Are you Sauzanne Khalilieh?

Claim your profile

Publications (7)55.45 Total impact

  • 06/2015; DOI:10.1038/protex.2015.025
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Psoriasis is a chronic inflammatory skin disorder that affects approximately 2-3% of the population worldwide and has severe effects on patients' physical and psychological well-being. The discovery that psoriasis is an immune-mediated disease has led to more targeted, effective therapies; recent advances have focused on the interleukin (IL)-12/23p40 subunit shared by IL-12 and IL-23. Evidence suggests that specific inhibition of IL-23 would result in improvement in psoriasis. Here we evaluate tildrakizumab, a monoclonal antibody that targets the IL-23p19 subunit, in a three-part, randomized, placebo-controlled, sequential, rising multiple-dose phase I study in patients with moderate-to-severe psoriasis to provide clinical proof that specific targeting of IL-23p19 results in symptomatic improvement of disease severity in human subjects. A 75% reduction in the psoriasis area and severity index (PASI) score (PASI75) was achieved by all subjects in parts 1 and 3 (pooled) in the 3 and 10 mg kg(-1) groups by day 196. In part 2, 10 out of 15 subjects in the 3 mg kg(-1) group and 13 out of 14 subjects in the 10 mg kg(-1) group achieved a PASI75 by day 112. Tildrakizumab demonstrated important clinical improvement in moderate-to-severe psoriasis patients as demonstrated by improvements in PASI scores and histological samples.
    Nature 03/2015; 521(7551). DOI:10.1038/nature14175 · 41.46 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The CXCR2 antagonist MK-7123 causes dose-dependent reductions in absolute neutrophil counts (ANC) and decreases neutrophil tissue responses, but its effects on bone marrow functions are not yet known. We conducted a double-blind, randomized study in 18 healthy subjects comparing the effects of either MK-7123 (30mg, po, daily for 28days) or placebo on peripheral blood counts and bone marrow myeloid cell populations. MK-7123 caused a reversible decrease (approximately 50%) in the ANC as demonstrated on days 1 and 28, the first and last days of the treatment period. Bone marrow aspirate smears and biopsy imprints did not differ in the proportion of mature neutrophils in pretreatment, day 28, day 56 or placebo samples. There were no treatment effects on biopsy or aspirate clot cellularity, myeloid to erythroid or myeloid post-mitotic to mitotic ratios; flow-cytometric analyses of aspirate cells; or bone marrow fat to cell balance as assessed by MRI. MK-7123 was generally well tolerated with neutropenia being the most common adverse event; however, there were no clinical symptoms associated with decreased ANCs. These findings indicate that the CXCR2 antagonist MK-7123 causes rapidly reversible decrease in the ANC without measurable myelosuppressive effects. The results support the development of CXCR2 antagonists as potentially useful anti-inflammatory agents, primarily interrupting neutrophil trafficking. Copyright © 2015. Published by Elsevier Ltd.
    Cytokine 02/2015; 72(2):197-203. DOI:10.1016/j.cyto.2015.01.002 · 2.66 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective: To evaluate the effect of ethnicity on the pharmacokinetics (PK) of tildrakizumab, a novel anti-IL-23 monoclonal antibody for the treatment of psoriasis. Materials and methods: This was an open-label, 2-part study in healthy adult subjects. In part 1, Japanese subjects and matched Caucasian and Chinese subjects (to Japanese) were assigned to 1 of 3 cohorts and administered tildrakizumab 50, 200, or 400 mg subcutaneously (SC). In part 2, Japanese subjects received tildrakizumab 10 mg/kg IV. Pre- and post-treatment antidrug antibodies were assessed. Safety and tolerability were assessed throughout the study. Results: 59 subjects were enrolled; 53 in part 1 and 6 in part 2. Overall geometric mean AUC∞ was 6.15, 6.05, and 6.32 day×μg/mL/mg in Japanese, Caucasian, and Chinese subjects, respectively, after administration of a single SC dose. Bioavailability was ~92%. Six out of 58 evaluable subjects were positive for post-treatment ADA; 2 of these positive subjects had reduced tildrakizumab exposure. Most AEs were mild in intensity and the most frequent treatment-related AEs were injection site hematoma (15%), injection site pain (10%), and injection site erythema (8%). Conclusions: The pharmacokinetics of tildrakizumab were similar in Japanese, Caucasian, and Chinese subjects. Tildrakizumab exposure increased proportionally with dose in the range of 50-400 mg. A single SC dose of 50, 200, and 400 mg or a single IV dose of 10 mg/kg was generally well tolerated.
    International journal of clinical pharmacology and therapeutics 12/2014; 53(02). DOI:10.5414/CP202176 · 1.22 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Antagonism of the chemokine receptor CXCR2 inhibits neutrophil trafficking and may thus be therapeutic in patients with chronic obstructive pulmonary disease and other lung disorders in which there is substantial infiltration by neutrophils. Here, we report the findings from a randomized, placebo-controlled, double-blind clinical trial of the small-molecule CXCR2 antagonist MK-7123 (formerly SCH 527123) that evaluated potential downstream effects of CXCR2 antagonism on immunogenic competency (B cell antibody response) in the adaptive immune system and delayed-type hypersensitivity (DTH) in healthy subjects (ages 34-65years) dosed once daily for 30days either with 30mg MK-7123 (n=24) or placebo (n=7). Eligible subjects were seronegative for anti-hepatitis A virus (HAV) immunoglobulin G (IgG) and positive for DTH response to intradermal injection of Candida albicans antigen at screening. Subjects were vaccinated for HAV on treatment Day 2. The primary endpoints were anti-HAV IgG titer on Day 30 and DTH response magnitude on Day 27. Pharmacokinetic and safety endpoints were also assessed. We observed that anti-HAV IgG titers and DTH responses did not differ significantly between MK-7123-treated and placebo-treated subjects. Twenty-eight days postvaccination, seroconversion (anti-HAV IgG titer≥10mIU/mL) was observed in 87.5% and 85.7% of MK-7123-treated and placebo-treated subjects, respectively; mean (±SE) titers were 27.3±5.5 and 21.4±4.3mIU/mL, respectively. Treatment with MK-7123 was generally well tolerated. Doses were followed by temporary reductions in absolute peripheral blood neutrophil count. In conclusion, this study found that B cell response and cell-mediated immunity were not altered by CXCR2 antagonism with MK-7123.
    International immunopharmacology 06/2013; 17(2). DOI:10.1016/j.intimp.2013.05.029 · 2.47 Impact Factor

