Loading ...
Sorry, an error occurred while loading the content.

FW: NATAP: HCV Drug ANA975 Toll-Like Receptor Agonist

Expand Messages
  • alleypat
    2 Toll Like Receptor Drugs TLR7 & TLR9 Agonists: ANA975 & CPG 10101 New Hep C Drug ANA975 Toll-Like Receptpr-7 (TLR7) Agonist Begins Phase Ib Study Anadys
    Message 1 of 1 , Dec 24, 2005
    • 0 Attachment
      2 Toll Like Receptor Drugs TLR7 & TLR9 Agonists: ANA975 & CPG 10101

      New Hep C Drug ANA975 'Toll-Like Receptpr-7 (TLR7)' Agonist Begins Phase Ib
      Study

      Anadys Pharmaceuticals to Initiate 28-Day Clinical Trial of ANA975 in
      Patients With Chronic Hepatitis C

      Proof-of-Concept Trial in U.S. and E.U. to Build on the Clinical Results
      of Previously Completed Phase I Studies 501, 502 and 503

      SAN DIEGO, Dec. 22 /PRNewswire-FirstCall/ -- Anadys Pharmaceuticals, Inc.
      (Nasdaq: ANDS) announced today that it plans to initiate a Phase Ib,
      placebo-controlled, multiple-dose clinical trial of ANA975 in chronic
      hepatitis C patients in January. The trial is designed to evaluate the
      safety, tolerability and viral load reduction of ANA975 in hepatitis C
      patients. ANA975, which Anadys is developing in collaboration with Novartis,
      is the oral prodrug of isatoribine, a proprietary Toll-Like Receptor-7
      (TLR7) agonist.

      "With this study we are seeking to extend the encouraging clinical results
      we obtained in several Phase I clinical trials -- Studies 501, 502 and
      503 -- with healthy volunteers that evaluated the safety, tolerability,
      pharmacokinetics and pharmacodynamics of ANA975," said Kleanthis G.
      Xanthopoulos, Ph.D., Anadys' President and CEO. "We reported the initial
      part of these studies at the recent annual meeting of the American
      Association for the Study of Liver Diseases (AASLD) in November 2005." (See
      Abstract below).

      "The data from ANA975 so far demonstrate the power of our unique and
      proprietary oral TLR-7 prodrug technology and build on the clinical
      experience
      of the active substance, isatoribine, that has demonstrated statistically
      significant antiviral activity in patients chronically infected with
      hepatitis C virus, as we have previously reported," said Steve Worland,
      Ph.D., Anadys' Executive Vice President, Pharmaceuticals. "We are excited to
      see ANA975 entering the clinic in hepatitis C patients."

      ANA975 has been administered to more than 90 healthy volunteers in three
      completed Phase I trials (501, 502, and 503), setting the stage for the
      upcoming 28-day clinical study in hepatitis C infected patients. Results
      from several clinical trials in hepatitis C patients receiving intravenous
      isatoribine for one week have demonstrated statistically significant and
      therapeutically relevant viral load reductions. Data from the previous Phase
      I clinical trials of ANA975 in healthy volunteers indicate that the
      bioavailability of ANA975 is greater than 80 percent and conversion to
      isatoribine in plasma is rapid and effective, delivering levels of
      isatoribine that have been shown to be clinically relevant.

      The trial, which will be conducted at multiple centers in the United States
      and the European Union, will evaluate the safety, tolerability and viral
      load reduction of ANA975 at multiple doses for 28 days in patients
      chronically infected with hepatitis C.

      Patients will be assigned randomly to one of two main categories. In one
      category patients will receive either a predetermined dose of ANA975 once a
      day for 28 days or a placebo. In a second category patients will receive a
      predetermined dose of ANA975 twice a day for 28 days or a placebo. Anadys
      expects to report clinical data from this study in the first half of 2006.

      Hepatitis C Virus

      Hepatitis C virus causes inflammation of the liver and degradation of liver
      function. Approximately 80% of individuals infected with hepatitis C
      progress to chronic hepatitis. The most common signs and symptoms of chronic
      hepatitis, which may show no symptoms for many years, include an enlarged
      liver and spleen, jaundice, muscle wasting, excoriations (the result of
      scratching), ascites (swelling of the abdomen) and swelling of the ankles.
      Chronic infection often progresses to further, more serious complications
      such as cirrhosis of the liver, liver cancer and death. Of those patients
      who progress to chronic hepatitis, 10%-20% develop cirrhosis over a period
      of 20 years, with approximately 1-5% of these patients progressing to
      end-stage liver disease or liver cancer in their lifetime. Hepatitis C is
      estimated to chronically infect more than 170 million people worldwide.

      The CDC reports that approximately 2.7 million Americans are chronically
      infected with hepatitis C and at risk of disease progression. There is no
      vaccine available to prevent the spread of hepatitis C.

