WO2012174224A2 - Procédés d'administration de produits thérapeutiques à base d'acide nucléique - Google Patents

Procédés d'administration de produits thérapeutiques à base d'acide nucléique Download PDF

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WO2012174224A2
WO2012174224A2 PCT/US2012/042433 US2012042433W WO2012174224A2 WO 2012174224 A2 WO2012174224 A2 WO 2012174224A2 US 2012042433 W US2012042433 W US 2012042433W WO 2012174224 A2 WO2012174224 A2 WO 2012174224A2
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seq
dose amount
sirna
strand
group
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WO2012174224A3 (fr
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Thomas Schluep
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Calando Pharmaceuticals Inc
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Calando Pharmaceuticals Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/0083—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the administration regime
    • 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
    • C12N15/111—General methods applicable to biologically active non-coding nucleic acids
    • 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
    • C12N2310/11—Antisense
    • 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 nucleic acids [NA]
    • 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
    • C12N2320/00—Applications; Uses
    • C12N2320/30—Special therapeutic applications
    • C12N2320/35—Special therapeutic applications based on a specific dosage / administration regimen

Definitions

  • the present application relates to methods of administering a nucleic acid-based therapeutic to treat a disease or disorder in a patient.
  • the methods suitably comprise administering a first dose amount of a nucleic acid-based therapeutic during a first treatment cycle, and administering a second dose amount of the nucleic acid-based therapeutic during subsequent treatment cycles, wherein the first dose amount is lower than the second dose amount.
  • the nucleic acid-based therapeutic is an siRNA that is part of a composition comprising a eyclodextrin polymer.
  • Nucleic acid-based therapeutics have the potential to play a critical role in the treatment and prevention of numerous diseases and disorders, including various cancers, AIDS, neurological disorders, and cardiovascular disorders.
  • Nucleic acid-based therapy centers on the introduction of nucleic acids into the cells or tissue of a patient, followed by processing of the information coded by the nucleic acids introduced.
  • DNA and RNA including plasmids containing transgenes for gene therapy, oligonucleotides for antisense and antigene applications, ribozymes, DNA ⁇ ymes, aptamers, msRNA, antlsense RNA, dsRNA, mRNA and siRNA, have demonstrated potential as therapeutic candidates.
  • RNA vectors include retroviruses, adenoviruses, and adeno-associated viruses.
  • Chemical methods to enhance delivery include calcium phosphate transfectiori, the use of oligonucleotides, lipopiexes and polypiexes, and dendrimers. Direct injection of naked DNA and RNA has also been demonstrated.
  • Injection can be performed directly with a syringe and needle into specific tissue, such as muscle, using particle bombardment (i.e., gene gun) techniques, eleetroporatsors and soitoporation, Direct injection techniques are simple and relatively safe but often result in poor efficiency of gene transfer, and a low level of stable integration of the nucleic acid.
  • particle bombardment i.e., gene gun
  • eleetroporatsors eleetroporatsors and soitoporation
  • RNA interference One class of nucleic acid-based therapeutic is RNA interference
  • dsRN refers to a double stranded RNA molecule capable of RNA interference (RNAi), including short interfering RNA (siRNA) (see for example, Bass, 2001, Nature, 411, 428-429; Elbashir et aL, 2001, Nature, 411, 494-49S and Kreutzer et L, PCT Publication No. WO 00/44895; Zer cka-Goetz et aL PCT Publication No. WO 01/36646; Fire, PCT Publication No. WO 99/32619; Flaetinek et aL, PCT Publication No.
  • RNAi RNA interference
  • siRNA short interfering RNA
  • RNAi provides a useful method of inhibiting or reducing gene expression in vitro or in vivo.
  • RNAi is the intracellular delivery to the specific tissues and organs that express the target gene. Upon introduction, the nucleic acid therapeutic must remain functional and be capable of reaching the cell nucleus, without a significant reduction in efficiency. Additionally, care must be taken to prevent the nucleic acid from initiating an mmune response in the patient Once the therapeutic reaches the cell, integration into the host genome must be prevented in order to avoid influencing expression of the host genes and potentially triggering the expression of an oncogene or destruction of a tumor suppressor gene.
  • methods are provided of administering a nucleic acid- based therapeutic to treat a disease or disorder in a patient.
  • the methods suitably comprise administering a first dose amount of a nucleic acid-based therapeutic during a first treatment cycle, and administering a second dose amount of the nucleic acid-based therapeutic during subsequent treatment cycles.
  • the first dose amount is lower than the second dose amount.
  • the first dose amount is about 9 mg m 2 to about 27 mg/m ⁇ or about 15 mg/ra 2 to about 20 mg/m", or more suitably about 18 mg/m ⁇
  • the second dose amount is about 20 mg/m 2 to about 50 mg m 2 , more suitably about 25 mg/m 2 to about 40 mg m 2
  • the first dose amount is about 20% to about 30% lower, about 30% to about 40% lower, about 40% to about 50% lower, about 50% to about 60% lower, about 60% to about 70% lower, about 70% to about S0% lower, about 80% to about 90% lower, or about 90% to about 99% lower than the second dose amount.
