APOL1 inhibitor dosages and methods of use thereof

Abstract

Provided herein are methods of treating a disease, disorder, or condition in a subject comprising administering Compound (I) or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, to the subject. Further provided herein are dosage forms comprising Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof.

Description

Attorney Docket No. 79275-20038.40 APOL1 INHIBITOR DOSAGES AND METHODS OF USE THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No.63 / 754,438, filed February 5, 2025, the entire contents of which are hereby incorporated by reference.BACKGROUND OF THE INVENTION

[0002] Apolipoprotein LI (APOL1) is a pore forming innate immunity factor, protecting individuals from trypanosome parasites (Vanhamme, L. et al. Nature (2003) 422, 83-87). The secreted form of APOL1 circulates in blood as part of distinct high-density lipoprotein (HDL) complexes, known as trypanosome lytic factors (TLFs) (Rifkin, M. R. Proc. Natl. Acad. Set. USA. (1978) 75, 3450-3454; Raper, J. et al. Infect. Immun. (1999) 67, 1910-1916). TLFs are internalized by the parasites through endocytosis (Hager, K. M. et al. J. Cell Biol. (1994) 126, 155-167). Within trypanosomes, APOL1 forms cation pores, causing ion flux, swelling, and eventual lysis (Rifkin, M. R. Exp. Parasitol. (1984) 58, 81-93; Molina-Portela, M. P. et al. Mol. Biochem. Parasitol. (2005) 144, 218-226; Perez-Morga, D. et al. Science. (2005) 309, 469-472; Thomson, R. & Finkelstein, A. Proc. Natl. Acad. Sci. USA. (2015) 112, 2894-2899).

[0003] Several Trypanosoma brucei subspecies (T.b. rhodesiense and T.b. gambiense) developed resistance mechanisms to APOL1 -dependent killing (Pays, E. et al. Nat. Rev.Microbiol. (2014) 12, 575-584). Positive selection resulted in APOL1 variants, G1 (S342G, I384M) and G2 (N388A, Y389A), capable of interfering with these resistance mechanisms (Genovese, G. et al. Science. (2010) 329, 841-845). However, individuals with any binary combination of these variants (Gl / Gl, G2 / G2, or G1 / G2), have a greater risk of developing a variety of chronic kidney diseases, including focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, human immunodeficiency virus-associated nephropathy (HIV AN) (Genovese, G. et al. Science. (2010) 329, 841-845; Tzur, S. et al. Hum. Genet. (2010) 128, 345-350; Kopp, J. B. et al. J. Am. Soc. Nephrol. (2011) 22, 2129-2137), sickle cell nephropathy (Ashley-Koch, A. E. et al. Br. J. Haematol. (2011) 155, 386-394), lupus nephritis (Freedman, B. I. et al. Arthritis Rheumatol. (2014) 66, 390-396), and an increased rate of1MF-366484133Attorney Docket No. 79275-20038.40 Glomerular Filtration Rate (GFR) decline in diabetic kidney disease (Parsa, A. et al. N. Engl. J. Med. (2013) 369, 2183-2196). The APOL1 high-risk genotype has also been associated with COVID-19 associated nephropathy and other viral nephropathies (Shetty, A. et al. J. Am. Soc. Nephrol. (2021) 32, 33-40; Chang, J. H. et al. Am. J. Kidney Dis. (2019) 73, 134-139). Moreover, decreased renal allograft survival has been observed after deceased-donor kidney transplantations from APOL1 high-risk genotype donors (Freedman, B. I. et al. Transplantation. (2016) 100, 194-202). In addition, having two APOL1 risk alleles increases risk for preeclampsia (Reidy, K. J. et al. Am. J. Hum. Genet. (2018) 103, 367-376) and sepsis (Chaudhary, N. S. et al. Clin. J. Am. Soc. Nephrol. (2019) 14, 1733-1740). There are no approved therapies for APOL1 -associated nephropathy, and patients are treated based on the standard of care for their underlying form of chronic kidney disease. This presents a clear unmet need for therapies targeted to people with the APOL1 high-risk genotype.

[0004] Numerous studies have shown that APOL1 risk variants are toxic when overexpressed in human cells (Wan, G. et al. J. Biol. Chem. (2008) 283, 21540-21549; Lan, X. et al. Am. J. Physiol. Renal Physiol. (2014) 307, F326-F336; Olabisi, O. A. et al. Proc. Natl. Acad. Sci. USA. (2016) 113, 830-837; Ma, L. et al. J. Am. Soc. Nephrol. (2017) 28, 1093-1105;Lannon, H. et al. Kidney Int. (2019) 96, 1303-1307). Recent findings suggest that this toxicity is associated with APOL1 pore function (Giovinazzo, J. A. et al. eLife. (2020) 9, e51185). Thus, there is a need to develop compounds suitable for inhibiting APOL1 activity and methods for inhibiting the activity of APOL1 using such compounds.BRIEF SUMMARY OF THE INVENTION

[0005] In one aspect, provided herein is a method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I):2MF-366484133Attorney Docket No. 79275-20038.40or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in a daily amount of about 20 mg to about 480 mg.

[0006] In one aspect, provided herein is a method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in a daily amount of about 250 mg.

[0007] In some embodiments, the disease, disorder, or condition is an APOL1-mediated chronic kidney disease (CKD). In some embodiments, the APOL1 -mediated CKD is focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, human immunodeficiency virus-associated nephropathy (HIV AN), sickle-cell nephropathy, lupus nephritis, diabetic kidney disease, APOL1 -associated nephropathy, viral nephropathy, or COVID-19 associated nephropathy.

[0008] In some embodiments, Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, is administered orally.

[0009] In some embodiments, the subject is a human.

[0010] In some embodiments, provided herein is a dosage form comprising Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in an amount of about 50 mg.3MF-366484133Attorney Docket No. 79275-20038.40DETAILED DESCRIPTION OF THE INVENTION

[0011] “Compound (I)” as used throughout this disclosure refers to 5-chloro-l'-[2-({l-[(cz )-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-lH-l,3-benzodiazol-5-yl}oxy)ethyl]-l,2-dihydrospiro[indole-3,4'-piperidin]-2-one. Compound (I) may also be referred to as 5-chloro-l'-(2-{l-[(cis)-3-hydroxy-3-methylcyclobutyl]-7-(trifluoromethyl)-lH-l,3-benzimidazol-5-yloxy}ethyl)spiro[indoline-3,4'-piperidin]-2-one. Compound (I) has the following structure:

[0012] Compound (I) is disclosed as Compound Number 352 at Example 76 in U.S. Pat. No. 11,976,067, the entirety of which is incorporated herein by reference.

[0013] In some embodiments of the methods described herein, Compound (I) is administered in the form of the free base. In some embodiments, Compound (I) is administered in the form of a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, Compound (I) is administered in the form of a pharmaceutically acceptable salt thereof. In some embodiments, Compound (I) is administered in the form of a hydrochloride salt thereof. In some embodiments, Compound (I) is administered in the form of a monohydrochloride salt thereof. In some embodiments, Compound (I) is administered in the form of a hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, Compound (I) is administered in the form of a hydrate of a hydrochloride salt thereof. In some embodiments, Compound (I) is administered in the form of a hydrate of a monohydrochloride salt thereof. In some embodiments, Compound (I) is administered in the form of a monohydrate of a hydrochloride salt thereof. In some embodiments, Compound (I) is administered in the form of a monohydrate of a monohydrochloride salt thereof.4MF-366484133Attorney Docket No. 79275-20038.40

[0014] In some embodiments of the dosage forms described herein, the dosage form comprises Compound (I) in the form of the free base. In some embodiments, the dosage form comprises Compound (I) in the form of a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises Compound (I) in the form of a pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises Compound (I) in the form of a hydrochloride salt thereof. In some embodiments, the dosage form comprises Compound (I) in the form of a monohydrochloride salt thereof. In some embodiments, the dosage form comprises Compound (I) in the form of a hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises Compound (I) in the form of a hydrate of a hydrochloride salt thereof. In some embodiments, the dosage form comprises Compound (I) in the form of a hydrate of a monohydrochloride salt thereof. In some embodiments, the dosage form comprises Compound (I) in the form of a monohydrate of a hydrochloride salt thereof. In some embodiments, the dosage form comprises Compound (I) in the form of a monohydrate of a monohydrochloride salt thereof.

[0015] “Subject” refers to mammals and includes humans and non-human mammals. Examples of subjects include, but are not limited to, mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows, and primates such as humans. In some embodiments, subject refers to a human.

[0016] As used herein, “about” a parameter or value includes and describes that parameter or value per se. For example, “about X” includes and describes X per se.

[0017] In some embodiments, the term “about,” when used in association with a measurement or to modify a parameter or a value or a range of values, refers to variations of that measurement, parameter, value, or range of values of + / - 10%, + / - 9%, + / - 8%, + / - 7%, + / - 6%, + / - 5%, + / - 4%, + / - 3%, + / - 2%, or + / - 1%. For example, in some embodiments, “about X” includes and describes X + / - 10%, + / - 9%, + / - 8%, + / - 7%, + / - 6%, + / - 5%, + / - 4%, + / - 3%, + / -2%, or + / - 1% of X. In some embodiments, the term “about” refers to variations of + / - 5%, + / -4%, + / - 3%, + / - 2%, or + / - 1%. In some embodiments, the term “about” refers to variations of + / -2% or + / - 1%. In some embodiments, the term “about” refers to variations of + / - 2%. In some embodiments, the term “about” refers to variations of + / - 1%.5MF-366484133Attorney Docket No. 79275-20038.40

[0018] As used herein, an “at risk” subject is a subject who is at risk of developing a disease or condition. A subject “at risk” may or may not have a detectable disease or condition, and may or may not have displayed detectable disease prior to the treatment methods described herein. “At risk” denotes that a subject has one or more so-called risk factors, which are measurable parameters that correlate with development of a disease or condition and are known in the art. A subject having one or more of these risk factors has a higher probability of developing the disease or condition than a subject without these risk factor(s).

[0019] Treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired results may include one or more of the following: decreasing one or more symptom resulting from the disease or condition; diminishing the extent of the disease or condition; slowing or arresting the development of one or more symptom associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition); and relieving the disease, such as by causing the regression of clinical symptoms (e.g., ameliorating the disease state, enhancing the effect of another medication, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival).

[0020] As used herein, “delaying” development of a disease or condition means to defer, hinder, slow, retard, stabilize and / or postpone development of the disease or condition. This delay can be of varying lengths of time, depending on the history of the disease and / or subject being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the subject does not develop the disease or condition.

[0021] As used herein, the term “therapeutically effective amount” or “effective amount” intends such amount of a compound of the disclosure or a pharmaceutically salt thereof sufficient to effect treatment when administered to a subject. As is understood in the art, an effective amount may be in one or more doses, e.g., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved.6MF-366484133Attorney Docket No. 79275-20038.40

[0022] As used herein, by “pharmaceutically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a subject without causing significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and / or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration, herein incorporated by reference in its entirety.

[0023] The terms “optional” and “optionally”, as used herein, mean that the subsequently described event or circumstance may or may not occur and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0024] It is understood that aspects and embodiments described herein as “comprising” include “consisting of’ and “consisting essentially of’ embodiments.

[0025] The term “pharmaceutically acceptable salt”, as used herein, refers to salts that retain the biological effectiveness and properties of the given compound and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” include, for example, salts with inorganic acids, and salts with an organic acid. In addition, if Compound (I) is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. See, e.g., Handbook of Pharmaceutical Salts Properties, Selection, and Use, International Union of Pure and Applied Chemistry, John Wiley & Sons (2008), which is incorporated herein by reference in its entirety. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids. Salts derived from inorganic acids include, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, e.g., acetic acid, propionic acid, gluconic acid, glycolic acid,7MF-366484133Attorney Docket No. 79275-20038.40 pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, trifluoroacetic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic or organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(z o-propyl) amine, tri(w-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.DOSAGE FORMS

[0026] Provided herein is a dosage form comprising Compound (I):Compound (I),or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in an amount of about 5 mg to about 480 mg.

[0027] Also provided herein is a dosage form comprising Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in an amount of about 5 mg.

[0028] Also provided herein is a dosage form comprising Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in an amount of about 20 mg.8MF-366484133Attorney Docket No. 79275-20038.40

[0029] Also provided herein is a dosage form comprising Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in an amount of about 50 mg.

[0030] In some embodiments, provided is a dosage form configured for daily administration. In some embodiments, provided is a dosage form configured for oral administration.

[0031] In some embodiments, the dosage form comprises one or more pharmaceutically acceptable carriers or excipients. In some embodiments pharmaceutically acceptable excipients may include, but are not limited to, binders, disintegrants, lubricants, preservatives, solubilizers, stabilizers, rewetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.Pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g., in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21st ed. (2005), which is incorporated herein by reference in its entirety. In some embodiments, the dosage form comprises microcrystalline cellulose, mannitol, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, and hypromellose.

