Methods for treating APOL1-mediated kidney disease

Abstract

The present disclosure provides methods for treating a disease associated with apolipoprotein L1 (APOL1) comprising administering an APOL1 oligonucleotide defined herein. The present disclosure also provides unit dosages comprising the APOL1 oligonucleotide.

Description

[0001] METHODS FOR TREATING APOL1-MEDIATED KIDNEY DISEASE

[0002] CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

[0003] This specification claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 650,195 (filed May 21, 2024) and U.S. Provisional Patent Application No. 63 / 730,153 (filed December 10, 2024). The entire contents of the above-referenced patent applications are incorporated by reference into this specification for all purposes.

[0004] SEQUENCE LISTING

[0005] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled 201385-PCT01-NP.xml created 31 March 2025, which is 12 kb in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety.

[0006] FIELD

[0007] The present disclosure provides methods for treating a disease associated with apolipoprotein LI (APOL1). The present disclosure also provides unit dosages suitable for use in said methods.

[0008] BACKGROUND

[0009] End-stage kidney disease (ESKD) affects over half a million individuals in the United States. In the US, the likelihood that individuals of African ancestry will develop ESKD is approximately twice that observed among other ethnic ancestry patients (McClellan W. et al. Am. J. Kidney Dis. 1988. 12: 285-290; Cowie CC. et al. N. Engl. J. Med. 1989. 321 : 1074- 1079). There are no specific therapies for the vast majority of kidney diseases. Antihypertensive and anti-inflammatory treatments have been found to slow progression and reduce symptoms in some patients for some types of chronic kidney disease (CKD), but they neither result in disease resolution nor completely halt disease progression.

[0010] Recent data has suggested the association of two common variants (G1 and G2) in the last exon of APOL1 among African ancestry patients and increased risk for developing CKD (Kao WH et al. Nat. Genet. 2008. 40: 1185-1192; Lipkowitz MS et al. Kidney Int. 2013. 83: 114-120; Genovese G. et al. Science. 2010. 329: 841-845; Tzur et al. Hum Genet. 2010; Kopp et al. J Am Soc Nephrol. 2011). In a 2013 study, G1 and G2 risk variants in APOL1 were associated with higher rates of ESKD and progression of CKD that were observed in African ancestry patients as compared to other ethnic ancestry groups, regardless of diabetes status (Parsa A et al. N. Engl. J. Med. 2013. 369: 2183-2196). Approximately 50% of African ancestry subjects carry one risk allele in APOL1 whilst approximately 13% of African ancestry subjects (~ five million individuals) carry two risk alleles in APOL1, a substantial fraction of which will develop CKD. Furthermore, a recent study has found that individuals with only one APOL1 risk variant have an increased likelihood of developing CKD (Gbadegesin et al, NJ KM, DOI: 10.1056 / NEJMoa2404211). This may be associated with the presence of one or more APOL3 null / truncating alleles in these individuals, resulting in the loss of a potential protective effect of wild-type APOL3 against AMKD (Zhang et al, JCL Insight, 2024, 9: e 181238).

[0011] APOL1 high-risk genotypes have been associated with many forms of kidney disease, including focal segmental glomerulosclerosis (FSGS), CKD, ESKD, HIV-associated nephropathy, hypertension-attributed nephropathy, COVID-associated nephropathy, lupus nephritis, and sickle cell disease nephropathy. This is collectively referred to as APOL1 -mediated kidney disease (AMKD). While AMKD can cover various forms of kidney disease, it often presents as glomerulosclerosis with accompanying tubulointerstitial and vascular changes.

[0012] Kidney disease generally requires long-term management; therefore, ease of dosing and administration are important for patient compliance. This is particularly critical for AMKD, where chronic kidney disease is often diagnosed at a relatively young age and progresses faster than in patients without the APOL1 high-risk genotype. There remains a need for therapeutics with increased efficacy and greater ease of dosing and administration, for the treatment of AMKD.

[0013] AZD2373 (INN: opemalirsen), referred to as Compound A herein, is an APOL1 antisense oligonucleotide therapeutic that has completed Phase 1 clinical studies (Clinicaltrials.gov Identifiers: NCT04269031 and NCT05351047) and may be useful in the treatment of diseases associated with APOL1, such as AMKD. The present disclosure provides methods of treatment and dosages using AZD2373.

[0014] SUMMARY

[0015] The present disclosure provides methods for treating a disease associated with APOL1, for example APOL1 -mediated kidney disease (AMKD), along with unit dosages.

[0016] In an aspect, provided herein is a method of treating a disease associated with APOL1 in a subject comprising administering Compound A or a pharmaceutically acceptable salt thereof at a dose of from about 10 mg to about 150 mg of the free acid, wherein the subject is human. In another aspect, Compound A or a pharmaceutically acceptable salt thereof is for use in any of the methods described herein. In another aspect, there is provided the use of Compound A in the manufacture of a medicament for use in any of the methods described herein.

[0017] In another aspect, provided herein is a unit dosage comprising Compound A or a pharmaceutically acceptable salt thereof in a quantity of about 10 mg to about 150 mg of the free acid.

[0018] In a further aspect, provided herein is a single-dose container comprising the unit dosage described herein.

[0019] Aspects and embodiments describing a mass (an amount by weight) of Compound A or a pharmaceutically acceptable salt thereof in the context of “the free acid” refer to the specified mass of Compound A (i.e. the free acid of Compound A) or an equivalent molar amount of a pharmaceutically acceptable salt of Compound A.

[0020] BRIEF DESCRIPTION OF THE DRAWINGS

[0021] FIGURE 1 is a schematic of a chemical structure of Compound A as described herein. This is the free acid form of Compound A.

[0022] FIGURE 2 is a schematic of a chemical structure of deprotonated Compound A.

[0023] FIGURE 3 is a schematic of Compound A sodium salt (pentadecasodium).

[0024] FIGURE 4 shows the geometric mean (90% confidence interval) percentage change in APOL1 plasma protein concentration (as compared to baseline) versus time by dose group of the SAD study of Example 1 (placebo, 10 mg, 30 mg, 75 mg and 150 mg).

[0025] FIGURE 5 shows geometric mean (90% confidence interval) percentage change in APOL1 plasma protein concentration (as compared to baseline) versus time by dose group of the MAD study of Example 2 (placebo, 20 mg, 50 mg and 150 mg; all administered QW).

[0026] FIGURE 6 A shows the predicted time-course of plasma APOL1 reduction over 24 weeks of QW administration of 3 dosages (20 mg, 50 mg and 150 mg), based on the results from the MAD study. The shaded area is the 90% confidence interval.

[0027] FIGURE 6B shows the predicted steady-state plasma APOL1 reduction versus dose, with QW administration, based on the results from the MAD study. The shaded area is the 90% confidence interval. DETAILED DESCRIPTION

[0028] Definitions

[0029] Generally, nomenclatures used herein are those well-known and commonly used in the art. Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted singleletter codes. Units, prefixes, and symbols are denoted in their International System of Units (SI) accepted form.

[0030] Numeric ranges disclosed herein are inclusive of the numbers defining the range. The ranges and / or individual values disclosed herein can be combined to obtain further subranges, which form part of the present disclosure.

[0031] Some of the quantitative expressions given herein are qualified with the term "about. " It is understood that whether the term "about" is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and / or measurement conditions for such given value. In some embodiments, "about” means within ±10% of a value.

[0032] “Active agent” refers to a compound that has measurable specified or selected physiologic activity when administered to a subject in a pharmaceutically effective amount. In the present disclosure, “active agent” refers to Compound A, which is an antisense oligonucleotide targeting APOL1 defined herein, or a pharmaceutically acceptable salt thereof.

[0033] “Administration” or “administering” refers to methods by which a compound (e.g. Compound A or a pharmaceutically acceptable salt thereof) or composition (e.g. a unit dosage) is introduced into an individual. In some embodiments, administration includes, but is not limited to parenteral administration, such as subcutaneous, intravenous, or intramuscular injection or infusion. In some embodiments, administration occurs after the onset of the disease or symptoms, for example, when a disease, or symptoms thereof, are being treated. In some embodiments, administration occurs before the onset of the disease or symptoms thereof, for example, when a disease or symptoms thereof are being prevented.

[0034] “Antisense oligonucleotide” (ASO) refers to an oligonucleotide that targets a transcript of a gene to reduce expression of the gene product. The antisense oligonucleotide described herein includes a sequence that is complementary to a target nucleic acid (APOL1) and reduces target nucleic acid levels as compared to target nucleic acid levels in the absence of the antisense oligonucleotide.

[0035] “Albuminuria” refers to the abnormal presence of albumin in the urine. Albumin is the dominant component of protein in the urine and its presence can be a manifestation of kidney disease. Albuminuria can be quantified by measuring the ratio of albumin to creatinine in the urine (“urinary albumin-creatinine ratio", uACR), e.g. using an accredited laboratory test. In some embodiments, albuminuria may be defined by a uACR of > 300 mg / g. In healthy individuals, uACR may be < 30 mg / g. A subject with minimal albuminuria (or “microalbuminuria”) may be defined as having from 30 mg / g to less than 300 mg / g uACR.

[0036] “Proteinuria” refers to the abnormal presence of protein in the urine, which can be a manifestation of kidney disease. Proteinuria can be quantified by measuring the ratio of protein and creatinine in the urine (“urinary protein / creatinine ratio”, uPCR), e.g. using an accredited laboratory test. In some embodiments, proteinuria may be defined as a protein-creatinine ratio >0.2 mg / mg. Proteinuria may alternatively be quantified by measuring by the amount of protein in the urine per day. In some embodiments, proteinuria may be defined as >150 mg / day protein in the urine. “Nephrotic range proteinuria” refers to high levels of proteinuria generally associated with nephrotic syndrome, and may be defined as >3.5 mg / mg protein-creatinine ratio or > 3.5 g / day protein in the urine.

[0037] “APOL1” (apolipoprotein LI) means any nucleic acid or protein of APOL1. “APOL1 nucleic acid” means any nucleic acid encoding APOL1. For example, in certain embodiments, an APOL1 nucleic acid includes a DNA sequence encoding APOL1, an RNA sequence transcribed from DNA encoding APOL1 (including genomic DNA comprising introns and exons), and an mRNA sequence encoding APOL1. “APOL1 mRNA” means an mRNA sequence encoding an APOL1 protein. The target may be referred to in either upper or lower case.

[0038] “A disease associated with APOL1” refers to any disease, disorder or condition that is completely or partially caused by or is the result of APOL1. In some embodiments, the disease, disorder or condition is due to aberrant APOL1 expression. In some embodiments, the disease, disorder or condition is due to APOL1 overexpression. In some embodiments, the disease, disorder or condition is due to aberrant upregulation of APOL1. A disease associated with APOL1 includes, but is not limited to, APOL1 -mediated kidney disease. In some embodiments of the methods described herein, “a disease associated with APOL1" refers to a disease associated with one or more APOL1 risk alleles (e.g. G1 or G2). Accordingly, in some embodiments, a subject described herein is a subject who has at least one APOL1 risk allele. In some embodiments, a subject described herein is homozygous or compound heterozygous for the G1 and / or G2 alleles of the APOL1 gene (i.e. genotypes Gl / Gl, G1 / G2, or G2 / G2). In some embodiments, a subject described herein is heterozygous for the G1 or G2 alleles of the APOL1 gene (i.e. genotypes G1 / G0 or G2 / G0). In some embodiments, the subject also has one or more APOL3 null alleles (for example, APOL3 p.Q58* as described in Zhang et al, JCL Insight, 2024, 9:el81238). An APOL3 null allele may also be referred to as an APOL3 truncating allele.

[0039] “APOL1 -mediated kidney disease” (AMKD) refers to a kidney disease associated with one or more APOL1 risk alleles (e.g. G1 or G2). Accordingly, in the methods of treating AMKD described herein, the subject is a subject who has one or more APOL1 risk alleles. In some embodiments, the subject is homozygous or compound heterozygous for the G1 and / or G2 alleles of the APOL1 gene (i.e. genotypes Gl / Gl, G1 / G2, or G2 / G2). In some embodiments, the subject is heterozygous for the G1 or G2 alleles of the APOL1 gene (i.e. genotypes G1 / G0 or G2 / G0). In some embodiments, the subject also has one or more APOL3 null alleles (for example, APOL3 p.Q58*). APOL1 -mediated kidney disease includes but is not limited to focal segmental glomerulosclerosis (FSGS), collapsing nephropathy, chronic kidney disease (CKD), end-stage kidney disease (ESKD), hypertension-attributed nephropathy, HIV-associated nephropathy, sickle cell nephropathy, arterionephrosclerosis, lupus nephritis, minimal change disease, membranous nephropathy, nephrotic syndrome, renal allograft dysfunction, acute kidney injury and COVID-19-associated nephropathy (COVAN).

[0040] “cE ’ or “constrained ethyl” refers to a bicyclic furanosyl sugar moiety that includes a bridge connecting the 4'-carbon and the 2'-carbon, in which the bridge has the formula: 4'-CH(CH3)- 0-2'. “cEt nucleoside” refers to a nucleoside that includes a cEt modified sugar moiety.

[0041] “Circulating level” refers to the level of a compound, for example APOL1, that is present in the blood, plasma or serum of a subject. “Serum APOL1” and “plasma APOL1” refer to APOL1 in the serum and plasma, respectively.

[0042] “Dose” refers to a specified quantity of a compound that is provided in a single administration. In some embodiments, a dose may be administered in two or more boluses, for example, if the desired dose requires a volume not easily accommodated by a single administration, for example, a single injection. “Unit dosage” refers to a physically discrete unit containing a predetermined quantity of an active agent such as Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, a “unit dosage” refers to physically discrete units suitable as single dosages for administration to a subject, such as a human. In some embodiments, the unit dosage comprises an active agent and a pharmaceutical diluent, carrier or vehicle. In some embodiments, a unit dosage is included in a container, such as a vial, ampule or syringe. In some embodiments, the unit dosage is included in a single dose container, or alternately in a multi-dose container. In some embodiments, the unit dosage is included in single-dose prefilled syringe. In some embodiments, the unit dosage is included in an autoinjector device.

[0043] “Loading dose” refers to one or more, or a series of doses administered at the beginning of a dosing regimen. In some embodiments, the loading dose is administered to achieve a desired condition in a subject, for example, a desired initial concentration of antisense oligonucleotide or desired physiological effect in the subject. In some embodiments, one or more, or a plurality of single unit loading doses are administered to a subject at the beginning of a course of treatment. In some embodiments, one loading dose is administered to a subject at the beginning of a course of treatment. In some embodiments, the loading dose is a single unit dosage that is administered to a subject at the beginning of a course of treatment. In some embodiments, the desired physiological effect is a reduced AP0L1 level in a patient. In some embodiments, the loading dose reduces a level of AP0L1 from a baseline level (e.g., pre-administration level) to a reduced level.

