Complement Factor B-Regulating Composition and Method of Using the Same

Abstract

Aspects of the present disclosure provide compounds, compositions, and methods for regulating the expression or activity of complement factor B (CFB). In some aspects, the compounds, compositions, and methods of the present disclosure may be used to reduce the expression of CFB mRNA in cells or animals. In some aspects, the compounds, compositions, and methods of the present disclosure may be used to reduce the expression of CFB protein in cells or animals.

Description

Technology Field

[0001] Cross-reference regarding related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 619,249, filed January 9, 2024, pursuant to 35 USC § 119(e), the entirety of which is incorporated herein by reference. Background Technology

[0003] Complement Factor B (CFB) is a key component of the alternative pathway for complement activation. CFB is a serine protease secreted by the liver. It circulates in the blood as a single-stranded polypeptide. When the alternative pathway is activated, it is cleaved by Complement Factor D to produce the non-catalytic chain Ba and the catalytic subunit Bb. The active subunit Bb is a serine protease that binds to C3b to form the alternative pathway C3-converterase. The production of C3-converterase induces the formation of C5-converterase, which cleaves C5, triggering an event that leads to the formation of the soluble membrane attack complex (MAC). The MAC forms transmembrane channels and disrupts the phospholipid bilayer of target cells, thereby inducing cell lysis.

[0004] Inappropriate complement activation is, for example, atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), for example, lupus nephritis, diabetic nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), and geographic atrophy secondary to AMD, It is the cause of various diseases including thrombotic microangiopathy, myasthenia gravis, ischemia and reperfusion injury, and rheumatoid arthritis (RA). Therefore, there is a need to find effective treatments for complement-related diseases.

[0005] The present disclosure provides a compound, a composition, and a method for regulating the expression or activity of complement factor B (CFB). In a specific embodiment, the compound, the composition, and the method may be used to reduce the expression of CFB mRNA in a cell or animal. In a specific embodiment, the compound, the composition, and the method may be used to reduce the amount of CFB protein in a cell or animal.

[0006] In a given embodiment, the animal has or is at risk of having a complement pathway-related disease, disorder, or condition or symptoms thereof. In a given embodiment, the disease, disorder, or condition is atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulonephropathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), e.g., lupus nephritis, diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy due to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA). Certain compounds, compositions, and methods provided herein relate to reducing tissue damage associated with dysregulation of the complement pathway, e.g., ocular damage or kidney damage. Certain compounds, compositions, and methods provided herein relate to reducing atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulonephropathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), e.g., lupus nephritis, diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy secondary to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA). In a given embodiment, the compounds and compositions provided herein have potent efficacy, excellent tolerability, and inhibit CFB expression, and can be used for the treatment, prevention, improvement, or delay of progression of tissue damage associated with dysregulation of the complement pathway, e.g., ocular damage or kidney damage.In a given embodiment, the compounds and compositions provided herein have potent efficacy, excellent tolerability, and inhibit CFB expression, which may be used for the treatment, prevention, improvement, or delay of progression of atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulonephropathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), e.g., lupus nephritis, diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy due to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA).

[0007] In a specific embodiment, the compound and composition include one or more features effective for increasing efficacy. In a specific embodiment, the compound and composition include one or more features effective for increasing tolerability. In a specific embodiment, the compound and composition include one or more features effective for targeting the said compound or composition to a cell or tissue. In a specific embodiment, the compound and composition have a stronger or higher therapeutic value than a publicly disclosed compound. Brief explanation of the drawing

[0008] The attached drawings of this application, which constitute part of this specification, illustrate various embodiments of this disclosure and serve to explain the principles of this disclosure together with the description attached herein. Fig. 1 This shows a schematic diagram of the Phase 1 clinical study of RD2830 as described in Example 4, where SAD means a single dose increase; SC means subcutaneous; and SRC means Safety Review Committee. Fig. 2It illustrates a decision tree illustrating the process for transitioning to Part B (treatment of PNH patients) of the clinical study described in Example 4. Fig. 3 This is a graph showing the mean relative plasma complement factor b (CFB) protein levels at days 7, 14, 21, 28, 35, 42, 49, 56, 63, and 70 after administration, obtained from cohort 1 (0.4 mg / kg) and cohort 4 (1 mg / kg) that received a single subcutaneous dose of RD2830. Fig. 4 This is a graph showing the mean relative plasma replacement pathway protein levels at days 7, 14, 21, 28, 35, 42, 49, 56, 63, and 70 after administration, obtained from cohort 1 (0.4 mg / kg) and cohort 4 (1 mg / kg) administered a single subcutaneous dose of RD2830. Fig. 5 This is a graph showing the mean relative plasma traditional pathway protein levels at days 7, 14, 21, 28, 35, 42, 49, 56, 63, and 70 after administration, obtained from cohort 1 (0.4 mg / kg) and cohort 4 (1 mg / kg) administered a single subcutaneous dose of RD2830. Figures 6a–6c It includes a diagram illustrating a decision tree for re-administration using RD2830 (ADX-038). Fig. 7 These are two graphs showing the pharmacokinetics of ADX-038 and present the plasma concentrations of ADX-038 in cohorts 1–4 over 30 hours (on a logarithmic scale over time). Fig. 8 This is a graph showing the pharmacodynamics of ADX-038, specifically the change in the mean (SE) percentage of alternative pathway (AP) activity levels from baseline over time in the ADX-038-101 study (preliminary results; PD population). Fig. 9 represents the proportion of subjects capable of achieving ≥ 95% inhibition of alternative pathway (AP) activity by the actual administered dose. Fig. 10 Figure 5 shows a general schematic diagram of the ADX-038 Phase 2a clinical study as described in Example 5. Fig. 11 Figure 6 shows a general schematic diagram of the ADX-038 Phase 2 clinical study as described in Example 6. Specific details for implementing the invention

[0009] The foregoing description of the invention and the specific details for implementing the invention described below are provided merely as examples and descriptions and should be understood not to limit the embodiments claimed. Section headings used herein are for structural purposes only and should not be interpreted as limiting the subject matter described herein.

[0010] All documents or parts of documents cited in this application, including but not limited to patents, patent applications, papers, books, academic papers, and GenBank, NCBI, and other sequence reference records, are expressly incorporated herein by reference as of the filing date of this application, as well as the parts discussed herein.

[0011] It should be understood that the sequences presented in each sequence number included herein are independent of any modifications to sugar moiety, internucleoside linkage, or nucleobase, even when presented in the context of modified compounds. As such, compounds defined by sequence numbers may independently include one or more modifications to sugar moiety, internucleoside linkage, or nucleobase. Oligomer compounds referenced by compound number or reference number represent a combination of nucleobase sequence, chemical modification, and motif.

[0012] In this document, the use of the singular form includes the plural form unless specifically stated otherwise. For example, the singular form is used in this document to refer to one or more (i.e., at least one) of the grammatical objects of the singular form. For example, “one element” means one element or two or more elements, e.g., plural elements. As used herein, the use of “or” means “and / or” unless otherwise stated. Additionally, the use of the term “including,” as well as, for example, “includes” and “included,” is non-restrictive and is used interchangeably with the phrase “includes, but is not limited thereto.”

[0013] definition

[0014] Unless otherwise specified, the following terms have the following meanings:

[0015] "Complement Factor B" is used interchangeably with the term "CFB" and refers to any nucleic acid or protein of CFB. Exemplary nucleotide and amino acid sequences of CFB can be found, for example, in GenBank accession number NM_001710.6 (incorporated herein as SEQ No. 1), nucleotides 31946095 to 31952084 of GenBank accession number NC_000006.12 (incorporated herein as SEQ No. 2), GenBank accession number NM_001710.6 (incorporated herein as SEQ No. 3), and nucleotides 3423522 to 3429511 of GenBank accession number NT_113891.3 (incorporated herein as SEQ No. 4). Additional examples of CFB sequences are readily available through publicly available databases, for example, GenBank, UniProt, and OMIM. Additional information regarding CFB can be found, for example, at https: / / www.ncbi.nlm.nih.gov / gene / ?term=CFB. As used herein, CFB also refers to variations of the CFB gene, including variants provided in SNP databases. Numerous sequence variations within the CFB gene have been identified and can be found, for example, in NCBI dbSNP and UniProt (see, for example, https: / / www.ncbi.nlm.nih.gov / snp / ?term=CFB). "CFB mRNA" refers to mRNA encoding the CFB protein. CFB may be written in uppercase or lowercase.

[0016] "CFB-specific inhibitor" refers to any agent capable of specifically inhibiting CFB RNA and / or CFB protein expression or activity at the molecular level. For example, CFB-specific inhibitors include nucleic acids (including oligonucleotide compounds), peptides, antibodies, small molecules, and other agents capable of inhibiting the expression of CFB RNA and / or CFB protein.

[0017] "2'-O-methoxyethyl" or "2'-MOE" refers to the 2'-O(CH2)2-OCH3 modification. The 2'-O-methoxyethyl modified sugar is a modified sugar in which 2'-O(CH2)2-OCH3 is located at the position of the 2'-OH group of the ribosyl ring.

[0018] "5' start site" refers to a nucleotide in a target nucleic acid or region aligned with the nucleoside closest to the 3' of the antisense oligonucleotide.

[0019] "3' stop site" refers to a nucleotide in a target nucleic acid or region aligned with the nucleoside closest to the 5' of an antisense oligonucleotide.

[0020] "Approximately" means within ±10% of the value. For example, if it is stated that "the compound achieved approximately 70% inhibition of CFB," this implies that the corresponding CFB level is inhibited within the range of 60% to 80%. If "approximately" precedes a series of numbers or ranges, it should be understood as modifying each of those numbers or ranges.

[0021] "To administer" or "administering" refers to the process of introducing a compound or composition provided herein into an individual to perform its intended function. As an example, routes of administration that may be used include, but are not limited to, parenteral administration such as subcutaneous, intravenous, or intramuscular injection or infusion.

[0022] "Improvement" refers to the improvement or reduction of at least one indicator, sign, or symptom of an associated disease, disorder, or condition. In a given embodiment, improvement includes delaying or slowing the progression or severity of one or more indicators of the condition or disease. The progression or severity of an indicator may be determined by subjective or objective measurements known to those skilled in the art.

[0023] "Animal" refers to non-human animals, including but not limited to mice, rats, rabbits, dogs, cats, pigs, and non-human primates including but not limited to monkeys and chimpanzees, or humans.

[0024] "Antisense oligonucleotide" or "antisense strand" refers to an oligonucleotide containing a region complementary to the target nucleic acid, for example, CFB RNA or a region thereof.

[0025] In references to oligonucleotides, "complementaryness" means that when two nucleotide sequences are aligned in opposite directions, the nucleotide sequence of the oligonucleotide or one or more regions thereof is complementary to the other oligonucleotide or nucleic acid or one or more regions thereof. Unless otherwise specified, the complementary nucleotides described herein are limited to adenine (A) and thymine (T), adenine (A) and uracil (U), and cytosine (C) and guanine (G) pairs. Complementary oligonucleotides and / or nucleic acids do not need to have nucleotide complementaryness in each nucleoside and may contain one or more nucleotide mismatches. In contrast, in references to oligonucleotides, "fully complementary" or "100% complementary" means that the oligonucleotide has nucleotide matching in each nucleoside without any nucleotide mismatches.

[0026] "Composition" or "pharmaceutical composition" means a mixture of substances suitable for administration to an individual. For example, a composition may include one or more compounds or salts thereof and a sterile aqueous solution.

[0027] "Concomitant administration" means administering two or more compounds in any manner that produces the pharmacological effects of all said compounds in the patient. In concomitant administration, it is not necessary for all compounds to be administered via the same route of administration or at the same time as a single pharmaceutical composition in the same dosage form. It is not necessary for the effects of all compounds to appear at the same time. The effects only need to overlap for a certain period of time and do not need to coexist. Concomitant administration includes the simultaneous or sequential administration of one or more compounds.

[0028] "Conjugate" refers to a group of atoms attached to an oligonucleotide. Conjugates are arbitrarily attached to the oligonucleotide via a conjugation linker. Conjugates can, for example, alter the distribution, targeting, or half-life of the incorporated compound. Conjugates include a targeting moiety.

[0029] "Conjugation linker" means a group of atoms containing at least one bond that connects a linkage moiety to an oligonucleotide.

[0030] In references to oligonucleotides, "identity" means that the nucleobase sequence of the oligonucleotide or one or more regions thereof matches that of another oligonucleotide or nucleic acid or one or more regions thereof. In the identity of an oligonucleotide with respect to another oligonucleotide or nucleic acid, each nucleobase does not need to match and may include one or more different nucleosbases. In contrast, "completely identical" or "100% identity" in references to oligonucleotides means that the oligonucleotide has the same nucleobase as another oligonucleotide or nucleic acid at each relative position along its length.

[0031] "Individual" refers to a human or non-human animal selected for treatment or therapy.

[0032] "Inhibition of expression or activity" referred to with respect to a target nucleic acid or protein means that the expression or activity of the corresponding target is reduced or blocked compared to the expression or activity of an untreated or control sample, and does not necessarily mean the complete elimination of expression or activity.

[0033] As used herein, the term “nucleoside linkage” refers to a covalent linkage between adjacent nucleosides in an oligonucleotide. As used herein, “modified nucleoside linkage” refers to any nucleoside linkage other than a phosphodiester nucleoside linkage. A “phosphorothioate nucleoside linkage” is a modified nucleoside linkage in which one of the non-crosslinked oxygen atoms of a phosphodiester nucleoside linkage is replaced by a sulfur atom.

[0034] Representative internucleoside linkages having a chiral center include, but are not limited to, alkylphosphons and phosphorothioates. Modified oligonucleotides containing internucleoside linkages having a chiral center may be prepared as a group of modified oligonucleotides containing stereorandom internucleoside linkages, or as a group of modified oligonucleotides containing phosphorothioate linkages of a specific stereochemical configuration described further below. Unless otherwise specified, the chiral internucleoside linkages of the modified oligonucleotides described herein may exist stereorandom or in a specific stereochemical configuration.

[0035] The compounds of the present disclosure may also contain one or more atomic isotopes of the atoms constituting these compounds in non-natural proportions. For example, the compounds may contain, for example, tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14It may be radiolabeled with a radioactive isotope such as C). All isotopic variants of the compounds of the present disclosure are encompassed within the scope of the present disclosure, regardless of whether they are radioactive.

[0036] The term “isotope variant” refers to a therapeutic agent comprising isotopes in unnatural proportions in one or more atoms constituting the therapeutic agent (e.g., compounds and / or modified oligonucleotides disclosed herein). In certain embodiments, the “isotope variant” of the therapeutic agent is hydrogen (H), deuterium ( 2 H), tritium ( 3 H), carbon-11( 11 C), carbon-12( 12 C), carbon-13( 13 C), carbon-14( 14 C), nitrogen-13( 13 N), Nitrogen-14( 14 N), Nitrogen-15( 15 N), Oxygen-14( 14 O), Oxygen-15( 15 O), Oxygen-16 ( 16 O), Oxygen-17( 17 O), Oxygen-18( 18 O), Fluorine-17( 17 F), Fluorine-18 ( 18 F), Phosphorus-31( 31 P), Phosphorus-32( 32 P), Phosphorus-33( 33 P), sulfur-32( 32 S), Sulfur-33( 33 S), Sulfur-34( 34 S), Sulfur-35( 35 S), Sulfur-36( 36 S), Chlorine-35( 35 Cl), Chlorine-36( 36 Cl), Chlorine-37( 37 Cl), Bromine-79( 79 Br), Bromine-81( 81 Br), iodine 123( 123 I), iodine-125( 125 I), iodine-127( 127I), iodine-129( 129 I), and iodine-131 ( 131 It contains one or more isotopes, including but not limited to I), in unnatural proportions. In a given embodiment, the "isotope variant" of the therapeutic agent is hydrogen (H), deuterium ( 2 H), tritium ( 3 H), carbon-11( 11 C), carbon-12( 12 C), carbon-13( 13 C), carbon-14( 14 C), nitrogen-13( 13 N), Nitrogen-14( 14 N), Nitrogen-15( 15 N), Oxygen-14( 14 O), Oxygen-15( 15 O), Oxygen-16 ( 16 O), Oxygen-17( 17 O), Oxygen-18( 18 O), Fluorine-17( 17 F), Fluorine-18 ( 18 F), Phosphorus-31( 31 P), Phosphorus-32( 32 P), Phosphorus-33( 33 P), sulfur-32( 32 S), Sulfur-33( 33 S), Sulfur-34( 34 S), Sulfur-35( 35 S), Sulfur-36( 36 S), Chlorine-35( 35 Cl), Chlorine-36( 36 Cl), Chlorine-37( 37 Cl), Bromine-79( 79 Br), Bromine-81( 81 Br), iodine 123( 123 I), iodine-125( 125 I), iodine-127( 127 I), iodine-129( 129 I), and iodine-131 ( 131 It contains one or more isotopes, including but not limited to I), in unnatural proportions.

[0037] In therapeutic agents (e.g., compounds and / or modified oligonucleotides disclosed herein), where feasible in the judgment of a person skilled in the art, any hydrogen is, for example, 2 It can be H, or any carbon, for example, 13 It could be C, or any nitrogen, for example, 15 It can be N, or any oxygen, for example, 18 It should be understood that it may be O. In a given embodiment, the 'isotope variant' of the therapeutic agent contains deuterium (D) in an unnatural proportion.

[0038] "Inconsistency" or "non-complementarity" means that when the first oligonucleotide / nucleic acid and the second oligonucleotide / nucleic acid are aligned in antiparallel orientation, the nucleobase of the first oligonucleotide or nucleic acid is not complementary to the corresponding nucleobase of the second oligonucleotide or nucleic acid. For example, nucleosides including, but not limited to, universal nucleosides, inosine, and hypoxanthine may hybridize with at least one nucleobase, but are still inconsistent or non-complementary with respect to the nucleobase to which they hybridize. As another example, when the first and second oligonucleotides are aligned in antiparallel orientation, the nucleobase of the first oligonucleotide / nucleic acid that cannot hybridize to the corresponding nucleobase of the second oligonucleotide / nucleic acid is an inconsistent or non-complementary nucleobase.

[0039] "Modified oligonucleotide" means an oligonucleotide in which at least one bond between a sugar, nucleobase, or nucleoside is modified.

[0040] "Regulating" refers to altering or adjusting characteristics in a cell, tissue, organ, or organism. For example, the regulation of CFB RNA may mean increasing or decreasing the levels of CFB RNA and / or CFB protein in a cell, tissue, organ, or organism. "Regulator" influences changes in a cell, tissue, organ, or organism. For example, a CFB compound may be a regulator that decreases the amount of CFB RNA and / or CFB protein in a cell, tissue, organ, or organism.

[0041] "Motif" refers to the pattern of non-modified and modified sugar moiety, nucleobase, and / or nucleoside linkages in an oligonucleotide.

[0042] "Nucleic acid" refers to a molecule composed of monomeric nucleotides. Nucleic acids include, but are not limited to, ribonucleic acid (RNA), deoxyribonucleic acid (DNA), single-stranded nucleic acids, and double-stranded nucleic acids.

[0043] "Nuclear base" refers to a heterocyclic moiety that can pair with a base of another nucleic acid. As used herein, "native nuclear bases" are adenine (A), thymine (T), cytosine (C), uracil (U), and guanine (G). "Modified nuclear bases" are naturally occurring nuclear bases that have been chemically modified. "Universal bases" or "universal nuclear bases" are nuclear bases other than naturally occurring nuclear bases and modified nuclear bases, and can pair with any nuclear base.

[0044] "Nuclear base sequence" means a sequence of adjacent nucleobases within a nucleic acid or oligonucleotide that is independent of any linkage between sugars or nucleosides.

[0045] "Nucleoside" means a compound containing a nucleobase and a sugar moiety. The nucleobase and the sugar moiety are each independently unmodified or modified. "Modified nucleoside" means a nucleoside containing a modified nucleobase and / or a modified sugar moiety. Modified nucleosides include non-basic nucleosides lacking a nucleobase.

[0046] "Oligomer compound" means a compound comprising one or more oligonucleotides and optionally one or more additional features, such as a splicer or a terminal. Examples of oligomer compounds include single-stranded and double-stranded compounds, such as oligonucleotides, antisense oligonucleotides, interfering RNA compounds (RNAi compounds), microRNA-targeting oligonucleotides, and occupancy-based compounds (e.g., mRNA processing or translation blocking compounds and splicing compounds). RNAi compounds include double-stranded compounds (e.g., short interfering RNA (siRNA) and double-stranded RNA (dsRNA)) and single-stranded compounds (e.g., single-stranded siRNA (ssRNA), single-stranded RNAi (ssRNAi), short hairpin RNA (shRNA), and microRNA mimics) that act at least partially through the RNA-induced silencing complex (RISC) pathway to cause sequence-specific degradation and / or sequestration of target nucleic acids through a process known as RNA interference (RNAi). The term "RNAi compound" refers to other terms used to describe nucleic acid compounds capable of mediating sequence-specific RNA interference, e.g., interfering RNA (iRNA), iRNA preparations, RNAi preparations, short interfering oligonucleotides, short interfering nucleic acids, short interfering modified oligonucleotides, chemically modified siRNA, and other equivalents. Additionally, the term "RNAi" refers to equivalents to other terms used to describe sequence-specific RNA interference.

[0047] "Oligonucleotide" refers to a polymer of linked nucleosides, each of which may or may not be modified and is independent of one another.

[0048] The term "oligomer dimer" refers to a dimer formed by two oligomer compounds having complementary nucleobase sequences. Each oligomer compound of the oligomer dimer may be referred to as a "doubled oligomer compound." The oligonucleotide of each oligomer compound of the oligomer dimer may include a non-complementary protruding nucleoside. In some embodiments, the terms "doubled oligomer compound" and "modified oligonucleotide" are used interchangeably. In other embodiments, the terms "oligomer dimer" and "compound" are used interchangeably.

[0049] "Parental administration" means administration via injection or infusion. Parenteral administration includes subcutaneous administration, intravenous administration, intramuscular administration, intra-arterial administration, intraperitoneal administration, or intracranial administration, e.g., intravertebral or intraventricular administration.

[0050] “Pharmaceuticalally acceptable carrier or diluent” means any substance suitable for use in administration to an individual. In certain embodiments, a pharmaceutically acceptable carrier or diluent may be included in the composition of the present disclosure to aid in the administration of the compound to an individual and absorption by the individual, without causing significant toxicological adverse effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, physiological saline, etc. For example, a pharmaceutically acceptable carrier may be a sterile aqueous solution, such as PBS or distilled water for injection. Those skilled in the art will recognize that other pharmaceutical excipients may be used in the present disclosure.

[0051] "Pharmaceutically acceptable salt" means or refers to a physiologically and pharmaceutically acceptable salt of a compound, such as an oligomer compound or an oligonucleotide, that is, a salt that retains the desirable biological activity of the parent compound but does not provide any undesirable toxicological effects thereon.

[0052] As used herein, a pharmaceutically acceptable salt is any salt of the compound provided herein that retains the biological properties of the said compound and is non-toxic or otherwise desirable for pharmaceutical use. A pharmaceutically acceptable salt of the therapeutic agent disclosed herein comprises a salt prepared with a relatively non-toxic acid or base, depending on a specific substituent found on the compound or modified oligonucleotide described herein.

[0053] If the compound of the present disclosure comprises a relative acidic functional group, the base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired base in a pure or suitable inert solvent.

[0054] If the compound of the present disclosure comprises a relatively basic functional group, the acid addition salt can be obtained by contacting a neutral form of the compound with a sufficient amount of the desired acid in a pure or suitable inert solvent.

[0055] Accordingly, the compounds of the present disclosure may exist as salts, for example, comprising pharmaceutically acceptable acids. Such salts may be derived from various organic and inorganic counter-ions known in the art. These salts include, but are not limited to: (1) organic or inorganic acids, such as hydrochloric acid, hydrobromide, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, glutaric acid, pyruvate, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, picric acid, cinnamic acid, mandelic acid, phthalic acid, lauric acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-Naphthalenesulfonic acid, 4-Toluenesulfonic acid, Camponic acid, Camposulfonic acid, 4-Methylbicyclo[2.2.An acid addition salt formed with an acid such as [2]-oct-2-en-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylsulfamic acid, quinic acid, muconic acid, or (2) an acidic proton present in the parent compound is replaced by (a) a metal ion, e.g., alkali metal ion, alkaline earth metal ion, or aluminum ion, or an alkali metal or alkaline earth metal hydroxide, e.g., sodium, potassium, calcium, magnesium, aluminum, lithium, zinc, and barium hydroxide, ammonia, or (b) an organic base, e.g., an aliphatic, alicyclic, or aromatic organic amine, e.g., ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, Salts formed upon coordination with ethylenediamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N-methylglucarmine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, etc. (e.g., see Berge et al. ["Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19)).

[0056] Pharmaceutically acceptable salts further comprise, merely as examples and without limitation, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., where the compound comprises a basic functional group, a salt of a non-toxic organic or inorganic acid, e.g., hydrohalides, e.g., hydrochloride and hydrobromide, sulfates, phosphates, sulfamates, nitrates, acetates, trifluoroacetates, trichloroacetate, propionates, hexanoates, cyclopentylpropionate, glycolates, glutarates, pyruvates, lactates, malonates, succinates, sorbates, ascorbates, maleates, maleates, fumarates, tartarates, citrates, benzoates, 3-(4-hydroxybenzoyl)benzoate, picrates, cinnamates, mandelates, phthalates, laurates, Includes methane sulfonate (mesylate), ethane sulfonate, 1,2-ethane-disulfonate, 2-hydroxyethane sulfonate, benzene sulfonate (besylate), 4-chlorobenzene sulfonate, 2-naphthalene sulfonate, 4-toluene sulfonate, camphorate, camphosulfonate, 4-methylbicyclo[2.2.2]-oct-2-en-1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethyl acetate, tert-butyl acetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexyl sulfamate, quinate, muconate, etc. In some embodiments, the pharmaceutically acceptable salt of the compound and modified oligonucleotide disclosed herein is a sodium or potassium salt. In some embodiments, the pharmaceutically acceptable salt of the compound and modified oligonucleotide disclosed herein is a sodium salt.

[0057] The neutral form of the compound is preferably regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents. In an embodiment, the compound of the present disclosure comprises both basic and acidic functional groups that cause the compound to be converted into a base or acid addition salt. The neutral form of the compound may be regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. Although the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, unless specifically stated otherwise, the salt disclosed herein is equivalent to the parent form of the compound for the purposes of the present disclosure.

[0058] "Therapeutic agent" refers to a compound that provides therapeutic benefits when administered to an individual.

[0059] "Phosphorothioate linkage" refers to a modified phosphate linkage in which one of the non-crosslinked oxygen atoms is replaced by a sulfur atom.

[0060] "Part" refers to a defined number of adjacent (i.e., connected) nucleobases of the nucleic acid. In a specific embodiment, the part is a defined number of adjacent nucleobases of the target nucleic acid. In a specific embodiment, the part is a defined number of adjacent nucleobases of the oligonucleotide.

[0061] "Prevent" refers to delaying or preventing the onset, development, or progression of a disease, disability, or pathological condition for a certain period of time.

[0062] "RNA interference compound" or "RNAi compound" means a compound that acts at least partially through the RNA-induced silencing complex (RISC) pathway or Ago2 but not through RNase H, and regulates a target nucleic acid and / or a protein encoded by the target nucleic acid. RNAi compounds include, but are not limited to, double-stranded siRNA, single-stranded siRNA, and microRNAs including microRNA mimics.

[0063] "Sense oligonucleotide" or "sense strand" refers to a strand of a double-stranded compound that includes a region substantially complementary to the region of the antisense strand of the compound.

[0064] In relation to a target nucleic acid or protein, "specifically inhibiting" means reducing or blocking the expression or activity of the target nucleic acid or protein while minimizing or eliminating the effect on non-target nucleic acids or proteins.

[0065] With respect to oligonucleotides, “subunit” means a nucleotide, nucleoside, nucleobase, or sugar provided herein or a modified nucleotide, nucleoside, nucleobase, or sugar.

[0066] "Target nucleic acid," "target RNA," and "nucleic acid target" all refer to nucleic acids that can be targeted by the compounds described herein.

[0067] "Target region" refers to a portion of a target nucleic acid to which one or more compounds are targeted.

[0068] "Target moiety" refers to a conjugate that provides enhanced affinity for a selected target, e.g., a molecule, cell, or cell type, compartment, e.g., a cell or organ compartment, tissue, organ, or region of the body, compared to, for example, a compound without such moiety.

[0069] "Terminal group" refers to a chemical group or atomic group covalently connected to the end of an oligonucleotide.

