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Double-Blind, Placebo-Controlled, Dose-Escalation Study to Evaluate the Pharmacologic Effect of CP-690,550 in Patients With Psoriasis

2009; Elsevier BV; Volume: 129; Issue: 9 Linguagem: Inglês

10.1038/jid.2009.25

1523-1747

M. Boy, Cunshan Wang, Bethanie Wilkinson, Vincent Fung-Sing Chow, Alan Clucas, James G. Krueger, Anderson S. Gaweco, Samuel H. Zwillich, Paul S. Changelian, Gary Chan,

Asthma and respiratory diseases

adverse events two times-daily dosing interleukin Janus kinase keratin 16 least squares mean Physician's Global Assessment (of Psoriasis) Psoriatic Lesion Severity Sum once-daily dosing standard deviation standard error TO THE EDITOR Aberrant activation of the cellular immune system is recognized as the driving pathogenic event of psoriasis (Krueger and Bowcock, 2005Krueger J.G. Bowcock A. Psoriasis pathophysiology: current concepts of pathogenesis.Ann Rheum Dis. 2005; 64: ii30-ii36Crossref PubMed Scopus (378) Google Scholar), confirmed by an infiltration of T-cells into psoriatic lesions (Gudjonsson et al., 2004Gudjonsson J.E. Johnston A. Sigmundsdottir H. Valdimarsson H. Immunopathogenic mechanisms in psoriasis.Clin Exp Immunol. 2004; 135: 1-8Crossref PubMed Scopus (291) Google Scholar). Inhibition of Janus kinase 3 (JAK3) in T cells is expected to uncouple early T-cell receptor-triggered signaling from downstream events (Pesu et al., 2005Pesu M. Candotti F. Husa M. Hofmann S.R. Notarangelo L.D. O'Shea J.J. Jak3, severe combined immunodeficiency, and a new class of immunosuppressive drugs.Immunol Rev. 2005; 203: 127-142Crossref PubMed Scopus (108) Google Scholar) and, for this reason, JAK3 inhibitors could be effective in T-cell-mediated disorders such as psoriasis. CP-690,550 is an orally active highly selective JAK inhibitor and potent inhibitor of JAK3, being developed as an immunosuppressive treatment for autoimmune diseases and for the prevention of allograft rejection (Changelian et al., 2003Changelian P.S. Flanagan M.E. Ball D.J. Kent C.R. Magnuson K.S. Martin W.H. et al.Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor.Science. 2003; 302: 875-878Crossref PubMed Scopus (551) Google Scholar). Repeat doses of CP-690,550 were studied in medically stable patients with psoriasis; the results suggest the potential for effectiveness of JAK3-mediated immunosuppression in this T-cell-mediated condition. In this phase 1, randomized, dose escalation, double-blind study, each of the six CP-690,550 dosage cohorts (oral administration of 5, 10, 20, 30, and 50mg two times-daily (b.i.d.) and 60mg once-daily (q.d.)) had a concurrent, parallel, placebo control. Cohorts were conducted sequentially except for the 60mg q.d. and 50mg b.i.d. cohorts, which were conducted concurrently. Patients received treatment for 14 days and follow-up assessments were conducted 4, 7, 14, and 28 days after the last dose and until any clinically relevant abnormalities relating to the study were resolved. Biopsies were conducted at baseline and at day 14. Institutional Review Board approval was obtained from the Human Volunteers Research Committee at Arkansas Research, and written informed consent was obtained from each patient. The Declaration of Helsinki protocols were followed. A total of 59 Caucasian patients (aged 23–63 years) with at least one evaluable plaque of psoriasis were enrolled in the placebo (n=13) or the CP-690,550 groups: five each at 5mg b.i.d. and 10mg b.i.d., 10 at 20mg b.i.d., nine each at 30mg b.i.d. and 60mg q.d., and eight at 50mg b.i.d. (CONSORT details for each cohort are provided in Figure S1). Index psoriasis lesions were assessed for erythema, induration, and scaling using a Psoriatic Lesion Severity Sum (PLSS) score; a total score of 5–12 and an induration score of 2–4 were required at baseline. Download .pdf (.31 MB) Help with pdf files Figure S1CONSORT details. Patient flow for each cohort throughout the study. Results showed a dose-dependent decrease (improvement) in the least squares mean (LSM) of percentage change in PLSS score from baseline to day 14 for all CP-690,550 doses except 5mg b.i.d. (P<0.01 vs placebo) (Figure 1). Three out of eight patients in the highest dose group (50mg b.i.d.) reduced their PLSS scores to 0 (from baseline scores of 4–6) on day 14. These results were also reflected in an analysis of the change from baseline in PLSS component scores (erythema, induration, and scaling) (data not shown). Physician's Global Assessment (PGA) scores for the index lesions at baseline were similar across the groups (mean±SD values 2.8±0.8–4.0±0.9, indicating moderate or mild-to-moderate disease). The LSM increase (signifying improvement) from baseline to day 14 in PGA scores was significantly greater (P<0.01) in the CP-690,550 30 and 50mg b.i.d. groups than in the placebo group. The percentage of patients with a day 14 PGA response (defined as 'almost clear' or 'clear' and ≥2-point PGA score improvement from baseline) was significantly higher (P<0.05) in the CP-690,550 50mg b.i.d. group than in the placebo group. A