-18, 6-18, 7-18, 8-18, 9-18, 10-18, 11-18, 12-18, 13- 18, 14-18, 15-18, 16-18, 17-18, 0-16, 1-16, 2-16, 3-16, 4-16, 5-16, 6-16, 7-16, 8-16, 9-16, 10- 16, 11-16, 12-16, 13-16, 14-16, 15-16, 0-15, 1-15, 2-15, 3-15, 4-15, 5-15, 6-15, 7-15, 8-15, 9- 15, 10-15, 11-15, 12-15, 13-15, 14-15, 0-13, 1-13, 2-13, 3-13, 4-13, 5-13, 6-13, 7-13, 8-13, 9- 13, 10-13, 11-13, 12-13, 0-12, 1-12, 2-12, 3-12, 4-12, 5-12, 6-12, 7-12, 8-12, 9-12, 10-12, 11- 12, 0-11, 1-11, 2-11, 3-11, 4-11, 5-11, 6-11, 7-11, 8-11, 9-11, 10-11, 0-10, 1-10, 2-10, 3-10,4-10, 5-10, 6-10, 7-10, 8-10, 9-10, 0-8, 1-8, 2-8, 3-8, 4-8, 5-8, 6-8, 7-8, 0-6, 1-6, 2-6, 3-6, 4-6,5-6, 0-5, 1-5, 2-5, 3-5, 4-5, 0-4, 1-4, 2-4, 3-4, 0-3, 1-3, 2-3, 0-2, 1-2, 18-20, 18-25, 18-30, 18-35, 18-40, 18-45, 18-50, 18-55, 18-60, 18-65, 18-70, 18-75, 18-80, 18-85, 18-90, 20-30, 20-40, 20-50, 20-60, 20-70, 20-70, 20-80, 20-90, 30-40, 30-50, 30-60, 30-70, 30-80, 30-90, 40-50, 40-60, 40-70, 40-80, 40-90, 50-60, 50-70, 50-80, 50-90, 60-70, 60-80, 60-90, 65-70, 65-75, 65-80, 65-85, or 65-90 years of age, or any range therein. In some embodiments, the subject is at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months of age.

[0065] In some embodiments, the subject is a human pediatric patient. In some embodiments, the human pediatric patient weighs about 5 kilograms (kg) to about 50 kg. In some embodiments, the human pediatric patient weighs less than about 50 kg. In some embodiments, the human pediatric patient weighs less than about 45 kg. In some embodiments, the human pediatric patient weighs less than about 40 kg. In some embodiments, the human pediatric patient weighs less than about 35 kg. In some embodiments, the human pediatric patient weighs less than about 30 kg. In some embodiments, the human pediatric patient weighs less than about 25 kg. In some embodiments, the human pediatric patient weighs less than about 20 kg. In some embodiments, the human pediatric patient weighs less than about 15 kg. In some embodiments, the human pediatric patient weighs less than about 10 kg. In some embodiments, the human pediatric patient weighs less than about 5 kg. In some embodiments, the human pediatric patient weighs about 5 kg to about 15 kg, about 10 kg to about 20 kg, about 15 kg to about 25 kg, about 20 kg to about 30 kg, about 30 kg to about 40 kg, about 35 kg to about 40 kg, or about 40 kg to about 50 kg.

[0066] In some embodiments, the subject is diagnosed with Stage 2 chronic kidney disease (CKD), which is typically defined as subjects having an estimated glomerular filtration rate (eGFR) of 60 to < 90 mL / min / 1.73 m2. In some embodiments, the subject is diagnosed with Stage 3a chronic kidney disease (CKD), which is typically defined as subjects having anestimated glomerular filtration rate (eGFR) of 45 to < 60 mL / min / 1.73 m2. In some embodiments, the subject is diagnosed with Stage 3b chronic kidney disease (CKD), which is typically defined as subjects having an estimated glomerular filtration rate (eGFR) of 30 to < 45 mL / min / 1.73 m2. In some embodiments, the subject is diagnosed with Stage 4 chronic kidney disease (CKD), which is typically defined as subjects having an estimated glomerular filtration rate (eGFR) of 15 to < 30 mL / min / 1.73 m2. In some embodiments, the subject is diagnosed with Stage 5 chronic kidney disease (CKD), which is typically defined as subjects having an estimated glomerular filtration rate (eGFR) of < 15 mL / min / 1 .73 m2. In some embodiments, subjects are diagnosed with a particular stage of CKD after two or more tests over the period of at least three months.

[0067] In some embodiments, provided herein are methods of treating transthyretin (TTR) amyloidosis, the method comprising administering to a subject (e.g., a human) in need thereof a therapeutically effective amount of Compound 1 , having the formula:or a pharmaceutically acceptable salt thereof, wherein the subject has an estimated glomerular filtration rate (eGFR) of < 30 mL / min / 1.73 m2.

[0068] In some embodiments, provided herein are methods of reducing the decline of renal function or improving renal function in a subject (e.g., a human) with transthyretin (TTR) amyloidosis, the method comprising administering to a subject in need thereof a therapeutically effective amount of Compound 1 , having the formula:or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has impaired renal function.

[0069] In some embodiments, the subject has an eGFR of < 90 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of < 60 mL / min / 1.73 nr. In some embodiments, the subject has an eGFR of < 55 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of < 50 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of < 45mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of < 40 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of < 35 mL / min / 1.73 nr. In some embodiments, the subject has an eGFR of < 30 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of < 29 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of < 28 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of < 27 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of < 26 mL / min / 1.73 nr. In some embodiments, the subject has an eGFR of < 25 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of < 24 mL / min / 1 .73 nr. In some embodiments, the subject has an eGFR of < 23 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of < 22 mL / min / 1.73 nr. In some embodiments, the subject has an eGFR of < 21 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of < 20 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of < 19 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of < 19 mL / min / 1.73 nr. In some embodiments, the subject has an eGFR of < 18 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of < 17 mL / min / 1.73 nr. In some embodiments, the subject has an eGFR of < 16 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of < 15 mL / min / 1.73 m2. In some embodiments, the subject is a human.

[0070] In some embodiments, the subject has an eGFR of 10 to 30 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 10 to 29 mL / min / 1.73 nr. In some embodiments, the subject has an eGFR of 10 to 28 mL / min / 1.73 nr. In some embodiments, the subject has an eGFR of 10 to 27 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 10 to 26 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 10 to 25 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 10 to 20 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 10 to 15 mL / min / 1.73 nr. In some embodiments, the subject has an eGFR of 15 to 30 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 15 to 29 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 15 to 28 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 15 to 27 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 15 to 26 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 15 to 25 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 15 to 20 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 10 to 40 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 15 to 40 mL / min / 1.73 nr. In some embodiments, the subject has an eGFR of 20 to 40 mL / min / 1.73 m2. In some embodiments, the subject hasan eGFR of 25 to 40 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 30 to 40 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 35 to 40 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 10 to 45 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 15 to 45 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 20 to 45 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 25 to 45 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 30 to 45 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 30 to 44 mL / min / 1 .73 m2. In some embodiments, the subject has an eGFR of 35 to 45 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 40 to 45 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 10 to 50 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 15 to 50 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 20 to 50 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 25 to 50 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 30 to 50 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 35 to 50 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 40 to 50 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 45 to 50 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 10 to 55 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 15 to 55 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 20 to 55 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 25 to 55 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 30 to 55 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 35 to 55 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 40 to 55 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 45 to 55 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 50 to 55 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 10 to 60 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 15 to 60 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 20 to 60 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 25 to 60 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 30 to 60 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 35 to 60 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 40 to 60 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 45 to 60 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 50 to 60 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 55 to 60 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 10 to 59 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 15 to 59 mL / min / 1.73 m2. In someembodiments, the subject has an eGFR of 20 to 59 mL / min / 1.73 n . In some embodiments, the subject has an eGFR of 25 to 59 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 30 to 59 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 35 to 59 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 40 to 59 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 45 to 59 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 50 to 59 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 55 to 59 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 60 to 90 mL / min / 1 .73 m2.

[0071] Without being bound to any particular theory, it is believed that the treatment of transthyretin (TTR) amyloidosis with Compound 1 or a pharmaceutically acceptable salt thereof does not directly improve, reduce, or otherwise alter kidney function, but the impaired or reduced renal function of a subject is not a disqualifying factor to receive treatment with Compound 1 or a pharmaceutically acceptable salt thereof. Accordingly, suitable subjects for the treatment methods described herein include those diagnosed with Stage 4 chronic kidney disease (CKD), Stage 5 chronic kidney disease (CKD), as well as those who are not diagnosed with a particular stage of CKD, but have a reduced eGFR such as the values and ranges described in the preceding paragraphs. In some embodiments, subjects have an eGFR as defined in the preceding paragraphs prior to administration of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, subjects have an eGFR as defined in the preceding paragraphs during administration of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, subjects have an eGFR above the defined values and ranges prior to their first administration of Compound 1 or a pharmaceutically acceptable salt thereof, but the renal (e.g., kidney) function of the subject deteriorates during treatment such that the eGFR of the subject decreases to an eGFR value or range as defined herein. In some embodiments, subjects have an eGFR value or range as defined herein prior to administration of Compound 1 or a pharmaceutically acceptable salt thereof, but the renal (e.g., kidney) function of the subject improves during treatment such that the eGFR of the subject raises above the eGFR values and ranges defined herein.

[0072] In some embodiments, subjects receiving a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof experience an increase in transthyretin (TTR) blood serum concentrations relative to baseline levels. In some embodiments, subjects receiving a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof experience at least about a 5%, 10%, 15%, 20%,25%, 30%, 35%, 40%, 45%, 50%, or greater increase in transthyretin (TTR) blood serum concentrations relative to baseline levels after 28 days of treatment. In some embodiments, subjects receiving a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof experience at least about a 25% increase in transthyretin (TTR) blood serum concentrations relative to baseline levels after 28 days of treatment. In some embodiments, subjects prior to treatment have TTR blood serum levels that are beneath a baseline serum TTR concentration (20 mg / dL TTR). In some embodiments, subjects receiving an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof for 28 days will experience increased blood serum TTR levels such that the level of blood serum TTR is above the baseline level. In some embodiments, subjects experiencing increased TTR levels are subjects diagnosed with transthyretin amyloidosis (ATTR) cardiomyopathy (ATTR-CM).

[0073] There are a variety of diseases or disorders associated with transthyretin (TTR) amyloidosis. These include, but are not limited to familial amyloid polyneuropathy, familial amyloid cardiomyopathy, senile systemic amyloidosis, central amyloidosis, ocular amyloidosis, Leptomeningeal amyloidosis, oculoleptomeningeal amyloidosis, vitreous amyloidosis, gastrointestinal amyloidosis, neuropathic amyloidosis, non-neuropathic amyloidosis, non-hereditary amyloidosis, reactive / secondary amyloidosis, and cerebral amyloidosis.

[0074] In some embodiments, the disease or disorder associated with transthyretin (TTR) amyloidosis is leptomeningeal amyloidosis. In some embodiments, subjects with leptomeningeal amyloidosis have a transthyretin protein with an aspartic acid to glycine mutation at position 18 (D18G). In some embodiments, subjects with leptomeningeal amyloidosis have a transthyretin protein with a glycine to arginine mutation at position 53 (G53R). The wild-type transthyretin (TTR) protein is provided herein as SEQ ID NO: 1.

[0075] In some embodiments, subjects with leptomeningeal amyloidosis have a transthyretin protein with a tyrosine to cysteine mutation at position 114 (Y114C). Subjects with the tyrosine to cysteine mutation at position 114 (Y 114C) can exhibit ATTRm-PN symptoms, leptomeningeal amyloidosis symptoms, or a combination of both.

[0076] In some embodiments, subjects with leptomeningeal amyloidosis have a transthyretin protein with a threonine to proline mutation at position 49 (T49P). Subjectswith the threonine to proline mutation at position 49 (T49P) can exhibit ATTRm-CM symptoms, leptomeningeal amyloidosis symptoms, or a combination of both.

[0077] In some embodiments, the transthyretin (TTR) amyloidosis disease is transthyretin amyloidosis (ATTR) cardiomyopathy or ATTR polyneuropathy. In some embodiments, the TTR amyloidosis is characterized by a TTR protein that comprises a threonine to alanine mutation at position 60 (T60A). In some embodiments, the TTR amyloidosis is characterized by a TTR protein that comprises a proline to serine mutation at position 24 (P24S). In some embodiments, the TTR amyloidosis is characterized by a TTR protein that comprises an aspartic acid to alanine mutation at position 38 (D38A). In some embodiments, the TTR amyloidosis is characterized by a TTR protein that comprises a leucine to histidine mutation at position 58 (L58H). Patients with these mutations often present a combination of both ATTR cardiomyopathy and ATTR polyneuropathy symptoms. The wild-type transthyretin (TTR) protein is provided herein as SEQ ID NO: 1 .

[0078] In some embodiments, the transthyretin (TTR) amyloidosis disease is transthyretin amyloidosis (ATTR) cardiomyopathy. In some embodiments, the transthyretin (TTR) amyloidosis disease is transthyretin amyloidosis (ATTR) polyneuropathy.

[0079] ATTR cardiomyopathy includes wild-type ATTR cardiomyopathy (ATTRwt-CM) and genetic (familial or hereditary) ATTR cardiomyopathy (ATTRm-CM). ATTRm-CM is caused by a mutation in the TTR protein, whereas ATTRwt-CM is not caused by a mutation. Instead, ATTRwt-CM is generally an age-related process. In some embodiments, the ATTR cardiomyopathy is wild- type ATTR cardiomyopathy (ATTRwt-CM). In some embodiments, the ATTR cardiomyopathy is familial ATTR cardiomyopathy (ATTRm-CM). In some embodiments, subjects with ATTRm-CM have a valine to isoleucine mutation at position 122 (VI 221) in the TTR protein. In some embodiments, subjects with ATTRm-CM have a transthyretin protein with a threonine to proline mutation at position 49 (T49P). Subjects with the threonine to proline mutation at position 49 (T49P) can exhibit ATTRm-CM symptoms, leptomeningeal amyloidosis symptoms, or a combination of both. The wild-type transthyretin (TTR) protein is provided herein as SEQ ID NO: 1.

[0080] ATTR polyneuropathy (ATTR-PN) includes both wild type and genetic (familial or hereditary) ATTR polyneuropathy. As discussed for cardiomyopathy, ATTRm-PN is caused by a mutation in the TTR protein, whereas ATTRwt-PN does not include a genetic component. In some embodiments ATTR polyneuropathy is wild-type ATTRpolyneuropathy (ATTRwt-PN). In some embodiments, ATTR polyneuropathy is familial ATTR polyneuropathy (ATTRm-PN). In some embodiments, the ATTRm-PN is characterized by a TTR protein that includes a valine to methionine mutation at position 30 (V30M). In some embodiments, the ATTRm-PN is characterized by a TTR protein that includes a phenylalanine to leucine mutation at position 64 (F64L). In some embodiments, the ATTRm-PN is characterized by a TTR protein that includes a tyrosine to cysteine mutation at position 114 (Y114C). Subjects with the tyrosine to cysteine mutation at position 1 14 (Y1 14C) can exhibit ATTRm-PN symptoms, leptomeningeal amyloidosis symptoms, or a combination of both. The wild-type transthyretin (TTR) protein is provided herein as SEQ ID NO: 1.

[0081] ATTR cardiomyopathy (both wild-type and familial) is a slowly progressive disease that causes heart failure and death in affected subjects. The methods of the present disclosure provide clinical improvement in subjects with ATTR cardiomyopathy by stopping or slowing the accumulation of TTR fibrils in the myocardium. Through this process, the currently described methods provide clinical improvements in ATTR cardiomyopathy subjects. Clinical improvements include, but are not limited to, improvement in New York Heart Association (NYHA) functional classification, improvements in Kansas City Cardiomyopathy Questionnaire responses, EuroQoL-5 Dimensions (EQ-5D-5L), improvement in 6-minute walk test performance, improvement in markers associated with cardiac health such as Troponin T, Troponin I, B-type natriuretic peptide (BNP), and N- terminal pro-BNP, decreasing the frequency of cardiovascular-related hospitalizations, and / or decreasing mortality.

