AVX-470, an orally delivered anti-tumour necrosis factor antibody for treatment of active ulcerative colitis

Results of a first-in-human trial

M. Scott Harris, Deborah Hartman, Brenda R. Lemos, Emma C. Erlich, Sharon Spence, Sally Kennedy, Theadore Ptak, Ronald Pruitt, Severine Vermeire, Barbara S. Fox

    Research output: Contribution to journalArticle

    19 Citations (Scopus)

    Abstract

    Background and Aims: AVX-470 is an oral, polyclonal bovine-derived anti-tumour necrosis factor (TNF) antibody in development for treatment of inflammatory bowel disease (IBD). AVX-470 neutralizes TNF locally in the gastrointestinal tract, minimizing systemic exposure. This was a double-blind, placebo-controlled, first-in-human trial designed to assess the safety, pharmacokinetics, immunogenicity and preliminary efficacy of 4 weeks of AVX-470 in patients with active ulcerative colitis (UC). Methods: Thirty-seven patients with active UC were randomized and 36 received AVX-470 (0.2, 1.6 or 3.5g/day) or placebo over 4 weeks. Endoscopic activity was assessed by colonoscopy pre- and post-treatment. The primary endpoint was safety. Secondary endpoints included pharmacokinetics and immunogenicity. Clinical and endoscopic response and remission were assessed as exploratory endpoints. Results: Thirty-three (92%) patients completed treatment and follow-up. The incidence of adverse events was similar across treatment groups and no allergic reactions or opportunistic infections were reported. AVX-470 therapy did not induce human anti-bovine antibodies (HABA). Bovine immunoglobulin (Ig) with TNF binding capacity was detected in stool, while bovine Ig levels in serum were low. Across all AVX-470 doses, 25.9% of patients achieved clinical response compared with 11.1% on placebo, with greatest improvements in the 3.5g/day group associated with proximal colon endoscopic improvement and reductions in serum CRP and IL-6. Conclusions: AVX-470 was safe and well tolerated in this first-in-human trial in UC, with efficacy trends for clinical, endoscopic and biomarker endpoints in the highest dose group (3.5g/day). Results suggest benefit of an orally delivered locally active agent in moderate to severe UC. Clinical Trial Registration Number: This trial was registered with Clinicaltrials.gov as study NCT01759056 and with EudraCT as study 2012-004859-27.

    Original languageEnglish (US)
    Pages (from-to)631-640
    Number of pages10
    JournalJournal of Crohn's and Colitis
    Volume10
    Issue number6
    DOIs
    StatePublished - Jun 1 2016

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    Ulcerative Colitis
    Tumor Necrosis Factor-alpha
    Antibodies
    Placebos
    Therapeutics
    Immunoglobulins
    Pharmacokinetics
    Safety
    Opportunistic Infections
    Colonoscopy
    AVX-470
    Serum
    Inflammatory Bowel Diseases
    Gastrointestinal Tract
    Anti-Idiotypic Antibodies
    Interleukin-6
    Hypersensitivity
    Colon
    Biomarkers
    Clinical Trials

    All Science Journal Classification (ASJC) codes

    • Gastroenterology

    Cite this

    AVX-470, an orally delivered anti-tumour necrosis factor antibody for treatment of active ulcerative colitis : Results of a first-in-human trial. / Harris, M. Scott; Hartman, Deborah; Lemos, Brenda R.; Erlich, Emma C.; Spence, Sharon; Kennedy, Sally; Ptak, Theadore; Pruitt, Ronald; Vermeire, Severine; Fox, Barbara S.

    In: Journal of Crohn's and Colitis, Vol. 10, No. 6, 01.06.2016, p. 631-640.

