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To provide recent population-based estimates of transthoracic needle biopsy (TTNB) complications and risk factors associated with these complications.This retrospective cohort analysis included adults from a nationally representative longitudinal insurance claims data set who underwent TTNB in 2017 or 2018. Complications that were evaluated included pneumothorax, hemorrhage, and air embolism. Separate logistic regression models estimated the association of pneumothorax or hemorrhage with the setting of care (ie, inpatient or outpatient) and selected baseline patient demographic and clinical characteristics including age, gender, history of chronic obstructive pulmonary disease, diagnosis of pleural effusion, tobacco use, use of oral anticoagulants and antiplatelet agents, prior lung cancer screening, previous bronchoscopy within 1 year, and Elixhauser comorbidity index.Among 16,971 patients who underwent TTNB, 25.8% experienced a complication within 3 days of the procedure (pneumothorax 23.3%, hemorrhage 3.6%, and air embolism 0.02%). Among patients who experienced pneumothorax, 31.9% required chest tube drainage. Among patients undergoing an outpatient TTNB (n = 12,443), 6.9% were hospitalized within 7 days. Biopsy in an inpatient setting, chronic obstructive pulmonary disease diagnosis, and prior bronchoscopy were associated with higher rates of both pneumothorax and hemorrhage. Prior lung cancer screening was associated with an increased risk of pneumothorax, and prior use of oral anticoagulants or antiplatelets was associated with higher rates of hemorrhage.This contemporary population-based cohort study demonstrated that approximately one-quarter of patients undergoing TTNB experienced a complication. Pneumothorax was the most frequent complication, and hemorrhage and air embolism were rare. Among outpatients, complications from TTNB are an important cause of hospitalization.

Background and Aims We assessed the effect of ustekinumab on health-related quality of life [HRQOL] in adults with Crohn's disease [CD]. Methods Patients with moderately to severely active CD and inadequate response or intolerance to tumour necrosis factor antagonists [UNITI-1, n = 741], or conventional therapy [UNITI-2, n = 627] were randomised to placebo, ustekinumab 130 mg, or 6 mg/kg intravenous induction therapy. At Week 8, ustekinumab-treated responders (Crohn's Disease Activity Index [CDAI] reduction ≥100 or CDAI

Background & Aims Ustekinumab is a monoclonal antibody that binds with high affinity to the p40 subunit of human interleukin 12 (IL12 and IL23) that has been approved for treatment of patients with moderate to severe Crohn's disease (CD). However, there are few data on its pharmacokinetic properties or the relationship between drug exposure levels and patient response. We collected data from 2 Phase 3 induction studies and 1 maintenance study to determine ustekinumab's pharmacokinetic features, relationship between exposure and response, and optimal serum concentrations for efficacy. Methods We collected data on serum concentrations of ustekinumab and efficacy from induction studies of patients with moderate to severe CD given ustekinumab for 8 weeks following a single intravenous dose (either 130 mg or approximately 6 mg/kg). We collected the same data from a maintenance study of patients with a response to ustekinumab in the induction study who then received subcutaneous injections (90 mg) every 8 or 12 weeks for 44 weeks. At week 44 of the maintenance study (52 weeks after treatment began), patients were evaluated for the primary endpoint of clinical remission (defined as a CD activity index score below 150 points), endoscopic markers of efficacy, and serum level of C-reactive protein. Ustekinumab concentration data were categorized into quartiles and relationships between exposure and response were assessed. Optimal concentration cutoff values were evaluated using receiver operating characteristic curve analysis. Results Serum concentrations of ustekinumab over time were proportional to dose and did not differ significantly between the induction studies. In the maintenance study, ustekinumab concentration reached the steady state by the second maintenance dose; the median trough concentration was approximately threefold higher in patients given ustekinumab at 8-week intervals compared with 12-week intervals. Ustekinumab serum concentrations associated with rates of clinical remission and endoscopic efficacy endpoints, correlated inversely with level of C-reactive protein, and did not associate with use of immunomodulators. Trough concentrations of ustekinumab of 0.8 (or even up to 1.4 μg/mL) or greater were associated with maintenance of clinical remission in a higher proportion of patients than patients with lower trough concentrations. Conclusions In an analysis of data from Phase 3 studies of patients with moderate to severe CD, we found serum concentrations of ustekinumab to be proportional to dose and associate with treatment efficacy. Concentrations of ustekinumab did not seem to be affected by cotreatment with immunomodulators. Clinicaltrials.gov no. NCT01369329 (UNITI 1), NCT01369342 (UNITI 2), and NCT01369355 (IM-UNITI).