  • the first and subsequent treatment cycles are i i day to 49 day treatment cycles, including 21 day treatment cycles.
  • the first and subsequent treatment cycles comprise administering on days 1 , 3. 8, and 10 of the treatment cycles.
  • the nucleic acid-based therapeutic is an siRNA, dsRNA, miRNA, antisense RNA, aptamer, ribozy ne, or an enzymatic nucleic acid.
  • the siRNA is an siRNA, dsRNA, miRNA, antisense RNA, aptamer, ribozy ne, or an enzymatic nucleic acid.
  • the siRNA is an siRNA, dsRNA, miRNA, antisense RNA, aptamer, ribozy ne, or an enzymatic nucleic acid.
  • the siRNA reduces the expression of a ribonucleotide reductase subunii 2 (R2) in a cell,
  • the siRNA reduces the expression of endothelial PAS domain protein 1 (EPAS1) in a cell
  • the nucleic acid-based therapeutic is part of a composition comprising the nucleic acid-based therapeutic and a cyelodextrm- containmg polymer
  • the composition further comprises a stabilizing agent, for example, a stabilizing agent comprising an adamantane (AD) group and a polyethylene glycol (PEG).
  • the composition further comprises a targeting agent, including a targeted agent comprising an adamantane (AD) group, a polyethylene glycol (PEG) and a targeting ligand, such as transferrin.
  • the cyeiodextrin-containing polymer is a ⁇ - cyclodextr in-containi n g po lymer ,
  • the disease or disorder is selected from the group consisting of cystic fibrosis, Gaucher's disease, muscular dystrophy, AIDS, cancer, progressive heart failure, restenosis, hemophilia and neurological conditions.
  • the cancer is multiple myeloma, leukemia, melanoma, or ovarian cancer,
  • the methods suitably comprise administering during a first treatment cycle a first dose amount of an siRNA composition comprising the siRNA, a cyeiodextrin-containing polymer, a stabilizing agent comprising an adamantane (AD) group and a polyethylene glycol (PEG), and a targeting agent comprising an adamantane (AD) group, a polyethylene glycol (PEG) and a targeting iigand.
  • the methods further comprise administering a second dose amount of the siRNA composition during subsequent treatment cycles.
  • the first dose amount is lower than the second dose amount.
  • the methods comprise administering during a first 21 day treatment cycle, a first dose of about I S rrsg/m 2 of an siRNA composition comprising, the siRNA, a cyclodextrin-containtng polymer, a stabilising agent comprising an adamantane (AD) group and a polyethylene glycol (PEG), and a targeting agent comprising an adamantane (AD) group, a polyethylene glycol (PEG) and transferrin.
  • the methods further comprise administering a second dose of about 25 nig/rn 2 to about 40 mg/m 2 of the siRNA composition during subsequent 21 day treatment cycles.
  • methods are provided of reducing an immune response to siRNA.
  • the methods suitably comprise administering during a first treatment cycle a first dose amount of an siRNA composition comprising the siRNA, a cyclodextrin-containing polymer, a stabilizing agent comprising an adamantane (AD) group and a polyethylene glycol (PEG), and a targeting agent comprising an adamantane (AD) group, a polyethylene glycol (PEG) and a targeting ligand.
  • the methods further comprise administering a second dose amount of the siRNA composition during subsequent treatment cycles.
  • the first dose amount is lower than the second dose amount.
  • the methods reduce levels of IL-6 and/or TNF-a.
  • FIGS. !A-tC show average Cycle I (over Days 1-10) and Cycle 2 ⁇ over Days 22-31) plasma concentrations of lL-10, IL-6 and TNF-a by dose level for an siRNA-cyelodextrin composition.
  • FIG. 2 shows average maximum plasma concentration of IL-10, IL-6 and TNF-a during Cycle I ("C I") as a function of siRNA-cycIodestrin composition dose level.
  • FIG. 3 shows plasma concentrations of cytokines IL ⁇ 6, T F ⁇ a and IL ⁇ 10 in a patient over Cycles 1 ⁇ 6.
  • methods are provided for administering a nucleic acid-based therapeutic to treat a disease or disorder in a patient.
  • the methods suitably comprise administering a first dose amount of a nucleic acid-based therapeutic during a first treatment cycle, and administering a second dose amount of the nucleic ae id-based therapeutic during subsequent treatment cycles.
  • the first dose amount is lower than the second dose amount.
  • nucleic acid-based therapeutic refers to an siRWA, dsRNA, miRNA, antisense RNA, aptamer, ribozyme, or an enzymatic nucleic acid
  • dsRNA refers to a double stranded RNA molecule capable of RNA interference (RNAi), including siRNA (see for example, Bass, 2001 , Nature, 41 1 , 428-429; Elbashir et al, 2001, Nature, 4 i l , 494.498: and Kreutzer et al., PCI Publication No, WO 00/44895; Zemicka- Goetz et al, PCT Publication No. WO 01/36646; Fire, PCX Publication No. WO 99/32 ? 9; P!aetinck et al., PCT Publication No. WO 00/01846; Me! So and Fire, PCX Publication No.