[0032] In some embodiments, the dosage form is configured for once daily administration. In some embodiments, the dosage form is configured for twice daily administration. In some embodiments, the dosage form is configured for daily administration multiple times per day.

[0033] In some embodiments, the dosage form comprises a therapeutically effective amount of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof.

[0034] In some embodiments, the dosage form comprises an amount of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, of about 5 mg. In some embodiments, the dosage form comprises an amount of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, of about 20 mg. In some embodiments, the dosage form comprises an9MF-366484133Attorney Docket No. 79275-20038.40 amount of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, of about 50 mg.

[0035] In some embodiments, the dosage form comprises an amount of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, of 5 mg. In some embodiments, the dosage form comprises an amount of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, of 20 mg. In some embodiments, the dosage form comprises an amount of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, of 50 mg.

[0036] In some embodiments, the dosage form is configured for oral administration.

[0037] As used herein, the amount of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, refers to the amount of Compound (I) free base equivalents present in the composition. The corresponding amount of pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, may be determined based on the form of Compound (I) used.

[0038] In some embodiments of, the dosage form comprises Compound (I) in the form of the free base. In some embodiments, the dosage form comprises Compound (I) in the form of a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises Compound (I) in the form of a pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises Compound (I) in the form of a hydrochloride salt thereof. In some embodiments, the dosage form comprises Compound (I) in the form of a monohydrochloride salt thereof. In some embodiments, the dosage form comprises Compound (I) in the form of a hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises Compound (I) in the form of a hydrate of a hydrochloride salt thereof. In some embodiments, the dosage form comprises Compound (I) in the form of a hydrate of a monohydrochloride salt thereof. In some embodiments, the dosage form comprises Compound (I) in the form of a monohydrate of a10MF-366484133Attorney Docket No. 79275-20038.40 hydrochloride salt thereof. In some embodiments, the dosage form comprises Compound (I) in the form of a monohydrate of a monohydrochloride salt thereof.METHODS OF TREATMENT

[0039] Provided herein is a method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I):Compound (I),

[0040] or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in a daily amount of about 20 mg to about 480 mg. In some embodiments, the subject has a chronic kidney disease (CKD). In some embodiments, provided herein is a method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in a daily amount of about 20 mg, about 60 mg, about 120 mg, about 240 mg, about 250 mg, about 350 mg, or about 480 mg. In some embodiments, provided herein is a method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in a daily amount of about 20 mg, about 60 mg, about 120 mg, about 240 mg, or about 480 mg. In some embodiments, provided herein is a method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in a daily amount of about 60 mg, about 120 mg, about 240 mg, about 350 mg, or about 480 mg. In some embodiments, provided herein is a method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I) in a daily amount of about 11MF-366484133Attorney Docket No. 79275-20038.40 20 mg, about 60 mg, about 120 mg, about 240 mg, about 250 mg, about 350 mg, or about 480 mg. In some embodiments, provided herein is a method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I) in a daily amount of about 20 mg, about 60 mg, about 120 mg, about 240 mg, or about 480 mg. In some embodiments, provided herein is a method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I) in a daily amount of about 60 mg, about 120 mg, about 240 mg, about 350 mg, or about 480 mg.

[0041] In some embodiments, provided herein is a method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in a daily amount of about 250 mg. In some embodiments, the method comprises administering to the subject one or more capsules containing Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, the capsule contains about 50 mg of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering 5 capsules to the subject. In some embodiments, the method comprises administering 5 capsules to the subject, wherein each capsule comprises about 50 mg of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering 5 capsules to the subject, wherein each capsule comprises 50 mg of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, the 5 capsules are administered at the same time. In some embodiments, the 5 capsules are administered at approximately the same time once daily. In some embodiments, the 5 capsules are administered daily in the morning at approximately the same time.

[0042] In some embodiments, the method comprises administering 7 capsules to the subject, wherein each capsule comprises about 50 mg of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, the capsule contains about 20 mg of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. In some12MF-366484133Attorney Docket No. 79275-20038.40 embodiments, the method comprises administering 1, 3, 6, 12, or 24 capsules to the subject, wherein each capsule comprises about 20 mg of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject 2 capsules comprising about 50 mg of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, and 1 capsule comprising about 20 mg of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject 4 capsules comprising about 50 mg of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, and 2 capsules comprising about 20 mg of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject 8 capsules comprising about 50 mg of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, and 4 capsules comprising about 20 mg of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof.

[0043] In some embodiments, provided herein is a method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in a daily amount of about 20 mg to about 480 mg, about 60 mg to about 480 mg, about 120 mg to about 480 mg, about 240 mg to about 480 mg, or about 350 mg to about 480 mg. In some embodiments, provided herein is a method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in a daily amount of about 20 mg to about 480 mg, about 20 mg to about 350 mg, about 20 mg to about 240 mg, about 20 mg to about 120 mg, or about 20 mg to about 60 mg.

[0044] In some embodiments, provided herein is a method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in a daily amount of about 20 mg to about 60 mg, about 60 mg to about 13MF-366484133Attorney Docket No. 79275-20038.40 120 mg, about 120 mg to about 240 mg, about 240 mg to about 350 mg, or about 350 mg to about 480 mg. In some embodiments, provided herein is a method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in a daily amount of about 60 mg to about 240 mg or about 60 mg to about 350 mg. In some embodiments, provided herein is a method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in a daily amount of about 120 mg to about 350 mg. In some embodiments, provided herein is a method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in a daily amount of about 225 mg to about 275 mg, about 230 mg to about 270 mg, about 235 mg to about 265 mg, or about 240 mg to about 260 mg.

[0045] In some embodiments, provided herein is a method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in a daily amount of about 20 mg to about 480 mg, about 60 mg to about 480 mg, about 120 mg to about 480 mg, about 240 mg to about 480 mg, or about 350 mg to about 480 mg. In some embodiments, provided herein is a method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in a daily amount of about 20 mg to about 480 mg, about 20 mg to about 240 mg, about 20 mg to about 120 mg, or about 20 mg to about 60 mg.

[0046] In some embodiments, provided herein is a method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in a daily amount of about 60 mg to about 480 mg, about 120 mg to about 480 mg, about 240 mg to about 480 mg, or about 350 mg to about 480 mg. In some embodiments, provided herein is a method of treating a disease, disorder, or condition in a subject 14MF-366484133Attorney Docket No. 79275-20038.40 in need thereof, comprising administering to the subject Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in a daily amount of about 60 mg to about 480 mg, about 60 mg to about 350 mg, about 60 mg to about 240 mg, or about 60 mg to about 120 mg.

[0047] In some embodiments, provided herein is a method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in a daily amount of 20 mg, 60 mg, 120 mg, 240 mg, 250 mg, 350 mg, or 480 mg. In some embodiments, provided herein is a method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in a daily amount of 20 mg, 60 mg, 120 mg, 240 mg, or 480 mg. In some embodiments, provided herein is a method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in a daily amount of 60 mg, 120 mg, 240 mg, 350 mg, or 480 mg.

[0048] In some embodiments, provided herein is a method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in a daily amount of 250 mg. In some embodiments, the method comprises administering to the subject one or more capsules containing Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, the capsule contains 50 mg of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering 5 capsules to the subject. In some embodiments, the 5 capsules are administered at the same time. In some embodiments, the 5 capsules are administered at approximately the same time once daily. In some embodiments, the 5 capsules are administered daily in the morning at approximately the same time.15MF-366484133Attorney Docket No. 79275-20038.40

[0049] In some embodiments, provided herein is a method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in a daily amount of 20 mg to 480 mg, 60 mg to 480 mg, 120 mg to 480 mg, 240 mg to 480 mg, or 350 mg to 480 mg. In some embodiments, provided herein is a method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in a daily amount of 20 mg to 480 mg, 20 mg to 350 mg, 20 mg to 240 mg, 20 mg to 120 mg, or 20 mg to 60 mg.

[0050] In some embodiments, provided herein is a method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in a daily amount of 20 mg to 480 mg, 60 mg to 480 mg, 120 mg to 480 mg, 240 mg to 480 mg, or 350 mg to 480 mg. In some embodiments, provided herein is a method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in a daily amount of 20 mg to 480 mg, 20 mg to 240 mg, 20 mg to 120 mg, or 20 mg to 60 mg.

[0051] In some embodiments, provided herein is a method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in a daily amount of 60 mg to 480 mg, 120 mg to 480 mg, 240 mg to 480 mg, or 350 mg to 480 mg. In some embodiments, provided herein is a method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in a daily amount of 60 mg to 480 mg, 60 mg to 350 mg, 60 mg to 240 mg, or 60 mg to 120 mg.

[0052] Also provided herein is a method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective16MF-366484133Attorney Docket No. 79275-20038.40 amount of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. Also provided herein is a method of delaying the development of a disease, disorder, or condition in a subject who is at risk of developing the disease, disorder, or condition, comprising administering to the subject a therapeutically effective amount of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof.

[0053] Also provided herein is a method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering to the subject a dosage form comprising Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. Also provided herein is a method of delaying the development of a disease, disorder, or condition in a subject who is at risk of developing the disease, disorder, or condition, comprising administering to the subject a dosage form comprising Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof.

[0054] Also provided herein is a method of treating an APOL1 -mediated disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in an amount sufficient to achieve a steady-state pharmacokinetic profile characterized by systemic exposure corresponding to an effective concentration producing about 90% to about 95% of the maximal pharmacological effect. Also provided herein is a method of treating an APOL1 -mediated disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in an amount sufficient to achieve a steady-state pharmacokinetic profile characterized by: (a) a peak-to-trough ratio consistent with once-daily dosing; and (b) systemic exposure corresponding to an effective concentration producing about 90% to about 95% of the maximal pharmacological effect. In some embodiments, the systemic exposure corresponds to an effective concentration producing about 95% of the maximal pharmacological effect. In some embodiments, the systemic exposure corresponds to an effective concentration producing about 92% of the maximal pharmacological effect. In some embodiments, the systemic exposure corresponds to an effective concentration 17MF-366484133Attorney Docket No. 79275-20038.40 producing about 90% of the maximal pharmacological effect. In some embodiments, the effective concentration of about 90% to about 95% is achieved at about 12 weeks after the start of treatment with Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof.

[0055] Also provided herein is a method of treating an APOL1 -mediated disease, disorder, or condition in a human subject comprising administering Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, according to a dosing regimen that produces a steady-state systemic exposure characterized by: (a) an AUC0-24 sufficient to achieve at least about 90% of maximal pharmacological effect; and (b) a Cmax that is below a dose-limiting toxicity threshold, wherein the dosing regimen is administered once daily. In some embodiments, the AUC0-24 is between about 10,000 ng / mL*hr and about 12,000 ng / mL*hr. In some embodiments, the AUC0-24 is between about 11,000 ng / mL*hr and about 11,600 ng / mL*hr. In some embodiments, the AUC0-24 is about 11,000 ng / mL*hr. In some embodiments, the AUC0-24 is about 11,600 ng / mL*hr. In some embodiments, the Cmax is between about 700 ng / mL and about 1100 ng / mL. In some embodiments, the Cmax is between about 800 ng / mL and about 1000 ng / mL. In some embodiments, the Cmax is between about 850 ng / mL and about 950 ng / mL. In some embodiments, the Cmax is between about 870 ng / mL and about 930 ng / mL. In some embodiments, the Cmax is about 870 ng / mL. In some embodiments, the Cmax is about 930 ng / mL.

[0056] Also provided herein is Compound (I) or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, for use in treating an APOL1-mediated disease, disorder, or condition in a subject in need thereof to achieve a steady-state pharmacokinetic profile characterized by systemic exposure corresponding to an effective concentration producing about 90% to about 95% of the maximal pharmacological effect.

[0057] Also provided herein is Compound (I) or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, for use in treating an APOL1-mediated disease, disorder, or condition in a subject in need thereof to achieve a steady-state pharmacokinetic profile characterized by: (a) a peak-to-trough ratio consistent with once-daily18MF-366484133Attorney Docket No. 79275-20038.40 dosing; and (b) systemic exposure corresponding to an effective concentration producing about 90% to about 95% of the maximal pharmacological effect.

[0058] Also provided herein is Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, for use in treating an APOL1-mediated disease, disorder, or condition in a subject in need thereof according to a dosing regimen that produces a steady-state systemic exposure characterized by: (a) an AUC0-24 sufficient to achieve at least about 90% of maximal pharmacological effect; and (b) a Cmax that is below a dose-limiting toxicity threshold, wherein the dosing regimen is administered once daily.

[0059] Also provided herein is Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, for use in treating an APOL1-mediated disease, disorder, or condition in a subject in need thereof.

[0060] Also provided herein is Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, for use in treating an APOL1-mediated disease, disorder, or condition in a subject in need thereof, wherein the subject has persistent urine albuminuria of at least about 300 mg / g before the start of treatment with Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof.

[0061] Also provided herein is Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, for use in treating an APOL1-mediated disease, disorder, or condition in a subject in need thereof, wherein the subject has an estimated glomerular filtration rate (eGFR) > 25 mL / min / 1.73 m2and < 90 mL / min / 1.73 m2before the start of treatment with Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof.