      About Anadys

      Anadys Pharmaceuticals, Inc. is a biopharmaceutical company committed to
      advancing patient care by discovering, developing and commercializing novel
      small molecule medicines for the treatment of hepatitis, other serious
      infections, and cancer. The Company has core expertise in Toll-Like
      Receptor-based small molecule therapeutics and structure-based drug design
      coupled with medicinal chemistry. Anadys' clinical development programs
      include ANA975 for the treatment of hepatitis C and hepatitis B, and ANA380
      for the treatment of hepatitis B. In addition, Anadys' therapeutic platform
      is designed to advance a strong and continual pipeline of drug candidates
      into the clinic.

      Two Studies of 2 Different Toll-Like Receptors at AASLD 2005 Nov

      ABSTRACT 858

      Pharmacokinetics, Safety, and Tolerability of the Isatoribine Oral Prodrug
      ANA975 in a Phase I Heakthy Volunteer Study

      Bradley Kerr, Anadys Pharmaceuticals Inc, San Diego, CA; Lisa Bauman,
      Stephen Webber, Alan Xiang, John Ng, Leo Kirkovsky, Darian Bartkowski, Kevin
      Steffy, Simon Fletcher, Robert Aust, Anadys Pharmaceuticals, Inc.,
      San Diego, CA; Jeffrey Theiss, SunCoast Tox, San Diego, CA; Devron
      Averett, Anadys Pharmaceuticals Inc, San Diego, CA

      Purpose: In a proof-of-concept (POC) clinical study, intravenous (IV)
      infusion of the TLR7 agonist isatoribine 800mg once daily x 7 days to
      patients chronically infected with hepatitis C virus (HCV) yielded a
      significant reduction of plasma HCV RNA that correlated with induction of
      2', 5'-oligoadenylate synthetase (OAS). Oral doses of isatoribine are poorly
      absorbed in multiple species. The prodrug ANA975 was developed to improve
      oral delivery of isatoribine to systemic circulation.

      Methods: Toxicology studies, including GLP oral multiple-dose studies in
      cynomolgus monkeys, were performed to enable clinical studies. An open
      label, rising dose level, single-dose study in healthy volunteers was
      performed in the United Kingdom according to institutional and local
      regulatory requirements. Thirty-six subjects each received a single oral
      dose of ANA975 administered
      as a 5mg/mL solution in the fasted state at doses of 400mg (n 6), 800mg (n
      18), or 1200mg (n 12).

      Results: Oral administration of ANA975 to monkeys resulted in efficient
      systemic delivery of isatoribine; the highest tolerated dose in monkey
      achieved plasma area-under-the-curve (AUC) values 6-13x higher than achieved
      with the 800mg IV dose in the clinical POC study. Monkeys showed a
      dose-related OAS induction in blood that persisted with once daily dosing
      for treatment periods up to at least 28 days.

      Single oral doses of ANA975 were well tolerated by healthy volunteers. There
      were no serious adverse events (AEs) and no withdrawals from the study. A
      total of 15 AEs were reported by 13 of 36 subjects. All reported AEs were
      mild (13 events) or moderate (2 events) in severity. The Investigator
      considered 1 AE (mild transient increase in CPK at 800mg) to be possibly
      related to ANA975 and all other AEs to be unlikely related or not related to
      ANA975. There were no reports of gastrointestinal AEs or flu-like syndrome.
      ANA975 was rapidly and extensively converted to isatoribine, with
      isatoribine Cmax typically occurring within 1 hour post-dose. At the highest
      tested dose, which has an isatoribine
      dose content of 988mg, plasma isatoribine AUC values (range 23-40, median
      27mg*h/L) were similar to those observed in the clinical POC study with
      daily 1-hour IV infusions of isatoribine 800mg (first dose AUC range 19-38,
      median 24mg*h/L). The similarity of AUC values at comparable molar doses of
      oral ANA975 and IV isatoribine indicates that fractional oral absorption and
      conversion of ANA975 to isatoribine was very high.

      Conclusion: ANA975 is an efficient oral prodrug that achieves plasma
      isatoribine exposures comparable to those previously shown to reduce plasma
      HCV RNA in chronically infected patients.