[0044] “Maintenance dose” refers to one or more, or a series of doses that are administered after the loading dose(s). In some embodiments, the maintenance dose is administered to a subject to maintain the desired condition which results from the loading dose(s). In some embodiments, one or more, or a plurality of single unit maintenance dosages are administered to a subject serially at a specified time period to maintain the desired condition obtained after administering the loading dose(s). In some embodiments, the desired condition includes a desired concentration of antisense oligonucleotide in the subject or desired physiological effect. In some embodiments, the desired physiological effect includes a reduced AP0L1 level in a patient. In some embodiments, the maintenance dose reduces a level of AP0L1 in a patient. In some embodiments, the maintenance dose is administered on a monthly basis. “Monthly” refers to administration of a compound once in about a 28- or 30-day period, or about once in a calendar month. “Monthly maintenance dose” refers to a regularly administered dosage within about four weeks or about 28 days or about 30 days from the preceding dose. In some embodiments, the preceding dose is the loading dose. In some embodiments, the preceding dose is a preceding maintenance dose. “Maintenance period” refers to a time period after a desired condition is achieved in a subject during which one or more maintenance doses are administered to the subject.

[0045] “Effective amount” refers to an amount of an active agent or compound that is sufficient to effectuate a desired physiological outcome in a subject. The effective amount can vary depending on the health and physical condition of the subject.

[0046] “Efficacy” refers to the ability of an active agent or compound to produce a desired effect.

[0047] “Excipient” refers to a substance other than the active agent or water that is included in a pharmaceutical formulation, including, but not limited to, a diluent, preservative, or stabilizing agent.

[0048] “Expression” includes all the functions by which a gene’s coded information is converted into structures present and operating in a cell. Such structures include, but are not limited to, the products of transcription and translation.

[0049] “Glomerular filtration rate (GFR)” refers to the total of the filtration rates of the functioning nephrons in the kidney, and is a measure of kidney function. Normal GFR varies according to age, sex, and body size, and declines with age. However, a decrease in GFR may also be a marker of kidney disease and precedes the onset of kidney failure. For example, for a subject having a GFR below 60 ml / min / 1.73 m2, the prevalence of complications of CKD increases, as does the risk of cardiovascular disease. In some embodiments, GFR refers to estimated GFR (eGFR). Typically, eGFR is obtained using a blood test that measures endogenous filtration markers such as creatinine and / or cystatin C levels. For example, eGFR may be obtained using a blood test measuring serum creatinine levels and applying the Chronic Kidney Disease Epidemiology Collaboration equation (e.g. 2021 version). In some embodiments, GFR refers to measured GFR (mGFR). This may be obtained, for example, by measuring clearance of exogenous filtration markers such as inulin, iohexol and iothalamate.

[0050] “Intemucleoside linkage” refers to a group or bond that forms a covalent linkage between adjacent nucleosides in an oligonucleotide. “Modified internucleoside linkage” refers to any internucleoside linkage other than a naturally occurring, phosphodiester intemucleoside linkage. Linkages other than phosphodiester linkages are referred to herein as modified intemucleoside linkages. In some embodiments, the modified intemucleoside linkage includes a “phosphorothioate linkage,” a modified phosphodiester linkage in which one of the nonbridging oxygen atoms is replaced with a sulfur atom.

[0051] “Nucleic acid” refers to molecules made up of monomeric nucleotides. A nucleic acid includes, but is not limited to, ribonucleic acids (RNA), deoxyribonucleic acids (DNA), single-stranded nucleic acids, and double-stranded nucleic acids.

[0052] “Nucleobase” refers to a heterocyclic moiety capable of pairing with a base of another nucleic acid. As used herein a “naturally occurring nucleobase” is adenine (A), thymine (T), cytosine (C), uracil (U), and guanine (G). A “modified nucleobase” is a naturally occurring nucleobase that is chemically modified. In some embodiments, the modified nucleobase is “5- methylcytosine”, a cytosine with a methyl group attached to the 5 position.

[0053] “Nucleobase sequence” refers to the order of contiguous nucleobases in a nucleic acid or oligonucleotide independent of any sugar or internucleoside linkage.

[0054] “Nucleoside” refers to a compound including a nucleobase and a sugar moiety. The nucleobase and sugar moiety can each be, independently, unmodified or modified. “Modified nucleoside” refers to a nucleoside including a modified nucleobase and / or a modified sugar moiety.

[0055] “Nucleotide” refers to a nucleoside in which a phosphate group is covalently linked to the sugar portion of the nucleoside.

[0056] “Oligonucleotide” refers to a polymer of linked nucleosides, each of which can be modified or unmodified, independent one from another. “Modified oligonucleotide” refers to an oligonucleotide, wherein at least one sugar, nucleobase, or internucleoside linkage is modified. “Unmodified oligonucleotide” refers to an oligonucleotide that does not include any sugar, nucleobase, or internucleoside modification.

[0057] “Parenteral administration” refers to administration through injection or infusion and includes, but is not limited to, subcutaneous administration, intravenous administration, intramuscular administration, intraarterial administration, intraperitoneal administration, and intracranial administration,

[0058] “Prevent” refers to delaying or forestalling the onset, development or progression of a disease, disorder, or condition for a period of time. In some embodiments, the term “prevent” refers to total or partial inhibition of the development, recurrence, onset or spread of a disease or disorder associated with AP0L1 and / or a symptom related thereto. “Reduce” means to bring down to a smaller extent, size, amount, or number. “Reduced level” refers to a level that is reduced as compared to a baseline level (wherein baseline level is a level prior to administration of an active agent or compound).

[0059] “Subject” and “patient” can be used interchangeably to refer to a mammal, for example, a human, that has or is at risk of developing a disease or one or more symptoms of a disease associated with AP0L1. In some embodiments, the subject is a mammal, for example a human, having a disease or one or more symptoms of a disease associated with AP0L1. In some embodiments, the subject is a mammal, for example a human, at risk of developing a disease or one or more symptoms of a disease associated with APOL 1. In some embodiments, a subj ect is a human. In some embodiments, a subject may be an adult (e.g. age 18 and above). In some embodiments, a subject may be a pediatric subject (e.g. age 10-17). In some embodiments, a subject may be an adolescent (e.g. age 12-17). In some embodiments, the subject may be a child (e.g. age 11 or below). In some embodiments, the subject may be defined by their age, as described herein.

[0060] “Therapeutically effective amount” refers to an amount of an active agent, for example, the antisense oligonucleotide described herein, that provides a therapeutic benefit to a subject.

[0061] “Treat”, “treatment”, and “treating” are used interchangeably to refer to administering an active agent to a subject to effect an alteration or improvement of a disease, disorder, or condition in the subject. In some embodiments, “treating” refers to a reduction or amelioration of the progression, severity, and / or duration of a disease associated with APOL1 resulting from administration of one or more therapies, by relieving or ameliorating one, some, or all of its symptoms, and / or by correcting or compensating for the underlying pathology. For example, “treating” may refer to remission of a disease associated with APOL1, such as AMKD.

[0062] Compound A

[0063] The present disclosure relates to methods for treating a disease associated with APOL1, such as APOL 1 -mediated kidney disease (AMKD), comprising administering Compound A or a pharmaceutically acceptable salt thereof. The present disclosure also provides unit dosages comprising Compound A or a pharmaceutically acceptable salt thereof.

[0064] Compound A is described in WO 2019 / 226611 Al, as ION 972190. Compound A may alternatively be referred to as AZD2373 or ION532. Compound A may also be referred to by its INN: opemalirsen. The structure of Compound A is shown in Figure 1. Compound A in its neutral form (Figure 1) may be referred to as the free acid. Compound A may also be depicted in its deprotonated form (Figure 2).

[0065] Compound A is a modified oligonucleotide 16 linked nucleobases in length having a nucleobase sequence TTTTGTAAGTGCAACC (SEQ ID NO: 1), wherein the modified oligonucleotide comprises: a gap segment consisting of nine linked deoxynucleosides; a 5’ wing segment consisting of three linked nucleoside; and a 3’ wing segment consisting of four linked nucleosides; wherein the gap segment is positioned between the 5’ wing segment and the 3’ wing segment; wherein the 5’ wing segment comprises constrained ethyl (cEt) nucleosides; wherein the 3’ wing segment comprises a cEt nucleoside, a cEt nucleoside, a cEt nucleoside, and 2’-O- methoxy ethyl nucleoside in the 5’ to 3’ direction; wherein each internucleoside linkage is a phosphorothioate linkage; and wherein each cytosine is a 5-methylcytosine.

[0066] Compound A can also be described using the following formula: Tks Tks Tks Tds Gds Tds Ads Ads Gds Tds Gds mCds Aks Aks mCks mCe (SEQ ID NO: 2), wherein,

[0067] A = an adenine, mC = a 5-methylcytosine

[0068] G = a guanine,

[0069] T = a thymine, e = a 2’ -O-m ethoxy ethyl (MOE) modified nucleoside, k = a constrained ethyl (cEt) modified nucleoside, d = a 2’ -deoxynucleoside, and s = a phosphorothioate internucleoside linkage.

[0070] Compound A can also be described using the following alternative nucleotide nomenclature:

[0071] [MeU] [MeU] [MeU]TGT AAGTGMeC[ A] [A] [MeC]MeC whereinMeU is 5-methyl uracil,MeC is 5-methylcytosine, bracketed residues represent constrained ethyl nucleotides, the underlined residue represents a 2'-O-methoxyethyl (MOE) nucleotide and all other residues are 2'-deoxynucleotides, and wherein each internucleoside linkage is a phosphorothioate linkage (SEQ ID NO: 2). In some embodiments, a pharmaceutically acceptable salt of Compound A is provided. In some embodiments, the pharmaceutically acceptable salt is a sodium salt; for example, a pentadecasodium salt as depicted in Figure 3. In some embodiments, the pharmaceutically acceptable salt is a potassium salt.

[0072] Method of treatment

[0073] Provided herein are methods of treating or preventing a disease associated with APOL1 comprising administering Compound A or a pharmaceutically acceptable salt thereof. Also provided is Compound A or a pharmaceutically acceptable salt thereof for use in any of the methods described herein. Further provided is the use of Compound A in the manufacture of a medicament for use in any of the methods described herein.

[0074] In one aspect, there is provided a method of treating a disease associated with APOL1 in a subject comprising administering Compound A or a pharmaceutically acceptable salt thereof at a dose of from about 10 mg to about 150 mg of the free acid, wherein the subject is human.

[0075] In some embodiments, the pharmaceutically acceptable salt of Compound A is a sodium salt (e.g. as depicted in Figure 3). In some embodiments, the pharmaceutically acceptable salt of Compound A is a potassium salt. In some embodiments, the sodium salt of Compound A is administered to the subject. In some embodiments, the potassium salt of Compound A is administered to the subject.

[0076] In some embodiments, the subject has at least one of APOL1 risk alleles G1 or G2. In further embodiments, the subject is homozygous or compound heterozygous for APOL1 risk alleles G1 and G2.

[0077] In some embodiments, the subject has been determined as having at least one of APOL1 risk alleles G1 or G2. In further embodiments, the subject has been determined as being homozygous or compound heterozygous for APOL1 risk alleles G1 and G2.

[0078] In some embodiments, the method comprises: (a) determining whether the subject has at least one of APOL1 risk alleles G1 or G2 (e.g. whether the subject is homozygous or compound heterozygous for APOL1 risk alleles G1 and G2) and (b) administering Compound A or a pharmaceutically acceptable salt thereof if the subject has at least one of APOL1 risk alleles G1 or G2 (e.g. if the subject is homozygous or compound heterozygous for APOL1 risk alleles G1 and G2). In some embodiments, the subject is heterozygous for APOL1 risk alleles G1 and G2 (i.e. G1 / G0, G2 / G0). In some embodiments, the subject further has at least one APOL3 null allele (e.g. APOL3 p.Q58*). In some embodiments, the subject is homozygous for the APOL3 null allele. In some embodiments, the subject is heterozygous for the APOL3 null allele. In some embodiments, the subject does not have any APOL3 null alleles.

[0079] In some embodiments, the subject is heterozygous for APOL1 risk alleles G1 and G2 and is homozygous or heterozygous for APOL3 null allele p.Q58*.

[0080] In some embodiments, the subject has been determined as being heterozygous for APOL1 risk alleles G1 and G2 (i.e. G1 / G0, G2 / G0) and as being homozygous or heterozygous for APOL3 null allele p.Q58*.

[0081] In some embodiments, the method comprises: (a) determining whether the subject has at least one of APOL1 risk alleles G1 or G2 and / or at least one of the APOL3 null alleles, and (b) administering Compound A or a pharmaceutically acceptable salt thereof if (i) the subject is homozygous or compound heterozygous for APOL1 risk alleles G1 and G2, or (ii) the subject is heterozygous for APOL1 risk alleles G1 and G2 and has at least one APOL3 null allele.

[0082] As described herein, the subject is human. In some embodiments, the subject is an adult. In some embodiments, the subject is a pediatric subject. In some embodiments, the subject is an adolescent. In some embodiments, the subject is a child. In some embodiments, the subject is age 16 or above, optionally age 17 or above, optionally age 18 or above. In some embodiments, the subject is age 10 or above, optionally age 12 or above. In some embodiments, the subject is age 10 to 18, optionally age 10 to 17, optionally age 10 to 16, optionally age 10 to 15. In some embodiments, the subject is age 12 to 18, optionally age 12 to 17, optionally age 12 to 16, optionally age 12 to 15. In some embodiments, the dosage of Compound A or a pharmaceutically acceptable salt thereof may depend on the age of the subject. For example, a lower dosage of Compound A or a pharmaceutically acceptable salt thereof may be administered to a pediatric subject than the dosage administered to an adult subject.

[0083] In some embodiments, the disease associated with APOL1 is APOL1 -mediated kidney disease (AMKD). In some embodiments, AMKD may be selected from focal segmental glomerulosclerosis (FSGS), collapsing nephropathy, chronic kidney disease (CKD), hypertension-attributed nephropathy, HIV-associated nephropathy, sickle cell nephropathy, arterionephrosclerosis, lupus nephritis, minimal change disease, membranous nephropathy, nephrotic syndrome, renal allograft dysfunction, acute kidney injury and COVID-19- associated nephropathy (COVAN), or a combination thereof.