[0082] In some embodiments, the methods provided herein improve, stabilize or delay worsening in New York Heart Association (NYHA) functional classification of subjects. The NYHA functional classification grades the severity of heart failure symptoms as one of four functional classes. The NYHA functional classification is widely used in clinical practice and in research because it provides a standard description of severity that can be used to assess response to treatment and to guide management. The NYHA functional classification is based on severity of symptoms and limitation of physical activity:Class I: No limitation of physical activity. Ordinary physical activity does not cause undue breathlessness, fatigue, or palpitations.Class II: Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in undue breathlessness, fatigue, or palpitations.Class III: Marked limitation of physical activity. Comfortable at rest, but less than ordinary physical activity results in undue breathlessness, fatigue, or palpitations. Class IV: Unable to carry on any physical activity without discomfort. Symptoms at rest can be present. If any physical activity is undertaken, discomfort is increased.

[0083] In some embodiments, administration of a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof maintains the New York Heart Association (NYHA) functional classification of the subject (i.e., the classification does not get worse). In some embodiments, the NYHA functional classification of the subject is class IV. In some embodiments, the NYHA functional classification of the subject is class III. In some embodiments, the NYHA functional classification of the subject is class II. In some embodiments, the NYHA functional classification of the subject is class I. In some embodiments, administration of a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof reduces the New York Heart Association (NYHA) functional classification of the subject. In some embodiments, the NYHA functional classification is reduced from class IV to class III, from class IV to class II, or from class IV to class I. In some embodiments, the NYHA functional classification is reduced from class IV to class III. In some embodiments, the NYHA functional classification is reduced from class IV to class II. In some embodiments, the NYHA functional classification is reduced from class III to class II. In some embodiments, the NYHA functional classification is reduced from class III to class I. In some embodiments, the NYHA functional classification is reduced from class II to class I. In some embodiments, the improvement is observed after treatment of the subject with Compound 1, or a pharmaceutical salt thereof, for at least about 1 month. In some embodiments, the improvement is observed after treatment of the subject with Compound 1, or a pharmaceutical salt thereof, for at least about 3 months. In some embodiments, the improvement is observed after treatment of the subject with Compound 1, or a pharmaceutical salt thereof, for at least about 6 months. In some embodiments, the improvement is observed after treatment of the subject with Compound 1, or a pharmaceutical salt thereof, for at least about 12 months. In some embodiments, the improvement is observed after treatment of the subject with Compound 1, or a pharmaceutical salt thereof, for at least about 18 months. In some embodiments, the improvement is observed after treatment of the subject with Compound 1, or a pharmaceutical salt thereof, for at least about 24 months. In some embodiments, theimprovement is observed after treatment of the subject with Compound 1, or a pharmaceutical salt thereof, for at least about 30 months.

[0084] In some embodiments, the methods provided herein improve, stabilize or delay worsening in Kansas City Cardiomyopathy Questionnaire (KCCQ) classification of subjects. In some embodiments, the methods described herein provide improved scores in the Kansas City Cardiomyopathy Questionnaire (KCCQ) (Green CP, et al. (2000) Journal of the American College of Cardiology 35: 1245-55), the contents of which are incorporated herein by reference for all purposes. The KCCQ contains specific questions related to cardiac health and provides valid, reliable and sensitive measures of disease-specific health-related quality of life.

[0085] The questions of the KCCQ ask subjects to assess how limited (e.g. severely limited, limited quite a bit, moderately limited, slightly limited, or did not limit at all) they are in performing normal aspects of their life. In some embodiments, subjects have an average improvement of at least one level (e.g. severely limited to limited quite a bit, limited quite a bit to moderately limited, moderately limited to slightly limited) on all questions of the questionnaire after treatment with Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the KCCQ score is measured out of 100. In some embodiments, patients receiving the treatment methods described herein have an average or mean improvement of at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4,4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, or more points in the KCCQ score. In some embodiments, patients receiving the treatment methods described herein have an average or mean improvement of at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more points in the KCCQ score. In some embodiments, patients receiving the treatment methods described herein have an average or mean improvement of at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1,1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, or more points in the KCCQ score as compared to the patient’ s baseline score before Compound 1 or a pharmaceutically acceptable salt thereof is administered. In some embodiments, patients receiving the treatment methods described herein have an average or mean improvement of at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more points in the KCCQ score as compared to the patient’s baseline score before Compound 1 or a pharmaceutically acceptable salt thereof is administered. In some embodiments, the average or mean improvement is measured in a patient after administration of Compound 1 or a pharmaceutically acceptable salt thereof for at least about 1 month. In some embodiments, the average or mean improvement is measuredin a patient after administration of Compound 1 or a pharmaceutically acceptable salt thereof for at least about 3 months. In some embodiments, the average or mean improvement is measured in a patient after administration of Compound 1 or a pharmaceutically acceptable salt thereof for at least about 6 months. In some embodiments, the average or mean improvement is measured in a patient after administration of Compound 1 or a pharmaceutically acceptable salt thereof for at least about 12 months. In some embodiments, the average or mean improvement is measured in a patient after administration of Compound 1 or a pharmaceutically acceptable salt thereof for at least about 18 months. In some embodiments, the average or mean improvement is measured in a patient after administration of Compound 1 or a pharmaceutically acceptable salt thereof for at least about 24 months. In some embodiments, the average or mean improvement is measured in a patient after administration of Compound 1 or a pharmaceutically acceptable salt thereof for at least about 30 months.

[0086] In some embodiments, the methods provided herein improve, stabilize or delay worsening in EuroQoL-5 Dimensions (EQ-5D-5L) score in subjects. EQ-5D-5L is a brief, self-administered generic health status instrument that takes about 5 minutes to complete. The instrument includes two parts. In the first part, respondents are asked to rate their current health state on 5 dimensions (mobility, self-care, usual activities, pain or discomfort, and anxiety or depression) with each dimension having five levels of function ino problem, 2-slight problem, 3-moderate problem, 4-severe problem, and 5-extreme problem). The second part is a respondents self-rating of current health status on a Visual Analog Scale (EQ VAS) with endpoints labeled “best imaginable health state” (score of 100) and “worst imaginable health state” (score of 0). The scores from the 5 dimensions may be used to calculate a single index value, also known as a utility score. The EQ-5D-5L questionnaire is in the public domain and can be obtained from EuroQoL.

[0087] In some embodiments, patients receiving the treatment methods described herein have an average or mean improvement of at least about 0.1 , 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, or more points in the EuroQoL-5 Dimensions (EQ-5D-5L) utility score. In some embodiments, patients receiving the treatment methods described herein have an average or mean improvement of at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more points in the EuroQoL-5 Dimensions (EQ-5D-5L) utility score. In some embodiments, patients receiving the treatment methods described herein have an average or mean improvement of at least five points in the EuroQoL-5Dimensions (EQ-5D-5L) utility score. In some embodiments, patients receiving the treatment methods described herein have an average or mean improvement of at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, or more points in the EuroQoL-5 Dimensions (EQ-5D-5L) utility score as compared to the patient’ s baseline score before Compound 1 or a pharmaceutically acceptable salt thereof is administered. In some embodiments, patients receiving the treatment methods described herein have an average or mean improvement of at least about 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, or more points in the EuroQoL-5 Dimensions (EQ-5D-5L) utility score as compared to the patient’ s baseline score before Compound 1 or a pharmaceutically acceptable salt thereof is administered. In some embodiments, patients receiving the treatment methods described herein have an average or mean improvement of at least five points in the EuroQoL-5 Dimensions (EQ-5D-5L) utility score as compared to the patient’s baseline score before Compound 1 or a pharmaceutically acceptable salt thereof is administered. In some embodiments, the average or mean improvement is measured in a patient after administration of Compound 1 or a pharmaceutically acceptable salt thereof for at least about 1 month. In some embodiments, the average or mean improvement is measured in a patient after administration of Compound 1 or a pharmaceutically acceptable salt thereof for at least about 3 months. In some embodiments, the average or mean improvement is measured in a patient after administration of Compound 1 or a pharmaceutically acceptable salt thereof for at least about 6 months. In some embodiments, the average or mean improvement is measured in a patient after administration of Compound 1 or a pharmaceutically acceptable salt thereof for at least about 12 months. In some embodiments, the average or mean improvement is measured in a patient after administration of Compound 1 or a pharmaceutically acceptable salt thereof for at least about 18 months. In some embodiments, the average or mean improvement is measured in a patient after administration of Compound 1 or a pharmaceutically acceptable salt thereof for at least about 24 months. In some embodiments, the average or mean improvement is measured in a patient after administration of Compound 1 or a pharmaceutically acceptable salt thereof for at least about 30 months.

[0088] In some embodiments, the methods described herein improve a subject’s 6-minute walk test (6MWT) performance. The 6-minute walk test is a self-paced timed walk for six minutes to assess the level of functional capacity of a subject. Subjects are allowed to stop and rest during the test if the levels of exertion exceed their comfort level. Assessmentbefore, after, and during treatment is relatively easy to assess and consists of measuring the distance the subject walks in a six-minute time period. Thus, in some embodiments, subjects increase total distance covered in the 6-minute walk test after treatment with Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, subjects walked at least 25 m further than a baseline distance measured prior to treatment with Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, subjects walked at least 30 m further than a baseline distance measured prior to treatment with Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, subjects walked at least 50 m further than a baseline distance measured prior to treatment with Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, subjects walked at least 75 m further than a baseline distance measured prior to treatment with Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, subjects walked at least 100 m further than a baseline distance measured prior to treatment with Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, subjects receiving the treatment methods described herein have a slowed reduction in six-minute walking distance.For example, in some embodiments, a subject maintains about the same six-minute walking distance as prior to treatment. In some embodiments, a subject covers 10 m less in a six- minute walk test. In some embodiments, the 6-minute walk test is used to compare the treatment group to the non-treatment group. In some embodiments, the between group mean change from baseline is at least 10 meters. In some embodiments, the between group mean change from baseline is at least 20 meters. In some embodiments, the between group mean change from baseline is at least 30 meters. In some embodiments, the treatment methods provided herein reduced the decline in the 6-minute walk test distance as compared to individuals not receiving treatment. In some embodiments, the improvement is observed after treatment of the subject with Compound 1, or a pharmaceutical salt thereof, for at least about 1 month. In some embodiments, the improvement is observed after treatment of the subject with Compound 1, or a pharmaceutical salt thereof, for at least about 3 months. In some embodiments, the improvement is observed after treatment of the subject with Compound 1, or a pharmaceutical salt thereof, for at least about 6 months. In some embodiments, the improvement is observed after treatment of the subject with Compound 1, or a pharmaceutical salt thereof, for at least about 12 months. In some embodiments, the improvement is observed after treatment of the subject with Compound 1, or a pharmaceutical salt thereof, for at least about 18 months. In some embodiments, the improvement is observed after treatment of the subject with Compound 1, or apharmaceutical salt thereof, for at least about 24 months. In some embodiments, the improvement is observed after treatment of the subject with Compound 1, or a pharmaceutical salt thereof, for at least about 30 months.

[0089] Troponin I, Brain natriuretic peptide (BNP), and N-terminal pro-BNP are polypeptides that are elevated in serum blood of subjects with poor myocardial health. In some embodiments, the level of Troponin I, BNP and / or N-terminal pro-BNP decrease after treatment with Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the level of Troponin I, BNP and / or N-terminal pro-BNP decrease about 10% as compared to a baseline level of Troponin I, BNP and / or N-terminal pro-BNP in the subject prior to treatment with Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the level of Troponin I, BNP and / or N-terminal pro-BNP decrease about 15% as compared to a baseline level of Troponin I, BNP and / or N-terminal pro-BNP in the subject prior to treatment with Compound 1 or a pharmaceutically acceptable salt thereof.

[0090] As discussed above, a clinical improvement provided in some embodiments of the disclosed methods, is that administration of a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof in a subject with ATTR cardiomyopathy decreases the frequency of cardiovascular-related hospitalizations as compared to subjects not receiving treatment. In some embodiments, subjects average at least 0.5, 1 , 1 .5, 2, 3, 4, 5 fewer cardiovascular-related hospitalizations per year as compared to those who do not receive treatment. In some embodiments, the subject is a human.

[0091] An additional clinical benefit that is provided in some embodiments of the methods disclosed herein, is that administration of a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof in a subject with ATTR cardiomyopathy decreases mortality rate as compared to subjects not receiving treatment. In some embodiments, mortality rate is reduced by about 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 25, 26, 28, 30 or more percent as compared to subjects who did not receive treatment. In some embodiments, mortality rate is reduced by about 25 percent as compared to subjects who did not receive treatment. In some embodiments, the subject is a human.

[0092] ATTR polyneuropathy is a disease where TTR amyloid (ATTR) deposits impair or otherwise compromise normal nerve function. ATTR polyneuropathy is a progressive disease that causes cachexia and death in affected subjects. The methods of the present disclosure, provide clinical improvement in subjects with ATTR polyneuropathy by stopping or slowingthe accumulation of TTR fibrils. Through this process, the currently described methods provide clinical improvements ATTR polyneuropathy subjects. Clinical improvements include, but are not limited to, improvements in Neuropathy Impairment Score (NIS) or modified Neuropathy Impairment Score+7 (mNIS+7), improvements in Norfolk Quality of Life Diabetic Neuropathy questionnaire, improvements in composite autonomic symptom score (COMPASS-31) score, improved nutritional status as measured by modified body mass index (mBMI), and / or improvements in a subject’s 10 meter walk test.

[0093] In some embodiments, the methods described herein provide improved Neuropathy Impairment Score (NIS). NIS refers to a scoring system that measures weakness, sensation, and reflexes. The NIS score evaluates a standard group of muscles for weakness (1 is 25% weak, 2 is 50% weak, 3 is 75% weak, 3.25 is movement against gravity, 3.5 is movement with gravity eliminated, 3.75 is muscle flicker without movement, and 4 is paralyzed), a standard group of muscle stretch reflexes (0 is normal, 1 is decreased, 2 is absent), and touchpressure, vibration, joint position and motion, and pinprick (all graded on index finger and big toe: 0 is normal, 1 is decreased, 2 is absent). Evaluations are corrected for age, gender, and physical fitness.

[0094] In some embodiments, the methods described herein slow the progression of the disease such that the rate of NIS score increase is reduced as compared to a subject who is not taking Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the methods described herein stop the progression of the disease such that there is no change in NIS score after treatment with Compound 1 or a pharmaceutically acceptable salt thereof.

[0095] In some embodiments, the methods described herein reduce the NIS score after treatment with Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the methods described herein reduced the NIS score by at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60% as compared to a baseline level measured prior to treatment with Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the methods described herein reduced the NIS score by at least 5 % as compared to a baseline level measured prior to treatment with Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the methods described herein reduced the NIS score by at least 10 % as compared to a baseline level measured prior to treatment with Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the methods describedherein reduced the NIS score by at least 15 % as compared to a baseline level measured prior to treatment with Compound 1 or a pharmaceutically acceptable salt thereof.

[0096] In some embodiments, the methods described herein provide improved modified Neuropathy Impairment Score (mNIS+7). mNIS+7 refers to a clinical exam-based assessment of neurologic impairment (NIS) combined with electrophysiological measures of small and large nerve fiber function (NCS and QST), and measurement of autonomic function (postural blood pressure). The mNIS+7 score is a modification of the NIS+7 score (which represents NIS plus seven tests). NIS+7 analyzes weakness and muscle stretch reflexes. Five of the seven tests include attributes of nerve conduction. These attributes are the peroneal nerve compound muscle action potential amplitude, motor nerve conduction velocity and motor nerve distal latency (MNDL), tibial MNDL, and sural sensory nerve action potential amplitudes. These values are corrected for variables of age, gender, height, and weight. The remaining two of the seven tests include vibratory detection threshold and heart rate decrease with deep breathing. The mNIS+7 score modifies NIS+7 to take into account the use of Smart Somatotopic Quantitative Sensation Testing, new autonomic assessments, and the use of compound muscle action potential of amplitudes of the ulnar, peroneal, and tibial nerves, and sensory nerve action potentials of the ulnar and sural nerves (Suanprasert, N. et al., Retrospective study of a TTR FAP cohort to modify NIS+7 for therapeutic trials, J. Neurol. Sci., 2014. 344(1-2): pgs. 121-128). Further details of the mNIS+7 exam can be found in U.S. Patent Publication No. 2017 / 0307608, the contents of which is incorporated herein by reference, for all purposes.

[0097] In some embodiments, the methods described herein slow the progression of the disease such that the rate of mNIS+7 score increase is reduced as compared to a subject who is not taking Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the methods described herein stop the progression of the disease such that there is no change in mNIS+7 score after treatment with Compound 1 or a pharmaceutically acceptable salt thereof.

