WO2013159109A1 - Modulation de l'expression du virus de l'hépatite b (hbv) - Google Patents

Modulation de l'expression du virus de l'hépatite b (hbv) Download PDF

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WO2013159109A1
WO2013159109A1 PCT/US2013/037642 US2013037642W WO2013159109A1 WO 2013159109 A1 WO2013159109 A1 WO 2013159109A1 US 2013037642 W US2013037642 W US 2013037642W WO 2013159109 A1 WO2013159109 A1 WO 2013159109A1
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compound
modified
hbv
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cro
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PCT/US2013/037642
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Eric E. Swayze
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Isis Pharmaceuticals, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1131—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against viruses
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering N.A.

Definitions

  • HBV The virus, HBV, is a double-stranded hepatotropic virus which infects only humans and non-human primates. Viral replication takes place predominantly in the liver and, to a lesser extent, in the kidneys, pancreas, bone marrow and spleen (Hepatitis B virus biology. Microbiol Mol Biol Rev. 64: 2000; 51-68.). Viral and immune markers are detectable in blood and characteristic antigen-antibody patterns evolve over time. The first detectable viral marker is hepatitis B s antigen (HBsAg), followed by hepatitis B e antigen (HBeAg) and HBV DNA.
  • HBsAg hepatitis B s antigen
  • HBV DNA hepatitis B e antigen
  • PCT applications have been published that relate to the RNAi phenomenon. These include: PCT publication WO 00/44895; PCT publication WO 00/49035; PCT publication WO 00/63364; PCT publication WO 01/36641 ; PCT publication WO 01/36646; PCT publication WO 99/32619; PCT publication WO 00/44914; PCT publication WO 01/29058; and PCT publication WO 01/75164.
  • oligonucleotide consisting of 8 to 35 linked nucleosides per strand and having a nucleobase sequence comprising at least 5 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 30-125.
  • oligonucleotide consisting of 8 to 35 linked nucleosides per strand, wherein the double- stranded oligonucleotide is complementary within the following nucleotide regions of SEQ ID NO: 1 : 56- 76, 58-78, 194-214, 196-216, 245-265, 247-267, 251-271, 253-273, 254-274, 256-276, 258-278, 259-279, 260-280, 261-281, 262-282, 263-283, 264-284, 265-285, 266-286, 268-288, 301-321, 303-323, 374-394, 376-396, 381-401, 383-403, 409-429, 411-431, 412-432, 414-434, 414-434, 416-436, 418-438, 455-475, 457-477, 463-483, 465-485, 637-657, 639-659,
  • one strand of the oligonucleotide is modified.
  • Alkyl refers to a saturated straight or branched hydrocarbon radical containing up to twenty four carbon atoms.
  • Bicyclic sugar means a furanose ring modified by the bridging of two non-geminal carbon atoms.
  • a bicyclic sugar is a modified sugar.
  • Bicyclic sugar modified nucleoside refers to nucleosides having a second ring formed from the bridging of 2 atoms of the ribose ring.
  • Designing or “Designed to” refer to the process of designing an oligomeric compound that specifically hybridizes with a selected nucleic acid molecule.
  • Double-stranded oligonucleotide Double-stranded oligonucleotide, double-stranded compound”, and “double-stranded composition” as used herein encompass the terms “ short interfering nucleic acid”, “short interfering RNA”, “siRNA”, “short interfering nucleic acid molecule”, “short interfering oligonucleotide molecule”, or “chemically modified short interfering nucleic acid molecule” as defined below.
  • double-stranded oligonucleotides are formed from only one strand, for example by taking the form of a self-complementary hairpin-type molecule that doubles back on itself to form a duplex.
  • Duration means the period of time during which an activity or event continues. In certain embodiments, the duration of treatment is the period of time during which doses of a pharmaceutical agent are administered.
  • Effective amount in the context of modulating an activity or of treating or preventing a condition means the administration of that amount of active ingredient to a subject in need of such modulation, treatment or prophylaxis, either in a single dose or as part of a series, that is effective for modulation of that effect, or for treatment or prophylaxis or improvement of that condition.
  • the effective amount will vary depending upon the health and physical condition of the subject to be treated, the taxonomic group of subjects to be treated, the formulation of the composition, the assessment of the medical situation, and other relevant factors.