  • RNAi RNA interference
  • RNAi is a term initially applied to a phenomenon observed in plants and worms where double-stranded RNA (dsRN.A) blocks gene expression in a specific and post-transcripiionai manner. RNAi provides a useful method of inhibiting or reducing gene expression in vitro or in vivo.
  • siRNA short interfering RNA f
  • siRNA short interfering nucleic acid
  • the siRNA can be a doubl -stranded polynucleotide molecule comprising self- complementary sense and antisense regions, wherein the antisense region comprises complementarity to a target gene.
  • siRNA can be a single- stranded hairpin polynucleotide having self-complementary sense and antisense regions, wherein the antisense region comprises complementarity to a target gene.
  • the siRNA can be a circular single-stranded polynucleotide having two or more loop structures and a stem comprising self-compienientary sense and antisense regions, wherein the antisense region comprises complementarity to a target gene, and wherein the circular polynucleotide can be processed either in vivo or ff vitro to generate an active siRNA capable of mediating RNAL
  • the si RNA cars also comprise a single stranded polynucleotide having complementarity to a target gene, wherein the single stranded polynucleotide can further comprise a terminal phosphate group, such as a S'-phosphate (see for example Martinez et aL, 2002, Cell, 1 10, 563-574), or S'jS'-diphosphate, n certain embodiments, the siRNAs are non-enzymatic nucleic acids that bind to a target nucleic acid and alter the activity of the target nucleic acid.
  • binding and/or activity of the siRNA may be facilitated by interaction with one or more protein or protein complexes, such as the RNA Induced Silencing Complex (or RISC).
  • the siRNAs comprise a sequence that is complementary to a target sequence along a single contiguous sequence of one strand of the siRNA molecule.
  • the siRNAs of the application contain a nucleotide sequence that hybridizes under physiologic conditions (e.g., in a cellular environment) to the nucleotide sequence of at least a portion of the mRNA transcript for the gene to be inhibited (the "target" gene).
  • the double-stranded RNA need only be sufficiently similar to natural RNA thai it has the ability to mediate RNAL
  • the application has the advantage of being able to tolerate sequence variations that might be expected due to genetic mutation, strain polymorphism or evolutionary divergence.
  • the number of tolerated nucleotide mismatches between the target sequence and the siRNA sequence Is no more than 1 in 5 basepairs, or 1 in 10 basepairs, or 1 in 20 basepairs, or 1 in 50 basepairs. Mismatches in the center of the siRNA duplex are most critical and may essentially abolish cleavage of the target RNA. In contrast, nucleotides at the 3' end of the siRNA strand that is complementary to the target RNA do not significantly contribute to specificity of the target recognition.
  • Sequence identity may be optimized by sequence comparison and alignmemt algorithms known in the art (see Gribskov and Devereux, Sequence Analysis Primer, Stockton Press, 199L and references cited therein) and calculating the percent difference between the nucleotide sequences by, for example, the Smith- Waterman algorithm as implemented in the BESTFIT software program using default parameters (e.g., University of Wisconsin Genetic Computing Group), Greater than 90%, 95%. 96%, 97%, 98%.
  • Altemativeiy ⁇ the duplex region of the R.NA may be defined functionally as a nucleotide sequence that is capable of hybridizing with a portion of the target gene transcript under stringent conditions (e.g handed 400 mM NaCl, 40 mM PIPES H 6.4, 1 rn . EDTA, 50 e C. or 70*C, hybridization for 12-16 hours; followed by washing).
  • the double-stranded structure of dsRNA may be formed by a single self-complementary NA strand, two complementary RNA strands, or a DNA strand and a complementary RNA strand,
  • RNA duplex formation may be initiated either inside or outside the ceil.
  • the RNA may be introduced in an amount which allows delivery of at least one copy per cell
  • Higher doses e.g., at least 5, 10, 100, 500 or 1000 copses per cell
  • Inhibition is sequence-specific m that nucleotide sequences corresponding to the duplex region of the RNA are targeted for inhibition.
  • siRNAs comprise a duplex region about 19-30 nucleotides in length, about 21-27 nucleotides in length, about 21-25 nucleotides in length, or about 21 -23 nucleotides in length.
  • the siRNAs are understood to recruit nuclease complexes and guide the complexes to the target gene transcript by pairing to the specific sequences. As a result, the target gene transcript is degraded by the nucleases in the protein complex.
  • the siRNA molecules comprise a 3' hydroxyl group.
  • the siRNA constructs can foe generated by processing of longer double-stranded RNAs, for example, in the presence of the enzyme dicer, in one embodiment, the Drosophila in vitro system is used, in this embodiment, ds NA is combined with a soluble extract derived from Drosophila embryo, thereby producing a combination. The combination is maintained under conditions in which the dsRNA is processed to RNA molecules of about 21 to about 27 nucleotides,
  • the siRNA molecules can be purified using a number of techniques known to those of skill in the art. For example, gel electrophoresis can be used to purify siR As.
