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Gordon K.,University of Chicago | Papp K.,Probity Medical Research | Poulin Y.,Center Dermatologique du Quebec Metropolitain | Gu Y.,Abbott Laboratories | And 2 more authors.
Journal of the American Academy of Dermatology | Year: 2012

Background: REVEAL was a 52-week phase III trial of adalimumab therapy for moderate to severe chronic plaque psoriasis. Patients from REVEAL could enter an open-label extension trial to receive adalimumab for approximately 3 years of total therapy. Objective: We sought to determine long-term efficacy and safety of continuous adalimumab therapy for patients from REVEAL. Methods: Efficacy and safety over greater than 3 years of treatment were analyzed for 4 groups of patients from REVEAL. Patients who received adalimumab continuously from baseline were grouped by their responses in REVEAL: (1) greater than or equal to 75% improvement in Psoriasis Area and Severity Index (PASI) score (PASI 75) at weeks 16 and 33 (sustained responders); (2) less than PASI 75 at week 16; and (3) greater than or equal to PASI 75 at week 16 with 50% to less than 75% improvement in PASI score at week 33. Results were also analyzed for patients who began adalimumab after 16 weeks of placebo therapy. Results: For patients with sustained PASI 75 responses during REVEAL, efficacy was generally well maintained over 3 years, with 75%/90%/100% improvement in PASI score response rates (last observation carried forward) of 83%/59%/33% after 100 weeks and 76%/50%/31% after 160 weeks of continuous therapy. Some patients with less than PASI 75 responses in REVEAL also achieved long-term PASI 75 responses. Efficacy in the placebo/adalimumab group was consistent with the ensemble of results from the other 3 groups. Adverse event rates were consistent with those during REVEAL. Limitations: The REVEAL study design prevented analyzing all patients from the adalimumab arm as one long-term cohort. Conclusion: Adalimumab efficacy was well maintained over more than 3 years of continuous therapy for patients with sustained initial PASI 75 responses. Maintenance was best at the PASI 100 level. © 2010 by the American Academy of Dermatology, Inc.

Papp K.A.,Probity Medical Research | Leonardi C.,Saint Louis University | Menter A.,Baylor University | Krueger J.G.,Rockefeller University | And 6 more authors.
New England Journal of Medicine | Year: 2012

BACKGROUND: In this phase 2, randomized, double-blind, placebo-controlled, dose-ranging study, we assessed the efficacy and safety of brodalumab (AMG 827), a human anti- interleukin-17-receptor monoclonal antibody, for the treatment of moderate-tosevere plaque psoriasis. METHODS:We randomly assigned patients with a score of 12 or higher on the psoriasis area-and-severity index (PASI, on which scores range from 0 to 72, with higher scores indicating more severe disease) and with 10% or more of their body-surface area affected by psoriasis to receive brodalumab (70 mg, 140 mg, or 210 mg at day 1 and weeks 1, 2, 4, 6, 8, and 10 or 280 mg monthly) or placebo. The primary end point was the percentage improvement from baseline in the PASI score at week 12. Secondary end points included improvement of at least 75% and at least 90% in the PASI score and the score on the static physician's global assessment at week 12. RESULTS: A total of 198 patients underwent randomization. At week 12, the mean percentage improvements in the PASI score were 45.0% among patients receiving 70 mg of brodalumab, 85.9% among those receiving 140 mg, 86.3% among those receiving 210 mg, 76.0% among those receiving 280 mg, and 16.0% among those receiving placebo (P<0.001 for all comparisons with placebo). An improvement of at least 75% and at least 90% in the PASI score at week 12 was seen in 77% and 72%, respectively, of the patients in the 140-mg brodalumab group and in 82% and 75%, respectively, of the patients in the 210-mg group, as compared with 0% in the placebo group (P<0.001 for all comparisons). The percentage of patients with a static physician's global assessment of clear or minimal disease was 26%, 85%, 80%, and 69% with the 70-mg, 140-mg, 210-mg, and 280-mg doses, respectively, of brodalumab, as compared with 3% with placebo (P<0.01 for all comparisons with placebo). Two cases of grade 3 neutropenia were reported in the 210-mg brodalumab group. The most commonly reported adverse events in the combined brodalumab groups were nasopharyngitis (8%), upper respiratory tract infection (8%), and injection-site erythema (6%). CONCLUSIONS:Brodalumab significantly improved plaque psoriasis in this 12-week, phase 2 study. (Funded by Amgen; ClinicalTrials.gov number, NCT00975637.) Copyright © 2012 Massachusetts Medical Society.

Haraoui B.,Rheumatology | Liu P.P.,11 Health | Papp K.A.,Probity Medical Research
Clinical Rheumatology | Year: 2012

The role of traditional risk factors in the development of cardiovascular disease has been well studied. However, the relationship between chronic inflammatory conditions and cardiovascular risk has only recently been appreciated. Expression of numerous pro-inflammatory cytokines is common to the pathogenesis of both atherosclerosis and other chronic inflammatory diseases and may suggest that systemic inflammation independently contributes to elevated risk. This article examines the magnitude of cardiovascular risk in several of the most common chronic inflammatory diseases and summarizes currently available data to discern whether this risk is largely due to the presence of co-existing traditional risk factors for cardiovascular disease or the effect of increased systemic inflammation. Evidence is summarized to show which therapies may positively or negatively impact cardiovascular risk. Evidence is discussed in context of practical patient management tools, appropriate treatment based on risk, and treatment targets for high-risk patients. Overall, patients with chronic inflammatory diseases are at an often underestimated increase in cardiovascular risk and require individualized therapy and specific patient management strategies to address the disease process, cardiovascular risk factors, and comorbidities. © 2012 Clinical Rheumatology.

