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 The leading web portal for pharmacy resources, news, education and careers September 22, 2017
Pharmacy Choice - Pharmaceutical News - "Methods and Compositions for Treating a Subject with a Smad7 Antisense Oligonucleotide" in Patent Application Approval Process (USPTO 20170240893) - September 22, 2017

Pharmacy News Article

 9/14/17 - "Methods and Compositions for Treating a Subject with a Smad7 Antisense Oligonucleotide" in Patent Application Approval Process (USPTO 20170240893)

By a News Reporter-Staff News Editor at Politics & Government Week A patent application by the inventor Monteleone, Giovanni (Grottaferrata, IT), filed on October 16, 2015, was made available online on August 31, 2017, according to news reporting originating from Washington, D.C., by VerticalNews correspondents.

This patent application is assigned to Nogra Pharma Limited.

The following quote was obtained by the news editors from the background information supplied by the inventors: "Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract suffered by approximately one million patients in the United States. The two most common forms of IBD are Crohn's disease (CD) and ulcerative colitis (UC). Although CD can affect the entire gastrointestinal tract, it primarily affects the ileum (the distal or lower portion of the small intestine) and the large intestine. UC primarily affects the colon and the rectum. Current treatment for both CD and UC include aminosalicylates (e.g., 5-aminosalicylic acid, sulfasalazine, and mesalamine), antibiotics (e.g., ciprofloxacin and metronidazole), corticosteroids (e.g., budesonide or prednisone), immunosuppressants (e.g., azathioprine or methotrexate), and tumor necrosis factor (TNF) antagonists (e.g., infliximab (Remicade.RTM.)). Patient response to these therapies varies with disease severity, and it can vary over cycles of active inflammation and remission. Moreover, many of the current therapies for IBD are associated with undesirable side effects.

"Although the etiologies of CD and UC are unknown, both are considered inflammatory diseases of the intestinal mucosa. Recent studies have demonstrated that TGF-.beta.1 acts as a potent immunoregulator able to control mucosal intestinal inflammation. TGF-.beta.1 binds a heterodimeric transmembrane serine/threonine kinase receptor containing two subunits, TGF-.beta.1 R1 and TGF-.beta.1 R2. Upon ligand binding, the TGF-.beta.1 R1 receptor is phosphorylated by the constitutively active TGF-.beta.1 R2 receptor and signal is propagated to the nucleus by proteins belonging to the SMAD family. Activated TGF-.beta.1 R1 directly phosphorylates SMAD2 and SMAD3 proteins, which then interact with SMAD4. The complex of SMAD2/SMAD3/SMAD4 translocates to the nucleus and modulates the transcription of certain genes.

"Additional studies have demonstrated that another SMAD protein, SMAD7, also plays a role in inflammation. SMAD7, an intracellular protein, has been shown to interfere with binding of SMAD2/SMAD3 to the TGF-.beta.1 R1, preventing phosphorylation and activation of these proteins. Further, increased expression of SMAD7 protein is associated with an inhibition of TGF-.beta.1 mediated-signaling. Mucosal samples from IBD patients are characterized by high levels of SMAD7 and reduced levels of phosphorylated-SMAD3 indicating that TGF-.beta.1-mediated signaling is compromised in these patients.

"Recent studies have focused on SMAD7 as a target for treating patients suffering from IBD. Such therapies include anti-SMAD7 antisense therapies."

In addition to the background information obtained for this patent application, VerticalNews journalists also obtained the inventor's summary information for this patent application: "The present invention is based on the development of methods for treating patient having inflammatory bowel disease using antisense therapeutics directed against SMAD7 that are tailored to the particular polymorphic form(s) of SMAD7 present in the patient. In a particular example, the presence of a single nucleotide polymorphism (Reference SNP rs144204026) that is present within nucleotides 108-128 of the coding sequence of SMAD7, which corresponds to the region of the SMAD7 mRNA targeted by the antisense therapeutic Mongersen, can make it desirable to target this region using a modified form of Mongersen that includes the polymorphism. Accordingly, the present invention features methods for treating subjects having polymorphism(s) in the SMAD7 mRNA sequence using an antisense therapeutic having a sequence specific for (e.g., matches exactly) the polymorphic gene sequence. The invention also features antisense oligonucleotides that include the polymorphic sequence.