[0084] In some embodiments, the AMKD is chronic kidney disease. In some embodiments, the subject has an AMKD which has not progressed to end-stage kidney disease. In some embodiments, an objective of the treatment is the prevention of end-stage kidney disease. Accordingly, in some embodiments, the method of treatment further comprises prevention of end-stage kidney disease.

[0085] In some embodiments, the AMKD is FSGS. In some embodiments, the subject may be suspected of having FSGS but without proteinuria or albuminuria sufficient to merit a confirmatory biopsy. Accordingly, in some embodiments, the subject may have unconfirmed (or suspected) FSGS.

[0086] In some embodiments, the AMKD is renal allograft dysfunction. In such embodiments, the kidney donor may have at least one of APOL1 risk alleles G1 or G2, as described herein. The subject (i.e. the kidney recipient) may or may not have any APOL1 risk alleles.

[0087] In some embodiments, administering Compound A or a pharmaceutically acceptable salt thereof reduces or prevents edema, proteinuria, albuminuria, GFR (glomerular filtration rate) decline, high plasma lipid levels, high plasma cholesterol levels, nephrotic syndrome, high blood pressure or hypertension, kidney damage, glomerular damage, kidney failure and / or secondary cardiovascular events.

[0088] In some embodiments, the dose of Compound A or a pharmaceutically acceptable salt thereof is from about 20 mg to about 150 mg of the free acid. In some embodiments, the dose of Compound A or a pharmaceutically acceptable salt thereof is from about 25 mg to about 150 mg of the free acid. In some embodiments, the dose of Compound A or a pharmaceutically acceptable salt thereof is from about 50 mg to about 150 mg of the free acid. In some embodiments, the dose of Compound A or a pharmaceutically acceptable salt thereof is from about 75 mg to about 150 mg of the free acid. In some embodiments, the dose of Compound A or a pharmaceutically acceptable salt thereof is from about 100 mg to about 150 mg of the free acid. In some embodiments, the dose of Compound A or a pharmaceutically acceptable salt thereof is from about 10 mg to about 100 mg of the free acid. In some embodiments, the dose of Compound A or a pharmaceutically acceptable salt thereof is from about 20 mg to about 100 mg of the free acid. In some embodiments, the dose of Compound A or a pharmaceutically acceptable salt thereof is from about 25 mg to about 100 mg of the free acid. In some embodiments, the dose of Compound A or a pharmaceutically acceptable salt thereof is from about 50 mg to about 100 mg of the free acid. In some embodiments, the dose of Compound A or a pharmaceutically acceptable salt thereof is from about 10 mg to about 75 mg of the free acid. In some embodiments, the dose of Compound A or a pharmaceutically acceptable salt thereof is from about 20 mg to about 75 mg of the free acid. In some embodiments, the dose of Compound A or a pharmaceutically acceptable salt thereof is from about 25 mg to about 75 mg of the free acid. In some embodiments, the dose of Compound A or a pharmaceutically acceptable salt thereof is about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg or about 150 mg of the free acid. In some embodiments, the dose of Compound A or a pharmaceutically acceptable salt thereof is about 25 mg of the free acid. In some embodiments, the dose of Compound A or a pharmaceutically acceptable salt thereof is about 50 mg of the free acid. In some embodiments, the dose of Compound A or a pharmaceutically acceptable salt thereof is about 75 mg of the free acid. In some embodiments, the dose of Compound A or a pharmaceutically acceptable salt thereof is about 100 mg of the free acid. In some embodiments, the dose of Compound A or a pharmaceutically acceptable salt thereof is about 125 mg of the free acid. In some embodiments, the dose of Compound A or a pharmaceutically acceptable salt thereof is about 150 mg of the free acid.

[0089] In some embodiments, one or more doses are administered to the subject during a certain period of time. The number of doses administered during the period or the duration of the period can vary depending on the individual subject and the desired outcome, for example reducing one or more symptoms of the disease, and / or preventing progression to end-stage kidney disease in a subject with AMKD. In some embodiments, the period includes about 1 or more, about 2 or more, about 3 or more, about 4 or more, about 5 or more, about 6 or more, about 7 or more, about 8 or more, about 9 or more, about 10 or more, about 11 or more, about 12 or more, about 13 or more, about 14 or more, about 15 or more, about 16 or more, about 17 or more, about 18 or more, about 19 or more, about 20 or more, about 25 or more, or about 50 or more doses. In some embodiments, the dose is administered for a period of at least about 4 months, at least about 1 year, at least about 2 years, at least about 5 years, at least about 10 years, or at least about 20 years. In some embodiments, the dose is administered for the lifetime of the subject. In some embodiments, the disease associated with APOL1 is AMKD and the dose is administered until the onset of end-stage kidney disease in the subject. In some embodiments, the period includes more than one dose and the doses administered during the period are all the same. In other embodiments, the doses administered during the period are not all the same. For example, in some embodiments, the amount of Compound A or a pharmaceutically acceptable salt thereof in the doses administered during the period increases over time. In some embodiments, the amount of Compound A or a pharmaceutically acceptable salt thereof in the doses administered during the period decreases over time.

[0090] In some embodiments, the dose is administered from about twice every week to about once every 3 months. In some embodiments, the dose is administered from about twice every week to about once every 2 months. In some embodiments, the dose is administered from about twice every week to about once every 6 weeks. In some embodiments, the dose is administered from about once every week to about once every 6 weeks. In some embodiments, the dose is administered from about once every week to about once every 4 weeks. In some embodiments, the dose is administered about twice weekly, about once weekly, about once every 2 weeks, about once every 3 weeks, about once every 4 weeks, about once monthly, about once every 5 weeks, about once every 6 weeks, about once every 2 months, or about once every 3 months. In some embodiments, the dose is administered once weekly. In some embodiments, the dose is administered once every two weeks. In some embodiments, the dose is administered once every 4 weeks. In some embodiments, the dose is administered once monthly. In some embodiments, the dose is administered once every 6 weeks. In some embodiments, the dose is administered once every 2 months.

[0091] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered by parenteral administration. In some embodiments, the parenteral administration is subcutaneous, intramuscular or intravenous administration. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered subcutaneously, for example by subcutaneous injection.

[0092] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered using a pre-filled syringe. In some embodiments, the pre-filled syringe is a single-dose prefilled syringe. In some embodiments, the pre-filled syringe is an accessorised single-dose prefilled syringe. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered using an autoinjector device. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is administered using a vial and syringe. In some embodiments, the method does not include separate loading and maintenance doses but just one or more doses of Compound A, or a pharmaceutically acceptable salt thereof, to the subject over a period of time.

[0093] Treatments with an Initial Loading Dose

[0094] In some embodiments, the method includes administering one or more loading doses and one or more maintenance doses of Compound A or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, the method comprises administering to the subject: (a) one or more loading doses of Compound A or a pharmaceutically acceptable salt thereof; and (b) one or more maintenance doses of Compound A or a pharmaceutically acceptable salt thereof; wherein the one or more loading doses is from about 10 mg to about 150 mg of the free acid of Compound A.

[0095] In some embodiments, the one or more maintenance doses comprise a lower amount of Compound A or a pharmaceutically acceptable salt thereof than the one or more loading doses.

[0096] In some embodiments, the amount of Compound A or a pharmaceutically acceptable salt thereof in each of the loading doses is the same. In some embodiments the amount of Compound A or a pharmaceutically acceptable salt thereof in each of the loading doses is not all the same. In some embodiments, the one or more loading doses is administered at the start of treatment. In some embodiments, one loading dose is administered at the start of treatment. In some embodiments, the loading dose of Compound A or a pharmaceutically acceptable salt thereof is from about 20 mg to about 150 mg of the free acid. In some embodiments, the loading dose of Compound A or a pharmaceutically acceptable salt thereof is from about 25 mg to about 150 mg of the free acid. In some embodiments, the loading dose of Compound A or a pharmaceutically acceptable salt thereof is from about 50 mg to about 150 mg of the free acid. In some embodiments, the loading dose of Compound A or a pharmaceutically acceptable salt thereof is from about 75 mg to about 150 mg of the free acid. In some embodiments, the loading dose of Compound A or a pharmaceutically acceptable salt thereof is from about 100 mg to about 150 mg of the free acid. In some embodiments, the loading dose of Compound A or a pharmaceutically acceptable salt thereof is from about 25 mg to about 100 mg of the free acid. In some embodiments, the loading dose of Compound A or a pharmaceutically acceptable salt thereof is from about 50 mg to about 100 mg of the free acid. In some embodiments, the loading dose of Compound A or a pharmaceutically acceptable salt thereof is from about 20 mg to about 75 mg of the free acid. In some embodiments, the loading dose of Compound A or a pharmaceutically acceptable salt thereof is from about 25 mg to about 75 mg of the free acid. In some embodiments, the loading dose of Compound A or a pharmaceutically acceptable salt thereof is about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg or about 150 mg of the free acid. In some embodiments, the loading dose of Compound A or a pharmaceutically acceptable salt thereof is about 50 mg of the free acid. In some embodiments, the loading dose of Compound A or a pharmaceutically acceptable salt thereof is about 75 mg of the free acid. In some embodiments, the loading dose of Compound A or a pharmaceutically acceptable salt thereof is about 100 mg of the free acid. In some embodiments, the loading dose of Compound A or a pharmaceutically acceptable salt thereof is about 125 mg of the free acid. In some embodiments, the loading dose of Compound A or a pharmaceutically acceptable salt thereof is about 150 mg of the free acid.

[0097] In some embodiments, one or more loading doses are administered to the subject during a certain period of time. In some embodiments, the period includes from 1 to 5 loading doses, optionally 2 loading doses, optionally 1 loading dose. In some embodiments, the loading dose is administered from about twice every week to about once every 2 months, optionally from about twice every week to about once every 6 weeks, optionally from about once every week to about once every 6 weeks, optionally from about once every week to about once every 4 weeks. In some embodiments, the loading dose is administered about twice weekly, about once weekly, about once every 2 weeks, about once every 3 weeks, about once every 4 weeks, about once monthly, about once every 5 weeks, about every 6 weeks, or about once every 2 months. In some embodiments, the loading dose is administered once weekly. In some embodiments, the loading dose is administered once every two weeks. In some embodiments, the loading dose is administered once every 4 weeks. In some embodiments, the loading dose is administered once monthly. In some embodiments, the loading dose is administered once every 2 months.

[0098] In some embodiments, the amount of Compound A or a pharmaceutically acceptable salt thereof in each of the maintenance doses is the same. In some embodiments the amount of Compound A or a pharmaceutically acceptable salt thereof in each of the maintenance doses is not all the same. In some embodiments, the amount of Compound A or a pharmaceutically acceptable salt thereof in each of the maintenance doses increases over time. In some embodiments, the amount of Compound A or a pharmaceutically acceptable salt thereof in each of the maintenance doses decreases over time. In some embodiments, the maintenance dose of Compound A or a pharmaceutically acceptable salt thereof is from about 10 mg to about 150 mg of the free acid. In some embodiments, the maintenance dose of Compound A or a pharmaceutically acceptable salt thereof is from about 20 mg to about 150 mg of the free acid. In some embodiments, the maintenance dose of Compound A or a pharmaceutically acceptable salt thereof is from about 50 mg to about 150 mg of the free acid. In some embodiments, the maintenance dose of Compound A or a pharmaceutically acceptable salt thereof is from about 10 mg to about 125 mg of the free acid. In some embodiments, the maintenance dose of Compound A or a pharmaceutically acceptable salt thereof is from about 20 mg to about 125 mg of the free acid. In some embodiments, the maintenance dose of Compound A or a pharmaceutically acceptable salt thereof is from about 20 mg to about 125 mg of the free acid. In some embodiments, the maintenance dose of Compound A or a pharmaceutically acceptable salt thereof is from about 10 mg to about 100 mg of the free acid. In some embodiments, the maintenance dose of Compound A or a pharmaceutically acceptable salt thereof is from about 20 mg to about 100 mg of the free acid. In some embodiments, the maintenance dose of Compound A or a pharmaceutically acceptable salt thereof is from about 25 mg to about 100 mg of the free acid. In some embodiments, the maintenance dose of Compound A or a pharmaceutically acceptable salt thereof is from about 50 mg to about 100 mg of the free acid. In some embodiments, the maintenance dose of Compound A or a pharmaceutically acceptable salt thereof is from about 10 mg to about 75 mg of the free acid. In some embodiments, the maintenance dose of Compound A or a pharmaceutically acceptable salt thereof is from about 20 mg to about 75 mg of the free acid. In some embodiments, the maintenance dose of Compound A or a pharmaceutically acceptable salt thereof is from about 25 mg to about 75 mg of the free acid. In some embodiments, the maintenance dose of Compound A or a pharmaceutically acceptable salt thereof is from about 10 mg to about 50 mg of the free acid. In some embodiments, the maintenance dose of Compound A or a pharmaceutically acceptable salt thereof is about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg or about 150 mg of the free acid. In some embodiments, the maintenance dose of Compound A or a pharmaceutically acceptable salt thereof is about 25 mg of the free acid. In some embodiments, the maintenance dose of Compound A or a pharmaceutically acceptable salt thereof is about 50 mg of the free acid. In some embodiments, the maintenance dose of Compound A or a pharmaceutically acceptable salt thereof is about 75 mg of the free acid. In some embodiments, the maintenance dose of Compound A or a pharmaceutically acceptable salt thereof is about 100 mg of the free acid. In some embodiments, the maintenance dose of Compound A or a pharmaceutically acceptable salt thereof is about 125 mg of the free acid.

[0099] In some embodiments, one or more maintenance doses are administered to the subject during a certain period of time. The number of maintenance doses administered during the period, or the duration of the period can vary depending on the individual subject and the desired outcome, for example reducing one or more symptoms of the disease and / or preventing progression to end-stage kidney disease in a subject with AMKD. In some embodiments, the period includes about 1 or more, about 2 or more, about 3 or more, about 4 or more, about 5 or more, about 6 or more, about 7 or more, about 8 or more, about 9 or more, about 10 or more, about 11 or more, about 12 or more, about 13 or more, about 14 or more, about 15 or more, about 16 or more, about 17 or more, about 18 or more, about 19 or more, about 20 or more, about 25 or more, or about 50 or more maintenance doses. In some embodiments, the maintenance dose is administered for a period of at least about 4 months, at least about 1 year, at least about 2 years, at least about 5 years, at least about 10 years, or at least about 20 years. In some embodiments, the maintenance dose is administered for the lifetime of the subject. In some embodiments, the disease associated with APOL1 is AMKD and the maintenance dose is administered until the onset of end-stage kidney disease in the subject. In some embodiments, the period includes more than one maintenance dose and the maintenance doses administered during the period are all the same. In some embodiments, the maintenance doses administered during the period are not all the same. In some embodiments, the amount of Compound A or a pharmaceutically acceptable salt thereof in the maintenance doses administered during the period increases over time. In some embodiments, the amount of Compound A or a pharmaceutically acceptable salt thereof in the maintenance doses administered during the period decreases over time.