  • “Fully complementary” or “100% complementary” means each nucleobase of a first nucleic acid has a complementary nucleobase in a second nucleic acid.
  • a first nucleic acid is a siRNA compound and a target nucleic acid is a second nucleic acid.
  • “Fully modified motif” refers to a siRNA compound comprising a contiguous sequence of nucleosides wherein essentially each nucleoside is a sugar modified nucleoside having uniform modification.
  • Halo and halogen refer to an atom selected from fluorine, chlorine, bromine and iodine.
  • HBV protein means any protein secreted by hepatitis B virus The term encompasses various HBV antigens, including core proteins such as “Hepatitis E antigen”, “HBeAg” or “HBeAG” and envelope proteins such as "HBV surface antigen", or "HBsAg”.
  • injection site reaction means inflammation or abnormal redness of skin at a site of injection in an individual.
  • Intravenous administration means administration into a vein.
  • Non-complementary nucleobase refers to a pair of nucleobases that do not form hydrogen bonds with one another or otherwise support hybridization.
  • Nucleobase means a heterocyclic moiety capable of pairing with a base of another nucleic acid.
  • Olemeric compound means a polymer of linked monomeric subunits which is capable of hybridizing to at least a region of a nucleic acid molecule.
  • Parenteral administration means administration through injection (e.g., bolus injection) or infusion.
  • Parenteral administration includes subcutaneous administration, intravenous administration, intramuscular administration, intraarterial administration, intraperitoneal administration, or intracranial administration, e.g., intrathecal or intracerebroventricular administration.
  • Prodrug means a therapeutic agent that is prepared in an inactive form that is converted to an active form (i.e., drug) within the body or cells thereof by the action of endogenous enzymes or other chemicals and/or conditions.
  • Protecting group refers to a labile chemical moiety which is known in the art to protect reactive groups including without limitation, hydroxyl, amino and thiol groups, against undesired reactions during synthetic procedures.
  • Side effects means physiological responses attributable to a treatment other than desired effects.
  • side effects include, without limitation, injection site reactions, liver function test abnormalities, renal function abnormalities, liver toxicity, renal toxicity, central nervous system abnormalities, and myopathies.
  • increased aminotransferase levels in serum may indicate liver toxicity or liver function abnormality.
  • increased bilirubin may indicate liver toxicity or liver function abnormality.
  • “Therapeutically effective amount” means an amount of a pharmaceutical agent that provides a therapeutic benefit to an individual.
  • the compounds or compositions comprise a modified double- stranded oligonucleotide 10 to 30 linked nucleosides in length targeted to HBV.
  • the HBV target can have a sequence recited in SEQ ID NO: 1 or a portion thereof or a variant thereof.
  • such compounds or oligonucleotides target the following nucleotide regions of SEQ ID NO: 1 : 56-76, 58-78, 194-214, 196-216, 245- 265, 247-267, 251-271, 253-273, 254-274, 256-276, 258-278, 259-279, 260-280, 261-281, 262- 282, 263-283, 264-284, 265-285, 266-286, 268-288, 301-321, 303-323, 374-394, 376-396, 381- 401, 383-403 , 409-429, 411-431, 412-432, 414-434, 414-434, 416-436, 418-438, 455-475, 457- 477, 463-483, 465-485, 637-657, 639-659, 668-688, 670-690, 677-697, 679-699, 685-705, 687- 707, 1253-1273, 1255
  • the human hepatitis B virus may be any of the human geographical genotypes: A (Northwest Europe, North America, Central America); B (Indonesia, China, Vietnam); C (East Asia, Korea, China, Japan, Polynesia, Vietnam); D (Mediterranean area, Middle East, India); E (Africa); F (Native Americans, Polynesia); G (United States, France); or H (Central America).
  • Certain embodiments provide a method for treating an animal with a HBV related disease, disorder or condition comprising: a) identifying said animal with the HBV related disease, disorder or condition, and b) administering to said animal a therapeutically effective amount of a compound or composition comprising a modified double-stranded oligonucleotide consisting of 10 to 30 linked nucleosides and having a nucleobase sequence at least 90% complementary to SEQ ID NO: 1, as measured over the entirety of said modified oligonucleotide.