  • non- denaturing methods such as non -denaturing column chromatography
  • chromatography e.g., size exclusion chromatography
  • glycerol gradient centriiugation e.g., glycerol gradient centriiugation
  • affinity purification with antibody e.g., affinity purification with antibody
  • dsRNAs e.g., siRNAs
  • Endogenous RNA polymerase of the treated cell may mediate transcription in vivo, or cloned RNA polymerase can be used for transcription in vitro.
  • dsRNA or siRNA molecules of the application need not be limited to those molecules containing only RNA > but further encompasses chemically-modified nucleotides and non-rsucieotides.
  • the nucleic acid-based therapeutics may include modifications to either the phosphate-sugar backbone or the nucleoside, e.g., to reduce susceptibility to cellular nucleases, improve bioavailability, improve formulation characteristics, and/or change other pharmacokinetic properties.
  • the phosphodiester linkages of natural RNA may be modified to include at least one of a nitrogen or sulfur heteroatom. Modifications in RNA structure may be tailored to allow specific genetic inhibition while avoiding a general response to dsRNA, Likewise, bases may be modified to block the acti vity of adenosine deaminase.
  • the dsRNAs may be produced enzymatically or by partial/total organic synthesis, any modified ribonucleotide can be introduced by in vitro enzymatic or organic synthesis.
  • Methods of chemically modifying RNA molecules can be adapted for modifying dsRNAs (see, e.g., Heidenreich et al (1997) Nucleic Acids Res, 25:776-780; Wilson et al. (1994) J MoS Recog 7:89-98; Chen et al. (1995) Nucleic Acids Res 23:2661-2668; Hirschbdn et al. (199?) Antisense Nucleic Acid Drug Dev 7:55-61).
  • th backbone of an ds NA or siRNA can be modified with phosphorothioates, phosphorarnidate, phosphodithioates, chimeric meihylphosphonate-phosphodiesters, peptide nucleic acids, 5-propynyt- pyrimidine containing oligomers or sugar modifications (e.g., 2' ⁇ substituted ribonucleosides, a-configuration).
  • the dsRNAs of the application lack 2'-hydroxy (2'-OH) containing nucleotides
  • the siRNA molecules comprise a phosphorotbloate sense strand.
  • the siRNA molecules comprise a phosphodiester antisense strand.
  • the first dose amount of the nucleic acid- based therapeutic is in the range of about 5 mg m 2 to about 40 mg/m 2 .
  • BSA body surface area
  • the first dose amount of the nucleic acid-based therapeutic is about 7 mg m 2 to about 30 mg/nr, about 9 mg m ⁇ to about 27 mg/m 2 , about 1 1 mg/m 2 to about 27 mg m 2 , about 15 mg m 2 to about 27 mg/m 2 , about 15 mg/m 2 to about 25 mg m". about 15 mg m 2 to about 23 mg/m 2 , about 15 mg/m 2 to about 20 mg m 2 , including any values in between these ranges, suitably about 15 mg/m 2 , about 16 mg m 2 , about 17 mg rn J ⁇ about 1 mg/m*. about 1 mg/m ⁇ or about 20 mg/m 2 .
  • the second dose amount of the nucleic acid-based therapeutic is about 10 mg/m 2 to about 50 mg m 2 , suitably about 15 mg/m 2 to about 50 mg/m 2 , about 18 mg/m 2 to about 50 m m , about 20 mg m' '' to about 50 mg/m 2 , about 20 mg m 2 to about 45 mg/m i .
  • the first dose amount of the nucleic acid- based therapeutic is in the range of at least about 5 mg/m 2 to at least about 40 g/m .
  • the first dose amount of the nucleic acid-based therapeutic is at least about 7 mg/m 2 to about at least 30 mg 2 , at least about 9 mg/m 2 to about at least 27 mg/m 2 , at least, about 11 mg m 2 to at least about 27 mg/m 2 , at least about 15 mg/m 2 to at least about 27 mg/m 2 , at least about 15 mg/m 2 to about at least 25 g/m 2 , at least about 15 mg/m 2 to at least about 23 mg/m 2 , at least about 15 mg/m 2 to at least about 20 mg m 2 , including any values in between these ranges, suitably at least about 15 mg/m 2 , at least about 16 mg/m' 1 . at least about 1 mg/m 2 , at least about 18 mg/m 2 , at least
  • the second dose amount of the nucleic aeid-hased therapeutic is at least about 10 mg/mf to at least about 50 mg/m 2 , suitably at least about 15 mg/m 2 to at least about 50 mg/m 2 , at least about I mg/m 2 to at least about 50 mg m 2 , at least about 20 mg m 2 to at least about 50 mg/m 2 , at least about 20 mg m 2 to at least about 45 mg m 2 , at least about 20 mg/m 2 to at least about 40 mg m 2 , at least about 25 mg m 2 to at least about 40 mg/m 2 , including values between these ranges, suitably at least about 25 mg/m 2 , at least about 26 mg/m 2 , at least about 27 mg/rrs 2 , at least about 28 mg/m 2 , at least about 29 mg/m 2 , at least about 30 mg m 2 , at least about 31 mg/m 2 , at least about 32 mg/m 2 ,
  • the first dose amount is about 1% to about 10% lower, about 10% to about 20% Sower, about 20% to about 30% lower, about 30% to about 40% lower, about 40% to about 50% Sower, about 50% to about 60% lower, about 60% to about 70% lower, about 70% to about 80% lower, about 80% to about 90% lower, or about 90% to about 99% lower than the second dose amount.