[0070] "Therapeutic effective dose" or "effective dose" means an amount of a compound, pharmaceutical preparation, or composition that provides therapeutic benefit to an individual. "Therapeutic effective dose" or "effective dose" is an amount sufficient to achieve the stated purpose (e.g., to achieve the administered effect, to treat, prevent, or improve a disease, or to reduce one or more symptoms of a disease or condition) compared to the absence of the compound. "Therapeutic effective dose" or "effective dose" is an amount sufficient to contribute to the treatment, prevention, improvement, or reduction of one or more symptoms of a disease. "Reduction of one or more symptoms" (and grammatical equivalents of the phrase) means a reduction in the severity or frequency of the symptom(s), or the elimination of the symptom(s). "Prophylactic effective dose" of a drug is an amount of drug that, when administered to a subject, produces an intended prophylactic effect, such as preventing or delaying the onset (or recurrence) of an injury, disease, pathology, or condition, or reducing the likelihood of the onset (or recurrence) of an injury, disease, pathology, or condition, or its symptoms. As used herein, the term “therapeutic effective dose” refers to an amount of therapeutic agent sufficient to provide therapeutic benefit to an individual, such as treating, preventing, or improving a disease or disorder or its symptoms, as described above. For example, for a given parameter, the therapeutic effective dose will represent an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Therapeutic efficacy may also be expressed as an increase or decrease of “~fold.” For example, the therapeutic effective dose may have an effect of at least 1.2 times, 1.5 times, 2 times, or 5 times or more compared to the control group.

[0071] The term “treating” or “treatment” refers to any successful indication or improvement in the therapy of an injury, disease, pathology, or condition, including any subjective or objective parameters such as alleviation; relief; reduction of symptoms or making the patient better able to tolerate the injury, pathology, or disease; slowing the rate of degeneration or decline, making the final degree of degeneration less debilitating, or promoting the patient’s physical or mental well-being. Treatment or improvement of symptoms may be based on objective or subjective parameters, including physical examination results. The term “treating” and its variations may include prevention of an injury, pathology, condition, or disease. In an embodiment, treatment is prevention. In an embodiment, treatment does not include prevention.

[0072] As used herein (and as understood in the art), “treating” or “treatment” in a broad sense also includes any approach to obtain beneficial or desirable results in the condition of the subject, including clinical outcomes. Beneficial or desirable clinical outcomes may include, but are not limited to, the alleviation or improvement of one or more symptoms or conditions, reduction of the scope of the disease, stabilization of the disease state (i.e., no worsening), prevention of the transmission or spread of the disease, delay or retardation of disease progression, improvement or temporary remission of the disease state, reduction of disease recurrence, and partial or total, detectable or undetectable remission. That is, “treatment” as used herein includes any cure, improvement, or prevention of the disease. Treatment may include prevention of the onset of the disease, inhibition of the spread of the disease, alleviation of the symptoms of the disease, complete or partial elimination of the underlying cause of the disease, reduction of the duration of the disease, or a combination thereof.

[0073] As used herein, “treating” and “treatment” include prophylactic treatment. A treatment method comprises the step of administering a therapeutically effective amount of the compound described herein to a subject. The administration step may consist of a single dose or may include a series of doses. The length of the treatment period depends on various factors, such as the severity of the condition, the age of the patient, the concentration of the compound, the activity of the composition used for treatment, or a combination thereof. It should also be understood that the effective dose of the agent used for treatment or prevention may be increased or decreased during a specific course of treatment or prophylactic therapy. In some cases, chronic administration may be required. For example, the composition is administered to the subject for a sufficient amount and duration to treat the patient.

[0074] "To treat" refers to administering a compound or pharmaceutical composition to an animal to alter or improve a disease, disorder, or pathological condition in the animal.

[0075] Specific compounds of the present disclosure possess an asymmetric carbon atom (optical or chiral center) or a double bond; enantiomers, racemics, diastereomers, tautomers, geometric isomers, and stereoisomer forms that can be defined as (R)- or (S)- or (D)- or (L)- with respect to amino acids in terms of absolute stereochemistry, each of which is included within the scope of the present disclosure. Compounds of the present disclosure do not include those known in the art to be highly unstable for synthesis and / or separation. The present disclosure is intended to include compounds in racemic forms and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthetic monomers or chiral reagents, or may be decomposed using conventional techniques. Where a compound described herein contains an olefin bond or other geometrically asymmetric center, such compound is intended to contain both E and Z geometric isomers unless otherwise specified.

[0076] As used herein, the term "isomer" refers to compounds that have the same number and type of atoms and, accordingly, the same molecular weight, but differ in terms of atomic arrangement or structural arrangement.

[0077] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomer form to another isomer form.

[0078] It will be apparent to those skilled in the art that certain compounds of the present disclosure may exist in tautomeric forms, and that all such tautomeric forms of said compounds are within the scope of the present disclosure.

[0079] Unless otherwise noted, it is intended that the structures described herein also include all stereochemical forms of said structures (i.e., R and S arrangements for each asymmetric center). Accordingly, not only single stereochemical isomers of the present compound but also mixtures of enantiomers and diastereomers are within the scope of this disclosure.

[0080] As used herein, "chiral enrichment group" means a plurality of molecules of the same molecular formula, wherein the number or percentage of molecules in the group containing a specific stereochemical configuration at a specific chiral center exceeds the number or percentage of molecules expected to contain the same specific stereochemical configuration at the same specific chiral center in the group, where the said specific chiral center is stereorandom. A chiral enrichment group of molecules having multiple chiral centers within each molecule may include one or more stereorandom chiral centers. In a given embodiment, the molecule is a modified oligonucleotide. In a given embodiment, the molecule is a compound containing a modified oligonucleotide.

[0081] Unless otherwise noted, the structures described herein are intended to also include compounds that differ only in the presence of one or more isotope-enriched atoms. For example, the substitution of hydrogen with deuterium or tritium, or 13 C- or 14 Compounds having this structure are within the scope of this disclosure, except for the substitution of carbon by C-enriched carbon.

[0082] As used herein, in the context of a group of molecules of the same molecular formula, "stereorandom chiral center" means a chiral center having a random stereochemical configuration. For example, in a group of molecules containing stereorandom chiral centers, the number of molecules having the (S) configuration of the stereorandom chiral center may be equal to, but not necessarily equal to, the number of molecules having the (R) configuration of the corresponding stereorandom chiral center. The stereochemical configuration of the chiral center is considered random if it is the result of a synthesis method not designed to control the stereochemical configuration. In a given embodiment, the stereorandom chiral center is a link between stereorandom phosphorothioate nucleosides.

[0083] Specific implementation example

[0084] In certain embodiments, the present disclosure relates to a method, a compound, and a composition for inhibiting CFB. In a specific embodiment, CFB is specifically inhibited. In a specific embodiment, CFB is specifically degraded. In a specific embodiment, CFB expression is inhibited. In a specific embodiment, CFB translation is inhibited. In a specific embodiment, CFB activity is inhibited. In a specific embodiment, CFB expression, translation, or activity is reduced by at least 10% compared to expression, translation, or activity in an untreated or control sample. For example, in a given embodiment, CFB expression, translation, or activity is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, 10-50%, 25-50%, 25-75%, 50-75%, 50-99%, or 75-99% compared to the expression, translation, or activity in an untreated or control sample. In a given embodiment, CFB expression, translation, or activity is reduced when measured by any suitable assay, including but not limited to immunoassays, hybridization-based assays, or sequence-based assays (e.g., RNA sequences).

[0085] In a specific aspect, the present disclosure relates to a compound that targets CFB nucleic acid. In a specific embodiment, the CFB nucleic acid has the sequences presented in GenBank accession number NM_001710.6 (incorporated herein as SEQ ID NO. 1), nucleotides 31946095 to 31952084 of GenBank accession number NC_000006.12 (incorporated herein as SEQ ID NO. 2), GenBank accession number NM_001710.6 (incorporated herein as SEQ ID NO. 3), and nucleotides 3423522 to 3429511 of GenBank accession number NT_113891.3 (incorporated herein as SEQ ID NO. 4).

[0086] In a specific embodiment, the compound is an oligomer compound. In a specific embodiment, the compound is a single strand. In a specific embodiment, the compound is a double strand.

[0087] A predetermined embodiment provides a compound comprising a modified oligonucleotide having a nucleobase comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths).

[0088] A specific embodiment provides a compound comprising a modified oligonucleotide having a nucleobase sequence including the nucleobase sequence of SEQ ID NO. 100 (e.g., 14 to 30 linked nucleosides, e.g., 14 to 23 linked nucleoside lengths).

[0089] A specific embodiment provides a compound comprising a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100.

[0090] In a specific embodiment, the modified oligonucleotide has a nucleobase sequence that is at least 80%, at least 85%, at least 90%, or at least 95% complementary to SEQ ID NO. 1 or 3. In a specific embodiment, the modified oligonucleotide comprises at least one modification selected from a modified nucleoside linkage, a modified sugar, and a modified nucleobase. In a specific embodiment, the compound is double-stranded.

[0091] A predetermined embodiment provides a compound comprising a modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 109 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths).

[0092] A specific embodiment provides a compound comprising a modified oligonucleotide having a nucleobase sequence including the nucleobase sequence of SEQ ID NO. 109 (e.g., 14 to 30 linked nucleosides, e.g., 14 to 23 linked nucleoside lengths).

[0093] A specific embodiment provides a compound comprising a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 109.

[0094] In a specific embodiment, the modified oligonucleotide has a nucleobase sequence that is at least 80%, at least 85%, at least 90%, or at least 95% identical to an equivalent length portion of SEQ ID NO. 1 or 3. In a specific embodiment, the modified oligonucleotide comprises at least one modification selected from a modified nucleoside linkage, a modified sugar, and a modified nucleobase. In a specific embodiment, the compound is double-stranded.

[0095] A predetermined embodiment provides a compound comprising a first modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 100 or 109 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths), and a second modified oligonucleotide having a complementary region to the first modified nucleobase (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths).

[0096] In a given embodiment, the compound provides a compound comprising a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of any one of the nucleobase sequences provided in SEQ ID NOs 2 to 3, and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths) having a complementary region to the first modified nucleoside.

[0097] A predetermined embodiment provides a compound comprising a first modified oligonucleotide having a nucleobase sequence including the nucleobase sequence of SEQ ID NO. 100 or 109 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths), and a second modified oligonucleotide having a complementary region to the first modified nucleoside (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths).

[0098] A specific embodiment provides a compound comprising a first modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100 or 109 and a second modified oligonucleotide having 19 to 23 linked nucleoside lengths having a complementary region to the first modified oligonucleotide.

[0099] In a given embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 109 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100. In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 109. In a specific embodiment, the compound comprises a first modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100 and a second modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 109.

[0100] In a specific embodiment, any of the compounds described above, the modified oligonucleotide or the first modified oligonucleotide, has at least 80%, at least 85%, at least 90%, or at least 95% complementarity or identity with SEQ ID NO. 1 or 3 over its length. In a specific embodiment, the modified oligonucleotide or the first modified oligonucleotide has at least one, at least two, or at least three discrepancies with respect to the region of SEQ ID NO. 1 or 3. In a specific embodiment, the length of the complementary region between the first modified oligonucleotide or the first strand and the second modified oligonucleotide or the second strand is 14 to 30 linked nucleoside lengths. In a specific embodiment, the length of the complementary region between the first modified oligonucleotide or the first strand and the second modified oligonucleotide or the second strand is 14 to 23 linked nucleoside lengths. In a specific embodiment, the length of the complementary region between the first modified oligonucleotide or the first strand and the second modified oligonucleotide or the second strand is 19 to 23 linked nucleoside lengths. In a specific embodiment, the length of the complementary region between the first modified oligonucleotide or the first strand and the second modified oligonucleotide or the second strand is 21 to 23 linked nucleoside lengths. In a specific embodiment, the first modified oligonucleotide is fully complementary to the second modified oligonucleotide.

[0101] In a specific embodiment, any one of the aforementioned compounds, or the first modified oligonucleotide, comprises at least one modification selected from a modified nucleoside linkage, a modified sugar, and a modified nucleobase. In a specific embodiment, any one of the aforementioned compounds, the second modified oligonucleotide, comprises at least one modification selected from the group consisting of a modified nucleoside linkage, a modified sugar, and a modified nucleobase. In a specific embodiment, the modified nucleoside linkage is a phosphorothioate nucleoside linkage or a methylphosphonate nucleoside linkage. In a specific embodiment, the phosphorothioate nucleoside linkage or the methylphosphonate nucleoside linkage is located at the 3' end of the first or second modified oligonucleotide or at the 5' end of the first modified oligonucleotide. In a specific embodiment, the modified sugar comprises a modification selected from the group consisting of a halogen, an alkoxy group, and a cyclic sugar. In a specific embodiment, the modified sugar comprises a 2'-F modification. In a specific embodiment, the modified sugar comprises a 2'-OMe modification. In a specific embodiment, each nucleoside of the first modified oligonucleotide comprises the modified sugar. In a specific embodiment, each nucleoside of the second modified oligonucleotide comprises the modified sugar. In a specific embodiment, the modified sugar comprises a modification selected from the group consisting of halogens, alkoxy groups, and cyclic sugars, or combinations thereof. In a specific embodiment, the modified sugar comprises a modification selected from the group consisting of 2'-MOE, 2'-F, and 2'-OMe, or combinations thereof. In a specific embodiment, the first modified oligonucleotide comprises 10 or fewer 2'-F sugar modifications. In a specific embodiment, the second modified oligonucleotide comprises 5 or fewer 2'-F sugar modifications.

[0102] In a specific embodiment, the compound of any one of the aforementioned embodiments comprises a conjugate. In a specific embodiment, the conjugate is attached to the 5' end of the modified oligonucleotide. In a specific embodiment, the conjugate is a targeting moiety. In a specific embodiment, the targeting moiety comprises one or more GalNAcs. In a specific embodiment, the modified oligonucleotide is a second modified oligonucleotide or a sense oligonucleotide. In a specific embodiment, one or more GalNAcs are attached to the 2' or 3' position of the ribosyl ring. In a specific embodiment, one or more GalNAcs are attached to the 5' nucleoside of the modified oligonucleotide. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide is selected from the following formula or its salt, solvate, or hydrate, wherein R is a part of the modified oligonucleotide other than the 5' nucleoside:

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111] In a given embodiment, Chemical Formula III The bonding group according to is presented by the following chemical formula:

[0112]

[0113] In a specific embodiment, R' is OH. In a specific embodiment, R' is SH. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula I, and R' is OH. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula I, and R' is SH. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula II, and R' is OH. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula II, and R' is SH. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula III, and R' is OH. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula III, and R' is SH. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula IV, and R' is OH. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula IV, and R' is SH. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula V, and R' is OH. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula V, and R' is SH. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula VI, and R' is OH. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula VI, and R' is SH. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula VII, and R' is OH. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula VII, and R' is SH. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula VIII, and R' is OH. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula VIII, and R' is SH. In a given embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula XII, and R' is OH.In a given embodiment, the 5' nucleoside of the modified oligonucleotide is of the chemical formula XII, and R' is SH.

[0114] In a specific embodiment, R' is OH. In a specific embodiment, R' is SH. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula I, and R' is OH. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula I, and R' is SH. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula II, and R' is OH. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula II, and R' is SH. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula III, and R' is OH. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula III, and R' is SH. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula IV, and R' is OH. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula IV, and R' is SH. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula V, and R' is OH. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula V, and R' is SH. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula VI, and R' is OH. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula VI, and R' is SH. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula VII, and R' is OH. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula VII, and R' is SH. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula VIII, and R' is OH. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula VIII, and R' is SH. In a given embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula XII, and R' is OH.In a given embodiment, the 5' nucleoside of the modified oligonucleotide is of the chemical formula XII, and R' is SH.

[0115] In a specific embodiment, R' is O. In a specific embodiment, R' is S. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula I, and R' is O. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula I, and R' is S. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula II, and R' is O. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula II, and R' is S. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula III, and R' is O. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula III, and R' is S. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula IV, and R' is O. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula IV, and R' is S. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula V, and R' is O. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula V, and R' is S. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula VI, and R' is O. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula VI, and R' is S. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula VII, and R' is O. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula VII, and R' is S. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula VIII, and R' is O. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula VIII, and R' is S. In a given embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula XII, and R' is O.In a given embodiment, the 5' nucleoside of the modified oligonucleotide is formula XII and R' is S.

[0116] A given embodiment provides a compound comprising a modified oligonucleotide having the following modified nucleobase sequence:

[0117] mU*fA*mG.fA.mC.fA.mU.fC.mC.fA.mG.fA.mU.fA.mA.fU.mC.fC.mU.fU*mC*mC

[0118] (Reference number: IA1016),

[0119] Here:

[0120] m is a 2'-O-methyl sugar modification;

[0121] f is a variant per 2'-F;

[0122] * is a phosphorothioate-nucleoside bond;

[0123] . is a link between phosphate nucleosides.

[0124] A given embodiment provides a compound comprising a modified oligonucleotide having the following modified nucleobase sequence:

[0125] H4*mG*mG.mA.mA.mG.mG.mA.fU.mU.fA.fU.fC.fU.mG.mG.mA.mU.mG.mU.mC.mU*mA*dQ

[0126] (Reference number: IS1252),

[0127] During the meal:

[0128] m is a 2'-O-methyl sugar modification;

[0129] f is a variant per 2'-F;

[0130] * is a phosphorothioate-nucleoside bond;

[0131] . is a link between phosphate nucleosides;

[0132] dQ is the inverse non-basic deoxyribose of the following chemical formula:

[0133] ;

[0134] H4 has the following chemical formula:

[0135] .

[0136] A specific embodiment provides a compound comprising a first modified oligonucleotide of IA1016 and a second modified oligonucleotide of IS1252.

[0137] In a specific embodiment, a compound comprising a first modified oligonucleotide of IA1016 and a second modified oligonucleotide of IS1252 is in the form of a pharmaceutically acceptable salt. In a specific embodiment, the pharmaceutically acceptable salt is a sodium salt. In a specific embodiment, the pharmaceutically acceptable salt is a potassium salt.

[0138] A given embodiment provides a compound as a stereoisomer comprising a first modified oligonucleotide of IA1016 and a second modified oligonucleotide of IS1252.

[0139] In one embodiment provided herein, a modified oligonucleotide according to the following chemical structural formula:

[0140]

[0141] Or a pharmaceutically acceptable salt or stereoisomer thereof is provided. In a given embodiment, reference number IA1016 is a modified oligonucleotide according to the chemical structure formula described above, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0142] In one embodiment provided herein, a modified oligonucleotide according to the following chemical structural formula:

[0143]

[0144] Or a pharmaceutically acceptable salt or stereoisomer thereof is provided. In a given embodiment, reference number IS1252 is a modified oligonucleotide according to the chemical structure formula described above, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0145] In one embodiment provided herein, a sodium salt of a modified oligonucleotide according to the following chemical structure formula:

[0146]

[0147] Or a stereoisomer thereof is provided. In a given embodiment, reference number IA1016 is a modified oligonucleotide according to the aforementioned chemical structure formula, or a stereoisomer thereof.

[0148] In one embodiment provided herein, a sodium salt of a modified oligonucleotide according to the following chemical structure formula:

[0149]

[0150] Or a stereoisomer thereof is provided. In a given embodiment, reference number IS1252 is a modified oligonucleotide according to the aforementioned chemical structure formula, or a stereoisomer thereof.

[0151] In one embodiment provided herein, a compound according to the following chemical structural formula:

[0152]

[0153] Or a pharmaceutically acceptable salt or stereoisomer thereof is provided. In a given embodiment, compound number RD2830 is a compound according to the chemical structure formula described above, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0154] In one embodiment provided herein, a sodium salt of a compound according to the following chemical structural formula:

[0155]

[0156] Or stereoisomers thereof are provided. In a given embodiment, compound number RD2830 is a compound according to the chemical structure formula described above, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0157] In a given embodiment, a group of modified oligonucleotides is provided herein, wherein all linkages between the phosphorothioate nucleosides of the modified oligonucleotides are stereorandom. In a given embodiment, a group of compounds is provided herein, wherein all linkages between the phosphorothioate nucleosides of the modified oligonucleotides are stereorandom.

[0158] A given embodiment provides a composition comprising a compound of any one of the embodiments described above and a pharmaceutically acceptable carrier.

[0159] A predetermined embodiment provides a composition comprising any one of the compounds of the above embodiments for use in treatment.

[0160] A predetermined embodiment provides a method for treating, preventing, or improving a disease, disorder, or pathological condition associated with CFB in an individual, said method comprising the step of treating, preventing, or improving the disease, disorder, or pathological condition by administering a compound targeted to CFB to said individual. In a predetermined embodiment, a compound or composition of any one of the aforementioned embodiments is administered to an individual. In a given embodiment, the disease, disorder, or condition is atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulonephropathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), e.g., lupus nephritis, diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy due to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA). In a given embodiment, the step of administering the compound suppresses, reduces, or improves atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulonephropathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), e.g., lupus nephritis, diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy due to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, rheumatoid arthritis (RA), or symptoms thereof.

[0161] In a specific embodiment, any one of the embodiments described herein, or a composition containing the compound, is administered to an individual in a therapeutically effective amount. In a specific embodiment, a composition containing any one of the embodiments described herein is administered to an individual at a dosage level sufficient to deliver about 1 to 100 mg / kg based on the individual's body weight. In a specific embodiment, any one of the embodiments described herein, or a composition containing the compound, is administered to an individual at a fixed dosage of about 25 mg to about 1,000 mg. In a specific embodiment, the compound or composition is administered to an individual at least once a day up to a maximum dosage level or a fixed dosage.

[0162] In a given embodiment, a compound of any one of the embodiments described herein or a composition comprising a compound is administered to an individual at a dosage level sufficient to deliver about 0.1 to 50 mg / kg, about 0.1 to 20 mg / kg, about 0.2 to 15 mg / kg, about 0.4 to 12 mg / kg, about 0.5 to 10 mg / kg, about 1 to 12 mg / kg, about 1 to 8 mg / kg, about 1 to 4 mg / kg, about 2 to 12 mg / kg, about 2 to 8 mg / kg, about 4 to 12 mg / kg, or about 4 to 8 mg / kg based on the individual's body weight. In a specific embodiment, the dosage level is sufficient to deliver about 0.1 mg / kg, about 0.2 mg / kg, about 0.4 mg / kg, about 0.8 mg / kg, about 1 mg / kg, about 2 mg / kg, about 4 mg / kg, about 6 mg / kg, about 8 mg / kg, about 10 mg / kg, about 12 mg / kg, about 15 mg / kg, or about 20 mg / kg based on the body weight of the individual. In a specific embodiment, the dosage level is sufficient to deliver about 0.4 mg / kg, about 1 mg / kg, about 2 mg / kg, about 4 mg / kg, about 8 mg / kg, or about 12 mg / kg based on the body weight of the individual. In a specific embodiment, the dosage level is sufficient to deliver about 4 mg / kg or about 8 mg / kg based on the body weight of the individual. In a specific embodiment, the compound or composition is administered to the individual at least once a day up to the maximum dosage level. In a specific embodiment, the compound or composition is administered to an individual as a single dose at the dose level. In a specific embodiment, the compound or composition is administered to an individual as multiple doses up to the daily dose level. In a specific embodiment where multiple doses are used, they may be administered simultaneously, individually, or sequentially. In a specific embodiment, the compound or composition is administered to an individual via injection or infusion. In a specific embodiment, the compound or composition is administered to an individual parenterally.In a specific embodiment, the compound or composition is administered to an individual subcutaneously, intravenously, intramuscularly, intra-arterly, intraperitoneally, or intracranially. In a specific embodiment, the compound or composition is administered to an individual via subcutaneous administration.

[0163] The dosage levels and fixed dosages described herein provide guidelines for administering the compound or composition to adults. For example, the amount to be administered to children or adolescents may be determined by a medical professional or a person skilled in the art, and may be lower than or equal to the amount administered to adults.

[0164] In a specific embodiment, a composition comprising any one of the compounds of the embodiments described herein is administered to an individual daily, weekly, monthly, quarterly, every four months, every five months, every six months, every seven months, every eight months, every nine months, every ten months, or annually. In a specific embodiment, any one of the compounds of the embodiments described herein or a composition comprising such compounds is administered to an individual approximately once per quarter (i.e., once every three months) to approximately once per year. In a specific embodiment, any one of the compounds of the embodiments described herein or a composition comprising such compounds is administered to an individual approximately once per quarter, approximately once every six months, or approximately once per year.

[0165] A predetermined embodiment provides a method for inhibiting the expression of CFB in a cell, said method comprising the step of inhibiting the expression of CFB in said cell by contacting said cell with a compound targeted to CFB. In a predetermined embodiment, the cell is a cell of an individual's liver. In a predetermined embodiment, the individual has or is at risk of having atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulonephropathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), e.g., lupus nephritis, diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy due to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA).

[0166] A predetermined embodiment provides a method for reducing or suppressing symptoms of atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), e.g., lupus nephritis, diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy due to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, rheumatoid arthritis (RA), or any one of these in an individual, wherein the method comprises administering a compound targeted to CFB to the individual, thereby reducing atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 The method includes a step of reducing or suppressing symptoms of glomerulonephropathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), e.g., lupus nephritis, diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy due to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, rheumatoid arthritis (RA), or any one of these.In a specific embodiment, the individual has symptoms of atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulonephropathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), e.g., lupus nephritis, diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy due to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, rheumatoid arthritis (RA), or any one of these, or has a risk of having such symptoms. In a specific embodiment, the compound is a compound targeted to CFB. In a specific embodiment, the compound is any one of the aforementioned compounds. In a specific embodiment, the compound or composition is administered parenterally.

[0167] A specific embodiment provides a use of a compound targeted to CFB for treating, preventing, or improving a disease, disorder, or condition associated with CFB. In a specific embodiment, the disease, disorder, or condition is atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulonephropathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), e.g., lupus nephritis, diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy due to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA). In a specific embodiment, the compound is a compound targeted to CFB. In a given embodiment, the compound is any one of the aforementioned compounds.

[0168] A specific embodiment provides the use of a compound targeting CFB in the manufacture of a medicine for treating, preventing, or improving a disease, disorder, or condition associated with CFB. In a specific embodiment, the disease, disorder, or condition is atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulonephropathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), e.g., lupus nephritis, diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy due to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA). In a specific embodiment, the compound is a compound targeted to CFB. In a given embodiment, the compound is any one of the aforementioned compounds.

[0169] Specific indications

[0170] In a specific embodiment, the present disclosure relates to a method for suppressing CFB expression, which may be useful for treating, preventing, or improving a disease, disorder, or pathological condition associated with CFB in an individual by administering a compound that targets CFB. In a specific embodiment, the compound may be a CFB-specific inhibitor. In a specific embodiment, the compound may be an antisense oligonucleotide, an oligomer compound, or an oligonucleotide targeted at CFB.

[0171] In certain aspects, the present disclosure relates to the treatment, prevention, or improvement of diseases, disorders, or conditions associated with CFB. In certain embodiments, diseases, disorders, or conditions associated with CFB that can be treated, / or prevented, or / or improved using the methods provided herein include atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulonephropathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), e.g., lupus nephritis, diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy due to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA). The specific compounds provided herein relate to compounds or compositions that reduce symptoms of atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulonephropathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), e.g., lupus nephritis, diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy secondary to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, rheumatoid arthritis (RA), or any one of these in animals.

[0172] In a specific embodiment, a method for treating, preventing, or improving a disease, disorder, or pathological condition associated with CFB in an individual comprises the step of treating, preventing, or improving said disease, disorder, or pathological condition by administering a compound comprising a CFB-specific inhibitor to said individual. In a specific embodiment, an individual is identified as having or being at risk of having a disease, disorder, or pathological condition associated with CFB. In a specific embodiment, the disease, disorder, or pathological condition is a liver, kidney, or eye disease. In a specific embodiment, the compound comprises an antisense oligonucleotide targeted to CFB. In a specific embodiment, the compound comprises an oligonucleotide targeted to CFB. In a specific embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising the nucleobase sequence of SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100. In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100 (e.g., 14 to 30 linked nucleosides, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100.

[0173] In any one of the embodiments described above, the compound may be single-stranded or double-stranded. In a specific embodiment, the length of the single-stranded compound may be 14 to 30, 14 to 23, 14 to 20, 16 to 20, or 14 to 16 linked nucleosides. In a specific embodiment, the length of the single-stranded compound may be 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 linked nucleosides. In a specific embodiment, the double-stranded compound may comprise two oligonucleotides of the same or different lengths as described elsewhere in this invention. In a given embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 109 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100. In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 109.In a given embodiment, the compound comprises a first modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100 and a second modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 109.