[0062] Also provided herein is Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, for use in treating an APOL1-mediated disease, disorder, or condition in a subject in need thereof, wherein the subject achieves at least about a 30% reduction relative to baseline in urine protein to creatinine ratio (UPCR) at19MF-366484133Attorney Docket No. 79275-20038.40 about 12 weeks after the start of treatment with Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof.

[0063] Also provided herein is the use of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an APOL1 -mediated disease, disorder, or condition in a subject in need thereof to achieve a steady-state pharmacokinetic profile characterized by systemic exposure corresponding to an effective concentration producing about 90% to about 95% of the maximal pharmacological effect.

[0064] Also provided herein is the use of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an APOL1 -mediated disease, disorder, or condition in a subject in need thereof to achieve a steady-state pharmacokinetic profile characterized by: (a) a peak-to-trough ratio consistent with once-daily dosing; and (b) systemic exposure corresponding to an effective concentration producing about 90% to about 95% of the maximal pharmacological effect.

[0065] Also provided herein is the use of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, for use in treating an APOL1 -mediated disease, disorder, or condition in a subject in need thereof according to a dosing regimen that produces a steady-state systemic exposure characterized by: (a) an AUCO-24 sufficient to achieve at least about 90% of maximal pharmacological effect; and (b) a Cmax that is below a dose-limiting toxicity threshold, wherein the dosing regimen is administered once daily.

[0066] Also provided here in is the use of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating an APOL1 -mediated disease, disorder, or condition in a subject in need thereof.

[0067] Also provided herein is the use of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in the20MF-366484133Attorney Docket No. 79275-20038.40 manufacture of a medicament for use in treating an AP0L1 -mediated disease, disorder, or condition in a subject in need thereof, wherein the subject has persistent urine albuminuria of at least about 300 mg / g before the start of treatment with Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof.

[0068] Also provided herein is the use of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating an APOL1 -mediated disease, disorder, or condition in a subject in need thereof, wherein the subject has an estimated glomerular filtration rate (eGFR) > 25 mL / min / 1.73 m2and < 90 mL / min / 1.73 m2before the start of treatment with Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof.

[0069] Also provided herein is the use of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating an APOL1 -mediated disease, disorder, or condition in a subject in need thereof, wherein the subject achieves at least about a 30% reduction relative to baseline in urine protein to creatinine ratio (UPCR) at about 12 weeks after the start of treatment with Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, the protein is albumin.

[0070] In some embodiments, the dosage form is any one of the dosage forms described herein. In some embodiments, the dosage form comprises about 5 mg to about 480 mg of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises about 5 mg to about 50 mg of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises about 5 mg of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises about 20 mg of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises about 50 mg of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a21MF-366484133Attorney Docket No. 79275-20038.40 pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises a therapeutically effective amount of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises 5 mg to 480 mg of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises 5 mg to 50 mg of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises 5 mg of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises 20 mg of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises 50 mg of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises a therapeutically effective amount of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof.

[0071] In some embodiments, the disease, disorder, or condition is an APOL1-mediated disease, disorder, or condition. In some embodiments, the disease, disorder, or condition is an APOL1 -mediated kidney disease. In some embodiments, the disease, disorder, or condition is an APOL1 -mediated chronic kidney disease (CKD). In some embodiments, the APOL1 -mediated chronic kidney disease (CKD) is focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, human immunodeficiency virus-associated nephropathy (HIV AN), sickle-cell nephropathy, lupus nephritis, diabetic kidney disease, APOL1 -associated nephropathy, viral nephropathy, or COVID-19 associated nephropathy. In some embodiments, the disease, disorder, or condition is focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, or diabetic kidney disease. In some embodiments, the disease, disorder, or condition is a chronic kidney disease (CKD). In some embodiments, the subject has an APOL1 -mediated chronic kidney disease (CKD) with concurrent diabetes. In some embodiments, the subject has an APOL1 -mediated chronic kidney disease (CKD) without concurrent diabetes. In some embodiments, the disease, disorder, or condition is chronic kidney disease (CKD) associated with focal segmental glomerulosclerosis (FSGS), hypertension, or22MF-366484133Attorney Docket No. 79275-20038.40 diabetes. In some embodiments, the disease, disorder, or condition is chronic kidney disease (CKD) associated with focal segmental glomerulosclerosis (FSGS). In some embodiments, the disease, disorder, or condition is chronic kidney disease (CKD) associated with hypertension. In some embodiments, the disease, disorder, or condition is chronic kidney disease (CKD) associated with diabetes.

[0072] In some embodiments, the APOL1 -mediated disease, disorder, or condition is a chronic kidney disease and the subject has any binary combination of G1 and G2 APOL1 risk alleles. In some embodiments, the chronic kidney disease is focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, human immunodeficiency virus-associated nephropathy (HIV AN), sickle cell nephropathy, viral nephropathy, COVID-19 associated nephropathy, lupus nephritis, diabetic kidney disease, or APOL1 -associated nephropathy.

[0073] In some embodiments, the individual has a gain-of-function mutation in APOL1. In some embodiments, the subject has asxAPOLl risk allele. In some embodiments, the APOL1 risk allele is a missense variant. In some embodiments, the APOL1 risk allele is a G1 variant. In some embodiments, the G1 variant is G1G(p.S342 G) or G1M(p.I384 M). In some embodiments, the APOL J risk allele is the G2 variant. In some embodiments, the G2 variant is NYK388-389K. In some embodiments, the APOL1 risk variant is a mutation in the serum resistance-associated (SRA) binding domain of the APOL1 protein. In some embodiments, the subject has two APOL1 risk alleles. In some embodiments, the subject has an APOL1 high risk genotype of Gl / Gl, G2 / G2, or G1 / G2.

[0074] In some embodiments, Compound (I) reduces or eliminates one or more symptoms of a kidney disease. In some embodiments, Compound (I) reduces nausea, vomiting, loss of appetite, fatigue and weakness, sleep problems, urinary frequency issues, muscle twinges and cramps, swelling, itching, chest pain, shortness of breath, and / or high blood pressure.

[0075] In some embodiments, Compound (I) reduces the rate of kidney damage and / or progression of kidney damage. In some embodiments, Compound (I) reduces the rate of kidney failure. In some embodiments, Compound (I) reverses kidney damage. In some embodiments, Compound (I) reduces the need for dialysis. In some embodiments, Compound (I) delays the23MF-366484133Attorney Docket No. 79275-20038.40 need for dialysis at least one month, at least two months, at least three months, or at least one year.

[0076] In some embodiments, Compound (I) reduces the rate of or delay the need for a kidney transplant. For example, in some embodiments, Compound (I) delays the need for a kidney transplant at least one month, at least two months, at least three months, at least six months, or at least one year. In some embodiments, Compound (I) eliminates the need for a kidney transplant.

[0077] In some embodiments, the subject has stage 1, stage 2, stage 3 A, stage 3B, stage 4, or stage 5 chronic kidney disease. In some embodiments, kidney function is evaluated using an estimated glomerular filtration rate (eGFR) kidney function test.

[0078] Also provided herein is a method of delaying or preventing proteinuria in a subject, comprising administering to the subject a therapeutically effective amount of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. Also provided herein is a method of delaying or preventing proteinuria, comprising administering to the subject a dosage form comprising Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. In one aspect, the methods herein comprise preventing or reducing protein in the urine, e.g., proteinuria. In some embodiments, the methods provided herein prevent proteinuria. In some embodiments, the methods reduce proteinuria. In some embodiments, the methods provided herein prevent albuminuria. In some embodiments, the methods reduce albuminuria. In some embodiments, the methods reduce urine albumin. In some embodiments, urine albumin is reduced by at least about 30%, at least about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%, or greater. In some embodiments, urine albumin is reduced by at least about 30%. In some embodiments, urine albumin is reduced by at least about 40%. In some embodiments, urine albumin is reduced by at least about 50%. In some embodiments, urine albumin is reduced by at least about 60%. In some embodiments, urine albumin is reduced by at least about 70%. In some embodiments, urine albumin is reduced by at least about 80%. In some embodiments, urine albumin is reduced by at least about 90%. In some embodiments, reduction of urine albumin is dose-dependent. In some embodiments, the methods provided herein reduce urine24MF-366484133Attorney Docket No. 79275-20038.40 albumin / creatinine ratio. In some embodiments, urine albumin / creatinine ratio (UACR) is reduced by at least about 30%, at least about 40%, at least about 50%, about 60%, about 70%, about 80%, or about 90%, or greater. In some embodiments, urine albumin / creatinine ratio is reduced by at least about 30%. In some embodiments, urine albumin / creatinine ratio is reduced by at least about 40%. In some embodiments, urine albumin / creatinine ratio is reduced by at least about 50%. In some embodiments, urine albumin / creatinine ratio is reduced by at least about 60%. In some embodiments, urine albumin / creatinine ratio is reduced by at least about 70%. In some embodiments, urine albumin / creatinine ratio is reduced by at least about 80%. In some embodiments, urine albumin / creatinine ratio is reduced by at least about 90%. In some embodiments, reduction of urine albumin / creatinine ratio is dose-dependent. In some embodiments, the methods reduce urine protein. In some embodiments, urine protein is reduced by at least about 30%, at least about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%, or greater. In some embodiments, urine protein is reduced by at least about 30%. In some embodiments, urine protein is reduced by at least about 40%. In some embodiments, urine protein is reduced by at least about 50%. In some embodiments, urine protein is reduced by at least about 60%. In some embodiments, urine protein is reduced by at least about 70%. In some embodiments, urine protein is reduced by at least about 80%. In some embodiments, urine protein is reduced by at least about 90%. In some embodiments, reduction of urine protein is dosedependent. In some embodiments, the methods provided herein reduce urine protein / creatinine ratio. In some embodiments, urine protein / creatinine ratio (UPCR) is reduced by at least about 30%, at least about 40%, at least about 50%, about 60%, about 70%, about 80%, or about 90%, or greater. In some embodiments, urine protein / creatinine ratio is reduced by at least about 30%. In some embodiments, urine protein / creatinine ratio is reduced by at least about 40%. In some embodiments, urine protein / creatinine ratio is reduced by at least about 50%. In some embodiments, urine protein / creatinine ratio is reduced by at least about 60%. In some embodiments, urine protein / creatinine ratio is reduced by at least about 70%. In some embodiments, urine protein / creatinine ratio is reduced by at least about 80%. In some embodiments, urine protein / creatinine ratio is reduced by at least about 90%. In some embodiments, reduction of urine protein / creatinine ratio is dose-dependent. In some embodiments, the reduction and / or ratios are measured according to assays detailed herein. In any of the aforementioned methods, the subject is a subject in need thereof, such as a subject having25MF-366484133Attorney Docket No. 79275-20038.40 an AP0L1 -mediated disease, disorder, or condition. In some embodiments, the APOL1 -mediated disease, disorder, or condition is a kidney disease. In some embodiments, the APOL1 -mediated disease, disorder, or condition is a chronic kidney disease (CKD). In some embodiments, the subject has hypertension-attributed kidney disease. In some embodiments, the kidney disease, disorder, or condition is selected from the group consisting of focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, viral nephropathy, COVID-19 associated nephropathy, human immunodeficiency virus-associated nephropathy (HIV AN), sickle-cell nephropathy, lupus nephritis, and diabetic kidney disease.

[0079] In some embodiments, the exposure at steady state in the subject following administration of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in an amount of about 250 mg is predicted to be a CMAX of about 871 ng / mL, and an AUC0-24 of about 11,600 hr*ng / mL, providing an EC92 for the predicted mean exposure. In some embodiments, the predicted exposure has an exposure margin of about 3.75-fold below the male rat AUC at the “no observed adverse effect level” (NOAEL) and about 4.4-fold lower than the male rat CMAX at the NOAEL.

[0080] In some embodiments, Compound (I), or a pharmaceutically acceptable salt thereof, is administered in a single dose. In some embodiments, the single dose contains Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in an amount of about 20 mg, about 60 mg, about 120 mg, about 240 mg, or about 480 mg. In some embodiments, the single dose contains Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in an amount of about 250 mg. In some embodiments, the single dose contains Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in an amount other than about 480 mg.

[0081] In some embodiments, Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, is administered in multiple doses. In some embodiments, each dose contains Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in an amount of about 60 mg, about 120 mg, about 240 mg, about 350 mg, or about 480 mg. In some26MF-366484133Attorney Docket No. 79275-20038.40 embodiments, Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, is administered in multiple doses, wherein each dose contains Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in an amount other than about 350 mg.

[0082] In some embodiments, Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, is administered in a split dose, wherein the total amount of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, is administered to the subject in two or more separate doses. In some embodiments, the split dose contains Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in a total amount of about 480 mg. In some embodiments, the two or more separate doses are administered hours apart. In some embodiments, the two or more separate doses are administered 2 hours apart. In some embodiments, the two or more separate doses contain equal amounts of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, the two or more separate doses contain different amounts of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, the split doses contain Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in two separate doses each comprising about 240 mg of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof.