"Accordingly in a first aspect, the invention features a method for treating or managing inflammatory bowel disease (IBD; e.g., Crohn's disease (CD) or ulcerative colitis (UC)) in a patient having IBD that carries at least one copy of a first polymorphic form of SMAD7 that differs from the consensus SMAD7 nucleotide sequence. The method includes administering to said patient an effective amount of a first SMAD7 antisense oligonucleotide that specifically targets said first polymorphic form of SMAD7. The polymorphic form of SMAD7 may include a single nucleotide polymorphism (SNP) and/or may include a polymorphism listed in Table 1 or in Table 2. The first polymorphic form may include a polymorphism in the region corresponding to nucleic acid positions 108-128 of SEQ ID NO:1 (e.g., an adenosine ('A') or a guanine ('G') at position 114 of SEQ ID NO:1); for example, where the polymorphic form includes the nucleic acid sequence of SEQ ID NO:9 (5'-GCTGCGGAGAGAAGGGGCGAC-3'). In some embodiments, the first polymorphic form may include the nucleic acid sequence of SEQ ID NO:3 (5'-GCTGCGGGGAGAAGGGGCGAC-3'). In particular embodiments, the first SMAD7 antisense oligonucleotide includes the nucleotide sequence of SEQ ID NO:11 (5'-GTCGCCCCTTCTCTCCGCAGC-3'), for example, where the first SMAD7 antisense oligonucleotide is an antisense oligonucleotide phosphorothioate including the following sequence: 5'-GTXGCCCCTTCTCTCXGCAGC-3' (SEQ ID NO:13) where X is 5-methyl-2'-deoxycytidine and where all internucleotide linkages are phosphorothioate linkages. In other particular embodiments, the first SMAD7 antisense oligonucleotide includes the nucleotide sequence of SEQ ID NO:5 (5'-GTCGCCCCTTCTCCCCGCAGC-3'), for example, where the first SMAD7 antisense oligonucleotide is an antisense oligonucleotide phosphorothioate including the following sequence: 5'-GTXGCCCCTTCTCCCXGCAGC-3' (SEQ ID NO:7) where X is 5-methyl-2'-deoxycytidine and where all internucleotide linkages are phosphorothioate linkages.