[0100] In some embodiments, the maintenance dose is administered from about twice every week to about once every 3 months. In some embodiments, the maintenance dose is administered from about twice every week to about once every 2 months. In some embodiments, the maintenance dose is administered from about twice every week to about once every 6 weeks. In some embodiments, the maintenance dose is administered from about once every week to about once every 6 weeks. In some embodiments, the maintenance dose is administered from about once every week to about once every 4 weeks. In some embodiments, the maintenance dose is administered about twice weekly, about once weekly, about once every 2 weeks, about once every 3 weeks, about once every 4 weeks, about once monthly, about once every 5 weeks, about every 6 weeks, about once every 2 months, or about once every 3 months. In some embodiments, the maintenance dose is administered once weekly. In some embodiments, the maintenance dose is administered once every two weeks. In some embodiments, the maintenance dose is administered once every 4 weeks. In some embodiments, the maintenance dose is administered once monthly. In some embodiments, the maintenance dose is administered once every 2 months. In some embodiments, the maintenance dose is administered once every 3 months.

[0101] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof (e.g. the loading dose, maintenance dose or both) is administered by parenteral administration. In some embodiments, the parenteral administration is subcutaneous, intramuscular or intravenous administration. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof (e.g. the loading dose, maintenance dose or both) is administered subcutaneously.

[0102] In some embodiments, Compound A or a pharmaceutically acceptable salt thereof (e.g. the loading dose, maintenance dose or both) are administered using a pre-filled syringe. In some embodiments, the pre-filled syringe is a single-dose prefilled syringe. In some embodiments, the pre-filled syringe is an accessorised single-dose prefilled syringe. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof (e.g. the loading dose, maintenance dose or both) is administered using an autoinjector device. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof (e.g. the loading dose, maintenance dose or both) is administered using a vial and syringe.

[0103] Prevention

[0104] Also provided herein is a method of preventing a disease associated with APOL1, such as AMKD, in a subject comprising administering Compound A or a pharmaceutically acceptable salt thereof at a dose of from about 10 mg to about 150 mg of the free acid, wherein the subject is human. Features of this method, including Compound A or a pharmaceutically acceptable salt thereof, dose, disease, and / or the subject, may be as described in relation to above methods of treatment.

[0105] In some embodiments, the pharmaceutically acceptable salt of Compound A is a sodium salt (e.g. as depicted in Figure 3). In some embodiments, the pharmaceutically acceptable salt of Compound A is a potassium salt. In some embodiments, the sodium salt of Compound A is administered to the subject. In some embodiments, the potassium salt of Compound A is administered to the subject.

[0106] In some embodiments, the subject may be a subject at risk of developing a disease associated with APOL1. In further embodiments, the subject has at least one of APOL1 risk alleles G1 or G2. In further embodiments, the subject is homozygous or compound heterozygous for APOL1 risk alleles G1 and G2. In some embodiments, the subject has been determined as having at least one of APOL1 risk alleles G1 or G2. In further embodiments, the subject has been determined as being homozygous or compound heterozygous for APOL1 risk alleles G1 and G2.

[0107] In some embodiments, the method comprises: (a) determining whether the subject has at least one of APOL1 risk alleles G1 or G2 (e.g. whether the subject is homozygous or compound heterozygous for APOL1 risk alleles G1 and G2) and (b) administering Compound A or a pharmaceutically acceptable salt thereof if the subject has at least one of APOL1 risk alleles G1 or G2 (e.g. if the subject is homozygous or compound heterozygous for APOL1 risk alleles G1 and G2).

[0108] In some embodiments, the subject is heterozygous for APOL1 risk alleles G1 and G2 (i.e. G1 / G0, G2 / G0). In some embodiments, the subject further has at least one APOL3 null allele (e.g. APOL3 p.Q58*). In some embodiments, the subject is homozygous for the APOL3 null allele. In some embodiments, the subject is heterozygous for the APOL3 null allele. In some embodiments, the subject does not have any APOL3 null alleles.

[0109] In some embodiments, the subject is heterozygous for APOL1 risk alleles G1 and G2 and is homozygous or heterozygous for APOL3 null allele p.Q58*.

[0110] In some embodiments, the subject has been determined as being heterozygous for APOL1 risk alleles G1 and G2 (i.e. G1 / G0, G2 / G0) and as being homozygous or heterozygous for APOL3 null allele p.Q58*.

[0111] In some embodiments, the method comprises: (a) determining whether the subject has at least one of APOL1 risk alleles G1 or G2 and / or at least one of the APOL3 null alleles, and (b) administering Compound A or a pharmaceutically acceptable salt thereof if (i) the subject is homozygous or compound heterozygous for APOL1 risk alleles G1 and G2, or (ii) the subject is heterozygous for APOL1 risk alleles G1 and G2 and has at least one APOL3 null allele. The AMKD may be as described herein, for example as described in relation to the above methods of treatment. In some embodiments of the method of preventing a disease associated with AP0L1, the disease is end-stage kidney disease.

[0112] In some embodiments, the subject is an adult. In some embodiments, the subject is a pediatric subject. In some embodiments, the subject is an adolescent. In some embodiments, the subject is a child. In some embodiments, the subject is age 16 or above, optionally age 17 or above, optionally age 18 or above. In some embodiments, the subject is age 10 or above, optionally age 12 or above. In some embodiments, the subject is age 10 to 18, optionally age 10 to 17, optionally age 10 to 16, optionally age 10 to 15. In some embodiments, the subject is age 12 to 18, optionally age 12 to 17, optionally age 12 to 16, optionally age 12 to 15.

[0113] In some embodiments, administering Compound A or a pharmaceutically acceptable salt thereof prevents edema, proteinuria, albuminuria, GFR (glomerular filtration rate) decline, high plasma lipid levels, high plasma cholesterol levels, nephrotic syndrome, high blood pressure or hypertension, kidney damage, glomerular damage, kidney failure and / or secondary cardiovascular events.

[0114] The dose of Compound A or a pharmaceutically acceptable salt thereof, including dose amount, dosing period, and dosing frequency, may be as described herein, for example as described in relation to the above methods of treatment.

[0115] Compound A or a pharmaceutically acceptable salt thereof may be administered as described herein, for example as described in relation to the above methods of treatment.

[0116] In some embodiments, the method does not include separate loading and maintenance doses but just one or more doses of Compound A, or a pharmaceutically acceptable salt thereof, to the subject over a period of time.

[0117] In some embodiments, the method includes administering one or more loading doses and one or more maintenance doses of Compound A or a pharmaceutically acceptable salt thereof to the subject, as described herein, for example as described in relation to the above methods of treatment.

[0118] APOL1 Levels

[0119] In any of the methods described herein, the level of APOL1 may be reduced in the subject following administration of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, level of APOL1 refers to level of APOL1 mRNA. In other embodiments, level of AP0L1 refers to level of AP0L1 protein. In some embodiments, level of AP0L1 refers to AP0L1 level in the kidney of the subject. In other embodiments, level of AP0L1 refers to the AP0L1 level in the liver of the subject. In other embodiments, level of AP0L1 refers to the circulating AP0L1 level in the subject, for example serum AP0L1 level or plasma AP0L1 level. In further embodiments, level of AP0L1 refers to the plasma AP0L1 level.

[0120] In some embodiments, the level of AP0L1 in the subject is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or at least about 70% after administration of Compound A or a pharmaceutically acceptable salt thereof, as compared to baseline level.

[0121] In some embodiments, the level of APOL1 in the subject is reduced by up to about 100%, up to about 95% or up to about 90% after administration of Compound A or a pharmaceutically acceptable salt thereof, as compared to baseline level.

[0122] In some embodiments, the APOL1 plasma protein level in the subject is reduced by at least about 30%, at least about 40%, or at least about 50% after administration of Compound A or a pharmaceutically acceptable salt thereof, as compared to baseline level.

[0123] In some embodiments, the APOL1 mRNA level in the kidney of the subject is reduced by at least about 10%, at least about 20%, at least about 30% after administration of Compound A or a pharmaceutically acceptable salt thereof, as compared to baseline level. In some embodiments, the APOL1 mRNA level in the kidney of the subject is reduced by at least about 30%, at least about 40%, at least about 50% after administration of Compound A or a pharmaceutically acceptable salt thereof, as compared to baseline level.

[0124] In some embodiments, the reduction of APOL1 level refers to reduction after a single dose of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the reduction of APOL1 level refers to reduction after repeat dosing of Compound A or a pharmaceutically acceptable salt thereof, for example once a steady state in APOL1 level is reached. In some embodiments, wherein the method comprises one or more loading doses and one or more maintenance doses, the reduction of APOL1 level refers to reduction after administration of the loading dose(s). In some embodiments, wherein the method comprises one or more loading doses and one or more maintenance doses, the reduction of APOL1 level refers to reduction after administration of one or more maintenance doses (e.g. once a steady state in APOL1 level is reached).

[0125] Albuminuria or Proteinuria Albuminuria or proteinuria can be a manifestation of kidney disease and may be a useful biomarker. However, evidence shows that APOL1 -mediated kidney disease can progress without albuminuria or proteinuria (e.g. Nguyen et al, Kidney Med., 2022, 4, 100563). Accordingly, subjects with and without albuminuria or proteinuria may be suitable for the treatment described herein.

[0126] In some embodiments, the subject has albuminuria prior to administration of Compound A or a pharmaceutically acceptable salt thereof. Albuminuria may be defined by a urinary albumincreatinine ratio (uACR) of > 300 mg / g. Accordingly, in some embodiments, the subject has a urinary albumin-creatinine ratio (uACR) of > 300 mg / g prior to administration of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, albuminuria is reduced after administration of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, uACR is reduced to < 300 mg / g after administration of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, uACR is reduced to < 30 mg / g after administration of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, uACR is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95% after administration of Compound A or a pharmaceutically acceptable salt thereof, as compared to baseline level. In some embodiments, uACR is reduced by at least about 40% after administration of Compound A or a pharmaceutically acceptable salt thereof, as compared to baseline level.

[0127] In other embodiments, the subject does not have albuminuria or has minimal albuminuria prior to administration of Compound A or a pharmaceutically acceptable salt thereof. A subject without albuminuria may be defined as having < 30 mg / g uACR. A subject with minimal albuminuria (or “microalbuminuria”) may be defined as having from 30 mg / g to less than 300 mg / g uACR. Accordingly, in some embodiments, the subject has a uACR of < 300 mg / g prior to administration of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has uACR of < 30 mg / g prior to administration of Compound A or a pharmaceutically acceptable salt thereof.

[0128] Proteinuria may be measured as an alternative to albuminuria. Proteinuria may be quantified by urinary protein / creatinine ratio (uPCR).

[0129] In some embodiments, the subject has proteinuria prior to administration of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the proteinuria is nephrotic range proteinuria. In further embodiments, proteinuria is reduced after administration of Compound A or a pharmaceutically acceptable salt thereof (e.g. to <3.5 mg / mg or <0.2 mg / mg uPCR). In some embodiments, proteinuria is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95% after administration of Compound A or a pharmaceutically acceptable salt thereof, as compared to baseline level.

[0130] In some embodiments, the subject does not have proteinuria prior to administration of Compound A or a pharmaceutically acceptable salt thereof.

[0131] In some embodiments, the reduction in albuminuria (e.g. uACR) or proteinuria (e.g. uPCR) refers to reduction after a single dose of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the reduction in albuminuria (e.g. uACR) or proteinuria (e.g. uPCR) refers to reduction after repeat dosing of Compound A or a pharmaceutically acceptable salt thereof, for example once a steady state is reached. In some embodiments, wherein the method comprises one or more loading doses and one or more maintenance doses, the reduction in albuminuria (e.g. uACR) or proteinuria (e.g. uPCR) refers to reduction after administration of the loading dose(s). In some embodiments, wherein the method comprises one or more loading doses and one or more maintenance doses, the reduction in albuminuria (e.g. uACR) or proteinuria (e.g. uPCR) refers to reduction after administration of one or more maintenance doses (e.g. once a steady state is reached).

[0132] Glomerular Filtration Rate (GFR)

[0133] GFR can be a useful biomarker to ascertain the severity of the disease (e.g. AMKD), the suitability of the subject to treatment, and / or the subject’s response to the treatment.

[0134] In some embodiments, the subject has a GFR of >60 mL / min / 1 ,73m2prior to administration of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a GFR <90 mL / min / 1.73m2prior to administration of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a GFR <60 mL / min / 1 ,73m2prior to administration of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a GFR of >25 mL / min / 1.73m2prior to administration of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a GFR of >25 mL / min / 1.73m2and <60 mL / min / 1.73m2prior to administration of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a decreasing GFR prior to administration of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the decline in GFR of the subject is at a greater rate than the decline in GFR of an individual who does not have a disease associated with APOL1, such as AMKD. In some embodiments, the decline in GFR in a subject, prior to administration of Compound A or a pharmaceutically acceptable salt thereof, is greater than about 1 mL / min / 1.73m2 / year.

[0135] In some embodiments, decline in GFR is reduced after administration of Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the decline in GFR is reduced by at least about 0.75 mL / min / 1.73m2 / year. In further embodiments, the decline in GFR is reduced by at least about 2 mL / min / 1.73m2 / year. In further embodiments, the decline in GFR is reduced by from about 2 mL / min / 1.73m2 / year to about 3 mL / min / 1.73m2 / year. In some embodiments, the decline in GFR is measured after repeat dosing of Compound A or a pharmaceutically acceptable salt thereof, for example after a dosing period of at least 1 year.

[0136] In some embodiments, GFR is estimated GFR (eGFR). In some embodiments, GFR is measured GFR (mGFR).

[0137] Unit Dosages and Single Dose Containers

[0138] Provided herein is a unit dosage comprising Compound A or a pharmaceutically acceptable salt thereof in a quantity of about 10 mg to about 150 mg of the free acid.

