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Articles Efficacy and safety of ustekinumab, a human ... - Huidarts.com

Articles Efficacy and safety of ustekinumab, a human ... - Huidarts.com

Articles Placebo-controlled phase (weeks 0–12) Placebo crossover phase (weeks 12–40) Randomised withdrawal phase (weeks 40–76)* Ustekinumab 45 mg (n=255) Ustekinumab 90 mg (n=255) Placebo (n=255) Ustekinumab 45 mg (n=255) Ustekinumab 90 mg (n=251) Placebo to ustekinumab 45 mg (n=123) Placebo to ustekinumab 90 mg (n=120) Maintenance therapy (n=161) Interrupted therapy (n=160) Mean duration of follow-up (weeks) 12·2 12·1 12·1 27·2 27·5 28·0 28·2 36·0 35·6 Patients with one or more adverse events 147 (57·6%) 131 (51·4%) 123 (48·2%) 146 (57·3%) 161 (64·1%) 79 (64·2%) 69 (57·5%) 108 (67·1%) 121 (75·6%) Common adverse events† Upper respiratory tract infection 18 (7·1%) 16 (6·3%) 16 (6·3%) 19 (7·5%) 28 (11·2%) 9 (7·3%) 9 (7·5%) 22 (13·7%) 21 (13·1%) Nasopharyngitis 26 (10·2%) 21 (8·2%) 22 (8·6%) 25 (9·8%) 22 (8·8%) 18 (14·6%) 13 (10·8%) 16 (9·9%) 17 (10·6%) Arthralgia 7 (2·7%) 6 (2·4%) 7 (2·7%) 11 (4·3%) 8 (3·2%) 5 (4·1%) 4 (3·3%) 3 (1·9%) 12 (7·5%) Headache 14 (5·5%) 13 (5·1%) 6 (2·4%) 10 (3·9%) 8 (3·2%) 6 (4·9%) 1 (0·8%) 6 (3·7%) 4 (2·5%) Adverse events leading to withdrawal of 1 (0·4%) 4 (1·6%) 6 (2·4%) 7 (2·7%) 5 (2·0%) 2 (1·6%) 1 (0·8%) 3 (1·9%) 3 (1·9%) study agent Serious adverse events‡ 2 (0·8%) 4 (1·6%) 2 (0·8%) 8 (3·1%) 4 (1·6%) 2 (1·6%) 2 (1·7%) 1 (0·6%) 7 (4·4%) Adverse events of special interest Infections 80 (31·4%) 66 (25·9%) 68 (26·7%) 79 (31·0%) 106 (42·2%) 46 (37·4%) 44 (36·7%) 71 (44·1%) 76 (47·5%) Serious infections 0 (0·0%) 2 (0·8%) 1 (0·4%) 1 (0·4%) 1 (0·4%) 0 (0·0%) 0 (0·0%) 0 (0·0%) 2 (1·3%) Cutaneous cancers§ 0 (0·0%) 0 (0·0%) 0 (0·0%) 1 (0·4%) 0 (0·0%) 1 (0·8%) 0 (0·0%) 2 (1·2%) 0 (0·0%) Non-cutaneous cancers 0 (0·0%) 0 (0·0%) 0 (0·0%) 2 (0·8%) 0 (0·0%) 0 (0·0%) 0 (0·0%) 0 (0·0%) 1 (0·6%) Cardiovascular events|| 1 (0·4%) 0 (0·0%) 0 (0·0%) 1 (0·4%) 0 (0·0%) 1 (0·8%) 1 (0·8%) 0 (0·0%) 0 (0·0%) *Includes only patients who were randomised at week 40 and subsequently treated. †Occurred in at least 5% of patients in any treatment group. ‡An adverse event that resulted in any of the following outcomes: death, a life-threatening condition, in-patient hospitalisation or prolongation of existing hospitalisation, persistent or significant disability or incapacity, or a congenital anomaly or birth defect, irrespective of its relationship to study agent. §Basal-cell carcinomas only. Include prostate, colon, and thyroid cancer. ||Any serious adverse events of sudden cardiac death, myocardial infarction, or stroke. Table 3: Adverse events during the three phases of the trial differentiation towards a T helper 17 (Th17) phenotype, 22 expression of interleukin 17, and increased keratinocyte expression of inducible nitric oxide synthase, which has also been implicated in the pathophysiology of psoriasis. 23,24 Cytokines produced by Th17 cells, including interleukin 20 and interleukin 22, have been implicated in the keratinocyte hyperproliferative response in psoriasis. 25,26 Although the mechanisms by which interleukin 12 and 23 contribute to the pathophysiology of psoriasis are incompletely understood, the shared p40 protein might have a key role in the inflammatory cascade. 27 Treatment with two 45 or 90 mg injections of ustekinumab at week 0 and week 4, followed by dosing every 12 weeks, led to PASI 75 response in more than three quarters of patients with moderate-to-severe psoriasis in both PHOENIX 1 and PHOENIX 2. 13 More than 90% of patients experienced clinically meaningful improvements, 28 and the PHOENIX 2 study further characterised determinants of treatment resistance as well as potential therapeutic approaches for the treatment resistant subpopulation. 13 Clinical improvements were paralleled by improvements in patient-reported outcomes, measured by dermatology life quality index. Onset of response was seen within 2 weeks of the first dose of ustekinumab, and psoriasis response was generally maintained for at least a year and a half in patients who received the drug every 12 weeks. In patients withdrawn from ustekinumab, psoriasis gradually recurred—showing that temporary blockade of interleukins 12 and 23 did not reverse the underlying causal mechanisms of psoriasis—and quality of life improvements were lost. Combined, these observations suggest that maintaining response and quality-of-life improvements could require continuous maintenance dosing. Among patients withdrawn