"In another aspect, the invention features a method for treating or managing IBD (e.g., CD or UC) in a patient having IBD. The method includes (a) analyzing the presence or absence of one or more SMAD7 polymorphic forms in the patient; and (b) administering one or more SMAD7 antisense oligonucleotides to the patient, based on the presence or absence of said polymorphic forms, where: (i) if a first SMAD7 polymorphic form (e.g., the wild type form) is present in the patient, then administering to the patient a first SMAD7 antisense oligonucleotide targeting the first SMAD7 polymorphic form; or (ii) if a second SMAD7 polymorphic form is present in the patient, then administering to the patient a second SMAD7 antisense oligonucleotide targeting the second SMAD7 polymorphic form; or (iii) if the first and the second SMAD7 polymorphic forms are present in the patient, then administering to the patient one or both of the first and the second SMAD7 antisense oligonucleotide targeting the first and the second SMAD7 polymorphic forms. The polymorphism can include an SNP and/or can include a polymorphism listed in Table 1 or in Table 2. The first polymorphism can occur in the region corresponding to nucleic acid positions 108-128 of SEQ ID NO:1 (e.g., where the first SMAD7 polymorphic variant includes a guanine ('G') at position 114 of SEQ ID NO:1). The second SMAD7 polymorphic form can include an adenine ('A') at position 114 of SEQ ID NO:1. In certain embodiments, the first SMAD7 polymorphic form includes the nucleic acid sequence of SEQ ID NO:3 (5'-GCTGCGGGGAGAAGGGGCGAC-3'). In particular embodiments, the first SMAD7 antisense oligonucleotide includes the nucleotide sequence of SEQ ID NO:5 (5'-GTCGCCCCTTCTCCCCGCAGC-3'), for example, where the first SMAD7 antisense oligonucleotide is an antisense oligonucleotide phosphorothioate including the following sequence: 5'-GTXGCCCCTTCTCCCXGCAGC-3' (SEQ ID NO:7) where X is 5-methyl-2'-deoxycytidine and where all internucleotide linkages are phosphorothioate linkages. In certain embodiments, the second SMAD7 polymorphic form includes the nucleic acid sequence of SEQ ID NO:9 (5'-GCTGCGGAGAGAAGGGGCGAC-3'). In particular embodiments, the second SMAD7 antisense oligonucleotide includes the nucleotide sequence of SEQ ID NO:11 (5'-GTCGCCCCTTCTCTCCGCAGC-3'), for example, where the second SMAD7 antisense oligonucleotide is an antisense oligonucleotide phosphorothioate including the sequence 5'-GTXGCCCCTTCTCTCXGCAGC-3' (SEQ ID NO:13) where X is 5-methyl-2'-deoxycytidine and where all internucleotide linkages are phosphorothioate linkages. The presence or absence of the one or more SMAD7 polymorphic forms may be analyzed by DNA sequencing, by gene-expression profiling, using next-generation sequencing, or using gene expression microarray analysis. The presence or absence of the one or more SMAD7 polymorphic forms may be analyzed in a sample (e.g., a liquid, a biopsy sample, or a tissue sample) obtained from the patient.

"In any of the above aspects, the first and/or the second SMAD7 antisense oligonucleotide may be administered to the patient having IBD at a dose of between 10 mg/day to about 300 mg/day, for example, at a dose of about 10 mg/day, 20 mg/day, about 30 mg/day, about 40 mg/day, about 50 mg/day, about 60 mg/day, about 70 mg/day, about 80 mg/day, about 90 mg/day, about 100 mg/day, about 110 mg/day, about 120 mg/day, about 130 mg/day, about 140 mg/day, about 150 mg/day, about 160 mg/day, about 170 mg/day, about 180 mg/day, about 190 mg/day, about 200 mg/day, about 210 mg/day, about 220 mg/day, about 230 mg/day, about 240 mg/day, about 250 mg/day, about 260 mg/day, about 270 mg/day, about 280 mg/day, about 290 mg/day, or about 300 mg/day. In particular embodiments, the first and/or the second SMAD7 antisense oligonucleotide is administered at a dose of about 40 mg/day, about 80 mg/day, or about 160 mg/day.

"In another aspect, the invention features: (a) a SMAD7 antisense oligonucleotide that includes the nucleotide sequence of SEQ ID NO:11, (b) a SMAD7 antisense oligonucleotide that includes the nucleotide sequence of SEQ ID NO:13, where X is a nucleotide including 5-methyl-2'-deoxycytidine and where all internucleotide linkages are phosphorothioate linkages; or a SMAD7 antisense oligonucleotide that includes the nucleotide sequence of SEQ ID NO:13, where X is 5-methyl-2'-deoxycytidine, or a complement thereof. The SMAD7 antisense oligonucleotide may include at least one internucleotide linkage that is a phosphorothioate linkage, e.g., where all internucleotide linkages are phosphorothioate linkages. The oligonucleotide may have 2'-deoxyribonucleotides replaced by corresponding ribonucleotides. The invention also features a pharmaceutical composition (e.g., a composition suitable for oral administration) including the SMAD7 antisense oligonucleotide and a pharmaceutically acceptable adjuvant and/or excipient.