[0174] In any one of the embodiments described above, the compound may be an antisense oligonucleotide or an oligomer compound. In a given embodiment, the compound comprises a first modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 100 or 109 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths), and a second modified oligonucleotide having a complementary region to the first modified nucleobase (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a first modified oligonucleotide having a nucleobase sequence comprising the nucleobase sequence of SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths), and a second modified oligonucleotide having a complementary region to the first modified nucleoside (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a first modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100 or 109 and a second modified oligonucleotide having a complementary region to the first modified oligonucleotide, having a linked nucleoside length of 19 to 23. In a specific embodiment, the compound is administered parenterally to an individual.In a given embodiment, the step of administering the compound improves, maintains, or prevents symptoms of atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulonephropathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), e.g., lupus nephritis, diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy due to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, rheumatoid arthritis (RA), or any one of these in animals.

[0175] In a given embodiment, a method for treating, preventing, or improving symptoms of atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulonephropathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), e.g., lupus nephritis, diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy due to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, rheumatoid arthritis (RA), or any one of these in animals is by administering a compound comprising a CFB-specific inhibitor to said individual, thereby treating atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 The method comprises a step of treating, preventing, or improving symptoms of glomerulonephropathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), e.g., lupus nephritis, diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy due to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, rheumatoid arthritis (RA), or any one of these. In a specific embodiment, the compound comprises an antisense oligonucleotide targeted to CFB. In a specific embodiment, the compound comprises an oligonucleotide targeted to CFB. In a given embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths).In a specific embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising the nucleobase sequence of SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100. In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100. In a given embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 109 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100. In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 109.In a given embodiment, the compound comprises a first modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100 and a second modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 109. In any one of the above embodiments, the compound may be single-stranded or double-stranded. In any one of the above embodiments, the compound may be an antisense oligonucleotide or an oligomer compound. In a given embodiment, the compound comprises a first modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 100 or 109 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths), and a second modified oligonucleotide having a complementary region to the first modified nucleobase (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a first modified oligonucleotide having a nucleobase sequence comprising the nucleobase sequence of SEQ ID NO. 100 or 109 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths), and a second modified oligonucleotide having a complementary region to the first modified nucleoside (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a first modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100 or 109 and a second modified oligonucleotide having a complementary region to the first modified oligonucleotide, having a linked nucleoside length of 19 to 23.In a given embodiment, the step of administering the compound improves, maintains, or prevents symptoms of atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulonephropathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), e.g., lupus nephritis, diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy due to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, rheumatoid arthritis (RA), or any one of these in an animal. In a given embodiment, the individual is identified as having or being at risk of having a disease, disorder, or pathological condition associated with CFB.

[0176] In a specific embodiment, a method for suppressing the expression of CFB in an individual having or at risk of having a disease, disorder, or pathological condition associated with CFB comprises the step of administering a compound comprising a CFB-specific inhibitor to the individual to suppress the expression of CFB in the individual. In a specific embodiment, the administration of the compound suppresses the expression of CFB in the liver. In a given embodiment, the disease, disorder, or condition is a complement pathway-related disease, disorder, or condition, or atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), e.g., lupus nephritis, diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy due to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA). In a specific embodiment, the individual has or is at risk of having atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), e.g., lupus nephritis, diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy due to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA). In a specific embodiment, the compound comprises an antisense oligonucleotide targeted to CFB. In a specific embodiment, the compound comprises an oligonucleotide targeted to CFB.In a specific embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising the nucleobase sequence of SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100. In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100. In a specific embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleos of the nucleobase sequence of SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths).In a specific embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 109 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100. In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 109. In a specific embodiment, the compound comprises a first modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100 and a second modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 109. In any one of the above embodiments, the compound may be single-stranded or double-stranded. In any one of the above embodiments, the compound may be an antisense oligonucleotide or an oligomer compound. In a given embodiment, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 100 or 109, and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths) having a complementary region to the first modified nucleoside.In a specific embodiment, the compound comprises a first modified oligonucleotide having a nucleobase sequence comprising the nucleobase sequence of SEQ ID NO. 100 or 109 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths), and a second modified oligonucleotide having a complementary region to the first modified nucleoside (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a first modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100 or 109 and a second modified oligonucleotide having a complementary region to the first modified oligonucleotide, having a linked nucleoside length of 19 to 23. In a specific embodiment, the compound is administered parenterally to an individual. In a given embodiment, the step of administering the compound improves, maintains, or prevents symptoms of atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulonephropathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), e.g., lupus nephritis, diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy due to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, rheumatoid arthritis (RA), or any one of these.

[0177] In a specific embodiment, a method for inhibiting the expression of CFB in a cell comprises the step of inhibiting the expression of CFB in the cell by contacting the cell with a compound comprising a CFB-specific inhibitor. In a specific embodiment, the cell is a liver cell. In a specific embodiment, the cell is a cell present in the liver. In a specific embodiment, the cell is a cell present in the liver of an individual having or at risk of having atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulonephropathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), e.g., lupus nephritis, diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy due to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA). In a specific embodiment, the compound comprises an antisense oligonucleotide targeted to CFB. In a specific embodiment, the compound comprises an oligonucleotide targeted to CFB. In a specific embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising the nucleobase sequence of SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100.In a specific embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100. In a specific embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 109 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100. In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 109. In a specific embodiment, the compound comprises a first modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100 and a second modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 109.

[0178] In any one of the above embodiments, the compound may be single-stranded or double-stranded. In any one of the above embodiments, the compound may be an antisense oligonucleotide or an oligomer compound. In a given embodiment, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 100 or 109, and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths) having a complementary region to the first modified nucleoside. In a specific embodiment, the compound comprises a first modified oligonucleotide having a nucleobase sequence comprising the nucleobase sequence of SEQ ID NO. 100 or 109 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths), and a second modified oligonucleotide having a complementary region to the first modified nucleoside (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a first modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100 or 109 and a second modified oligonucleotide having a complementary region to the first modified oligonucleotide, having a linked nucleoside length of 19 to 23.

[0179] In a given embodiment, a method for reducing or inhibiting complement pathway-related diseases, disorders, or conditions, or atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), e.g., lupus nephritis, diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy due to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA) in said subject by administering a compound comprising a CFB-specific inhibitor to said subject, thereby reducing or inhibiting complement pathway-related diseases, disorders, or conditions, or atypical hemolysis in said subject. It includes steps to reduce or inhibit uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulonephropathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), e.g., lupus nephritis, diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy due to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA).In a specific embodiment, the individual has or is at risk of having atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), e.g., lupus nephritis, diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy due to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA). In a specific embodiment, the compound comprises an antisense oligonucleotide targeted to CFB. In a specific embodiment, the compound comprises an oligonucleotide targeted to CFB. In a specific embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising the nucleobase sequence of SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide comprising the nucleobase sequence of SEQ ID NO. 100. In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100 (e.g., 14 to 30 linked nucleosides, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100.In a given embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 109 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100. In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 109. In a specific embodiment, the compound comprises a first modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100 and a second modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 109. In any one of the aforementioned embodiments, the compound may be single-stranded or double-stranded. In any one of the aforementioned embodiments, the compound may be an antisense oligonucleotide or an oligomer compound.In a given embodiment, the compound comprises a first modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 100 or 109 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths), and a second modified oligonucleotide having a complementary region to the first modified nucleobase (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a first modified oligonucleotide having a nucleobase sequence comprising the nucleobase sequence of SEQ ID NO. 100 or 109 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths), and a second modified oligonucleotide having a complementary region to the first modified nucleoside (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a first modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100 or 109 and a second modified oligonucleotide having a complementary region to the first modified oligonucleotide, having a linked nucleoside length of 19 to 23. In a specific embodiment, the compound is administered parenterally to an individual. In a specific embodiment, the individual is identified as having or being at risk of having a disease, disorder, or condition associated with CFB.

[0180] A specific embodiment relates to a compound comprising a CFB-specific inhibitor for use in the treatment of diseases, disorders, or conditions associated with CFB. In a specific embodiment, the disease, disorder, or condition is atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulonephropathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), e.g., lupus nephritis, diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy due to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA). In a specific embodiment, the compound comprises an antisense oligonucleotide targeted to CFB. In a specific embodiment, the compound comprises an oligonucleotide targeted to a CFB. In a specific embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising the nucleobase sequence of SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide comprising the nucleobase sequence of SEQ ID NO. 100. In a given embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence including SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths).In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100. In a specific embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 109 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100. In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 109. In a specific embodiment, the compound comprises a first modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100 and a second modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 109. In any one of the aforementioned embodiments, the compound may be single-stranded or double-stranded. In any one of the aforementioned embodiments, the compound may be an antisense oligonucleotide or an oligomer compound.In a given embodiment, the compound comprises a first modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 100 or 109 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths), and a second modified oligonucleotide having a complementary region to the first modified nucleobase (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a first modified oligonucleotide having a nucleobase sequence comprising the nucleobase sequence of SEQ ID NO. 100 or 109 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths), and a second modified oligonucleotide having a complementary region to the first modified nucleoside (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a first modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100 or 109 and a second modified oligonucleotide having a complementary region to the first modified oligonucleotide, having a linked nucleoside length of 19 to 23. In a specific embodiment, the compound is administered parenterally to an individual.

[0181] A specific embodiment relates to a compound comprising a CFB-specific inhibitor for use in reducing or suppressing symptoms of complement pathway-related diseases, disorders, or conditions, or atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), e.g., lupus nephritis, diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy due to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, rheumatoid arthritis (RA), or any one of these. In a specific embodiment, the compound comprises an antisense oligonucleotide targeted to CFB. In a specific embodiment, the compound comprises an oligonucleotide targeted to a CFB. In a specific embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising the nucleobase sequence of SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide selected from the nucleobase sequence of SEQ ID NO. 100. In a given embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence including SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths).In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100. In a specific embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 109 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100. In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 109. In a specific embodiment, the compound comprises a first modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100 and a second modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 109. In any one of the aforementioned embodiments, the compound may be single-stranded or double-stranded. In any one of the aforementioned embodiments, the compound may be an antisense oligonucleotide or an oligomer compound.In a given embodiment, the compound comprises a first modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 100 or 109 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths), and a second modified oligonucleotide having a complementary region to the first modified nucleobase (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a first modified oligonucleotide having a nucleobase sequence comprising the nucleobase sequence of SEQ ID NO. 100 or 109 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths), and a second modified oligonucleotide having a complementary region to the first modified nucleoside (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a first modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100 or 109 and a second modified oligonucleotide having a complementary region to the first modified oligonucleotide, having a linked nucleoside length of 19 to 23.

[0182] A specific embodiment relates to the use of a compound comprising a CFB-specific inhibitor for the preparation or manufacture of a medicine for the treatment of a disease, disorder, or pathological condition associated with CFB. A specific embodiment relates to the use of a compound comprising a CFB-specific inhibitor for the manufacture of a medicine for the treatment of a disease, disorder, or pathological condition associated with CFB. In a specific embodiment, the disease, disorder, or pathological condition is a complement pathway-related disease, disorder, or pathological condition. In a specific embodiment, the disease, disorder, or condition is atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), e.g., lupus nephritis, diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy due to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA). In a specific embodiment, the compound comprises an antisense oligonucleotide targeted to CFB. In a specific embodiment, the compound comprises an oligonucleotide targeted to CFB. In a specific embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising the nucleobase sequence of SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths).In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100. In a specific embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100. In a specific embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 109 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100. In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 109. In a specific embodiment, the compound comprises a first modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100 and a second modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 109. In any one of the aforementioned embodiments, the compound may be single-stranded or double-stranded. In any one of the aforementioned embodiments, the compound may be an antisense oligonucleotide or an oligomer compound.In a given embodiment, the compound comprises a first modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 100 or 109 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths), and a second modified oligonucleotide having a complementary region to the first modified nucleobase (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a first modified oligonucleotide having a nucleobase sequence comprising the nucleobase sequence of SEQ ID NO. 100 or 109 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths), and a second modified oligonucleotide having a complementary region to the first modified nucleoside (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a first modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100 or 109 and a second modified oligonucleotide having a complementary region to the first modified oligonucleotide, having a linked nucleoside length of 19 to 23.

[0183] A specific embodiment relates to the use of a compound comprising a CFB-specific inhibitor for the preparation or manufacture of a medicine to reduce or suppress complement pathway-related diseases, disorders, or conditions, or symptoms thereof, in individuals who have or are at risk of having complement pathway-related diseases. In a given embodiment, the complement pathway-related disease is atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulonephropathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), e.g., lupus nephritis, diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy due to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA). A given embodiment relates to the use of a compound comprising a CFB-specific inhibitor for the manufacture of a medicine for the treatment of diseases, disorders, or conditions associated with CFB. In a specific embodiment, the disease, disorder, or condition is atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), e.g., lupus nephritis, diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy due to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA). In a specific embodiment, the compound comprises an antisense oligonucleotide targeted to CFB. In a specific embodiment, the compound comprises an oligonucleotide targeted to CFB.In a specific embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising the nucleobase sequence of SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100. In a specific embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100. In a specific embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 100 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths).In a specific embodiment, the compound comprises a modified oligonucleotide having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 109 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100. In a specific embodiment, the compound comprises a modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 109. In a specific embodiment, the compound comprises a first modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100 and a second modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 109. In any one of the above embodiments, the compound may be single-stranded or double-stranded. In any one of the above embodiments, the compound may be an antisense oligonucleotide or an oligomer compound. In a given embodiment, the compound comprises a first modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths) having a nucleobase sequence comprising at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 adjacent nucleosides of the nucleobase sequence of SEQ ID NO. 100 or 109, and a second modified oligonucleotide (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths) having a complementary region to the first modified nucleoside.In a specific embodiment, the compound comprises a first modified oligonucleotide having a nucleobase sequence comprising the nucleobase sequence of SEQ ID NO. 100 or 109 (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths), and a second modified oligonucleotide having a complementary region to the first modified nucleoside (e.g., 14 to 30, e.g., 14 to 23 linked nucleoside lengths). In a specific embodiment, the compound comprises a first modified oligonucleotide having the nucleobase sequence of SEQ ID NO. 100 or 109 and a second modified oligonucleotide having a complementary region to the first modified oligonucleotide, having a linked nucleoside length of 19 to 23.

[0184] In any one of the methods or uses described above, the compound may be an oligomer compound. In any one of the methods or uses described above, the compound may be single-stranded or double-stranded. In any one of the methods or uses described above, the compound may be targeted to a CFB. In a specific embodiment, the compound comprises or consists of a modified oligonucleotide. In a specific embodiment, the compound comprises one or more modified oligonucleotides. In a specific embodiment, the compound comprises a first modified oligonucleotide and a second modified oligonucleotide. In a specific embodiment, the length of the modified oligonucleotide is 8 to 80 linked nucleoside lengths, 10 to 30 linked nucleoside lengths, 14 to 30 linked nucleoside lengths, 14 to 23 linked nucleoside lengths, or 19 to 23 linked nucleoside lengths. In a specific embodiment, the modified oligonucleotide is at least 80%, at least 85%, at least 90%, at least 95%, or 100% complementary to any one of the nucleobase sequences mentioned in SEQ ID NO. 1 or 3 over its length. In a specific embodiment, the modified oligonucleotide comprises at least one modified nucleoside linkage, at least one modified sugar, and / or at least one modified nucleobase. In a specific embodiment, the modified nucleoside linkage is a phosphorothioate nucleoside linkage. In a specific embodiment, the modified sugar is a cyclic sugar, 2'-MOE, 2'-F, or 2'-OMe. In a specific embodiment, the modified nucleobase is 5-methylcytosine. In any one of the aforementioned embodiments, the length of each modified oligonucleotide is independently 12 to 30, 14 to 30, 14 to 25, 14 to 24, 14 to 23, 16 to 23, 17 to 23, 18 to 23, 19 to 23, 19 to 22, or 19 to 20 linked nucleosides.In a given embodiment, the modified oligonucleotide has at least one, at least two, or at least three discrepancies for the region of sequence number 1 or 3.

[0185] In any one of the methods or uses described above, the compound comprises first and second modified oligonucleotides, wherein a complementary region exists between the first modified oligonucleotide and the second modified oligonucleotide. In a specific embodiment, the length of the complementary region between the first oligonucleotide and the second oligonucleotide is 14 to 23, 19 to 23, or 21 to 23 linked nucleoside lengths. In a specific embodiment, the first modified oligonucleotide is fully complementary to the second modified oligonucleotide. In a specific embodiment, the first modified oligonucleotide comprises at least one modification selected from modified nucleoside linkages, modified sugars, and modified nucleobases. In a specific embodiment, the second modified oligonucleotide comprises at least one modification selected from the group consisting of modified nucleoside linkages, modified sugars, and modified nucleobases. In a specific embodiment, the modified nucleoside linkages are phosphorothioate nucleoside linkages or methylphosphonate nucleoside linkages. In a specific embodiment, the linkage between the modified nucleosides is at the 3' end of the first or second modified oligonucleotide, or at the 5' end of the first or second modified oligonucleotide. In a specific embodiment, the first or second modified oligonucleotide comprises one or more modified sugars. In a specific embodiment, each nucleoside of the first or second modified oligonucleotide comprises a modified sugar. In a specific embodiment, the modified sugar comprises a modification selected from the group consisting of halogens, alkoxy groups, and cyclic sugars. In a specific embodiment, the modified sugar comprises a modification selected from the group consisting of 2'-MOE, 2'-F, and 2'-OMe, or a combination thereof. In a specific embodiment, the first or second modified oligonucleotide comprises 10 or fewer 2'-F sugar modifications. In a specific embodiment, the first or second modified oligonucleotide comprises 5 or fewer 2'-F sugar modifications.

[0186] In any one of the methods or uses described above, the compound comprises a conjugate. In a specific embodiment, the conjugate is attached to the 5' end of the modified oligonucleotide. In a specific embodiment, the conjugate is a targeting moiety. In a specific embodiment, the targeting moiety comprises one or more GalNAcs. In a specific embodiment, one or more GalNAcs are attached to the 2' or 3' position of the ribosyl ring. In a specific embodiment, one or more GalNAcs are attached to the 5' nucleoside of the modified oligonucleotide. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide is selected from formulas I through VIII, or their salts, solvates, or hydrates, wherein R is a modified oligonucleotide other than the 5' nucleoside. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide is formula I, and R' is O. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide is formula I, and R' is S. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula II, and R' is O. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula II, and R' is S. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula III, and R' is O. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula III, and R' is S. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula IV, and R' is O. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula IV, and R' is S. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula V, and R' is O. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula V, and R' is S. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula VI, and R' is O.In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula VI, and R' is S. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula VII, and R' is O. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula VII, and R' is S. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula VIII, and R' is O. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula VIII, and R' is S.

[0187] In any one of the aforementioned methods or uses, in a given embodiment, the compound comprises a modified oligonucleotide having the following modified nucleobase sequence:

[0188] mU*fA*mG.fA.mC.fA.mU.fC.mC.fA.mG.fA.mU.fA.mA.fU.mC.fC.mU.fU*mC*mC

[0189] (Reference number: IA1016),

[0190] During the meal:

[0191] m is a 2'-O-methyl sugar modification;

[0192] f is a variant per 2'-F;

[0193] * is a phosphorothioate-nucleoside bond;

[0194] . is a link between phosphate nucleosides.

[0195] In any one of the aforementioned methods or uses, in a given embodiment, the compound comprises a modified oligonucleotide having the following modified nucleobase sequence:

[0196] H4*mG*mG.mA.mA.mG.mG.mA.fU.mU.fA.fU.fC.fU.mG.mG.mA.mU.mG.mU.mC.mU*mA*dQ

[0197] (Reference number: IS1252),

[0198] During the meal:

[0199] m is a 2'-O-methyl sugar modification;

[0200] f is a variant per 2'-F;

[0201] * is a phosphorothioate-nucleoside bond;

[0202] . is a link between phosphate nucleosides;

[0203] dQ is the inverse non-basic deoxyribose of the following chemical formula:

[0204] ;

[0205] H4 has the following chemical formula:

[0206] .

[0207] In any one of the methods or uses described above, in a specific embodiment, the compound comprises a first modified oligonucleotide of reference number IA1016 and a second modified oligonucleotide of 14 to 21 linked nucleosides lengths that is completely complementary to the first modified oligonucleotide. A specific embodiment provides a compound comprising a first modified oligonucleotide of reference number IA1016 and a second modified oligonucleotide of reference number IS1252.

[0208] In a specific embodiment, the compound is in the form of a pharmaceutically acceptable salt. In a specific embodiment, the pharmaceutically acceptable salt is a sodium salt. In a specific embodiment, the pharmaceutically acceptable salt is a potassium salt. In a specific embodiment, the composition comprises a compound of any one of the aforementioned embodiments and a pharmaceutically acceptable carrier.

[0209] In any one of the methods or uses described above, the compound of any one of the embodiments described above or a composition comprising the compound is administered to an individual in a therapeutically effective amount. In a specific embodiment, the compound of any one of the embodiments described above or a composition comprising the compound is administered to an individual at a dosage level sufficient to deliver about 1 to 100 mg / kg based on the individual's body weight. In a specific embodiment, the compound of any one of the embodiments described above or a composition comprising the compound is administered to an individual at a fixed dosage of about 25 mg to about 1,000 mg. In a specific embodiment, the composition is administered to an individual at least once a day up to a maximum dosage level or a fixed dosage.

[0210] In a given embodiment, a compound of any one of the embodiments described herein or a composition comprising a compound is administered to an individual at a dosage level sufficient to deliver about 0.1 to 50 mg / kg, about 0.1 to 20 mg / kg, about 0.2 to 15 mg / kg, about 0.4 to 12 mg / kg, about 0.5 to 10 mg / kg, about 1 to 12 mg / kg, about 1 to 8 mg / kg, about 1 to 4 mg / kg, about 2 to 12 mg / kg, about 2 to 8 mg / kg, about 4 to 12 mg / kg, or about 4 to 8 mg / kg based on the individual's body weight. In a specific embodiment, the dosage level is sufficient to deliver about 0.1 mg / kg, about 0.2 mg / kg, about 0.4 mg / kg, about 0.8 mg / kg, about 1 mg / kg, about 2 mg / kg, about 4 mg / kg, about 6 mg / kg, about 8 mg / kg, about 10 mg / kg, about 12 mg / kg, about 15 mg / kg, or about 20 mg / kg based on the body weight of the individual. In a specific embodiment, the dosage level is sufficient to deliver about 0.4 mg / kg, about 1 mg / kg, about 2 mg / kg, about 4 mg / kg, about 8 mg / kg, or about 12 mg / kg based on the body weight of the individual. In a specific embodiment, the dosage level is sufficient to deliver about 4 mg / kg or about 8 mg / kg based on the body weight of the individual. In a specific embodiment, the compound or composition is administered to the individual at least once a day up to the maximum dosage level. In a specific embodiment, the compound or composition is administered to an individual as a single dose at the dose level. In a specific embodiment, the compound or composition is administered to an individual as multiple doses up to the daily dose level. In a specific embodiment where multiple doses are used, they may be administered simultaneously, individually, or sequentially. In a specific embodiment, the compound or composition is administered to an individual via injection or infusion. In a specific embodiment, the compound or composition is administered to an individual parenterally.In a specific embodiment, the compound or composition is administered to an individual subcutaneously, intravenously, intramuscularly, intra-arterly, intraperitoneally, or intracranially. In a specific embodiment, the compound or composition is administered to an individual via subcutaneous administration.

[0211] The dosage levels and fixed dosages described herein provide guidelines for administering the compound or composition to adults. For example, the amount to be administered to children or adolescents may be determined by a medical professional or a person skilled in the art, and may be lower than or equal to the amount administered to adults.

[0212] In a specific embodiment, a composition comprising any one of the compounds of the embodiments described herein is administered to an individual daily, weekly, monthly, quarterly, every four months, every five months, every six months, every seven months, every eight months, every nine months, every ten months, or annually. In a specific embodiment, any one of the compounds of the embodiments described herein or a composition comprising such compounds is administered to an individual approximately once per quarter (i.e., once every three months) to approximately once per year. In a specific embodiment, any one of the compounds of the embodiments described herein or a composition comprising such compounds is administered to an individual approximately once per quarter, approximately once every six months, or approximately once per year.

[0213] specific compounds

[0214] In a given embodiment, the present disclosure relates to a compound comprising or composed of an oligomer compound. In a given embodiment, the oligomer compound comprises a nucleobase sequence complementary to the nucleobase sequence of a target nucleic acid.

[0215] In a specific embodiment, the present disclosure relates to a compound comprising or consisting of a modified oligonucleotide. In a specific embodiment, the modified oligonucleotide has a nucleobase sequence complementary to the nucleobase sequence of a target nucleic acid.

[0216] In a specific embodiment, the present disclosure relates to a compound comprising or composed of an antisense oligonucleotide. In a specific embodiment, the antisense oligonucleotide has a nucleobase sequence complementary to the nucleobase sequence of a target nucleic acid.

[0217] In a specific embodiment, the present disclosure relates to a compound that is a single-stranded compound. In a specific embodiment, the single-stranded compound comprises or consists of an oligomer compound. In a specific embodiment, such an oligomer compound comprises or consists of an oligonucleotide and optionally a splicing group. In a specific embodiment, the oligonucleotide is a modified oligonucleotide. In a specific embodiment, the oligonucleotide is an antisense oligonucleotide. In a specific embodiment, the oligonucleotide or modified oligonucleotide of the single-stranded compound comprises a self-complementary nucleobase sequence.

[0218] In a specific embodiment, the present disclosure relates to a compound that is a double-stranded compound. In a specific embodiment, the double-stranded compound comprises or is composed of an oligomer compound. In a specific embodiment, the double-stranded compound comprises a first oligonucleotide and a second oligonucleotide. In a specific embodiment, the first oligonucleotide has a region complementary to the target nucleic acid, and the second oligonucleotide has a region complementary to the first modified oligonucleotide. In a specific embodiment, the double-stranded compound comprises a modified oligonucleotide. In a specific embodiment, the modified oligonucleotide has a region complementary to the target nucleic acid. In a specific embodiment, the double-stranded compound comprises a first modified oligonucleotide and a second modified oligonucleotide. In a specific embodiment, the first modified oligonucleotide has a region complementary to the target nucleic acid, and the second modified oligonucleotide has a region complementary to the first modified oligonucleotide. In a specific embodiment, the oligonucleotide or modified oligonucleotide of the double-stranded compound is an RNA oligonucleotide. In this embodiment, the thymine nucleobase of the modified oligonucleotide is replaced with a uracil nucleobase.

[0219] In a specific embodiment, the compound described herein comprises a conjugate. In a specific embodiment, the first oligonucleotide or the first modified oligonucleotide of the double-stranded compound comprises a conjugate. In a specific embodiment, the second oligonucleotide or the second modified oligonucleotide of the double-stranded compound comprises a conjugate. In a specific embodiment, the first oligonucleotide or the first modified oligonucleotide of the double-stranded compound and the second oligonucleotide or the second modified oligonucleotide of the double-stranded compound each comprise a conjugate.

[0220] In a specific embodiment, the length of the compound is 14 to 30 linked nucleoside lengths. In a specific embodiment, the length of the first oligonucleotide or the first modified oligonucleotide of the double-stranded compound is 14 to 30 linked nucleoside lengths. In a specific embodiment, the length of the second oligonucleotide or the second modified oligonucleotide is 14 to 30 linked nucleoside lengths. In a specific embodiment, the oligonucleotide or the modified oligonucleotide of the double-stranded compound forms a blunt end at one or both of the ends of the compound. In a specific embodiment, the oligonucleotide or the modified oligonucleotide of the double-stranded compound comprises a non-complementary overhang nucleoside at one or both of the ends of the compound.

[0221] In a specific embodiment, the compound has a nucleobase sequence comprising at least 14 consecutive nucleosides of SEQ ID NO. 100. In a specific embodiment, one of the oligonucleotide or modified oligonucleotide of the double-stranded compound has a nucleobase sequence comprising at least 14 consecutive nucleosides of SEQ ID NO. 100.