  • the therapeutically effective amount of the compound or composition administered to the animal treats or reduces the HBV related disease, disorder or condition, or a symptom thereof, in the animal.
  • the one or more second agents are an HBV agent.
  • the HBV agent can include, but is not limited to, interferon alpha-2b, interferon alpha-2a, and interferon alphacon-1 (pegylated and unpegylated), ribavirin; an HBV RNA replication inhibitor; a second antisense oligomer; an HBV therapeutic vaccine; an HBV prophylactic vaccine; lamivudine (3TC); entecavir (ETV); tenofovir diisoproxil fumarate (TDF); telbivudine (LdT); adefovir; or an HBV antibody therapy (monoclonal or polyclonal).
  • a method for reducing an amount of HBV mRNA, DNA, protein and/or an amount of HBV antigen in a mammal infected with a hepatitis B virus comprising administering a therapeutically effective amount of a pharmaceutical composition as described above to a mammal in need thereof so as to reduce the hepatitis B virus infection and the hepatitis B antigen, compared to the amount of HBV mRNA, protein and an amount of HBV antigen in the mammal before treatment, wherein the amount of mRNA is reduced at least 75% compared to the amount before administration of the double- stranded compound.
  • a method for reducing an amount of HBV mRNA, DNA, protein and/or an amount of HBV antigen in a mammal infected with a hepatitis B virus comprising administering a therapeutically effective amount of a pharmaceutical composition as described above to a mammal in need thereof so as to reduce the hepatitis B virus infection and the hepatitis B antigen, compared to the amount of HBV mRNA, protein and an amount of HBV antigen in the mammal before treatment, wherein the amount of mRNA is reduced at least 80% compared to the amount before administration of the modified double-stranded compound.
  • a method for reducing an amount of HBV mRNA, DNA, protein and/or an amount of HBV antigen in a mammal infected with a hepatitis B virus, the method comprising administering a therapeutically effective amount of a pharmaceutical composition as described above to a mammal in need thereof so as to reduce the hepatitis B virus infection and the hepatitis B antigen, compared to the amount of HBV mRNA, protein and an amount of HBV antigen in the mammal before treatment, wherein the amount of mRNA is reduced at least 95% compared to the amount before administration of the double-stranded compound.
  • the HBV antigen may be HBsAg or may be HBeAg, and more particularly, the amount of HBV antigen may be sufficiently reduced to result in seroconversion, defined as serum HBeAg absence plus serum HBeAb presence if monitoring HBeAg as the determinant for seroconversion, or defined as serum HBsAg absence if monitoring HBsAg as the determinant for seroconversion, as determined by currently available detection limits of commercial ELISA systems.
  • Certain embodiments provide the use of a compound or composition as described herein in the manufacture of a medicament for treating, ameliorating, delaying or preventing liver disease in an animal.
  • kits for treating, preventing, or ameliorating an HBV- related disease, disorder or condition, or a symptom thereof as described herein wherein the kit comprises: a) a compound or compositions as described herein; and optionally b) an additional agent or therapy as described herein.
  • the kit can further include instructions or a label for using the kit to treat, prevent, or ameliorate the HBV-related disease, disorder or condition. Double-stranded Oligonucleotides
  • the double-stranded oligonucleotide molecules can be a double-stranded polynucleotide molecule comprising self-complementary sense and antisense regions, wherein the antisense region comprises nucleotide sequence that is complementary to nucleotide sequence in a target nucleic acid molecule or a portion thereof and the sense region having nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof.
  • the double-stranded oligonucleotide is assembled from a single oligonucleotide, where the self-complementary sense and antisense regions of the siRNA are linked by means of a nucleic acid based or non-nucleic acid-based linker(s).
  • the double-stranded oligonucleotide can be a polynucleotide with a duplex, asymmetric duplex, hairpin or asymmetric hairpin secondary structure, having self-complementary sense and antisense regions, wherein the antisense region comprises nucleotide sequence that is complementary to nucleotide sequence in a separate target nucleic acid molecule or a portion thereof and the sense region having nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof.
  • double-stranded oligonucleotides need not be limited to those molecules containing only RNA, but further encompasses chemically modified nucleotides and non- nucleotides.