[0098] In some embodiments, the methods described herein reduce the mNIS+7 score after treatment with Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the methods described herein reduced the mNIS+7score by at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60% as compared to a baseline level measured prior to treatment with Compound 1 or a pharmaceutically acceptable salt thereof. In someembodiments, the methods described herein reduced the mNIS+7 score by at least 5 % as compared to a baseline level measured prior to treatment with Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the methods described herein reduced the mNIS+7 score by at least 10 % as compared to a baseline level measured prior to treatment with Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the methods described herein reduced the mNIS+7 score by at least 15 % as compared to a baseline level measured prior to treatment with Compound 1 or a pharmaceutically acceptable salt thereof.

[0099] In some embodiments, the methods described herein provide improved scores in the Norfolk Quality of Life Diabetic Neuropathy (QOL-DN) questionnaire. This questionnaire is well known to a person of skill in the art, and is a validated questionnaire that captures pain related to large fiber, small fiber, and autonomic neuropathy. The questionnaire includes items related to symptoms experienced by the subject and questions related to the impact of neuropathy on the daily activities of a subject.

[0100] In some embodiments, the methods described herein slow the progression of the disease such that the rate of the Norfolk QOL-DN score decline is reduced as compared to a subject who is not taking Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the methods described herein stop the progression of the disease such that there is no change in the Norfolk QOL-DN score after treatment with Compound 1 or a pharmaceutically acceptable salt thereof.

[0101] In some embodiments, the methods described herein slow the progression of the disease such that there is no change in the Norfolk QOL-DN score after treatment with Compound 1 or a pharmaceutically acceptable salt thereof.

[0102] In some embodiments, the methods described herein improve the Norfolk QOL-DN score after treatment with Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the methods described herein improve the Norfolk QOL-DN by at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60% as compared to a baseline level measured prior to treatment with Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the methods described herein improve the Norfolk QOL-DN score by at least 5 % as compared to a baseline level measured prior to treatment with Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the methods described herein improve the Norfolk QOL-DN score by at least 10 % as compared to a baseline levelmeasured prior to treatment with Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the methods described herein improve the Norfolk QOL-DN score by at least 15 % as compared to a baseline level measured prior to treatment with Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the methods described herein provide a change in a subject’s Norfolk QOL-DN of about -1.5, -2.0, -2.5, -3.0, -3.5, - 4.0, -4.5, -5.0, - 5.5, -6.0, -6.7, -7.0, -7.5, -8.0, -8.5, -9.0, -9.5, or-10.0 as compared to a subject’s baseline score.

[0103] In some embodiments, the methods disclosed herein provide improved composite autonomic symptom score (COMPASS-31). The composite autonomic symptom score (COMPASS-31) is a patient questionnaire that assesses symptoms of dysautonomia. In one embodiment, the methods of the invention provide to the subject an improvement versus baseline in a COMPASS-31 score. Such an improvement can take the form of an increase of at least 0.1 , for example at least 0.2, at least 0.3, at least 0.4, or at least 0.5, e.g., 0.1 , 0.2, 0.3, 0.4, or 0.5, points of the subject' s COMPASS-31 score. In some embodiments, the methods slow the progression of the disease such that there is no change in the COMPASS-31 score. In yet other embodiments, the methods of the invention slow the rate at which a COMPASS - 31 score decreases, e.g., the rate of decrease of a COMPASS-31 score in a subject treated with Compound 1 or a pharmaceutically acceptable salt thereof as compared to the rate of decrease of a COMPASS-31 score in a subject that is not treated with Compound 1 or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments, the methods disclosed herein provide improved nutritional status as measured by modified body mass index (mBMI), which is determined by multiplying the BMI of an individuals by their serum albumin levels. The calculation of mBMI accounts for the contribution of edema to total weight. In one embodiment, the methods of the disclosure provide to the subject an improvement versus baseline in mBMI. Such an improvement can take the form of a mBMI score decrease of about 2, 5, 7, 10, 12, 15, 20, or about 25. In other embodiments, the methods arrest an increasing mBMI index score, e.g., the methods result in a 0% increase of the mBMI score. In yet other embodiments, the methods of the invention slow the rate at which mBMI score increases, e.g., the rate of increase of a mBMI score in a subject treated with Compound 1 or a pharmaceutically acceptable salt thereof as compared to the rate of increase of a mBMI score in a subject that is not treated with Compound 1 or a pharmaceutically acceptable salt thereof.

[0105] In some embodiments, the methods disclosed herein provide improvements in the 10-meter walk test. This test measures a walking speed of an individual over 10 meters. In one embodiment, the methods of the disclosure provide to the subject an increase from baseline in the 10-meter walk test. In some embodiments, the increase from baseline in the 10-meter walk test is about 0.025, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0. 4.5, or about 5.0 meters / second.

[0106] In some embodiments, the methods disclosed herein provide improved Dyck / Rankin scores. The Dyck / Rankin score is known in the art, and is assigned by a physician after assessing the patient’s symptoms, neuropathic impairments, test results, and reviewing a patient’s ability to perform acts of daily living. Only disability related to peripheral neuropathy is graded. In deciding whether the patient has difficulty or inability to perform certain tasks or acts of daily living, more than the patient’s report should be used for judgment; the physician should use objective criteria. The stages (0-8) are outlined below:0. No neuropathy• No symptoms (NSS < 1), signs (NIS < 2 points); or tests (e.g. 7 tests < 97.5th) abnormalities of neuropathy.1. Minimal neuropathy (only one of A, B. C are abnormal) a) Tests, are the only abnormality (e.g. 7 test > 97.5th); or b) Neuropathy signs, are the only abnormality (e.g. NIS > 2 points); or c) Neuropathy symptoms are the only abnormality (e.g. NSS >1)2. Minimal neuropathy: la + lb.3. Symptomatic neuropathy: la, la+lc; la+lc or Ib+lc. The patient is able to continue with usual acts of daily living, work or recreational activity, and can meet usual-family and social responsibilities.* Symptoms of neuropathy: NSS > 1 symptoms of muscle weakness, atrophy orcramps; negative or positive, neuropathic sensory symptoms (N-NNS,P-NSS); or neuropathic autonomic symptoms.Usual acts of daily living, work, recreational and social and family activities: Despite neuropathic symptoms, the patient is able to work at his usual activity, maintain his usual home obligations and participate in recreational activities. Generally, the patient can carry-on despite some motor, sensory or autonomic symptoms. The patients may be unable to perform extraordinary activities e.g. competitive sports, feats of endurance, etc. Symptomatic neuropathy (defined in 3) interfering and limiting work, usual acts of daily living, recreational activity or family and social obligations but independent function is possible without the help of others. At this score, there is an unequivocal limitation of usual* work, acts of living or recreational, family or social obligations * because of neuropathy.* The degree of motor, sensory or autonomic symptoms or impairment is of a sufficient degree to limit the ability to work, to perform usual acts of daily living, recreational activities or to meet family and usual social responsibilities. The use of a can or orthotic device probably places the patient in this (or a higher) category unless the patient is able to perform “usual” acts of daily living, recreational activities and meet social and family responsibilities (then they would fall into lower category). Symptomatic neuropathy (defined in 3) restricting acts of daily living, work and recreational activities. The help of other care-givers* (<21 hrs / day) is needed. If use of a wheelchair is mandatory for acts of daily loving, recreational activities or social and family responsibilities, the patient would usually fall into this or a higher score (> 5).* A member of the family or visiting nurse is needed to provide acts of daily living (bathing, shaving, tooth brushing, feeding, etc.), daily management of analgesics or opiates or help with management of autonomic dysfunction which the patient is not able to perform adequately or safely on their own. Symptomatic neuropathy (defended in 3) requiring the help of caregivers > 2I / 2 hrs to < 8 hrs / day as described in 5. Symptomatic neuropathy (defined in 3) requiring the help of care giver > 8 hrs / day but not continuously as in stage 8. Symptomatic neuropathy (defined in 3) requiring constant care in an intensive care unit.

[0107] The time period for administration will depend on a number of factors including the specific disease being treated. For example, in particular transthyretin (TTR) amyloidosis diseases or conditions, there is a genetic component such that chronic (i.e. continuous, long term) administration may be required. However, in some embodiments, administration of Compound 1 or a pharmaceutically acceptable salt thereof to subject with a genetic TTR amyloidosis disease will continue while the subject is demonstrating or experiencing symptoms related to the TTR amyloidosis disease or condition, or for a set period of time after a particular end point is met (e.g. reduction or complete elimination of symptoms). If the symptoms of the TTR amyloidosis disease return or begin to reappear, administration of Compound 1 or a pharmaceutically acceptable salt is re-started.

[0108] For subjects with a non-genetic linked TTR amyloidosis disease, a number of administration options are available and will depend on the severity of the disease and the clinical symptoms presented. In some embodiments, long term administration of Compound 1 or a pharmaceutically acceptable salt is necessary. In some embodiments, shorter term, or acute, administration of Compound 1 or a pharmaceutically acceptable salt is necessary. In some embodiments, administration of Compound 1 or a pharmaceutically acceptable salt to a subject with a non-genetic linked TTR amyloidosis disease is continued while the subject is demonstrating or experiencing symptoms related to the TTR amyloidosis disease or condition, or for a set period of time after a particular end point is met (e.g. reduction or complete elimination of symptoms). If the symptoms of the TTR amyloidosis disease return or begin to reappear, administration of Compound 1 or a pharmaceutically acceptable salt is re-started.

[0109] Advantageously, agents used in diuretic therapy have not been observed to alter the exposure of Compound 1 or a pharmaceutically acceptable salt thereof during treatment in clinical studies. As such, patients receiving diuretic therapy can be administered Compound 1 or a pharmaceutically acceptable salt thereof without altered or specialized dosing regimens. Thus, in some embodiments, the methods described herein further comprise administering to the subject a diuretic therapy agent. Diuretic therapy agents include, but are not limited to, ethacrynic acid, bumetanide, furosemide, and torsemide. In some embodiments, the diuretic therapy agent is furosemide or torsemide.Renal Methods

[0110] In another embodiment, the present disclosure provides a method of treating, delaying the progression of, ameliorating, reducing, eliminating, delaying the development of, reducing the risk of developing, or preventing the development of impaired renal (e.g., kidney) function, the method comprising administering a therapeutically effective amount of acoramidis, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, the present disclosure provides a method of treating impaired renal (e.g., kidney) function, the method comprising administering a therapeutically effective amount of acoramidis, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In another embodiment, the present disclosure provides a method of reducing the risk of developing, delaying the development of, or delaying the progression of impaired renal (e.g., kidney) function, the method comprising administering a therapeutically effective amount of acoramidis, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In another embodiment, the present disclosure provides a method of stabilizing renal (e.g., kidney) function, the method comprising administering a therapeutically effective amount of acoramidis, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In a related embodiment, the present disclosure provides a method of improving renal (e.g., kidney) function, the method comprising administering a therapeutically effective amount of acoramidis, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In a related embodiment, the present disclosure provides a method of ameliorating, improving, delaying the development of, delaying the progression of, reducing, treating, preventing the development of, reducing the risk of developing, or eliminating one or more symptoms of impaired renal (e.g., kidney) function, the method comprising administering a therapeutically effective amount of acoramidis, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In a related embodiment, the present disclosure provides a method of ameliorating, improving, or eliminating one or more symptoms of impaired renal (e.g., kidney) function, the method comprising administering a therapeutically effective amount of acoramidis, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, the subject is a human.

[0111] In some embodiments, renal (e.g., kidney) function of a subject is considered stabilized if the subject does not progress to a higher stage of chronic kidney disease (CKD) after about 28 days of administration. In some embodiments, renal (e.g., kidney) function of a subject is considered stabilized if the subject does not progress to a higher stage of chronickidney disease (CKD) after about 3, 6, 12, 18, 24, or 30 months of administration. In some embodiments, renal (e.g., kidney) function of a subject is considered stabilized if the subject moves to a lower stage of chronic kidney disease (CKD) after about 28 days of administration. In some embodiments, renal (e.g., kidney) function of a subject is considered stabilized if the subject moves to a lower stage of chronic kidney disease (CKD) after about 3, 6, 12, 18, 24, or 30 months of administration. In some embodiments, renal (e.g., kidney) function of a subject is considered stabilized if the eGFR remains substantially unchanged after about 28 days of administration. In some embodiments, the eGFR of the subject remains substantially unchanged after about 3, 6, 12, 18, 24, or 30 months of administration. In some embodiments, renal (e.g., kidney) function of a subject is considered stabilized if the eGFR of the subject decreases by less than about 20% after about 28 days of administration. In some embodiments, the eGFR of the subject decreases by 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% after about 28 days of administration. In some embodiments, renal (e.g., kidney) function of a subject is considered stabilized if the eGFR of the subject decreases by less than about 20% after about 3 months of administration. In some embodiments, the eGFR of the subject decreases by 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 1 1%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% after about 3 months of administration. In some embodiments, renal (e.g., kidney) function of a subject is considered stabilized if the eGFR of the subject decreases by less than about 20% after about 6 months of administration. In some embodiments, the eGFR of the subject decreases by 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% after about 6 months of administration. In some embodiments, renal (e.g., kidney) function of a subject is considered stabilized if the eGFR of the subject decreases by less than about 20% after about 12 months of administration. In some embodiments, the eGFR of the subject decreases by 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 1 1%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% after about 12 months of administration. In some embodiments, renal (e.g., kidney) function of a subject is considered stabilized if the eGFR of the subject decreases by less than about 20% after about 18 months of administration. In some embodiments, the eGFR of the subject decreases by 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 1 1%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% after about 18 months of administration. In some embodiments, renal (e.g., kidney) function of a subject is considered stabilized if the eGFR of the subject decreases by less than about 20% after about 24 months of administration. In some embodiments, the eGFR of the subject decreases by 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%,4%, 3%, 2%, or 1% after about 24 months of administration. In some embodiments, renal (e.g., kidney) function of a subject is considered stabilized if the eGFR of the subject decreases by less than about 20% after about 30 months of administration. In some embodiments, the eGFR of the subject decreases by 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% after about 30 months of administration.

[0112] In some embodiments, a symptom of impaired renal (e.g., kidney) function is loss of appetite, general ill feeling, fatigue, headaches, itching (pruritus), dry skin, rash, nausea, unintentional weight loss, abnormally dark or light skin (skin discoloration), bone pain, drowsiness, difficulty concentrating, dizziness, numbness in hands or feet, muscle twitching cramps, breath odor, metallic taste in mouth, easy bruising, blood in stool, excessive thirst, frequent hiccups, sexual dysfunction, amenorrhea, shortness of breath, sleep problems, swelling in extremities, vomiting, changes in urination, anemia, cold feeling, high blood pressure (hypertension), chest pain, or a combination thereof.

[0113] In some embodiments, impaired renal function is determined by the subject’s diagnosis with chronic kidney disease (CKD). In some embodiments, the subject has chronic kidney disease (CKD). In some embodiments the subject has Stage 1 CKD, Stage 2 CKD, Stage 3 CKD, Stage 3a CKD, Stage 3b CKD, Stage 4 CKD, or Stage 5 CKD. In some embodiments, impaired renal function is determined by a patient’s diagnosis with an acute kidney or renal issue, such as an acute kidney injury (AKI). In some embodiments, impaired renal function is associated with or caused, at least in part, by another condition, such as autoimmune and / or genetic condition.

[0114] In some embodiments, the subject is diagnosed with Stage 2 chronic kidney disease (CKD), which is typically defined as subjects having an estimated glomerular filtration rate (eGFR) of 60 to < 90 mL / min / 1.73 m2. In some embodiments, the subject is diagnosed with Stage 3a chronic kidney disease (CKD), which is typically defined as subjects having an estimated glomerular filtration rate (eGFR) of 45 to < 60 mL / min / 1.73 nr. In some embodiments, the subject is diagnosed with Stage 3b chronic kidney disease (CKD), which is typically defined as subjects having an estimated glomerular filtration rate (eGFR) of 30 to < 45 mL / min / 1.73 m2. In some embodiments, the subject is diagnosed with Stage 4 chronic kidney disease (CKD), which is typically defined as subjects having an estimated glomerular filtration rate (eGFR) of 15 to < 30 mL / min / 1 .73 m2. In some embodiments, the subject isdiagnosed with Stage 5 chronic kidney disease (CKD), which is typically defined as subjects having an estimated glomerular filtration rate (eGFR) of < 15 mL / min / 1.73 m2. In some embodiments, subjects are diagnosed with a particular stage of CKD after two or more tests over the period of at least three months.