from ustekinumab, response was generally restored within 12 weeks of reinitiating treatment. Rates and types of adverse events, serious adverse events, adverse events leading to treatment discontinuation, and laboratory abnormalities were generally comparable between patients receiving placebo, ustekinumab 45 mg, and ustekinumab 90 mg during both the placebo-controlled and randomised withdrawal phases. No dose-response in safety events was apparent throughout the study. The observation of higher rates of hyperglycaemia in ustekinumab-treated patients in a previous trial 11 was not apparent in this larger study. Rates of serious infections and malignancies were low in all treatment groups during the placebo-controlled phase and comparative rates did not suggest an association with ustekinumab. Similarly, serious cardiovascular events, which were observed in a previous trial 11 and which are reported to be a population risk in patients with psoriasis, 29,30 were uncommon during the placebo-controlled phase of the study. No increase in the frequency of adverse events or serious adverse events, including serious infections, malignancies, or cardiovascular events, was apparent over time with maintenance dosing. No mycobacterial 1672 www.thelancet.com Vol 371 May 17, 2008

Articles or salmonella infections, which have been reported in individuals congenitally deficient in interleukin 12 p40 or interleukin 12 receptor β1, 31,32 and no cases of lymphoma or demyelinating disease were reported throughout the study. Our results do not reveal any major safety concerns in blocking interleukin 12 and 23 for periods as long as a year and a half. However, the size and duration of the trial do not rule out a potential effect of ustekinumab on uncommon events or events that occur after longer duration of exposure or in larger patient populations, although additional follow-up will result from long-term extension of this study for a total of 5 years of treatment. Together with the safety profile observed in the PHOENIX 2 trial, 13 these results indicate that ustekinumab is well tolerated during treatment lasting at least a year. Our results suggest that ustekinumab could be an important therapeutic agent for treating patients with psoriasis. Recognising the limitations of comparisons across studies, the high level of efficacy noted in this study compares favourably with that reported for currently available intramuscularly or subcutaneously administered biological therapeutic agents for psoriasis. 33 The high level of efficacy was generally maintained with dosing every 12 weeks, a schedule that could offer a novel level of convenience for patients and physicians. These attributes might be particularly important for treatment compliance, which is low in patients with psoriasis and could, at least in part, result from dissatisfaction with effectiveness or convenience of available treatments. 34,35 Contributors The steering committee consisted of CLL, ABK, KAP, and KBG. NY, YW, and KBG wrote the original draft of the manuscript. All authors participated in the design and conduct of the study, the analysis or interpretation of the data, and the writing and review of the manuscript. All authors agreed to submit the manuscript for publication and approved the final version. PHOENIX 1 study investigators D Nieves (Psoriasis Treatment Center of New Jersey, East Windsor, NJ, USA), D Baker (Allergy, Asthma and Dermatology Research, Lake Oswego, OR, USA), F Behringer Jr (Renstar Medical Research, Ocala, FL, USA), C Birbara (Clinical Pharmacology Study Group, Worcester, MA, USA), D Fiorentino (Stanford University School of Medicine, Stanford, CA, USA), S Fretzin (Dawes Fretzin Clinical Research Group, Indianapolis, IN, USA), B Goffe (Dermatology Associates, Seattle, WA, USA), T Hamilton (Atlanta Dermatology, Vein and Research Center, Alpharetta, GA, USA), D Johnson (Honolulu, HI, USA), S Kempers (Minnesota Clinical Study Center, Fridley, MN, USA), W Ko (Radiant Research, Phoenix, AZ, USA), C Leonardi (Central Dermatology, St Louis, MO, USA), J Zeichner (Mt Sinai School of Medicine, New York, NY, USA), M Ling (MedaPhase Inc, Newman, GA, USA), K Loven (Rivergate Dermatology, Goodlettsville, TN, USA), J Maloney (Cherry Creek Research Inc, Denver, CO, USA), R Matheson (Oregon Medical Research Center, Portland, OR, USA), A Menter (Baylor Research Institute, Dallas TX, USA), S Mings (Covance CRU Inc, Boise, ID, USA), E Monroe (Advanced Healthcare, Milwaukee, WI, USA), A Nayak (Sneeze, Wheeze and Itch