[0222] Examples of single-stranded and double-stranded compounds include, but are not limited to, oligonucleotides, antisense oligonucleotides, siRNA, microRNA-targeting oligonucleotides, occupancy-based compounds (e.g., mRNA processing or translation blocking compounds and splicing compounds), and single-stranded RNAi compounds (e.g., short hairpin RNA (shRNA), single-stranded siRNA (ssRNA), and microRNA mimics).

[0223] In a given embodiment, the compound described herein has a nucleobase sequence comprising the reverse complementary sequence of the target region of the target nucleic acid to which the compound is targeted, when indicated in the 5' to 3' direction.

[0224] In a specific embodiment, the compound described herein comprises oligonucleotides of 12 to 30 linked subunit lengths. In a specific embodiment, the compound described herein comprises oligonucleotides of 12 to 23 linked subunit lengths. In a specific embodiment, the compound described herein comprises oligonucleotides of 14 to 30 linked subunit lengths. In a specific embodiment, the compound described herein comprises oligonucleotides of 14 to 23 linked subunit lengths. In a specific embodiment, the compound described herein comprises oligonucleotides of 15 to 30 linked subunit lengths. In a specific embodiment, the compound described herein comprises oligonucleotides of 15 to 23 linked subunit lengths. In a specific embodiment, the compound described herein comprises oligonucleotides of 16 to 30 linked subunit lengths. In a specific embodiment, the compound described herein comprises oligonucleotides of 16 to 23 linked subunit lengths. In a specific embodiment, the compound described herein comprises oligonucleotides of 17 to 30 linked subunit lengths. In a specific embodiment, the compound described herein comprises oligonucleotides of 17 to 23 linked subunit lengths. In a specific embodiment, the compound described herein comprises oligonucleotides of 18 to 30 linked subunit lengths. In a specific embodiment, the compound described herein comprises oligonucleotides of 18 to 23 linked subunit lengths. In a specific embodiment, the compound described herein comprises oligonucleotides of 19 to 30 linked subunit lengths. In a specific embodiment, the compound described herein comprises oligonucleotides of 19 to 23 linked subunit lengths.That is, each of these oligonucleotides is 12 to 30 linked subunits, 12 to 23 linked subunits, 14 to 30 linked subunits, 14 to 23 linked subunits, 15 to 30 linked subunits, 15 to 23 linked subunits, 16 to 30 linked subunits, 16 to 23 linked subunits, 17 to 30 linked subunits, 17 to 23 linked subunits, 18 to 30 linked subunits, 18 to 23 linked subunits, 19 to 30 linked subunits, or 19 to 23 linked subunits. In a given embodiment, the compound described herein comprises an oligonucleotide of length 14 linked subunits. In a specific embodiment, the compound described herein comprises 16 linked subunit length oligonucleotides. In a specific embodiment, the compound described herein comprises 17 linked subunit length oligonucleotides. In a specific embodiment, the compound described herein comprises 18 linked subunit length oligonucleotides. In a specific embodiment, the compound described herein comprises 19 linked subunit length oligonucleotides. In a specific embodiment, the compound described herein comprises 20 linked subunit length oligonucleotides. In a specific embodiment, the compound described herein comprises 21 linked subunit length oligonucleotides. In a specific embodiment, the compound described herein comprises 22 linked subunit length oligonucleotides. In a specific embodiment, the compound described herein comprises 23 linked subunit length oligonucleotides.In another embodiment, the compound described herein comprises oligonucleotides of 8 to 80, 12 to 50, 13 to 30, 13 to 50, 14 to 30, 14 to 50, 15 to 30, 15 to 50, 16 to 30, 16 to 50, 17 to 30, 17 to 50, 18 to 23, 18 to 24, 18 to 25, 18 to 50, 19 to 23, 19 to 30, 19 to 50, 20 to 23, or 20 to 30 linked subunits. In these specific embodiments, the compounds described herein comprise 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 linked subunits, or oligonucleotides in a range defined by any two of the aforementioned values.

[0225] In a specific embodiment, the compound may further comprise an additional moiety, such as a conjugate or a transfer moiety. In a specific embodiment, the compound is an oligomer compound, and the additional moiety is attached to an oligonucleotide. In a specific embodiment, the conjugate is attached to a nucleoside of the oligonucleotide.

[0226] In a given embodiment, the compound may be shortened or cleaved. For example, one or more subunits may be deleted from the 5' end (5' cleavage) of the oligonucleotide, or alternatively from the 3' end (3' cleavage).

[0227] In a given embodiment, the compound may be extended. For example, one or more subunits may be attached to the 3' end or 5' end of the oligonucleotide. In a given embodiment, at least one subunit (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more subunits) is attached to the 5' end of the oligonucleotide. In a given embodiment, at least one subunit (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more subunits) is attached to the 3' end of the oligonucleotide. In a given embodiment, at least one subunit may be attached to the 3' end or 5' end of an oligonucleotide of a double-stranded compound to form a 3' and / or 5' end overhang. In a given embodiment, at least one subunit (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more subunits) is attached to the 5' end of both oligonucleotides of the double-stranded compound.In a given embodiment, at least one subunit (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more subunits) is attached to the 3' end of both oligonucleotides of the double-stranded compound. In a specific embodiment, a subunit is attached to both oligonucleotides of a double-stranded compound at the same end (e.g., a subunit is attached to the 3' end of one oligonucleotide and a subunit is attached to the 5' end of the other oligonucleotide). In a specific embodiment, where a subunit is attached to both oligonucleotides of a double-stranded compound at the same end, the number of subunits attached to each oligonucleotide may be the same or different. In a specific embodiment, where a subunit is attached to both oligonucleotides of a double-stranded compound at the same end, the number of subunits attached to each oligonucleotide is the same. In a specific embodiment, where a subunit is attached to both oligonucleotides of a double-stranded compound at the same end, the number of subunits attached to each oligonucleotide is different. This scenario in which a subunit is attached to both oligonucleotides of a double-stranded compound at the same end may occur at one or both ends of the double-stranded compound. In a given embodiment, the subunit attached to the 3' and / or 5' ends is deformed.

[0228] In a specific embodiment, the compound described herein is an oligonucleotide. In a specific embodiment, the compound described herein is a modified oligonucleotide. In a specific embodiment, the compound described herein is an antisense oligonucleotide. In a specific embodiment, the compound described herein is an oligomer compound. In a specific embodiment, the compound described herein is an RNAi compound. In a specific embodiment, the compound described herein is an siRNA compound.

[0229] In a specific embodiment, the compound described herein may comprise any one of the oligonucleotide sequences targeted to the CFB described herein. In a specific embodiment, the compound may be double-stranded.

[0230] In a specific embodiment, the compound comprises an oligonucleotide comprising at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleobase portions of SEQ ID NO. 100. In a specific embodiment, the compound comprises a second oligonucleotide. In a specific embodiment, the compound comprises an oligonucleotide comprising at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleobase portions of SEQ ID NO. 109. In a given embodiment, the compound comprises a first oligonucleotide comprising at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleobase portions of SEQ ID NO. 100, and a second oligonucleotide comprising at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleobase portions of SEQ ID NO. 109.

[0231] In a specific embodiment, the compound comprises a ribonucleotide, wherein the oligonucleotide has uracil (U) instead of thymine (T) for any one of the sequences provided herein. In a specific embodiment, the compound comprises a deoxyribonucleotide, wherein the oligonucleotide has thymine (T) instead of uracil (U) for any one of the sequences provided herein.

[0232] specific mechanism

[0233] In a specific embodiment, the compound described herein comprises or consists of a modified oligonucleotide. In a specific embodiment, the compound described herein comprises or consists of an antisense oligonucleotide. In a specific embodiment, the compound comprises or consists of an oligomer compound. In a specific embodiment, the compound described herein may hybridize to a target nucleic acid. In a specific embodiment, the compound described herein selectively affects one or more target nucleic acids. Such a compound comprises a nucleobase sequence that hybridizes to one or more target nucleic acids to produce one or more desired activities and does not hybridize to one or more non-target nucleic acids, or does not hybridize to one or more non-target nucleic acids in a manner that produces significant undesirable activities.

[0234] In a given embodiment, hybridization of the compound described herein with the target nucleic acid results in the recruitment of one or more proteins that cause cleavage of the target nucleic acid. For example, a specific compound or a portion of a compound described herein is loaded into an RNA-induced silencing complex (RISC) to ultimately cause cleavage of the target nucleic acid. For example, a specific compound described herein causes cleavage of the target nucleic acid by Argonaute. The compound loaded into the RISC is an RNAi compound. The RNAi compound may be double-stranded (siRNA) or single-stranded (ssRNA).

[0235] In a specific embodiment, hybridization of the compound described herein with the target nucleic acid does not cause recruitment of a protein that cleaves the target nucleic acid. In such a specific embodiment, hybridization of the compound with the target nucleic acid causes a change in the splicing of the target nucleic acid. In such a specific embodiment, hybridization of the compound with the target nucleic acid causes inhibition of binding interactions between the target nucleic acid and a protein or other nucleic acid. In such a specific embodiment, hybridization of the compound with the target nucleic acid causes a change in RNA processing. In such a specific embodiment, hybridization of the compound with the target nucleic acid causes a change in the translation of the target nucleic acid.

[0236] Activity caused by hybridization of a compound with respect to a target nucleic acid can be observed directly or indirectly. In a given embodiment, observation or detection of activity includes a change in the amount of the target nucleic acid or the protein encoded by the target nucleic acid, a change in the ratio of splicing variants of the nucleic acid or protein, and / or observation or detection of a change in the phenotype of a cell or animal.

[0237] Specific variations

[0238] In a specific embodiment, the present disclosure relates to a compound comprising or consisting of an oligonucleotide. An oligonucleotide consists of linked nucleosides. In a specific embodiment, the oligonucleotide may be unmodified RNA or DNA, or may be modified. In a specific embodiment, the oligonucleotide is a modified oligonucleotide. In a specific embodiment, the modified oligonucleotide comprises at least one modified sugar, a modified nucleobase, or a link between modified nucleosides relative to the unmodified RNA or DNA. In a specific embodiment, the oligonucleotide has a modified nucleoside. The modified nucleoside may comprise a modified sugar, a modified nucleobase, or both the modified sugar and the modified nucleobase. The modified oligonucleotide may also comprise end modifications, e.g., 5'-end modifications and 3'-end modifications.

[0239] Party variations and motifs

[0240] In a specific embodiment, the modified sugar is a substituted furanosyl sugar or a non-cyclic modified sugar. In a specific embodiment, the modified sugar is a cyclic or tricyclic modified sugar. In a specific embodiment, the modified sugar is a sugar substitute. The sugar substitute may include one or more of the substitutions described herein.

[0241] In a specific embodiment, the modified sugar is a substituted furanosyl or non-cyclic modified sugar. In a specific embodiment, the furanosyl sugar is a ribosyl sugar. In a specific embodiment, the furanosyl sugar comprises one or more substituents, which include but are not limited to substituents at the 2', 3', 4', and 5' positions.

[0242] In a specific embodiment, the substituent at the 2' position includes, but is not limited to, F and OCH3 ('OMe', 'O-methyl', or 'methoxy'). In a specific embodiment, the substituent at the 2' position suitable for the non-cyclic modified sugar includes, but is not limited to, halo, allyl, amino, azido, SH, CN, OCN, CF3, OCF3, F, Cl, Br, SCH3, SOCH3, SO2CH3, ONO2, NO2, N3, and NH2. In a specific embodiment, the substituent at the 2' position is O-(C1-C 10 ) Includes, but is not limited to, alkoxy, alkoxyalkyl, O-alkyl, S-alkyl, N-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, O-alkynyl, S-alkynyl, N-alkynyl, O-alkyl-O-alkyl, and alkynyl, wherein the alkyl, alkenyl, and alkynyl are substituted or unsubstituted C1 to C 10 alkyl or C2 to C 10 It may be alkenyl and alkynyl. In a specific embodiment, the substituent at the 2' position includes, but is not limited to, alkalyl, aralkyl, -O-alkalyl, and -O-aralkyl. In a specific embodiment, these 2' substituents may be further substituted with one or more substituents independently selected from hydroxyl, alkoxy, carboxyl, benzyl, phenyl, nitro(NO2), thiol, thioalkoxy, thioalkyl, halogen, alkyl, aryl, alkenyl, and alkynyl. In a specific embodiment, the substituent at the 2' position is O[(CH2) n O] m CH3, O(CH2) n OCH3, O(CH2) n CH3, O(CH2) n ONH2, O(CH2) n NH2, O(CH2) n SCH3, and O(CH2) n ON[(CH2) nCH3)]2 includes, but is not limited to, where n and m are independently 1 to about 10. In a given embodiment, the substituent at the 2' position includes, but is not limited to, OCH2CH2OCH3("MOE"), O(CH2)2ON(CH3)2("DMAOE"), O(CH2)2O(CH2)2N(CH3)2("DMAEOE"), and OCH2C(=O)-N(H)CH3("NMA").

[0243] In a specific embodiment, the substituent at the 4' position suitable for the non-cyclic modified sugar includes, but is not limited to, alkoxy (e.g., methoxy), alkyl, and those described in WO 2015 / 106128 Manoharan et al. In a specific embodiment, the substituent at the 5' position suitable for the non-cyclic modified sugar includes, but is not limited to, methyl ('Me') (R or S), vinyl, and methoxy. In a specific embodiment, the substituents described herein for the 2', 4', and 5' positions may be added to other specific positions of the sugar. In a specific embodiment, these substituents may be added to the 3' position of the sugar on a 3'-terminal nucleoside, or to the 5' position of a 5'-terminal nucleoside. In a specific embodiment, the non-cyclic modified sugar may comprise two or more non-crosslinked sugar substituents. In these specific embodiments, the non-cyclic modified sugar substituent includes, but is not limited to, 5'-Me-2'-F, 5'-Me-2'-OMe (including both R and S isomers). In specific embodiments, the modified sugar substituent includes those described in WO 2008 / 101157 by Migawa et al. and US 2013 / 0203836 by Rajeev et al.

[0244] In a specific embodiment, the modified sugar is a bicyclic sugar. The bicyclic sugar is a modified sugar comprising two rings, wherein the second ring is formed through a crosslink connecting two atoms of the first ring to form a bicyclic structure. In a specific embodiment, the bicyclic sugar comprises a crosslinking substituent that crosslinks two atoms of the furanosyl ring to form the second ring. In a specific embodiment, the bicyclic sugar does not comprise a furanosyl moiety. A "bicyclic nucleoside" ("BNA") is a nucleoside having a bicyclic sugar. In a specific embodiment, the bicyclic sugar comprises a crosslink between the 4' and 2' furanosyl ring atoms. In a specific embodiment, the bicyclic sugar comprises a crosslink between the 5' and 3' furanosyl ring atoms. In such a specific embodiment, the furanosyl ring is a ribose ring. In a given embodiment, the 4' to 2' crosslinking substituent comprises, but is not limited to: 4'-CH2-2', 4'-(CH2)2-2', 4'-(CH2)3-2', 4'-CH2-O-2'("LNA"), 4'-CH2-S-2', 4'-(CH2)2-O-2'("ENA"), 4'-CH(CH3)-O-2'(where S is the configuration, "limited ethyl" or "cEt"), 4'-CH2-O-CH2-2', 4'-CH2-N(R)-2', 4'-CH(CH2OCH3)-O-2'("limited MOE" or "cMOE") and analogs thereof (e.g., U.S. Patent No. 7,399,845), 4'-C(CH3)(CH3)-O-2' and analogs thereof (e.g., U.S. Patent No. 8,278,283), 4'-CH2-N(OCH3)-2' and analogs thereof (e.g., U.S. Patent No. 8,278,425), 4'-CH2-ON(CH3)-2' (e.g., U.S. Patent Publication No. 2004 / 0171570), 4'-CH2-N(R)-O-2' (wherein R is H, C1-C 12Alkyl, or a protecting group (e.g., U.S. Patent No. 7,427,672), 4'-CH2-C(H)(CH3)-2' (e.g., the work of Chattopadhyaya et al. [J. Org. Chem., 2009, 74, 118-134]), and 4'-CH2-C(=CH2)-2' and analogs thereof (e.g., U.S. Patent No. 8,278,426). The full contents of each of the foregoing documents are incorporated herein by reference. Additional representative U.S. patents and U.S. patent publications teaching the preparation of cyclic nucleic acid nucleotides include, but are not limited to: U.S. Patent No. 6,268,490; No. 6,525,191; No. 6,670,461; No. 6,770,748; No. 6,794,499; No. 6,998,484; No. 7,053,207; No. 7,034,133; No. 7,084,125; No. 7,399,845; No. 7,427,672; No. 7,569,686; No. 7,741,457; No. 8,022,193; No. 8,030,467; No. 8,278,425; No. 8,278,426; No. 8,278,283; US 2008 / 0039618; and US 2009 / 0012281, US 2013 / 0190383; and WO 2013 / 036868, the full contents of each of these are incorporated herein by reference. Any of the aforementioned cyclic nucleosides may be prepared to have one or more stereochemical sugar configurations, for example, including α-L-ribofuranose and β-D-ribofuranose (see, for example, WO99 / 14226). Unless otherwise specified, the cyclic nucleosides specified herein exist in a β-D configuration.

[0245] In a specific embodiment, the modified sugar is a sugar substitute. In a specific embodiment, the sugar substitute is one in which an oxygen atom is replaced, for example, by a sulfur, carbon, or nitrogen atom. In such a specific embodiment, the sugar substitute may also include crosslinking and / or non-crosslinking substituents as described herein. In a specific embodiment, the sugar substitute includes a ring having no more than five atoms. In such a specific embodiment, the sugar substitute includes a cyclobutyl moiety instead of a pentopuranosyl sugar. In a specific embodiment, the sugar substitute includes a six-membered ring instead of a pentopuranosyl sugar. In a specific embodiment, the sugar substitute includes tetrahydropyran ("THP") instead of a pentopuranosyl sugar. In a specific embodiment, the sugar substitute includes morpholino instead of a pentopuranosyl sugar. Representative U.S. patents teaching the manufacture of such modified structures include, but are not limited to: U.S. Patents No. 4,981,957, No. 5,118,800, No. 5,166,315, No. 5,185,444, No. 5,319,080, No. 5,359,044, No. 5,393,878, No. 5,446,137, No. 5,466,786, No. 5,514,785, No. 5,519,134, No. 5,567,811, No. 5,576,427, No. 5,591,722, No. 5,597,909, No. 5,610,300, No. 5,627,053, No. 5,639,873, No. 5,646,265, No. 5,658,873, No. 5,670,633, No. 5,700,920, No. 7,875,733, No. 7,939,677, No. 8,088,904, No. 8,440,803, and No. 9,005,906, the full contents of each of these are incorporated herein by reference.

[0246] In some embodiments, the sugar substitute comprises an acyclic moiety. In some embodiments, the sugar substitute is an unlocked nucleic acid (“UNA”). UNA is an unlocked acyclic nucleic acid, wherein any one of the bonds of the corresponding sugar is removed to form an unlocked “sugar” residue. As an example, UNA also comprises a monomer in which the bond between C1’ and C4’ (i.e., the covalent carbon-oxygen-carbon bond between the C1’ and C4’ carbons) is removed. As another example, the C2’-C3’ bond of the sugar (i.e., the covalent carbon-carbon bond between the C2’ and C3’ carbons) is removed. Representative U.S. patent publications teaching the preparation of UNA include, but are not limited to: U.S. Patent No. 8,314,227, and U.S. Patent Publications No. 2013 / 0096289, No. 2013 / 0011922, and No. 2011 / 0313020, the full contents of each of which are incorporated herein by reference. In certain embodiments, sugar substitutes include peptide nucleic acids ("PNA"), acyclic butyl nucleic acids (e.g., Kumar et al. [Org. Biomol. Chem., 2013, 11, 5853-5865]), and nucleosides and oligonucleotides described in US2013 / 130378 by Manoharan et al., the entire contents of which are incorporated herein by reference. A number of other cyclic and tricyclic sugar and sugar substitute ring systems that can be used for modified nucleosides are known in the art.

[0247] In a given embodiment, the present disclosure relates to a compound comprising at least one oligonucleotide, wherein the nucleoside of the oligonucleotide comprises one or more types of modified sugars and / or unmodified sugars arranged along the oligonucleotide or a region thereof in the form of a defined pattern or "sugar motif." In a given case, such sugar motifs comprise, but are not limited to, any one of the sugar modification patterns described herein.

[0248] In a specific embodiment, the oligonucleotide comprises a gapmer sugar motif. The gapmer oligonucleotide comprises or consists of two outer "wing" regions and a region having a central or inner "gap" region. The gap and wing regions form a continuous sequence of nucleosides, wherein most of the nucleoside sugars of each wing differ from most of the nucleoside sugars of the gap. In a specific embodiment, the wing regions comprise most of the modified sugars, and the gap comprises most of the unmodified sugars. In a specific embodiment, the nucleosides of the gap are deoxynucleosides. Compounds comprising the gapmer sugar motif are described, for example, in U.S. Patent No. 8,790,919, the whole of which is incorporated herein by reference.

[0249] In a specific embodiment, one or both of the oligonucleotides of the double-stranded compound comprise a trimeric sugar motif. The oligonucleotide comprising the trimeric sugar motif comprises three identical sugar modifications on three consecutive nucleosides. In a specific embodiment, the trimeric element is present at or near the cleavage site of the oligonucleotide. In a specific embodiment, the oligonucleotide of the double-stranded compound may contain two or more trimeric sugar motifs. In a specific embodiment, the identical sugar modification of the trimeric sugar motif is a 2'-F modification. Compounds comprising the trimeric sugar motif are disclosed, for example, in U.S. Patent No. 10,668,170, the entire contents of which are incorporated herein by reference.

[0250] In a specific embodiment, one or both of the oligonucleotides of the double-stranded compound contain a tetramer sugar motif. The oligonucleotide containing the tetramer sugar motif contains four identical sugar modifications on four consecutive nucleosides. In a specific embodiment, the tetramer is present at or near the cleavage site. In a specific embodiment, the oligonucleotides of the double-stranded compound may contain two or more tetramer sugar motifs. In a specific embodiment, the identical sugar modification of the tetramer sugar motif is a 2'-F modification. For a double-stranded compound having a dimer region of 19 to 23 nucleotides in length, the cleavage sites of the antisense oligonucleotide are generally at positions approximately 10, 11, and 12 from the 5' end. In a given embodiment, the tetramer motif is located at positions 8, 9, 10, 11, 9, 11, 12, 10, 11, 12, 13, 11, 12, 13, 14, or 12, 13, 14, 15 of the sense oligonucleotide when counting from the first nucleoside of the 5'-end of the sense oligonucleotide, or when counting starts from the first pair of nucleotides within the dimer region from the 5'-end of the sense oligonucleotide. In a given embodiment, the tetramer motif is located at positions 8, 9, 10, 11, 9, 11, 12, 10, 12, 13, 11, 12, 13, 14, or 12, 14, 15 of the antisense oligonucleotide when counting is started from the first nucleoside of the 5'-end of the antisense oligonucleotide, or when counting is started from the first pair of nucleotides within the dimer region from the 5'-end of the antisense oligonucleotide. The cleavage site may vary depending on the length of the dimer region of the double-stranded compound, and accordingly, the position of the tetramer may also vary.

[0251] In a specific embodiment, the oligonucleotide comprises an alternating sugar motif. In a specific embodiment, one or both of the oligonucleotides of the double-stranded compound comprise an alternating sugar motif. An oligonucleotide having an alternating sugar motif comprises at least two different sugar modifications, wherein one or more consecutive nucleosides comprising a first sugar modification are alternated with one or more consecutive nucleosides comprising a second sugar modification and one or more consecutive nucleosides comprising a third sugar modification, etc. For example, if A, B, and C each represent one type of modification for a nucleoside, the corresponding alternating motif may be "ABABABABABAB...", "AABBAABBAABB...", "AABAABAABAAB...", "AAABAAABAAAB...", "AAABBBAAABBB...", or "ABCABCABCABC..." etc. In a specific embodiment, the alternating sugar motif is repeated for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 consecutive nucleobases along the oligonucleotide. In a specific embodiment, the alternating sugar motif consists of two different sugar modifications. In a specific embodiment, the alternating sugar motif includes 2'-OMe and 2'-F sugar modifications.

[0252] In a specific embodiment, each nucleoside of the oligonucleotide is independently modified by one or more sugar modifications provided herein. In a specific embodiment, each oligonucleotide of the double-stranded compound has one or more sugar motifs provided herein. In a specific embodiment, the oligonucleotide containing the sugar motif is entirely modified in such a way that each nucleoside other than the nucleoside containing the sugar motif contains the sugar modification.

[0253] Nucleobase modifications and motifs

[0254] In a specific embodiment, the compound described herein comprises a modified oligonucleotide. In a specific embodiment, the modified oligonucleotide comprises one or more nucleosides comprising a modified nucleobase. In a specific embodiment, the modified oligonucleotide comprises one or more nucleosides that do not comprise a nucleobase, referred to as a non-base nucleoside.

[0255] In a given embodiment, the modified nucleus is selected from the following: 5-substituted pyrimidine, 6-azapyrimidine, alkyl or alkynyl-substituted pyrimidine, alkyl-substituted purine, and N-2, N-6, and O-6-substituted purine. In a given embodiment, the modified nucleus is selected from the following. 2-aminopropyladenine, 5-hydroxymethylcytosine, 5-methylcytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-N-methylguanine, 6-N-methyladenine, 2-propyladenine, 2-thiouracil, 2-thiothimine and 2-thiocytosine, 5-propynyl(C≡C-CH3)uracil, 5-propynylcytosine, 6-azouracil, 6-azocytosine, 6-azothimine, 5-ribosyluracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl, 8-aza and other 8-substituted purines, 5-halo, particularly, 5-bromo, 5-trifluoromethyl, 5-halouracil, and 5-halocytosine, 7-methylguanine, 7-methyladenine, 2-F-adenine, 2-aminoadenine, 7-deazaguanine, 7-deazadenine, 3-deazaguanine, 3-deazadenine, 6-N-benzoyladenine, 2-N-isobutyrylguanine, 4-N-benzoylcytosine, 4-N-benzoyluracil, 5-methyl 4-N-benzoylcytosine, 5-methyl 4-N-benzoyluracil, universal bases, hydrophobic bases, irregular bases, size-extending bases, and fluorinated bases. Additional modified nuclei include tricyclic pyrimidines, such as 1,3-diazafenoxazine-2-one, 1,3-diazafenothiazine-2-one, and 9-(2-aminoethoxy)-1,3-diazafenoxazine-2-one (G-clamp). Modified nuclei may also include those in which a purine or pyrimidine base is replaced by another heterocycle, such as 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine, and 2-pyridone.

[0256] Additional nucleosides include those described in the following literature: U.S. Patent No. 3,687,808; [Modified Nucleosides in Biochemistry, Biotechnology and Medicine, Herdewijn, P. ed. Wiley-VCH, 2008]; [The Concise Encyclopedia of Polymer Science and Engineering, pages 858-859]; Kroschwitz [JL, Ed., John Wiley & Sons, 1990, 858-859]; Englisch et al. [Angewandte Chemie, International Edition, 1991, 30, 613]; Sanghvi, YS [Chapter 15, dsRNA Research and Applications, pages 289-302]; References [Antisense Research and Applications, Crooke, ST and Lebleu, B., Eds., CRC Press, 1993, 273-288]; References [Antisense Drug Technology, Crooke ST, Ed., CRC Press, 2008, 163-166 and 442-443 (Chapters 6 and 15)], each incorporated herein by reference.

[0257] Public documents teaching the preparation of the specific modified nucleobases and other modified nucleobases described above include, but are not limited to: U.S. Patent Applications No. 2003 / 0158403 and No. 2003 / 0175906, U.S. Patents No. 4,845,205, No. 5,130,302, No. 5,134,066, No. 5,175,273, No. 5,367,066, No. 5,432,272, No. 5,434,257, No. 5,457,187, No. 5,459,255, No. 5,484,908, No. 5,502,177, No. 5,525,711, No. 5,552,540, No. 5,587,469, No. 5,594,121, No. 5,596,091, No. 5,614,617, No. 5,645,985, No. 5,681,941, No. 5,811,534, No. 5,750,692, No. 5,948,903, No. 5,587,470, No. 5,457,191, No. 5,763,588, No. 5,830,653, No. 5,808,027, No. 6,005,096, No. 6,015,886, No. 6,147,200, No. 6,166,197, No. 6,166,199, No. 6,222,025, No. 6,235,887, No. 6,380,368, No. 6,528,640, No. 6,639,062, No. 6,617,438, No. 7,045,610, No. 7,427,672, and No. 7,495,088, the full contents of each of these are incorporated herein by reference.