  • the first and/or second dose amounts can be administered to the patient via any suitable administration route, including, but not limited to, topical, intravenous, intramuscular, intraarterial, intrathecal intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal intrasternal injection and infusion, and intrahepatic arterial administration (including intrahepatic injection and intrahepatic infusion),
  • an infusion e.g., an intravenous infusion
  • the administration can take place over any suitable infusion time, for example, over the course of at least about 15 minutes, at least about 30 minutes, at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, etc.
  • treatment cycle refers to the period over which the nucleic acid-based therapeutic is administered to a patient.
  • the treatment cycle begins on the first day thai the treatment is administered and ends on the day prior to beginning a new, subsequent treatment cycle, or ends on the last day of ail administrations.
  • the treatment cycle is a 7 day to a 60 day treatment cycle, suitably a 7 day to 42 day treatment cycle, more suitably a 7, 8, % 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 2 h 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 or 42 day treatment cycle.
  • Other treatment cycles can be determined and utilized by a person of ordinary skill in the art.
  • the first dos amount is administered to the patient on the first day of the first treatment cycle (i.e., day 1 of the first treatinent cycle).
  • “subsequent treatment days of the treatment cycle” refers to any day after day I of a treatment cycle.
  • the first dose is then suitably administered on subsequent treatment days of the first treatment cycle.
  • the first dose amount can be administered on days 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 etc., of the first treatment cycle, or on ny individual day(s) or combination of day ⁇ s) of this first treatment cycle.
  • the first dose amount can be administered on day 1 , day 3, day 8 and day 10 of the first treatment cycle (i.e., a 21 day treatment cycle), or day 1, day 3, day 8, day 10, day 14 of the first treatment cycle, or on every day, or any combination of days, of the first treatment cycle,
  • the second dose amount of the nucleic acid-based therapeutic is suitably administered during subsequent treatment cycles.
  • the second dose amount is administered during subsequent treatment cycles, i.e., any or all subsequent treatment cycles following the first treatment cycle.
  • the first treatment cycle can comprise an 1 1 day to a 49 day treatment cycle, including a 21 day treatment cycle.
  • Subsequent treatment cycles can also comprise 1 1 days to 49 days, following the end of the first treatment cycle.
  • the total treatment regimen comprises all of the treatment cycles administered to a patient, i.e., the first treatment cycle and any and all subsequent treatment cycles.
  • the total treatment regimen will comprise a first treatment cycle, followed by any suitable number of subsequent treatment cycles, i.e., at least S, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc., subsequent treatment cycles.
  • the first treatment cycle and subsequent treatment cycles can comprise the same number of total days (i.e., 14, 21, 28, days, etc), or they can comprise different numbers of total days.
  • the first treatment cycle can comprise more total treatment days (i.e., 28 days/treatment cycle), and the subsequent treatment cycles can comprise less total treatments days (I.e., 21 days/treatment cycle).
  • the first treatment cycle can comprise less total treatment days (i.e., 21 days/treatment cycle), and the subsequent treatment cycles can comprise more total treatments days (Le., 28 days/treatment cycle).
  • Other total numbers of treatment days, as described herein, can be utilized as well.
  • the second dose is then suitably administered on subsequent treatment days of the subsequent treatment cycles.
  • the second dose amount can be administered on days 2, 3. 4, 5, 6, 7, 8, 9, 10, 1 1 » 12» 13* 14 » 15, 16, 17, I S, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, etc., of the subsequent treatment cycle(s), or on any individual day(s), or combination of day(s) of the subsequent treatment cycle(s).
  • the second dose amount can be administered on day 1, day 3, da S and day 10 of the subsequent treatment cyele(s) (i.e..
  • the second dose amount can be administered on any subsequent day of the subsequent treatment cycle(s), and can be repeated on any subsequent day or subsequent days of the subsequent treatment eycle(s).
  • the fsrst treatment cycle and subsequent treatment cycles can comprise administering on days 1, S, 15, for every 28 days of a treatment cycle, on days 1 and 15 of every 28 days of a treatment cycle, or on days 1 and 8 of every 2! day treatment cycle, or on every day, or any combination of days, of a 21 or 28 day treatment cycle,
  • the second dose amount is administered during any and all subsequent treatment cycles.
  • the second dose amount can be varied from one subsequent treatment cycle to another subsequent treatment cycle, arid can either be more or less than any other subsequent treatment cycle.
  • a treatment regimen comprises a first treatment cycle followed by 1 , 2, 3, 4 or 5 subsequent treatment cycles.
  • the firsi dose amount Is administered during the first treatment cycle, and the second dose amount is administered during subsequent treatment cycles, e.g., dur ng subsequent treatment cycles 2, 3 S 4, 5 S etc.
  • the first dose amount can be administered during the first treatment cycle, as well as any of the subsequent treatment cycles, to further increase the toierance of the patient.