The purpose of this study is to evaluate the pharmacokinetics, immunogenicity, safety, and tolerability of guselkumab, a human monoclonal antibody with high affinity and specificity for binding to interleukin-23.In this first-in-human, phase 1, randomized study, a single intravenous (IV; 0.03-10 mg/kg) or subcutaneous (SC; 10-300 mg) dose of guselkumab was administered to 47 healthy subjects, and a single SC dose (placebo, 10, 30, 100, 300 mg) was administered to 24 patients with moderate-to-severe psoriasis.Mean maximum observed serum concentration and area under the zero-to-infinity serum concentration-time curve of guselkumab increased in an approximately dose-proportional manner over the dose range of 0.03-10 mg/kg following a single IV administration or 10-300 mg following a single SC administration. Mean clearance and volume of distribution ranged from 3.62-6.03 mL/day/kg and 99.38-123.22 mL/kg, respectively. Mean half-life ranged from 12 to 19 days in healthy subjects and patients with psoriasis. Among guselkumab-treated subjects/patients, 1/30 (3.3 %) healthy subjects in the IV group, 0/6 healthy subjects in the SC group, and 1/20 (5.0 %) patients with psoriasis tested positive for antibodies to guselkumab. No clinically significant adverse events were identified in this study.Guselkumab pharmacokinetic profiles were generally comparable between healthy subjects and patients with psoriasis. Guselkumab, administered as an IV infusion or SC injection, was well tolerated in healthy subjects and patients with psoriasis.

BACKGROUND & AIMS: The efficacy of antibody-based therapeutics depends on their pharmacokinetics. The pharmacokinetic and exposure response profiles of ustekinumab, a monoclonal antibody against interleukin 12/interleukin 23, are known in patients with Crohn's disease, yet there are few data from patients with ulcerative colitis. We characterized ustekinumab's pharmacokinetics, exposure response, and optimal serum concentrations in patients with ulcerative colitis. METHODS: We collected data from 2 phase 3 trials (1 induction and 1 maintenance), in which patients with moderate to severe ulcerative colitis received an intravenous induction dose of ustekinumab (130 mg, n = 320; or approximately 6 mg/kg, n = 322). Responders were assigned randomly to groups that received subcutaneous maintenance ustekinumab (90 mg) every 8 weeks (n = 176) or 12 weeks (n = 172), or placebo (n = 175). We evaluated the association between ustekinumab concentration and efficacy, serum based on clinical effects (Mayo score), histologic features, and inflammation (measurement of C-reactive protein, fecal calprotectin, and fecal lactoferrin), as well as safety (infections, serious infections, and serious adverse events), during induction and maintenance therapy. Optimal serum concentrations of ustekinumab were identified using receiver operating characteristic curve analyses. RESULTS: In patients with ulcerative colitis, dose-proportional serum concentrations of ustekinumab, unaffected by prior biologic or concomitant immunomodulator therapy, reached steady state by the second maintenance dose; the median trough concentration for dosing every 8 weeks was approximately 3-fold that of dosing every 12 weeks. Serum concentrations were associated with clinical and histologic features of efficacy and normalization of inflammation markers. The week-8 concentration threshold for induction of response was 3.7 μg/mL. A steady-state trough serum concentration of 1.3 μg/mL or higher was associated with a higher rate of clinical remission compared with patients who had lower serum concentrations. Serum concentrations of ustekinumab were not associated with infections, serious infections, or serious adverse events. CONCLUSIONS: In an analysis of data from 2 phase 3 trials of patients with ulcerative colitis, we found that serum concentrations of ustekinumab were proportional to dose, unaffected by prior biologic or concomitant immunomodulator therapies, associated with clinical and histologic efficacy and markers of inflammation, and were not associated with safety events at doses evaluated. Ustekinumab pharmacokinetics are consistent between patients with Crohn's disease vs ulcerative colitis. ispartof: CLINICAL GASTROENTEROLOGY AND HEPATOLOGY vol:18 issue:10 pages:2244-+ ispartof: location:United States status: published