[0139] In some embodiments, the pharmaceutically acceptable salt of Compound A is a sodium salt (e.g. as depicted in Figure 3). In some embodiments, the pharmaceutically acceptable salt of Compound A is a potassium salt. In some embodiments, the unit dosage comprises the sodium salt of Compound A. In some embodiments, the unit dosage comprises the potassium salt of Compound A.

[0140] In some embodiments, the quantity of Compound A or a pharmaceutically acceptable salt thereof in the unit dosage is from about 20 mg to about 150 mg of the free acid. In some embodiments, the quantity of Compound A or a pharmaceutically acceptable salt thereof in the unit dosage is from about 25 mg to about 150 mg of the free acid. In some embodiments, the quantity of Compound A or a pharmaceutically acceptable salt thereof is from about 50 mg to about 150 mg of the free acid. In some embodiments, the quantity of Compound A or a pharmaceutically acceptable salt thereof is from about 75 mg to about 150 mg of the free acid. In some embodiments, the quantity of Compound A or a pharmaceutically acceptable salt thereof is from about 100 mg to about 150 mg of the free acid. In some embodiments, the quantity of Compound A or a pharmaceutically acceptable salt thereof is from about 10 mg to about 125 mg of the free acid. In some embodiments, the quantity of Compound A or a pharmaceutically acceptable salt thereof is from about 20 mg to about 125 mg of the free acid. In some embodiments, the quantity of Compound A or a pharmaceutically acceptable salt thereof is from about 25 mg to about 125 mg of the free acid. In some embodiments, the quantity of Compound A or a pharmaceutically acceptable salt thereof is from about 10 mg to about 100 mg of the free acid. In some embodiments, the quantity of Compound A or a pharmaceutically acceptable salt thereof is from about 20 mg to about 100 mg of the free acid. In some embodiments, the quantity of Compound A or a pharmaceutically acceptable salt thereof is from about 25 mg to about 100 mg of the free acid. In some embodiments, the quantity of Compound A or a pharmaceutically acceptable salt thereof is from about 50 mg to about 100 mg of the free acid. In some embodiments, the quantity of Compound A or a pharmaceutically acceptable salt thereof is from about 10 mg to about 75 mg of the free acid. In some embodiments, the quantity of Compound A or a pharmaceutically acceptable salt thereof is from about 20 mg to about 75 mg of the free acid. In some embodiments, the quantity of Compound A or a pharmaceutically acceptable salt thereof is from about 25 mg to about 75 mg of the free acid. In some embodiments, the quantity of Compound A or a pharmaceutically acceptable salt thereof is from about 10 mg to about 50 mg of the free acid. In some embodiments, the quantity of Compound A or a pharmaceutically acceptable salt thereof is about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg or about 150 mg of the free acid. In some embodiments, the quantity of Compound A or a pharmaceutically acceptable salt thereof is about 25 mg of the free acid. In some embodiments, the quantity of Compound A or a pharmaceutically acceptable salt thereof is about 50 mg of the free acid. In some embodiments, the quantity of Compound A or a pharmaceutically acceptable salt thereof is about 75 mg of the free acid. In some embodiments, the quantity of Compound A or a pharmaceutically acceptable salt thereof is about 100 mg of the free acid. In some embodiments, the quantity of Compound A or a pharmaceutically acceptable salt thereof is about 125 mg of the free acid. In some embodiments, the quantity of Compound A or a pharmaceutically acceptable salt thereof is about 150 mg of the free acid.

[0141] In some embodiments, the unit dosage is formulated for parenteral administration. In some embodiments, the parenteral administration is subcutaneous, intramuscular or intravenous administration. In some embodiments, the unit dosage is formulated for subcutaneous administration.

[0142] In some embodiments, the unit dosage further comprises a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutically acceptable excipient is saline, for example, buffered saline solution.

[0143] In some embodiments, a unit dosage as described herein is used in the manufacture of a medicament for treating a disease associated with APOL1 (such as AMKD) in a subject, wherein the subject is human. In some embodiments, a unit dosage as described herein is used in the manufacture of a medicament for preventing a disease associated with APOL1 (such as AMKD) in a subject, wherein the subject is human. Features of the disease, treatment and / or prevention may be as described in relation to the methods disclosed herein.

[0144] In some embodiments of the methods described herein, Compound A or a pharmaceutically acceptable salt thereof is administered as the unit dosage described herein.

[0145] Also provided herein is a single-dose container comprising the unit dosage described herein. In some embodiments, the single-dose container is a pre-filled syringe. In some embodiments, the single-dose container is an accessorized pre-filled syringe. In some embodiments, the single-dose container is an autoinjector device.

[0146] Kits

[0147] In an aspect, a kit is provided for treating an APOL1 -mediated disease (such as AMKD), comprising a unit dosage or single dose container, wherein the unit dosage and single dose container are as described herein. In another aspect, a kit is provided for preventing an AP0L1- mediated disease (such as AMKD), comprising a unit dosage or single dose container, wherein the unit dosage and single dose container are as described herein.

[0148] In some embodiments, the kit includes one or more unit dosages as described herein. In embodiments, the kit includes one unit dosage as described herein. In embodiments, the kit includes multiple unit dosages as described herein. In some embodiments, the kit further comprises instructions for use, for example instructions for use in treating or preventing (e.g. treating) an AP0L1 -mediated disease (such as AMKD).

[0149] All possible combinations of the above aspects, embodiments and features are considered to be embraced within the scope of this disclosure. EXAMPLES

[0150] List of Abbreviations and Definitions of Terms

[0151] Preclinical studies

[0152] Aghajan et al (JCI Insight, 2019s4(12), el 26124; incorporated by reference in its entirety) relates to the development of an APOL1 transgenic mouse model and the effect of Compound A (referred to as IONIS-APOL1 RXtherein) on this model. Aghajan describes a novel physiologically-relevant genomic mouse model of APOL1 -associated renal disease that expresses human APOL1 from the endogenous human promoter, resulting in expression in similar tissues and at similar relative levels as humans. While naive APOL1 transgenic mice did not exhibit a renal disease phenotype, administration of interferon gamma (FFNy) was sufficient to robustly induce proteinuria in APOL1 G1 mice only, despite inducing kidney APOL1 expression in both GO and G1 mice, serving as a clinically-relevant “second hit.” Treatment of APOL1 G1 mice with Compound A prior to fFNy challenge robustly and dose- dependently inhibited kidney and liver APOL1 expression and protected against IFNy- induced proteinuria, indicating that the disease-relevant cell types are sensitive to Compound A treatment.

[0153] Example 1 : Phase 1 SAD study in healthy volunteers (Clinicaltrials.gov Identifier: NCT04269031)

[0154] Table 1: Geometric Mean (CV%) AZD2373 PK Parameters Following Single Subcutaneous Dose Administration of AZD2373 to Healthy Male Subjects of African Ancestry

[0155] a median (min-max) presented.

[0156] Abbreviations: CV = geometric coefficient of variance (%); N = number of subjects in the PK analysis set; Min = minimum; Max = maximum. Table 2: Assessment of AZD2373 Dose Proportionality

[0157] Abbreviations: CI = confidence interval; n = number of data points used in regression

[0158] Example 2: Phase 1 MAD study in healthy volunteers (Clinicaltrials.gov Identifier:

[0159] NCT05351047) Study Design:

[0160] This was a Phase I, randomized, single blind, placebo-controlled, MAD, sequential group study to assess the safety, tolerability and PK of AZD2373 following SC MAD administrations in healthy male participants of sub-Saharan West African ancestry. Study center personnel remained blinded until the post treatment phase for the Safety Review Committee (SRC), until evaluation of data from the cohort was conducted.

[0161] The study included 3 multiple dose cohorts. Eight participants per cohort were enrolled and were dosed in a ratio of 6:2 (AZD2373: placebo).

[0162] Male participants aged 18 to 55 years (inclusive) were selected based on the results of the prescreening study with regards to AP0L1 GO, Gl, and G2 allele status. It was planned to enroll a minimum of 9 participants carrying a Gl allele and 9 participants carrying a G2 allele in total, and it was planned to enroll a minimum of 3 Gl and 3 G2 carriers in each cohort. If a participant was G1 / G2 they were counted toward both the Gl and G2 groups.

[0163] The following cohorts were dosed during this study:

[0164] • Cohort 1 was dosed with 20 mg AZD2373 or placebo, with a dosing regimen of weekly dosing for 6 weeks with dosing Days 1, 8, 15, 22, 29, and 36.

[0165] • Cohort 2 was dosed with 50 mg AZD2373 or placebo, with a dosing regimen of weekly dosing for 6 weeks with dosing on Days 1, 8, 15, 22, 29, and 36.

[0166] • Cohort 3 was dosed with 150 mg AZD2373 or placebo, with a dosing regimen of weekly dosing for 6 weeks with dosing on Days 1, 8, 15, 22, 29, and 36.

[0167] Eight participants were enrolled in each cohort and within each cohort; 6 participants received AZD2373, and 2 participants received placebo. Dosing for each cohort proceeded with 3 participants in a sentinel cohort, such that 2 participants were randomized to receive AZD2373, and 1 participant was randomized to receive placebo. For Cohort 1 the remaining participants were dosed 22 days after first dose in the sentinel cohort. In subsequent cohorts the remaining cohort participants were dosed 29 days after first dose in the sentinel cohort. The study comprised of:

[0168] • A Screening Period of up to 60 days.

[0169] • A Treatment Period during which participants were resident at the study center from the day before their first AZD2373 dose administration (Day -1) until the post last dose data (at least 24 hours) had been reviewed by the Investigator. the Investigator that could have interfered with the interpretation of QTc interval changes, including abnormal ST-T-wave morphology, particularly in the protocol defined primary lead or left ventricular hypertrophy at the Screening Visit and / or on Day -1. Out of range tests could have been repeated once for each visit at the discretion of the Investigator.

[0170] (a) Prolonged QTcF > 450 ms.

[0171] (b) Shortened QTcF < 340 ms.

[0172] (c) Family history of long QT syndrome.

[0173] (d) PR(PQ) interval shortening < 120 ms (PR > 110 ms but < 120 ms was acceptable if there was no evidence of ventricular pre-excitation).

[0174] (e) PR(PQ) interval prolongation (> 240 ms) intermittent second (Wenckebach block while asleep was not exclusive) or third-degree AV block, or AV dissociation.

[0175] (f) Persistent or intermittent complete BBB, IBBB, or IVCD with QRS > 110 ms. Participants with QRS > 110 ms but < 115 ms were acceptable if there was no evidence of, eg, ventricular hypertrophy or pre-excitation.

[0176] 14 Known or suspected history of drug abuse as judged by the Investigator.

[0177] 15 Current smokers or those who had smoked or used nicotine products (including e- cigarettes) within the previous 3 months.

[0178] 16 History of alcohol abuse or excessive intake of alcohol as judged by the Investigator.

[0179] 17 Positive screen for drugs of abuse or cotinine (nicotine) at Screening or admission to the study center or positive screen for alcohol on admission to the study center prior to administration of the study intervention on Study Day 1.

[0180] 18 History of severe allergy / hypersensitivity or ongoing clinically important allergy / hypersensitivity, as judged by the Investigator or history of hypersensitivity to drugs with a similar chemical structure or class to AZD2373.

[0181] 19 Excessive intake of caffeine-containing drinks or food (eg, coffee, tea, chocolate,) as judged by the Investigator.

[0182] 20 Use of any prescribed or non-prescribed medication including antacids, analgesics (other than paracetamol / acetaminophen), herbal remedies, mega-dose vitamins (intake of 20 to 600 times the recommended daily dose) or minerals during the 2 weeks prior to the first administration of study intervention or longer if the medication had a long t’A.

[0183] 21 Plasma donation within one month of the Screening Visit or any blood donation / blood loss > 500 mL during the 3 months prior to the Screening Visit. 22 Had received another new chemical entity (defined as a compound which had not been approved for marketing) less than 30 days prior to administration of the study intervention on Study Day 1, or less than 5 half-lives of the study intervention in a prior study (whichever was longer).

[0184] Note: Participants consented and screened, but not randomized in this study or a previous Phase I study, were not excluded.

[0185] 23 Participants who previously received AZD2373. Participants carrying a G2 allele who were enrolled in the AZD2373 SAD study but did not receive AZD2373 were not excluded.

[0186] 24 History of severe infection, chronic or recurrent infectious disease or ongoing febrile illness within 30 days prior to Screening.

[0187] 25 Evidence of CKD and / or proteinuria.

[0188] 26 Blood dyscrasias with increased risk of bleeding including idiopathic thrombocytopenic purpura and thrombotic thrombocytopenic purpura or symptoms of increased risk of bleeding (frequent bleeding gums or nose bleeds).

[0189] 27 Involvement of any AstraZeneca or study center employee or their close relatives.

[0190] 28 Judgment by the Investigator that the participant should not have participated in the study if they had any ongoing or recent (ie, during the Screening Period) minor medical complaints that could have interfered with the interpretation of study data or were considered unlikely to have complied with study procedures, restrictions and requirements.

[0191] 29 Participants who were vegans or had medical dietary restrictions that would have made them unable to comply with the diet provided for the in-house study center stays.

[0192] 30 Participants who could not communicate reliably with the Investigator.

[0193] 31 Vulnerable participants, eg, kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.

[0194] 32 History of Trypanosomiasis (African sleeping sickness or Chagas disease), or Leishmaniasis.

[0195] 33 Participants who had a planned visit to a tropical or subtropical region within 10 weeks after administration of the study intervention or 5 * t’ of AZD2373 (whichever was longer).

[0196] 34 Participants with sickle cell disease were excluded but not individuals with heterozygous sickle cell trait.

[0197] In addition, any of the following was regarded as a criterion for exclusion from the APOL1 Statistical Methods:

[0198] Determination of Sample Size:

[0199] This was a Phase I study to investigate the safety and tolerability of a novel compound. The sample size of 24 participants was chosen to obtain reasonable evidence of safety and tolerability without exposing undue numbers of participants to the compound at this phase of clinical development. Previous experience in Phase I studies has shown that the sample size being proposed was reasonable to accomplish the objectives of the study.

[0200] Presentation and Analysis of Pharmacokinetic Data:

[0201] Pharmacokinetic blood and urine sample collection times including derived sampling time deviations were listed. Plasma concentrations and plasma and urine PK parameters were summarized by treatment dose level using descriptive statistics.

[0202] Individual plasma concentrations versus actual time, as well as combined individual plasma concentration per treatment dose level versus actual times were plotted in linear and semi- logarithmic scale. Figures for the arithmetic mean concentration time data were presented for all treatment doses on both a linear and semi-logarithmic scale.