[0258] In a specific embodiment, the compound described herein comprises an oligonucleotide. In a specific embodiment, the oligonucleotide comprises modified and / or non-modified nucleobases arranged in the form of a pattern or motif defined along the oligonucleotide or a region thereof. In a specific embodiment, each nucleobase is modified. In a specific embodiment, none of the nucleobases are modified. In a specific embodiment, each purine or each pyrimidine is modified. In a specific embodiment, each adenine is modified. In a specific embodiment, each guanine is modified. In a specific embodiment, each thymine is modified. In a specific embodiment, each uracil is modified. In a specific embodiment, each cytosine is modified. In a specific embodiment, some or all of the cytosine nucleobases of the modified oligonucleotide are 5-methylcytosine.

[0259] In a specific embodiment, the modified oligonucleotide comprises a block of modified nucleobases. In such a specific embodiment, the block is located at the 3'-end of the oligonucleotide. In a specific embodiment, the block is located within three nucleosides at the 3'-end of the oligonucleotide. In a specific embodiment, the block is located at the 5'-end of the oligonucleotide. In a specific embodiment, the block is located within three nucleosides at the 5'-end of the oligonucleotide.

[0260] Nucleoside linkage modifications and motifs

[0261] Phosphodiester linkages from 3' to 5' are naturally occurring nucleoside linkages of RNA and DNA. In certain embodiments, the compounds described herein have one or more modified, i.e., non-naturally occurring nucleoside linkages. Certain non-naturally occurring nucleoside linkages can impart desirable properties, such as, for example, enhanced cellular uptake, enhanced affinity for target nucleic acids, and increased stability in the presence of nucleases. Representative phosphorus-containing modified nucleoside linkages include, but are not limited to, phosphotriesters, alkylphosphons (e.g., methylphosphonates), phosphoramidates, and phosphorothioates ("P=S") and phosphorodithioates ("HS-P=S"). Representative non-phosphorus containing nucleoside linkers are methylenemethylimino(-CH2-N(CH3)-O-CH2), thiodiesters, thionocarbamates (-OC(=O)(NH)-S-), and siloxanes (-O-SiH2-O-); and N,N'-dimethylhydrazine (-CH2-N((CH3)-N((CH3)-). Methods for preparing phosphorus-containing and non-phosphorus-containing internucleoside linkages are known to those skilled in the art. Neutral internucleoside linkages include, but are not limited to, phosphotriesters, methylphosphonates, MMI (3'-CH2-N(CH3)-O-5'), amide-3 (3'-CH2-C(=O)-N(H)-5'), amide-4 (3'-CH2-N(H)-C(=O)-5'), formacetal (3'-O-CH2-O-5'), methoxypropyl, and thioformacetal (3'-S-CH2-O-5'). Additional neutral internucleoside linkages include siloxanes (dialkylsiloxanes), carboxylate esters, carboxyamides, sulfides, and sulfonates. It includes nonionic bonds including esters and amides (e.g., the literature [Carbohydrate Modifications in Antisense Research; YS Sanghvi and PD Cook, Eds.[See ACS Symposium Series 580; Chapters 3 and 4, 40-65]). Additional neutral nucleoside bonds include nonionic bonds containing mixed N, O, S, and CH2 component portions.

[0262] In a given embodiment, the compound provided herein comprises at least one modification nucleoside linkage. The modification nucleoside linkage may be located at any position of the oligonucleotide. In the case of a double-stranded compound, the modification nucleoside linkage may be located within the sense oligonucleotide, the antisense oligonucleotide, or both of the oligonucleotides of the double-stranded compound.

[0263] In a specific embodiment, internucleoside linkage modifications may occur on all nucleosides of the oligonucleotide. In a specific embodiment, internucleoside linkage modifications may occur in an alternating pattern along the oligonucleotide. In a specific embodiment, each internucleoside linker is essentially a phosphate internucleoside link (P=O). In a specific embodiment, each internucleoside linker of the modified oligonucleotide is a phosphorothioate (P=S). In a specific embodiment, each internucleoside linker of the modified oligonucleotide is independently selected from phosphorothioate and phosphate internucleoside linkages. In a specific embodiment, the pattern of internucleoside linkage modifications on each oligonucleotide of the double-stranded compound is identical. In a specific embodiment, the pattern of internucleoside linkage modifications on each oligonucleotide of the double-stranded compound is different. In a specific embodiment, the double-stranded compound contains 6 to 8 modified internucleoside linkages. In a specific embodiment, the 6 to 8 modification nucleoside linkages are phosphorothioate nucleoside linkages or alkylphosphonate nucleoside linkages. In a specific embodiment, the sense oligonucleotide comprises at least two modification nucleoside linkages at one or both of the 5'-end and the 3'-end. In this specific embodiment, the modification nucleoside linkages are phosphorothioate nucleoside linkages or alkylphosphonate nucleoside linkages. In a specific embodiment, the antisense oligonucleotide comprises at least two modification nucleoside linkages at one or both of the 5'-end and the 3'-end. In this specific embodiment, the modification nucleoside linkages are phosphorothioate nucleoside linkages or alkylphosphonate nucleoside linkages.

[0264] In a specific embodiment, the double-stranded compound comprises an overhang region. In a specific embodiment, the double-stranded compound comprises a phosphorothioate or alkylphosphonate nucleoside linkage modification in the overhang region. In a specific embodiment, the double-stranded compound comprises a phosphorothioate or alkylphosphonate nucleoside linkage that links an overhang nucleotide to a paired nucleotide adjacent to the overhang nucleotide. For example, there may be at least two phosphorothioate nucleoside linkages between the three terminal nucleosides, two of which are overhang nucleosides, and a third is a paired nucleoside adjacent to these overhang nucleosides. These three terminal nucleosides may be at the 3'-end of an antisense oligonucleotide, the 3'-end of a sense oligonucleotide, the 5'-end of an antisense oligonucleotide, or the 5'-end of an antisense oligonucleotide.

[0265] In a given embodiment, the modified oligonucleotide comprises one or more internucleoside linkages having a chiral center. Representative chiral internucleoside linkages include, but are not limited to, alkylphosphons and phosphorothioates. The modified oligonucleotide comprising internucleoside linkages having a chiral center may be prepared as a group of modified oligonucleotides comprising stereorandom internucleoside linkages, or as a group of modified oligonucleotides comprising phosphorothioate linkages of a specific stereochemical configuration. In a given embodiment, the group of modified oligonucleotides comprises phosphorothioate internucleoside linkages, wherein all phosphorothioate internucleoside linkages are stereorandom. Such modified oligonucleotides may be produced using a synthetic method that randomly selects the stereochemical arrangement of each phosphorothioate linkage. As fully understood by those skilled in the art, each individual phosphorothioate of each individual oligonucleotide molecule has a defined stereoconfiguration. In a specific embodiment, a group of modified oligonucleotides is enriched with modified oligonucleotides comprising one or more specific phosphorothioate nucleoside linkages in a specific independently selected stereochemical configuration. In a specific embodiment, a specific configuration of specific phosphorothioate linkages appears in at least 65% of the molecules in the group. In a specific embodiment, a specific configuration of specific phosphorothioate linkages appears in at least 70% of the molecules in the group. In a specific embodiment, a specific configuration of specific phosphorothioate linkages appears in at least 80% of the molecules in the group. In a specific embodiment, a specific configuration of specific phosphorothioate linkages appears in at least 90% of the molecules in the group. In a specific embodiment, a specific configuration of specific phosphorothioate linkages appears in at least 99% of the molecules in the group.A population enriched with such modified oligonucleotides can be produced using synthetic methods known in the art, for example, the literature of Oka et al. [JACS 125, 8307 (2003)], the literature of Wan et al. [Nuc. Acid. Res. 42, 13456 (2014)], and the method described in WO 2017 / 015555. In a specific embodiment, the population of modified oligonucleotides is enriched with a modified oligonucleotide having at least one indicated phosphorothioate in the (Sp) configuration. In a specific embodiment, the population of modified oligonucleotides is enriched with a modified oligonucleotide having at least one phosphorothioate in the (Rp) configuration.

[0266] connector

[0267] In a specific embodiment, the compound described herein comprises or consists of one or more oligonucleotides and optionally one or more conjugates. The conjugate may be attached to one or both of the ends of the oligonucleotide and / or any internal position. In a specific embodiment, the conjugate is attached to the 3' end of the oligonucleotide. In a specific embodiment, the conjugate is attached to the 5' end of the oligonucleotide. In a specific embodiment, the oligonucleotide is covalently attached to one or more conjugates.

[0268] In a specific embodiment, the conjugate is a terminal group attached to one or both ends of the oligonucleotide. In this specific embodiment, the terminal group is attached to the 3' end of the oligonucleotide. In this specific embodiment, the terminal group is attached to the 5' end of the oligonucleotide. In a specific embodiment, the terminal group comprises, but is not limited to, two or more independently modified or unmodified nucleosides, such as a capping group, a phosphate moiety, a protecting group, a modified or unmodified nucleoside, and an overhang.

[0269] In a given embodiment, the conjugate modifies one or more properties of the attached oligonucleotide, including but not limited to pharmacokinetics, pharmacodynamics, stability, activity, half-life, binding, absorption, tissue distribution, cell distribution, cell uptake, charge, and clearance rate. In some embodiments, the conjugate enhances the affinity of the compound for a selected target, e.g., a molecule, cell or cell type, compartment, e.g., a cell or organ compartment, tissue, organ, or region of the body, compared, for example, with a compound without such conjugate. In a given embodiment, the conjugate imparts new properties to a fluorescent marker or reporter that enables the detection of the attached oligonucleotide, e.g., the oligonucleotide.

[0270] In a given embodiment, the conjugate comprises, but is not limited to, an intercalator, a reporter molecule, a polyamine, a polyamide, a peptide, a carbohydrate, a vitamin moiety, a polyethylene glycol, a thioether, a polyether, cholesterol, a thiocholesterol, a cholinenic acid moiety, folic acid, a lipid, a phospholipid, a biotin, phenazine, phenanthridine, anthraquinone, adamantane, acridine, fluorescein, rhodamine, coumarin, a fluorescent dye, and a dye.

[0271] In a given embodiment, the conjugate comprises an active pharmaceutical ingredient, e.g., aspirin, warfarin, phenylbutazone, ibuprofen, suprofen, fenbufen, ketoprofen, (S)-(+)-pranoprofen, carprofen, dansilsarcosine, 2,3,5-triiodobenzoic acid, fingolimod, flufenamic acid, folinic acid, benzothiadiazide, chlorothiazide, diazepine, indomethicine, barbiturate, cephalosporin, sulfa drug, antidiabetic agent, antimicrobial agent, or antibiotic.

[0272] In a specific embodiment, the conjugate is a targeting moiety. In a specific embodiment, the targeting moiety comprises, but is not limited to, a lectin, glycoprotein, lipid, protein, peptide, peptide mimic, receptor ligand, antibody, thyrotrophin, melanotrophin, surfactant protein A, carbohydrate, carbohydrate derivative, modified carbohydrate, carbohydrate cluster, polysaccharide, modified polysaccharide, or polysaccharide derivative, mucin carbohydrate, polylactose, polygalactose, N-acetylgalactosamine (GalNAc), N-acetylglucosamine, polymannose, polyfucose, glycosylated polyamino acid, polygalactose, transferrin, bisphosphonate, polyglutamate, polyaspartate, lipid, cholesterol, steroid, bile acid, folic acid, vitamin B12, vitamin A, biotin, or RGD peptide or RGD peptide mimic.

[0273] In a given embodiment, the conjugate comprises, but is not limited to, the conjugates described in the following references: e.g., cholesterol (e.g., Letsinger et al. [Proc. Natl. Acid. Sci. USA, 1989, 86: 6553-6556]), choline acid (e.g., Manoharan et al. [Biorg. Med. Chem. Let., 1994, 4:1053-1060]), thioether, e.g., hexyl-S-tritylthiol (e.g., Manoharan et al. [Ann. NY. Acad. Sci., 1992, 660:306-309]; Manoharan et al. [Biorg. Med. Chem. Let., 1993, 3:2765-2770]), thiocholesterol (e.g., Oberhauser et al. [Nucl. Acids Res., 1992, 20:533-538]), aliphatic chains, e.g., do-decane-diol or undecyl residues (e.g., Saison-Behmoaras et al. [EMBO J, 1991, 10:1111-1118], Kabanov et al. [FEBS Lett., 1990, 259:327-330], Svinarchuk et al. [Biochimie, 1993, 75:49-54]), phospholipids, e.g., di-hexadecyl-rac-glycerol or triethyl-ammonium 1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate (e.g., Manoharan et al. [Tetrahedron Lett., 1995, 36:3651-3654], Shea et al. [Nucl. Acids [Res., 1990, 18:3777-3783]), polyamine or polyethylene glycol chains (e.g., Manoharan et al. [Nucleosides & Nucleotides, 1995, 14:969-973]), adamantane acetic acid (e.g., Manoharan et al. [Tetrahedron Lett., 1995, 36:3651-3654]), palmityl (e.g., Mishra et al. [Biochim.Biophys. Acta, 1995, 1264:229-237]), octadecylamine or hexylamino-carbonyloxycholesterol moiety (e.g., Crooke et al. [J. Pharmacol. Exp. Ther., 1996, 277:923-937]), tocopherol (e.g., Nishina et al. [Molecular Therapy Nucleic Acids, 2015, 4, e220] and Nishina et al. [Molecular Therapy, 2008, 16:734-740]), GalNAc and other carbohydrates (e.g., Maier et al. [Bioconjugate Chemistry, 2003, 14, 18-29], Rensen et al. [J. Med. Chem. 2004, 47, 5798-5808], WO2009 / 073809 and U.S. Patents No. 8,106,022; No. 8,450,467 and No. 8,828,957; and WO2014 / 179445; WO2014 / 179620 and U.S. Patents No. 9,127,276, No. 9,181,549 and No. 10,844,379), the full contents of each of these are incorporated herein by reference.

[0274] The conjugate may be attached to an oligonucleotide via a conjugate linker. In a specific embodiment, the conjugate linker comprises a chain structure, such as a hydrocarbyl chain, or an oligomer of repeating units, or a combination of such repeating units. In a specific embodiment, the conjugate linker comprises one or more groups selected from alkyl, amino, oxo, amide, disulfide, polyethylene glycol, ether, thioether, and hydroxylamino. In a specific embodiment, the conjugate linker comprises at least one phosphorus group. In a specific embodiment, the conjugate linker comprises at least one phosphate group. In a specific embodiment, the conjugate linker comprises at least one neutral linker. In a specific embodiment, the conjugate linker comprises, but is not limited to, pyrrolidine, 8-amino-3,6-dioxaoctanic acid (ADO), succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), and 6-aminohexanoic acid (AHEX or AHA). Other junctional linkers are substituted or non-substituted C1-C 10 Alkyl, substituted, or unsubstituted C2-C 10 Alkenyl, or substituted or non-substituted C2-C 10A non-limiting list of preferred substituents, including but not limited to alkynyl, comprises hydroxyl, amino, alkoxy, carboxyl, benzyl, phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl, alkenyl, and alkynyl. In a given embodiment, the conjugated linker comprises 1 to 10 linker-nucleosides. In a given embodiment, these linker-nucleosides may be modified or unmodified nucleosides. Generally, it is desirable for the linker-nucleosides to be cleaved from the compound after reaching the target tissue. Thus, the linker-nucleosides of the present invention may be linked to each other via cleaving bonds and may also be linked to the remainder of the compound. In the present invention, the linker-nucleosides are not considered to be part of the oligonucleotide. Accordingly, in an embodiment in which a compound comprises an oligonucleotide consisting of a specified number or range of linked nucleosides and / or a specified percentage of complementarity with respect to a reference nucleic acid, and the compound also comprises a conjugate comprising a conjugate linker comprising a linker-nucleoside, such linker-nucleosides are not counted as the length of the oligonucleotide and are not used to determine the percentage of complementarity of the oligonucleotide with respect to the reference nucleic acid.

[0275] In a given embodiment, the bonder and bonding linker, as well as other variations, include but are not limited to those described in the following references: U.S. Patent No. 5,994,517, U.S. Patent No. 6,300,319, U.S. Patent No. 6,660,720, U.S. Patent No. 6,906,182, U.S. Patent No. 7,262,177, U.S. Patent No. 7,491,805, U.S. Patent No. 8,106,022, U.S. Patent No. 7,723,509, U.S. Patent No. 9,127,276, U.S. Patent No. 2006 / 0148740, U.S. Patent No. 2011 / 0123520, WO2013 / 033230, WO2012 / 037254, and the work of Biessen et al. [J. Med. Chem. 1995, 38, 1846-1852]; Lee et al. [Bioorganic & Medicinal Chemistry 2011, 19, 2494-2500]; Rensen et al. [J. Biol. Chem. 2001, 276, 37577-37584]; Rensen et al. [J. Med. Chem. 2004, 47, 5798-5808]; Sliedregt et al. [J. Med. Chem. 1999, 42, 609-618]; Valentijn et al. [Tetrahedron, 1997, 53, 759-770]; Lee [Carhohydr Res, 1978, 67, 509-514]; Connolly et al. [J Biol Chem, 1982, 257, 939-945]; Pavia et al. [Int J Pep Protein Res, 1983, 22, 539-548]; Lee et al. [Biochem, 1984, 23, 4255-4261]; Lee et al. [Glycoconjugate J, 1987, 4, 317-328]; Toyokuni et al. [Tetrahedron Lett, 1990, 31, 2673-2676]; Biessen et al. [J Med Chem, 1995, 38, 1538-1546];Valentijn et al. [Tetrahedron, 1997, 53, 759-770]; Kim et al. [Tetrahedron Lett, 1997, 38, 3487-3490]; Lee et al. [Bioconjug Chem, 1997, 8, 762-765]; Kato et al. [Glycohiol, 2001, 11, 821-829]; Rensen et al. [J Biol Chem, 2001, 276, 37577-37584]; Lee et al. [Methods Enzymol, 2003, 362, 38-43]; Westerlind et al. [Glycoconj J, 2004, 21, 227-241]; Lee et al. [Bioorg Med Chem Lett, 2006, 16(19), 5132-5135]; Maierhofer et al. [Bioorg Med Chem, 2007, 15, 7661-7676]; Khorev et al. [Bioorg Med Chem, 2008, 16, 5216-5231]; Lee et al. [Bioorg Med Chem, 2011, 19, 2494-2500]; Kornilova et al. [Analyt Biochem, 2012, 425, 43-46]; Pujol et al. [Angew Chemie Int Ed Engl, 2012, 51, 7445-7448]; Biessen et al. [J Med Chem, 1995, 38, 1846-1852]; Sliedregt et al. [J Med Chem, 1999, 42, 609-618]; Rensen et al. [J Med Chem, 2004, 47, 5798-5808]; Rensen et al. [Arterioscler Thromh Vase Biol, 2006, 26, 169-175]; van Rossenberg et al. [Gene Ther, 2004, 11, 457-464]; Sato et al. [JAm Chem Soc, 2004, 126, 14013-14022];Lee et al. [J Org Chem, 2012, 77, 7564-7571]; Biessen et al. [FASEB J, 2000, 14, 1784-1792]; Rajur et al. [Bioconjug Chem, 1997, 8, 935-940]; Duff et al. [Methods Enzymol, 2000, 313, 297-321]; Maier et al. [Bioconjug Chem, 2003, 14, 18-29]; Jayaprakash et al. [Org Lett, 2010, 12, 5410-5413]; Manoharan [Antisense Nucleic Acid Drug Dev, 2002, 12, 103-128]; Merwin et al. [Bioconjug Chem, 1994, 5, 612-620]; Tomiya et al. [Bioorg Med Chem, 2013, 21, 5275-5281]; International patent applications WO1998 / 013381; WO2011 / 038356; WO1997 / 046098; WO2008 / 098788; WO2004 / 101619; WO2012 / 037254; WO2011 / 120053; WO2011 / 100131; WO2011 / 163121; WO2012 / 177947; WO2013 / 033230; WO2013 / 075035; WO2012 / 083185; WO2012 / 083046; WO2009 / 082607; WO2009 / 134487; WO2010 / 144740; WO2010 / 148013; WO1997 / 020563; WO2010 / 088537; WO2002 / 043771; WO2010 / 129709; WO2012 / 068187; WO2009 / 126933; WO2004 / 024757; WO2010 / 054406; WO2012 / 089352; WO2012 / 089602; WO2013 / 166121; WO2013 / 165816; U.S. Patent No. 4,751,219; No. 7,582,744; No. 8,552,163; No. 8,137,695;No. 6,908,903; No. 6,383,812; No. 7,262,177; No. 6,525,031; No. 5,994,517; No. 6,660,720; No. 6,300,319; No. 7,723,509; No. 8,106,022; No. 7,491,805; No. 7,491,805; No. 8,541,548; No. 8,344,125; No. 8,313,772; No. 8,349,308; No. 8,450,467; No. 8,501,930; No. 8,158,601; No. 7,262,177; No. 6,906,182; No. 6,620,916; No. 8,435,491; No. 8,404,862; No. 7,851,615; Published U.S. Patent Applications US2011 / 0097264; US2011 / 0097265; US2013 / 0004427; US2003 / 0119724; US2011 / 0207799; US2012 / 0035115; US2012 / 0230938; US2005 / 0164235; US2006 / 0183886; US2012 / 0136042; US2012 / 0095075; US2013 / 0109817; US2006 / 0148740; US2008 / 0206869; US2012 / 0165393; US2012 / 0101148; US2013 / 0121954; US2011 / 0123520; US2003 / 0077829; US2008 / 0108801; and US2009 / 0203132; the full contents of each of these are incorporated herein by reference.;

[0276] Specific targeting moiety

[0277] In a specific embodiment, the compound provided herein comprises a conjugate. In a specific embodiment, the oligonucleotide provided herein comprises a conjugate. In a specific embodiment, the conjugate is a targeting moiety. In a specific embodiment, the targeting moiety comprises one or more GalNAcs. In a specific embodiment, one or more GalNAcs are attached to one or more positions on the furanose ring. In a specific embodiment, one or more GalNAcs are attached to the 2' or 3' position of the furanose ring. In a specific embodiment, the furanose ring is a subunit of the oligonucleotide. In a specific embodiment, the furanose ring is the 5' nucleoside sugar of the oligonucleotide. In a specific embodiment, the furanose ring is the 5' nucleoside sugar of the sense oligonucleotide. In a specific embodiment, the compound or oligonucleotide comprises one or more subunits having the following chemical formula, or a salt, solvate, or hydrate thereof:

[0278]

[0279] During the meal:

[0280] R 1 is H, adenine, guanine, thymine, cytosine, uracil, carbocyclil, heterocyclil, aryl, heteroaryl, or a nucleobase isostere;

[0281] R 2 is an oligonucleotide sequence;

[0282] L 1 is alkyl, or alkyl-C(=O)-NH-alkyl;

[0283] L 2 is an alkyl, or an alkyl-C(=O)-NH-alkyl;

[0284] L 3It is a bond, phosphodiester bond, phosphorothioate bond, triazole, tetrazole, amide, reverse-amide, carbamate, carbonate, urea, O, S, S(=O), S(=O)2, NH, substituted N group, alkyl, alkenyl, dienyl, alkynyl, heteroalkyl, phosphate;

[0285] R 3 H, -C=(O)-NH-(CH2CH2O) j -GalNAc, or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc;

[0286] R 4 is H, -C=(O)-NH-(CH2CH2O) k -GalNAc, or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc;

[0287] R 5 -C=(O)-NH-(CH2CH2O) m -GalNAc, or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc;

[0288] R 6 -C=(O)-NH-(CH2CH2O) n -GalNAc, or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc;

[0289] W and Q are each independently O, NH, CH2, or CH2O;

[0290] S 1 and S 2 Each is independently C(R 7 ) or N, provided that in each case, R 7 is independently H, alkyl, heteroalkyl, or halogen;

[0291] j is an integer from 1 to 10 (including the endpoint);

[0292] k is an integer from 1 to 10 (including the endpoint);

[0293] m is an integer from 1 to 10 (including the endpoint);

[0294] n is an integer from 1 to 10 (including the end point).

[0295] In a given embodiment, R 3 , R 4 , R 5 , and R 6 is identical. In a given embodiment, R 3 , R 5 , and R 6 is identical. In a given embodiment, R 3 or R 4 is H.

[0296] In a given embodiment, L 1 and L 2 is the same.

[0297] In a given embodiment, L 1 and L 2 are each independently alkyl; R 3 H, -C=(O)-NH-(CH2CH2O) j -GalNAc, or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc and; R 4 is H, -C=(O)-NH-(CH2CH2O) k -GalNAc, or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc and; R 5 -C=(O)-NH-(CH2CH2O) m -GalNAc, or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc and; R 6 -C=(O)-NH-(CH2CH2O) n It is -GalNAc, or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc.

[0298] In a given embodiment, L 1 and L 2 are each independently alkyl-C(=O)-NH-alkyl; R 3 H, -C=(O)-NH-(CH2CH2O) j-GalNAc, or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc and; R 4 is H, -C=(O)-NH-(CH2CH2O) k -GalNAc, or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc and; R 5 Is

[0299] -C=(O)-NH-(CH2CH2O) m -GalNAc, or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc and; R 6 -C=(O)-NH-(CH2CH2O) n It is -GalNAc, or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc.

[0300] In a given embodiment, R 4 is H.

[0301] In a given embodiment, L 1 and L 2 are each independently alkyl; R 3 -C=(O)-NH-(CH2CH2O) j -GalNAc, or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc and; R 4 is H and; R 5 -C=(O)-NH-(CH2CH2O) m -GalNAc, or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc and; R 6 -C=(O)-NH-(CH2CH2O) n It is -GalNAc, or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc.

[0302] In a given embodiment, L 1 and L 2 are each independently alkyl-C(=O)-NH-alkyl; R 3 silver

[0303] -C=(O)-NH-(CH2CH2O) j-GalNAc, or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc and; R 4 is H and; R 5 -C=(O)-NH-(CH2CH2O) m -GalNAc, or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc and; R 6 -C=(O)-NH-(CH2CH2O) n It is -GalNAc, or -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc.

[0304] In a given embodiment, R 3 -C=(O)-NH-(CH2CH2O) j -GalNAc and; R 4 is H and; R 5 -C=(O)-NH-(CH2CH2O) m -GalNAc and; R 6 -C=(O)-NH-(CH2CH2O) n -GalNAc.

[0305] In a given embodiment, R 3 is -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc and R 4 is H and; R 5 is -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc and R 6 It is -C(=O)-NH-alkyl-NH-C(=O)-alkyl-O-GalNAc.

[0306] In a given embodiment, the compound or oligonucleotide comprises one or more subunits having the following chemical formula, or a salt, solvate, or hydrate thereof:

[0307]

[0308] During the meal:

[0309] R 9is H, adenine, guanine, thymine, cytosine, or uracil, or adenine, guanine, thymine, cytosine, or uracil, each comprising a protecting group (PG), a modified nucleobase, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted carbocyclyl, an optionally substituted heterocyclyl, or a nucleobase isopair electron;

[0310] L is a bond, a phosphodiester bond, a phosphorothioate bond, a triazole, a tetrazole, an amide, an inverse amide, a carbamate, a carbonate, an urea, an alkyl, or a heteroalkyl;

[0311] R 2 is an oligonucleotide sequence;

[0312] Y1 is O, CH2, CH2O, or arbitrarily substituted NH;

[0313] Y2 is O, CH2, CH2O, or arbitrarily substituted NH;

[0314] Y3 is CO, SO2, P(O)O, CH2-OC(O), CH2-NH-C(O), CH2-NH-SO2, or CH2;

[0315] Y4 is CO, SO2, P(O)O, CH2-OC(O), CH2-NH-C(O), CH2-NH-SO2, or CH2;

[0316] n2 is 0, 1, 2, 3, 4, 5, or 6;

[0317] Each of n1, n3, n4, and n5 is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0318] In a given embodiment, the compound or oligonucleotide comprises one or more subunits having the following chemical formula, or a salt, solvate, or hydrate thereof:

[0319]

[0320] During the meal:

[0321] Each n is independently 1, 2, 3, 4, or 5;

[0322] Each m is independently 0, 1, 2, 3, 4, 5, or 6;

[0323] Each o is independently 0, 1, 2, 3, 4, 5, or 6;

[0324] Each of L1, L2, and L3 is independently absent, C(=O), or C(=O)NH;

[0325] Each Y1 is independently O, CH(R a ), S, S(=O), S(=O)2, NH, substituted N group, NHC(=O), C(=O)NH, P(=O)2-O-, P(=O)(=S)-O, P(=S)2-O, -OP(=O)2-O-, -OP(=O)(=S)-O-, -OP(=S)2-O-, -OP(=O)2-, -OP(=O)(=S)-, -OP(=S)2- and;

[0326] Each Y2 is independently O, CH(R b ), S, S(=O), S(=O)2, NH, substituted N group, NHC(=O), C(=O)NH, P(=O)2-O-, P(=O)(=S)-O, P(=S)2-O, -OP(=O)2-O-, -OP(=O)(=S)-O-, -OP(=S)2-O-, -OP(=O)2-, -OP(=O)(=S)-, -OP(=S)2- and;

[0327] Each of Het1, Het2, and Het3 is independently an arbitrarily substituted heteroaryl or an arbitrarily substituted heterocyclyl;

[0328] R 1 It is an oligonucleotide sequence linked via a bond, phosphodiester bond, phosphorothioate bond, triazole, tetrazole, amide, reverse-amide, carbamate, carbonate, urea, alkyl, or heteroalkyl;

[0329] Each of R5, R6, and R7 is independently And;

[0330] R9 is an arbitrarily substituted heterocyclyl;

[0331] Each R a is independently H, alkyl, halo, OR c , or SR c And;

[0332] Each R b is independently H, alkyl, halo, OR c , or SR c And;

[0333] Each R c is independently H or alkyl.