"In another aspect, the invention features a method of treating IBD (e.g., CD or UC), including administering (e.g., orally) to a patient in need thereof an effective amount of the SMAD7 antisense oligonucleotide of the previous aspect, where the SMAD7 antisense oligonucleotide is effective to treat IBD.

"Antisense oligonucleotides are short synthetic oligonucleotide sequences that are complementary to a messenger RNA (mRNA) transcribed from a target gene (e.g., a polymorphic form of SMAD7). Antisense oligonucleotide sequences hybridize to the mRNA and produce a double-strand hybrid that can lead to the activation of ubiquitary catalytic enzymes, such as RNase H, which degrades DNA/RNA hybrid strands, thus preventing protein translation. Without being bound by theory, an antisense oligonucleotide provided herein can hybridize to its target sequence as RNA or DNA. Thus, even if a DNA sequence is provided as target, the corresponding RNA sequence (including uracil instead of thymine) is included.

"In another aspect, the present invention provides an antisense therapeutic directed against SMAD7 as described above for use as a medicament. The present invention provides an antisense therapeutic directed against SMAD7 which has been tailored to the particular polymorphic form(s) of SMAD7 present in the patient, for use in a method for treating patient having inflammatory bowel disease. In a particular example, the presence of a single nucleotide polymorphism (Reference SNP rs144204026) that is present within nucleotides 108-128 of the coding sequence of SMAD7, which corresponds to the region of the SMAD7 mRNA targeted by the antisense therapeutic Mongersen, can make it desirable to target this region using a modified form of Mongersen that includes the polymorphism. The present invention also provides an antisense therapeutic for use in a method for treating subjects having polymorphism(s) in the SMAD7 mRNA sequence, said antisense therapeutic having a sequence specific for (e.g., matches exactly) the polymorphic gene sequence.

"The present invention also provides a SMAD7 antisense oligonucleotide for use in a method for treating or managing inflammatory bowel disease (IBD; e.g., Crohn's disease (CD) or ulcerative colitis (UC)) in a patient having IBD that carries at least one copy of a first polymorphic form of SMAD7 that differs from the consensus SMAD7 nucleotide sequence. Preferably, the SMAD7 antisense oligonucleotide specifically targets said first polymorphic form of SMAD7. The polymorphic form of SMAD7 may include a single nucleotide polymorphism (SNP) and/or may include a polymorphism listed in Table 1 or in Table 2 or as listed in paragraph .

"The present invention also provides a SMAD7 antisense oligonucleotide for use in a method of treating or managing inflammatory bowel disease (IBD; e.g., Crohn's disease (CD) or ulcerative colitis (UC)) in a patient having IBD. Preferably the method (a) analyzing the presence or absence of one or more SMAD7 polymorphic forms in the patient; and (b) administering one or more SMAD7 antisense oligonucleotides to the patient, based on the presence or absence of said polymorphic forms, where: (i) if a first SMAD7 polymorphic form (e.g., the wild type form) is present in the patient, then administering to the patient a first SMAD7 antisense oligonucleotide targeting the first SMAD7 polymorphic form; or (ii) if a second SMAD7 polymorphic form is present in the patient, then administering to the patient a second SMAD7 antisense oligonucleotide targeting the second SMAD7 polymorphic form; or (iii) if the first and the second SMAD7 polymorphic forms are present in the patient, then administering to the patient one or both of the first and the second SMAD7 antisense oligonucleotide targeting the first and the second SMAD7 polymorphic forms. The polymorphism can include an SNP and/or can include a polymorphism listed in Table 1 or in Table 2 or as listed in paragraph .

"In another aspect, the invention provides an effective amount of the SMAD7 antisense oligonucleotide as described above for use in a method of treating IBD (e.g., CD or UC), wherein said method includes administering (e.g., orally) to a patient in need thereof an effective amount of the SMAD7 antisense oligonucleotide, where the SMAD7 antisense oligonucleotide is effective to treat IBD.