[0203] The time dependency of the PK (temporal change parameter in systemic exposure [TCP]) was evaluated by comparing AUCT after last dose with AUCinf of Day 1. The ratio between AUCT on Day 36 and AUCinf (Day 1) was calculated by back-transforming the arithmetic mean difference between the log transformed AUCs. Using the computed estimate, 90% confidence intervals (Cis) were calculated for the difference and then back-transformed.

[0204] Presentation and Analysis of Pharmacodynamic Data:

[0205] Apolipoprotein LI plasma protein concentration listings were presented for the PD analysis set and included all reportable individual APOL1 concentration measurements. For each cohort and treatment (dose level of AZD2373, total AZD2373 and pooled placebo) APOL1 plasma protein concentration summaries were presented for the PD analysis set including tabulation and graphical presentation of actual change from baseline and percentage change from baseline over time. Baseline for APOL1 was calculated as the mean of the concentrations in the samples collected on Day -1 and pre-dose on Day 1.

[0206] Summary tabulations for plasma levels of APOL1 were also presented by cohort / treatment (data from all cohorts were pooled) and time point. Changes from baseline and percentage change from baseline were calculated and presented for all post-baseline time points including the Follow-up Visit. Geometric mean plasma levels of AP0L1 ± gSD were plotted on both the linear and semi- logarithmic scale by cohort / treatment (pooled data from all cohorts for placebo) for all visits. Percentage change from baseline in plasma levels of AP0L1 were plotted on linear scale by cohort / treatment (pooled data based from all cohorts for placebo) versus nominal time. Treatment effect on the changes from baseline in plasma level of AP0L1 were analyzed using an analysis of covariance (ANCOVA) model with treatment as a fixed effect, and baseline in plasma level of AP0L1 as a covariate. Analyses were performed on log-transformed data. The n, least squares mean, standard error, and 95% CI were calculated for each treatment (dose level of AZD2373 or placebo). The least squares mean difference between each dose level of AZD2373 and placebo were calculated and their standard errors and 95% Cis were also calculated. Statistics were transformed back to the original scale to yield geometric least squares mean ratios and geometric 95% Cis, which were then transformed to percentage change from baseline.

[0207] Presentation and Analysis of Safety Data:

[0208] All safety data (scheduled and unscheduled) were presented in the data listings. Continuous variables were summarized using descriptive statistics (n, mean, standard deviation [SD], minimum, median, maximum) by treatment (dose level of AZD2373, total AZD2373, and pooled placebo). Categorical variables were summarized in frequency tables (frequency and proportion) by treatment (dose level of AZD2373, total AZD2373, and pooled placebo). All summaries were based on the safety analysis set, unless otherwise stated.

[0209] • Participant disposition was listed and summarized, including the number of withdrawals and the primary reason for withdrawal. Participants excluded from any analysis set were listed including the reasons for exclusion.

[0210] • Use of concomitant medication was reported.

[0211] • Adverse events were coded using the applicable dictionary and summarized by system organ class and preferred term. Additional summaries by severity and causality were presented.

[0212] • SARS-CoV-2 positive results were reported as AEs / serious adverse events (SAEs) depending on the reported events (if any).

[0213] • Vital signs measurements and laboratory results were listed and summarized including changes from baseline. Any out of range vital signs measurements and laboratory results

[0214] Table 3A: Summary Statistics of AZD2373 PK Parameters Following Single Subcutaneous Dose Administration of AZD2373 to Healthy Male Participants of sub-Saharan West African Ancestry

[0215] Table 3B: Summary Statistics of AZD2373 PK Parameters Following Multiple Subcutaneous Doses Administration of AZD2373 to Healthy Male Participants of sub-Saharan West African Ancestry

[0216] Table 4A: Assessment of AZD2373 Dose Proportionality for Single Dose Table 4B: Assessment of AZD2373 Dose Proportionality for Multiple Weekly Doses

[0217] Table 5: Assessment of AZD2373 Time-dependency; Comparison with Day 1 (Day 36 A UCT versus Day l AUCinf)

[0218] GMR = geometric mean ratio; CI = confidence ratio

[0219] Table 6: Number of Participants with Adverse Events Assessed to be Possibly Related to Study Intervention by System Organ Class and Preferred Term aPossibly related, as assessed by the Investigator.

[0220] Example 3: Phase 2 study design

[0221] General Design A phase 2 study will be conducted to assess the efficacy and safety of AZD2373 in patients diagnosed with AMKD who are homozygotes or compound heterozygotes for AP0L1 high risk genotypes (G1 and G2). AZD2373 will be administered to treatment groups at doses of 50 mg or 150 mg, or at dose(s) within these end-points, once weekly by subcutaneous injection, for a period of treatment. A placebo arm may be included. A further treatment arm may also be included, within the above dosing range, but once every other week administration. Patients with two APOL1 risk alleles and chronic kidney disease (CKD) will be enrolled (males and females aged 18-65). Screening to identify patients for enrolment will either be carried out as part of the phase 2 study, or as a separate pre-screening study.

[0222] The primary outcome measure will be change from baseline in uACR, to assess the effect of AZD2373 in reducing albuminuria.

[0223] Secondary outcome measures may include one or more of: assessing the effect of AZD2373 versus placebo in reducing albuminuria from baseline assessing the proportion of patients achieving a 40% or greater uACR reduction by treatment assessing eGFR change from baseline by treatment assessing pooled AZD2373 doses vs placebo on eGFR change assessing the proportion of patients achieving complete remission of albuminuria

[0224] Safety and tolerability will also be assessed.

[0225] At specified study visits participants will undergo a general physical examination, assessment of disease related parameters (uACR, eGFR, etc.), provide samples for safety and biomarker evaluation, and patient and clinician reported outcomes.

[0226] The treatment groups may be, for example:

[0227] • 50mg AZD2373 sc injection once weekly, e.g. n = 32 or 48 randomized participants.

[0228] • 150mg AZD2373 sc injection once weekly, e.g. n = 32 or 48 randomized participants.

[0229] • Placebo sc injection once weekly, e.g. n = 32 or 48 randomized participants.

[0230] • Optionally, 150mg AZD2373 sc injection once every other week, e.g. 32 or 48 randomized participants.

[0231] The treatment period may be, for example, 30 weeks of dosing.

[0232] Dosage Rationale

[0233] Weekly dosing (QW): The dose strategy for this study is informed by data from the SAD and MAD studies (Examples 1 and 2, respectively), which demonstrated the safety of AZD2373 up to 150 mg subcutaneous administered weekly for 6 weeks, and target engagement (reduction in plasma APOL1 levels). The toxicological profile and associated exposure margins are also taken into consideration for the dose strategy.

[0234] The dose strategy is also supported by the APOL1 transgenic mouse study (Aghajan et al, JCI Insight, 2019, 4(12), el 26124), where a 30% reduction in kidney APOL1 mRNA expression correlated with a 50% decrease in plasma APOL1 protein and resulted in a 78% prevention of albuminuria. In two separate patient cohort studies the difference in APOL1 kidney mRNA expression between patients with a high-risk APOL1 genotype and a low-risk genotype was approximately 30%. A study in a cohort of patients with FSGS demonstrated that in those patients with a high-risk APOL1 status, the APOL1 mRNA expression levels were 30% higher than in those with a low-risk genotype (McNulty et al, Kidney Int., 2022, 102(1), 136-148). In another study, APOL1 mRNA levels were compared in kidney samples from high risk APOL1 individuals with FSGS or no CKD, and a 24% difference was observed (Bekerman et al, Nat. Med, 2017, 23(4), 429-438). Based on these preclinical and clinical observations, it is thought that a 30% knockdown of APOL1 mRNA in the kidney will result in a meaningful treatment effect in patients.

[0235] Based on the MAD study data (Example 2), 50 mg AZD2373 SC once weekly is expected to generate approximately 50% knockdown of plasma APOL1 at steady state (see Figures 6A and 6B). In the transgenic APOL1 mouse model, 50% plasma knockdown was associated with a 30% decrease in kidney APOL1 mRNA and 78% prevention of albuminuria. Based on the MAD study data, 150 mg AZD2373 SC once weekly is expected to generate approximately 80% knockdown of plasma APOL1 at steady state. In the transgenic APOL1 mouse model, 80% plasma knockdown was associated with a 40% decrease in kidney APOL1 mRNA and 84% prevention of albuminuria.

[0236] In summary, based on the above data taken together, the Phase 2 study doses of AZD2373 are selected in the range of 50 to 150 mg once weekly.

[0237] Fortnightly dosing (Q2W): Dosing AZD2373 once every two weeks would minimize the number of injections required. A dose of 150 mg every two weeks is predicted to provide equivalent exposure to 75 mg once weekly (approximately 65% knock-down of plasma APOL1). Phase 2b protocol (QW)

[0238] Design synopsis:

[0239] This Phase 2b study is designed to assess the efficacy and safety of AZD2373 in participants diagnosed with AMKD who are homozygotes or compound heterozygotes for AP0L1 high- risk genotypes (G1 and G2). The study is a double-blind, placebo-controlled, Phase 2b doseranging study conducted in approximately 96 participants on background standard treatment as per local guidelines. An OLE will be offered under a separate study protocol.

[0240] The primary hypothesis to be evaluated is that AZD2373, compared with placebo, will result in a greater reduction in UACR as assessed by the relative change from Baseline in UACR at Week 30. Participants who have high-risk APOL1 genotype (Gl / Gl; G1 / G2; G2 / G2), with 300 mg / g or greater UACR and eGFR > 25mL / min / 1.73m2will be recruited into the study. Participants on kidney replacement therapy (dialysis or kidney transplant) or any other organ transplant will be excluded. The primary objective is placebo corrected relative change in UACR from Baseline at Week 30.

[0241] All participants will remain in the study on treatment until the last participant has completed 30 weeks of treatment.

[0242] The treatment duration will be up to minimum of 30 weeks of study treatment.

[0243] The visit frequency will be:

[0244] • Screening Phase: Once every 2 weeks (Visit 1 and 2, Weeks -16 and -14) until the first visit of run-in period (Visit 3, Week - 12).

[0245] • Run-in period: Participants will return to the study clinic once every 4 weeks until the Baseline visit (Visit 6 - Week 0).

[0246] • Treatment period: Beginning at Week 0, treatment period will have study visits once every 2 weeks until Week 16 (Visit 7 to Visit 14 - Week 2 to Week 16) and then every 4 weeks until Week 28 (Visit 15 to Visit 17 - Week 20 to Week 28) after which the participants will have Week 30 (Visit 18). Participants will have study visits once in every 4 weeks until the last participant completes Week 30 (Visit 18). This visit will mark EoT of the study.

[0247] • Safety follow-up period: Safety follow-up visits will be conducted at every 4 weeks, ie, 4, 8, and 12 weeks after the EoT. The last safety follow-up visit will mark EoS for the participant. This will only occur in participants who do not enter the OLE study. Objectives and endpoints:

[0248] Number of Participants:

[0249] Approximately 96 participants will be randomized to study intervention (32 participants in each treatment group) and at least 27 evaluable participants per treatment group.

[0250] Note: ‘Screened’ means a participant, or their legally acceptable representative’s, agreement to participate in a clinical study following completion of the informed consent process. Potential participants who are screened for the purpose of determining eligibility for the study, but are not randomized / assigned in the study, are considered ‘screen failures’, unless otherwise specified in the protocol.

[0251] Study Arms and Duration:

[0252] The study will comprise of 3 periods:

[0253] • Screening Phase: 4 weeks

[0254] • Run-in period: 12 weeks

[0255] • Treatment period: Each participant will receive treatment for a minimum of 30 weeks which will mark the EoT and will continue treatment until the last participant completes 30 weeks of treatment, which will mark EoT period.

[0256] • At the end of the treatment period, participants will have the option to enter an OLE where efficacy, safety, and tolerability will continue to be monitored. Participants who discontinue the Phase 2b study or do not enter the OLE (including placebo) will have a safety follow-up at 4, 8, and 12 weeks after their last dose. When the last participant has completed 30-week treatment, there will be a data cut allowing for analysis of Phase 2b treatment efficacy, safety, and tolerability. Full database lock will occur once 12-week safety follow-up is complete.

[0257] An OLE will be offered under a separate study protocol.

[0258] The background therapy will be optimized during a 12-week run-in period. At the end of the run-in period, participants will be randomized at a 1 : 1 : 1 ratio to 3 study treatment arms.

[0259] • Placebo group

[0260] • AZD2373 50 mg dose group • AZD2373 150 mg dose group.

[0261] Participants in each group will receive SC injection of the assigned dose once a week on top of local background SoC treatment. An accessorized prefilled syringe will be used for selfadministration by participants, or administration by caregivers or health care professionals. All participants will remain on treatment until the last enrolled participant completes at least 30- week dosing.

[0262] Statistical Methods

[0263] The primary hypothesis for this study is that AZD2373, compared with placebo, will result in a greater reduction in UACR as assessed by the relative change from Baseline in UACR at Week 30. This analysis will be performed on the Full Analysis Set. Each dose group will be tested against the placebo using a hierarchical testing approach.

[0264] The primary objective will be addressed by an estimand that reflects the treatment effect per randomized IMP, irrespective of concomitant treatment or discontinuation of IMP, and in the absence of death, initiation of dialysis or kidney transplant, withdrawal of consent, and lost to follow-up.

[0265] Baseline UACR will be determined by the geometric mean of 3 consecutive daily First Morning Void urine samples prior to first dose.

[0266] Based on the assumption of UACR following a log-normal distribution, the analysis will be conducted using an ANCOVA model with the dependent variable of change from Baseline to Week 30 in log-transformed UACR. The model will include the treatment group as fixed effect (placebo as reference) and adjusting for Baseline log-transformed UACR values and presence of a diabetes diagnosis [yes or no]. The estimated change (least square means) from Baseline for each treatment arm as well as the difference between the 2 dose arms and placebo will be transformed onto relative changes (%) from Baseline and the relative difference (%) between treatments. The results are displayed as change, along with the two-sided 90% CI and two- sided p-value (significance declared < 0.10).

[0267] For the primary analysis, first the 150 mg dose arm will be tested against placebo at 0.10 significance level and then the 50 mg dose arm will be tested against placebo at 0.10 significance level. The full analysis set will be used for the efficacy analysis. Sensitivity analyses will be described in the SAP. Safety and tolerability will be evaluated in terms of AE, clinical laboratory variables, vital signs, and ECG. Exposure to IMP will be described. Safety analyses will be performed on the Full Analysis Set.