[0083] In some embodiments, the subject is in a fasted state. In some embodiments, the subject is in a fed state.

[0084] In some embodiments, Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, is administered for a duration of about 1 to about 10 days. In some embodiments, Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, is administered for a duration of at least 10 days. In some embodiments, Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, is administered27MF-366484133Attorney Docket No. 79275-20038.40 once daily for a duration of at least 10 days. In some embodiments, Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, is administered twice daily for a duration of at least 10 days. In some embodiments, Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, is administered multiple times daily for a duration of at least 10 days.

[0085] In some embodiments, the subject is at least 18 years of age. In some embodiments, the subject is at most 65 years of age. In some embodiments, the subject is 18-65 years of age, inclusive. In some embodiments, the subject has a body mass index (BMI) of between about 18 kg / m2and about 45 kg / m2. In some embodiments, the subject has a total weight of at least about 40 kg.

[0086] In some embodiments, the subject has an estimated glomerular filtration rate (eGFR) between about 25 mL / min / 1.73 m2and about 90 mL / min / 1.73 m2before the start of treatment with Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, the subject has an estimated glomerular filtration rate (eGFR) of > 25 mL / min / 1.73 m2and < 90 mL / min / 1.73 m2before the start of treatment with Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof.

[0087] In some embodiments, the subject has persistent high urine albuminuria. In some embodiments, the subject has persistent urine albuminuria measured by urine albumin to creatinine ratio (UACR) at least about 300 mg / g before the start of treatment with Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof.

[0088] In some embodiments, the subject is receiving standard of care treatment for chronic kidney disease (CKD) prior to the administration of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, the subject is receiving standard of care treatment for chronic kidney disease (CKD) for at least about 14 weeks prior to the administration of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt28MF-366484133Attorney Docket No. 79275-20038.40 thereof. In some embodiments, the standard of care treatment for chronic kidney disease (CKD) comprises administering one or more renin-angiotensin-aldosterone system (RAAS) inhibitors to the subject. In some embodiments, the standard of care treatment for chronic kidney disease (CKD) further comprises administering one or more SGLT2 inhibitors, one or more mineralocorticoid receptor antagonists, or one or more GLP-1 receptor agonists, or any combination of the foregoing, to the subject. In some embodiments, the standard of care treatment for chronic kidney disease (CKD) further comprises administering one or more antihypertensive treatments to the subject.

[0089] In some embodiments, the subject is diabetic. In some embodiments, the subject has Type 2 diabetes mellitus. In some embodiments, the subject is diabetic and has been on stable regimen of one or more antidiabetic medications and / or insulin for at least about 14 weeks prior to receiving treatment with Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, the subject is not diabetic. In some embodiments, the subject has received a diagnosis of chronic kidney disease (CKD) attributable to hypertension and / or focal segmental glomerulosclerosis (FSGS).

[0090] In some embodiments, the subject is administered an amount of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, sufficient to achieve an effective concentration of about 90% to about 95%. In some embodiments, the subject is administered an amount of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, sufficient to achieve at least about a 30% reduction relative to baseline in urine albumin to creatinine ratio (UACR) at about 12 weeks after the start of treatment with Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, the subject is administered an amount of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, sufficient to achieve at least about a 30% reduction relative to baseline in urine protein to creatinine ratio (UPCR) at about 12 weeks after the start of treatment with Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof.29MF-366484133Attorney Docket No. 79275-20038.40

[0091] In some embodiments, the subject does not have: (1) a history of cancer within past 2 years, excepted for treated non-melanoma skin cancer, stage 0 cervical cancer, or stage 1 prostate cancer; (2) clinically significant liver disease; (3) unstable cardiac disease, including history of unstable angina, myocardial infarction or stroke within 12 months prior; (4) requirement for supplemental oxygen or history of intubation within 6 months prior; (5) organ or bone marrow transplantation; (6) clinically significant and active infection; (7) uncontrolled hypothyroidism; (8) a history of thromboembolism within 1 year prior to screening; (9) ongoing alcohol or substance abuse; (10) conditions that may alter drug absorption, e.g., history of bariatric surgery; or (11) pregnancy or currently nursing; or any combination of the foregoing.

[0092] In some embodiments, the subject is not using any potent immunosuppressants within 5 PK half-lives or 12 weeks prior to screening, whichever is longer, including but not limited to: abatacept, adalimumab, anakinra, azathioprine, cyclophosphamide, certolizumab, etanercept, golimumab, infliximab, rituximab, ruxolitinib, sarilumab, tofacitinib, or tocilizumab, or any combination thereof. In some embodiments, the subject is taking cyclosporine, mycophenolate mofetil, and / or tacrolimus as part of a stable regimen and dose for at least 8 weeks prior to screening.

[0093] In some embodiments, the subject is not using oral corticosteroids equivalent to prednisone >10 mg / day for more than 1 day within 8 weeks prior to screening and / or use of any other systemic corticosteroid equivalent to prednisone >10 mg / day within 8 weeks prior to screening.

[0094] In some embodiments, the subject does not have: (1) total bilirubin >1.5 x upper limit of normal (ULN); (2) aspartate transaminase (AST) or alanine transaminase (ALT) >2 x ULN; (3) serum albumin <2 g / dL; (4) TSH >10 mIU / L; (5) potassium >ULN; (6) hemoglobin <10 g / dL; or (7) absolute Neutrophil Count (ANC) <1000 cells / pL; or any combination of the foregoing.

[0095] In some embodiments, the subject does not have a clinically abnormal ECG, including but not limited to QTcF >450 ms or history of QT interval prolongation.30MF-366484133Attorney Docket No. 79275-20038.40

[0096] In some embodiments, the subject has (1) systolic blood pressure of 90 to 180 mg Hg, inclusive; (2) diastolic blood pressure of 40 to 100 mg Hg, inclusive; and (3) heart rate of 50 to 99 bpm, inclusive.

[0097] In some embodiments, the subject has not taken medications that are strong CYP3A4 inhibitors or inducers (e.g., rifampin, carbamazepine, clarithromycin, itraconazole), including herbal supplements (e.g., St. John’s wort), grapefruit, Seville-oranges, or poppy seeds, within 14 days of treatment with Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, and is not taking said medications while receiving treatment with Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof.

[0098] In some embodiments, the subject has not taken proton pump inhibitors within 14 days of receiving treatment with Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, and is not taking said inhibitors while receiving treatment with Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof.

[0099] In some embodiments, the subject has not taken any investigational drug within 8 weeks or <5 half-lives, whichever is longer, prior to the screening.

[0100] In some embodiments, the subject does not have hypersensitivity to Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, or any dosage form comprising Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof.

[0101] In some embodiments, the subject does not have a kidney biopsy result indicating severe or >50% tubulointerstitial fibrosis.

[0102] In some embodiments, the subject does not have planned travel to regions with endemic trypanosomiasis.

[0103] In some embodiments, the subject does not have glycosylated hemoglobin Ale >8.0% at screening or brittle diabetes.31MF-366484133Attorney Docket No. 79275-20038.40

[0104] In some embodiments, the subject has not received a diagnosis of Type I diabetes mellitus. In some embodiments, the subject does not have kidney disease attributed to known causes including but not limited to: active infection, autoimmune disease (e.g., lupus nephritis, IgA nephropathy, membranous nephropathy, glomerular basement membrane disease), toxins, drugs (e.g., bisphosphonate, interferon), congenital abnormalities (except unilateral renal agenesis), malignancy, minimal change disease, previously diagnosed genetic kidney disease (e.g., autosomal dominant polycystic kidney disease, Alport syndrome), sickle cell disease, or amyloidosis. In some embodiments, the subject has sickle trait. In some embodiments, the subject has solitary native kidney.

[0105] In some embodiments, the subject is not currently receiving treatment with an antidiabetic medication and / or insulin. In some embodiments, the subject does not have glycosylated hemoglobin Ale >6.5% at screening. In some embodiments, the subject does not have a medical history of fasting glucose >126 mg / dL on 2 separate days or 2-hour plasma glucose >200 mg / dL during an oral glucose tolerance test. In some embodiments, the subject does not have kidney disease attributed to known causes including but not limited to: Type 1 or 2 diabetes mellitus, active infection, autoimmune disease (e.g., lupus nephritis, IgA nephropathy, membranous nephropathy, anti-glomerular basement membrane disease), toxins, drugs (e.g., bisphosphonate, interferon), congenital abnormalities (except unilateral renal agenesis), malignancy, minimal change disease, previously diagnosed genetic kidney disease (e.g., autosomal dominant polycystic kidney disease, Alport syndrome), or sickle cell disease.

[0106] In some embodiments, the dosage form comprising Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, is administered for a duration of about 12 weeks. In some embodiments, the dosage form comprising Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, is administered for a duration of at least about 12 weeks. In some embodiments, the dosage form comprising Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, is administered for a duration of about 16 weeks.32MF-366484133Attorney Docket No. 79275-20038.40

[0107] In some embodiments, Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, is administered orally. In some embodiments, the dosage form comprising Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, is administered orally.

[0108] In some embodiments of the methods described herein, Compound (I) is administered in the form of the free base. In some embodiments, Compound (I) is administered in the form of a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, Compound (I) is administered in the form of a pharmaceutically acceptable salt thereof. In some embodiments, Compound (I) is administered in the form of a hydrochloride salt thereof. In some embodiments, Compound (I) is administered in the form of a monohydrochloride salt thereof. In some embodiments, Compound (I) is administered in the form of a hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, Compound (I) is administered in the form of a hydrate of a hydrochloride salt thereof. In some embodiments, Compound (I) is administered in the form of a hydrate of a monohydrochloride salt thereof. In some embodiments, Compound (I) is administered in the form of a monohydrate of a hydrochloride salt thereof. In some embodiments, Compound (I) is administered in the form of a monohydrate of a monohydrochloride salt thereof.

[0109] In some embodiments of the methods of treating chronic kidney disease (CKD) described herein, Compound (I) is administered in the form of the free base. In some embodiments, Compound (I) is administered in the form of a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, Compound (I) is administered in the form of a pharmaceutically acceptable salt thereof. In some embodiments, Compound (I) is administered in the form of a hydrochloride salt thereof. In some embodiments, Compound (I) is administered in the form of a monohydrochloride salt thereof. In some embodiments, Compound (I) is administered in the form of a hydrate of a pharmaceutically acceptable salt thereof. In some embodiments, Compound (I) is administered in the form of a hydrate of a hydrochloride salt thereof. In some embodiments, Compound (I) is administered in the form of a hydrate of a monohydrochloride salt thereof. In some embodiments, Compound (I) is administered in the form of a monohydrate of a hydrochloride salt thereof. In some33MF-366484133Attorney Docket No. 79275-20038.40 embodiments, Compound (I) is administered in the form of a monohydrate of a monohydrochloride salt thereof.[OHO] In some embodiments, the subject is a human.[OlH] In some embodiments, the subject is a human with APOL1 high risk genotype, proteinuric kidney disease, and concurrent diabetes, and the subject is administered a hydrate of a monohydrochloride salt of the compound in a once daily dose of 250 mg.

[0112] In some embodiments, the subject is a human with APOL1 high risk genotype and proteinuric kidney disease, and without concurrent diabetes, and the subject is administered a hydrate of a monohydrochloride salt of the compound in a once daily dose of 250 mg.ENUMERATED EMBODIMENTS

[0113] The following embodiments are also contemplated:

[0114] Embodiment 1. A method of treating a disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I):Compound (I),or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in a daily amount of about 20 mg to about 480 mg.

[0115] Embodiment 2. The method of embodiment 1, wherein Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt34MF-366484133Attorney Docket No. 79275-20038.40 thereof, is administered in a daily amount of about 20 mg, about 60 mg, about 120 mg, about 240 mg, about 250 mg, about 350 mg, or about 480 mg.

[0116] Embodiment 3. The method of embodiment 1 or embodiment 2, wherein Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, is administered in a daily amount of about 20 mg, about 60 mg, about 120 mg, about 240 mg, or about 480 mg.

[0117] Embodiment 4. The method of embodiment 1 or embodiment 2, wherein Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, is administered in a daily amount of about 60 mg, about 120 mg, about 240 mg, about 350 mg, or about 480 mg.

[0118] Embodiment 5. The method of embodiment 1 or embodiment 2, wherein Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, is administered in a daily amount of about 250 mg.

[0119] Embodiment 6. The method of any of embodiments 1-5, wherein Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, is administered in a single dose.

[0120] Embodiment 7. The method of any of embodiments 1-5, wherein Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, is administered in multiple doses.

[0121] Embodiment 8. The method of any of embodiments 1-7, wherein Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, is administered in a split dose.

[0122] Embodiment 9. The method of any of embodiments 1-8, wherein the disease, disorder, or condition is an APOL1 -mediated disease, disorder, or condition.

[0123] Embodiment 10. The method of any of embodiments 1-9, wherein the disease, disorder, or condition is a chronic kidney disease (CKD).

[0124] Embodiment 11. The method of any of embodiments 1-10, wherein the disease, disorder, or condition is focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, or diabetic kidney disease.35MF-366484133Attorney Docket No. 79275-20038.40

[0125] Embodiment 12. The method of any of embodiments 1-10, wherein the disease, disorder, or condition is chronic kidney disease (CKD) associated with focal segmental glomerulosclerosis (FSGS), hypertension, or diabetes.