  • the short interfering nucleic acid molecules lack 2'- hydroxy (2'-OH) containing nucleotides.
  • short interfering nucleic acids optionally do not include any ribonucleotides (e.g., nucleotides having a 2'-OH group).
  • double-stranded oligonucleotides that do not require the presence of ribonucleotides within the molecule to support RNAi can however have an attached linker or linkers or other attached or associated groups, moieties, or chains containing one or more nucleotides with 2'-OH groups.
  • double-stranded oligonucleotides can comprise ribonucleotides at about 5, 10, 20, 30, 40, or 50% of the nucleotide positions.
  • RNAi is meant to be equivalent to other terms used to describe sequence specific RNA interference, such as post transcriptional gene silencing, translational inhibition, or epigenetics.
  • sequence specific RNA interference such as post transcriptional gene silencing, translational inhibition, or epigenetics.
  • double- stranded oligonucleotides can be used to epigenetically silence genes at both the post-transcriptional level and the pre-transcriptional level.
  • RNAi mechanism including, e.g., "hairpin” or stem-loop double-stranded RNA effector molecules in which a single RNA strand with self-complementary sequences is capable of assuming a double-stranded conformation, or duplex dsRNA effector molecules comprising two separate strands of RNA.
  • RNA/DNA hybrids include a DNA strand or region that is an antisense strand or region (e g, has at least 70, 80, 90, 95, 98, or 100% complementarity to a target nucleic acid) and an RNA strand or region that is a sense strand or region (e.g, has at least 70, 80, 90, 95, 98, or 100% identity to a target nucleic acid), and vice versa.
  • an antisense strand or region e g, has at least 70, 80, 90, 95, 98, or 100% complementarity to a target nucleic acid
  • RNA strand or region that is a sense strand or region e.g, has at least 70, 80, 90, 95, 98, or 100% identity to a target nucleic acid
  • the RNA/DNA hybrid is made in vitro using enzymatic or chemical synthetic methods such as those described herein or those described in WO 00/63364, filed Apr. 19, 2000, or U.S. Ser. No. 60/130,377, filed Apr. 21, 1999.
  • a DNA strand synthesized in vitro is complexed with an RNA strand made in vivo or in vitro before, after, or concurrent with the transformation of the DNA strand into the cell.
  • any of the dsRNAs may be expressed in vitro or in vivo using the methods described herein or standard methods, such as those described in WO 00/63364.
  • multiple anti-HBV and/or anti-HCV dsRNA effector molecules of the invention are transcribed in a mammalian cell from one or more expression constructs each comprising multiple polymerase III promoter expression cassettes as described in more detail in U. S. Pat. No. 60/603622; U.S. Pat. No. 60/629942; and PCT7US05/29976; "Multiple Polymerase III Promoter Expression Constructs".
  • siRNA compounds defined by a SEQ ID NO may comprise, independently, one or more modifications to a sugar moiety, an internucleoside linkage, or a nucleobase.
  • siRNA compounds described by Isis Numbers (Isis No) indicate a combination of nucleobase sequence and motif.
  • the compounds, or portions thereof are at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to one or more of the double-stranded compounds or SEQ ID NOs, or a portion thereof, disclosed herein.
  • the compounds disclosed herein may comprise of alkyl groups.
  • the compounds disclosed herein may comprise of aryl or aromatic groups.
  • aryl groups include, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyl and the like.
  • Aryl groups as used herein may optionally include further substituent groups.
  • the compounds disclosed herein may comprise of protecting group.
  • protecting groups are typically used selectively and/or orthogonally to protect sites during reactions at other reactive sites and can then be removed to leave the unprotected group as is or available for further reactions.
  • Protecting groups as known in the art are described generally in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).
  • any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration unless the text so states; thus a carbon-carbon double bond or carbon-heteroatom double bond depicted arbitrarily herein as trans may be cis, trans, or a mixture of the two in any proportion.
  • each sugar modified nucleoside is selected from 2'-modified nucleosides, 4'-thio modified nucleosides, 4'-thio-2'-modified nucleosides and nucleosides having bicyclic sugar moieties.
  • chemically modified double-stranded compounds comprise a 2'-modified nucleoside such as 2'-OCH 3 , 2'-F, or 2'-OCH 3 sugar modifications.
