Early Clinical Evaluation of the Intranasal TLR7 Agonist GSK2245035: Use of Translational Biomarkers to Guide Dosing and Confirm Target Engagement

Clinical Pharmacology and Therapeutics

Volumn 98, Issue 4, 2015, Pages 369-380

  Tsitoura, D ^a   Ambery, C ^a   Price, M ^a   Powley, W ^a   Garthside, S ^a   Biggadike, K ^a   Quint, D ^a,b  

^a GLAXOSMITHKLINE   (United Kingdom)

^b CIRCASSIA LTD   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA INTERFERON; BIOLOGICAL MARKER; C REACTIVE PROTEIN; GAMMA INTERFERON INDUCIBLE PROTEIN 10; GSK 2245035; INTERLEUKIN 6; MONOCYTE CHEMOTACTIC PROTEIN 1; PLACEBO; TOLL LIKE RECEPTOR 7; TOLL LIKE RECEPTOR AGONIST; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG; ADENINE; ANTIALLERGIC AGENT; CXCL10 PROTEIN, HUMAN; GSK2245035; PIPERIDINE DERIVATIVE; TLR7 PROTEIN, HUMAN;

ADULT; ALLERGIC RHINITIS; ANIMAL EXPERIMENT; ARTICLE; CONTROLLED STUDY; CYTOKINE RELEASE SYNDROME; DOSE RESPONSE; DOUBLE BLIND PROCEDURE; DRUG BLOOD LEVEL; DRUG DOSE ESCALATION; DRUG DOSE REGIMEN; DRUG SAFETY; DRUG SCREENING; DRUG TOLERABILITY; FEVER; HEADACHE; HUMAN; IN VIVO STUDY; LIMIT OF QUANTITATION; LOW DRUG DOSE; MACACA FASCICULARIS; MAJOR CLINICAL STUDY; MALE; MYALGIA; NAUSEA; NONHUMAN; PRIORITY JOURNAL; PROTEIN BLOOD LEVEL; PROTEIN EXPRESSION; RANDOMIZED CONTROLLED TRIAL; REPEATED DRUG DOSE; UPREGULATION; ADOLESCENT; AGONISTS; ANALOGS AND DERIVATIVES; ANIMAL; BLOOD; DRUG ADMINISTRATION; FEMALE; IMMUNOLOGY; INTRANASAL DRUG ADMINISTRATION; MIDDLE AGED; NO-OBSERVED-ADVERSE-EFFECT LEVEL; RHINITIS, ALLERGIC; RISK ASSESSMENT; TREATMENT OUTCOME; YOUNG ADULT;

ADENINE; ADMINISTRATION, INTRANASAL; ADOLESCENT; ADULT; ANIMALS; ANTI-ALLERGIC AGENTS; BIOMARKERS; CHEMOKINE CXCL10; DOUBLE-BLIND METHOD; DRUG ADMINISTRATION SCHEDULE; FEMALE; HUMANS; MACACA FASCICULARIS; MALE; MIDDLE AGED; NO-OBSERVED-ADVERSE-EFFECT LEVEL; PIPERIDINES; RHINITIS, ALLERGIC; RISK ASSESSMENT; TOLL-LIKE RECEPTOR 7; TREATMENT OUTCOME; YOUNG ADULT;

EID: 84952760881     PISSN: 00099236     EISSN: 15326535     Source Type: Journal    
DOI: 10.1002/cpt.157     Document Type: Article

References (38)