[0126] Embodiment 13. The method of any of embodiments 1-12, wherein the subject has nAPOLl high risk genotype of Gl / Gl, G2 / G2, or G1 / G2.

[0127] Embodiment 14. The method of any of embodiments 1-13, wherein the subject has persistent urine albuminuria of at least about 300 mg / g.

[0128] Embodiment 15. The method of any of embodiments 1-14, wherein the subject has an estimated glomerular filtration rate (eGFR) > 25 mL / min / 1.73 m2and < 90 mL / min / 1.73 m2before the start of treatment.

[0129] Embodiment 16. The method of any of embodiments 1-15, wherein the subject is diabetic.

[0130] Embodiment 17. The method of any of embodiments 1-16, wherein the subject has Type 2 diabetes mellitus.

[0131] Embodiment 18. The method of any of embodiments 1-15, wherein the subject is not diabetic.

[0132] Embodiment 19. The method of any of embodiments 1-18, wherein the subject is in a fasted state.

[0133] Embodiment 20. The method of any of embodiments 1-19, wherein Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, is administered once daily.

[0134] Embodiment 21. The method of any of embodiments 1-20, wherein Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, is administered orally.

[0135] Embodiment 22. The method of any of embodiments 1-21, wherein the subject is administered an amount of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, sufficient to achieve an effective concentration of about 90% to about 95%.

[0136] Embodiment 23. The method of any of embodiments 1-22, wherein the subject is administered an amount of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, sufficient to achieve at least about a 30%36MF-366484133Attorney Docket No. 79275-20038.40 reduction relative to baseline in urine albumin to creatinine ratio (UACR) at about 12 weeks after the start of treatment.

[0137] Embodiment 24. The method of any of embodiments 1-23, wherein the subject is administered an amount of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, sufficient to achieve at least about a 30% reduction relative to baseline in urine protein to creatinine ratio (UPCR) at about 12 weeks after the start of treatment.

[0138] Embodiment 25. The method of any of embodiments 1-24, wherein the subject is receiving standard of care treatment for chronic kidney disease (CKD) prior to the administration of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof.

[0139] Embodiment 26. The method of embodiment 25, wherein the standard of care treatment for chronic kidney disease (CKD) comprises administering one or more renin-angiotensin-aldosterone system (RAAS) inhibitors to the subject.

[0140] Embodiment 27. The method of embodiment 26, wherein the standard of care treatment for chronic kidney disease (CKD) further comprises administering one or more SGLT2 inhibitors, one or more mineralocorticoid receptor antagonists, or one or more GLP-1 receptor agonists, or any combination of the foregoing, to the subject.

[0141] Embodiment 28. The method of embodiment 26 or embodiment 27, wherein the standard of care treatment for chronic kidney disease (CKD) further comprises administering one or more anti-hypertensive treatments to the subject.

[0142] Embodiment 29. The method of any of embodiments 1-28, wherein Compound (I) is administered to the subject.

[0143] Embodiment 30. The method of any of embodiments 1-28, wherein a pharmaceutically acceptable salt of Compound (I) is administered to the subject.

[0144] Embodiment 31. The method of any of embodiments 1-28 and 30, wherein a hydrochloride salt of Compound (I) is administered to the subject.

[0145] Embodiment 32. The method of any of embodiments 1-28, 30, and 31, wherein a monohydrochloride salt of Compound (I) is administered to the subject.

[0146] Embodiment 33. The method of any of embodiments 1-28, wherein a monohydrate of a monohydrochloride salt of Compound (I) is administered to the subject.37MF-366484133Attorney Docket No. 79275-20038.40

[0147] Embodiment 34. The method of any of embodiments 1-33, wherein the subject is a human.

[0148] Embodiment 35. A dosage form comprising Compound (I):Compound (I),or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in an amount of about 5 mg to about 480 mg.

[0149] Embodiment 36. The dosage form of embodiment 35, wherein the dosage form comprises Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in an amount of about 5 mg.

[0150] Embodiment 37. The dosage form of embodiment 35, wherein the dosage form comprises Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in an amount of about 20 mg.

[0151] Embodiment 38. The dosage form of embodiment 35, wherein the dosage form comprises Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in an amount of about 50 mg.

[0152] Embodiment 39. The dosage form of any of embodiments 35-38, wherein the dosage form further comprises a pharmaceutically acceptable carrier or excipient.

[0153] Embodiment 40. The dosage form of any of embodiments 35-39, wherein the dosage form is configured for daily administration.

[0154] Embodiment 41. The dosage form of any of embodiments 35-40, wherein the dosage form is configured for oral administration.38MF-366484133Attorney Docket No. 79275-20038.40

[0155] Embodiment 42. The dosage form of any of embodiments 35-41, wherein the dosage form comprises Compound (I).

[0156] Embodiment 43. The dosage form of any of embodiments 35-41, wherein the dosage form comprises a pharmaceutically acceptable salt of Compound (I).

[0157] Embodiment 44. The dosage form of any of embodiments 35-41 and 43, wherein the dosage form comprises a hydrochloride salt of Compound (I).

[0158] Embodiment 45. The dosage form of any of embodiments 35-41, 43, and 44, wherein the dosage form comprises a monohydrochloride salt of Compound (I).

[0159] Embodiment 46. The dosage form of any of embodiments 35-41, wherein the dosage form comprises a monohydrate of a monohydrochloride salt of Compound (I).EXAMPLESSynthetic Examples

[0010] Example 76 of U.S. Pat. No. 11,976,067, which is herein incorporated by reference in its entirety, and specifically with respect to Example 76, is illustrative of the methods by which Compound (I) can be synthesized. Various modifications to the synthetic reaction scheme can be made, as will be apparent to those of ordinary skill in the art.

[0161] The starting materials and the intermediates of the synthetic reaction scheme can be isolated and purified if desired using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data. Although certain exemplary embodiments are depicted and described in U.S. Pat. No. 11,976,067, Compound (I) may be prepared using appropriate starting materials according to the methods described generally therein and / or by methods available to one of ordinary skill in the art.

[0162] The drug substance (Compound (I) HC1 H2O) is manufactured by chemical synthesis in four linear steps from two starting materials (Compound (I)-Rl and Compound (I)-R2) followed by milling. The manufacturing process is outlined below:39MF-366484133Attorney Docket No. 79275-20038.40<Biological ExamplesExample B-lPreclinical Studies

[0163] Primary pharmacodynamics (PD) of Compound (I) was evaluated using in vitro and in vivo assays. In vitro primary PD studies conducted demonstrated low nanomolar cellular unbound potencies of Compound (I) in trypanosomes (0.19-0.32 nM ECso values), HEK293 cells (1.3-2.4 nM ECso values), and podocytes expressing human APOL1 GO, G1 or G2 variants (0.072-0.285 nM ECso values). The low micromolar potency of Compound (I) against APOLl-induced calcium (Ca2+) flux (IC500.90 pM) or ion channel current in HEK293 cells (IC500.75-0.86 pM) demonstrated that, under the assay conditions used, higher concentrations of Compound (I) were required to inhibit ion flux through the APOL1 channel.

[0164] Consistent with in vitro cytotoxicity results, data from in vivo primary PD studies demonstrated that Compound (I) was highly potent in preventing APOL1 G1 and G2-mediated hepatotoxicity following BID PO administration of Compound (I) to C57Bl / 6n mice40MF-366484133Attorney Docket No. 79275-20038.40 (IDso values ranging from 0.50 to 0.89 mg / kg BID). In a renal dysfunction model using G2 HOM B AC-Tg mice, the ID50 value of Compound (I), with respect to inhibition of the elevated urinary albumin creatinine ratio (UACR), was 0.39 mg / kg BID PO.

[0165] Secondary PD studies in vitro indicated that Compound (I) was highly selective for APOL1, as Compound (I) only had activity against a small number of other molecular targets at a concentration range close to that anticipated in clinical studies. Of the > 400 proteins evaluated (including kinases, ligand-gated or G-protein coupled receptors, transporters, or ion channels) Compound (I) demonstrated the most potent inhibition (IC50 value of 17.9 nM) of the human adenosine transporter. Many structurally diverse small molecules are known to bind to the adenosine transporter (Ribeiro and Storer, Toxicol. Appl. Pharmacol. 2017, 317:41-50; herein incorporated by reference in its entirety). The selectivity of Compound (I) for APOL1 G1 or G2 in the cytotoxicity assays over the adenosine and dopamine transporters was > 7.5 and > 688-fold, respectively. Compound (I) (1 pM) was associated with 78% and 59% inhibition of binding to the human al A adrenoceptor and sodium (site 2) channel, respectively. In a cell-based functional assay, Compound (I) had an antagonist equilibrium dissociation constant (KB) value of 0.31 pM for the human al A adrenoceptor, and no agonist activity at concentrations up to 10 pM. A comparison of the inhibitory potencies of Compound (I) for hNavl.5 and hCavl.2 (alC / p2a / a261) ion channels to its APOL1 cytotoxicity potency indicates that Compound (I) had an APOL1 selectivity of > 8158. These selectivity assessments indicate that there is a low risk for potential off-target mediated adverse effects with Compound (I) in humans.

[0166] Compound (I) did not cause adverse effects in any of the in vivo safety pharmacology assessments. The IC50 for the GLP in vitro hERG assay (0.65 ± 0.46 pM) indicates that there should be little risk of QTc prolongation at doses anticipated to demonstrate efficacy given the very high (> 99%) PPB of Compound (I). There were no discernible effects on neurobehavior at any dose level of Compound (I) in either male (high dose of 100 mg / kg / day) or female rats (high dose of 300 mg / kg / day) in the 28-day study. In vivo respiratory and cardiovascular safety pharmacology evaluations conducted in the 28-day cynomolgus monkey study found no evidence of Compound (I)-related altered respiratory or cardiovascular parameters at any dose level over the 28-day study (high dose of 100 mg / kg / day).41MF-366484133Attorney Docket No. 79275-20038.40

[0167] The drug metabolism and pharmacokinetic characteristics of Compound (I) were determined using in vitro tools as well as in vivo assessments. In vitro assessment with Caco-2 cells indicated that Compound (I) would be highly permeable, which was subsequently confirmed by moderate to high bioavailability (F) in all nonclinical species examined including: C57Bl / 6n mice, SD rats, beagle dogs, and cynomolgus monkeys. Plasma protein binding of Compound (I) was consistently high (> 99% bound) across all species, and the observed volumes of distribution after IV administration were approximately 2- to 6-fold greater than total body water (0.6 L / kg), indicating significant tissue distribution.

[0168] In vitro Compound (I) was metabolized via a mixture of Phase 1, Phase 2, and Phase 1 plus Phase 2 processes. CYP3 A was the only recombinant CYP that demonstrated the ability to metabolize Compound (I). Direct sulfation was also observed and appeared to be catalyzed by SULTs 1A2, 1A1*2 and 2A1. There was no indication of reactive metabolite formation in vitro in any species. All the in vitro human metabolites were also observed with rats and cynomolgus monkeys, the nonclinical safety species, indicating that toxicity assessments in these species are likely to include all human metabolites. Excretion of unchanged Compound (I) after IV administration to male bile-duct cannulated rats was minimal (< 5.2% of dose), indicating that metabolism is likely the primary clearance pathway in rats.

[0169] The IND-enabling toxicology program identified dose-limiting toxicities with 28-day repeat dose GLP studies that supported the safety of the doses proposed for the Phase 1 study. Subsequent 13-week GLP studies in rats and monkeys support longer duration of oral dosing in humans, as the risk-benefit ratio of exposure in these species remained the same as was determined in the 28-day studies.

[0170] Higher doses in the Wistar-Han (WH) rat dose range-finding (DRF) study showed moderate dose-dependent changes in liver enzymes as well as Compound (I)-related changes in direct and total bilirubin, and creatine kinase. These findings were consistent with microscopic findings of hepatocellular apoptosis / single cell necrosis in both males and females at 1000 mg / kg / day. At 300 mg / kg / day there was increased total cholesterol and triglycerides, as well as increases in red blood cell distribution width in females. These findings were not considered adverse due to the lack of any microscopic correlates. In the 28-day study, similar observations of42MF-366484133Attorney Docket No. 79275-20038.40 non-adverse changes in total protein, albumin, and globulin were noted at the higher dose levels. Total cholesterol was increased mildly in females at 300 mg / kg / day, but with no microscopic correlate and therefore considered non-adverse. Microscopic changes in the jejunum consisted of multifocal dilation of the villi within the lymphatics at > 100 mg / kg / day, but these findings were considered non-adverse due to the lack of any associated inflammatory infiltrate or any pathologic finding.