      Abstract 131

      RELATIONSHIPS OF HCV RNA RESPONSES TO CPG 10101, A TLR9 AGONIST:
      PHARMACODYNAMICS AND PATIENT CHARACTERISTICS

      John McHutchinson, Duke University, Durham, NC; Bruce Bacon, St. Louis
      University Hospital, St. Louis, MO; Stuart C. Gordon, Henry Ford Hospital,
      Detroit, MI; Eric Lawitz, Alamo Medical Research, San Antonio, TX; Mitchell
      Shiffman, Medical College of Virginia, Richmond, VA; Nezam H. Afdhal, Beth
      Israel Deaconess, Boston, MA; Ira Jacobson, Cornell University, New
      York, NY; Andrew Muir, Duke University, Durham, NC; Susan Efler, Coley
      Pharmaceutical Group, Ottawa, Canada; Mohammed Al-Adhami, Coley
      Pharmaceutical Group, Wellesley, MA; Heather Davis, Coley Pharmaceutical
      Group, Ottawa, Canada; Tess Schmalbach, Coley Pharmaceutical Group,
      Wellesley, MA

      Introduction: CPG 10101 is the first of a new class of Toll-like receptor 9
      (TLR9) agonist immunomodulatory antiviral drugs. CPG 10101 is a synthetic
      oligodeoxynucleotide with a phosphorothioate backbone conveying relative
      resistance to nucleases. The immunomodulatory/antiviral activity of CPG
      10101 is due to CpG motifs which are unmethylated cytosine-guanosine
      dinucleotides within certain flanking sequences. CpG motif binding to TLR9
      receptors initiate both innate and adaptive immune responses which can be
      quantified. These assessments include cytokines with known antiviral effect,
      NK cell enumeration/activity, which could lead to early viral load
      reduction, and promotion of Th1-type adaptive immunity with induction of
      virus-specific Th1 T cell responses. The adaptive immune response composed
      of CD8
      cytotoxic T lymphocytes (CTL) is critical for long-term control of
      chronic viral infections.

      Methods: A Phase Ib trial, randomized HCV positive subjects to CPG 10101 (n
      6 or 7) or placebo (n 2) in 5 sequential cohorts (0.25, 1, 4, 10 or 20 mg
      SC) twice weekly, or 0.5 or 0.75 mg/kg once weekly for 4 weeks. Subjects
      were evaluated for tolerability, pharmacokinetics, pharmacodynamics and HCV
      RNA level.

      Results: Cytokine/chemokine induction was demonstrated. IP-10, IFNa and 2,5
      OAS increased, versus baseline, in all subjects treated with 1.0 mg or more
      CPG 10101 and the magnitude of the increases was related to dose. Increases
      in IP-10 correlated to HCV RNA reduction. HCV RNA reduction of 1 log or
      more (responding subjects) was observed in Genotype 1 subjects who were
      naive, intolerant or relapsed following PEG-IFN plus ribavirin therapy.
      Declines in HCV RNA were observed within 24h of the first dose
      of CPG 10101 and in some subjects was followed by slower decline
      on continued dosing; early decline was associated with response.
      Responses occurred in subjects with high (>600,000 IU/ml) and low baseline
      HCV RNA levels. The mean weight of responders was less than non-responders,
      and a greater number of subjects receiving higher doses responded. HCV
      specific immune response is being assessed with ELISpot assays, and will be
      extended in longer trials.

      Summary: Evidence of innate immune activation by the novel TLR9 agonist is
      demonstrated by cytokine and chemokine release. Longer dosing is planned to
      examine induction of adaptive immune responses including induction of virus
      specific T cell response anticipated to develop over 6-12 weeks of therapy.
      Dosing of CPG 10101 should be adjusted for weight to maximize anti-viral
      activity. Results to date justify longer term trials and treatment in
      combination with IFN/R or other antivirals.

      Toll-Like Receptor Research in HIV & HCV: search of NATAP Website search
      engines yields these stories

      New Toll-like Receptor Drug Actilon for HCV Therapy
      Actilon acts through the Toll-like receptor 9 found in dendritic cells and B
      cells, which are mainstays of the immune system. Shares of Coley were up
      $1.52, ...
      www.natap.org/2005/HCV/092905_07.htm

      Toll-Like Receptors: new therapy to stimulate immune systemToll-like
      receptor 5, for instance, recognizes a protein in the tails that some
      bacteria use to swim. The biggest focus for drug developers so far has been
      ...
      www.natap.org/2005/HCV/100605_01.htm

      SAFETY, PHARMACODYNAMIC (PD) & PHARMACOKINETIC (PK) PROFILES OF ...Coley is
      focusing its efforts initially on the discovery and development of TLR
      Therapeutics which target and stimulate Toll-like receptor 9 (TLR9), ...
      www.natap.org/2005/ddw/ddw_12.htm

      Joseph F. O'Neill, MD, Former Director of the Office of National ...A new
      HIV immune-based therapy, IR103, which incorporates a Toll-like receptor
      (TLR) agonist-based adjuvant from Idera Pharmaceuticals Inc. (AMEX:IDP), ...
      www.natap.org/2005/newsUpdates/110205_03.htm - 14k - <nCached - SimilarB
      pages

      New HCV & HBV Drugs: toll-like receptors... manufacture and commercialize
      ANA975 and additional Toll-Like Receptor 7 (TLR7) oral prodrugs for chronic
      hepatitis C virus (HCV) and hepatitis B virus ...
      www.natap.org/2005/HCV/060105_01.htm