Associates, Normal, IL, USA), J Powers (Radiant Research, Scottsdale, AZ, USA), P Rich (Oregon Dermatology and Research Center, Portland, OR, USA), M Saruk (Atlantic Skin and Cosmetic Surgery Group, Malvern PA, USA), J Schlessinger (Skin Specialists, Omaha, NE, USA), S Smith (Dermatology and Advanced Aesthetics, Lake Charles, LA, USA), H Sofen (Los Angeles, CA, USA), E Tschen (Academic Dermatology Associates, Albuquerque, NM, USA), P Yamauchi (Clinical Research Specialists Inc, Santa Monica, CA, USA), R Bissonnette (Innovaderm Research Inc, Quebec, Canada), M Bourcier (Dermatology Clinic, New Brunswick, Canada), W Carey (Siena Medical Research, Quebec, Canada), D Gratton (International Dermatology Research Inc, Quebec, Canada), L Guenther (Guenther Dermatology Research Centre, Ontario, Canada), Z Tomi (New Lab Clinical Research Inc, NL, Canada), R Langley (Eastern Canada Cutaneous Research Associates, Nova Scotia, Canada), B Lasko (Manna Research, Ontario, Canada), K Papp (K Papp Clinical Research, Ontario, Canada), Y Poulin (Centre Dermatologique du Quebec Metropolitain, Quebec, Canada), C Maari (Innovaderm Research Laval Inc, Quebec, Canada), L Rosoph (North Bay Dermatology Centre, Ontario, Canada), J Tan (Windsor Clinical Research, Ontario, Canada), J-S Gauthier (replaced M Tolszczuk, Q&T Research Inc, Quebec, Canada), D Toth (XLR8 Research, Ontario, Canada), N Wasel (Stratica Medical, Alberta, Canada), M Heenen (Erasmus University Hospital, Brussels, Belgium), J Lambert (Universitair Ziekenhuis Antwerpen, Edegem, Belgium), P Ghislain (Catholic University of Louvain, Brussels, Belgium). Conflict of interest statement CLL has served as a consultant for Abbott, Amgen, Centocor, and Genentech, as an investigator for Abbott, Allergan, Altana, Alza, Amgen, Astellas, Celgene, Centocor, Genentech, Bristol Myers, Eli Lilly, Fujisawa, Galderma, CombinatoRx, 3M Pharmaceuticals, Perrigo Isreal Pharamceutical, ScheringPlough, Serono, RTL, Novartis, Vitae, and Wyeth, and as a speaker for Abbott, Amgen, Centocor, Genentech, and Warner Chilcott. ABK has served as an investigator and consultant for Abbott, Amgen, and Centocor and has been a study steering committee member, speaker, and fellowship funding recipient from Centocor. KAP has served as a consultant and advisory board member for Abbott, Alza, Amgen, Celgene, Centocor, Johnson and Johnson, Isotechnika, Janssen Ortho Biotech, Medimmune, MerckSerono, and Wyeth. KBG has served as a consultant for Abbott, Amgen, Astellas, Centocor, and Genentech and has received grant support from Abbott, Astellas, and Centocor. NY, CG, YW, SL, and LTD are employees of Centocor and own stock in Johnson and Johnson. Acknowledgments This study was supported by Centocor Inc. The authors thank Y You for her programming and analysis support, J Benson for her critical review of the manuscript, and C Arnold for her writing support; all are employees of Centocor. References 1 Krueger G, Koo J, Lebwohl M, Menter A, Stern RS, Rolstad T. The impact of psoriasis on quality of life: results of a 1998 National Psoriasis Foundation Patient-Membership Survey. Arch Dermatol 2001; 137: 280–84. 2 Schon MP, Boehncke W-H. Psoriasis. N Engl J Med 2005; 352: 1899–912. 3 Nickoloff BJ, Stevens SR. What have we learned in dermatology from the biologic therapies? J Am Acad Dermatol 2006; 54 (3 suppl 2): S143–51. 4 Sterry W, Barker J, Boehncke W-H, et al. Biological therapies in the systemic management of psoriasis. Br J Dermatol 2004; 151: 3–17. 5 Cargill M, Schrodi SJ, Chang M, et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet 2007; 80: 273–90. 6 Duerr RH, Taylor KD, Brant SR, et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 2006; 314: 1461–63. 7 Capon F, Di Meglio P, Szaub J, et al. Sequence variants in the genes for the interleukin-23 receptor (IL23R) and its ligand (IL12B) confer protection against psoriasis. Hum Genet 2007; 122: 201–06. 8 Piskin G, Sylva-Steenland RMR, Bos JD, Teunissen MBM. In vitro and in situ expression of IL-23 by keratinocytes in healthy skin and psoriasis lesions: enhanced expression in psoriatic skin. J Immunol 2006; 176: 1908–15. 9 Hong K, Chu A, Ludviksson BR, Berg EL, Ehrhardt RO. IL-12, independently of IFN-γ, plays a crucial role in the pathogenesis of a murine psoriasis-like skin disorder. J Immunol 1999; 162: 7480–91. 10 Torti DC, Feldman SR. Interleukin-12, interleukin-23, and psoriasis: current prospects. J Am Acad Dermatol 2007; 57: 1059–68. www.thelancet.com Vol 371 May 17, 2008 1673

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