[0268] Assignment to Treatment Groups

[0269] Participants will be randomized at a 1 : 1 : 1 ratio to placebo, AZD2373 50 mg, and AZD2373 150 mg groups. Randomization will be stratified by the presence of a diabetes diagnosis (yes or no) and / or UACR > 1500 mg / g (yes or no) to ensure treatment groups are balanced with respect to prognostics variables within groups.

[0270] Sample Size Determination

[0271] A total of 27 evaluable participants per treatment group will provide approximately 80% power to detect a 45% reduction in UACR at Week 30 assuming a standard deviation of 0.87 in the log scale (two-sided test; alpha = 10%). To account for approximately 15% drop-out, 32 participants will be randomly assigned to each of the 3 treatment groups.

[0272] Example 4: Phase 2 study design - APOL3 null / heterozygous APOL1 population

[0273] Study purpose: To assess efficacy and safety of AZD2373 in patients diagnosed with CKD who are heterozygous for APOL1 G1 or G2 and heterozygous / homozygous for Q58* APOL3.

[0274] Treatment: AZD2373 to be administered to treatment groups at doses of 50 mg or 150 mg, or at dose(s) within these end-points, once weekly and / or once fortnightly by subcutaneous injection, for a period of treatment. A placebo arm may be included.

[0275] Inclusion Criteria: CKD patients with one APOL1 risk allele (G1 or G2) and at least one APOL3 Q58* allele; males and females aged 18-65. Further inclusion criteria may include 300 mg / g or greater UACR and eGFR > 25mL / min / 1.73m2.

[0276] Primary outcome measure: change from baseline in uACR, to assess the effect of AZD2373 in reducing albuminuria. Secondary outcome measures may include assessing eGFR change from baseline. Safety and tolerability to also be assessed.

[0277] At specified study visits, participants to undergo a general physical examination, assessment of disease related parameters (uACR, eGFR, etc.), provide samples for safety and biomarker evaluation, and patient and clinician reported outcomes. NUMBERED EMBODIMENTS:

[0278] 1. A method of treating a disease associated with AP0L1 in a subject comprising administering Compound A or a pharmaceutically acceptable salt thereof at a dose of from about 10 mg to about 150 mg of the free acid, wherein the subject is human and wherein Compound A has the structure:

[0279] 2. The method according to embodiment 1, wherein the disease associated with APOL1 is APOL1 -mediated kidney disease. 3. The method according to embodiment 2, wherein the AP0L1 -mediated kidney disease is selected from focal segmental glomerulosclerosis (FSGS), collapsing nephropathy, chronic kidney disease (CKD), hypertension-attributed nephropathy, HIV-associated nephropathy, sickle cell nephropathy, arterionephrosclerosis, lupus nephritis, minimal change disease, membranous nephropathy, nephrotic syndrome, renal allograft dysfunction, acute kidney injury and COVID-19-associated nephropathy (COVAN), or a combination thereof.

[0280] 4. The method according to embodiment 3, wherein the AP0L1 -mediated kidney disease is FSGS.

[0281] 5. The method according to embodiment 3, wherein the AP0L1 -mediated kidney disease is CKD.

[0282] 6. The method according to any preceding embodiment, wherein the subject has been determined as having at least one of AP0L1 risk alleles G1 or G2.

[0283] 7. The method according to embodiment 6, wherein the subject has been determined as being homozygous or compound heterozygous for AP0L1 risk alleles G1 and G2.

[0284] 8. The method according to any preceding embodiment, wherein the subject is an adult.

[0285] 9. The method according to any of embodiments 1 to 7, wherein the subject is a pediatric subject.

[0286] 10. The method according to any of embodiments 1 to 7, wherein the subject is age 16 or above, optionally age 17 or above, optionally age 18 or above.

[0287] 11. The method according to any of embodiments 1 to 7, wherein the subject is: (a) age 12 or above, optionally age 12 to 17, optionally age 12 to 16, optionally age 12 to 15; or (b) age 10 or above, optionally age 10 to 17, optionally age 10 to 16, optionally age 10 to 15.

[0288] 12. The method according to any preceding embodiment, wherein the pharmaceutically acceptable salt is a sodium salt.

[0289] 13. The method according to any of embodiments 1 to 11, wherein the pharmaceutically acceptable salt is a potassium salt. 14. The method according to any of embodiments 1 to 11, wherein Compound A or a pharmaceutically acceptable salt thereof is a sodium salt of Compound A having the structure: 15. The method according to any preceding embodiment, wherein the dose of Compound

[0290] A or a pharmaceutically acceptable salt thereof is from about 20 mg to about 150 mg of the free acid.

[0291] 16. The method according to any preceding embodiment, wherein the dose of Compound A or a pharmaceutically acceptable salt thereof is from about 50 mg to about 150 mg of the free acid. 17. The method according to any of embodiments 1 to 14, wherein the dose of Compound A or a pharmaceutically acceptable salt thereof is about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg or about 150 mg of the free acid.

[0292] 18. The method according to embodiment 17, wherein the dose of Compound A or a pharmaceutically acceptable salt thereof is about 25 mg of the free acid.

[0293] 19. The method according to embodiment 17, wherein the dose of Compound A or a pharmaceutically acceptable salt thereof is about 50 mg of the free acid.

[0294] 20. The method according to embodiment 17, wherein the dose of Compound A or a pharmaceutically acceptable salt thereof is about 75 mg of the free acid.

[0295] 21. The method according to embodiment 17, wherein the dose of Compound A or a pharmaceutically acceptable salt thereof is about 150 mg of the free acid.

[0296] 22. The method according to any preceding embodiment, wherein the dose is administered from about twice every week to about once every 2 months.

[0297] 23. The method according to any preceding embodiment, wherein the dose is administered from about twice every week to about once every 6 weeks.

[0298] 24. The method according to any preceding embodiment, wherein the dose is administered from about once every week to about once every 4 weeks.

[0299] 25. The method according to any of embodiments 1 to 22, wherein the dose is administered about twice weekly, about once weekly, about once every 2 weeks, about once every 3 weeks, about once every 4 weeks, about once monthly, about once every 5 weeks, about once every 6 weeks, or about once every 2 months.

[0300] 26. The method according to embodiment 25, wherein the dose is administered once weekly.

[0301] 27. The method according to embodiment 25, wherein the dose is administered once every two weeks.

[0302] 28. The method according to embodiment 25, wherein the dose is administered once monthly. 29. The method according to any preceding embodiment, wherein the dose is administered for a period of at least about 4 months, at least about 1 year, at least about 2 years, at least about 5 years, at least about 10 years, or at least about 20 years.

[0303] 30. The method according to any of embodiments 1 to 28, wherein the dose is administered for the lifetime of the subject.

[0304] 31. The method according to any of embodiments 1 to 28, wherein the disease associated with APOL1 is APOL1 -mediated kidney disease and the dose is administered until the onset of end-stage kidney disease in the subject.

[0305] 32. The method according to any of embodiments 1 to 14, which comprises administering to the subject:

[0306] (a) one or more loading doses of Compound A or a pharmaceutically acceptable salt thereof; and

[0307] (b) one or more maintenance doses of Compound A or a pharmaceutically acceptable salt thereof; wherein the one or more loading doses is from about 10 mg to about 150 mg of the free acid.

[0308] 33. The method according to embodiment 32, wherein the one or more maintenance doses comprise a lower amount of Compound A or a pharmaceutically acceptable salt thereof than the one or more loading doses.

[0309] 34. The method according to embodiment 32 or 33, wherein the method comprises administering one loading dose of Compound A or a pharmaceutically acceptable salt thereof.

[0310] 35. The method according to any of embodiments 32 to 34, wherein the loading dose of Compound A or a pharmaceutically acceptable salt thereof is from about 20 mg to about 150 mg of the free acid.

[0311] 36. The method according to any of embodiments 32 to 35, wherein the loading dose of Compound A or a pharmaceutically acceptable salt thereof is from about 50 mg to about 150 mg of the free acid.

[0312] 37. The method according to embodiment 32 or 34, wherein the loading dose of Compound A or a pharmaceutically acceptable salt thereof is about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg or about 150 mg of the free acid.

[0313] 38. The method according to embodiment 37, wherein the loading dose of Compound A or a pharmaceutically acceptable salt thereof is about 50 mg of the free acid.

[0314] 39. The method according to embodiment 37, wherein the loading dose of Compound A or a pharmaceutically acceptable salt thereof is about 75 mg of the free acid.

[0315] 40. The method according to embodiment 37, wherein the loading dose of Compound A or a pharmaceutically acceptable salt thereof is about 150 mg of the free acid.

[0316] 41. The method according to any of embodiments 32 to 40, wherein the maintenance dose of Compound A or a pharmaceutically acceptable salt thereof is from about 10 mg to about 150 mg of the free acid.

[0317] 42. The method according to any of embodiments 32 to 41, wherein the maintenance dose of Compound A or a pharmaceutically acceptable salt thereof is from about 20 mg to about 150 mg of the free acid.

[0318] 43. The method according to any of embodiments 32 to 42, wherein the maintenance dose of Compound A or a pharmaceutically acceptable salt thereof is from about 50 mg to about 150 mg of the free acid.

[0319] 44. The method according to any of embodiments 32 to 41, wherein the maintenance dose of Compound A or a pharmaceutically acceptable salt thereof is about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg or about 150 mg of the free acid.

[0320] 45. The method according to embodiment 44, wherein the maintenance dose of Compound A or a pharmaceutically acceptable salt thereof is about 25 mg of the free acid.

[0321] 46. The method according to embodiment 44, wherein the maintenance dose of Compound A or a pharmaceutically acceptable salt thereof is about 50 mg of the free acid.

[0322] 47. The method according to embodiment 44, wherein the maintenance dose of Compound A or a pharmaceutically acceptable salt thereof is about 75 mg of the free acid. 48. The method according to embodiment 44, wherein the maintenance dose of Compound A or a pharmaceutically acceptable salt thereof is about 100 mg of the free acid.

[0323] 49. The method according to any of embodiments 32 to 48, wherein the maintenance dose is administered from about twice every week to about once every 2 months.

[0324] 50. The method according to any of embodiments 32 to 49, wherein the maintenance dose is administered from about twice every week to about once every 6 weeks.

[0325] 51. The method according to any of embodiments 32 to 50, wherein the maintenance dose is administered from about once every week to about once every 4 weeks.

[0326] 52. The method according to any of embodiments 32 to 49, wherein the maintenance dose is administered about twice weekly, about once weekly, about once every 2 weeks, about once every 3 weeks, about once every 4 weeks, about once monthly, about once every 5 weeks, about once every 6 weeks, or about once every 2 months.

[0327] 53. The method according to embodiment 52, wherein the maintenance dose is administered once weekly.

[0328] 54. The method according to embodiment 52, wherein the maintenance dose is administered once every two weeks.

[0329] 55. The method according to embodiment 52, wherein the maintenance dose is administered once monthly.

[0330] 56. The method according to any of embodiments 32 to 55, wherein the maintenance dose is administered for a period of at least about 4 months, at least about 1 year, at least about 2 years, at least about 5 years, at least about 10 years, or at least about 20 years.

[0331] 57. The method according to any of embodiments 32 to 55, wherein the maintenance dose is administered for the lifetime of the subject.

[0332] 58. The method according to any of embodiments 32 to 55, wherein the disease associated with APOL1 is APOL1 -mediated kidney disease and the maintenance dose is administered until the onset of end-stage kidney disease in the subject.

[0333] 59. The method according to any preceding embodiment, wherein Compound A or a pharmaceutically acceptable salt thereof is administered by parenteral administration.

[0334] 60. The method according to embodiment 59, wherein the parenteral administration is subcutaneous, intramuscular or intravenous administration. 61. The method according to embodiment 59 or 60, wherein Compound A or a pharmaceutically acceptable salt thereof is administered subcutaneously.

[0335] 62. The method according to any of embodiments 59 to 61, wherein Compound A or a pharmaceutically acceptable salt thereof is administered using a pre-filled syringe.

[0336] 63. The method according to embodiment 62, wherein the pre-filled syringe is a singledose prefilled syringe.

[0337] 64. The method according to embodiment 62 or 63, wherein the pre-filled syringe is an accessorised single-dose prefilled syringe.

[0338] 65. The method according to any of embodiments 59 to 61, wherein Compound A or a pharmaceutically acceptable salt thereof is administered using an autoinjector device.

[0339] 66. The method according to any of embodiments 59 to 61, wherein Compound A or a pharmaceutically acceptable salt thereof is administered using a vial and syringe.

[0340] 67. The method according to any preceding embodiment, wherein the level of APOL1 in the subject is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or at least about 70% after administration of Compound A or a pharmaceutically acceptable salt thereof, as compared to baseline level.

[0341] 68. The method according to any preceding embodiment, wherein the level of APOL1 in the subject is reduced by up to about 100%, up to about 95% or up to about 90% after administration of Compound A or a pharmaceutically acceptable salt thereof, as compared to baseline level.

[0342] 69. The method according to embodiment 67 or 68, wherein the level of APOL1 is the APOL1 level in the kidney of the subject.

[0343] 70. The method according to embodiment 67 or 68, wherein the level of APOL1 is the APOL1 level in the liver of the subject.

[0344] 71. The method according to embodiment 67 or 68, wherein the level of APOL1 is the APOL1 level in the plasma of the subject.

[0345] 72. The method according to any of embodiments 67 to 71, wherein the level of APOL1 is the APOL1 protein level. 73. The method according to any of embodiments 67 to 71, wherein the level of AP0L1 is the AP0L1 mRNA level.

[0346] 74. The method according to any of embodiments 1 to 68, wherein the AP0L1 plasma protein level in the subject is reduced by at least about 30%, at least about 40%, or at least about 50% after administration of Compound A or a pharmaceutically acceptable salt thereof, as compared to baseline level.

[0347] 75. The method according to any of embodiments 1 to 68, wherein the APOL1 mRNA level in the kidney of the subject is reduced by at least about 10%, at least about 20% or at least about 30% after administration of Compound A or a pharmaceutically acceptable salt thereof, as compared to baseline level.

[0348] 76. The method according to any preceding embodiment, wherein administering Compound A or a pharmaceutically acceptable salt thereof reduces or prevents edema, proteinuria, albuminuria, GFR (glomerular filtration rate) decline, high plasma lipid levels, high plasma cholesterol levels, nephrotic syndrome, high blood pressure or hypertension, kidney damage, glomerular damage, kidney failure and / or secondary cardiovascular events.