      HIV Microbocides at the 11th Retrovirus ConferenceToll-like receptor 4
      (TLR4) non-responsive HEN mouse spleen cells were used as a negative
      control. Explant cultures from 7 of the 8 women demonstrated 10 to ...
      www.natap.org/2004/CROI/croi_26.htm

      New Drug Targets for HIV and Hepatitis C Virus Coinfection... Anadys245) is
      thought to stimulate immune responses and raise levels of IFN-a and TNF-a by
      reacting with a receptor on WBCs called Toll-like receptor. ...
      www.natap.org/2005/HCV/060605_03.htm

      Small Molecule, Toll-Like Receptor 7 Agonist, a Potential ..."We are using
      our expertise in Toll-Like Receptor-based biology and chemistry to build a
      strong portfolio of product candidates. ...
      www.natap.org/2005/HCV/020205_09.htm

      HCV Nucleoside Analogue Studied in Chronically Infected Patients ...ANA245,
      the company's nucleoside analogue believed to interact with Toll-like
      receptor 7, or TLR7, on certain immune system cells, had been administered
      to ...
      www.natap.org/2003/nov/111903_1.htm

      New HBV Therapy Research for siRNAsRecent reports have highlighted the
      sequence-specific activation of innate immunity by siRNA, apparently through
      engagement of Toll-like receptor 7 (refs. ...
      www.natap.org/2005/HBV/093005_02.htm

      Hepatitis C Selected ArticlesNew Toll-like Receptor Drug Actilon for HCV
      Therapy - (09/29/05) ... Small Molecule, Toll-Like Receptor 7 Agonist, a
      Potential Frontline Oral Treatment for ...
      natap.org/hcv.htm

      How Hepatitis C Short-Circuits the Immune SystemImmune evasion by hepatitis
      C virus NS3 4A protease-mediated cleavage of the Toll-like receptor 3
      adaptor protein TRIF Kui Li*b , Eileen Foyb!, Josephine C. ...
      www.natap.org/2005/HCV/022205_05.htm

      New HCV Drug Reduces HCV RNAActilon is a synthetic agonist of the Toll-like
      receptor 9 (TLR9). By stimulating TLR9 in vitro, Actilon works directly and
      selectively on dendritic cells ...
      www.natap.org/2005/HCV/011005_05.htm

      Coley Pharmaceutical Group Initiates Phase I Clinical Trials of
      ...Actilon(TM) is a member of Coley's Toll-like receptor 9 (TLR9) agonist
      family of compounds, a new class of investigational pharmaceutical products
      that ...
      www.natap.org/2004/jan/011604_02.htm

      Isatoribine, an agonist of TLR7, reduces plasma virus ...Toll-like receptors
      (TLRs) are now established to be a family of pathogen ... of a host receptor
      rather than through inhibition of a viral receptor. ...
      www.natap.org/2005/HCV/090505_15.htm

      New HBV Therapy Research for siRNAs
      Recent reports have highlighted the sequence-specific activation of innate
      immunity by siRNA, apparently through engagement of Toll-like receptor 7
      (refs. ...
      www.natap.org/2005/HBV/093005_02.htm

      Hepatitis C Selected ArticlesNew Toll-like Receptor Drug Actilon for HCV
      Therapy - (09/29/05) ... Small Molecule, Toll-Like Receptor 7 Agonist, a
      Potential Frontline Oral Treatment for ...
      natap.org/hcv.htm

      How Hepatitis C Short-Circuits the Immune SystemImmune evasion by hepatitis
      C virus NS3 4A protease-mediated cleavage of the Toll-like receptor 3
      adaptor protein TRIF Kui Li*b , Eileen Foyb!, Josephine C. ...
      www.natap.org/2005/HCV/022205_05.htm

      New HCV Drug Reduces HCV RNAActilon is a synthetic agonist of the Toll-like
      receptor 9 (TLR9). By stimulating TLR9 in vitro, Actilon works directly and
      selectively on dendritic cells ...
      www.natap.org/2005/HCV/011005_05.htm

      Coley Pharmaceutical Group Initiates Phase I Clinical Trials of
      ...Actilon(TM) is a member of Coley's Toll-like receptor 9 (TLR9) agonist
      family of compounds, a new class of investigational pharmaceutical products
      that ...
      www.natap.org/2004/jan/011604_02.htm

      Isatoribine, an agonist of TLR7, reduces plasma virus ...Toll-like receptors
      (TLRs) are now established to be a family of pathogen ... of a host receptor
      rather than through inhibition of a viral receptor. ...
      www.natap.org/2005/HCV/090505_15.htm


      [Non-text portions of this message have been removed]
    Your message has been successfully submitted and would be delivered to recipients shortly.