[0171] At the end of the 28-day treatment period in the IND-enabling study, the NOAEL was determined to be 30 mg / kg / day for male, and 300 mg / kg / day for female rats. In the 13-week GLP toxicity study in WH rats, the highest doses evaluated were 30 mg / kg / day in male rats, and 300 mg / kg / day in female rats. There were no adverse effects observed at these doses at the end of the treatment period, and exposures were similar to those of the 28-day study, indicating the benefit risk assessment and therapeutic exposure ratio based on the lowest NOAEL of 30 mg / kg / day in male rats was the same even with longer duration of dosing. The systemic exposure values (CMAX and AUCO-24H) in male rats at 30 mg / kg / day at steady state were 3850 ng / mL and 43500 hr*ng / mL, respectively.

[0172] High doses (> 300 mg / kg / day) of Compound (I) administered PO to cynomolgus monkeys resulted in dose-limiting toxicities that included “cold to touch” observations, and decreased activity. Dosing holidays and lowered dose levels allowed most of the animals to recover and complete the study. The high dose of 100 mg / kg / day in the 28-day repeat dose study was well-tolerated in both sexes and the earlier toxicity was not observed over the longer duration of the 100 mg / kg / day dose level, confirming the toxicities were dosedependent. Safety pharmacology assessments within the pivotal study confirmed that 100 mg / kg / day of Compound (I) had no effect on QTc or any cardiovascular parameter assessed in the study. Compound (I) had no effect on any respiratory parameter assessed up to 100 mg / kg / day dose. The average (male and female) monkey steady-state (Day 28) systemic exposures (CMAX and AUCO-24H) of Compound (I) at the 100 mg / kg / day NOAEL were 65,500 h*ng / mL 5,380 ng / mL, respectively. As there were no adverse findings in the 13-week study the highest dose of 100 mg / kg / day in cynomolgus monkeys was the NOAEL. The combined exposures (CMAX and AUCO-24H) for males and females at the end of the 13-week treatment were 9,110 ± 1,750 ng / mL and 135,000 ± 31,600 hr*ng / mL, higher than observed at the end of the 28-day treatment at the 43MF-366484133Attorney Docket No. 79275-20038.40 NOAEL. The risk benefit exposure margin from nonclinical studies uses the calculation from the 30 mg / kg / day male rat NOAEL as that is the lowest NOAEL exposure.Example B-2: Phase I Study

[0173] The first-in-human study of Compound (I) assessed the safety, tolerability, and pharmacokinetics of single and multiple ascending doses in 111 healthy adult participants. The study was performed using a hydrate of an HC1 salt of Compound (I). There were no severe AEs or serious adverse events (SAEs) reported during the study across all cohorts. There were no clinically significant changes in vital signs, laboratory values, ECGs, and clinical examination during the study. Compound (I) was well-tolerated at single doses up to 480 mg and multiple doses up to 350 mg once-daily for 7 days. In these cohorts combined, all treatment-related adverse events (TRAEs) were reported as mild and transient. Headache was the only TRAE reported in >3 participants (20% vs. 4%, Compound-(I)-treated vs. placebo) in these cohorts. Linear and dose proportional plasma PK, relatively low PK variability, low (<1%) urinary excretion, and a food effect (increase of approximately 30-50%) were observed. Compound (I) had linear PK with dose proportional increases in plasma PK parameters (AUC, Cmax) in the 20 mg to 480 mg dose range. The median time to maximum concentrations (Tmax) was 2.66 hours and ti / 2 was 18.3 hours. Multiple dose PK was consistent with that observed after single dose administration. Mean increases in plasma exposures of 35% (AUC) and 33% (Cmax) were observed between Day 1 and 7. Urinary excretion of Compound (I) was minimal (< 1% of dose) and consistent across SAD cohorts. Administration of Compound (I) with high-fat meal prolonged median Tmax to 4.03 hours and increased mean Cmax and AUCinf by 33% and 50%, respectively.

[0174] Dose-related headache, nausea, and vomiting were observed at projected supratherapeutic doses. Mild TRAEs of headache, nausea, and vomiting were reported in a 480 mg split-dose cohort. In the 480 mg QD cohort, mild and moderate TRAEs of headache, vomiting, and nausea were reported. All TRAEs resolved upon discontinuation of Compound (I).44MF-366484133Attorney Docket No. 79275-20038.40 Example B-3: Phase 2 Study

[0175] A Phase 2, open-label study of Compound (I) in adults aged 18 to 65 years with proteinuric chronic kidney disease (CKD) and the APOL1 high risk genotype, or APOL1 Kidney Disease (AKD) is described herein. Up to 68 participants will be enrolled in the study with approximately 28 to 34 participants in each cohort.

[0176] The study consists of 2 cohorts comprised of approximately 28-34 participants. Cohort 1 comprises participants with the APOL1 high risk genotype, proteinuric kidney disease and concurrent diabetes. Cohort 2 comprises participants with the APOL1 high risk genotype, proteinuric kidney disease and without concurrent diabetes.• Cohort 1 : CKD with concurrent diabetes administered Compound (I) 250 mg once daily • Cohort 2: CKD without concurrent diabetes administered Compound (I) 250 mg once daily

[0177] Cohort 2 is targeted to enroll a minimum of 5 participants with FSGS confirmed by biopsy with no evidence of severe or more than 50% tubulointerstitial fibrosis.

[0178] A once daily dose of Compound (I) of 250 mg will be administered to participants in both cohorts and is predicted to be in the efficacious dose range (~EC9o-9s) based on in vivo pharmacology models and in an exposure range that was well-tolerated in the Phase 1 study. The 250 mg dose is compatible with the 50-mg unit dosage strength capsules, eliminating the need to combine different dosage strengths, as was done in the Phase 1 study, and reducing the risk of potential medication errors. The dose of 250 mg administered for 12 weeks is supported by the safety, tolerability, and PK profile observed in the Phase 1 study and the completed 13-week nonclinical toxicity studies. In the 13-week toxicity studies, the NOAEL in male rats remained 30 mg / kg / day while for female rats remained 300 mg / kg / day. In monkeys, the 13-week toxicity study NOAEL in both males and females was the highest dose tested (100 mg / kg / day). No dose-limiting toxi cities were observed in either of the 13-week GLP toxicity studies at any dose. The exposure at steady state in humans at the 250 mg dose is predicted to be a CMAX of 871 ng / mL, and an AUC0-24 of 11,600 hr*ng / mL, providing an EC92 for the predicted mean exposure. This predicted exposure has an exposure margin of 3.75-fold below the male rat45MF-366484133Attorney Docket No. 79275-20038.40 AUC at the NOAEL and 4.4-fold lower than the male rat CMAX at the NOAEL. The observed exposure margins at steady state are summarized in Table 1 below as well as predicted margins for the Phase 2 dose of 250 mg.Table 1. Human Exposure Margins at Observed 240 mg and Predicted 250 mg Doses at Steady- State.

[0179] The study includes a Screening Period (Day -42 to -1) which can be conducted over two separate visits. The first visit at minimum will include informed consent, demographics, and APOL1 genotyping. Once genotyping results are available, participant can return to complete the remainder of the Screening visit procedures.

[0180] Following Screening, participants meeting all eligibility criteria for a cohort are enrolled and receive once-daily oral doses of Compound (I) during the open-label 12-week treatment period. Upon completion of the treatment period, participants return for an Exit visit at Week 16.Number of Participants and Number of Study Centers

[0181] Up to 68 participants are planned to be enrolled with approximately 28 to 34 participants in each cohort across approximately 100 global study centers. At least 5 participants in Cohort 2 should have FSGS confirmed by biopsy.Study Duration46MF-366484133Attorney Docket No. 79275-20038.40

[0182] The study duration for individual participants will be up to 22 weeks which includes up to 6 weeks in Screening, 12 weeks on study drug, and 4 weeks of follow-up.Dose

[0183] A dose of 250 mg of Compound (I) once daily was selected based on the clinical safety, tolerability, and PK data from Example B-2 conducted in healthy adults, toxicology data, and preclinical pharmacodynamic data. Population-pharmacokinetic modeling (two-compartment model with inter-subject variability on clearance, central volume, absorption and peripheral volume, allometric scaling on clearance and volume) was used to project plasma PK exposure for the selected dose across bodyweight ranges expected in population to be assessed in this study. The expected exposure for the selected 250 mg dose was well tolerated in Example B-l and expected to be efficacious based on plasma PK exposure and %UACR reduction relationship established in the BAC transgenic mouse model of APOL1 kidney disease. Human plasma exposures after 250 mg dose correspond to a predicted effective concentration of 90% to 95% (~EC9O-95).End of Study Definition

[0184] A participant is considered to have completed the study if he / she has completed all periods of the study, including the Exit visit at Week 16. The end of the study is defined as the date of the last visit of the last participant in the study.Study Population

[0185] Participants not meeting all inclusion criteria, or meeting at least one exclusion criterion, may be re-screened once if there is a reasonable possibility of eligibility. Inclusion in the study of any participant who meets all eligibility criteria on rescreening will be at the discretion of the Investigator.Inclusion Criteria

[0186] Participants eligible for inclusion in this study must meet all of the following criteria:47MF-366484133Attorney Docket No. 79275-20038.40 For All Participants (Cohort 1 & Cohort 2):• 18 to 65 years of age (inclusive) at the time of signing the informed consent• Body mass index (BMI) of 18 to <45 kg / m2and total body weight of >40 kg• Confirmed APOL1 high risk genotype of Gl / Gl, G2 / G2, or G1 / G2• Diagnosis of chronic kidney disease with persistent high urine albuminuriao Confirmed by UACR >300 mg / g. Based on the average of 3 consecutive first morning void samples collected during the Screening Period. Collection should be completed by Day -10 for confirmation of eligibility.• Estimated glomerular filtration rate (eGFR) >25 mL / min / 1.73 m2to <90 mL / min / 1.73 m2at Screening based on the Chronic Kidney Disease Epidemiology Collaboration (2021 CKD-EPI Creatinine-Cystatin C) equation.• Stable doses of background standard-of-care treatment for CKD for at least 8 weeks prior to Screening, including but not limited to:o Renin-angiotensin-aldosterone system (RAAS) inhibitors (required unless not tolerated or contraindicated)o SGLT2 inhibitors, mineralocorticoid receptor antagonists, GLP-1 receptor agonists (permitted but not required)o Anti-hypertensive treatment (if indicated)• Negative tests for HBcAb, HBsAg, HCV antibody, and HIV antibody at Screening. o Participants with positive anti -HCV antibody are allowed if HCV RNA PCR is negative.• Women of childbearing potential must have a negative pregnancy test at Screening (serum) and at Day 1 (serum or urine).• Participants who are completely abstinent from sexual intercourse (if this is the participant’s usual and preferred lifestyle) or in same sex relationships do not require contraception. For other participants, use of highly effective contraception is required. • Post-menopausal female participants do not require contraception if >12 months without menses and follicle-stimulating hormone (FSH) documented in post-menopausal range (>40 IU / L).48MF-366484133Attorney Docket No. 79275-20038.40 Cohort 1 :• Diagnosis of Type 2 diabetes mellitus on a stable regimen of antidiabetic medication(s) and / or insulin for at least 8 weeks prior to Screening• Participants with a concurrent diagnosis of hypertension-related CKD or focal segmental glomerulosclerosis (FSGS; with or without confirmation by biopsy and without a known cause other than AP0L1) are eligible provided other selection criteria for Cohort 1 are met.Cohort 2:• Diagnosis of CKD attributed to any of the following:o Hypertensiono FSGS with or without confirmation by biopsy and without a known cause other than AP0L1Exclusion Criteria