1. Broide, D. H. Molecular and cellular mechanisms of allergic disease. J. Allergy Clin. Immunol. 108 (suppl. 2), S65-S71 (2001).
2. Kay, A. B. The role of T lymphocytes in asthma. Chem. Immunol. Allergy 91, 59-75 (2006).
3. Horner, A. A. Toll-like receptor ligands and atopy: A coin with at least two sides. J. Allergy Clin. Immunol. 117, 1133-1140 (2006).
4. Feleszko, W., Jaworska, J. & Hamelmann, E. Toll-like receptors-novel targets in allergic airway disease (probiotics, friends and relatives). Eur. J. Pharmacol. 533, 308-318 (2006).
5. Akira, S., Yamamoto, M. & Takeda, K. Role of adapters in Toll-like receptor signalling. Biochem. Soc. Trans. 31(Pt 3), 637-642 (2003).
6. Kawai, T. & Akira, S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat. Immunol. 11, 373-384 (2010).
7. Dudek, A. Z. et al. First in human phase I trial of 852A, a novel systemic toll-like receptor 7 agonist, to activate innate immune responses in patients with advanced cancer. Clin. Cancer Res. 13, 7119-7125 (2007).
8. Miller, R. L., Meng, T. C. & Tomai, M. A. The antiviral activity of Toll-like receptor 7 and 7/8 agonists. Drug News Perspect. 21, 69-87 (2008).
9. Fidock, M. D. et al. The innate immune response, clinical outcomes, and ex vivo HCV antiviral efficacy of a TLR7 agonist (PF-4878691). Clin. Pharmacol. Ther. 89, 821-829 (2011).
10. Horsmans, Y. et al. Isatoribine, an agonist of TLR7, reduces plasma virus concentration in chronic hepatitis C infection. Hepatology 42, 724-731 (2005).
11. Rosewich, M., Lee, D. & Zielen, S. Pollinex Quattro: An innovative four injections immunotherapy in allergic rhinitis. Hum. Vaccin. Immunother. 9, 1523-1531 (2013).
12. Klimek, L. et al. Assessment of clinical efficacy of CYT003-QbG10 in patients with allergic rhinoconjunctivitis: A phase IIb study. Clin. Exp. Allergy 41, 1305-1312 (2011).
13. Creticos, P. S. et al. Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis. N. Engl. J. Med. 355, 1445-1455 (2006).
14. Beeh, K. M. et al. The novel TLR-9 agonist QbG10 shows clinical efficacy in persistent allergic asthma. J. Allergy Clin. Immunol. 131, 866-874 (2013).
15. Moller-Larsen, S., Nyegaard, M., Haagerup, A., Vestbo, J., Kruse, T. A. & Borglum, A. D. Association analysis identifies TLR7 and TLR8 as novel risk genes in asthma and related disorders. Thorax 63, 1064-1069 (2008).
16. Camateros, P. et al. Chronic asthma-induced airway remodeling is prevented by Toll-like receptor-7/8 ligand S28463. Am. J. Respir. Crit. Care Med. 175, 1241-1249 (2007).
17. Moisan, J. et al. TLR7 ligand prevents allergen-induced airway hyperresponsiveness and eosinophilia in allergic asthma by a MYD88-dependent and MK2-independent pathway. Am. J. Physiol. Lung Cell. Mol. Physiol. 290, L987-995 (2006).
18. Xirakia, C. et al. Toll-like receptor 7-triggered immune response in the lung mediates acute and long-lasting suppression of experimental asthma. Am. J. Respir. Crit. CareMed. 181, 1207-1216 (2010).
19. Duechs, M. J. et al. TLR agonist mediated suppression of allergic responses is associated with increased innate inflammation in the airways. Pulm. Pharmcol. Ther. 24, 203-214 (2011).
20. Krieg, A. M. & Vollmer, J. Toll-like receptors 7, 8, and 9: linking innate immunity to autoimmunity. Immunol. Rev. 220, 251-269 (2007).
21. Wagner, T. L. et al. Induction of cytokines in cynomolgus monkeys by the immune response modifiers, imiquimod, S-27609 and S-28463. Cytokine 9, 837-845 (1997).
22. Ketloy, C. et al. Expression and function of Toll-like receptors on dendritic cells and other antigen presenting cells from non-human primates. Vet. Immuno. Immunopathol. 125, 18-30 (2008).
23. Food and Drug Administration Guidance for Industry-estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers. . (2005). Accessed 25 February 2015.
24. Greiff, L. et al. Repeated intranasal TLR7 stimulation reduces allergen responsiveness in allergic rhinitis. Respir. Res. 13, 53 (2012).
25. Horak, F. VTX-1463, a novel TLR8 agonist for the treatment of allergic rhinitis. Expert. Opin. Investig. Drugs 20, 981-986 (2011).
26. Aryan, Z., Holgate, S. T., Radzioch, D. & Rezaei, N. A new era of targeting the ancient gatekeepers of the immune system: Toll-like agonists in the treatment of allergic rhinitis and asthma. Int. Arch. Allergy Immunol. 164, 46-63 (2014).
27. Roponen, M., Yerkovich, S. T., Hollams, E., Sly, P. D., Holt, P. G. & Upham, J. W. Toll-like receptor 7 function is reduced in adolescents with asthma. Eur. Respir. J. 35, 64-71 (2010).
28. Bratke, K., Prieschenk, C., Garbe, K., Kuepper, M., Lommatzsch, M. & Virchow, J. C. Plasmacytoid dendritic cells in allergic asthma and the role of inhaled corticosteroid treatment. Clin. Exp. Allergy 43, 312-321 (2013).
29. Hayashi, T. et al. Prevention of autoimmune disease by induction of tolerance to Toll-like receptor 7. Proc. Natl. Acad. Sci. U. S. A. 106, 2764-2769 (2009).
30. Broad, A., Kirby, J. A. & Jones, D. E. Toll-like receptor interactions: Tolerance of MyD88-dependent cytokines but enhancement of MyD88-independent interferon-beta production. Immunology 120, 103-111 (2007).
31. Bagchi, A. et al. MyD88-Dependent and MyD88-Independent pathways in synergy, priming, and tolerance between TLR agonists. J. Immunol. 178, 1164-1171 (2007).
32. Broad, A., Jones, D. E. & Kirby, A. Toll-like receptor (TLR) response tolerance: A key physiological "damage limitation" effect and an important potential opportunity for therapy. Curr. Med. Chem. 13, 2487-2502 (2006).
33. Medvedev, A. E., Sabroe, I., Hasday, J. D. & Vogel, S. N. Tolerance to microbial TLR ligands: molecular mechanisms and relevance to disease. J. Endotox. Res. 12, 133-150 (2006).
34. Nahid, M. A., Satoh, M. & Chan, E. K. L. MicroRNA in TLR signaling and endotoxin tolerance. Cell. Mol. Immunol. 8, 388-403 (2011).
35. Bourquin, C. et al. Systemic cancer therapy with a small molecule agonist of Toll-like receptor 7 can be improved by circumventing TLR tolerance. Cancer Res. 71, 5123-5133 (2011).
36. Lawitz, E. et al. Safety, pharmacokinetics and pharmacodynamics of the oral Toll-like receptor 7 agonist GS-9620 in treatment-naive patients with chronic hepatitis C. Antivir. Ther.; e-pub ahead of print 2014.
37. Lopatin, U. et al. Safety, pharmacokinetics and pharmacodynamics of GS-9620, an oral Toll-like receptor 7 agonist. Antivir. Ther. 18, 409-418 (2013).
38. National Cancer Institute Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events (CTCAE). . (2010). Accessed 25 February 2015.