    Research output: Contribution to journalArticle

    Harris, MS, Hartman, D, Lemos, BR, Erlich, EC, Spence, S, Kennedy, S, Ptak, T, Pruitt, R, Vermeire, S & Fox, BS 2016, 'AVX-470, an orally delivered anti-tumour necrosis factor antibody for treatment of active ulcerative colitis: Results of a first-in-human trial', Journal of Crohn's and Colitis, vol. 10, no. 6, pp. 631-640. https://doi.org/10.1093/ecco-jcc/jjw036
    Harris, M. Scott ; Hartman, Deborah ; Lemos, Brenda R. ; Erlich, Emma C. ; Spence, Sharon ; Kennedy, Sally ; Ptak, Theadore ; Pruitt, Ronald ; Vermeire, Severine ; Fox, Barbara S. / AVX-470, an orally delivered anti-tumour necrosis factor antibody for treatment of active ulcerative colitis : Results of a first-in-human trial. In: Journal of Crohn's and Colitis. 2016 ; Vol. 10, No. 6. pp. 631-640.
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    abstract = "Background and Aims: AVX-470 is an oral, polyclonal bovine-derived anti-tumour necrosis factor (TNF) antibody in development for treatment of inflammatory bowel disease (IBD). AVX-470 neutralizes TNF locally in the gastrointestinal tract, minimizing systemic exposure. This was a double-blind, placebo-controlled, first-in-human trial designed to assess the safety, pharmacokinetics, immunogenicity and preliminary efficacy of 4 weeks of AVX-470 in patients with active ulcerative colitis (UC). Methods: Thirty-seven patients with active UC were randomized and 36 received AVX-470 (0.2, 1.6 or 3.5g/day) or placebo over 4 weeks. Endoscopic activity was assessed by colonoscopy pre- and post-treatment. The primary endpoint was safety. Secondary endpoints included pharmacokinetics and immunogenicity. Clinical and endoscopic response and remission were assessed as exploratory endpoints. Results: Thirty-three (92{\%}) patients completed treatment and follow-up. The incidence of adverse events was similar across treatment groups and no allergic reactions or opportunistic infections were reported. AVX-470 therapy did not induce human anti-bovine antibodies (HABA). Bovine immunoglobulin (Ig) with TNF binding capacity was detected in stool, while bovine Ig levels in serum were low. Across all AVX-470 doses, 25.9{\%} of patients achieved clinical response compared with 11.1{\%} on placebo, with greatest improvements in the 3.5g/day group associated with proximal colon endoscopic improvement and reductions in serum CRP and IL-6. Conclusions: AVX-470 was safe and well tolerated in this first-in-human trial in UC, with efficacy trends for clinical, endoscopic and biomarker endpoints in the highest dose group (3.5g/day). Results suggest benefit of an orally delivered locally active agent in moderate to severe UC. Clinical Trial Registration Number: This trial was registered with Clinicaltrials.gov as study NCT01759056 and with EudraCT as study 2012-004859-27.",
    author = "Harris, {M. Scott} and Deborah Hartman and Lemos, {Brenda R.} and Erlich, {Emma C.} and Sharon Spence and Sally Kennedy and Theadore Ptak and Ronald Pruitt and Severine Vermeire and Fox, {Barbara S.}",
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    T2 - Results of a first-in-human trial

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    AU - Hartman, Deborah

    AU - Lemos, Brenda R.

    AU - Erlich, Emma C.

    AU - Spence, Sharon

    AU - Kennedy, Sally

    AU - Ptak, Theadore

    AU - Pruitt, Ronald

    AU - Vermeire, Severine

    AU - Fox, Barbara S.

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    AB - Background and Aims: AVX-470 is an oral, polyclonal bovine-derived anti-tumour necrosis factor (TNF) antibody in development for treatment of inflammatory bowel disease (IBD). AVX-470 neutralizes TNF locally in the gastrointestinal tract, minimizing systemic exposure. This was a double-blind, placebo-controlled, first-in-human trial designed to assess the safety, pharmacokinetics, immunogenicity and preliminary efficacy of 4 weeks of AVX-470 in patients with active ulcerative colitis (UC). Methods: Thirty-seven patients with active UC were randomized and 36 received AVX-470 (0.2, 1.6 or 3.5g/day) or placebo over 4 weeks. Endoscopic activity was assessed by colonoscopy pre- and post-treatment. The primary endpoint was safety. Secondary endpoints included pharmacokinetics and immunogenicity. Clinical and endoscopic response and remission were assessed as exploratory endpoints. Results: Thirty-three (92%) patients completed treatment and follow-up. The incidence of adverse events was similar across treatment groups and no allergic reactions or opportunistic infections were reported. AVX-470 therapy did not induce human anti-bovine antibodies (HABA). Bovine immunoglobulin (Ig) with TNF binding capacity was detected in stool, while bovine Ig levels in serum were low. Across all AVX-470 doses, 25.9% of patients achieved clinical response compared with 11.1% on placebo, with greatest improvements in the 3.5g/day group associated with proximal colon endoscopic improvement and reductions in serum CRP and IL-6. Conclusions: AVX-470 was safe and well tolerated in this first-in-human trial in UC, with efficacy trends for clinical, endoscopic and biomarker endpoints in the highest dose group (3.5g/day). Results suggest benefit of an orally delivered locally active agent in moderate to severe UC. Clinical Trial Registration Number: This trial was registered with Clinicaltrials.gov as study NCT01759056 and with EudraCT as study 2012-004859-27.

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