"An antisense oligonucleotide that 'specifically targets' a polymorphic form of a gene that differs from a consensus sequence includes a nucleotide sequence with a substitution, relative to the gene or transcript consensus sequence, that increases hybridization of the antisense oligonucleotide to the polymorphic form, as compared to the consensus sequence. For example, a polymorphic form that includes a guanosine to adenine (G.fwdarw.A) change in the target sequence would be specifically targeted by an antisense oligonucleotide containing a cytosine to thymine (C.fwdarw.T) substitution at the corresponding position in the oligonucleotide.

"The 'consensus' SMAD7 nucleotide sequence means the RNA sequence or DNA sequences associated with the 'wild-type' sequence of a gene described in the reference databases. For example, consensus sequences for SMAD7 can be found under Accession numbers NM-005904.3, NM-001190821.1, NM-001190822.1, and NM-001190823.1, which are reference transcripts for human SMAD7 in the National Center for Biotechnology Information (NCBI) database.

"By 'treating' is meant reducing at least one symptom associated with the disease or condition being treated.

"The terms 'manage,' 'management,' 'managing' and the like are used herein to generally mean controlling the severity or manifestation of symptoms of a disease, or the means of treating the disease. Generally, management is used to obtain a desired pharmacological and/or physiological effect. The effect may be therapeutic in terms of partially or completely curing a disease and/or adverse effect attributed to the disease or ensuring that a particular symptom or manifestation of the disease does not occur or reoccur in a patient or does not rise to an undesirable or intolerable level in a patient. The term 'management' as used herein covers any management of a disease in a mammal, particularly a human, and includes: (a) inhibiting the disease, i.e., preventing the disease from increasing in severity or scope; (b) relieving the disease, i.e., causing partial or complete amelioration of the disease; or preventing relapse of the disease, e.g., preventing the disease from returning to an active state following previous successful treatment of symptoms of the disease or treatment of the disease. 'Management' as used herein may also be used with reference to administration of a specific treatment for the disease, for example, a SMAD7 antisense oligonucleotide.

"A 'subject' or 'patient' as described herein, refers to any animal at risk for, suffering from or diagnosed for IBD, including, but not limited to, mammals, primates, and humans. In certain embodiments, the subject may be a non-human mammal such as, for example, a cat, a dog, or a horse. In a preferred embodiment, the subject is a human subject. A subject may be an individual diagnosed with a high risk of developing IBD, someone who has been diagnosed with IBD, someone who previously suffered from IBD, or an individual evaluated for symptoms or indications of IBD, for example, a high CDAI index score.

"'A patient with IBD,' as used herein, refers to a patient suffering from any of the symptoms or manifestations of IBD, a patient who may suffer from any of the symptoms or manifestations of IBD, or any patient who might benefit from a method of the invention for treating or evaluating treatment for IBD. A patient in need may include a patient who is diagnosed with a risk of developing IBD, a patient who has suffered from IBD in the past, or a patient who has previously been treated for IBD. Of particular relevance are individuals that suffer from IBD associated with increased levels of CRP, TNF.alpha., and/or IL8 expression. In some embodiments, the patient with IBD is a Crohn's disease (CD) patient. In some embodiments, the patient with IBD is an ulcerative colitis (UC) patient.

"As used herein, 'Crohn's Disease Activity Index' or 'CDAI' refers to a measurement or index used to assess the progress of patients suffering from CD as described by Best et al., Gastroenterology, 70:439-44 (1976). CDAI scores of 150 or below are generally associated with inactive disease and are indicative of better prognosis than higher scores. Values above 150 are generally associated with active disease and values above 450 are associated with extremely severe disease. CDAI scores may be used to determine how well a patient is responding to therapy and may be used to identify patients in remission. In certain embodiments, a benchmark clinical response means that the subject displays a decrease in CDAI score by at least 100 points. In a clinical trial, a CDAI score of 150 or below is generally associated with remission.