[0115] In some embodiments, the subject does not progress to a higher Stage of CKD compared to baseline after about 28 days of administration. In some embodiments, the subject does not progress to a higher Stage of CKD compared to baseline after about 3 months of administration. In some embodiments, the subject does not progress to a higher Stage of CKD compared to baseline after about 6 months of administration. In some embodiments, the subject does not progress to a higher Stage of CKD compared to baseline after about 12 months of administration. In some embodiments, the subject does not progress to a higher Stage of CKD compared to baseline after about 18 months of administration. In some embodiments, the subject does not progress to a higher Stage of CKD compared to baseline after about 24 months of administration. In some embodiments, the subject does not progress to a higher Stage of CKD compared to baseline after about 30 months of administration. In some embodiments, the subject moves to a lower Stage of CKD compared to baseline after about 28 days of administration. In some embodiments, the subject moves to a lower Stage of CKD compared to baseline after about 3 months of administration. In some embodiments, the subject moves to a lower Stage of CKD compared to baseline after about 6 months of administration. In some embodiments, the subject moves to a lower Stage of CKD compared to baseline after about 12 months of administration. In some embodiments, the subject moves to a lower Stage of CKD compared to baseline after about 18 months of administration. In some embodiments, the subject moves to a lower Stage of CKD compared to baseline after about 24 months of administration. In some embodiments, the subject moves to a lower Stage of CKD compared to baseline after about 30 months of administration. In some embodiments, the subject is a human.

[0116] In some embodiments, the subject is at least 18 years of age. In some embodiments, the subject is less than 18 years of age (e.g., a human child). In some embodiments, the subject is a pediatric human patient. In some embodiments, the subject is less than 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 years of age. In some embodiments, the subject is at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95 years of age. In some embodiments, the subject is between 0-18, 1-18, 2-18, 3-18, 4-18, 5-18, 6-18, 7-18, 8-18, 9-18, 10-18, 11-18, 12-18, 13-18, 14-18, 15-18, 16-18, 17-18, 0-16, 1-16, 2-16, 3-16, 4-16, 5-16, 6-16, 7-16, 8-16, 9-16, 10- 16, 11-16, 12-16, 13-16, 14-16, 15-16, 0-15, 1-15, 2-15, 3-15, 4-15, 5-15, 6-15, 7-15, 8-15, 9- 15, 10-15, 11-15, 12-15, 13-15, 14-15, 0-13, 1-13, 2-13, 3-13, 4-13, 5-13, 6-13, 7-13, 8-13, 9- 13, 10-13, 11-13, 12-13, 0-12, 1-12, 2-12, 3-12, 4-12, 5-12, 6-12, 7-12, 8-12, 9-12, 10-12, 11- 12, 0-11, 1-11, 2-11, 3-11, 4-11, 5-11, 6-11, 7-11, 8-11, 9-11, 10-11, 0-10, 1-10, 2-10, 3-10,4-10, 5-10, 6-10, 7-10, 8-10, 9-10, 0-8, 1-8, 2-8, 3-8, 4-8, 5-8, 6-8, 7-8, 0-6, 1-6, 2-6, 3-6, 4-6,5-6, 0-5, 1-5, 2-5, 3-5, 4-5, 0-4, 1-4, 2-4, 3-4, 0-3, 1-3, 2-3, 0-2, 1-2, 18-20, 18-25, 18-30, 18-35, 18-40, 18-45, 18-50, 18-55, 18-60, 18-65, 18-70, 18-75, 18-80, 18-85, 18-90, 20-30, 20-40, 20-50, 20-60, 20-70, 20-70, 20-80, 20-90, 30-40, 30-50, 30-60, 30-70, 30-80, 30-90, 40-50, 40-60, 40-70, 40-80, 40-90, 50-60, 50-70, 50-80, 50-90, 60-70, 60-80, 60-90, 65-70, 65-75, 65-80, 65-85, or 65-90 years of age, or any range therein. In some embodiments, the subject is at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months of age.

[0117] In some embodiments, the subject is a human pediatric patient. In some embodiments, the human pediatric patient weighs about 5 kg to about 50 kg. In some embodiments, the human pediatric patient weighs less than about 50 kg. In some embodiments, the human pediatric patient weighs less than about 45 kg. In some embodiments, the human pediatric patient weighs less than about 40 kg. In some embodiments, the human pediatric patient weighs less than about 35 kg. In some embodiments, the human pediatric patient weighs less than about 30 kg. In some embodiments, the human pediatric patient weighs less than about 25 kg. In some embodiments, the human pediatric patient weighs less than about 20 kg. In some embodiments, the human pediatric patient weighs less than about 15 kg. In some embodiments, the human pediatric patient weighs less than about 10 kg. In some embodiments, the human pediatric patient weighs less than about 5 kg. In some embodiments, the human pediatric patient weighs about 5 kg to about 15 kg, about 10 kg to about 20 kg, about 15 kg to about 25 kg, about 20 kg to about 30 kg, about 30 kg to about 40 kg, about 35 kg to about 40 kg, or about 40 kg to about 50 kg.

[0118] In some embodiments, the subject has an eGFR of < 90 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of < 60 mL / min / 1.73 nr. In some embodiments, the subject has an eGFR of < 55 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of < 50 mL / min / 1 .73 m2. In some embodiments, the subject has an eGFR of < 45 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of < 40 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of < 35 mL / min / 1.73 m2. In someembodiments, the subject has an eGFR of < 30 mL / min / 1.73 nr. In some embodiments, the subject has an eGFR of < 29 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of < 28 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of < 27 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of < 26 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of < 25 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of < 24 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of < 23 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of < 22 mL / min / 1 .73 m2. In some embodiments, the subject has an eGFR of < 21 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of < 20 mL / min / 1.73 nr. In some embodiments, the subject has an eGFR of < 19 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of < 19 mL / min / 1.73 nr. In some embodiments, the subject has an eGFR of < 18 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of < 17 mL / min / 1.73 nr. In some embodiments, the subject has an eGFR of < 16 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of < 15 mL / min / 1.73 nr. In some embodiments, the subject is a human.

[0119] In some embodiments, the subject has an eGFR of 10 to 30 mL / min / 1.73 nr. In some embodiments, the subject has an eGFR of 10 to 29 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 10 to 28 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 10 to 27 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 10 to 26 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 10 to 25 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 10 to 20 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 10 to 15 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 15 to 30 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 15 to 29 mL / min / 1.73 nr. In some embodiments, the subject has an eGFR of 15 to 28 mL / min / 1.73 nr. In some embodiments, the subject has an eGFR of 15 to 27 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 15 to 26 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 15 to 25 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 15 to 20 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 10 to 40 mL / min / 1.73 nr. In some embodiments, the subject has an eGFR of 15 to 40 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 20 to 40 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 25 to 40 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 30 to 40 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 35 to 40mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 10 to 45 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 15 to 45 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 20 to 45 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 25 to 45 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 30 to 45 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 30 to 44 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 35 to 45 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 40 to 45 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 10 to 50 mL / min / 1 .73 m2. In some embodiments, the subject has an eGFR of 15 to 50 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 20 to 50 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 25 to 50 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 30 to 50 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 35 to 50 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 40 to 50 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 45 to 50 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 10 to 55 mL / min / 1.73 nr. In some embodiments, the subject has an eGFR of 15 to 55 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 20 to 55 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 25 to 55 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 30 to 55 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 35 to 55 mL / min / 1.73 nr. In some embodiments, the subject has an eGFR of 40 to 55 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 45 to 55 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 50 to 55 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 10 to 60 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 15 to 60 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 20 to 60 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 25 to 60 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 30 to 60 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 35 to 60 mL / min / 1.73 nr. In some embodiments, the subject has an eGFR of 40 to 60 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 45 to 60 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 50 to 60 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 55 to 60 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 10 to 59 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 15 to 59 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 20 to 59 mL / min / 1.73 nr. In some embodiments, the subject has an eGFR of 25 to 59 mL / min / 1.73 m2. In some embodiments, the subject hasan eGFR of 30 to 59 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 35 to 59 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 40 to 59 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 45 to 59 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 50 to 59 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 55 to 59 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of 60 to 90 mL / min / 1.73 m2.

[0120] In some embodiments, the eGFR of the subject decreases by about 13.9% compared to baseline after 28 days of administration. In some embodiments, the eGFR of the subject decreases by less than about 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, or 5% compared to baseline after 28 days of administration. In some embodiments, the eGFR of the subject decreases by less than about 15% compared to baseline after 28 days of administration. In some embodiments, the eGFR of the subject decreases by less than about 14% compared to baseline after 28 days of administration. In some embodiments, the eGFR of the subject decreases by about 1% to about 5%, about 5% to about 10%, about 10% to about 15%, about 15% to about 20%, about 20% to about 25%, or about 25% to about 30% compared to baseline after 28 days of administration. In other embodiments, the eGFR of the subject decreases by about 1% to about 10%, about 5% to about 15%, about 10% to about 20%, about 15% to about 25%, or about 20% to about 30% compared to baseline after about 28 days of administration. In other embodiments, the eGFR of the subject decreases by greater than about 5% or greater than about 10% compared to baseline after about 28 days of administration. In other embodiments, the eGFR of the subject decreases by about 11% to about 17% compared to baseline after about 28 days of administration. In some embodiments, the subject is a human. In some embodiments, the eGFR of the human decreases by about 5% to about 15% compared to baseline after 28 days of administration. In some embodiments, the eGFR of the human decreases by about 13.9% compared to baseline after 28 days of administration

[0121] In some embodiments, the eGFR of the subject decreases by about 9.5% compared to baseline after 30 months of administration. In some embodiments, the eGFR of the subject decreases by about 1% to about 5%, about 5% to about 10%, about 10% to about 15%, about 15% to about 20%, about 20% to about 25%, or about 25% to about 30% compared to baseline after about 30 months of administration. In other embodiments, the eGFR of the subject decreases by about 1% to about 10%, about 5% to about 15%, about 10% to about 20%, about 15% to about 25%, or about 20% to about 30% compared to baseline after about30 months of administration. In other embodiments, the eGFR of the subject decreases by greater than about 5% or greater than about 9% compared to baseline after about 30 months of administration. In other embodiments, the eGFR of the subject decreases by about 6.5% to about 12.5% compared to baseline after about 30 months of administration. In some embodiments, the subject is a human. In some embodiments, the eGFR of the human decreases by about 9.5% compared to baseline after 30 months of administration.

[0122] In some embodiments, the eGFR of the subject remains substantially unchanged compared to baseline after about 28 days of administration. In some embodiments, the eGFR of the subject remains substantially unchanged compared to baseline after about 3, 6, 12, 18, 24, or 30 months of administration.

[0123] In some embodiments, the eGFR of the subject increases by at least about 1% compared to baseline after about 7 days of administration. In some embodiments, the eGFR of the subject increases by at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, or more after about 7 days of administration. In some embodiments, the eGFR of the subject increases by at least about 1% compared to baseline after about 14 days of administration. In some embodiments, the eGFR of the subject increases by at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1 1 %, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, or more after about 14 days of administration. In some embodiments, the eGFR of the subject increases by at least about 1% compared to baseline after about 28 days of administration. In some embodiments, the eGFR of the subject increases by at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, or more after about 28 days of administration. In some embodiments, the eGFR of the subject increases by at least about 1% compared to baseline after about 3 months of administration. In some embodiments, the eGFR of the subject increases by at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, or more after about 3 months of administration. In some embodiments, the eGFR of the subject increases by at least about 1% compared to baseline after about 6 months of administration. In some embodiments, the eGFR of the subject increases by at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, or more after about 6 months of administration. In some embodiments, the eGFR of the subject increases by at least about 1% compared to baseline after about 12 months of administration. In some embodiments, the eGFR of the subject increases by at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%,11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, or more after about 12 months of administration. In some embodiments, the eGFR of the subject increases by at least about 1% compared to baseline after about 18 months of administration. In some embodiments, the eGFR of the subject increases by at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, or more after about 18 months of administration.

[0124] In some embodiments, the subject does not need dialysis or a kidney transplant after 30 months of administration. In some embodiments, the subject’s need for dialysis or a kidney transplant is delayed compared to a subject who does not receive administration. In some embodiments, the subject’s need for dialysis is delayed by about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, or about 16 weeks compared to a subject who does not receive administration. In some embodiments, the subject’s need for dialysis or a kidney transplant is delayed by about 1 to 2 weeks, about 2 to 3 weeks, about 3 to 4 weeks, about 4 to 5 weeks, about 5 to 6 weeks, about 6 to 7 weeks, about 7 to 8 weeks, about 8 to 9 weeks, about 9 to 10 weeks, about 10 to 11 weeks, about 11 to 12 weeks, about 12 to 13 weeks, about 13 to 14 weeks, about 14 to 15 weeks, or about 15 to 16 weeks compared to a subject who does not receive administration.

[0125] In some embodiments, the serum creatinine concentration of the subject increases by about 17.5% compared to baseline after 28 days of administration. In some embodiments, the serum creatinine concentration of the subject increases by about 1% to about 5%, about 5% to about 10%, about 10% to about 15%, about 15% to about 20%, about 20% to about 25%, about 25% to about 30%, or about 30% to about 35% compared to baseline after about 28 days of administration. In other embodiments, the serum creatinine concentration of the subject increases by about 1% to about 10%, about 5% to about 15%, about 10% to about 20%, or about 15% to about 25%, about 20% to about 30%, or about 25% to about 35% compared to baseline after about 28 days of administration. In other embodiments, the serum creatinine concentration of the subject increases by greater than about 10% or greater than about 15% compared to baseline after about 28 days of administration. In other embodiments the serum creatinine concentration of the subject increases by about 14.5% to about 20.5% compared to baseline after about 28 days of administration. In some embodiments, thesubject is a human. In some embodiments, the serum creatinine concentration of the human increases by about 17.5% compared to baseline after 28 days of administration.

[0126] In some embodiments, the serum creatinine concentration of the subject increases by about 12.2 % compared to baseline after 30 months of administration. In some embodiments, the serum creatinine concentration of the subject increases by about 1% to about 5%, about 5% to about 10%, about 10% to about 15%, about 15% to about 20%, about 20% to about 25%, about 25% to about 30%, or about 30% to about 35% compared to baseline after about 30 months of administration. In other embodiments, the serum creatinine concentration of the subject increases by about 1% to about 10%, about 5% to about 15%, about 10% to about 20%, or about 15% to about 25%, about 20% to about 30%, or about 25% to about 35% compared to baseline after about 30 months of administration. In other embodiments, the serum creatinine concentration of the subject increases by greater than about 5% or greater than about 10% compared to baseline after about 30 months of administration. In other embodiments, the serum creatinine concentration of the subject increases by about 9% to about 15% compared to baseline after about 30 months of administration. In some embodiments, the serum creatinine concentration of the human increases by about 12.2% compared to baseline after 30 months of administration.

[0127] In some embodiments, the subject is not in need of transthyretin (TTR) stabilization. In some embodiments, the subject does not have transthyretin amyloidosis (ATTR). In some embodiments, the subject does not have ATTR-cardiomyopathy (ATTR-CM). In some embodiments, the subject does not have ATTR-polyneuropathy (ATTR-PN). In some embodiments, the subject has not been diagnosed with transthyretin amyloidosis (ATTR). In some embodiments, the subject has not been diagnosed with ATTR-cardiomyopathy (ATTR- CM). In some embodiments, the subject has not been diagnosed with ATTR-polyneuropathy (ATTR-PN). In some embodiments, the subject is a human.

[0128] In another embodiment, provided herein are methods of treating or preventing proteinuria, the method comprising administering a therapeutically effective amount of acoramidis, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, provided herein are methods of treating proteinuria, the method comprising administering a therapeutically effective amount of acoramidis, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, the subject is a human.

[0129] Proteinuria is a condition characterized by elevated protein levels in the urine. Proteinuria is associated with a urine albumin-to-creatinine ratio (UACR) of 30 mg / g or higher, urine protein excretion above 150 mg / day, or urine albumin excretion above 30 mg / day.