[0334] In a specific embodiment, the subunit is selected from formulas I to VIII, or a salt, solvate, or hydrate thereof, wherein R is a modified oligonucleotide other than a 5' nucleoside. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has formula I, and R' is O. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has formula I, and R' is S. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has formula II, and R' is O. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has formula II, and R' is S. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has formula III, and R' is O. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has formula III, and R' is S. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has formula IV, and R' is O. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula IV, and R' is S. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula V, and R' is O. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula V, and R' is S. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula VI, and R' is O. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula VI, and R' is S. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula VII, and R' is O. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula VII, and R' is S. In a specific embodiment, the 5' nucleoside of the modified oligonucleotide has the chemical formula VIII, and R' is O. In a given embodiment, the 5' nucleoside of the modified oligonucleotide is of the chemical formula VIII, and R' is S.

[0335] Target nucleic acid and target area

[0336] In a specific embodiment, the compound described herein comprises or consists of an oligonucleotide containing a region complementary to the target nucleic acid. In a specific embodiment, the target nucleic acid is an endogenous RNA molecule. In a specific embodiment, the target nucleic acid encodes a protein. In a specific embodiment, the target nucleic acid is not coded. In this specific embodiment, the target nucleic acid is selected from mRNA and pre-mRNA comprising introns, exons, and untranslated regions. In a specific embodiment, the target RNA is mRNA. In a specific embodiment, the target nucleic acid is pre-mRNA. In this specific embodiment, the target region is entirely within an exon. In this specific embodiment, the target region is entirely within an intron. In a specific embodiment, the target region spans an intron / exon junction. In a specific embodiment, at least 50% of the target region is within an intron.

[0337] In a specific embodiment, the compound disclosed herein hybridizes with a CFB nucleic acid. The most common mechanism of hybridization involves hydrogen bonding between complementary nucleobases of a nucleic acid molecule. Hybridization can occur under various conditions. Hybridization conditions are sequence-dependent and are determined by the properties and composition of the nucleic acid molecule to be hybridized. Methods for determining whether a sequence specifically hybridizes to a target nucleic acid are known in the art. In a specific embodiment, the compound provided herein specifically hybridizes with a CFB nucleic acid.

[0338] The nucleotide sequence encoding CFB includes, but is not limited to: GenBank accession number NM_001710.6 (incorporated herein as SEQ NO. 1), nucleotides 31946095 to 31952084 of GenBank accession number NC_000006.12 (incorporated herein as SEQ NO. 2), GenBank accession number NM_001710.6 (incorporated herein as SEQ NO. 3), and nucleotides 3423522 to 3429511 of GenBank accession number NT_113891.3 (incorporated herein as SEQ NO. 4).

[0339] Complementarity

[0340] The oligonucleotides provided herein may have a defined percentage of complementarity with respect to a specific nucleic acid, target region, oligonucleotide, or portion thereof. Non-complementary nucleotides may be permitted as long as the oligonucleotide is maintained in a state where it can specifically hybridize to the nucleic acid, oligonucleotide, or portion thereof. In a given embodiment, the oligonucleotide provided herein or a specific portion thereof is at least or up to 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% complementary to the target nucleic acid, target region, oligonucleotide, or a specific portion thereof. In a given embodiment, the oligonucleotide or a specific portion thereof provided herein is complementary to the target nucleic acid, target region, oligonucleotide or a specific portion thereof by 70% to 75%, 75% to 80%, 80% to 85%, 85% to 90%, 90% to 95%, 95% to 100%, or any degree between these ranges. The percentage of complementarity between the target nucleic acid, target region, oligonucleotide or a specific portion thereof and the oligonucleotide can be determined using conventional methods. For example, if 18 of the 20 nucleotides of the oligonucleotide are complementary to the target region, the specifically hybridized oligonucleotide exhibits 90% complementarity. In this example, the remaining non-complementary nucleotides may be clustered or interspersed among the complementary nucleotides and do not need to be continuous with respect to each other or to the complementary nucleotides. Therefore, an oligonucleotide of 18 nucleotides in length having 4 non-complementary nucleotides flanked by 2 regions that are completely complementary to the target nucleic acid has 77.8% total complementarity with the target nucleic acid.The percentage of complementarity between a region of the target nucleic acid, the target region, the oligonucleotide, or a specific part thereof and the oligonucleotide can typically be determined using a BLAST program (a basic local alignment search tool) known in the art. In certain embodiments, the oligonucleotide or a specific part thereof described herein is fully complementary (i.e., 100% complementary) to the target nucleic acid, the target region, the oligonucleotide, or a specific part thereof. For example, the oligonucleotide may be fully complementary to the target nucleic acid, the target region, the oligonucleotide, or a specific part thereof. As used herein, "fully complementary" means that each nucleobase of the corresponding oligonucleotide is complementary to the corresponding nucleobase of the target nucleic acid, the target region, the oligonucleotide, or a specific part thereof. For example, a 20-nucleobase oligonucleotide is fully complementary to a target sequence of 400 nucleobase length insofar as there is a corresponding 20-nucleobase portion of the target nucleic acid that is fully complementary to the compound. "Completely complementary" may also be used in relation to specific parts of the first and / or second nucleic acids. For example, a 20-nucleotide portion of a 30-nucleotide oligonucleotide may be "completely complementary" to a 20-nucleotide region of a target sequence that is 400 nucleotides long. A 20-nucleotide portion of such a 30-nucleotide compound is completely complementary to the target sequence if the target sequence has a corresponding 20-nucleotide portion, where each nucleotide is complementary to the 20-nucleotide portion of the compound. At the same time, the entire 30-nucleotide compound may or may not be completely complementary to the target sequence, depending on whether the remaining 10 nucleotides of the compound are also complementary to the target sequence.

[0341] In a specific embodiment, the oligonucleotide described herein comprises one or more mismatched nucleotides with respect to the target nucleic acid, target region, oligonucleotide, or a specific portion thereof. In a specific embodiment, the oligonucleotide described herein, which is a nucleotide of length 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23, or at most the length thereof, comprises four or fewer, three or fewer, two or fewer, or one or fewer non-complementary nucleotides with respect to the target nucleic acid or a specific portion thereof. In a specific embodiment, the oligonucleotide described herein, which is a length of 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides or a maximum length thereof, comprises six or fewer, five or fewer, four or fewer, three or fewer, two or fewer, or one or fewer non-complementary nucleotide(s) relative to the target nucleic acid, target region, oligonucleotide, or a specific portion thereof. In a specific embodiment, the mismatch is present at position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 from the 5'-end of the oligonucleotide. In a specific embodiment, the mismatch is located at positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, 13, or 14 from the 3'-end of the oligonucleotide. In a specific embodiment, the mismatch forms a wobble base pair with a corresponding nucleobase on the target nucleic acid. For example, in a specific embodiment, the mismatch forms a wobble base pair selected from hypoxanthine (a nucleobase of inosine) and uracil (I:U base pair); guanine and uracil (G:U base pair); hypoxanthine and adenine (I:A base pair); and hypoxanthine and cytosine (I:C base pair). Accordingly, in a specific embodiment, the mismatch nucleobase on the oligonucleotide comprises hypoxanthine, guanine, or uracil.

[0342] In a specific embodiment, the oligonucleotide described herein may be complementary to a portion of the nucleic acid. As used herein, “part” refers to a defined number of consecutive nucleotides within a region of the nucleic acid. “Part” may also refer to a defined number of consecutive nucleotides of the oligonucleotide. In a specific embodiment, the oligonucleotide is complementary to at least eight nucleotide portions of the nucleic acid. In a specific embodiment, the oligonucleotide is complementary to at least nine nucleotide portions of the nucleic acid. In a specific embodiment, the oligonucleotide is complementary to at least ten nucleotide portions of the nucleic acid. In a specific embodiment, the oligonucleotide is complementary to at least eleven nucleotide portions of the nucleic acid. In a specific embodiment, the oligonucleotide is complementary to at least twelve nucleotide portions of the nucleic acid. In a specific embodiment, the oligonucleotide is complementary to at least thirteen nucleotide portions of the nucleic acid. In a specific embodiment, the oligonucleotide is complementary to at least fourteen nucleotide portions of the nucleic acid. In a specific embodiment, the oligonucleotide is complementary to at least 15 nucleobase portions of the nucleic acid. In a specific embodiment, the oligonucleotide is complementary to at least 16 nucleobase portions of the nucleic acid. Additionally, an oligonucleotide is considered to be complementary to at least 9, 10, 17, 18, 19, 20, 21, 22, 23 or more nucleobase portions of the nucleic acid, or to a range defined by any two of these values. In a specific embodiment, the oligonucleotide is an antisense oligonucleotide. In a specific embodiment, a portion of the antisense oligonucleotide is compared to a portion of the target nucleic acid of the same length. In a specific embodiment, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobase portions are compared with a portion of the same length of the target nucleic acid. In a specific embodiment, the oligonucleotide is a sense oligonucleotide.In a specific embodiment, a portion of the sense oligonucleotide is compared with a portion of the same length of the antisense oligonucleotide. In a specific embodiment, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobase portions of the sense oligonucleotide are compared with a portion of the same length of the antisense oligonucleotide.

[0343] sameness

[0344] The oligonucleotides provided herein may also have a defined percentage of identity with respect to a specific nucleic acid, target region, oligonucleotide, or a specific portion thereof. As used herein, if an oligonucleotide has the same nucleobase pairing ability, it is identical to the sequence disclosed herein. For example, DNA containing thymidine instead of uracil in the disclosed RNA sequence will be considered identical to the disclosed RNA sequence, since both uracil and thymidine pair with adenine. Shortened and extended versions of compounds having bases that are not identical to the compounds provided herein, as well as the compounds described herein, are also considered. Non-identical bases may be adjacent to one another or distributed throughout the compounds. The percentage of identity of an oligonucleotide is counted according to the number of bases having the same base pairing ability with respect to the sequence being compared. In a specific embodiment, the oligonucleotide or a portion thereof described herein is identical to, or at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to, one or more nucleic acids, oligonucleotides, or portions thereof disclosed herein. In a specific embodiment, the oligonucleotide described herein is about 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to, or any percentage between these values.

[0345] In a specific embodiment, the oligonucleotide may have one or more mismatched nucleobases. In a specific embodiment, such mismatches are located at positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 from the 5'-end of the oligonucleotide. In a specific embodiment, such mismatches are located at positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, 13, or 14 from the 3'-end of the oligonucleotide. In a specific embodiment, a portion of the oligonucleotide is compared to a portion of the same length of the target nucleic acid. In a specific embodiment, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobase portions are compared with a portion of the same length of the target nucleic acid. In a specific embodiment, the oligonucleotide is a sense oligonucleotide. In a specific embodiment, a portion of the sense oligonucleotide is compared with a portion of the same length of the target nucleic acid. In a specific embodiment, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobase portions are compared with a portion of the same length of the target nucleic acid.

[0346] Pharmaceutical compositions and formulations

[0347] The compounds described herein may be mixed with pharmaceutically acceptable active or inactive substances for the preparation of pharmaceutical compositions or formulations. The composition and the method of formulation of the pharmaceutical composition depend on a number of criteria, which include, but are not limited to, the route of administration, the severity of the disease, or the dosage to be administered. Certain embodiments provide a pharmaceutical composition comprising one or more compounds or salts thereof. In certain embodiments, the compound is an antisense oligonucleotide. In certain embodiments, the compound is an oligomeric compound. In certain embodiments, the compound comprises or consists of one or more modified oligonucleotides. In these specific embodiments, the pharmaceutical composition comprises one or more compounds and a pharmaceutically acceptable diluent or carrier suitable therefor. In certain embodiments, the pharmaceutical composition comprises one or more compounds and sterile saline. In certain embodiments, such a pharmaceutical composition consists of one or more compounds and sterile saline. In certain embodiments, the sterile saline is pharmaceutical-grade saline. In certain embodiments, the pharmaceutical composition comprises one or more compounds and sterile water. In a specific embodiment, the pharmaceutical composition comprises one compound and sterile water. In a specific embodiment, the sterile water is pharmaceutical-grade water. In a specific embodiment, the pharmaceutical composition comprises one or more compounds and phosphate-buffered saline (PBS). In a specific embodiment, the pharmaceutical composition comprises one compound and sterile PBS. In a specific embodiment, the sterile PBS is pharmaceutical-grade PBS.

[0348] The compounds described herein targeted for CFB may be utilized in pharmaceutical compositions by combining said compounds with a suitable pharmaceutically acceptable diluent or carrier. In a specific embodiment, the pharmaceutically acceptable diluent is water, e.g., sterile water suitable for injection. Thus, in one embodiment, a pharmaceutical composition comprising a compound targeted for CFB and a pharmaceutically acceptable diluent is used in the method described herein. In a specific embodiment, the pharmaceutically acceptable diluent is water. In a specific embodiment, the compound comprises or consists of one or more of the modified oligonucleotides provided herein.

[0349] A pharmaceutical composition comprising the compound provided herein comprises any pharmaceutically acceptable salt, ester, or salt of such ester, or any other oligonucleotide that, upon administration to an animal including humans, may provide (directly or indirectly) a biologically active metabolite or a residue thereof. In a specific embodiment, the compound is an antisense oligonucleotide. In a specific embodiment, the compound is an oligomeric compound. In a specific embodiment, the compound comprises or consists of one or more modified oligonucleotides. Thus, for example, the present disclosure also relates to a pharmaceutically acceptable salt of the compound, a prodrug, a pharmaceutically acceptable salt of such prodrug, and other biological equivalents. Suitable pharmaceutically acceptable salts include, but are not limited to, sodium salts and potassium salts. The prodrug may comprise a form in which an additional nucleoside is incorporated into one or both of the ends of the compound cleaved by an endogenous nuclease in the body to form an active compound. In a specific embodiment, the compound or composition further comprises a pharmaceutically acceptable carrier or diluent.

[0350] Examples

[0351] The following example describes a method for characterizing the compound RD2830 targeted for CFB.

[0352] In the following examples and the list of related sequences submitted with this application, the sequences are referred to as "RNA " Alternatively, they may be specified as “DNA,” but as disclosed herein, these sequences may be modified through any combination of chemical modifications. Those skilled in the art will readily recognize that designating any sequence as “RNA” or “DNA” is optional in certain cases. For example, an oligonucleotide comprising a nucleoside containing a 2’-OH sugar moiety and a thymine base may be described as DNA having a modified sugar (2’-OH in the case of the natural 2’-H of DNA) or as RNA having a modified base (methylated uracil in the case of the natural uracil of RNA). Accordingly, nucleic acid sequences provided herein, including but not limited to the sequences presented in the sequence list, are intended to include nucleic acids containing any combination of natural or modified RNA and / or DNA, including but not limited to the corresponding nucleic acid having a modified nucleobase.

[0353] Each document cited in this application is incorporated herein by reference in its entirety.

[0354] Abbreviations for chemical modifications are provided in Table 1. IA and IS identify the antisense strand and sense strand, respectively.

[0355]

[0356] Example 1: Compound RD2830

[0357] The unmodified and modified antisense and sense sequences of compound RD2830 are presented below.

[0358]

[0359] Example 2: Effects of RD2830 on Synomolgus Monkeys

[0360] Compound RD2830 was evaluated in cynomolgus monkeys. Prior to the study, the monkeys were isolated, and their general health status was monitored daily. On Day 1 of the study, a single subcutaneous dose of 4 mg / kg was injected into each of the two cynomolgus monkeys. During the study period, signs of disease or pain were observed daily in the monkeys. Blood samples were collected from the animals on Days 1 (before administration), 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 85, and 96.

[0361] In addition, complement factor B (CFB) levels in the serum of cynomolgus monkeys were evaluated using immunoblotting. After serum collection, the serum was diluted in 1 X PBS buffer and mixed with loading buffer and reducing agents suitable for SDS-PAGE. The samples were heated to 70°C for 10 minutes and analyzed by SDS-PAGE. After the samples were phoretically transferred through the pAGE, the proteins were transferred to nitrocellulose or other suitable membranes. The membranes were stained with Revert 700, and the total protein of each sample was quantified using an Odyssey CLx detection system.

[0362] The membrane was blocked with Intercept® blocking buffer (P / N: 927-60001) and then probed with a primary antibody specific to CFB (ProteinTech, catalog number 10170-1-AP). The antibody was diluted with Intercept® antibody diluent (P / N: 927-75001). After incubating the membrane with the primary antibody, the membrane was washed and then probed with a secondary antibody (IgG P / N: 926-32211). The antibody was diluted with Intercept® antibody diluent (P / N: 927-75001). Subsequently, the membrane was analyzed on an Odyssey CLx detection system to determine the CFB levels of each sample. The data for each sample were normalized to the total protein loaded in each lane, and the CFB levels were quantified using Image Studio Lite. The CFB inhibition data shown in the table below are presented as the percentage change from the pre-administration level.

[0363]

[0364] Inhibition of alternative complement pathway activity was evaluated using the WIESLAB assay (COMPL AP330) according to the protocol recommended by the manufacturer. The table below provides the corresponding data.

[0365]

[0366] Inhibition of replacement hemolysis was evaluated as follows using 5.6% serum, 25% Er (Complement Technologies, Inc.), and buffer GVB° + MgEDTA. NHP serum (5.6%) was added to 5 mM EGTA (Er, Complement Technology, Tyler, Texas) containing GVB° (Complement Technology, Tyler, Texas) and 25% rabbit erythrocytes. The samples were incubated at 37°C for 1 hour with intermittent shaking. Hemolysis was stopped by adding GVBE (Complement Technology, Tyler, Texas) to the samples in a 1:1 ratio. Subsequently, the samples were centrifuged, and the supernatant was transferred to a new 96-well plate. Absorbance was measured at 412 nm. Replacement hemolytic activity was determined by subtracting the OD value from the negative control samples (buffer and Er alone) and normalizing each sample to the positive control samples (water and Er alone). Next, samples at individual time points were normalized with respect to the average pre-administration sample and are presented in the table below.

[0367]

[0368] Example 3: Effects of RD2830 in Spragg-Dowley rats

[0369] Sprague-Dowley rats (8–9 weeks of age, main test group: 3 males and 3 females per group (groups 1–5), toxicokinetic test group: 1 male and 1 female per group (groups 6–9)) were administered vehicle control (group 1) or 30, 60, 150, or 300 mg / kg / dose RD2830 (groups 2 and 6, 3 and 7, 4 and 8, or 5 and 9, respectively) via SC injection at a dose volume of 5 mL / kg on days 1 and 21.

[0370] Observations included cage-side observations (general signs of toxicity, including fecal and urine quality), physical examination (pre-administration), body weight (days 1, 5, 8, 12, 15, 19, and 21 (toxicokinetics test group) and day 26 (main test group)), and quantitative food intake (weekly). Blood samples were collected on day 26 for clinical chemistry, hematology, and coagulation tests. Termination was performed on day 26. Necropsy included gross examination of external abnormalities, abdomen, thorax, and cranial abnormalities. Organ weights (heart, kidney, liver, spleen, and thymus) were recorded. Histology and micropathology (heart, kidney, lesion, liver, lung, lymph nodes, injection site, skin, spleen, and thymus) were performed.

[0371] RD2830 administered as a single SC dose of 30, 60, 150, and 300 mg / kg / dose on days 1 and 21 was considered to be generally tolerable in male and female rats.

[0372] Example 4: A Phase 1, randomized, placebo-controlled, double-blind, single-escalation clinical trial in healthy volunteers to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of RD2830 (ADX-038), and a subsequent open-label treatment clinical trial in patients with paroxysmal nocturnal hemoglobinuria.

[0373] reason

[0374] Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening hematological disease characterized by chronic intravascular hemolysis resulting from uncontrolled activation of the terminal complement pathway.

[0375] RD2830 ("ADX-038") is intended for the treatment of patients with PNH and other complement-mediated diseases N It is an acetylgalactosamine (GalNAc)-conjugated double-strand (ds) inhibitory RNA (siRNA) oligonucleotide. ADX-038 prevents the expression of complement factor B (CFB) by affecting the RISC-mediated cleavage of the mRNA transcript of the gene encoding CFB.

[0376] CFB plays a role in activating the alternative complement pathway. The CFB gene encodes Complement Factor B, a component of the alternative pathway for complement activation. Factor B circulates in the blood as a single-stranded polypeptide. When the alternative pathway is activated, it is cleaved by Complement Factor D to produce the non-catalytic chain Ba and the catalytic subunit Bb. The active subunit Bb is a serine protease that binds to C3b to form the alternative pathway C3-converting enzyme. Bb is involved in the proliferation of pre-activated B lymphocytes, while Ba inhibits their proliferation. Inappropriate activation of the complement system is involved in the initiation or spread of numerous different diseases, including C3 glomerulopathy, systemic lupus erythematosus, and PNH. Currently, treatments for PNH are limited and can be complex to use.

[0377] ADX-038 is highly selective and exhibits complete inhibition of the alternative complement pathway, while having no effect on the classical complement pathway. The primary risk to healthy participants is associated with infection by encapsulated organisms, however, this risk is mitigated by the selectivity of ADX-038 for alternative pathway inhibition coupled with vaccination (Muri et al. ["Alternative complement pathway inhibition abrogates pneumococcal opsonophagocytosis in vaccine-naive, but not vaccinated individuals." Front Immunol ., 2001 , 12, 732146]; Ispasanie et al. [“Alternative complement pathway inhibition does not abrogate meningococcal killing by serum of vaccinated individuals.” Front Immunol. , 2001[Refer to , 12, 747594]). To be selected for the clinical trial, potential participants and PNH patients must provide evidence of prior vaccination against Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae at least 3 weeks prior to ADX-038 administration, or receive such vaccination during the screening period. If a participant does not receive the vaccination or refuses vaccination, that potential participant will no longer be considered eligible to participate in this clinical trial.

[0378] ADX-038 has demonstrated a long duration of action in primates, and it is expected that administration via subcutaneous injection will be possible for half a year or a year.

[0379] The first human Phase 1 clinical trial described herein will evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ADX-038 in both healthy volunteers (Table 5) and PNH patients (Table 6). Data obtained from this trial will enable the definition of the safety profile of ADX-038 and the identification of dosage levels and therapeutic regimens to be used for further evaluation of its therapeutic utility in PNH patients in subsequent Phase 2 clinical trials.

[0380]

[0381]

[0382] Overall design

[0383] The clinical trial described herein is a Phase 1, multicenter clinical trial evaluating the safety, tolerability, PK, and PD of ADX-038. This clinical trial consists of two parts:

[0384] ● Part A: A randomized, double-blind, placebo-controlled, parallel-group, single-escalation dose (SAD) clinical trial in healthy volunteers, involving up to five dose cohorts at a single Phase 1 site. The planned dosing schedule is as follows:

[0385]

[0386] That is, the remaining cohort participants (5 active, 1 placebo) followed by 2 preliminary participants (1 active, 1 placebo). Administration was performed under fasting conditions (at least 8 hours, water allowed).

[0387] ● Part B : Open-label, placebo-free, single-dose cohort(s) in participants with PNH at selected dosages:

[0388]

[0389] This part will begin with the dose level(s) determined from Part A based on the available blinded safety and PK / PD data collected at least 2 months after administration for each participant in the enrolled healthy participant dose cohort.

[0390] An overview of the clinical trial is presented in Figure 1.

[0391] A decision tree to illustrate the process for transitioning to Part B is presented in Fig. 2.

[0392] The Safety Review Committee (SRC) will monitor the safety of participants during the clinical trial period and make decisions regarding dose escalation for Part A and dose selection for each enrolled Part A and Part B cohort.

[0393] Both clinical trial parts include a screening period, a treatment period, and a follow-up period. Throughout the entire clinical trial period, all participants are evaluated as specified in the Schedule of Activities (SoA) in Table 7 (Part A SAD Cohort) and Table 8 (Part B Extended Cohort). The following brief description applies to both clinical trial parts unless otherwise noted.

[0394] After signing the Participant Information Form and the PICF, the participant is screened for eligibility. To be eligible for Part A, the participant must be healthy, and for Part B, the participant must have a documented diagnosis of PNH.

[0395] In both clinical trial parts, participants are admitted to the Phase 1 institution on Day -1 of Part A and Day 1 of Part B. Eligible participants in Part A receive the investigational drug (ADX-038 or placebo) on Day 1 (in Part A, according to the assigned cohort and randomization described in detail below, and in Part B, according to the dosage selected by the SRC based on Part A data and alternative route-level simulations). Participants are discharged from the institution on Day 2 (after collecting a blood sample 30 hours post-administration for PK / PD). Participants visit weekly for the first 4 weeks after administration and then every 2 weeks until Week 14 after administration for safety and PK / PD follow-up. If CFB levels do not recover to ≥ 80% baseline levels by Day 99 (Week 14), PD monitoring continues every 4 weeks until CFB levels reach > 80% of baseline levels (based on two consecutive measurements) or until Day 183 (Week 26), whichever occurs earlier. If alternative pathway activity does not recover to ≥ 50% of baseline levels by Day 183 (Week 26), monitoring continues every 4 weeks until alternative pathway activity reaches ≥ 50% of baseline levels (based on two consecutive measurements) or until Day 365 (Week 52), whichever occurs earlier. End of Study (EOS) is defined as the earliest of the visit date when CFB levels recover to ≥ 80% baseline levels by Day 183, the visit date when alternative pathway activity recovers to ≥ 50% baseline levels, or the visit date on Day 365. Repeated measurements of CFB or alternative paths for verification should be performed at least at weekly intervals.

[0396] Part A Randomization and Dose Escalation

[0397] For each cohort enrolled in Part A (SAD), 8 participants are randomized in a 3:1 ratio, 6 participants are assigned to the active group (ADX-038), and 2 participants are randomized to the control group (corresponding placebo). Randomization takes place on Day 1.

[0398] At the initiation phase, two scout participants (one active and one placebo) will be randomized, and administration will take place accordingly. The scout participants will be evaluated for safety over 48 hours, and the investigator will conduct an evaluation to determine whether the participants have Grade 3 or higher post-treatment events, investigational drug-related adverse events (AEs), or SAEs. Within one business day following the investigator's evaluation, an independent medical monitor will determine the randomization and administration of the remaining six participants (five active and one placebo) according to the randomization schedule.

[0399] Decisions regarding the continuation of administration between cohorts—that is, increasing, maintaining, or decreasing the dosage level—are made by a Safety Review Committee (SRC) composed of at least the sponsor representative(s), independent clinical trial medical monitors, and the principal investigator of the clinical trial site. The SRC reviews all available blinded safety, PK, and PD data for participants of each cohort and all previous cohorts, with additional details provided in the SRC Charter. The SRC determines the next dosage level by reviewing safety data up to at least 28 days after administration (Day 29 of the trial visit), along with available PK / PD data up to 30 hours after administration for the final participant. Prior to enrollment in Selective Cohort 4 or 5, all available blinded safety, PK, and PD data for each cohort and all previous cohorts at least 8 weeks (Day 57) after administration from Cohort 3 or 4 (i.e., the cohort preceding each Selective Cohort) are reviewed. All data accumulated in each cohort will be reviewed along with data collected up to day 57 of the clinical trial visit for the final participants before proceeding to Part B.

[0400] Part B Additional Information

[0401] In Part B, participants with PNH are monitored as described above regarding HV in Part A. Clinical trial participants must notify the investigator on the same day or by the following day if breakthrough hemolysis requiring treatment or a hospital visit occurs. The occurrence of breakthrough hemolysis by a clinical trial participant, particularly if it occurs early in treatment, may be an indicator that the drug effect has not reached its peak due to the relatively slow onset of action of CFB inhibition by ADX-038. Therefore, clinical trial investigators must determine whether the occurrence and severity of the hemolytic event result in termination of participation in the clinical trial and resumption of previous treatment, or the use of rescue medication and continuation of the clinical trial.