"As used herein, 'Ulcerative Colitis Disease Activity Index' or 'UCDAI' refers to a measurement or index used to assess the progress of patients suffering from UC as described by Sutherland et al., Gastroenterology, 92:1894-98 (1987). The UCDAI is a series of qualifiers about the symptoms of UC including stool frequency, rectal bleeding, the appearance of the colon lining, and a physician's rating of disease activity. Each of these qualifiers is given a number from 0 to 3, with 3 being the highest disease activity. In a clinical trial, remission is often defined as a UCDAI score of 1 or less, and improvement is a reduction of 3 or more points from the score at the beginning of the trial. UCDAI may be used in clinical trials to determine how well a patient is responding to therapy and may be used to identify patients in remission. Other commonly used indices for measuring disease severity in UC patients include the Truelove and Witts Index, the St. Mark's Index, the Simple Clinical Colitis Activity Index (SCCAI), the Lichtiger Index, the Ulcerative Colitis Symptom Score (UCSS), and the Mayo Clinic Score.

"As used herein, 'SMAD7' (also known as CRCS3, FLJ16482, MADH7, MADH8, MAD (mothers against decapentaplegic, Drosophila) homolog 7, MAD homolog 8, SMAD, mothers against DPP homolog 7, mothers against DPP homolog 8) means the human protein or any of the mRNA transcripts encoded by the gene identified by Entrez GeneID No. 4092 and allelic variants thereof.

"As used herein, 'CRP' (also known as C-reactive protein, pentraxin-related; Pentraxin; and PTX1) means the human protein or any of the mRNA transcripts encoded by the gene identified by Entrez GeneID No. 1401 and allelic variants thereof.

"As used herein, 'IL8' (also known as Interleukin-8 (IL-8); Tumor Necrosis Factor-Induced Gene 1; NAF; Granulocyte Chemotactic Protein 1 (GCP1); LECT; LUCT; Protein 3-10C; Beta-Thromboglobulin-Like Protein; Neutrophil-Activating Peptide 1; Neutrophil-Activating Protein 1 (NAP1; NAP-1); Emoctakin; GCP-1; LYNAP; Lymphocyte Derived Neutrophil Activating Peptide; Lung Giant Cell Carcinoma-Derived Chemotactic Protein; Small Inducible Cytokine Subfamily B, Member 8; Beta Endothelial Cell-Derived Neutrophil Activating Peptide; Monocyte-Derived Neutrophil Chemotactic Factor (MDNCF); Monocyte-Derived Neutrophil-Activating Peptide (MONAP); Alveolar Macrophage Chemotactic Factor I; CXC Motif Chemokine 8; and Chemokine (CXC Motif) Ligand 8 (CXCL8)) means the human protein or any of the mRNA transcripts encoded by the gene identified by Entrez GeneID No. 3576 and allelic variants thereof.

"As used herein, 'TNF.alpha.' (also known as Tumor Necrosis Factor, DIF, Tumor Necrosis Factor Ligand Superfamily Member 2 (TNFSF2), APC1 Protein, cachectin, Tumor Necrosis Factor A (TNFA), Tumor Necrosis Factor-.alpha. (TNF-.alpha.), and Tumor Necrosis Factor-alpha (TNF-alpha)) means the human protein or any of the mRNA transcripts encoded by the gene identified by Entrez GeneID No. 7124 and allelic variants thereof."

URL and more information on this patent application, see: Monteleone, Giovanni. Methods and Compositions for Treating a Subject with a Smad7 Antisense Oligonucleotide. Filed October 16, 2015 and posted August 31, 2017. Patent URL: http://appft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PG01&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.html&r=1&f=G&l=50&s1=%2220170240893%22.PGNR.&OS=DN/20170240893&RS=DN/20170240893

Keywords for this news article include: Genetics, Cytokines, Chemokines, Phagocytes, Proteomics, Neutrophils, DNA Research, Granulocytes, Membrane Proteins, Biological Factors, Risk and Prevention, Nogra Pharma Limited, Inflammation Mediators, Tumor Necrosis Factors, Intercellular Signaling Peptides and Proteins.

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