  • the first dose amount can be administered during the first treatment cycle, as well as during a second, third, fourth, etc., subsequent treatment cycle, and then the second dose amount can be administered during further subsequent treatment cycles.
  • the nucleic acid-based therapeutic is an siRNA.
  • the siRMA reduces the expression of a ribonucleotide reductase subunit 2 (R2) of a ceil.
  • R2 ribonucleotide reductase subunit 2
  • Exemplary siRNA sequences that reduce the expression of 2 are known in the art, and disclosed for example, in U.S. Patent No. 7,427,605, the disclosure of which is incorporated by reference herein in its entirety.
  • the siRNA comprises a first strand of 15 to 30 nucleotides In length comprising a sequence selected from the group consisting of SEQ ID NOs: 1-3 as set forth in Table I below, and (ii) a second strand of 15 to 30 nucleotides In iersgth, wherein at least 12 nucleotides of the first and second strands are complementary to each other and form a double-stranded nucleic acid under physiological conditions.
  • the first strand comprises a sequence selected from, the group consisting of SEQ ID NOs: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 2S, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90 and 92 of Table 2
  • the second strand comprises a sequence selected from the group consisting of SEQ ID NO: 5, 7, 9, 1 1 , 13, 15, 1.7, 19, 2L 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61 , 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, 91 and 93of Tabic 2.
  • the first strand of the siRNA consists of SEQ ID NO: 60 and the second strand consists of SEQ NO: 1, as set forth in Table 2,
  • the siRNA reduces the expression of endothelial PAS domain protein 1 (EPAS1) in a cell.
  • EPAS1 endothelial PAS domain protein 1
  • Exemplary siRNA sequences that reduce the expression of EPAS 1 are well known in the art, including those disclosed in Published U.S. Patent Application No. 2010/0010071, the disclosure of which is incorporated by reference herein in its entirety.
  • the siRNA comprises: (i) a first strand of about 15 to about 30 nucleotides in length that comprises a sequence selected from SEQ ID NOs: 94-96 of Table 3, and (ii) a second strand of about 15 to about 30 nucleotides in length, wherein at least 12 nucleotides of the first and second strands arc complementary to each other and form a double- stranded nucleic acid under physiological conditions.
  • the first strand comprises a sequence selected from SEQ ID NOs: 97, 99, 101, 103, 105, 107, 109, 111, 113, 1 15. 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149, 151 , 153, 155, 157, 159, 161, 163, 165, 167, 169, 171 and 173 of Table 4; the second strand comprises a sequence selected front SEQ D NO: 98, 100, 102, 104, 106, 108, 110, 112, 1 14, 1 16, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172 and 174
  • the nucleic acid-based therapeutic is part of a composition comprising the nucleic acid-based therapeutic a d a polymer.
  • the polymer may be a linear or branched polymer.
  • the polymer may be a homopoly ier or a co-polymer, If a co-polymer is used, the co-polymer may be a random copolymer or a branched co-polymer.
  • the polymer is water-dlsperstble and more preferabiy water soluble.
  • suitable polymers include, but are not limited to polysaccharides, polyesters, polyamldes, polyeihers, polycarbonates, polyacrylates. etc.
  • the polymer should have a low toxicity profile and preferably are not toxic or cyctotoxic.
  • a suitable polymer for use in a composition of the Invention is a cyclodextrin-based polymer (i.e., to form an siRNA-cyelodextrin composition).
  • Water soluble linear eyclodextrin copolymers having molecular weights in the range of 3,000 to 100,000 are suitable and those having molecular weights of 3,000 to 50,000 are more suitable,
  • the polymer in the composition may be a single polymer or a mixture of two or more polymers, which can be the same or different polymers.
  • Each polymer of the composition can further contain or may be further modified to contain a crossHnking group through, which association of the polymers to form the particulate composite can be achieved.
  • At least one polymer of the compositions is suitable a polymer capable of forming an inclusion complex, as disclosed in U.S. Patent No. 7,166,302, the disclosure of which is incorporated by reference herein in its entirety.
  • a "polymer capable of forming an inclusion complex” can he any polymer capable of one or more host-guest associations via nonbonding interactions ⁇ e.g. van der Waals forces, hydrogen bonding, dipole-dipole interactions, ion- paring, soluophobie interactions, etc.) with another compound (the eomplexing agent) or s hstkuent on a compound.
  • At least one polymer has host or guest functionality to form an inclusion complex with a compiexing agent or a substkuent on the complexing agent.
  • the host or guest functionality may be part of the polymer backbone or may be present as a substituent or in a pendant or branched chain.
  • An example of a polymer having host functionality in the polymer backbone is a linear cycSodextrsn polymer.
  • An example of a polymer having guest functionality not as part of the polymer backbone would he a polymer having pendant adamantane groups.
  • Suitable "hosts” which may be employed with the polymer include, but are not limited to, carceronds, cavitands, crown ethers, crypiands, cucurbiiuriis, calixarenes, spherarsds and the like,
  • inclusion guests suitable for such hosts include those known in the art such as, but not limited to, adamantane, diadamantane, naphthalene, and cholesterol,
  • the polymer used to form the compositions is a cyciodextriu-containing polymer, more suitably a substantially linear cyclodextrin polymer.