  • chemically modified double-stranded compounds comprise ⁇ -D-ribonucleoside For example using 2'-MOE (2'-0-(CH 2 ) 2 -OCH 3 ) modifications in the wings of the sense strand increases the efficiency of the antisense strand.
  • the compounds disclosed herein may comprise of universal base moieties.
  • the universal base need not contribute to hybridization, but should not significantly detract from hybridization and typically refers to a monomer in a first sequence that can pair with a naturally occuring base, i.e A, C, G, T or U at a corresponding position in a second sequence of a duplex in which one or more of the following is true: (1) there is essentially no pairing (hybridization) between the two; or (2) the pairing between them occurs non- discriminant with the universal base hybridizing one or more of the the naturally occurring bases and without significant destabilization of the duplex.
  • Exemplary universal bases include, without limitation, inosine, 5-nitroindole and 4-nitrobenzimidazole.
  • G-clamps examples include substituted phenoxazine cytidine (e.g. 9-(2- aminoethoxy)-H-pyrimido[5,4-b][l,4]benzoxazin-2(3H)-one), carbazole cytidine (2H- pyrimido[4,5-b]indol-2-one) and pyridoindole cytidine (H-pyrido[3',2':4,5]pyrrolo[2,3- d]pyrimidin-2-one).
  • substituted phenoxazine cytidine e.g. 9-(2- aminoethoxy)-H-pyrimido[5,4-b][l,4]benzoxazin-2(3H)-one
  • carbazole cytidine 2H- pyrimido[4,5-b]indol-2-one
  • pyridoindole cytidine H-pyrido[3'
  • Representative cytosine analogs that make 3 hydrogen bonds with a guanosine in a second oligonucleotide include l,3-diazaphenoxazine-2-one (Kurchavov et al., Nucleosides and Nucleotides, 1997, 16, 1837-1846), l,3-diazaphenothiazine-2-one (Lin et al., J. Am. Chem. Soc. 1995, 117, 3873-3874) and 6,7,8,9-tetrafluoro-l,3-diazaphenoxazine-2-one (Wang et al., Tetrahedron Lett. 1998, 39, 8385-8388).
  • these base modifications hybridized with complementary guanine (the latter also hybridized with adenine) and enhanced helical thermal stability by extended stacking interactions (see U. S. Serial Number 10/013,295).
  • Exemplary cycloalkylene groups include C3-C12 cycloalkylene groups, such as cyclopropylene, cyclobutylene, cyclopentanyl-l,3-ene, cyclohexyl- 1,4-ene, etc.
  • Exemplary arylene linking moietys include, but are not limited to, mono- or bicyclic arylene groups having from 6 to about 14 carbon atoms, e.g. phenyl- 1,2-ene, naphthyl-l,6-ene, napthyl- 2,7-ene, anthracenyl, etc.
  • heteroaryl groups that may be mentioned as being within the scope of the embodiments include: pyrrolidinyl, piperidinyl (e.g. 2,5-piperidinyl, 3,5-piperidinyl), piperazinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydro quinolinyl, tetrahydro isoquinolinyl, tetrahydroquinazolinyl, tetrahydroquinoxalinyl, etc.
  • Exemplary heteroarylene groups include mono- or bicyclic aryl groups having from about 4 to about 12 carbon atoms and about 1 to about 4 hetero atoms, such as N, O and S.
  • the compounds disclosed herein may comprise of modified internucleoside linkages.
  • modified linkages include those that have a phosphorus atom and those that do not have a phosphorus atom.
  • Internucleoside linkages containing a phosphorus atom therein include, for example, phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkylphosphotriesters, methyl and other alkyl phosphonates including 3'-alkylene phosphonates, 5'-alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates including 3 '-amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters, selenophosphates and boranophosp hates having normal 3 '-5' linkages, 2'-5' link
  • Phosphonomonoester nucleic acids have useful physical, biological and pharmacological properties in the areas of inhibiting gene expression (antisense oligonucleotides, ribozymes, sense oligonucleotides and triplex-forming oligonucleotides), as probes for the detection of nucleic acids and as auxiliaries for use in molecular biology.