Background and aims Janus kinase [JAK] inhibitors have shown efficacy in ulcerative colitis [UC]. We studied the dose-response, efficacy, and safety of peficitinib, an oral JAK inhibitor, in patients with moderate-to-severe UC. Methods In this Phase 2b, dose-ranging trial, we evaluated peficitinib at 25 mg once daily [o.d.], 75 mg o.d., 150 mg o.d., and 75 mg twice daily versus placebo for efficacy and safety in 219 patients with moderate-to-severe UC. The primary outcome was peficitinib dose-response at Week 8, with response assessed using Mayo score change from baseline. Secondary endpoints were clinical response, clinical remission, mucosal healing, change from baseline in Inflammatory Bowel Disease Questionnaire [IBDQ], and normalisation of inflammatory biomarkers at Week 8; other secondary endpoints were treatment response through Week 16 and through Week 32 for patients in clinical response at Week 8. Safety was assessed through Week 36 or 4 weeks after the last dose. Results A statistically significant peficitinib dose-response was not demonstrated at Week 8, although a numerically greater proportion of patients receiving peficitinib ≥75 mg o.d. achieved clinical response, remission, and mucosal healing at Week 8, supported by IBDQ improvement and inflammatory biomarker normalisation. Treatment-emergent adverse event [TEAE] rates reported through Week 8 and the final safety visit were higher in the combined peficitinib group than in the placebo group; patients receiving doses of ≥75 mg o.d. peficitinib reported TEAEs more frequently. Conclusions No dose-response in patients with moderate-to-severe UC was demonstrated with peficitinib, but evidence of efficacy was suggested at doses ≥75 mg o.d. The safety profile of peficitinib was consistent with current information. ClinicalTrials.gov NCT01959282.

BACKGROUND: Ustekinumab (UST) is well-established in psoriasis (PsO) & psoriatic arthritis (PsA) with up to 5 years safety data from psoriasis clinical trials with 3117 pts & 8998 patient years (PY). However, limited safety data have been presented in Crohn’s disease (CD). In CD, Phase 2/3 data show that UST is safe & effective. AIMS: Here we present CD safety data & compare it to safety from psoriatic diseases. METHODS: Safety data from 5 CD (2 Ph2/3Ph3) trials were analyzed with the previously reported PsO (1 Ph2/3Ph3) & PsA (1 Ph2/2 Ph3) trials. Psoriatic pts received UST 45 or 90mg SC; Ph3 CD pts received one IV UST dose (130mg or ~6 mg/kg) then 90mg SC q8w or q12w. Permitted concurrent treatments differed by indication: PsO – none; PsA – methotrexate; CD - immunosuppressives & corticosteroids. All pts who received ≥1 dose of UST were included. Outcomes are presented as events per 100 PY. RESULTS: In the PBO-control period, 3636 pts received UST (1582 PsO, 692 PsA & 1362 CD). Treated pts with ≥1 reported event PBO vs UST in pooled indications (events/100 PY): AEs 556.1 vs 594.3; SAEs 19.5 vs16.4; infections 135.8 vs138.1; serious infections 2.9 vs 3.3; MACE 0.26 vs 0.60; malignancies 0.26 vs 0.12; deaths 0 vs 0.12. Through 1 year, 5884 pts received UST (3117 PsO, 1018 PsA, & 1749 CD) over 4521 PY. Rates of AEs, SAEs, & infections were similar between UST & PBO (Table) across all groups. Event rates in the combined CD studies were also similar between groups with more frequent overall AEs, & infections in CD pts. CONCLUSIONS: UST has a favorable safety profile in CD with one IV induction dose up to 6mg/kg & SC maintenance up to 90mg q8wks. Evaluation of the CD experience did not alter the safety profile of UST established in pts with psoriatic disease treated up to 5 years. FUNDING AGENCIES: Janssen Research & Development, LLC