[0187] Participants meeting any of the following criteria are not eligible for inclusion in this study:For All Participants (Cohort 1 & Cohort 2):• Any condition that in the opinion of the Investigator would interfere with the evaluation of the investigational product or lead to increased risk of harm. This may include, but is not limited to, the following:o History of cancer within past 2 years, excepted for treated non-melanoma skin cancer, stage 0 cervical cancer, or stage 1 prostate cancero Clinically significant liver diseaseo Unstable cardiac disease, including history of unstable angina, myocardial infarction or stroke within 12 months prior to Screening49MF-366484133Attorney Docket No. 79275-20038.40 o Requirement for supplemental oxygen or history of intubation within 6 months prior to Screeningo Organ or bone marrow transplantationo Clinically significant and active infectiono Uncontrolled hypothyroidismo History of thromboembolism within 1 year prior to Screeningo Ongoing alcohol or substance abuse as determined by the Investigator o Conditions that may alter drug absorption, e.g., history of bariatric surgery o Pregnancy or currently nursing• Use of any potent immunosuppressants within 5 PK half-lives or 12 weeks prior to Screening, whichever is longer, including but not limited to: abatacept, adalimumab, anakinra, azathioprine, cyclophosphamide, certolizumab, etanercept, golimumab, infliximab, rituximab, ruxolitinib, sarilumab, tofacitinib, or tocilizumabo Cyclosporine, mycophenolate mofetil, and / or tacrolimus are permitted if stable regimen and dose for at least 8 weeks prior to Screening• Use of oral corticosteroids equivalent to prednisone >10 mg / day for more than 1 day within 8 weeks prior to Screening and / or use of any other systemic corticosteroid equivalent to prednisone >10 mg / day within 8 weeks prior to Screening.• Clinically significant abnormal laboratory test results with the exception of abnormalities considered by the Investigator to be the result of underlying disease. Test results within the following ranges at Screening will exclude a patient from participation in the study:o Total bilirubin >1.5 x upper limit of normal (ULN)o Aspartate transaminase (AST) or alanine transaminase (ALT) >2 x ULN o Serum albumin <2 g / dLo TSH>10 mIU / Lo Potassium >ULNo Hemoglobin <10 g / dLo Absolute Neutrophil Count (ANC) <1000 cells / pL50MF-366484133Attorney Docket No. 79275-20038.40 o Clinically significant abnormal Screening ECG, including but not limited to QTcF >450 ms or history of QT interval prolongation• Vital Signs outside the following ranges (assessment may be repeated at the Investigator’s discretion) at the Screening visit:o Systolic blood pressure 90 to 180 mg Hg, inclusiveo Diastolic blood pressure 40 to 100 mg Hg, inclusiveo Heart rate 50 to 99 bpm, inclusive• Medications that are strong CYP3 A4 inhibitors or inducers (e.g., rifampin, carbamazepine, clarithromycin, itraconazole), including herbal supplements (e.g., St. John’s wort), grapefruit, Seville-oranges, or poppy seeds within 14 days of study drug administration and throughout the study.• Proton pump inhibitors within 14 days of study drug administration and throughout the study• Have used any investigational drug within 8 weeks or <5 half-lives, whichever is longer, prior to the Screening visit• Hypersensitivity to Compound (I) or its components• For participants with kidney biopsy: biopsy result indicating severe or >50% tubulointerstitial fibrosis• Planned travel during the study to regions with endemic trypanosomiasisCohort 1 :• Glycosylated hemoglobin Ale >8.0% at Screening or brittle diabetes per Investigator judgement• Diagnosis of Type I diabetes mellitus• Kidney disease attributed to other known causes including but not limited to: active infection, autoimmune disease (e.g., lupus nephritis, IgA nephropathy, membranous nephropathy, glomerular basement membrane disease), toxins, drugs (e.g., bisphosphonate, interferon), congenital abnormalities (except unilateral renal agenesis), malignancy, minimal change disease, previously diagnosed genetic kidney disease (e.g.,51MF-366484133Attorney Docket No. 79275-20038.40 autosomal dominant polycystic kidney disease, Alport syndrome), sickle cell disease, amyloidosiso Sickle trait is permittedo Solitary native kidney is permittedCohort 2:• Current treatment with an antidiabetic medication and / or insulin, glycosylated hemoglobin Ale >6.5% at Screening, or any of the following in the medical history:o Fasting glucose >126 mg / dL on 2 separate dayso 2-hour plasma glucose >200 mg / dL during an oral glucose tolerance test• Kidney disease attributed to other known causes including but not limited to Type 1 or 2 diabetes mellitus, active infection, autoimmune disease (e.g., lupus nephritis, IgA nephropathy, membranous nephropathy, anti-glomerular basement membrane disease), toxins, drugs (e.g., bisphosphonate, interferon), congenital abnormalities (except unilateral renal agenesis), malignancy, minimal change disease, previously diagnosed genetic kidney disease (e.g., autosomal dominant polycystic kidney disease. Alport syndrome), sickle cell diseaseo Sickle trait is permittedo Solitary native kidney is permittedRescreening

[0188] Any participant who initially fails eligibility criteria may be rescreened once at the discretion of the Investigator. Sponsor to be consulted to determine which screening procedures need to be repeated.Replacement of Participants

[0189] Participants who discontinue early from the study for non-safety related reasons may be replaced at the discretion of the Sponsor.52MF-366484133Attorney Docket No. 79275-20038.40 Lifestyle Considerations

[0190] Participants should be advised to maintain their usual diet (including typical protein consumption) and activity levels throughout the study. Strenuous exertion 24 hours prior to urine collection should be avoided when possible.Study Drug Administered

[0191] The investigational product for this study is Compound (I) supplied as 50 mg hard-shell capsules comprising a hydrate of an HC1 salt of Compound (I) and pharmaceutically acceptable excipients.Dosing and Administration

[0192] During the study, participants will be instructed to take five (5) Compound (I) HC1 capsules (50 mg each) orally once daily for a total dose of 250 mg at approximately the same time each morning in a fasted state. Water is permitted as desired along with study drug administration.

[0193] Study dosing will start in the clinic on Day 1 and the last dose of study drug will be in the clinic on Day 84. During in-clinic visits, study drug administration will occur at the clinic. Study participants will complete a daily dosing diary to record date, time, and amount for daily dose administration.Prohibited Treatments

[0194] The decision to administer a prohibited medication / treatment is done with the safety of the study participant as the primary consideration. When possible, Sponsor or designee should be notified before the prohibited medication / treatment is applied.

[0195] The following medications are prohibited:• Use of medications that are strong CYP3 A4 inhibitors or inducers (e.g., rifampin, carbamazepine, clarithromycin, itraconazole, etc.), including herbal supplements (e.g., St.53MF-366484133Attorney Docket No. 79275-20038.40 John’s wort), grapefruit, Seville-oranges, or poppy seeds are prohibited within 14 days of study drug administration and throughout the study.• Use of proton pump inhibitors within 14 days of study drug administration and throughout the study. Participants on proton pump inhibitors at the Screening visit should be switched to shorter-acting anti-reflux medications (i.e., U-blockers or antacids) at least 14 days prior to the Day 1 visit if medically appropriate.• Use of oral corticosteroids equivalent to prednisone >10 mg / day for more than 1 day within 8 weeks prior to Screening. Use of any other systemic corticosteroid equivalent to prednisone >10 mg / day within 8 weeks prior to Screening will be prohibited.• Use of any potent immunosuppressants within 5 PK half-lives or 12 weeks prior to Screening, whichever is longer, including but not limited to: abatacept, adalimumab, anakinra, azathioprine, cyclophosphamide, certolizumab, etanercept, golimumab, infliximab, rituximab, ruxolitinib, sarilumab, tofacitinib, or tocilizumab.• Use of any other investigational drugs are not allowed at any point during this study. In cases where an investigational drug has been used prior to the study, 5 PK half-lives or 8 weeks, whichever is longer, must have passed prior to Screening.Permitted Treatments

[0196] Treatment consistent with local standard of care for CKD and / or diabetes is permitted provided the medication regimen and dosing have been stable for at least 8 weeks prior to Screening. Effort should be made to maintain a stable regimen as medically appropriate for the duration of the study.

[0197] Permitted treatments may include one or more of the following, but not limited to:• Sodium-glucose co-transporter 2 (SGLT2) inhibitors• Mineralocorticoid receptor antagonist (MRA)• Renin-angiotensin-aldosterone system (RAAS) inhibitors (required unless not tolerated or contraindicated)• Glucagon-like peptide- 1 (GLP-1) receptor agonists54MF-366484133Attorney Docket No. 79275-20038.40

[0198] Other permitted treatments include the following immunosuppressants if the regimen and dose have been stable for at least 8 weeks prior to Screening:• Cyclosporine, mycophenolate mofetil, and / or tacrolimus• Corticosteroids (<10 mg per day of prednisone or equivalent)

[0199] Permitted treatments for gastroesophageal reflux include H2-blockers and antacids. These medications should be administered as follows:• H2-blockers should be administered at least 10 hours before study drug administration and / or no sooner than 2 hours after study drug administration• Antacids should be administered at least 2 hours before study drug administration and / or no sooner than 2 hours after study drug administrationStudy Assessments and ProceduresAPOL1 Genotyping

[0200] A peripheral blood sample will be obtained at Screening to genotype participants for APOL1 risk alleles (Gl, G2) using qPCR, sequencing, or other standard genotyping methods if the participant’s genotype status has not been previously determined by a Sponsor approved vendor.

[0201] After the Screening visit, participants should be instructed to collect their first morning urine void at home for 3 consecutive days within the 10 days prior to the Day 1 visit. For all other visits, participants should be instructed to collect their first morning urine void at home for 3 consecutive days prior to each in-clinic or home health visit. The third day of collection should be the day of the study visit. Participants should be reminded to abstain from strenuous activity (e.g., more than 20 minutes per day of running, swimming, weightlifting or other physical activities exceeding their usual level of daily exertion) where possible 24 hours prior to urine collection.55MF-366484133Attorney Docket No. 79275-20038.40 Kidney Disease Qualify of Life Questionnaire (KDQOL-36)

[0202] KDQOL-36 is a validated survey that measures the impact of kidney disease on patients’ health-related quality of life and will be administered at Week 1 and Week 12. It includes the SF-12 as a generic core and three kidney disease-specific scales: burden, symptoms, and effects. Hays RD, et. al. (1997). Kidney Disease Quality of Life Short Form (KDQOL-SF™), Version 1.3: A Manual for Use and Scoring. Santa Monica, CA: RAND, P-7994; herein incorporated by reference in its entirety.Efficacy Endpoints

[0203] A binary endpoint (30% reduction at Week 12 compared to baseline in UACR), the proportion of responders along with 90% confidence intervals (CI) will be presented as a secondary endpoint. Continuous endpoints, mean changes from baseline and 90% CI will be presented as exploratory endpoints. Similar analyses will be conducted based on UPCR as additional exploratory endpoints. Data may be log-transformed as appropriate.

[0204] Individual plasma drug concentrations will be listed and summarized by cohort and timepoint. These plasma drug concentrations may be assessed using population PK analysis modeling. Exploratory exposure-response analyses may be conducted. In addition, other analyses on samples may be performed to characterize Compound (I) PK, biomarkers, and its variability.Safety AnalysesDefinition of Adverse Event

[0205] An adverse event (AE) is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study drug or other protocol-imposed intervention, whether or not considered related to the study drug.

[0206] Events meeting the AE definition include the following:56MF-366484133Attorney Docket No. 79275-20038.40 • Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital signs measurements), including those that worsen from baseline, considered clinically significant in the medical and scientific judgment of the Investigator (i.e., not related to progression of underlying disease)• Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and / or intensity of the condition• New condition detected or diagnosed after study drug administration even though it may have been present before the start of the study• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug or a concomitant medication. Overdose per se will not be reported as an AE / SAE unless it is an intentional overdose taken with possible suicidal / self-harming intent. Such overdoses should be reported regardless of sequelae.

[0207] Events not meeting the AE definition include the following:• Any clinically significant abnormal laboratory findings or other abnormal safety assessments that are associated with the underlying disease, unless judged by the Investigator to be more severe than expected for the participant’s condition• The disease / disorder being studied or expected progression, signs, or symptoms of the disease / disorder being studied, unless more severe than expected for the participant’s condition• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to the procedure is the AE• Situations in which an untoward medical occurrence did not occur (social and / or convenience admission to a hospital)57MF-366484133Attorney Docket No. 79275-20038.40 • Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsenDefinition of Serious Adverse Event

[0208] A serious adverse event (SAE) is any untoward medical occurrence that, at any dose, meets 1 or more of the following criteria:• Is fatal (i.e., the AE actually causes or leads to death)• Is life-threatening (i.e., the AE, in the view of the Investigator, places the participant at immediate risk of death at the time of the event; it does not refer to an event which might hypothetically have caused death if more severe)• Requires or prolongs inpatient hospitalization• Results in persistent or significant disability / incapacity (i.e., the AE results in substantial disruption of the participant’s ability to conduct normal life functions)• Is a congenital anomaly / birth defect in a neonate / infant born to a mother exposed to the investigational product(s)• Is considered a significant medical event by the Investigator (i.e., may jeopardize the participant or may require medical / surgical intervention to prevent one of the outcomes listed above)

[0209] All AEs that do not meet any of the criteria for serious should be regarded as nonserious AEs. Elective hospitalizations for conditions that existed before administration of the study drug are not to be considered SAEs. However, pre-study conditions that worsen during the course of the study and meet the SAE criteria above would be considered SAEs.

[0210] The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of an AE (as in mild, moderate, or severe pain); the event itself may be of relatively minor medical significance (such as severe headache). “Serious” is a regulatory definition and is based on participant or event outcome or action criteria usually associated with events that pose58MF-366484133Attorney Docket No. 79275-20038.40 a threat to a participant’s life or vital functions. Seriousness (not severity) serves as the guide for defining regulatory reporting obligations. Severity and seriousness should be independently assessed when recording AEs and SAEs.Assessment of Severity

[0211] Assessment of severity for each AE and SAE reported during the study and assign it to one of the following categories:• Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations only;intervention not indicated.• Moderate: Minimal, local or noninvasive intervention indicated; limiting age- appropriate instrumental activities of daily living (ADL). Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc.• Severe: Severe or medically significant but not immediately life-threatening;hospitalization or prolongation of hospitalization indicated; disabling, limiting self-care ADL. Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedriddenAssessment of Causality

[0212] The relationship between study drug and each occurrence of each AE / SAE will be assessed using clinical judgment and the following guidelines:• Related: After consideration of factors including timing of the event, biologic plausibility, clinical judgment, and potential alternative causes, there is sufficient evidence (information) to suggest a causal relationship with study drug.• Not Related: After consideration of factors including timing of the event, biologic plausibility, clinical judgment, and potential alternative causes, there is insufficient evidence (information) to suggest a causal relationship with study drug.59MF-366484133Attorney Docket No. 79275-20038.40

[0213] Adverse events will be coded by system organ class and preferred terms using the Medical Dictionary for Regulatory Activities (MedDRA version 27.0). Treatment-emergent AEs (TEAEs) will be defined as AEs that start at or after study drug dosing. The number and percentage of participants experiencing TEAEs along with the severity and relationship to study drug will be summarized by cohort.