  • double-stranded oligonucleotides can comprise nucleosides that are joined by internucleoside linkages that do not have phosphorus atoms.
  • Non-phosphorus containing internucleoside linkages include short chain alkyl, cycloalkyl, mixed heteroatom alkyl, mixed heteroatom cycloalkyl, one or more short chain heteroatomic and one or more short chain heterocyclic.
  • patents that teach the preparation of the above oligonucleosides include, but are not limited to, U.S.: 5,034,506; 5, 166,315; 5, 185,444; 5,214, 134; 5,216, 141; 5,235,033; 5,264,562; 5,264,564; 5,405,938; 5,434,257; 5,466,677; 5,470,967; 5,489,677; 5,541,307; 5,561,225; 5,596,086; 5,602,240; 5,610,289; 5,602,240; 5,608,046; 5,610,289; 5,618,704; 5,623,070; 5,663,312; 5,633,360; 5,677,437; 5,792,608; 5,646,269 and 5,677,439.
  • the MMI type and amide internucleoside linkages are disclosed in the below referenced U. S. patents 5,489,677 and 5,602,240, respectively.
  • Conjugate groups include but are not limited to lipid moieties such as a cholesterol moiety (Letsinger et al., Proc. Natl. Acad. Sci. USA, 1989, 86, 6553-6556), cholic acid (Manoharan et al., Bioorg. Med. Chem. Let., 1994, 4, 1053-1060), a thioether, e.g., hexyl-S- tritylthiol (Manoharan et al., Ann. N.Y. Acad. Sci., 1992, 660, 306-309; Manoharan et al., Bioorg. Med. Chem.
  • lipid moieties such as a cholesterol moiety (Letsinger et al., Proc. Natl. Acad. Sci. USA, 1989, 86, 6553-6556), cholic acid (Manoharan et al., Bioorg. Med. Chem. Let., 1994, 4, 1053-10
  • Acids Res., 1990, 18, 3777-3783 a polyamine or a polyethylene glycol chain (Manoharan et al., Nucleosides & Nucleotides, 1995, 14, 969-973), or adamantane acetic acid (Manoharan et al., Tetrahedron Lett., 1995, 36, 3651- 3654), a palmityl moiety (Mishra et al., Biochim. Biophys. Acta, 1995, 1264, 229-237), or an octadecylamine or hexylamino-carbonyl-oxycholesterol moiety (Crooke et al., J. Pharmacol. Exp. Ther., 1996, 277, 923-937).
  • Double-stranded compounds used in the compositions of the present embodiments can also be modified to have one or more stabilizing groups that are generally attached to one or both termini of double-stranded compounds to enhance properties such as for example nuclease stability. Included in stabilizing groups are cap structures.
  • the terms "cap structure” or “terminal cap moiety,” as used herein, refer to chemical modifications, which can be attached to one or both of the termini of an oligomeric compound. These terminal modifications protect the oligomeric compounds having terminal nucleic acid moieties from exonuclease degradation, and can help in delivery and/or localization within a cell.
  • Particularly suitable 3 '-cap structures of the present embodiments include, for example 4', 5 '-methylene nucleotide; 1 -(beta-D-erythrofuranosyl) nucleotide; 4'-thio nucleotide, carbocyclic nucleotide; 5'-amino-alkyl phosphate; l,3-diamino-2-propyl phosphate, 3- aminopropyl phosphate; 6-aminohexyl phosphate; 1,2-aminododecyl phosphate; hydroxypropyl phosphate; 1,5-anhydrohexitol nucleotide; L-nucleotide; alpha-nucleotide; modified base nucleotide; phosphorodithioate; threo-pentofuranosyl nucleotide; acyclic 3',4'-seco nucleotide; 3,4-dihydroxybutyl nucle
  • 3' and 5 '-stabilizing groups that can be used to cap one or both ends of an oligomeric compound to impart nuclease stability include those disclosed in WO 03/004602.
  • the double-stranded compounds of several embodiments include any pharmaceutically acceptable salts, esters, or salts of such esters, or any other compound which, upon admini- stration to an animal including a human, is capable of providing (directly or indirectly) the biologically active metabolite or residue thereof. Accordingly, for example, the disclosure is also drawn to prodrugs and pharmaceutically acceptable salts of the compounds of the embodiments, pharmaceutically acceptable salts of such prodrugs, and other bioequivalents. For oligonucleotides, examples of pharmaceutically acceptable salts and their uses are further described in U. S. Patent 6,287,860.