  • the polymer can also be a polyethyleneimine (PEl) or a polymer having pendant cyclodexlrms.
  • a linear eyclodextrin copolymer is a polymer containing eyclodextrin moieties as an integral part of its polymer backbone. Polymers having pendant eyclodextrin moieties not a part of the main polymer chain but rather attached off the polymer backbone can also be used in the compositions described herein.
  • a linear cyciodextrin-conteimng polymer can be any linear polymer containing at least one eyclodextrin moiety as part of the polymer backbone.
  • the cycSodexirin-contaming polymer is preferably water-soluble. More suitably, the linear c clodextrin-containing polymer is a linear eyclodextrin copolymer or a linear oxidized eyclodextrin copolymer.
  • the eyclodextrin groups within the polymer provide host functionality to the polymer allowing it to form inclusion complexes.
  • the substantially linear polymer capable of inclusion complex formation can further contain or can be further modified to contain an additional functional group (e.g. thiol group).
  • the polymer is a cyclodextrin-containing polymer.
  • exemplary eyclodextrin polymers for use in the methods described herein include ⁇ -cyeiodextnn poiymers.
  • Examples of p-cyclodextrin polymers for use in the methods described herein are well known in the art, and are disclosed for example, In U.S. Patent Nos. 6,509.323; 6,884,789; 7,091,192 and 7,270,808, the disclosures of each of which are incorporated by reference herein in their entireties,
  • the eyclodexrin polymer is a water-soluble., linear eyclodextrin copolymer comprising repeating units of formula la, lb or both: la
  • C is a substitiiied or nnsitbstituted cyclodexirin monomer and A is a co onomer bound to cyclodexirin €.
  • the cyclodexirin is a comonomer of an ot, ⁇ . or ⁇ -eyclodextrin, or combination thereof.
  • the ⁇ -eyc!odexrin polymer of the compositions is represented below:
  • Ihe composition further comprises a stabilizing agent.
  • Exemplary stabilizing agents include those disclosed in U,S. Patent. NGS, 7,018,609 and 7, 166,302, the disclosures of which are incorporated by- reference herein in their entireties, in U.S. Patent NGS. 7,018,609 and 7, 166302, exemplary stabilizing agents are often referred to as complexmg agents.
  • the stabilizing agent comprises an adaman ane (AD) group a polyethylene glycol (PEG),
  • AD adaman ane
  • PEG polyethylene glycol
  • Such stabilizing agents include, tor example agent shown below.
  • Any suitable molecular weight PEG can be used in the stabilizing agents, including for example, PEG 500 to PEG 10,000, and particularly PEG 600, PEG 3400, and PEG 5000,
  • compositions suitably also comprise a targetmg agent.
  • the targetmg agent can be any agent (or multiple agents) that allows for targeting and/or binding to a desired cell.
  • targeting and binding to a ceil may include cell receptor attachment which in turn may lead to receptor mediated endocytosis.
  • the targeting agent comprises an adaniantane (AD) group, a polymer, such as a poly(ethylcne glycol) (PEG) and a targeting ligand.
  • AD adaniantane
  • PEG poly(ethylcne glycol)
  • Any suitable molecular weight PEG can be utilized in the targeting agents described herein,
  • Suitable targeting ligands include, but are not limited to. vitamins (e.g. folic acid), proteins (e.g. transferrin, and monoclonal antibodies), monosaccharides (e.g. galactose), peptides, and polysaccharides.
  • ligand may vary depending upon the type of delivery desired, If two or more ligands or targeting agents are attached, the ligands/targeting agents may be the same or different, As another example, the ligand may be membrane permeabili ing or membrane permeable agent such as the TAT protein from HiV-h
  • the TAT protein is a viral franseriptlonal activation that is actively imported into the ceil nucleus. Torchtlin, V. P. et at FN AS, 98, 8786 8791 , (2001).
  • the targeting Hgand is a transferrin (Tf) molecule.
  • exemplary diseases and disorders that can he treated include, but are not limited to, cystic fibrosis, Gaucher's disease, muscular dystrophy, AIDS, cancer, progressive heart failure, restenosis, hemophilia and neurological conditions, in exemplary embodiments, the disease or disorder is cancer, Including for example, multiple myeloma, leukemia, melanoma, or ovarian cancer.
  • methods are provided of administering an siRNA to treat a disease or disorder in a patient.
  • the methods suitably comprise administering during a first treatment cycle a first dose amount of an siRNA composition comprising the siRNA, a eyciodextrin-eontaining polymer, a stabilizing agent comprising an adamantane (AD) group and a polyethylene glycol (PEG), and a targeting agent comprising an adamantane (AD) group, a polyethylene glycol (PEG) and a targeting Hgand.
  • a second dose amount of the siRNA composition is administered during subsequent treatment cycles.
  • the first dose amount is lower than the second dose amount.
  • the first dose amount is about 18 mg/ ' ra ⁇ and the second dose amount is about 25 g/m 2 to about 40 mg/m 2 .