[0214] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entireties, to the same extent as if each were incorporated by reference individually.

[0215] It is to be understood that, while the disclosure has been described in conjunction with the above embodiments, the foregoing description and examples are intended to illustrate and not limit the scope of the disclosure. Other aspects, advantages and modifications within the scope of the disclosure will be apparent to those skilled in the art to which the disclosure pertains.60MF-366484133

Claims

1. Attorney Docket No. 79275-20038.40CLAIMSWhat is claimed is:

1. A method of treating an APOL1 -mediated disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I):Compound (I),or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in a daily amount of about 20 mg to about 480 mg.

2. The method of claim 1, wherein Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, is administered in a daily amount of about 20 mg, about 60 mg, about 120 mg, about 240 mg, about 250 mg, about 350 mg, or about 480 mg.

3. The method of claim 1 or claim 2, wherein Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, is administered in a daily amount of about 20 mg, about 60 mg, about 120 mg, about 240 mg, or about 480 mg.

4. The method of claim 1 or claim 2, wherein Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, is administered in a daily amount of about 60 mg, about 120 mg, about 240 mg, about 350 mg, or about 480 mg.61MF-366484133Attorney Docket No. 79275-20038.40 5. The method of claim 1 or claim 2, wherein Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, is administered in a daily amount of about 250 mg.

6. The method of any of claims 1-5, wherein Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, is administered in a single dose.

7. The method of any of claims 1-5, wherein Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, is administered in multiple doses.

8. The method of any of claims 1-7, wherein Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, is administered in a split dose.

9. The method of any of claims 1-8, wherein the disease, disorder, or condition is a chronic kidney disease (CKD).

10. The method of any of claims 1-9, wherein the disease, disorder, or condition is focal segmental glomerulosclerosis (FSGS), hypertension-attributed kidney disease, or diabetic kidney disease.

11. The method of any of claims 1-9, wherein the disease, disorder, or condition is chronic kidney disease (CKD) associated with focal segmental glomerulosclerosis (FSGS), hypertension, or diabetes.

12. The method of any of claims 1-11, wherein the subject has an APOL1 high risk genotype of Gl / Gl, G2 / G2, or G1 / G2.62MF-366484133Attorney Docket No. 79275-20038.40 13. The method of any of claims 1-12, wherein the subject has persistent urine albuminuria of at least about 300 mg / g before the start of treatment with Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof.

14. The method of any of claims 1-13, wherein the subject has an estimated glomerular filtration rate (eGFR) > 25 mL / min / 1.73 m2and < 90 mL / min / 1.73 m2before the start of treatment with Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof.

15. The method of any of claims 1-14, wherein Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, is administered once daily.

16. The method of any of claims 1-15, wherein Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, is administered orally.

17. The method of any of claims 1-16, wherein the subject is administered an amount of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, sufficient to achieve a steady-state pharmacokinetic profile characterized by systemic exposure corresponding to an effective concentration producing about 90% to about 95% of the maximal pharmacological effect at about 12 weeks after the start of treatment with Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof.

18. The method of any of claims 1-17, wherein the subject is administered an amount of Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, sufficient to achieve at least about a 30% reduction relative to baseline in urine protein to creatinine ratio (UPCR) at about 12 weeks after the start of treatment with Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof.63MF-366484133Attorney Docket No. 79275-20038.4019. The method of claim 18, wherein the protein in the urine protein to creatinine ratio (UPCR) is albumin.

20. A method of treating an APOL1 -mediated disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I):Compound (I),or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in an amount sufficient to achieve a steady-state pharmacokinetic profile characterized by systemic exposure corresponding to an effective concentration producing about 90% to about 95% of the maximal pharmacological effect.

21. A method of treating an APOL1 -mediated disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I):Compound (I),64MF-366484133Attorney Docket No. 79275-20038.40 or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in an amount sufficient to achieve a steady-state pharmacokinetic profile characterized(a) a peak-to-trough ratio consistent with once-daily dosing; and(b) systemic exposure corresponding to an effective concentration producing about 90% to about 95% of the maximal pharmacological effect.

22. The method of claim 20 or claim 21, wherein the systemic exposure corresponds to an effective concentration producing about 92% of the maximal pharmacological effect.

23. A method of treating an APOL1 -mediated disease, disorder, or condition in a human subject comprising administering to the subject Compound (I):or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, according to a dosing regimen that produces a steady-state systemic exposure characterized by:(a) an AUC0-24 sufficient to achieve at least about 90% of maximal pharmacological effect; and(b) a Cmax that is below a dose-limiting toxicity threshold,wherein the dosing regimen is administered once daily.

24. The method of claim 23, wherein the AUC0-24 is between about 11,000 ng / mL*hr and about 11,600 ng / mL*hr.

25. The method of claim 23 or claim 24, wherein the AUC0-24 is about 11,000 ng / mL*hr.65MF-366484133Attorney Docket No. 79275-20038.4026. The method of claim 23 or claim 24, wherein the AUC0-24 is about 11,600 ng / mL*hr.

27. The method of claim 23, wherein the Cmax is between about 870 ng / mL and about 930 ng / mL.

28. The method of claim 23 or claim 27, wherein the Cmax is about 870 ng / mL.

29. The method of claim 23 or claim 27, wherein the Cmax is about 930 ng / mL.

30. A method of treating an APOL1 -mediated disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I):or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, wherein the subject has persistent urine albuminuria of at least about 300 mg / g before the start of treatment with Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof.

31. A method of treating an APOL1 -mediated disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I):66MF-366484133Attorney Docket No. 79275-20038.40Compound (I),or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, wherein the subject has an estimated glomerular filtration rate (eGFR) > 25 mL / min / 1.73 m2and < 90 mL / min / 1.73 m2before the start of treatment with Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof.

32. A method of treating an APOL1 -mediated disease, disorder, or condition in a subject in need thereof, comprising administering to the subject Compound (I):or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, wherein the subject achieves at least about a 30% reduction relative to baseline in urine protein to creatinine ratio (UPCR) at about 12 weeks after the start of treatment with Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof.

33. The method of claim 32, wherein the protein in the urine protein to creatinine ratio (UPCR) is albumin.67MF-366484133Attorney Docket No. 79275-20038.40 34. The method of any of claims 1-33, wherein the subject is diabetic.

35. The method of any of claims 1-34, wherein the subject has Type 2 diabetes mellitus.

36. The method of any of claims 1-33, wherein the subject is not diabetic.

37. The method of any of claims 1-36, wherein Compound (I) is administered to the subject.

38. The method of any of claims 1-36, wherein a hydrochloride salt of Compound (I) is administered to the subject.

39. The method of any of claims 1-38, wherein the subject is a human.

40. The method of any of claims 1, 2, 5, 6, 9, 12-35, and 39, wherein the subject is a human with APOL1 high risk genotype, proteinuric kidney disease, and concurrent diabetes, and the subject is administered the compound in a once daily dose of 250 mg.

41. The method of any of claims 1, 2, 5, 6, 9, 12-32, 36, and 39, wherein the subject is a human with APOL1 high risk genotype and proteinuric kidney disease, and without concurrent diabetes, and the subject is administered the compound in a once daily dose of 250 mg.

42. A dosage form comprising Compound (I):Compound (I),or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in an amount of about 5 mg to about 480 mg.68MF-366484133Attorney Docket No. 79275-20038.4043. The dosage form of claim 42, wherein the dosage form comprises Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in an amount of about 5 mg.

44. The dosage form of claim 42, wherein the dosage form comprises Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in an amount of about 20 mg.

45. The dosage form of claim 42, wherein the dosage form comprises Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in an amount of about 50 mg.

46. The dosage form of any of claims 42-45, wherein the dosage form further comprises a pharmaceutically acceptable carrier or excipient.

47. The dosage form of any of claims 42-46, wherein the dosage form is configured for daily administration.

48. The dosage form of any of claims 42-47, wherein the dosage form is configured for oral administration.

49. The dosage form of any of claims 42-48, wherein the dosage form comprises Compound (I).

50. The dosage form of any of claims 42-48, wherein the dosage form comprises a hydrochloride salt of Compound (I).

51. Compound (I):69MF-366484133Attorney Docket No. 79275-20038.40or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, for use in treating an APOL1 -mediated disease, disorder, or condition in a subject in need thereof to achieve a steady-state pharmacokinetic profile characterized by systemic exposure corresponding to an effective concentration producing about 90% to about 95% of the maximal pharmacological effect.

52. Compound (I):Compound (I),or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, for use in treating an AP0L1 -mediated disease, disorder, or condition in a subject in need thereof to achieve a steady-state pharmacokinetic profile characterized by:(a) a peak-to-trough ratio consistent with once-daily dosing; and(b) systemic exposure corresponding to an effective concentration producing about 90% to about 95% of the maximal pharmacological effect.

53. Compound (I):MF-366484133Attorney Docket No. 79275-20038.40Compound (I),or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, for use in treating an AP0L1 -mediated disease, disorder, or condition in a subject in need thereof according to a dosing regimen that produces a steady-state systemic exposure characterized by:(a) an AUC0-24 sufficient to achieve at least about 90% of maximal pharmacological effect; and(b) a Cmax that is below a dose-limiting toxicity threshold,wherein the dosing regimen is administered once daily.

54. Compound (I):Compound (I),or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, for use in treating an AP0L1 -mediated disease, disorder, or condition in a subject in need thereof.

55. Compound (I):71MF-366484133Attorney Docket No. 79275-20038.40Compound (I),or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, for use in treating an AP0L1 -mediated disease, disorder, or condition in a subject in need thereof, wherein the subject has persistent urine albuminuria of at least about 300 mg / g before the start of treatment with Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof.

56. Compound (I):or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, for use in treating an APOL1 -mediated disease, disorder, or condition in a subject in need thereof, wherein the subject has an estimated glomerular filtration rate (eGFR) > 25 mL / min / 1.73 m2and < 90 mL / min / 1.73 m2before the start of treatment with Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof.

57. Compound (I):72MF-366484133Attorney Docket No. 79275-20038.40or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, for use in treating an APOL1 -mediated disease, disorder, or condition in a subject in need thereof, wherein the subject achieves at least about a 30% reduction relative to baseline in urine protein to creatinine ratio (UPCR) at about 12 weeks after the start of treatment with Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof.

58. Use of Compound<Compound (I),or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an AP0L1 -mediated disease, disorder, or condition in a subject in need thereof to achieve a steady-state pharmacokinetic profile characterized by systemic exposure corresponding to an effective concentration producing about 90% to about 95% of the maximal pharmacological effect.

59. Use of Compound (I):73MF-366484133Attorney Docket No. 79275-20038.40or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an AP0L1 -mediated disease, disorder, or condition in a subject in need thereof to achieve a steady-state pharmacokinetic profile characterized by:(a) a peak-to-trough ratio consistent with once-daily dosing; and(b) systemic exposure corresponding to an effective concentration producing about 90% to about 95% of the maximal pharmacological effect.

60. Use of Compoundor a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, for use in treating an APOL1 -mediated disease, disorder, or condition in a subject in need thereof according to a dosing regimen that produces a steady-state systemic exposure characterized by:(a) an AUC0-24 sufficient to achieve at least about 90% of maximal pharmacological effect; and(b) a Cmax that is below a dose-limiting toxicity threshold,wherein the dosing regimen is administered once daily.74MF-366484133Attorney Docket No. 79275-20038.4061. Use of CompoundCompound (I),or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating an AP0L1 -mediated disease, disorder, or condition in a subject in need thereof.

62. Use of CompoundCompound (I),or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating an AP0L1 -mediated disease, disorder, or condition in a subject in need thereof, wherein the subject has persistent urine albuminuria of at least about 300 mg / g before the start of treatment with Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof.

63. Use of Compound (I):75MF-366484133Attorney Docket No. 79275-20038.40Compound (I),or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating an AP0L1 -mediated disease, disorder, or condition in a subject in need thereof, wherein the subject has an estimated glomerular filtration rate (eGFR) > 25 mL / min / 1.73 m2and < 90 mL / min / 1.73 m2before the start of treatment with Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof.

64. Use of Compound<Compound (I),or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating an AP0L1 -mediated disease, disorder, or condition in a subject in need thereof, wherein the subject achieves at least about a 30% reduction relative to baseline in urine protein to creatinine ratio (UPCR) at about 12 weeks after the start of treatment with Compound (I), or a pharmaceutically acceptable salt, hydrate, or hydrate of a pharmaceutically acceptable salt thereof.76MF-366484133

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