  • the compounds and compositions provided herein may also be admixed, encapsulated, conjugated or otherwise associated with other molecules, molecule structures or mixtures of compounds, as for example, liposomes, PEG (e.g. PEG-C-DMA, PEG-DMG), cholesterol, lipids, albumin, nucleic-acid-lipid particles, lipid nanoparticles, micelles, virosomes, or virus like particles (VLP) for assisting in uptake, distribution and/or absorption.
  • PEG e.g. PEG-C-DMA, PEG-DMG
  • cholesterol lipids
  • albumin lipids
  • nucleic-acid-lipid particles lipid nanoparticles
  • micelles virosomes
  • VLP virus like particles
  • compositions provided herein may be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including vaginal and rectal delivery), pulmonary, e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.
  • compositions provided herein include, but are not limited to, solutions, emulsions, foams and liposome-containing formulations.
  • the pharmaceutical compositions and formulations of the present embodiments may comprise one or more penetration enhancers, carriers, excipients or other active or inactive ingredients.
  • formulations are routinely designed according to their intended use, i.e. route of administration.
  • Suitable formulations for topical administration include those in which the compounds of the embodiments are in admixture with a topical delivery agent such as lipids, liposomes, fatty acids, fatty acid esters, steroids, chelating agents and surfactants.
  • a topical delivery agent such as lipids, liposomes, fatty acids, fatty acid esters, steroids, chelating agents and surfactants.
  • Suitable lipids and liposomes include neutral (e.g. dioleoylphosphatidyl DOPE ethanolamine, dimyristoylphosphatidyl choline DMPC, distearolyphosphatidyl choline) negative (e.g. dimyristoylphosphatidyl glycerol DMPG) and cationic (e.g.
  • compositions and formulations for oral administration include powders or granules, microparticulates, nanoparticulates, suspensions or solutions in water or non-aqueous media, capsules, gel capsules, sachets, tablets or minitablets. Thickeners, flavoring agents, diluents, emulsifiers, dispersing aids or binders may be desirable.
  • Suitable oral formulations are those in which oligonucleotides of the embodiments are administered in conjunction with one or more penetration enhancers surfactants and chelators.
  • Suitable surfactants include fatty acids and/or esters or salts thereof, bile acids and/or salts thereof. Suitable bile acids/salts and fatty acids and their uses are further described in U.
  • Transfection reagents commonly used to introduce double- stranded oligonucleotides into cultured cells includes the cationic lipid transfection reagent LIPOFECTIN, LIPOFECTAMINE, LIPOFECTAMINE in OPTI-MEM 1, and by the electroporation method.
  • Gene (or RNA) target quantities obtained by real time PCR are normalized using either the expression level of a gene whose expression is constant, such as cyclophilin A, or by quantifying total RNA using RIBOGREEN (Invitrogen, Inc. Carlsbad, CA). Cyclophilin A expression is quantified by real time PCR, by being run simultaneously with the target, multiplexing, or separately. Total RNA is quantified using RIBOGREEN RNA quantification reagent (Invetrogen, Inc. Eugene, OR). Methods of RNA quantification by RIBOGREEN are taught in Jones, L.J., et al, (Analytical Biochemistry, 1998, 265, 368-374). A CYTOFLUOR 4000 instrument (PE Applied Biosystems) is used to measure RIBOGREEN fluorescence.
  • Quantitation of target DNA levels may be accomplished by quantitative real-time PCR using the ABI PRISM 7600, 7700, or 7900 Sequence Detection System (PE-Applied Biosystems, Foster City, CA) according to manufacturer's instructions. Methods of quantitative real-time PCR are well known in the art.
  • Probes and primers are designed to hybridize to a HBV nucleic acid.
  • Methods for designing real-time PCR probes and primers are well known in the art, and may include the use of software such as PRIMER EXPRESS Software (Applied Biosystems, Foster City, CA).
  • Double-stranded compounds are tested in animals to assess their ability to inhibit expression of HBV and produce phenotypic changes. Testing may be performed in normal animals, or in experimental disease models.