  • American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California; 05/2012
  • O Holz · S Khalilieh · A Ludwig-Sengpiel · Hl Watz · P Stryszak · P Soni · M Tsai · J Sadeh · H Magnussen ·
    [Show abstract] [Hide abstract]
    ABSTRACT: SCH527123 is a novel, selective CXC chemokine receptor 2 antagonist that inhibits neutrophil activation and modulates neutrophil trafficking in animal models, characteristics that may be beneficial in the treatment of conditions with unbalanced pulmonary neutrophilia, such as chronic obstructive pulmonary disease. The purpose of this proof-of-principle study was to determine whether SCH527123 inhibits ozone-induced neutrophil recruitment in healthy humans. In a randomised, double-blind, placebo-controlled, three-way crossover study, oral SCH527123 (50 mg once daily, 4 days), prednisolone (50 mg once), or placebo was alternated with 2-week washouts. 18 healthy ozone responders (>20% increase in sputum neutrophils) underwent ozone challenge tests (250 ppb, 3 h intermittent exercise) 1 h after the last treatment dose. Sputum was induced at 3 h post-challenge. After SCH527123 treatment, the ozone challenge resulted in significantly lower sputum neutrophil counts (0.13x10(6).mL(-1)) compared with prednisolone (0.84x10(6).mL(-1); p<0.001) or placebo (2.98x10(6).mL(-1); p<0.001). Comparable results were obtained for total cell count, percentage of sputum neutrophils, and for interleukin-8 and myeloperoxidase in sputum supernatant. Post-challenge, SCH527123 inhibited neutrophilia in peripheral blood but significantly less than in sputum. All treatments were safe and well tolerated. SCH527123 causes significant attenuation of ozone-induced airway neutrophilia in healthy subjects. Further evaluation in a large trial of patients with pulmonary disorders is warranted.
    European Respiratory Journal 07/2009; 35(3):564-70. DOI:10.1183/09031936.00048509 · 7.64 Impact Factor