  • the first dose amount is about 20% to about 30% lower, about 30% to about 40% lower, about 40% to about 50% lower, about 50% to about 60% lower, about 60% to about 70% lower, about 70% to about 80% lower, about 80% to about 90% Sower, or about 90% to about 99% lower than the second dose amount,
  • J Exemplary treatment cycles are described throughout, and Include for example, a first and subsequent treatment cycles of 21 days.
  • the first dose amount and the second dose amount are administered on days 1, 3, 8, and/or ⁇ 0 of the treatment cycles.
  • siRNAs are described throughout, and include siRNAs that reduce the expression of a ribonucleotide reductase subunit 2 (R2) n a ceil and siRNAs that reduce the expression of endothelial PAS domain protein 1 (EPAS1) In a cell. Suitable sequences for such siRNAs arc described in the tables herein and in U.S. Patent No. 7,427,605 and Published U.S. Patent Application No. 2010/0010071.
  • R2 ribonucleotide reductase subunit 2
  • EPAS1 endothelial PAS domain protein 1
  • the targeting ligand of the targeting agent can be any suitable ligand. including for example, transferrin.
  • methods for administering an sIRNA to treat a disease or disorder in a patient.
  • the methods suitably comprise administering during a first 21 day treatment cycle, a first dose of about 18 mg/m * of an siRNA composition.
  • the siRNA composition suitably comprises the siRNA, a cyeiodextrin-eonta mg polymer, a stabilizing agent comprising an adamantane (AD) group and a polyethylene glycol (PEG), and a targeting agent comprising an adamantane (AD) group, a polyethylene glycol (PEG) and transferrin.
  • a second dose of about 25 mg/ ⁇ to about 40 mgfm 1 of the siRNA composition Is administered during subsequent 2! day treatment cycles,
  • the first dose and second dose are administered on days ! 5 3 5 8, arid/or 10 of the treatment cycles.
  • Suitable si NAs include siRNAs that reduce the expression of a ribonucleotide reductase subunit 2 (R2) in a cell and siRNAs that reduce the expression of endothelial PAS domain protein 1 (EPAS1 ) in a cell. Exemplary sequences for these siRNAs are described herein,
  • methods are provided of reducing an immune response to siRNA.
  • the methods suitably comprise, administering during a first treatment cycle a first dose amount of an siRNA composition comprising, the siRNA, a cyciodextrin-eontainmg polymer, a stabilizing agent comprising an adamantane (AD) group and a polyethylene glycol (PEG), and a targeting agent comprising an adamantane (AD) group, a polyethylene glycol (PEG) and a targeting Hgand.
  • the methods suitably comprise administering a second dose amount of the siRNA composition during subsequent treatment cycles.
  • the first dose amount is lower than the second dose amount.
  • the methods reduce the level of iL-6 or TNF-a produced by the patient.
  • the levels of other cytokines e.g., IL-10, 1L ⁇ 2 5 IL4, IFN-y, IL ⁇ 12p40 and lL12p70
  • IL-10, 1L ⁇ 2 5 IL4, IFN-y, IL ⁇ 12p40 and lL12p70 can also be modified (i.e., increased or decreased) as a result of the methods described herein,
  • Cycle 1 proinflammatory cytokine levels were consistently elevated but showed a decreasing trend towards a lower maximum concentration (c fE!8x ) in Cycle 2,
  • the anti-inflammatory cytokine IL-10 showed the opposite trend, with e max increasing during Cycle 2 (vs. Cycle I).
  • Table 6 Changes in T F ⁇ levels between Cycles 1 and 2 for subjects who received more than one cycle of the siRNA-cyeiodextrm composition. Number of subjects who received 2 or more cycles (n) and total number of subjects per cohort (N) are listed in column "n N”.
  • Table 7 Changes In IL ⁇ 6 levels between Cycles I nd 2 for subjects who received more than one cycle of the siRNA-cyclodextrm composition , Number of subjects who received 2 or more cycles (n) and total number of subjects per cohort. (N) are listed in column * n/NP ⁇
  • Table 8 Changes in IL-IG levels between Cycles 1 and 2 for subjects who received more than one cycle of the siRNA-cyclodextrin composition. Number of subjects who received 2 or more cycles (n) and total number of subjects per cohort (N) are listed in column "n N”.

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Abstract

La présente invention concerne des procédés d'administration d'un produit thérapeutique à base d'acide nucléique pour traiter une maladie ou un trouble chez un patient. Les procédés comprennent de façon appropriée l'administration d'une première quantité posologique d'un produit thérapeutique à base d'acide nucléique au cours d'un premier cycle de traitement et l'administration d'une seconde quantité posologique du produit thérapeutique à base d'acide nucléique au cours de cycles de traitement ultérieurs, la première quantité posologique étant inférieure à la seconde quantité posologique. Dans divers modes de réalisation, le produit thérapeutique à base d'acide nucléique est un siARN qui fait partie d'une composition comprenant un polymère cyclodextrine.
PCT/US2012/042433 2011-06-17 2012-06-14 Procédés d'administration de produits thérapeutiques à base d'acide nucléique Ceased WO2012174224A2 (fr)

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