  • siRNA oligonucleotides are formulated in a pharmaceutically acceptable diluent, such as phosphate- buffered saline.
  • Administration includes parenteral routes of administration, such as intraperitoneal, intravenous, subcutaneous, intrathecal, and intracerebroventricular. Calculation of double-stranded oligonucleotide dosage and dosing frequency is within the abilities of those skilled in the art, and depends upon factors such as route of administration and animal body weight.
  • RNA is isolated from liver tissue and changes in HBV nucleic acid expression are measured. Changes in HBV DNA levels are also measured. Changes in HBV protein levels are also measured. Changes in HBV HBeAg levels are also measured. Changes in HBV HBsAg levels are also measured.
  • the individual has been identified as in need of treatment for an HBV-related condition.
  • methods for prophylactically reducing HBV expression in an individual Certain embodiments include treating an individual in need thereof by administering to an individual a therapeutically effective amount of a siRNA compound targeted to an HBV nucleic acid.
  • HBV hepatitis C
  • interferons e.g., interferon alpha-2b, interferon alpha-2a, and interferon alphacon- 1.
  • interferon alpha-2b interferon alpha-2b
  • interferon alpha-2a interferon alpha-2a
  • interferon alphacon- 1 interferon alphacon- 1.
  • pegylated interferon interferon attached to a polyethylene glycol moiety which improves its pharmacokinetic profile.
  • administration of a therapeutically effective amount of a siRNA compound targeted to an HBV nucleic acid is accompanied by monitoring of HBV S antigen (HBsAg) levels in the serum of an individual to determine an individual' s response to administration of the siRNA compound.
  • administration of a therapeutically effective amount of a siRNA compound targeted to an HBV nucleic acid is accompanied by monitoring of HBV E antigen (HBeAg) levels in the serum of an individual to determine an individual' s response to administration of the siRNA compound.
  • An individual's response to administration of the siRNA compound is used by a physician to determine the amount and duration of therapeutic intervention.
  • administration of a double-stranded compound targeted to an HBV nucleic acid results in reduction of HBV expression by at least 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 99%, or a range defined by any two of these values.
  • administration of a siRNA compound targeted to an HBV nucleic acid results in reduced symptoms associated with the HBV-related condition and reduced HBV- related markers in the blood.
  • compositions comprising a double-stranded compound targeted to HBV are used for the preparation of a medicament for treating a patient suffering or susceptible to an HBV-related condition.
  • the double- stranded compounds disclosed are administered in combination with an HCV agent.
  • the HCV compound is administered simultaneously as the siRNA compound; in other embodiments, the HCV compound is administered separately; so that a dose of each of the HCV agent and the siRNA compound overlap, in time, within the patient's body.
  • Each double-stranded siRNA compound listed in Table 1 is targeted to the viral genomic sequence, designated herein as SEQ ID NO: 1 (GENBANK Accession No. U95551.1).
  • SEQ ID NO: 1 GenBANK Accession No. U95551.1
  • Each antisense strand has two mismatched nucleosides inserted at the 3 ' end, as indicated by the asterisk above the relevant nucleoside in the Chemistry column; the remaining nucleosides have 100% complementarity to the target region.
  • Each sense strand has two nucleosides inserted at the 5' end, as indicated by the asterisk above the relevant nucleoside in the Chemistry column; the remaining nucleosides have 100% complementarity to the target region.

Abstract

La présente invention concerne des composés, des compositions, et des méthodes destinées à diminuer l'expression de l'ARNm, de l'ADN et des protéines du virus de l'hépatite B (HBV). De tels méthodes, composés, et compositions sont utiles dans le traitement, la prévention, ou l'amélioration de maladies, troubles ou états pathologiques associés au HBV. Plusieurs modes de réalisation concernent des composés comprenant un oligonucléotide double brin constitué de 10 à 30 nucléosides liés par brin et possédant une séquence comprenant au moins 8 nucléobases contiguës parmi les séquences de nucléobases de la SEQ ID NOs: 30-125.
PCT/US2013/037642 2012-04-20 2013-04-22 Modulation de l'expression du virus de l'hépatite b (hbv) WO2013159109A1 (fr)

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