Papp K.A.,Probity Medical Research | Kaufmann R.,Goethe University Frankfurt | Thaci D.,Goethe University Frankfurt | Hu C.,Celgene | And 2 more authors.
Journal of the European Academy of Dermatology and Venereology | Year: 2013

Background Apremilast, a small molecule specific inhibitor of phosphodiesterase 4, works intracellularly to modulate pro-inflammatory and anti-inflammatory mediator production. Objective Assess apremilast efficacy and safety in moderate to severe plaque psoriasis. Methods Phase II, 12-week, multicenter, double-blind, placebo-controlled, parallel-group, dose-comparison study of 259 subjects randomized 1: 1: 1 to placebo, apremilast 20 mg QD or apremilast 20 mg BID. Results More subjects receiving apremilast 20 mg BID achieved ≥ 75% reduction in Psoriasis Area and Severity Index (PASI-75) vs. placebo (24.4% vs. 10.3%; P = 0.023). A similar proportion of subjects receiving apremilast 20 mg QD and placebo achieved PASI-75 at week 12 [9/87 (10.3%, each group)]. Mean per cent reduction in PASI from baseline was 17.4% for placebo, 30.3% for apremilast 20 mg QD (P = 0.021 vs. placebo) and 52.1% for apremilast 20 mg BID (P < 0.001). Apremilast 20 mg BID significantly decreased mean body surface area involvement vs. placebo (30.8% vs. 3.2%; P < 0.001). The most common adverse events were headache, nasopharyngitis, diarrhoea and nausea. Most events (> 90%) were mild to moderate and did not lead to study discontinuation. Serious adverse events occurred in four placebo subjects (panic attack, hospitalization for rehabilitation, hospitalization for alcoholism, worsening psoriasis), one receiving apremilast 20 mg QD (knee surgery) and in one receiving apremilast 20 mg BID (worsening psoriasis). The panic attack was considered treatment-related; both cases of worsening psoriasis occurred after medication discontinuation. No deaths or opportunistic infections were reported. Conclusion Apremilast 20 mg BID for 12 weeks was effective and well tolerated in subjects with moderate to severe plaque psoriasis. © 2012 European Academy of Dermatology and Venereology.

Papp K.,Probity Medical Research | Cather J.C.,Modern Research Associates | Rosoph L.,North Bay Dermatology Center | Sofen H.,Dermatology Research Associates | And 4 more authors.
The Lancet | Year: 2012

Background Apremilast, a small-molecule inhibitor of phosphodiesterase 4, works intracellularly to modulate proinflammatory and anti-inflammatory mediator production, and doses of 20 mg twice daily have shown efficacy in the treatment of moderate to severe plaque psoriasis in a 12-week phase 2 study. We assessed the clinical efficacy and safety of different doses of apremilast in the treatment of patients with moderate to severe plaque psoriasis. Methods In this phase 2b, multicentre, randomised, placebo-controlled, dose-ranging study, patients (aged =18 years) with moderate to severe psoriasis were randomly assigned (in a 1:1:1:1 ratio) to receive oral placebo or apremilast 10, 20, or 30 mg twice daily at 35 US and Canadian sites between Sept 24, 2008, and Oct 21, 2009. At week 16, patients in the placebo group were assigned apremilast 20 or 30 mg twice daily until week 24. Randomisation was generated with a permuted-block randomisation list via interactive voice response system. For the first 16 weeks, treatment assignment was concealed from both investigators and participants. During weeks 16-24, investigators and participants all knew that treatment was active, but the dose was concealed. The primary endpoint was the proportion of patients achieving at least 75% reduction from baseline psoriasis area and severity index (PASI-75) at week 16. Analyses were by intention to treat; missing values were imputed by last-observation-carried-forward. This trial is registered with ClinicalTrials.gov, number NCT00773734. Findings 89 patients were randomly assigned apremilast 10 mg, 87 apremilast 20 mg, and 88 apremilast 30 mg twice daily; 88 were assigned placebo. At week 16, PASI-75 was achieved in five patients (6%) assigned placebo, ten (11%) assigned apremilast 10 mg, 25 (29%) assigned 20 mg, and 36 (41%) assigned 30 mg. Apremilast 10 mg did not differ significantly from placebo in achievement of the endpoint (odds ratio 2.10; 95% CI 0.69-6.42); for both apremilast 20 mg (6.69; 2.43-18.5; p<0.0001) and apremilast 30 mg (11.5; 4.24-31.2; p<0.0001), the differences from placebo were significant. Most adverse events (96%) were mild or moderate; at least 5% of patients had nausea, upper respiratory tract infection, diarrhoea, nasopharyngitis, headache, arthralgia (placebo), gastroenteritis, or dyspepsia. Eight serious adverse events occurred (three each, placebo and apremilast 20 mg; two, apremilast 30 mg); none were judged to be related to apremilast. Apremilast had no apparent effect on the results of haematological, urinalysis, immunological or inflammation, serum chemistry, or electrocardiographic tests. Interpretation Apremilast, given orally at 20 or 30 mg twice daily, seems to be efficacious, safe, and tolerable for patients with moderate to severe plaque psoriasis. Our results support continuing, longer-term studies. Funding Celgene Corporation.

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