total of six patients receiving CP-690,550 (5mg b.i.d., n=1; 20mg b.i.d., n=1; 30mg b.i.d., n=4) and two patients receiving placebo had evaluable biopsies at day 14. When compared with baseline biopsies, a marked histological improvement (to normal or near normal) was seen in three of the biopsied patients receiving CP-690,550, all at the higher dose of 30mg b.i.d. A clear histological improvement was observed in one of the biopsied patients receiving placebo. The remaining biopsied patients showed minimal or no changes compared with baseline. Examples of immunohistochemistry of biopsies from patients who received placebo or CP-690,550 30mg b.i.d. are shown in Figure 2. In all patients with biopsies, baseline keratin 16 (K16, a keratinocyte growth-activation marker) expression was normal (score of 0 on the 5-point (0–4) scale) or near normal (score of 1) in the nonlesional biopsy but highly abnormal (score of 4) in the lesional biopsy. At day 14, lesional biopsy K16 expression had improved to normal or near normal in three of the four patients in the 30mg b.i.d. group (including the patient shown in Figure 2), had improved (to a score of 2) in 1 of the 2 placebo recipients, and remained unchanged in the four other patients who underwent skin biopsy. Improvement in the 30mg b.i.d. group was also evidenced by a day 14 decrease from baseline in mean±SD lesion thickness (-157±165 microns) and in the number of cells positive for tested biomarkers per linear millimeter of lesion biopsy: CD3+ (-40±103 epidermal, -35±94 dermal), CD8+ (-57±20 epidermal, -33±91 dermal), CD11c+ (-64±63 epidermal, -181±189 dermal), CD25+ (-36±24 epidermal, -45±55 dermal), and CD83+ (-16±11 epidermal, -15±9 dermal). There were 16 adverse events (AEs) in 10 patients, most commonly headache (n=5) and nausea (n=3); all but three occurred in patients receiving CP-690,550. All were mild except for moderate worsening psoriasis (n=1). There was one serious AE, mild atrial fibrillation (10mg b.i.d. group), which was not considered treatment-related. Overall, there was no evidence of dose–response in AE occurrence, and no dose-related or clinically significant changes in vital signs or electrocardiograms. Total cholesterol in the 30 and 50mg b.i.d. groups, low-density lipoprotein cholesterol in the 30mg b.i.d. group, and triglycerides in the 50mg b.i.d. group were elevated relative to placebo. Other abnormal safety laboratory tests showed no clear relationship to CP-690,550 dose. These findings demonstrate that JAK3 inhibition may provide a viable mechanism of action for the treatment of psoriasis, and to our knowledge this is previously unreported. Through inhibition of JAK3, CP-690,550 is thought to suppress the intracellular signal transduction from the common γ chain receptors for the cytokines IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 (Borie et al., 2004Borie D.C. O'Shea J.J. Changelian P.S. JAK3 inhibition, a viable new modality of immunosuppression for solid organ transplants.Trends Mol Med. 2004; 10: 532-541Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar), thereby disrupting the activation, proliferation, and homeostasis of helper and cytotoxic T lymphocytes. The inhibition of IL-15 activity may be of particular relevance because IL-15 shows high levels of expression and enhanced binding activity in psoriasis lesions, and is also associated with increases in the apoptotic resistance of keratinocytes (Ruckert et al., 2000Ruckert R. Asadullah K. Seifert M. Budagian V.M. Arnold R. Trombotto C. et al.Inhibition of keratinocyte apoptosis by IL-15: a new parameter in the pathogenesis of psoriasis?.J Immunol. 2000; 165: 2240-2250Crossref PubMed Scopus (177) Google Scholar). The sample size of this study was relatively small, no adjustments were made for multiple comparisons due to the exploratory nature of the analyses, and placebo patients across the six cohorts were combined into a single group for all analyses. Despite these limitations, this study demonstrated substantial improvement in psoriatic lesion severity suggesting that CP-690,550 is a potent immunosuppressant. Further studies with CP-690,550 in immune-mediated disorders are warranted. James G. Krueger received a research grant from Pfizer Inc., to do the histology analysis that is a part of this article. Mary G. Boy, Cunshan Wang, Bethanie E. Wilkinson, Vincent Fung-Sing Chow, Alan T. Clucas, Samuel H. Zwillich, and Gary Chan, are employees of Pfizer Inc., Mary G. Boy, Cunshan Wang, Bethanie E. Wilkinson, Vincent Fung-Sing Chow, Alan T. Clucas, Samuel H. Zwillich, and Gary Chan are eligible to receive Pfizer stock options. Anderson S. Gaweco and Paul S. Changelian were employees of Pfizer at the time of this research. This study was sponsored by Pfizer Inc. Editorial support for this article was provided by Dean Clarke at Complete Medical Communications. The clinical phase of the study was conducted at Arkansas Research, 1207 Rebsamen Park Road, Little Rock, Arkansas, 72202 USA. Figure S1. CONSORT details. Patient flow for each cohort throughout the study.