[0402] Number of participants

[0403] Up to 40 healthy volunteers are enrolled in Part A, and 2 to 10 participants are enrolled in Part B.

[0404] period

[0405] Each participant in Clinical Trial Part A is expected to remain in this clinical trial as follows:

[0406]

[0407] Each participant in Clinical Trial Part B is expected to remain in this clinical trial as follows:

[0408]

[0409] All participants enrolled in Part B receive ADX-038. No participants enrolled in Part B receive a placebo.

[0410] result

[0411] A Phase 1 clinical trial was initiated, and data were obtained for participants in Cohort 1 (0.4 mg / kg) and Cohort 2 (1 mg / kg). (For reference, the protocol includes maximum Dosage (i.e., for Cohort 2) maximum Although 1.5 mg / kg was specified, 1 mg / kg was administered to the relevant cohort during the clinical trial.

[0412] Figure 3 is a graph showing the mean relative plasma complement factor b (CFB) protein levels (i.e., percentage decrease from baseline) at days 7, 14, 21, 28, 35, 42, 49, 56, 63, and 70 after administration, obtained from cohort 1 (0.4 mg / kg) and cohort 4 (1 mg / kg) administered a single subcutaneous dose of ADX-038.

[0413] Figure 4 is a graph showing the mean relative plasma replacement pathway protein levels (i.e., percentage decrease from baseline) at days 7, 14, 21, 28, 35, 42, 49, 56, 63, and 70 after administration, obtained from cohort 1 (0.4 mg / kg) and cohort 4 (1 mg / kg) administered a single subcutaneous dose of ADX-038.

[0414] Figure 5 is a graph showing the mean relative plasma classical pathway protein levels (i.e., percentage decrease from baseline) at days 7, 14, 21, 28, 35, 42, 49, 56, 63, and 70 after administration, obtained from cohort 1 (0.4 mg / kg) and cohort 4 (1 mg / kg) administered a single subcutaneous dose of ADX-038.

[0415] A dose-dependent decrease in serum CFB and AP activity was observed.

[0416] Over a period of 70 days, no change in CP activity was observed.

[0417] The decrease in serum CFB and AP activity in Cohort 1 (0.4 mg / kg) persisted until day 70.

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428] Example 4A: Protocol Revision: Phase 1, randomized, double-blind, placebo-controlled, single-escalation-dose clinical trial in healthy volunteers to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of RD2830 (ADX-038), followed by a Phase 2a open-label clinical trial in participants with paroxysmal nocturnal hemoglobinuria and residual anemia.

[0429] The subsequent protocol modified the dosage administered to clinical trial participants and adjusted the patient population to include patients with PNH and residual anemia.

[0430] ADX-038 is being developed for the treatment of PNH and other complement-mediated disorders. It is a double-stranded harmless ribonucleic acid (siRNA) conjugated with triantennae N-acetylgalactosamine on the sense strand to facilitate uptake by hepatocytes. In hepatocytes, ADX-038 utilizes an RNA interference (RNAi) mechanism to induce the catalytic degradation of messenger RNA (mRNA) for complement factor B (CFB). The CFB protein is a regulator of the alternative pathway (AP); accordingly, blocking CFB protein synthesis consequently downregulates AP activity. As demonstrated in the complement activation cascade, the activation of the classical and lectin pathways (CP, LP) is not affected by the blocking of CFB protein synthesis. The regulation of complement-mediated hyperinflammation through CFB inhibition is a clinically validated therapeutic approach for treating a number of complement-mediated disorders (CMDs), including paroxysmal nocturnal hemoglobinuria (PNH).

[0431] This therapeutic approach is predicted to have an advantage in safety compared to terminal pathway inhibitors (e.g., ravulizumab, eculizumab), which are therapeutic strategies associated with severe infections caused by encapsulated bacteria that completely dislodge the complement membrane attack complex (SOLIRIS USPI Sep 2024, ULTOMIRIS USPI Sep 2024).

[0432] Pharmacodynamic (PD) data in non-human primates demonstrated that a single subcutaneous injection of ADX-038 was associated with sustained reductions in CFB protein and AP activity levels, while CP activity levels remained essentially unchanged. This favorable PD profile supports the development of ADX-038 as a therapeutic agent for CMD, formulated as a subcutaneous injection that can be administered at low frequencies to reduce the high therapeutic burden associated with approved complement inhibitor regimens. The first human Phase 1 / 2a clinical trial will characterize the safety, tolerability, pharmacokinetics (PK), and PD of ADX-038 in healthy participants, and subsequently demonstrate proof of concept for ADX-038 as a potential therapeutic agent for PNH in participants suffering from PNH and residual anemia.

[0433]

[0434]

[0435]

[0436]

[0437] Overall clinical trial design

[0438] The clinical trial described in this protocol is a Phase 1 / 2a, multicenter clinical trial evaluating the safety, tolerability, PK, and PD of ADX-038. This clinical trial consists of multiple parts:

[0439] ● Phase 1 clinical trial design: A randomized, double-blind, placebo-controlled, parallel-group, single-escalation dose (SAD) clinical trial in healthy participants involving up to five dose cohorts.

[0440] ● Phase 2a clinical trial design: Open-label, placebo-free, two-dose clinical trial in participants with PNH and residual anemia. The fixed-dose regimen evaluated in this phase is selected based on available safety, PK, and PD data from the Phase 1 clinical trial.

[0441] Both phases include a screening period, a single dose of ADX-038 (Phase 1) or two doses of ADX-038 (Phase 2a), and a follow-up period after administration. Participants visit for clinical trial evaluation as specified in the respective Schedule of Activities (SoA).

[0442] Phase 1

[0443] This clinical trial is a Phase 1, multi-center study evaluating the safety, tolerability, PK, and PD of ADX-038. After signing the informed consent form, participants undergo screening over a period of up to 49 days. Eligible participants are admitted on Day 1 and receive the study drug on Day 1 (according to the assigned cohort and randomization, as detailed below). Participants are discharged on Day 2 (after the collection of a blood sample 30 hours post-administration for PK / PD). Participants visit the clinical research site for safety, PK, and PD evaluations. The duration of each participant's participation in the clinical trial is based on the follow-up period for the assigned cohort.

[0444] For participants who have completed the Day 351 visit and whose AP activity has not recovered to within 27 percentage points (absolute) of the baseline value, follow-up is extended. Extended follow-up consists of visits to the clinical trial site every three months to collect blood samples to gather information on SAEs and to assess CFB protein levels and AP activity. Follow-up continues until the participant's AP activity returns to within 27 percentage points (absolute) of the baseline value or until the participant discontinues participation in the clinical trial.

[0445] An overview of the Phase 1 clinical trial is presented in Figure 6a.

[0446] Random assignment

[0447] For each cohort of Phase 1 (SAD), 8 participants are randomized in a 3:1 ratio; 6 participants are assigned to the active group (ADX-038); and 2 participants are randomized to the control group (corresponding placebo). Randomization takes place on Day 1. At the start, 2 scout participants (1 active and 1 placebo) are randomized, and administration is performed accordingly. The scout participants are evaluated for safety over 48 hours, and the investigator performs an evaluation to determine whether the participants have Grade 3 or higher post-treatment events, or investigational drug-related adverse events (AEs) or SAEs. Within 1 business day following the investigator's evaluation, an independent medical monitor determines the randomization and administration of the remaining 6 participants (5 active and 1 placebo).

[0448] Increased dosage

[0449] The dosage escalation plan is presented in Table 11.

[0450]

[0451] Recommendations for increasing the dosage to the next level are made by the Safety Review Committee (SRC), which consists of at least the sponsor's medical representative, an independent clinical trial medical monitor, and the principal investigator of the clinical trial site. Phase 1 data is used to select the dosage for evaluation in the Phase 2a clinical trial.

[0452] Each participant in the Phase 1 clinical trial is expected to remain in the clinical trial as described in Table 12.

[0453]

[0454] If a participant meets any of the following criteria, they will be considered to have completed the main clinical trial.

[0455] ● Cohorts 1–2: The earliest fulfillment of the following: recovery of CFB protein levels to within 20% of baseline levels, recovery of AP activity to within 50% of baseline levels, or completion of the Day 365 visit

[0456] ● Cohorts 3–5: Recovering AP activity to within 27 percentage points (absolute) of baseline by the Day 351 visit, or completing the Day 365 visit, whichever is faster.

[0457] If follow-up continues until AP activity recovers to within 27 percentage points (absolute) of baseline, the participant is considered to have completed the extended follow-up period.

[0458] 2a phase

[0459] This clinical trial is a Phase 2a, open-label, single-arm (ADX-038), two-dose clinical trial consisting of (i) screening (up to 42 days); (ii), and (iii) treatment (two doses). Follow-up after administration is up to 183 days after each dose.

[0460] Eligible PNH participants with residual anemia who have been receiving stable anti-C5 therapy of ravulizumab or eculizumab for at least 3 months receive treatment with ADX-038 administered by subcutaneous injection on Day 1 (dose 1). The subject is eligible for a re-administration of ADX-038 on Day 183 (dose 2), or earlier if there is evidence of a decrease in the therapeutic effect (DTE) before Day 183, i.e., an initial improvement in hemoglobin concentration or a decrease in hemoglobin concentration after stabilization.

[0461] At the re-administration visit, an in-participant dose reduction for tolerability issues or a dose increase to extend the duration of the therapeutic effect until day 183 will be permitted. If the effect of the first dose persists until day 183, the participant receives the same dose as the first treatment on day 183.

[0462] In Phase 2a, ADX-038 is administered in an outpatient setting. However, an option for inpatient administration is provided for participants who agree to participate in intensive PK sample collection up to 30 hours after administration. Inpatient participants are admitted to the inpatient study facility on the day before administration (Day -1). Clinical trial evaluations for non-inpatient and inpatient participants are performed as specified in the SoA.

[0463] Participants receive up to two doses of ADX-038. Depending on the availability of data supporting the safety of chronic ADX-038 administration, the clinical trial protocol will be revised to provide access to ADX-038 treatment for eligible participants who experienced therapeutic benefit from initial ADX-038 treatment. An overview of the Phase 2a clinical trial is presented in Figure 6b.

[0464] Each participant in the clinical trial is expected to remain in the clinical trial as described in Table 13. All participants enrolled in the clinical trial will receive ADX-038, and participants enrolled in this clinical trial will not receive a placebo.

[0465]

[0466] Phase 2a - ADX-038 Dosage

[0467] Safety, PK, and PD data derived from all fixed doses based on the corresponding body weight of each healthy participant and the relevant body weight-based doses administered in Phase 1 will be reviewed to support the selection of doses for evaluation in the next phase of the clinical trial. The selected doses described below will not be higher than the highest dose evaluated in the Phase 1 clinical trial and will be the doses determined to be safe by the SRC.

[0468] Before the first PNH participant is administered in the Phase 2a clinical trial, the initial planned doses of L1, L0, and L2 will be updated for PNH researchers and the Pharmacy Manual.

[0469] ● L1 (Level 1) is the starting dose (Dose 1) to be administered to the PNH participant on Day 1. If the participant tolerates L1 and there is no apparent DTE for that dose prior to Day 183, and L1 is re-administered at the re-administration visit on Day 183, L1 may become the second dose (Dose 2).

[0470] ● L0 (Level 0) is a reduced dose of L1, i.e., a dose ≥ 25% lower, which may be administered at the re-administration visit (i.e., between day 99 and day 183 after the detection of L1 DTE) if a drug-related Grade 3 AE is experienced after receiving L1. In this scenario, if the drug-related Grade 3 AE (excluding allergic reactions such as generalized rash, anaphylaxis or hypersensitivity, or potential Hy's Law cases) resolves, improves, or stabilizes to a level deemed acceptable by the researcher, the participant may be re-administered only with a reduced dose of ADX-038.

[0471] ● L2 (Level 2) is an increased dose ≥ 25% higher than L1 that may be administered at a re-administration visit (i.e., between day 99 and day 183 after DTE is detected at L1) if the participant tolerates L1 but DTE for that dose is detected before day 183.

[0472] Dose 2 will be administered to the PNH participant at the re-administration visit (i.e., at the time point between day 99 and day 183), and the choice of the dose to be administered, i.e., L1, L0, or L2, will be based on an evaluation of safety, tolerability, and the time point of DTE of L1. The selection of the dose at the re-administration is provided in FIG. 6.

[0473] PNH participants are considered to have completed the Phase 2a trial when they complete the visit on Day 183 after administering Dose 2.

[0474] 2a Award: Selection Criteria

[0475] PNH participants must meet all of the following selection criteria:

[0476] 1. Male or female aged 18 or older.

[0477] 2. History of PNH based on documented RBC and / or granulocyte clone size ≥ 10% as measured by flow cytometry with GPI deficiency.

[0478] 3. Receiving stable anti-C5 therapy (ravulizumab or eculizumab regardless of dose / therapy) for ≥ 12 weeks prior to Day 1. Stable is defined as no change in dose or therapy for at least 12 weeks.

[0479] 4. Screen up to 4 participants for hemoglobin concentrations of 10.5 to < 12 g / dL (105 to < 120 g / L); screen the remaining participants for hemoglobin concentrations of < 10.5 g / dL (105 g / L). All participants who have received a history of concentrated red blood cell (PRBC) transfusion within 12 weeks prior to screening must schedule a visit to the screening laboratory at least 4 weeks after the PRBC transfusion to minimize the impact of the transfusion on the hemoglobin concentration screening.

[0480] 5. All fertile participants (male or female) must consent to use a highly effective method of contraception during the clinical trial period (starting Day 1). Female participants using hormonal contraceptives must have started highly effective contraception during at least one menstrual cycle prior to administration and during the clinical trial period up to the final study visit. Female participants must not donate oocytes during this period. Male participants accompanied by a fertile female partner must continuously use a highly effective method of contraception from the time of subject consent until the final study visit. Male participants must consent not to donate sperm during this period.

[0481] Special Note: Permitted if abstinence is the participant's daily lifestyle and preferred method of contraception. The use of contraception by men or women must comply with local regulations regarding contraception for members participating in the clinical trial.

[0482] 6. At screening, the serum pregnancy test result must be negative, and the urine pregnancy test result must be negative before Day 1 administration (non-hospitalized participants) or Day -1 (hospitalized participants). WOCBP must consent to undergo pregnancy testing during the clinical trial period in accordance with the applicable SoA.

[0483] 7. Female participants who are not at risk of pregnancy must be surgically infertile (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or postmenopausal, which is defined as amenorrhea for 12 months without other medical causes at the time of screening, and FSH levels must be within the postmenopausal range (for women not using hormonal contraceptives or hormone replacement therapy).

[0484] 8. Is willing and able to provide informed consent and is willing and able to comply with all clinical trial visits and procedures as specified in the clinical trial protocol.

[0485] 9. Meningitis bacteria ( Neisseria meningitidisVaccination against infection is required. If the participant has not been previously vaccinated or requires a booster shot, the vaccine must be administered within 2 weeks of the Day 1 ADX-038 administration (before / after) in accordance with local guidelines / regulations. If ADX-038 is administered within 2 weeks of vaccination, prophylactic antibiotic administration must be initiated.

[0486] 10. If not previously administered, Streptococcus pneumoniae ( Streptococcus pneumoniae ), and Haemophilus influenzae ( Hemophilus influenzae Vaccination against the infection should be administered according to local guidelines / regulations within 2 weeks (before / after) the administration of ADX-038 on Day 1, where possible. If ADX-038 is administered within 2 weeks after vaccination, prophylactic antibiotic administration should be initiated.

[0487] Special Note: The selection of vaccines related to selection criteria 9 and 10 must consider the most common serotypes in the geographical area where clinical trial participants will be enrolled.

[0488] Phase 2a: Exclusion Criteria

[0489] Participants must not meet any of the following exclusion criteria:

[0490] 1. Known or suspected genetic or acquired complement deficiency.

[0491] 2. History of hematopoietic stem cell transplantation.

[0492] 3. History of recurrent invasive infections caused by encapsulated bacteria, e.g., Neisseria meningitidis or Streptococcus pneumoniae.

[0493] 4. Severe renal disease (e.g., estimated glomerular filtration rate < 30 mL / min / 1.73 m²) 2Major comorbidities including, but not limited to, dialysis), progressive heart disease (e.g., New York Heart Association Grade IV), or severe lung disease (e.g., severe pulmonary hypertension [World Health Organization Grade IV]).

[0494] 5. History of active malignancies and / or malignancies over the past 5 years with no evidence of recurrence for at least 3 months prior to administration of ADX-038 on Day 1, excluding completely resected non-melanoma skin cancer or low-grade cervical intraepithelial neoplasm.

[0495] 6. Active systemic viral (including COVID-19), bacterial, or fungal infection within 14 days prior to administration of ADX-038 on Day 1.

[0496] 7. History of splenectomy.

[0497] 8. Any other significant medical condition that may make a participant unsuitable for selection into the clinical trial, interfere with the evaluation of the clinical trial, or place the participant at risk of experiencing significant adverse effects during the clinical trial.

[0498] 9. Liver disease, for example

[0499] a. Hepatitis B virus infection defined as HBsAg positive

[0500] b. Active HCV virus infection defined as HCV antibody positive with detectable RNA concentration

[0501] c. Liver damage detected as any of the following liver function test abnormalities during screening:

[0502] i. Total bilirubin > 1.5 × ULN (exceptions apply if confirmed to be consistent with a history of Gilbert's syndrome or PNH-related hemolysis or treatment as confirmed by a researcher)

[0503] ii. ALT > 1.5 × ULN (exceptions apply if confirmed by a researcher to be consistent with PNH-related hemolysis or treatment)

[0504] iii. AST > 1.5 × ULN (exceptions apply if confirmed by a researcher to be consistent with PNH-related hemolysis or treatment)

[0505] 10. Laboratory evidence of bone marrow failure:

[0506] a. Reticulocyte count < 75 × 10 9 / L (<75 × 10 6 / mL)

[0507] b. Platelet count < 30 × 10 9 / L (<30 × 10 6 / mL)

[0508] a. Neutrophil count < 500 × 10 6 / L (<500 × 10 3 / mL)

[0509] 11. Clinically significant abnormalities on screening ECG, e.g., QTcF interval > 470 ms

[0510] 12. There is an HIV infection defined as positive for HIV antibodies.

[0511] 13. During administration of immunosuppressants such as cyclosporine, tacrolimus, mycophenolate or mycophenolic acid, cyclophosphamide, methotrexate, or intravenous immunoglobulin, provided that stable therapy was received for ≥ 3 months prior to administration of ADX-038 on Day 1.

[0512] 14. During systemic corticosteroid administration, provided that prednisolone ≤ 20 mg / day or an equivalent stable regimen was administered for ≥ 4 weeks prior to ADX-038 administration on Day 1.

[0513] 15. Known hypersensitivity to either the test drug component or penicillin.

[0514] 16. Treatment with another investigational agent within 30 days prior to administration of ADX-038 on Day 1 or within the expected holiday period of the investigational agent (at least 5 half-lives), whichever is longer.

[0515] 17. Female participants who are breastfeeding, pregnant, or intend to become pregnant during the course of the clinical trial.

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527] Example 4B: Phase 1 result

[0528] Data on 33 healthy volunteers in a Phase 1 blinded study who received a single dose of the drug (ADX-038 n=25, or placebo n=8) are available. The ADX-038 dosage ranged from 0.4 to 4.0 mg / kg (actual dosage of 25 to 340 mg based on body weight). The follow-up period after administration ranged from 49 to 352 days.

[0529] PK was evaluated in an ongoing Phase 1 / 2a study for ADX-038. Blood samples for PK were collected before administration on Day 1; at 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 24, and 30 hours after administration; and on Day 15. Plasma concentrations of ADX-038 were measured using a validated liquid chromatography-fluorescence detection (LC-FLD) method with a peptide nucleic acid (PNA) probe detecting the antisense strand of ADX-038. PK parameters were determined using a non-compartmental method (Model 200-202, extravascular input and linear up / log down methodology).

[0530] Preliminary PK results for 24 healthy volunteers in cohorts 1 through 4 who received a single dose of ADX-038 (0.4 to 4.0 mg / kg) are available. Table 19 presents a summary of the PK parameters. Dose-dependent increases in AUClast and Cmax were demonstrated, approaching dose proportionality. When the ADX-038 dose was increased tenfold from 0.4 to 4.0 mg / kg, the mean AUClast increased from 1,910 to 21,100 ng / mL (11.0-fold increase), and the mean Cmax increased from 132 to 1,390 ng / mL (10.5-fold increase). The median Tmax ranged from 5.00 to 8.00 hours across all four cohorts, and the mean terminal half-life t1 / 2 ranged from 3.46 to 5.64 hours. All concentration data on day 15 (nominal 336 hours after administration) were below the limit of quantification (LLOQ = 2.5 ng / mL).

[0531] The PK profiles for the four cohorts were characterized by a more rapid terminal phase following an extended early phase (Figure 7, showing the mean and standard error of the ADX-038 plasma concentration-time profiles (linear and semi-log plots) after a single dose administration). A change in profile occurred at approximately 16 hours after administration, and the terminal t1 / 2 values ​​were calculated using these late data.

[0532]

[0533] Pharmacodynamics

[0534] Changes in CFB, AP activity, and CP activity are being evaluated in an ongoing Phase 1 / 2a clinical trial (clinical trial ADX-038-101).

[0535] Preliminary results are available for 24 healthy volunteers in cohorts 1 to 4 who received a single dose of ADX-038 (0.4 to 4.0 mg / kg). Dose-dependent reductions in CFB and inhibition of AP activity were observed, both in trough values ​​and inhibition intensity maintained up to day 99, while CP activity remained relatively unchanged. In particular, the 4 mg / kg cohort (average dose of 280 mg, range of 220 to 340 mg) was able to maintain 99.1% inhibition of AP activity at day 99, compared to 86.5% in the 2.5 mg / kg cohort.

[0536] When analyzed by the actual dose administered, the results were similar. Fixed doses are commonly used with liver-targeting siRNAs, and accordingly, three of the five approved liver-targeting siRNAs using fixed doses (AMVUTTRA USPI Feb 2023, LEQVIO USPI Jun 2024, ONPATTRO USPI Jan 2023) will be used in future studies.

[0537]

[0538]

[0539] Figure 8 (change in mean (SE) percentage of AP activity levels over time in clinical trial ADX-038-101 (preliminary results; PD population)) shows the mean change in AP activity over time from baseline due to the actual dose administered. Subjects administered an ADX-038 dose of > 250 mg (n = 4; mean 305 mg, median 300 mg) exhibited profound and sustained inhibition of AP activity (i.e., inhibition ≥ 99% from baseline), which was observed as early as day 15 and maintained until day 99 (the last available data point).

[0540]

[0541] Figure 9 (Percentage of subjects who achieved ≥ 95% inhibition of AP activity over time in clinical trial ADX-038-101 (preliminary results; PD population)) represents the proportion of subjects who could achieve ≥ 95% inhibition of AP activity by the actual dose administered. All subjects administered > 250 mg of ADX-038 achieved ≥ 95% inhibition by day 21, and this was maintained until day 99 (last available time).

[0542] Example 5: Phase 2a, open-label clinical trial to evaluate ADX-038 in subjects with complement-mediated renal disease

[0543] The complement pathway is a crucial component of the innate immune system. Three pathways—the classical pathway, the lectin pathway, and the replacement pathway—converge on a common terminal pathway, ultimately leading to the formation of membrane attack complexes. Dysregulation of the complement replacement pathway (AP) plays a significant role in the pathophysiology of various diseases, including various renal disorders such as IgA, C3G, and IC-MPGN. Renal injury may result from the deposition of circulating active complement fragments in the glomerulus or from locally generated and activated complement components in the kidney (Maillard, N, RJ Wyatt, BA Julian et al. (2015) ["Current Understanding of the Role of Complement in IgA Nephropathy." J Am Soc Nephrol 26 (7): 1503-1512.], Rizk, DV, N Maillard, BA Julian, et al. (2019) [“The Emerging Role of Complement Proteins as a Target for Therapy of IgA Nephropathy.” Front Immunol 10[: 504.]). CFB is an essential component of AP; it binds to C3b to form the C3bB complex, which is subsequently cleaved by factor D to produce active C3 convertase (C3bBb), thereby amplifying the complement cascade and inducing the formation of the terminal membrane attack complex. Selective inhibition of CFB prevents the formation of AP C3 convertase (C3[H2O]Bb and C3bBb) and AP C5 convertase (C3bBb3b) while preserving the formation of C3 and C5 convertases (C4b2b and C4b2b3b) produced through the lectin pathway and the classical pathway. CFB inhibition is a proven therapeutic approach for complement-mediated diseases because it can inhibit AP activity while maintaining the activity of classical and lectin pathways, which is supported by the approval of iptacopan, an oral CFB inhibitor for paroxysmal nocturnal hemoglobinuria (PNH) and IgAN (FABHALTA USPI (Aug 2024). "FABHALTA (iptacopan capsules) [USPI]. East Hanover, NJ: Novartis Pharmaceuticals."). In addition, positive Phase 3 results for Iptacopan were reported in C3G, where a 35% reduction in proteinuria was observed after 6 months of treatment (Nester, CM, RJ Smith, D Kavanagh et al. (2024b) [Efficacy and Safety of Iptacopan in Patients with C3 Glomerulopathy: 12-Month Results from the Phase 3 APPEAR-C3G Study. Abstract presented at American Society of Nephrology Kidney Week, October 24-27, 2024; San Diego, CA. Abstract SA-OR66.]).Additionally, the CFB mRNA antisense oligonucleotide IONIS-FB-LRx demonstrated 69% CFB inhibition along with 39% AP activity inhibition, which reduced urinary proteinuria by 41% after 6 months in IgA patients (Barbour, S, M Hladunewich, J Irvine et al. (2022) ["An Exploratory Trial of an Investigational RNA Therapeutic, IONIS-FB-LRx, for Treatment of IgA Nephropathy: SA-PO714." Journal of the American Society of Nephrology. 33 : 800-800.]), Phase 3 research on IgAN is currently underway.

[0544] Immunoglobulin A nephropathy (IgAN)

[0545] IgAN (also known as Berger's disease) is a serious, progressive autoimmune disease and is the most common primary glomerulonephritis worldwide. Although the prevalence of IgAN is uncertain due to differences in biopsy practices, diagnostic criteria, and a lack of adequate records, the global incidence is estimated to be about 2.5 per 100,000 people per year (Zaidi (2024)). Prevalence varies significantly by geography, highlighting the potential genetic and environmental contributions to IgAN susceptibility and the risk of disease progression. The highest prevalence is observed in East Asian countries, while it is lower in North America and Europe.

[0546] It is widely accepted that the pathogenesis of IgAN involves a multiple-hit hypothesis involving genetic and environmental influences that modulate immune function and lead to IgAN (Cheung (2024)). Patients exhibit increased circulating levels of galactose-deficient IgA1 in the presence of galactose-deficient O-glycans in the hinge region of IgA1 (Gd-IgA1). Abnormalities in O-glycan biosynthesis lead to the exposure of terminal GalNAc residues (Pattrapornpisut (2021)). These residues subsequently promote the formation of anti-glycan IgG autoantibodies. Circulating immune complexes are deposited in the glomerular mesangium, causing inflammation and damage (Medjeral-Thomas (2021)). Since these immune complexes contain complement C3, the activation of the complement cascade is considered to play a significant role in the pathogenesis of IgAN. For the confirmation of IgAN, major or co-major glomerular mesangial IgA deposition must be observed on the immunofluorescence of the kidney biopsy tissue, regardless of whether capillary loop staining is present; these depositions are accompanied by varying degrees of IgG and IgM staining, and complement C3 is present in up to 90% of cases.

[0547] There are several systemic conditions associated with the development of histological and clinical manifestations of IgAN (referred to as "secondary IgAN"), such as malignancies, gastrointestinal diseases (e.g., inflammatory bowel disease), and infections (e.g., hepatitis B and C). It can be difficult to distinguish between primary and secondary IgAN. Regardless of morphology, IgAN can present with various clinical syndromes, but most commonly, corresponding adults present with asymptomatic hematuria accompanied by proteinuria and varying degrees of renal impairment. Although there is significant variability in the clinical course, proteinuria has been proven to be a dominant risk factor for disease progression, which can lead to renal failure requiring renal replacement therapy in up to 20% to 40% of patients within 10 to 20 years of diagnosis (Hassler (2020), Jarrick (2019), Kwon (2021), Pattrapornpisut (2021), Pitcher (2023), Schena (2018)). In addition, IgAN patients may experience a decline in quality of life due to pain, fatigue, and poor mental health (Hassler (2020)).