[0349] 77. The method according to any preceding embodiment, wherein the subject has a urinary albumin-creatine ratio (uACR) of > 300 mg / g prior to administration of Compound A or a pharmaceutically acceptable salt thereof.

[0350] 78. The method according to embodiment 77, wherein uACR is reduced to < 300 mg / g after administration of Compound A or a pharmaceutically acceptable salt thereof.

[0351] 79. The method according to embodiment 77, wherein uACR is reduced to < 30 mg / g after administration of Compound A or a pharmaceutically acceptable salt thereof.

[0352] 80. The method according to any preceding embodiment, wherein uACR is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95% after administration of Compound A or a pharmaceutically acceptable salt thereof, as compared to baseline level.

[0353] 81. The method according to embodiment 80, wherein uACR is reduced by at least about 40% (optionally, at least about 45%) after administration of Compound A or a pharmaceutically acceptable salt thereof, as compared to baseline level. 82. The method according to any of embodiments 1 to 76 and 80, wherein the subject has a uACR of < 300 mg / g prior to administration of Compound A or a pharmaceutically acceptable salt thereof.

[0354] 83. The method according to any of embodiments 1 to 76, wherein the subject has a uACR of < 30 mg / g prior to administration of Compound A or a pharmaceutically acceptable salt thereof.

[0355] 84. The method according to any preceding embodiment, wherein the subject has a GFR of >60 mL / min / 1.73m2prior to administration of Compound A or a pharmaceutically acceptable salt thereof.

[0356] 85. The method according to any of embodiments 1 to 83, wherein the subject has a GFR of >25 mL / min / 1.73m2prior to administration of Compound A or a pharmaceutically acceptable salt thereof.

[0357] 86. The method according to any preceding embodiment, wherein decline in GFR is reduced after administration of Compound A or a pharmaceutically acceptable salt thereof.

[0358] 87. The method according to embodiment 86, wherein the decline in GFR is reduced by at least about 0.75 mL / min / 1.73m2 / year.

[0359] 88. The method according to embodiment 86, wherein the decline in GFR is reduced by from about 2 mL / min / 1.73m2 / year to about 3 mL / min / 1.73m2 / year.

[0360] 89. The method according to any of embodiments 84 to 88, wherein GFR is estimated GFR (eGFR).

[0361] 90. The method according to any of embodiments 84 to 88, wherein GFR is measured GFR (mGFR).

[0362] 91. A unit dosage comprising Compound A or a pharmaceutically acceptable salt thereof in a quantity of about 10 mg to about 150 mg of the free acid, wherein Compound A has the structure:

[0363] 92. The unit dosage according to embodiment 91, wherein the pharmaceutically acceptable salt is a sodium salt. 93. The unit dosage according to embodiment 91 , wherein the pharmaceutically acceptable salt is a potassium salt.

[0364] 94. The unit dosage according to embodiment 91, wherein Compound A or a pharmaceutically acceptable salt thereof is a sodium salt of Compound A having the structure: The unit dosage according to any of embodiments 91 to 94, wherein the quantity of Compound A or a pharmaceutically acceptable salt thereof is from about 20 mg to about 150 mg of the free acid. The unit dosage according to any of embodiments 91 to 95, wherein the quantity of Compound A or a pharmaceutically acceptable salt thereof is from about 50 mg to about 150 mg of the free acid. The unit dosage according to any of embodiments 91 to 94, wherein the quantity of Compound A or a pharmaceutically acceptable salt thereof is about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg or about 150 mg of the free acid.

[0365] 98. The unit dosage according to embodiment 97, wherein the quantity of Compound A or a pharmaceutically acceptable salt thereof is about 25 mg of the free acid.

[0366] 99. The unit dosage according to embodiment 97, wherein the quantity of Compound A or a pharmaceutically acceptable salt thereof is about 50 mg of the free acid.

[0367] 100. The unit dosage according to embodiment 97, wherein the quantity of Compound A or a pharmaceutically acceptable salt thereof is about 75 mg of the free acid.

[0368] 101. The unit dosage according to embodiment 97, wherein the quantity of Compound A or a pharmaceutically acceptable salt thereof is about 150 mg of the free acid.

[0369] 102. The unit dosage according to any of embodiments 91 to 101, formulated for parenteral administration.

[0370] 103. The unit dosage according to embodiment 102, wherein the parenteral administration is subcutaneous, intramuscular or intravenous administration.

[0371] 104. The unit dosage according to embodiment 102 or 103, formulated for subcutaneous administration.

[0372] 105. The unit dosage of any of embodiments 91 to 104, further comprising a pharmaceutically acceptable excipient.

[0373] 106. The unit dosage of embodiment 105, wherein the pharmaceutically acceptable excipient is saline. 07. A single-dose container comprising the unit dosage of any of embodiments 91 to 106. 08. The single-dose container of embodiment 107, which is a pre-filled syringe,09. The single-dose container of embodiment 107, which is an accessorized prefilled syringe.

[0374] 110. The single-dose container of embodiment 107, which is an autoinjector device. 111. The method according to any of embodiments 1 to 90, wherein the subject has been determined as having at least one of APOL3 null alleles p.Q58*.

[0375] 112. The method according to any of embodiments 1 to 6 or 8 to 90, wherein the subject has been determined as being heterozygous for APOL1 risk alleles G1 and G2 and as having at least one of APOL3 null alleles p.Q58*.

[0376] ***

[0377] The above description of illustrative embodiments is intended only to acquaint others skilled in the art with the specification, its principles, and its practical application so that others skilled in the art may readily adapt and apply the specification in its numerous forms, as they may be best suited to the requirements of a particular use. This description and its specific examples, while indicating embodiments of this specification, are intended for purposes of illustration only. This specification, therefore, is not limited to the illustrative embodiments described in this specification, and may be variously modified. In addition, it is to be appreciated that various features of the specification that are, for clarity reasons, described in the context of separate embodiments, also may be combined to form a single embodiment. Conversely, various features of the specification that are, for brevity reasons, described in the context of a single embodiment, also may be combined to form sub-combinations thereof.

Claims

WHAT IS CLAIMED IS:

1. A method of treating a disease associated with AP0L1 in a subject comprising administering Compound A or a pharmaceutically acceptable salt thereof at a dose of from about 10 mg to about 150 mg of the free acid, wherein the subject is human and wherein Compound A has the structure:

2. The method according to claim 1, wherein the disease associated with APOL1 is APOL1- mediated kidney disease.

3. The method according to claim 2, wherein the AP0L1 -mediated kidney disease is selected from focal segmental glomerulosclerosis (FSGS), collapsing nephropathy, chronic kidney disease (CKD), hypertension-attributed nephropathy, HIV-associated nephropathy, sickle cell nephropathy, arterionephrosclerosis, lupus nephritis, minimal change disease, membranous nephropathy, nephrotic syndrome, renal allograft dysfunction, acute kidney injury and COVID-19-associated nephropathy (COVAN), or a combination thereof.

4. The method according to claim 3, wherein the AP0L1 -mediated kidney disease is FSGS.

5. The method according to claim 3, wherein the AP0L1 -mediated kidney disease is CKD.

6. The method according to any preceding claim, wherein the subject has been determined as having at least one of AP0L1 risk alleles G1 or G2.

7. The method according to claim 6, wherein the subject has been determined as being homozygous or compound heterozygous for AP0L1 risk alleles G1 and G2.

8. The method according to any preceding claim, wherein the subject has been determined as having at least one of AP0L3 null alleles p.Q58*.

9. The method according to any of claims 1 to 6, wherein the subject has been determined as being heterozygous for AP0L1 risk alleles G1 and G2 and as having at least one of AP0L3 null alleles p.Q58*.

10. The method according to any preceding claim, wherein the subject is an adult.

11. The method according to any of claims 1 to 9, wherein the subject is a pediatric subject.

12. The method according to any of claims 1 to 9, wherein the subject is age 16 or above, optionally age 17 or above, optionally age 18 or above.

13. The method according to any of claims 1 to 9, wherein the subject is: (a) age 12 or above, optionally age 12 to 17, optionally age 12 to 16, optionally age 12 to 15; or (b) age 10 or above, optionally age 10 to 17, optionally age 10 to 16, optionally age 10 to 15.

14. The method according to any preceding claim, wherein the pharmaceutically acceptable salt is a sodium salt or a potassium salt.

15. The method according to any of claims 1 to 14, wherein Compound A or a pharmaceutically acceptable salt thereof is a sodium salt of Compound A having the structure:

16. The method according to any preceding claim, wherein the dose of Compound A or a pharmaceutically acceptable salt thereof is from about 20 mg to about 150 mg or from about 50 mg to about 150 mg of the free acid.

17. The method according to any of claims 1 to 15, wherein the dose of Compound A or a pharmaceutically acceptable salt thereof is about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg or about 150 mg of the free acid.

18. The method according to claim 17, wherein the dose of Compound A or a pharmaceutically acceptable salt thereof is about 25 mg, about 50 mg, about 75 mg or about 150 mg of the free acid.

19. The method according to any preceding claim, wherein the dose is administered from about twice every week to about once every 2 months, from about twice every week to about once every 6 weeks, or from about once every week to about once every 4 weeks.

20. The method according to any of claims 1 to 18, wherein the dose is administered about twice weekly, about once weekly, about once every 2 weeks, about once every 3 weeks, about once every 4 weeks, about once monthly, about once every 5 weeks, about once every 6 weeks, or about once every 2 months.

21. The method according to claim 20, wherein the dose is administered once weekly or once every two weeks.

22. The method according to any preceding claim, wherein the dose is administered for a period of at least about 4 months, at least about 1 year, at least about 2 years, at least about 5 years, at least about 10 years or at least about 20 years, or wherein the dose is administered for the lifetime of the subject.

23. The method according to any of claims 1 to 21, wherein the disease associated with APOL1 is APOL1 -mediated kidney disease and the dose is administered until the onset of end-stage kidney disease in the subject.

24. The method according to any of claims 1 to 15, which comprises administering to the subject:(a) one or more loading doses of Compound A or a pharmaceutically acceptable salt thereof; and(b) one or more maintenance doses of Compound A or a pharmaceutically acceptable salt thereof; wherein the one or more loading doses is from about 10 mg to about 150 mg of the free acid.

25. The method according to any preceding claim, wherein Compound A or a pharmaceutically acceptable salt thereof is administered by parenteral administration, such as subcutaneous, intramuscular or intravenous administration.

26. The method according to claim 25, wherein Compound A or a pharmaceutically acceptable salt thereof is administered subcutaneously.

27. The method according to any preceding claim, wherein:(a) the level of AP0L1 in the subject is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or at least about 70% after administration of Compound A or a pharmaceutically acceptable salt thereof, as compared to baseline level; and / or(b) the level of APOL1 in the subject is reduced by up to about 100%, up to about 95% or up to about 90% after administration of Compound A or a pharmaceutically acceptable salt thereof, as compared to baseline level.

28. The method according to any of claims 1 to 27, wherein the APOL1 plasma protein level in the subject is reduced by at least about 30%, at least about 40%, or at least about 50% after administration of Compound A or a pharmaceutically acceptable salt thereof, as compared to baseline level.

29. The method according to any of claims 1 to 27, wherein the APOL1 mRNA level in the kidney of the subject is reduced by at least about 10%, at least about 20% or at least about 30% after administration of Compound A or a pharmaceutically acceptable salt thereof, as compared to baseline level.

30. The method according to any preceding claim, wherein administering Compound A or a pharmaceutically acceptable salt thereof reduces or prevents edema, proteinuria, albuminuria, GFR (glomerular filtration rate) decline, high plasma lipid levels, high plasma cholesterol levels, nephrotic syndrome, high blood pressure or hypertension, kidney damage, glomerular damage, kidney failure and / or secondary cardiovascular events.

31. The method according to any preceding claim, wherein the subj ect has a urinary albumincreatine ratio (uACR) of > 300 mg / g prior to administration of Compound A or a pharmaceutically acceptable salt thereof.

32. The method according to claim 30, wherein uACR is reduced to < 300 mg / g or < 30 mg / g after administration of Compound A or a pharmaceutically acceptable salt thereof.

33. The method according to any preceding claim, wherein uACR is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, atleast about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95% after administration of Compound A or a pharmaceutically acceptable salt thereof, as compared to baseline level; optionally wherein uACR is reduced by at least about 40% after administration of Compound A or a pharmaceutically acceptable salt thereof, as compared to baseline level.

34. The method according to any of claims 1 to 30 and 33, wherein the subject has a uACR of < 300 mg / g or < 30 mg / g prior to administration of Compound A or a pharmaceutically acceptable salt thereof.

35. The method according to any preceding claim, wherein the subject has a GFR of >60 mL / min / 1 ,73m2prior to administration of Compound A or a pharmaceutically acceptable salt thereof.

36. The method according to any of claims 1 to 34, wherein the subject has a GFR of >25 mL / min / 1 ,73m2prior to administration of Compound A or a pharmaceutically acceptable salt thereof.

37. The method according to any preceding claim, wherein decline in GFR is reduced after administration of Compound A or a pharmaceutically acceptable salt thereof, for example wherein the decline in GFR is reduced by at least about 0.75 mL / min / 1.73m2 / year, or wherein the decline in GFR is reduced by from about 2 mL / min / 1 ,73m2 / year to about 3 mL / min / 1.73m2 / year.

38. A unit dosage comprising Compound A or a pharmaceutically acceptable salt thereof in a quantity of about 10 mg to about 150 mg of the free acid, wherein Compound A has the structure:

39. The unit dosage according to claim 38, wherein the pharmaceutically acceptable salt is a sodium salt or a potassium salt.

40. The unit dosage according to claim 39, wherein Compound A or a pharmaceutically acceptable salt thereof is a sodium salt of Compound A having the structure:

41. The unit dosage according to any of claims 38 to 40, wherein the quantity of Compound A or a pharmaceutically acceptable salt thereof is from about 20 mg to about 150 mg or from about 50 mg to about 150 mg of the free acid.

42. The unit dosage according to any of claims 38 to 40, wherein the quantity of Compound A or a pharmaceutically acceptable salt thereof is about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg or about 150 mg of the free acid.

43. The unit dosage according to claim 42, wherein the quantity of Compound A or a pharmaceutically acceptable salt thereof is about 25 mg, about 50 mg, about 75 mg or about 150 mg of the free acid.

44. The unit dosage according to any of claims 38 to 43, formulated for subcutaneous administration.

45. The unit dosage of any of claims 38 to 44, further comprising a pharmaceutically acceptable excipient, such as saline.

46. A single-dose container comprising the unit dosage of any of claims 38 to 45.

Images