[0130] In some embodiments, the UACR of the subject is less than about 30 milligrams per gram (mg / g) after treatment. Treatment can include administration of acoramidis, or a pharmaceutically acceptable salt thereof for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, or more weeks. In some embodiments, treatment includes administration of acoramidis, or a pharmaceutically acceptable salt thereof for about 5 to about 25 weeks. In some embodiments, treatment includes administration of acoramidis, or a pharmaceutically acceptable salt thereof for about 10 to about 20 weeks. In some embodiments, treatment includes administration of acoramidis, or a pharmaceutically acceptable salt thereof for about 10 weeks. In some embodiments, treatment includes administration of acoramidis, or a pharmaceutically acceptable salt thereof for about 20 weeks. In some embodiments, the subject is a human. In some embodiments, the urine albumin-to-creatinine ratio (UACR) of the human is less than about 30 milligrams per gram (mg / g) after about 10 weeks of treatment. In some embodiments, the urine albumin-to-creatinine ratio (UACR) of the human is less than about 30 milligrams per gram (mg / g) after about 20 weeks of treatment.

[0131] In some embodiments, the UACR of the subject decreases by at least about 30% compared to baseline after treatment. Treatment can include administration of acoramidis, or a pharmaceutically acceptable salt thereof for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, or more weeks. In some embodiments, treatment includes administration of acoramidis, or a pharmaceutically acceptable salt thereof for about 5 to about 25 weeks. In some embodiments, treatment includes administration of acoramidis, or a pharmaceutically acceptable salt thereof for at about 10 to about 20 weeks. In some embodiments, treatment includes administration of acoramidis, or a pharmaceutically acceptable salt thereof for about 10 weeks. In some embodiments, treatment includes administration of acoramidis, or a pharmaceutically acceptable salt thereof for about 20 weeks. In some embodiments, the subject is a human. In some embodiments, the urine albumin-to-creatinine ratio (UACR) of the human decreases byat least about 30% compared to baseline after about 10 weeks of treatment. In some embodiments, the urine albumin-to-creatinine ratio (UACR) of the human decreases by at least about 30% compared to baseline after about 20 weeks of treatment

[0132] In some embodiments, the urine protein excretion of the subject is less than about 150 mg / day after treatment. Treatment can include administration of acoramidis, or a pharmaceutically acceptable salt thereof for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, or more weeks. In some embodiments, treatment includes administration of acoramidis, or a pharmaceutically acceptable salt thereof for about 5 to about 25 weeks. In some embodiments, treatment includes administration of acoramidis, or a pharmaceutically acceptable salt thereof for about 10 to about 20 weeks. In some embodiments, treatment includes administration of acoramidis, or a pharmaceutically acceptable salt thereof for about 10 weeks. In some embodiments, treatment includes administration of acoramidis, or a pharmaceutically acceptable salt thereof for about 20 weeks. In some embodiments, the subject is a human. In some embodiments, the urine protein excretion of the human is less than about 150 mg / day after about 10 weeks of treatment. In some embodiments, the urine protein excretion of the human is less than about 150 mg / day after about 20 weeks of treatment.

[0133] In some embodiments, the urine protein excretion of the subject decreases by at least about 30% compared to baseline after treatment. Treatment can include administration of acoramidis, or a pharmaceutically acceptable salt thereof for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, or more weeks. In some embodiments, treatment includes administration of acoramidis, or a pharmaceutically acceptable salt thereof for about 5 to about 25 weeks. In some embodiments, treatment includes administration of acoramidis, or a pharmaceutically acceptable salt thereof for at least 10 to 20 weeks. In some embodiments, treatment includes administration of acoramidis, or a pharmaceutically acceptable salt thereof for about 10 weeks. In some embodiments, treatment includes administration of acoramidis, or a pharmaceutically acceptable salt thereof for about 20 weeks. In some embodiments, the subject is a human. In some embodiments, the urine protein excretion of the human decreases by at least about 30% compared to baseline after about 10 weeks of treatment. Insome embodiments, the urine protein excretion of the human decreases by at least about 30% compared to baseline after about 20 weeks of treatment.

[0134] In some embodiments, the urine albumin excretion of the subject is less than about 30 mg / day after treatment. Treatment can include administration of acoramidis, or a pharmaceutically acceptable salt thereof for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, or more weeks. In some embodiments, treatment includes administration of acoramidis, or a pharmaceutically acceptable salt thereof for about 5 to about 25 weeks. In some embodiments, treatment includes administration of acoramidis, or a pharmaceutically acceptable salt thereof for at least 10 to 20 weeks. In some embodiments, treatment includes administration of acoramidis, or a pharmaceutically acceptable salt thereof for about 10 weeks. In some embodiments, treatment includes administration of acoramidis, or a pharmaceutically acceptable salt thereof for about 20 weeks. In some embodiments, the subject is a human. In some embodiments, the urine albumin excretion of the human is less than about 30 mg / day after about 10 weeks of treatment. In some embodiments, the urine albumin excretion of the human is less than about 30 mg / day after about 20 weeks of treatment.

[0135] In some embodiments, the urine albumin excretion of the subject decreases by at least about 30% compared to baseline after treatment. Treatment can include administration of acoramidis, or a pharmaceutically acceptable salt thereof for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, or more weeks. In some embodiments, treatment includes administration of acoramidis, or a pharmaceutically acceptable salt thereof for about 5 to about 25 weeks. In some embodiments, treatment includes administration of acoramidis, or a pharmaceutically acceptable salt thereof for at least 10 to 20 weeks. In some embodiments, treatment includes administration of acoramidis, or a pharmaceutically acceptable salt thereof for about 10 weeks. In some embodiments, treatment includes administration of acoramidis, or a pharmaceutically acceptable salt thereof for about 20 weeks. In some embodiments, the subject is a human. In some embodiments, the urine albumin excretion of the human decreases by at least about 30% compared to baseline after about 10 weeks of treatment. In some embodiments, the urine albumin excretion of the human decreases by at least about 30% compared to baseline after about 20 weeks of treatment.

[0136] In some embodiments, the subject has chronic kidney disease (CKD). In some embodiments the subject has Stage 1 CKD, Stage 2 CKD, Stage 3 CKD, Stage 3a CKD, Stage 3b CKD, Stage 4 CKD, or Stage 5 CKD. In some embodiments, the subject does not progress to a higher Stage of CKD compared to baseline after about 28 days of administration. In some embodiments, the subject does not progress to a higher Stage of CKD compared to baseline after about 3 months of administration. In some embodiments, the subject does not progress to a higher Stage of CKD compared to baseline after about 6 months of administration. In some embodiments, the subject does not progress to a higher Stage of CKD compared to baseline after about 12 months of administration. In some embodiments, the subject does not progress to a higher Stage of CKD compared to baseline after about 18 months of administration. In some embodiments, the subject does not progress to a higher Stage of CKD compared to baseline after about 24 months of administration. In some embodiments, the subject does not progress to a higher stage of CKD compared to baseline after about 30 months of administration. In some embodiments, the subject moves to a lower stage of CKD compared to baseline after about 28 days of administration. In some embodiments, the subject moves to a lower Stage of CKD compared to baseline after about 3 months of administration. In some embodiments, the subject moves to a lower Stage of CKD compared to baseline after about 6 months of administration. In some embodiments, the subject moves to a lower Stage of CKD compared to baseline after about 12 months of administration. In some embodiments, the subject moves to a lower Stage of CKD compared to baseline after about 18 months of administration. In some embodiments, the subject moves to a lower Stage of CKD compared to baseline after about 24 months of administration. In some embodiments, the subject moves to a lower stage of CKD compared to baseline after about 30 months of administration. In some embodiments, the subject is a human.

[0137] In some embodiments, the subject is not in need of transthyretin (TTR) stabilization. In some embodiments, the subject does not have transthyretin amyloidosis (ATTR). In some embodiments, the subject does not have ATTR-cardiomyopathy (ATTR-CM). In some embodiments, the subject does not have ATTR-polyneuropathy (ATTR-PN). In some embodiments, the subject has not been diagnosed with transthyretin amyloidosis (ATTR). In some embodiments, the subject has not been diagnosed with ATTR-cardiomyopathy (ATTR- CM). In some embodiments, the subject has not been diagnosed with ATTR-polyneuropathy (ATTR-PN). In some embodiments, the subject is a human.Administration and Dosages

[0138] In some embodiments, the acoramidis or a pharmaceutically acceptable salt thereof is administered to the subject for about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 weeks. In some embodiments, the acoramidis or a pharmaceutically acceptable salt thereof is administered to the subject for about 1 to about 3, about 2 to about 4, about 3 to about 5, about 4 to about 6, about 5 to about 7, about 6 to about 8, about 7 to about 9, about 8 to about 10, about 9 to about 11, about 10 to about 12, about 11 to about 13, about 12 to about 14, about 13 to about 15, about 14 to about 16, about 15 to about 17, about 16 to about 18, about 17 to about 19, or about 18 to about 20 weeks. In some embodiments, the acoramidis or a pharmaceutically acceptable salt thereof is administered to the subject for about 1 week to about 20 weeks. In some embodiments, the acoramidis or a pharmaceutically acceptable salt thereof is administered to the subject for about 1 month, about 2 months, about 3 months, about 4 months, or about 5 months. In some embodiments, the acoramidis or a pharmaceutically acceptable salt thereof is administered to the subject for more than 5 months. In some embodiments, the subject is a human.

[0139] In some embodiments, the acoramidis or a pharmaceutically acceptable salt thereof is administered to the subject for at least about 1 , at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, or at least about 20 weeks. In some embodiments, the subject is a human.

[0140] In some embodiments, the acoramidis or a pharmaceutically acceptable salt thereof is administered to the subject for about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, or about 30 months. In some embodiments, the acoramidis or a pharmaceutically acceptable salt thereof is administered to the subject for about 1 to about 5 months, about 5 to about 10 months, about 10 to about 15 months, about 15 to about 20 months, about 20 to about 25 months, or about 25 to about 30 months. In some embodiments, the acoramidis or a pharmaceutically acceptable salt thereof is administered to the subject for about 1 to about 10 months, about 5 to about 15 months, about 10 to about 20months, about 15 to 25 months, or about 20 to about 30 months. In some embodiments, the acoramidis or a pharmaceutically acceptable salt thereof is administered to the subject for more than 30 months. In some embodiments, the subject is a human.

[0141] In some embodiments, the acoramidis or a pharmaceutically acceptable salt thereof is administered to the subject for at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, at least about 26, at least about 27, at least about 28, at least about 29, or at least about 30 months. In some embodiments, the subject is a human.

[0142] In some embodiments, Compound 1 or a pharmaceutically acceptable salt is administered for at least 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 days or longer. In some embodiments, Compound 1 or a pharmaceutically acceptable salt is administered for 7, 14, 21 , 28, 35, 42, 49, or 56 days. In some embodiments, Compound 1 or a pharmaceutically acceptable salt is administered for 28 days. In some embodiments, Compound 1 or a pharmaceutically acceptable salt is administered for 56 days. In some embodiments, Compound 1 or a pharmaceutically acceptable salt is administered for 84 days.

[0143] In some embodiments, Compound 1 or a pharmaceutically acceptable salt is administered for at least 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 months or more. In some embodiments, Compound 1 or a pharmaceutically acceptable salt is administered for 10, 15, 20, 25, 30, 35, 40, 45, or 50 months. In some embodiments, Compound 1 or a pharmaceutically acceptable salt is administered for 6 months. In some embodiments, Compound 1 or a pharmaceutically acceptable salt is administered for 12 months. In some embodiments, Compound 1 or a pharmaceutically acceptable salt is administered for 18 months. In some embodiments, Compound 1 or a pharmaceutically acceptable salt is administered for 24 months. In some embodiments, Compound 1 or a pharmaceutically acceptable salt is administered for 30 months. In someembodiments, Compound 1 or a pharmaceutically acceptable salt is administered for 36 months. In some embodiments, Compound 1 or a pharmaceutically acceptable salt is administered for 42 months.

[0144] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered chronically.

[0145] In some embodiments, the therapeutically effective amount is a total daily dosage of about 10 mg to 2,500 mg of the HC1 salt form of Compound 1. In some embodiments, the total daily dosage of the HC1 salt form of Compound 1 is about 10 mg to 50 mg, 50 mg to 300 mg, 50 mg to 150 mg, 150 mg to 800 mg, 800 mg to 1,600 mg or 1,600 mg to 2,500 mg. In some embodiments, the total daily dosage of the HC1 salt form of Compound 1 is about 10 mg to 50 mg. In some embodiments, the total daily dosage of the HC1 salt form of Compound 1 is about 50 mg to 300 mg. In some embodiments, the total daily dosage of the HC1 salt form of Compound 1 is about 50 mg to 150 mg. In some embodiments, the total daily dosage of the HC1 salt form of Compound 1 is about 150 mg to 800 mg. In some embodiments, the total daily dosage of the HC1 salt form of Compound 1 is about 800 mg to 1,600 mg. In some embodiments, the total daily dosage of the HC1 salt form of Compound 1 is about 1,600 mg to 2,500 mg. It is understood that in the present disclosure the amount of Compound 1 listed is the amount of HC1 salt form of Compound 1 administered unless otherwise indicated. A person of skill in the art would recognize that in order to administer the same amount of Compound 1 in free base or in a different salt form, small adjustments in overall amount administered may be necessary.

[0146] In some embodiments the total daily dosage of the HC1 salt form of Compound 1 is about 10 mg. In some embodiments the total daily dosage of the HO salt form of Compound 1 is about 25 mg. In some embodiments the total daily dosage of the HC1 salt form of Compound 1 is about 50 mg. In some embodiments the total daily dosage of the HC1 salt form of Compound 1 is about 1000 mg. In some embodiments the total daily dosage of the HC1 salt form of Compound 1 is about 150 mg. In some embodiments the total daily dosage of the HC1 salt form of Compound 1 is about 200 mg. In some embodiments the total daily dosage of the HC1 salt form of Compound 1 is about 300 mg. In some embodiments the total daily dosage of the HC1 salt form of Compound 1 is about 600 mg. In some embodiments the total daily dosage of the HC1 salt form of Compound 1 is about 800 mg. In some embodiments the total daily dosage of the HO salt form of Compound 1 is about 1 ,600 mg.In some embodiments the total daily dosage of the HC1 salt form of Compound 1 is about 2,500 mg.

[0147] In some embodiments, 800 mg of the HC1 salt form of Compound 1 or an equivalent amount of Compound 1 in free base form or in a different salt form is administered in the morning, and 800 mg the HC1 salt form of Compound 1 or an equivalent amount of Compound 1 in free base form or in a different salt form is administered in the evening. In some embodiments, 800 mg of the HC1 salt form of Compound 1 is administered in the morning, and 800 mg of the HC1 salt form of Compound 1 is administered in the evening. A person of ordinary skill in the art will recognize that 800 mg of the HC1 salt form of Compound 1 is equivalent to 712 mg of Compound 1 in free base form.

[0148] In some embodiments, the HC1 salt form of Compound 1 is administered. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is the HC1 salt form of Compound 1 , having the structure:(Compound 1»HC1).

[0149] In some embodiments, a free base form of Compound 1 is administered. In some embodiments, Compound 1 has the structure:

[0150] Compound 1 or a pharmaceutically acceptable salt thereof can be administered using any known means of administration known in the art. In some embodiments Compound 1 or a pharmaceutically acceptable salt thereof is administered orally.

[0151] Compound 1 or a pharmaceutically acceptable salt thereof can be administered once (SID or qd), twice (BID or ql2h), three (TID), or four times (QID) a day. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered once daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily. In some embodiments, Compound 1 or a pharmaceuticallyacceptable salt thereof is administered three times daily. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered four times daily.

[0152] In some embodiments, about 50 mg of the HC1 salt form of Compound I is administered once daily. In some embodiments, about 150 mg of the HC1 salt form of Compound 1 is administered once daily. In some embodiments, about 300 mg of the HC1 salt form of Compound 1 is administered once daily. In some embodiments, about 800 mg of the HC1 salt form of Compound 1 is administered once daily.

[0153] In some embodiments, about 100 mg of the HC1 salt form of Compound 1 is administered twice daily. In some embodiments, about 300 mg of the HC1 salt form of Compound 1 is administered twice daily. In some embodiments, about 400 mg of the HC1 salt form of Compound 1 is administered twice daily. In some embodiments, about 800 mg of the HC1 salt form of Compound 1 is administered twice daily.

[0154] In some embodiments, 800 mg of the HC1 salt form of Compound 1 or an equivalent amount of Compound 1 in free base form or in a different salt form is administered in the morning, and 800 mg the HC1 salt form of Compound 1 or an equivalent amount of Compound 1 in free base form or in a different salt form is administered in the evening. In some embodiments, 800 mg of the HC1 salt form of Compound 1 is administered in the morning, and 800 mg of the HC1 salt form of Compound 1 is administered in the evening. A person of ordinary skill in the art will recognize that 800 mg of the HC1 salt form of Compound 1 is equivalent to 712 mg of Compound 1 in free base form.