[0548] The primary treatment for the management of IgAN has been supportive therapy, which includes smoking cessation, blood pressure control, and the use of nephroprotective therapies such as RAAS blockade. Traditionally, corticosteroids and other broad-spectrum immunosuppressants (e.g., cyclophosphamide, azathioprine, and mycophenolate mofetil) have been successfully used; however, treatment efficacy varies significantly among patients, and careful management is required due to potential side effects associated with these agents. Since 2021, three drugs have been approved for adults with primary IgAN at risk of disease progression: ipsilopan (FABHALTA), sparsentan (FILSPARI), and budesonide (TARPEYO) (FABHALTA USPI Aug 2024, FILSPARI USPI Sep 2024, TARPEYO USPI Jun 2024). Ipsilopan is a CFB inhibitor, and sparsentan is an endothelin and angiotensin II receptor antagonist. Both include boxed warnings / safety warnings: for Iptacopan, a warning about an increased risk of serious and life-threatening infection by encapsulated bacteria, and for Sparsentan, a warning about hepatotoxicity and fetal toxicity. Budesonide is a targeted-release corticosteroid, and given the potential adverse effect profile of chronic corticosteroid use, long-term use is not recommended. Additionally, Sparsentan and Budesonide are not specific disease-modifying therapies for IgAN. They are used as adjunctive therapy in combination with other therapies (e.g., ACEi, ARB, and SGLT2 inhibitors) to control blood pressure and reduce proteinuria (Cheung (2024), Hassler (2020), Pitcher (2023)). Since these treatments are not disease-modifying treatments, patients may still experience progressive deterioration of renal function, eventually leading to renal failure.The ultimate goal is to develop a safe, targeted, effective, and convenient therapeutic agent like ADX-038 that can address complement system dysregulation and fundamentally alter disease progression in IgANs.

[0549] Complement 3 glomerulonephropathy (C3G) and immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN)

[0550] Membranoproliferative glomerulonephritis (MPGN) defines a glomerular histopathological lesion characterized by hypercellularity, dilation of the glomerular stromal matrix, and duplication of the glomerular basement membrane. While MPGN has been observed in secondary conditions, it has also been observed in rare primary forms based on immunofluorescence findings. IC-MPGN is characterized by both C3 and immunoglobulin deposits, while C3G is characterized by dominant or exclusive C3 deposition.

[0551] Both IC-MPGN and C3G are rare kidney diseases characterized by the overactivation of AP, which leads to C3 deposition in the glomeruli. It is presumed that both genetic and acquired factors contribute to their pathogenesis. C3G has two major subgroups of the disease distinguished by electron microscopy: dense deposition disease (DDD) and C3 glomerulonephritis (C3GN). Although the subgroups share similar clinical features, DDD is not as common as C3GN and is generally diagnosed in childhood or early adulthood.

[0552] About 25% of C3G patients C3 and CFB They may possess rare or unique variants of complement-related genes, such as C3 nephropathy factor. Autoantibodies targeting complement proteins and complexes, such as C3 nephropathy factor, can contribute to the acquired components of the disorder.

[0553] IC-MPGN is a much rarer condition that shares many clinical and pathological features with C3G but is differentiated by the extensive deposition of immunoglobulins other than C3. While C3G is primarily associated with dysregulation of AP, IC-MPGN may manifest abnormalities resulting from the activation of CP. Despite these differences in underlying mechanisms, the clinical manifestations of IC-MPGN are often similar to those of C3G. The possibility of secondary forms of glomerulonephritis (GN), such as post-infectious GN, autoimmune diseases, and monoclonal gammopathy, must be ruled out prior to diagnosis. While the incidence of IC-MPGN is unclear, the global prevalence of C3G is 8–12 per million people (Thomas (2014)), and the annual incidence is 1–2 per million people. Patients with C3G and IC-MPGN generally present with proteinuria, hematuria, edema, and hypertension in addition to low levels of C3, which reflect complement abnormalities. The overall prognosis for both is poor. About 50% of patients develop end-stage renal disease (ESRD) within 10 years of diagnosis and require dialysis and kidney transplantation, yet the recurrence rate after kidney transplantation is up to 86%.

[0554] Due to the lack of currently approved or effective treatments, there is a high unmet need for therapies to treat C3G and IC-MPGN. Management of the disease primarily involves supportive therapy. ACE inhibitors, angiotensin II receptor blockers, and other nephroprotective agents are first-line agents prescribed to reduce proteinuria and improve renal hemodynamics. Other drugs currently in use are broad-spectrum immunosuppressant therapies such as corticosteroids and mycophenolate mofetil, but their efficacy is limited due to mixed results in clinical studies. Given the underlying pathogenesis of C3G and IC-MPGN, therapies targeting the complement system are of interest. Eculizumab, a terminal complement C5 inhibitor, has shown some evidence of improvement in C3G in a small-scale Phase 1 clinical trial. However, eculizumab blocks terminal complement activation rather than upstream inhibition of AP, and as demonstrated in a rat nephritis model that glomerular C3 deposition is reduced after AP inhibition, upstream inhibition may provide greater benefits in controlling glomerular disease.

[0555] In C3G, the potential clinical benefits of CFB targeting are supported by Phase 2 and Phase 3 studies in C3G using the oral CFB inhibitor iptacopan, in which a reduction of 45% and 35% in proteinuria was observed, respectively.

[0556]

[0557] Overall design

[0558] This clinical trial is a Phase 2a, open-label, parallel-group clinical trial of ADX-038 in adults with complement-mediated renal disease. An overview of the clinical trial is presented in Figure 10.

[0559] This clinical trial includes two cohorts of subjects with different complement-mediated renal diseases receiving up to ACEi and ARB therapy (depending on tolerance). The two cohorts are enrolled simultaneously and independently (approximately 15 subjects per cohort): Cohort 1: IgAN; Cohort 2: C3G or IC-MPGN.

[0560] Screening period

[0561] This clinical trial includes a run-in screening period of up to 100 days. During screening, subjects are required to complete at least two site visits and collect two 24-hour urine samples for UPCR analysis. A second screening visit should only be performed after the site has received the results of the relevant first screening visit and the subject remains eligible. Subjects are required to have an average UPCR based on two 24-hour urine samples of ≥ 0.8 g / g. Researchers must also confirm the safety of antihypertensive and other renoprotective therapies, review the subject's past kidney biopsy reports to confirm the diagnosis, and verify that the subject meets the eligibility criteria. Subjects without a suitable kidney biopsy report within the required period will undergo a biopsy during screening to confirm eligibility provided other key criteria are met (sponsor verification is required).

[0562] Subjects who have not received the required vaccination but meet all other eligibility criteria must be vaccinated. All mandatory vaccinations must be administered at least 2 weeks prior to the first dose of the investigational treatment. The vaccine should cover as many serotypes as possible (including meningococcal serotypes A, C, Y, W-135, and B). To minimize the burden on participants, the use of multivalent vaccines is recommended as locally available and in accordance with local guidelines and regulations (e.g., a quadrivalent vaccine against meningococcus covering serotypes A, C, W, and W-135, and Pneumovax-23 covering 23 types of pneumococcus).

[0563] Treatment and follow-up period

[0564] Subjects who meet all clinical trial eligibility criteria will receive ADX-038 via SC injection Q3 months x 4 times, starting on Day 1 and continuing until the final dose on approximately Day 90. Subjects will be followed up for safety, efficacy, PK, and PD for up to 6 months after the administration of Dose 4.

[0565] Subjects who have not received all doses should also be encouraged to remain in the clinical trial and complete the relevant clinical trial visits (including subjects starting additional therapy). Subjects receiving a second dose should also be encouraged to complete all clinical trial visits. Subjects who wish to stop clinical trial visits and discontinue participation in the clinical trial must complete the EOS visit. If a subject receives four doses of ADX-038 and completes the 6-month follow-up after the fourth dose, that subject will be considered to have completed the study.

[0566] Extended follow-up period

[0567] For subjects who have completed the final visit and whose AP activity has not recovered to within 30 percentage points (absolute) of the baseline value, follow-up is extended. Extended follow-up consists of visits to the clinical trial site every three months to collect information on SAEs and to collect blood samples to assess CFB protein levels and AP activity. Follow-up will continue until the subject's AP activity recovers to within 30 percentage points (absolute) of the baseline value, or they start a complement inhibitor known to affect AP activity (e.g., iptacopan), or they discontinue participation in the clinical trial, whichever occurs first.

[0568] Selective evaluation

[0569] This clinical trial also includes optional pre- and post-treatment kidney biopsies, optional blood sample genetic testing, and additional optional visits to collect blood samples for PK analysis. Subjects consenting to kidney biopsies and / or genetic testing will be required to provide additional informed consent.

[0570] Sample size (planned): Approximately 30 subjects are registered: about 15 with IgAN and about 15 with C3G or IC-MPGN.

[0571] Key Eligibility Criteria: In this clinical study, subjects aged ≥ 18 years who have biopsy-confirmed IgAN, C3G, or IC MPGN, have an average UPCR ≥ 0.8 g / g despite maximum ACEi and ARB therapy (depending on tolerance); have an estimated glomerular filtration rate (eGFR) ≥ 30 mL / min / 1.73m2; and meet vaccination and / or antibiotic requirements will be enrolled.

[0572] Subjects must have been receiving a stable regimen of ACEi or ARB at the locally approved maximum daily dose or maximum tolerated dose for at least 90 days prior to Day 1 (in the researcher's judgment and according to local practice). Subjects with allergies or intolerances to ACEi / ARBs are also eligible, but the researcher must document the reason for not using the medication.

[0573] If the subject is receiving a diuretic, another antihypertensive agent, or another antiprotein / nephroprotective therapy, the dosage must be stable for at least 90 days prior to Day 1.

[0574] Clinical Trial Evaluation: Safety, PK, and PD evaluations are summarized below.

[0575] Safety assessment: Recording of adverse events (AEs), physical examination, vital signs, electrocardiogram (ECG), and clinical safety laboratory tests (including hematology, serum chemistry, coagulation, thyroid-stimulating hormone [TSH], lipids, and urinalysis).

[0576] Efficacy: UPCR, urinary albumin-to-creatinine ratio (UACR), and eGFR via 24-hour urine collection and spot collection.

[0577] Evaluation of PK and immunogenicity: Blood samples will be collected for the analysis of PK, anti-drug antibodies (ADA), and anti-polyethylene glycol (PEG) antibodies. If necessary, the presence of neutralizing antibodies may be analyzed.

[0578] PD Assessment: Blood samples will be collected for the analysis of CFB protein levels, C3, and complement pathway functions (AP and CP). Urine and blood samples will also be collected and stored for exploratory PD and biomarker analysis.

[0579] Selective Kidney Biopsy (Selected Sites): Evaluating tissue from subjects who have provided written informed consent for a kidney biopsy before and / or after treatment can identify the diagnosis and severity of the disease, as well as potential biomarkers. Sponsor verification is required.

[0580] Selective Genetic Testing: By analyzing blood samples from subjects who have provided written informed consent for genetic testing, potential genetic factors that may indicate the severity of a disease or predictors of disease and treatment response can be evaluated.

[0581]

[0582]

[0583]

[0584]

[0585]

[0586] Example 6: Phase 2, randomized, masked, placebo-controlled clinical trial to evaluate the efficacy and safety of ADX-038 in subjects with geographic atrophy (GA) attributable to age-related macular degeneration (AMD).

[0587] GA is a progressive form of AMD characterized by atrophic lesions that originate in the outer layer of the retina and progressively extend into the macula and fovea, causing severe visual impairment and ultimately leading to vision loss. GA can significantly impact patients' quality of life by interfering with daily activities and reducing their independence. It is estimated that GA affects approximately 5 million people worldwide. The underlying pathophysiology of GA is believed to involve chronic inflammation resulting from the overactivation of the complement system. Patients with AMD have higher serum levels of multiple complement factors, such as Complement Factor B (CFB), an activator of the alternative pathway, which is also a potential therapeutic target.

[0588] This Phase 2 clinical trial was designed to evaluate the efficacy of ADX-038 compared to placebo in subjects with GA attributable to AMD. Safety, pharmacokinetics (PK), and PD are also evaluated.

[0589] Overall Design: This clinical trial is a Phase 2, randomized, masked, placebo-controlled clinical trial in subjects with GA attributable to AMD. An overview of the clinical trial is presented in Figure 11.

[0590] This clinical trial consists of a 28-day screening period, a 12-month treatment period, and a follow-up period of approximately 6 months. Approximately 240 subjects who meet eligibility criteria are randomized into one of two treatment groups in a 2:1 ratio (Rx:placebo). Randomization is stratified based on whether the photoreceptor / retinal pigment epithelial (PR / RPE) loss ratio at screening of the study eye, as evaluated by spectral domain optical coherence tomography (SD-OCT), is ≥ 2.8 (yes / no), as well as the location of the lesion (non-infrafoveal or infrafoveal).

[0591] ● Group 1: ADX-038 300 mg, SQ, every 3 months (N~160) Group 2: Placebo (N~80)

[0592] Clinical Trial Evaluation: The evaluations of efficacy, safety, pharmacokinetics (PK), and pharmacokinetics (PD) are summarized below. Refer to the activity schedule for the timeframes for each evaluation.

[0593] Efficacy Evaluation: The following ocular efficacy evaluation and imaging were performed on both eyes:

[0594] ● Normal Luminance Maximum Corrected Visual Acuity (NL-BCVA): Evaluated using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart at a starting distance of 4 m under normal luminance.

[0595] ● Low-light maximum corrected visual acuity (LL-BCVA): Evaluated by the ETDRS chart at a starting distance of 4 m under low-light conditions.

[0596] ● SD-OCT Imaging.

[0597] ● Autofluorescent fundus (FAF) imaging.

[0598] ● Color fundus photograph

[0599] ● Fluorescent angiography

[0600] ● Microvisualization (Selective Sub-study)

[0601] SD-OCT and FAF images are transmitted to a central reading center for analysis. Clinical trial site personnel performing imaging must receive appropriate training and certification, and the trial images, systems, and software must be certified and validated.

[0602] Safety Assessment: Safety monitoring includes recording of adverse events (AEs), physical examination, vital signs, electrocardiogram (ECG), and clinical safety laboratory tests (hematology, serum chemistry, coagulation, lipid panel, and urinalysis). In addition, the following ocular-specific safety assessments are performed for both eyes:

[0603] ● External examination of the eye, adnexa, and eyelid / pupil reactivity (including ptosis, abnormal pupil shape, pupillary immobility, abnormal response to light, and afferent pupillary disorders).

[0604] ● Intraocular pressure (IOP) measurement: Performed using a consistent method throughout the study.

[0605] ● Slit lamp examination (cornea, anterior chamber, iris, lens, aqueous humor reaction [cells and redness]).

[0606] ● Dilated fundus examination including evaluation of the retina and vitreous humor (i.e., posterior segment abnormalities, retinal hemorrhage / detachment, and vitreous hemorrhage density and vitreous cells).

[0607] PK and immunogenicity evaluation: Blood samples will be collected for the analysis of PK, anti-drug antibodies (ADA), and anti-polyethylene glycol (PEG) antibodies.

[0608] PD Assessment: Blood samples will be collected for the analysis of CFB protein levels and complement pathway functions (AP and CP). Bone marrow samples will be collected. Other complement-related biomarkers may also be analyzed.

[0609] Genetics: Selective blood collection may be performed for genetic analysis.

[0610] The PR / RPE ratio in RetInsight's GA monitor software will be used not only as a stratification criterion but also for the analysis of secondary and exploratory OCT biomarkers. The secondary reading center will handle eligibility related to FAF, as well as semi-automatic / manual classification of primary endpoints and other secondary and exploratory endpoints.

[0611]

[0612]

[0613] ocular safety assessment

[0614] Ocular-specific safety assessments will be performed on both eyes as described in the following section. Researchers must consider any abnormal findings that meet the definition of an SAE or require medical intervention to be clinically significant and record them as an AE.

[0615] i. External eye examination

[0616] Ocular examination is performed prior to pupil dilation and includes an evaluation of both eyes, adnexa, and eyelid / pupil reactivity (including ptosis, abnormal pupil shape, pupillary immobility, abnormal response to light, and afferent pupillary disorders).

[0617] ii. IOP Measurement

[0618] IOP will be measured using a Tono-Pen or Goldmann applanation tonometer. This evaluation must be performed before pupil dilation, and the same method must be used for all measurements in the same subject throughout the entire clinical trial.

[0619] iii. Slit Ramp Inspection

[0620] Slit lamp examination is performed after pupil dilation and includes evaluation of the cornea, anterior chamber, iris, lens, and aqueous humor response (cells and redness).

[0621] iv. Dilated fundus examination

[0622] Digital fundus examination is performed after pupil dilation and includes evaluation of the retina and vitreous humor (i.e., posterior segment abnormalities, retinal hemorrhage / detachment, and vitreous hemorrhage density and vitreous cells).

[0623] Selection Criteria

[0624] To be eligible for participation in this clinical trial, subjects must meet all of the following selection criteria. Subjects must possess a single eye that meets all eye selection criteria, namely the "clinical trial eye." If both eyes meet the selection criteria, the eye with the higher PR / RPE loss ratio at the screening visit will be designated as the "clinical trial eye." The other eye will be designated as the "other eye." If both eyes have the same PR / RPE loss ratio, the right eye will be selected as the clinical trial eye.

[0625] 1. Age ≥ 60 at the time of signing the subject consent form.

[0626] 2. Provided written informed consent and all authorizations required by local laws, and intends to comply with all clinical trial requirements during the clinical trial period.

[0627] clinical trial eye

[0628] 3. Clinical diagnosis of GA of the macula attributable to AMD at the time of researcher determination.

[0629] 4. When GA lesions are determined through fundus autofluorescence imaging evaluation at the Central Reading Center during screening, the following criteria must be met:

[0630] a. ≥ 2.5 to ≤ 12.5 mm 2 GA lesions

[0631] b. If the GA is multifocal, at least one focal lesion is ≥ 1.25 mm 2 It must be (0.5DA), and the total aggregation area of ​​GA is as specified in 4a.

[0632] c. The entire GA lesion must be fully visualized in the central macular image, be imageable in its entirety, and not adjacent to any area of ​​peripapillary atrophy.

[0633] d. Presence of any high autofluorescence (AF) pattern at the boundary of the GA (exception is the absence of high AF).

[0634] e. Lesions involving the fovea will be limited to 30% of the total population.

[0635] 5. When using the ETDRS chart, the maximum corrected visual acuity is 24 characters or more.

[0636] 6. When a GA lesion is determined by evaluation of screening SD-OCT images by a GA monitor or a central reading center, it must meet the following criteria.

[0637] a. The GA lesion must be within the entire 6 mm x 6 mm OCT imaging frame.

[0638] b. EZ loss must be included in the ...

Claims

Claim 1 A compound comprising a modified oligonucleotide having the nucleobase sequence of SEQ ID NO.

100. Claim 2 A compound comprising a modified oligonucleotide having the nucleobase sequence of SEQ ID NO.

109. Claim 3 A compound comprising a modified oligonucleotide having the following modified nucleobase sequence: mU*fA*mG.fA.mC.fA.mU.fC.mC.fA.mG.fA.mU.fA.mA.fU.mC.fC.mU.fU*mC*mC (Reference No.: IA1016), wherein: m is a 2'-O-methyl sugar modification; f is a 2'-F sugar modification; * is a phosphorothioate nucleoside linkage; and . is a phosphate nucleoside linkage. Claim 4 A compound comprising a modified oligonucleotide having the following modified nucleobase sequence: H4*mG*mG.mA.mA.mG.mG.mA.fU.mU.fA.fU.fC.fU.mG.mG.mA.mU.mG.mU. mC.mU*mA*dQ (Reference No.: IS1252), where: m is a 2'-O-methyl sugar modification; f is a 2'-F sugar modification; * is a phosphorothioate internucleoside linkage; . is a phosphate internucleoside linkage; and dQ is an inversion non-basic deoxyribose of the following chemical formula: ;H4 is a compound having the following chemical formula: . Claim 5 A compound comprising the first modified oligonucleotide of reference number IA1016 and the second modified oligonucleotide of reference number IS1252. Claim 6 A compound in any one of paragraphs 1 to 5, wherein the compound is in a pharmaceutically acceptable salt form. Claim 7 In paragraph 6, the pharmaceutically acceptable salt is a compound that is a sodium salt. Claim 8 In paragraph 6, the pharmaceutically acceptable salt is a compound that is a potassium salt. Claim 9 The following chemical structural formula: Or a modified oligonucleotide that is a pharmaceutically acceptable salt or stereoisomer thereof. Claim 10 In paragraph 9, the modified oligonucleotide, the pharmaceutically acceptable salt is a sodium salt or a potassium salt. Claim 11 In paragraph 9, a sodium salt according to the following chemical structural formula: Or a modified oligonucleotide that is a stereoisomer thereof. Claim 12 The following chemical structural formula: Or a modified oligonucleotide according to a pharmaceutically acceptable salt or stereoisomer thereof. Claim 13 In paragraph 12, the modified oligonucleotide, the pharmaceutically acceptable salt is a sodium salt or a potassium salt. Claim 14 In paragraph 12, a sodium salt according to the following chemical structural formula: Or a modified oligonucleotide that is a stereoisomer thereof. Claim 15 The following chemical structural formula: or a compound that is a pharmaceutically acceptable salt or stereoisomer thereof. Claim 16 In paragraph 15, the pharmaceutically acceptable salt is a compound that is a sodium salt or a potassium salt. Claim 17 In paragraph 15, a sodium salt according to the following chemical structural formula: or a compound that is a stereoisomer thereof. Claim 18 A composition comprising a compound or modified oligonucleotide of any one of claims 1 to 17, and a pharmaceutically acceptable carrier. Claim 19 A composition comprising a compound or modified oligonucleotide of any one of claims 1 to 17 for use in a therapeutic regimen. Claim 20 A method for treating, preventing, or improving a disease, disorder, or pathological condition associated with CFB in an individual, the method comprising the step of treating, preventing, or improving said disease, disorder, or pathological condition by administering a compound or modified oligonucleotide of any one of claims 1 to 17 to said individual. Claim 21 A method comprising the step of administering to an individual a compound or modified oligonucleotide of any one of claims 1 to 17, or a composition of claim 18 or 19. Claim 22 In paragraph 20 or 21, the disease, disorder, or condition is atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy due to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA). Claim 23 In paragraph 22, the step of administering the compound is a method for inhibiting, reducing, or improving atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulonephropathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy due to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA). Claim 24 A method for inhibiting the expression of CFB in a cell, wherein the method comprises the step of inhibiting the expression of CFB in the cell by contacting the cell with a compound or modified oligonucleotide of any one of claims 1 to 17. Claim 25 In paragraph 24, the cell is located within the individual's liver, in a method. Claim 26 In paragraph 25, the individual has or is at risk of having atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulonephropathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy due to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA). Claim 27 A method for reducing or inhibiting atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulonephropathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy due to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA) in an individual, wherein the method comprises administering a compound of any one of claims 1 to 17 or a modified oligonucleotide to the individual, thereby reducing atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulonephropathy (C3G), IgA A method comprising a step of reducing or inhibiting nephropathy (IgAN), systemic lupus erythematosus (SLE), diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy due to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA). Claim 28 In paragraph 27, the individual has or is at risk of having atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulonephropathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy due to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA). Claim 29 A method according to any one of claims 20 to 28, wherein the compound or modified oligonucleotide is administered parenterally. Claim 30 A method according to any one of paragraphs 20 to 28, wherein the compound or modified oligonucleotide is administered subcutaneously. Claim 31 The use of a compound or modified oligonucleotide of any one of claims 1 to 17 for treating, preventing, or improving diseases, disorders, or pathological conditions associated with CFB. Claim 32 In paragraph 31, the use is that the disease, disorder, or condition is atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy due to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA). Claim 33 The use of a compound or modified oligonucleotide of any one of claims 1 to 17 in the manufacture of a medicine for treating, preventing, or improving diseases, disorders, or pathological conditions associated with CFB. Claim 34 In paragraph 33, the use is for a disease that is atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulonephropathy (C3G), IgA nephropathy (IgAN), systemic lupus erythematosus (SLE), diabetic nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), polycystic kidney disease, age-related macular degeneration (AMD), geographic atrophy due to AMD, thrombotic microangiopathy, myasthenia gravis, ischemia, reperfusion injury, or rheumatoid arthritis (RA). Claim 35 A method or use according to any one of paragraphs 20 to 34, wherein the compound or composition is administered to an individual approximately once every three months to approximately once every year. Claim 36 A method or use according to any one of paragraphs 20 to 34, wherein the compound or composition is administered to an individual approximately once every three months, approximately once every six months, or approximately once every year. Claim 37 A method for treating, preventing, or improving a disease, disorder, or pathological condition associated with CFB in humans, wherein the method comprises the step of treating, preventing, or improving said disease, disorder, or pathological condition by administering a compound of any one of claims 15 to 17 to said individual. Claim 38 In paragraph 37, a method in which the compound is administered approximately once every 3 months, approximately once every 6 months, or approximately once every year. Claim 39 In paragraph 37, the administration of the compound causes a relative decrease in plasma complement factor b (CFB) protein levels. Claim 40 In paragraph 39, a method in which the relative plasma complement factor b (CFB) protein level is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%. Claim 41 A method according to claim 39 or 40, wherein the relative decrease in plasma complement factor b (CFB) protein levels is observable on days 7, 14, 21, 28, 35, 42, 49, 56, 63, or 70 after administration of the compound. Claim 42 A method according to claim 39 or 40, wherein the relative decrease in plasma complement factor b (CFB) protein levels is observable at day 7, day 14, day 21, month 1, month 2, month 3, month 4, month 5, month 6, month 7, month 8, month 9, month 10, month 11, or month 12 after administration of the compound. Claim 43 A method according to claim 39 or 40, wherein the relative decrease in plasma complement factor b (CFB) protein levels is observable at 1 month, 3 months, 6 months, 9 months, or 12 months after administration of the compound. Claim 44 In paragraph 39, a method in which the relative plasma complement factor b (CFB) protein level is reduced to at least 80% observable on day 28 after administration of the compound. Claim 45 In paragraph 39, a method in which the relative plasma complement factor b (CFB) protein level is reduced by at least 50% observable on day 70 after administration of the compound. Claim 46 In paragraph 37, a method in which about 0.4 mg / kg of the compound is administered. Claim 47 A method according to claim 37, wherein about 1.0 to about 1.5 mg / kg of the compound is administered. Claim 48 In paragraph 37, a method in which about 2.5 mg / kg of the compound is administered. Claim 49 In paragraph 37, a method in which about 4 mg / kg of the compound is administered. Claim 50 In paragraph 37, a method in which about 8 mg / kg of the compound is administered. Claim 51 In paragraph 37, a method in which about 21 mg / kg of the compound is administered. Claim 52 A method according to claim 37, wherein about 0.25 to about 15 mg / kg of the compound is administered. Claim 53 A method in which, in any one of paragraphs 20, 22, 23, or 26, the individual has or is at risk of having paroxysmal nocturnal hemoglobinuria (PNH). Claim 54 A method in which, in any one of paragraphs 20, 22, 23, or 26, the individual has or is at risk of having C3 glomerulonephropathy (C3G), IgA nephropathy (IgAN), membranoproliferative glomerulonephritis (MPGN), or immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN). Claim 55 A method in which, in any one of paragraphs 20, 22, 23, or 26, the individual has or is at risk of having age-related macular degeneration (AMD) or geographic atrophy attributable to AMD. Claim 56 A method in which, in any one of paragraphs 53 to 55, the compound is administered subcutaneously. Claim 57 In paragraph 56, a method in which the compound is administered to an individual approximately once every three months, approximately once every six months, or approximately once every year. Claim 58 In paragraph 32 or 34, the use is that the disease, disorder, or condition is paroxysmal nocturnal hemoglobinuria (PNH). Claim 59 In paragraph 32 or 34, the use is that the disease, disorder, or condition is C3 glomerulonephropathy (C3G), IgA nephropathy (IgAN), membranoproliferative glomerulonephritis (MPGN), or immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN). Claim 60 In paragraph 32 or 34, the use is that the disease, disorder, or condition is age-related macular degeneration (AMD) or geographic atrophy caused by AMD. Claim 61 In any one of paragraphs 58 to 60, the compound is used for subcutaneous administration. Claim 62 In paragraph 61, a method in which the compound is administered to an individual approximately once every three months, approximately once every six months, or approximately once every year.

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