[0155] In some embodiments, the therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily as about 712 milligrams (mg) of Compound 1 in free base form or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount of Compound 1 , or a pharmaceutically acceptable salt thereof, is administered twice daily as about 712 milligrams (mg) of Compound 1 in free base form. In some embodiments, the therapeutically effective amount of Compound 1 , or a pharmaceutically acceptable salt thereof, is administered twice daily as about 800 milligrams (mg) of the HC1 salt form of Compound 1. A person of ordinary skill in the art will recognize that 800 mg the HC1 salt form of Compound 1 is equivalent to 712 mg Compound 1 in free base form.

[0156] In some embodiments, the therapeutically effective amount of acoramidis, or a pharmaceutically acceptable salt thereof, is administered twice daily as about 712 milligrams(mg) of free acoramidis or an equivalent amount of a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutically effective amount of acoramidis, or a pharmaceutically acceptable salt thereof, is administered twice daily as about 712 milligrams (mg) of free acoramidis. In some embodiments, the therapeutically effective amount of acoramidis, or a pharmaceutically acceptable salt thereof, is administered twice daily as about 800 milligrams (mg) of acoramidis hydrochloride. A person of ordinary skill in the art will recognize that 800 mg acoramidis hydrochloride is equivalent to 712 mg free acoramidis.Pharmaceutical Compositions

[0157] Compound 1 or a pharmaceutically acceptable salt can be prepared in various compositions suitable for delivery to a subject. A composition suitable for administration to a subject typically comprises Compound 1, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In some embodiments, the subject is a human.

[0158] The pharmaceutical compositions for the administration of Compound 1 or a pharmaceutically acceptable salt can conveniently be presented in unit dosage form and can be prepared by any of the methods known in the art of pharmacy and drug delivery. All methods include the step of bringing the active ingredient into association with a carrier containing one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.

[0159] Suitable formulations for use in the present invention are found in Remington: THE SCIENCE AND PRACTICE OF PHARMACY, 21st Ed., Gennaro, Ed., Lippincott Williams & Wilkins (2003), which is hereby incorporated herein by reference. The pharmaceutical compositions described herein can be manufactured in a manner that is known to those of skill in the art, i.e., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. The following methods and excipients are merely exemplary and are in no way limiting.

[0160] Compound 1 or a pharmaceutically acceptable salt can be incorporated into a variety of formulations for therapeutic administration. More particularly, Compound 1 or a pharmaceutically acceptable salt can be formulated into pharmaceutical compositions, together or separately, by formulation with appropriate pharmaceutically acceptable carriersor diluents, and can be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, pills, powders, granules, dragees, gels, slurries, ointments, solutions, suppositories, injections, inhalants and aerosols. As such, administration of a compound of the present invention can be achieved in various ways, including oral, buccal, parenteral, intravenous, intradermal (e.g., subcutaneous, intramuscular), transdermal, etc., administration. Moreover, Compound 1 or a pharmaceutically acceptable salt can be administered in a local rather than systemic manner, for example, in a depot or sustained release formulation.

[0161] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. Additionally, emulsions can be prepared with a non-water miscible ingredient such as oils and stabilized with surfactants such as mono-diglycerides, PEG esters and the like.

[0162] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy- propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n- propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0163] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

[0164] In some embodiments, pharmaceutical compositions of Compound 1 or a pharmaceutically acceptable salt are prepared as described in International Patent Application No. PCT / US2019 / 046789, filed August 16, 2019, or U.S. Patent No. 11,260,047, the contents of each are incorporated herein for all purposes.IV. Examples

[0165] The following examples are offered to illustrate, but not to limit, the claimed invention.Materials and Methods

[0166] The following general materials and methods were used, where indicated, or may be used in the Examples below:Determination of AGIO Blood Plasma Concentration

[0167] Human plasma containing AGIO and the internal standard, AGIO-De, was extracted using protein precipitation and analyzed by a Sciex API4000 LC-MS-MS equipped with an HPLC column. The peak area of the AGIO product ion was measured against the peak area of the AG10-D6 internal standard product ion. Quantitation was performed using a weighted 1 / x2linear least squares regression analysis generated from calibration standards prepared on the day of extraction.Fluorescent Probe Exclusion Assay (FPE)

[0168] Occupancy of Compound 1 in the thyroxine binding pocket of tetrameric TTR is determined by the ability of a fluorescent probe (Probe) to covalently bind to free tetrameric TTR binding sites in serum over a 6 hr. reaction time.

[0169] Aliquots of each serum sample are plated in 96 well plates. The fluorescence changes (kex= 328 nm and Xem = 384 nm) after addition of probe are monitored every 15 min using a fluorescent capable microplate for 6 hr. at RT.Western Blot for Evaluating Stabilization of Tetrameric TTR

[0170] Stabilization of the tetramer of TTR by Compound 1 is determined by comparing the amount of tetrameric TTR protein remaining after acid denaturation for 72 hr. to theinitial amount of tetrameric TTR protein as determined by densitometric measurement of western blot gels.

[0171] Blood plasma samples from the subject are diluted with acidification buffer (sodium acetate, KC1, EDTA, DTT, pH about 4.0) for both the 0 and 72 hour time point. Time 0 hr. samples are directly cross-linked with glutaraldehyde, and then quenched. 72 hr. samples are incubated at room temperature for 72 hr. and then cross-linked and quenched by the same protocol. All samples are then denatured by adding SDS gel loading buffer and boiled prior to gel loading. Each sample is separated in SDS -PAGE gels and analyzed by immunoblotting using anti-TTR antiserum (Polyclonal Rabbit Anti-Human Prealbumin. DAKO Cat# A0002). The density of all TTR bands are quantified using infrared LICOR imaging system or Fluorescence Imaging system and reported. Normalization by IgG band using LICOR 925-32232 or Invitrogen 84546.

[0172] In the Experiments, Tables, and Figures discussed in further detail below, nominal times of blood draw are used for all pharmacokinetic and pharmacodynamic data.Example 1: Phase 3 Clinical Study - ATTR-CM: ATTRibute-CM

[0173] This prospective, Phase 3, randomized, multicenter, parallel-group study will evaluate the efficacy and safety of Compound 1 in symptomatic subjects compared to placebo, administered on a background of stable heart failure therapy. Screening and randomization will be followed by a total of 30 months of blinded, placebo-controlled treatment. At the end of 12 months of treatment (Part A) efficacy of Compound 1 will be assessed through analyses of the functional (6MWT) and health-related QoL (as measured by HF-specific instrument KCCQ) endpoints. At the end of 30 months of treatment (Part B), efficacy of Compound 1 will be further assessed through analysis of All-cause mortality, cumulative frequency of CV-related hospitalization, change from baseline in NT-proBNP, and change from baseline in 6MWT.

[0174] Subjects are not allowed to be treated with any ATTR-CM specific therapy during the first 12 months of the study. If a subject chooses treatment with ATTR-CM specific therapy, they will be asked to complete an early termination visit prior to discontinuation / withdrawal.

[0175] If, during participation in the study, tafamidis becomes available for the indication of ATTR-CM and subjects have access to it, subjects will be permitted to initiate therapywith tafamidis as a concomitant medication if they have completed at least 12 months of blinded study therapy. Currently, tafamidis is approved for the treatment of ATTR-CM in some regions. Subjects initiating therapy with tafamidis indicated for ATTR-CM must have completed the Month 12 visit. If a subject plans to initiate therapy with tafamidis more than 7 days after the Month 12 visit or a later scheduled visit, that subject should have an unscheduled visit with study assessments prior to initiation of the concomitant therapy. No other approved or investigational treatments, or therapies used off-label or as nonprescription supplements for the treatment of ATTR-CM will be permitted at any time during the study.

[0176] If a subject chooses to discontinue investigational medicinal product (IMP), discontinue or withdraw from the trial at any time, they will be asked to complete an early termination visit and associated procedures. If a subject chooses to initiate treatment with another therapy, including tafamidis in the first 12 months of the study, they will be asked to complete an ET visit and associated procedures prior to discontinuation / withdrawal. Subjects will continue monthly telephone contact up to Month 30. All participating subjects will be asked to consent to determination of vital status (alive, death, heart transplant, receiving cardiac mechanical assist device [CMAD]) at Month 30, either via direct contact or through public records, regardless of discontinuation or withdrawal status. Unless precluded by governing law or regulation, consent for determination of vital status through public records may not be withdrawn.

[0177] All subjects who complete 30 months of blinded study therapy and the final assessments of the double-blind treatment period (Month 30 visit) may be eligible to participate in an Open Label Extension (OLE) study (Study AG 10-304, a separate protocol) of long-term Compound 1 treatment.

[0178] Eligible subjects will be randomized in a 2:1 ratio to Compound 1 HC1 (the HC1 salt form of Compound 1) 800 mg or matching placebo administered orally BID. Subjects will be stratified at randomization based on whether they have wild-type ATTR-CM (ATTRwt-CM) or mutant ATTR-CM (ATTRm-CM) with a target of 20% of subjects with ATTRm-CM. Subjects will also be stratified according to NT-proBNP level (< 3000 vs > 3000 pg / mL) and renal function defined by eGFR (> 45 vs < 45 mL / min / 1.73 m2) at Screening. Samples for plasma PK and serum / plasma PD will be collected in the PK-PD substudy.

[0179] Information on AEs and concomitant medications will be collected throughout the study. The safety and conduct of the study will be monitored by an independent Data Monitoring Committee (DMC).

[0180] A summary of the trial design in shown in FIG. 1.Inclusion CriteriaTo be eligible to participate in the study, subjects must meet all the following criteria:1. Have the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures.2. Male or female > 18 to < 90 years of age at time of randomization.3. Have an established diagnosis of ATTR-CM with either wild-type TTR or a variant TTR genotype (confirmed by genotyping) based on either:1. endomyocardial biopsy with confirmatory TTR amyloid typing by either mass spectrometry, immunoelectron microscopy, or immunohistochemistry; or2. positive technetium-99m (^^mTc)-pyrophosphate (PYP) or -bisphosphonate (DPD or HMDP / HDP) scan, combined with accepted laboratory criteria excluding a diagnosis of AL amyloidosis (based on both immunofixation electrophoresis (IFE) of serum and urine, and serum free light chain (sFLC) analysis).Subjects with concurrent monoclonal gammopathy of undetermined significance (MGUS) may require confirmation of the diagnosis of ATTR-CM by tissue biopsy with confirmatory TTR amyloid typing by either mass spectrometry, immunoelectron microscopy, or immunohistochemistry.4. Have a. a history of heart failure evidenced by at least one prior hospitalization for heart failure or b. clinical evidence of heart failure without prior heart failure hospitalization manifested by signs or symptoms of volume overload or elevated intracardiac pressures (e.g., elevated jugular venous pressure, shortness of breath or signs of pulmonary congestion on x-ray or auscultation, or peripheral edema) or c. heart failure symptoms that required or require ongoing treatment with a diuretic.5. Have NYHA Class I-III symptoms due to ATTR-CM.6. Female subjects of childbearing potential who engage in heterosexual intercourse must agree to use a highly effective method of contraception beginning with randomization and continuing for 30 days after the last dose of IMP. A male subject who is sexually active with a female of childbearing potential and has not had a vasectomy must agree to use a double-barrier method of birth control.7. Subjects taking cardiovascular medical therapy, with the exception of diuretic dosing, must be on stable doses (defined as no greater than 50% dose adjustment and no categorical changes of medications) for at least 2 weeks prior to Screening.8. Have completed > 150 m on the 6MWT on at least 2 tests > 24 hours to < 3 weeks apart and prior to randomization. The distance walked must be within 15% on two tests.If one of the first two tests is not > 150 m or the first two tests are not within 15% of distance walked, a third test must be conducted < 3 weeks of the first test. If the third test is still not > 150 m or within 15% of one of the first two tests, the subject will not be eligible for participation.9. Must have NT-proBNP levels > 300 pg / mL at Screening.10. Must have LV wall (interventricular septum or LV posterior wall) thickness > 12 mm as measured by transthoracic echocardiogram (ECHO) or cardiac magnetic resonance (CMR) documented in medical history within 10 years of Screening or at Screening ECHO or CMR.Exclusion Criteria

[0181] Subjects who meet any of the following criteria at the Screening visit will not be eligible to participate in the study:1. Acute myocardial infarction, acute coronary syndrome or coronary revascularization within 90 days prior to Screening.2. Stroke or transient ischemic attack (TIA) within 90 days prior to Screening.3. Has hemodynamic instability at Screening or Randomization that, in the judgment of the Investigator, would pose too great a risk for participation in the study.4. Is likely to undergo heart transplantation within a year of Screening.5. Has confirmed diagnosis of light-chain (AL) amyloidosis.6. Has abnormal liver function tests at Screening, defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 x upper limit of normal (ULN) or total bilirubin > 3 x ULN.7. Has NT-proBNP levels > 8500 pg / mL at Screening.8. Has estimated glomerular filtration rate (eGFR) by modification of diet for renal disease (MDRD) formula < 15 mL / min / 1.73 nr at Screening.9. Known hypersensitivity to IMP (Compound 1 or placebo), its metabolites, or formulation excipients.10. Treatment for ATTR-CM with tafamidis, with marketed drug products lacking a labeled indication for ATTR-CM (e.g., diflunisal, doxycycline), or with natural products or derivatives used as unproven therapies for ATTR-CM (e.g., green tea extract, tauroursodeoxycholic acid [TUDCA] / ursodiol) within 14 days prior to dosing; treatment with patisiran, inotersen, or other gene silencing agent: within 90 days for patisiran, 180 days for inotersen, and 5 half-lives for any other gene silencing agent, prior to dosing.If, during participation in the study, subjects gain access to tafamidis, they will be permitted to initiate therapy with tafamidis as a concomitant medication if they have completed at least 12 months of blinded study therapy.11. Requires treatment with calcium channel blockers with conduction system effects (e.g., verapamil, diltiazem). The use of dihydropyridine calcium channel blockers is allowed. The use of digitalis will only be allowed if required for management of atrial fibrillation with rapid ventricular response.12. Females who are pregnant or breastfeeding. Lactating females must agree to discontinue nursing before IMP is administered. A negative urine pregnancy test at Screening and at Randomization are required for female subjects of childbearing potential.13. In the judgment of the Investigator or Medical Monitor, has any clinically important ongoing medical condition or laboratory abnormality or condition that might jeopardize the subject’s safety, increase their risk from participation, or interfere with the study.14. Participation in another investigational clinical trial within 30 days prior to dosing with potential residual effects that might confound the results of this study. Participation in observational and / or registry studies should be discussed with the Medical Monitor.15. Has any condition that, in the opinion of the Investigator or Medical Monitor, would preclude compliance with the study protocol such as a history of substance abuse, alcoholism or a psychiatric condition.Subject Population and Stratification

[0182] Approximately 510 males and females > 18 and < 90 years of age (at time of randomization) with chronic, stable, symptomatic (NYHA Class I-III) ATTR-CM will be randomized in a 2:1 ratio (340 subjects to active treatment, 170 to matching placebo) in the study. Subjects will be stratified at randomization based on whether they have ATTRwt-CM or ATTRm-CM with a target of 20% of subjects with ATTRm-CM. Subjects will also be stratified according to NT-proBNP level (< 3000 vs > 3000 pg / mL) and renal function defined by eGFR (> 45 vs < 45 mL / min / 1.73 m2) at Screening.Duration of Treatment

[0183] Subjects will be treated with the IMP (Compound 1 or placebo) for 30 months. IMP may be discontinued without discontinuing / withdrawing from the study.

[0184] Part A and Part B will be reported separately. All subjects who complete 30 months of blinded study therapy and the final assessments of the double-blind treatment period may be eligible to participate in an Open Label Extension (OLE) study (Study AGIO-304, a separate protocol) of long-term Compound 1 treatment.Treatments Administered

[0185] Subjects who meet eligibility criteria will be randomized in a 2:1 manner (Compound 1 :placebo) to receive the following treatment arms in a double-blind fashion:• 800 mg Compound 1 hydrochloride (HC1) BID, orally (two 400 mg Compound 1 HC1 tablets (equivalent to 356 mg Compound 1), BID)• Matching placebo BID, orally (two matching placebo tablets, BID)Prohibited Medications

[0186] Use of patisiran, inotersen, tafamidis (see Note below) or any other approved or investigational agent for the treatment of ATTR-CM is prohibited during the study.

[0187] Use of marketed drug products lacking a labeled indication for ATTR-CM (e.g., diflunisal, doxycycline) or of natural products or derivatives used as unproven therapies forATTR-CM (e.g., green tea extract, tauroursodeoxycholic acid [TUDCA] / ursodiol) is prohibited.

[0188] Use of calcium channel blockers with conduction system effects (e.g., verapamil, diltiazem) is prohibited. Use of dihydropyridine calcium channel blockers is allowed. The use of digitalis will only be allowed if required for management of atrial fibrillation with rapid ventricular response.

[0189] Note: If, during participation in the study, tafamidis becomes available for the indication of ATTR-CM and subjects have access to it, subjects will be permitted to initiate therapy with tafamidis as a concomitant medication if they have completed at least 12 months of blinded study therapy. (Currently, tafamidis is approved for the treatment of ATTR-CM in some regions.) Subjects initiating therapy with tafamidis indicated for ATTR-CM must have completed the Month 12 visit. If a subject plans to initiate therapy with tafamidis more than 7 days after the Month 12 visit or a later scheduled visit, they should have an unscheduled visit with study assessments prior to initiation of the concomitant therapy.Study ProceduresSchedule of Assessments

[0190] The descriptions of the procedures to be performed throughout the study are provided below.Screening (Day -35 to Day -1)

[0191] Screening will be performed within < 35 days before administration of the first dose of IMP. The following procedures will be performed at Screening:• Informed consent administration• Review Inclusion / Exclusion criteria to confirm subject is eligible• Confirm genotype either through existing documentation or testing during Screening. Genotyping must be confirmed prior to randomization.• Submission of source documents required for the Diagnostic Confirmation Committee (DCC) should be completed as early as possible during the Screening period and must include either:- endomyocardial biopsy report with confirmatory TTR amyloid typing by either mass spectrometry, immunoelectron microscopy, or immunohistochemistry ;OR- positive "mTc-PYP or -bisphosphonate (DPD or HMDP / HDP) scan,- AND clinical laboratory evidence excluding the diagnosis of AL amyloidosis (based on both IFE of serum and urine, and sFLC analysis);- Subjects with concurrent MGUS may require confirmation of the diagnosis of ATTR-CM by tissue biopsy with confirmatory TTR amyloid typing by either mass spectrometry, immunoelectron microscopy, or immunohistochemistry.• Medical and surgical history assessment• NYHA Class assessment• Physical examination including body weight and height measurements• Vital signs assessment• 12-lead resting ECG (in a supine position after a 5-minute rest)• Resting transthoracic ECHO or CMR, if LV wall (interventricular septum or LV posterior wall) thickness not documented in medical history within 10 years of Screening based on ECHO or CMR• Six-Minute Walk Test (6MWT), two assessments > 24 hours to < 3 weeks apart. If one of the first two tests is not > 150 m or the first two tests are not within 15% of distance walked, a third test must be conducted < 3 weeks of the first test. If the third test is still not > 150 m or within 15% of one of the first two tests, the subject will not be eligible for participation• Blood sample collection for hematology, serum chemistry (including circulating biomarkers), urinalysis• Blood sample collection for serum and plasma exploratory tests• Urine pregnancy test, for female subjects of childbearing potential only• Prior and concomitant medication use assessmentTreatment Days

[0192] Study procedures are listed below by study day, ideally performed in the order listed below, for each day.

[0193] Screening safety assessments completed on the same day as Day 1 (e.g., physical exam, vital signs, ECG, clinical laboratory tests) may be used as Day 1 assessments at the investigator’s discretion provided that they are predose.Day 1 and Repeated Assessments

[0194] These assessments will occur in-clinic at Day 1 and Months 3, 6, 9, 15, 18, 21, 24, and 27 (±7 Days):• Review Inclusion / Exclusion criteria to confirm subject is eligible (Day 1)• Randomize subject to treatment arm and assign randomization number (Day 1)• NYHA Class assessment• Physical examination including body weight measurement• Vital signs assessment• 12-lead resting ECG (in a supine position after a 5-minute rest)• KCCQ• EQ-5D-5L• 6MWT• Blood sample collection for hematology, serum chemistry (including circulating biomarkers), urinalysis• Urine pregnancy test, for female subjects of childbearing potential only• PD blood sample collection for analysis of TTR stabilization (predose) in PK-PD substudy• PK blood sample collection (predose) in PK-PD substudy• Prealbumin blood sample collection (predose)• Dispense / collect and administer IMP with designated witness (i.e., site personnel)• Concomitant medication use assessment• AE / Vital status assessment / Hospitalization determination• IMP compliance assessment (all visits except Day 1)Day 28 (±3 Days)• NYHA Class assessment• Physical examination including body weight measurement• Vital signs assessment• 12-lead resting ECG at predose (in a supine position after a 5-minute rest) and at 1-hour postdose• Blood sample collection for hematology, serum chemistry (including circulating biomarkers), urinalysis• Urine pregnancy test, for female subjects of childbearing potential only• PD blood sample collection for analysis of TTR stabilization (predose and at 1 - hour postdose) in PK-PD substudy• PK blood sample collection (predose and at 1 -hour postdose) in PK-PD substudy• Prealbumin blood sample collection (predose)• Dispense / collect and administer IMP with designated witness (i.e., site personnel)• Concomitant medication use assessment• AE / Vital status assessment / Hospitalization determination• IMP compliance assessmentMonth 12 (±7 Days)• NYHA Class assessment• Physical examination including body weight measurement• Vital signs assessment• 12-lead resting ECG (in a supine position after a 5-minute rest)• KCCQ• EQ-5D-5L• 6MWT• Blood sample collection for hematology, serum chemistry (including circulating biomarkers), urinalysis• Urine pregnancy test, for female subjects of childbearing potential only• PD blood sample collection for analysis of TTR stabilization (predose) in PK-PD substudy• PK blood sample collection (predose) in PK-PD substudy• Prealbumin blood sample collection (predose)• Dispense / collect and administer IMP with designated witness (i.e., site personnel)• Concomitant medication use assessment• AE / Vital status assessment / Hospitalization determination• IMP compliance assessmentMonthly Telephone Contact (+7 Days)

[0195] These telephone contacts will occur during months without scheduled in clinic visits(e.g., Months 2, 4, 5, 7, 8, 10, 11, 13, 14, 16, 17, 19, 20, 22, 23, 25, 26, 28, and 29):• Concomitant medication use assessment• AE / Vital status assessment / Hospitalization determination• IMP compliance assessment

[0196] Subjects who discontinue IMP may be asked to continue monthly phone contacts and determination of vital status at Month 30.Month 30 ( ±7 Days)• NYHA Class assessment• Physical examination including body weight measurement• Vital signs assessment• 12-lead resting ECG (in a supine position after a 5-minute rest)• KCCQ• EQ-5D-5L• 6MWT• Blood sample collection for hematology, serum chemistry (including circulating biomarkers), urinalysis• Urine pregnancy test, for female subjects of childbearing potential only• PD blood sample collection for analysis of TTR stabilization (predose) in PK-PD substudy• PK blood sample collection (predose) in PK-PD substudy• Prealbumin blood sample collection (predose)• Collect IMP with designated witness (i.e., site personnel)• Concomitant medication use assessment• AE / Vital status assessment / Hospitalization determination• IMP compliance assessment

[0197] Subjects who complete the 30-months of double-blinded study treatment and the Month 30 visit assessments, may be eligible to enroll into the OLE study (AGIO-304).Subjects who are planning to enroll in Study AGIO-304 should take the evening dose of IMP the day before the Month 30 visit and should not take the morning dose on the day of the Month 30 visit.Follow-up 30 days After Last Dose of IMP (± 7 Days)

[0198] Subjects who complete the Month 30 visit will have a visit 30 days (± 7 days) after the last dose of IMP. Subjects who choose to enroll in the OLE Study (AGIO-304) the same day as completing the Month 30 visit in ATTRibute-CM (also referred to as Study AG 10- 301) will not be required to have the 30-day follow-up visit (in Study AG10-301). The following procedures will be performed:• NYHA Class assessment• Physical examination including body weight measurement• Vital signs assessment• 12-lead resting ECG (in a supine position after a 5-minute rest)• Blood sample collection for hematology, serum chemistry, urinalysis• Urine pregnancy test, for female subjects of childbearing potential only• Concomitant medication use assessment• AE / Vital status assessment / Hospitalization determination

[0199] Any clinically relevant findings obtained during the final examination, including clinically relevant laboratory abnormalities and the manner in which they are treated, will be followed until the condition returns to pre-study status, has resolved or stabilized, or has been determined to be unrelated to the IMP.Drug Concentration MeasurementsPK Blood Draw Schedule

[0200] In a subgroup of subjects at participating sites, PK samples will be collected at the following times to determine Compound 1 plasma concentrations:• Day 1 : Predose• Day 28: Predose and 1-hour postdose• Months 3 - 27 : Predose• Month 12: Predose• Month 30: Predose• ET• Unscheduled visit (e.g., Investigator’s discretion)PD Blood Draw Schedule

[0201] In a subgroup of subjects at participating sites, PD properties of Compound 1 will be assessed by established assays of TTR stabilization, including fluorescent probe exclusion (FPE) assay and Western blot. Sampling will be done at the following times to perform these PD assays:• Day 1 : Predose• Day 28: Predose and 1-hour postdose• Months 3 - 27 : Predose• Month 12: Predose• Month 30: Predose• ET• Unscheduled visit (e.g., Investigator’s discretion)Prealbumin Blood Sampling ProceduresTo measure prealbumin concentrations, blood sampling will be done at the following times:• Day 1 : Predose• Day 28: Predose• Months 3 - 27: Predose• Month 12: Predose• Month 30: Predose• ET• Unscheduled visit (e.g., Investigator’s discretion)Six-Minute Walk Test (6MWT)

[0202] Prior to randomization, two 6MWTs will be conducted > 24 hours to < 3 weeks apart. The walking distances must be > 150 meters and the distance walked must be within 15% on two tests on different days. If one of the first two tests is not > 150 m or the first two test results are not within the 15% of distance walked, a third test must be conducted < 3 weeks of the first test. If the third test is still not > 150 m or within 15% of one of the first two tests, the subject will not be eligible for participation.

[0203] If the subject has a need for a walking aid (e.g., cane) or supplemental oxygen at baseline, it must be used consistently at each subsequent 6MWT throughout the study. If asubject develops a need for a walking aid (e.g., cane) or supplemental oxygen after baseline, it must be used consistently at each subsequent 6MWT throughout the study.

[0204] The 6MWT should be conducted after completion of the KCCQ and EQ-5D-5L at the visits where required.

[0205] The 6MWT with Borg Scale will be conducted based on the guidelines of the American Thoracic Society with appropriate modifications for the subject population. Complete details on the procedures for the 6MWT are provided in a Study Procedures Manual.Kansas City Cardiomyopathy Questionnaire (KCCQ)

[0206] The KCCQ is a 23-item questionnaire developed to measure health status and health-related quality of life (QoL) in subjects with heart failure. Items include heart failure symptoms, impact on physical and social functions, and how their heart failure impacts their quality of life. It should be completed by the subject at predose. Complete details are provided in a Study Procedures Manual.EuroQoL-5 Dimensions (EQ-5D-5L)

[0207] EQ-5D-5L is a brief, self-administered generic health status instrument that takes about 5 minutes to complete and should be conducted after completion of the KCCQ. The instrument includes two parts. In the first part, respondents are asked to rate their current health state on 5 dimensions (mobility, self-care, usual activities, pain or discomfort, and anxiety or depression) with each dimension having five levels of function (1-no problem, 2- slight problem, 3-moderate problem, 4-severe problem, and 5-extreme problem). The second part is a respondent’s self-rating of current health status on a EuroQol- Visual Analog Scale (EQ VAS) with endpoints labeled “best imaginable health state” (score of 100) and “worst imaginable health state” (score of 0). The scores from the 5 dimensions may be used to calculate a single index value, also known as a utility score. Complete details administration and scoring are provided in a Study Procedures Manual.Clinical Laboratory Determinations

[0208] Blood and urine samples for clinical laboratory tests will be collected at the times detailed in the Schedule of Assessments. At Screening, the Investigator will assess the clinical relevance of any values outside the reference ranges provided by the laboratory, and subjects with abnormalities judged to be clinically relevant will be excluded from the study.Additional information on laboratory tests performed can be found in the supplementary Laboratory Manual.

[0209] The following clinical laboratory tests will be performed:Vital Signs

[0210] Vital signs will be assessed at the times detailed in the Schedule of Assessments).Study center personnel will assess vital signs predose after a 5-minute rest. The investigator will determine whether abnormal vital signs are clinically relevant. Any abnormal vital sign that is deemed clinically relevant by the Investigator (e.g., is associated with symptoms and / or requires medical intervention) will be recorded as an AE. Electrocardiograms

[0211] A standard 12-lead ECG will be assessed at the times detailed in the Schedule of Assessments. ECGs will be performed in the supine position after a 5-minute rest at predose and 1-hour postdose on Day 28.

[0212] The Investigator or qualified Sub-Investigator will review all ECG interpretations and interval duration measurements for clinical relevance. Any ECG interpretation deemed to be clinically relevant (e.g., is associated with symptoms and / or requires medical intervention) will be reported as an AE.Physical Examinations

[0213] At the times detailed in the Schedule of Assessments, subjects will undergo a complete physical examination (PE) including body weight and height measurements, which is to be completed by a physician or an appropriately trained health professional. Any abnormal physical examination finding that is deemed clinically relevant by the Investigator (e.g., is associated with symptoms and / or requires medical intervention) will be recorded as an AE.Definition of Cardiac Mechanical Assist Device, Cardiovascular-related Hospitalization and Events of Clinical Interest

[0214] In this study, CMAD and heart transplant are included in the “All-cause mortality” component of the primary endpoint for Part B, and therefore should be collected for all randomized patients even if they discontinued treatment permanently or withdrew consent. CMAD is defined as a durable CMAD implanted in a patient with end-stage heart failure as a bridge to transplant or as a destination therapy. Temporary cardiac mechanical support (i.e., those interventions that can only be employed in the inpatient setting, e.g., Intra-Aortic Balloon Pump [IABP], Impella, or Extra-corporeal membrane oxygenation [ECMO]) are not considered CMAD. In addition, other cardiac interventions such as pacemaker, implantable cardioverter defibrillator (ICD), cardiac resynchronization therapy (CRT), percutaneous coronary intervention (PCI), coronary artery bypass surgery (CABG), valvular percutaneous intervention or surgery are not considered CMAD.

[0215] A CV-related hospitalization is defined as a non-elective admission to an acute care setting for CV-related morbidity that results in > 24 hours stay (or a date change if the time of admission / discharge is not available).

[0216] EOCI is defined as medical visits (e.g., emergency department / ward, urgent care clinic, day clinic, etc.) of < 24 hours where diagnosis and interventions indicate that the purpose of the visit was for intravenous diuretic therapy for management of decompensated heart failure. EOCI are considered as part of the efficacy endpoint of Part B CV-related hospitalizations.

[0217] The Investigator is responsible for ensuring potential study endpoints, including dates of admissions and discharge, are collected and well documented for adjudication purposes (this includes but is not limited to: admission notes describing signs and symptoms, cardiology or other relevant clinical notes, hospital discharge summary); for providing Investigator assessment whether the hospitalization is CV-related; and for submitting the SAE Form for all AEs that result in deaths or hospitalizations.Example 2; Sub-Analysis Comparing Compound 1 and Placebo in Stage 4 CKD

[0218] Patients with eGFR <30 mL / min / 1.73 m2(Stage 4 CKD) were enrolled in the trial described in Example 1 to explore safety and potential efficacy in this high-risk subpopulation. The results from subpopulation were not included in earlier reports describing outcomes in ATTRibute-CM, and for efficacy for both Parts A and B, the primary analysis population excluded subjects with baseline eGFR < 30 mL / min / 1.73 m2.

[0219] The composition of the Stage 4 CKD participants is illustrated in FIG. 2.

[0220] Baseline characteristics of the Stage 4 CKD population and eGFR >30 mL / min / 1.73 m2population are shown in Table 1, below:Table 1: Baseline Characteristics of the mITT and the High-RiskStage 4 CKD Populations

[0221] Measurements of all-cause mortality over the 30-month trial in the High-Risk Stage 4 CKD Population (eGFR <30 mL / min / 1.73 m2) and the eGFR >30 mL / min / 1.73 m2population are show in Table 2, below:Table 2: Baseline Characteristics of the mITT and the High-Risk Stage 4 CKD Populations

[0222] In high-risk participants with stage 4 CKD, treatment with Compound 1 was associated with 25% fewer observed deaths at Month 30 versus placebo, consistent with the observations in the eGFR >30 mL / min / 1.73 m2population, and with no safety signals of potential clinical concern.

[0223] This study is the first ATTR-CM outcomes study to include participants with eGFR<25 mL / min / 1.73 m2.Example 3; Renal Protective Effect

[0224] In the ATTRibute-CM Phase 3 clinical study described in Example 1 (also referred to as Study AG10-301), 421 patients received acoramidis (800 mg acoramidis hydrochloride twice daily) and 211 patients received placebo. In the acoramidis group, the mean serum creatinine at baseline was 1 10.0 pmol / L and the mean eGFR was 60.9 mL / min / 1 .73 m2. In the placebo group, the mean serum creatinine at baseline was 109.0 pmol / L and the mean eGFR was 61.0 mL / min / 1.73 m2. At Day 28, there was a change from baseline in the mean serum creatinine and eGFR that was greater in the acoramidis group (observed values on Day 28 serum creatinine: 129.3 pmol / L, eGFR: 52.4 mL / min / 1.73 m2) compared with the placebo group (observed values on Day 28 serum creatinine: 110.6 pmol / L, eGFR: 60.0 mL / min / 1.73 m2). After Day 28, serum creatinine and eGFR remained stable for patients receiving acoramidis for the remainder of the study.

[0225] There was a progressive rise in serum creatinine, and corresponding progressive decrease in eGFR, in the placebo group from baseline through Month 30. At Month 30, serum creatinine was 123.4 pmol / L (eGFR: 55.1 mL / min / 1.73 m2) and 117.2 pmol / L (eGFR: 57.2 mL / min / 1.73 m2) for acoramidis and placebo respectively. These changes in serum creatinine concentrations over time are shown in FIG. 3. The observed increase in serum creatinine, and corresponding decrease in eGFR, observed in acoramidis treated patients was non-progressive and reversible upon interruption of therapy. These findings are summarized in Table 3.Table 3: Renal effects of acoramidis in ATTRibute-CM

[0226] ATTRibute-CM also observed favorable profiles for both UACR and urine albumin excretion after 28 days and 30 months. These findings are summarized in Tables 4 and 5.Table 4. Shift for urine albumin / creatinine (g / mol) results from baseline by visit inATTRibute-CM at Day 281 : Baseline is the last assessment obtained before the first dose of acoramidis or placebo.2: Normal: UACR <3 g / mol (normal / minimally increased); Moderate: UACR 3 - 30 g / mol (moderate or “microalbuminuria’"); Severe: UACR > 30 g / mol (severe or‘ ‘macroalbuminuria”) . Table 5: Shift for urine albumin / creatinine (g / mol) results from baseline by visit inATTRibute-CM at 30 months1 : Baseline is the last assessment obtained before the first dose of acoramidis or placebo. 2: Normal: UACR <3 g / mol (normal / minimally increased); Moderate: UACR 3 - 30 g / mol (moderate or “microalbuminuria”); Severe: UACR > 30 g / mol (severe or ‘ ‘macroalbuminuria”) .

[0227] Worsening kidney function, both acute and chronic, is strongly associated with higher mortality and poor cardiovascular (CV) outcomes, especially heart failure hospitalizations (Hillege et al. 2006, Damman et al. 2009). In ATTRibute-CM, CV outcomes (including heart failure hospitalizations and cardiovascular mortality) and all-cause mortality were lower in the acoramidis group versus placebo group, suggesting that there was no apparent adverse effect of the observed creatinine changes on these clinical outcomes. The favorable profiles for both UACR and urine albumin excretion (a marker of kidney injury) compared to placebo, lack of greater creatinine effects in participants with lower levels of baseline kidney function (i.e., eGFR < 60 mL / min / 1.73 m2), lack of evidence of worse kidney outcomes, and significantly improved CV outcomes and survival in participants treated with acoramidis (versus placebo) are, taken together, not consistent with kidney injury. These findings are consistent with a renal hemodynamic effect, and thus indicative of improved long-term cardiac and renal outcomes.

[0228] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications may be practiced within the scope of theappended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference. Where a conflict exists between the instant application and a reference provided herein, the instant application shall dominate.SEQUENCES<210> SEQ ID NO: 1<211 > LENGTH: 127<212> TYPE: PRT<213> ORGANISM: Homo sapiensYoshikazu et al. J. Biol. Chem. (1974) 249(21):6796-805<400> SEQUENCE: 1GPTGTGESKCPLMVKVLDAVRGSPA 25INVAVHVFRKAADDTWEPFASGKTS 50ESGELHGLTTEEEFVEGIYKVEIDT 75KSYWKALGI SPFHEHAEWFTANDS 100GPRRYTIAALLSPYSYSTTAWTNP 125KE 127

Claims

1. WHAT IS CLAIMED IS:

1. A method of treating transthyretin (TTR) amyloidosis, the method comprising administering to a human in need thereof a therapeutically effective amount of Compound 1 , having the formula:(Compound 1) or a pharmaceutically acceptable salt thereof, wherein the human has impaired renal function.

2. The method of claim 1, wherein the impaired renal function is determined by the human’s diagnosis with Stage 4 or Stage 5 chronic kidney disease (CKD).

3. The method of claim 1, wherein the impaired renal function is determined by the human’s diagnosis with Stage 4 chronic kidney disease (CKD).

4. The method of claim 1, wherein the impaired renal function is determined by the human’s diagnosis with Stage 5 chronic kidney disease (CKD).

5. The method of claim 1, wherein the human has an eGFR of < 30 mL / min / 1.73 m2.

6. The method of claim 1, wherein the human has an eGFR of < 25 mL / min / 1.73 m2.

7. The method of claim 1, wherein the human has an eGFR of < 20 mL / min / 1.73 m2.

8. The method of any one of claims 1 to 7, wherein the therapeutically effective amount is a total daily dosage of about 10 mg to 2,500 mg of the HC1 salt form of Compound 1 or an equivalent amount of Compound 1 in free base form or in a different salt form.

9. The method of any one of claims 1 to 7, wherein the therapeutically effective amount is a total daily dosage of about 800 mg to 1,600 mg of the HC1 salt form of Compound 1 or an equivalent amount of Compound 1 in free base form or in a different salt form.

10. The method of any one of claims 1 to 7, wherein the therapeutically effective amount is a total daily dosage of about 1,600 mg of the HC1 salt form of Compound 1 or an equivalent amount of Compound 1 in free base form or in a different salt form.

11. The method of any one of claims 1 to 7, wherein the therapeutically effective amount is a total daily dosage of about 10 mg to 2,500 mg of the HC1 salt form of Compound 1.

12. The method of any one of claims 1 to 7, wherein the therapeutically effective amount is a total daily dosage of about 800 mg to 1,600 mg of the HC1 salt form of Compound 1.

13. The method of any one of claims 1 to 7, wherein the therapeutically effective amount is a total daily dosage of about 1,600 mg of the HC1 salt form of Compound 1.

14. The method of any one of claims 1 to 7, wherein the therapeutically effective amount of Compound 1 , or a pharmaceutically acceptable salt thereof, is administered twice daily as about 712 milligrams (mg) of Compound 1 in free base form or an equivalent amount of a pharmaceutically acceptable salt thereof.

15. The method of any one of claims 1 to 7, wherein the therapeutically effective amount of Compound 1 , or a pharmaceutically acceptable salt thereof, is administered twice daily as about 712 milligrams (mg) of Compound 1 in free base form.

16. The method of any one of claims 1 to 7, wherein the therapeutically effective amount of Compound 1 , or a pharmaceutically acceptable salt thereof, is administered twice daily as about 800 milligrams (mg) of the HC1 salt form of Compound 1.

17. The method of any one of claims 1 to 14 or 16, wherein the pharmaceutically acceptable salt of Compound 1 is the HC1 salt form of Compound 1 , having the structure:(Compound 1*HC1).Eidos Docket No. Eidos-8.WO118. The method of any one of claims 1 to 15, wherein Compound 1 has the structure:(Compound 1).

19. The method of any one of claims 1 to 18, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered orally.

20. The method of any one of claims 1 to 19, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered once daily.

21. The method of any one of claims 1 to 19, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily.

22. The method of any one of claims 1 to 21, wherein the TTR amyloidosis is a disease or condition selected from the group consisting of familial amyloid polyneuropathy, familial amyloid cardiomyopathy, senile systemic amyloidosis, central amyloidosis, ocular amyloidosis, Leptomeningeal amyloidosis, oculoleptomeningeal amyloidosis, vitreous amyloidosis, gastrointestinal amyloidosis, neuropathic amyloidosis, non-neuropathic amyloidosis, non-hereditary amyloidosis, reactive / secondary amyloidosis, and cerebral amyloidosis.

23. The method of any one of claims 1 to 21, wherein the TTR amyloidosis is transthyretin amyloidosis (ATTR) cardiomyopathy (ATTR-CM).

24. The method of claim 23, wherein the ATTR cardiomyopathy is wildtype ATTR cardiomyopathy (ATTRwt-CM).

25. The method of claim 23, wherein the ATTR cardiomyopathy is familial ATTR cardiomyopathy (ATTRm-CM).

26. The method of any one of claims 23 to 25, wherein administration of a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereofin a human with ATTR cardiomyopathy decreases the frequency of cardiovascular-related hospitalizations as compared to humans not receiving treatment.

27. The method of any one of claims 23 to 26, wherein administration of a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof in a human with ATTR cardiomyopathy decreases mortality rate as compared to humans not receiving treatment.

28. The method of any one of claims 1 to 21, wherein the TTR amyloidosis is transthyretin amyloidosis (ATTR) polyneuropathy (ATTR-PN).

29. The method of claim 28, wherein the ATTR polyneuropathy is wildtype ATTR polyneuropathy (ATTRwt-PN).

30. The method of claim 28, wherein the ATTR polyneuropathy is familial ATTR polyneuropathy (ATTRm-PN).

31. The method of any one of claims 1 to 30, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered chronically.

32. The method of any one of claims 1 to 31, further comprising administering to the human a diuretic therapy agent.

33. The method of claim 32, wherein the diuretic therapy agent is furosemide or torsemide.

34. A method of stabilizing kidney function, the method comprising administering a therapeutically effective amount of acoramidis, or a pharmaceutically acceptable salt thereof, to a human in need thereof.

35. The method of claim 34, wherein the human has chronic kidney disease (CKD).

36. The method of claim 35, wherein the human does not progress to a higher Stage of CKD compared to baseline after 28 days of administration.

37. The method of claim 35 or 36, wherein the human does not progress to a higher Stage of CKD compared to baseline after 3, 6, 12, 18, 24, or 30 months of administration.

38. The method of any one of claims 35 to 37, wherein the human moves to a lower Stage of CKD compared to baseline after 28 days of administration.

39. The method of any one of claims 35 to 38, wherein the human moves to a lower Stage of CKD compared to baseline after 3, 6, 12, 18, 24, or 30 months of administration.

40. The method of any one of claims 34 to 39, wherein the eGFR of the human decreases by less than about 15% compared to baseline after 28 days of administration.

41. The method of any one of claims 34 to 39, wherein the eGFR of the human decreases by about 13.9% compared to baseline after 28 days of administration.

42. The method of any one of claims 34 to 39, wherein the eGFR of the human decreases by about 9.5% compared to baseline after 30 months of administration.

43. The method of any one of claims 34 to 39, wherein the eGFR of the human remains substantially unchanged compared to baseline after 28 days of administration.

44. The method of claim 43, wherein the eGFR of the human remains substantially unchanged compared to baseline after 3, 6, 12, 18, 24, or 30 months of administration.

45. The method of any one of claims 34 to 44, wherein the serum creatinine concentration of the human increases by about 17.5% compared to baseline after 28 days of administration.

46. The method of any one of claims 34 to 44, wherein the serum creatinine concentration of the human increases by about 12.2% compared to baseline after 30 months of administration.

47. The method of any one of claims 34 to 46, wherein the therapeutically effective amount of acoramidis, or a pharmaceutically acceptable salt thereof, is administered twice daily as about 712 milligrams (mg) of free acoramidis or an equivalent amount of a pharmaceutically acceptable salt thereof.

48. The method of any one of claims 34 to 46, wherein the therapeutically effective amount of acoramidis, or a pharmaceutically acceptable salt thereof, is administered twice daily as about 712 milligrams (mg) of free acoramidis.

49. The method of any one of claims 34 to 46, wherein the therapeutically effective amount of acoramidis, or a pharmaceutically acceptable salt thereof, is administered twice daily as about 800 milligrams (mg) of acoramidis hydrochloride.

50. The method of any one of claims 34 to 49, wherein the human is not in need of transthyretin (TTR) stabilization.

51. The method of any one of claims 34 to 50, wherein the human does not have transthyretin amyloidosis (ATTR).

52. The method of any one of claims 34 to 51, wherein the human does not have ATTR-cardiomyopathy (ATTR-CM).

53. The method of any one of claims 34 to 52, wherein the human does not have ATTR-poly neuropathy (ATTR-PN).

54. A method of treating proteinuria, the method comprising administering a therapeutically effective amount of acoramidis, or a pharmaceutically acceptable salt thereof, to a human in need thereof.

55. The method of claim 54, wherein the urine albumin-to-creatinine ratio (UACR) of the human is less than about 30 milligrams per gram (mg / g) after about 10 weeks of treatment.

56. The method of claim 54 or 55, wherein the urine albumin-to-creatinine ratio (UACR) of the human decreases by at least about 30% compared to baseline after about 10 weeks of treatment.

57. The method of any one of claims 54 to 56, wherein the urine protein excretion of the human is less than about 150 mg / day after about 10 weeks of treatment.

58. The method of any one of claims 54 to 57, wherein the urine protein excretion of the human decreases by at least about 30% compared to baseline after about 10 weeks of treatment.

59. The method of any one of claims 54 to 58, wherein the urine albumin excretion of the human is less than about 30 mg / day after about 10 weeks of treatment.

60. The method of any one of claims 54 to 59, wherein the urine albumin excretion of the human decreases by at least about 30% compared to baseline after about 10 weeks of treatment.

61. The method of any one of claims 54 to 60, wherein the human has chronic kidney disease (CKD).

62. The method of claim 61, wherein the human does not progress to a higher Stage of CKD compared to baseline after 28 days of treatment.

63. The method of claim 61 or 62, wherein the human does not progress to a higher Stage of CKD compared to baseline after 30 months of treatment.

64. The method of any one of claims 61 to 63, wherein the human moves to a lower Stage of CKD compared to baseline after 28 days of treatment.

65. The method of any one of claims 61 to 64, wherein the human moves to a lower Stage of CKD compared to baseline after 30 months of treatment.

66. The method of any one of claims 54 to 65, wherein the therapeutically effective amount of acoramidis, or a pharmaceutically acceptable salt thereof, is administered twice daily as about 712 milligrams (mg) of free acoramidis or an equivalent amount of a pharmaceutically acceptable salt thereof.

67. The method of any one of claims 54 to 65, wherein the therapeutically effective amount of acoramidis, or a pharmaceutically acceptable salt thereof, is administered twice daily as about 712 milligrams (mg) of free acoramidis.

68. The method of any one of claims 54 to 65, wherein the therapeutically effective amount of acoramidis, or a pharmaceutically acceptable salt thereof, is administered twice daily as about 800 milligrams (mg) of acoramidis hydrochloride.

69. The method of any one of claims 54 to 68, wherein the human is not in need of transthyretin (TTR) stabilization.

70. The method of any one of claims 54 to 69, wherein the human does not have transthyretin amyloidosis (ATTR).

71. The method of any one of claims 54 to 70, wherein the human does not have ATTR-cardiomyopathy (ATTR-CM).

72. The method of any one of claims 54 to 71, wherein the human does not have ATTR-poly neuropathy (ATTR-PN).

73. The method of any one of claims 34 to 72, wherein the acoramidis, or a pharmaceutically acceptable salt thereof, is administered to the human for about 1 week to about 20 weeks.

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