AIMS: Ustekinumab (UST) has been shown to induce and maintain clinical response and remission in moderate-severe Crohn’s disease (CD) in 2 induction (UNITI-1 & 2) and 1 maintenance (IM-UNITI) randomized, PBO-controlled Phase 3 trials. We evaluated the efficacy of UST in 2 additional groups in IM-UNITI: patients (pts) who dose adjusted following loss of response (LOR) and pts who did not have a clinical response to IV UST during induction and had an additional subcutaneous (SC) dose. METHODS: Pts in clinical response [CR-100] (≥ 100 point decrease in CDAI) after single dose IV dose were randomized to SC PBO, UST 90mg q12w or q8w. Pts who met LOR criteria, defined as a CDAI score of ≥ 220 and a ≥ 100 point increase from the IM-UNITI baseline CDAI score, between wks8 and 32 of IM-UNITI could undergo a single dose adjustment as follows: PBO→q8w, q12w→q8w, and q8w→q8w (no adjustment) and were assessed for CR-100 and clinical remission (CDAI < 150) 16wks later. Separately, UST IV non-responders received SC UST 90mg, then continued SC UST 90mg q8w if in CR 8wks later. RESULTS: 51 (39%), 29 (23%), and 28 (22%) pts in the PBO, q12w and q8w groups, respectively, underwent dose adjustment after meeting LOR criteria. Among these pts, clinical remission and CR-100 were observed in 39% and 71% of pts adjusting PBO→q8w (a situation similar to a drug holiday), 41% and 55% in the q12w→q8w group, and 32% and 46% in the q8w→q8w group when assessed 16wks later (Table 1). Median change in CDAI after adjustment was -121, -141 and -78.5 in the PBO→q8w, q12w→q8w and q8w→q8w groups, respectively. Of 467 pts not in response to UST following IV induction in UNITI1&2, 50.5% and 28.9% were in clinical response and remission 8wks after one additional UST dose (90mg SC). Among the 251 of these pts continuing dosing at wk8 of maintenance, 68.1% were in CR-100 and 50.2% were in remission at wk44. No increases or changes in patterns of adverse events were seen among pts who dose adjusted. CONCLUSIONS: In pts who met LOR criteria, dose adjustment from UST 90mg q12w to 90mg q8w provided some additional clinical benefit compared to pts who remained on UST 90mg q8w. Additionally, pts who were initial induction non-responders can benefit from continued treatment with at least 1 SC UST dose 8wks after IV induction. FUNDING AGENCIES: Janssen Research & Development, LLC

Background & Aims We evaluated the ability of ustekinumab, a monoclonal antibody against the p40 subunit of interleukins 12 and 23, to induce endoscopic healing in patients with moderate to severe Crohn's disease (CD). Methods We performed an endoscopy substudy of 334 patients with moderate to severe CD participating in 3 randomized controlled phase 3 studies to determine the safety and efficacy of ustekinumab induction and maintenance therapy. All patients underwent colonoscopy at baseline and week 8 of the induction studies and at week 44 of the maintenance study; all colonoscopies were assessed by a blinded central reader. During the induction studies, patients were randomly assigned to groups given intravenous ustekinumab (130 mg or 6 mg/kg) or placebo. At the baseline time point of the maintenance study (week 8 of the induction studies), patients with a clinical response to ustekinumab were randomly assigned to groups given subcutaneous ustekinumab (90 mg every 12 weeks or 8 weeks) or placebo. Additional maintenance analysis populations were patients who did not respond to ustekinumab or placebo during the induction studies, and patients who responded to placebo during the induction studies; we performed a post-hoc pooled analysis of randomly assigned and non-randomly assigned patients of the maintenance study. We analyzed data from patients with an ulcer in at least 1 segment at baseline of the induction studies. The primary end point was change in the Simplified Endoscopic Activity Score for Crohn's Disease (SES-CD), from baseline, at week 8. We also assessed the efficacy of maintenance therapy. Results Patients given ustekinumab had a greater reduction in SES-CD from the induction baseline time point until week 8 than placebo (reduction of 2.8 in patients given ustekinumab vs a reduction of 0.7 points in patients given placebo; P = .012). Results were similar among patients in different induction studies and patients given different doses of ustekinumab. At week 44, reductions in the SES-CD from the induction baseline were greater in patients given ustekinumab (for combined groups, a reduction of 2.5; P = .176 and for every 8 weeks, a reduction of 3.1; P = .107) than patients given placebo (reduction of 1.9 points). Maintenance results were similar for the larger pooled post-hoc analysis. Conclusions In an analysis of data from 3 trials of patients with moderate to severe CD, ustekinumab (intravenous induction and subcutaneous maintenance) reduces SES-CD compared with placebo. We observed significant reductions in endoscopic disease activity at week 8 of induction therapy with ustekinumab. (ClinicalTrials.gov numbers, NCT01369329, NCT01369342, and NCT01369355).

Informative exposure-response modeling of clinical endpoints is important in drug development to identify optimum dose and dosing regimens. Despite much recent progress in mechanism-based longitudinal modeling of clinical data, challenges remain in clinical trials of diseases such as Crohn's disease, where a commonly used composite endpoint Crohn's Disease Activity Index (CDAI) has considerable variation in its administration and scoring between different assessors and complex study designs typically include maintenance phases with randomized withdrawal re-randomizations and other response driven dose adjustments. This manuscript illustrates the complexities of exposure-response modeling of such composite endpoint data through a latent-variable based Indirect Response model framework for CDAI scores using data from three phase III trials of ustekinumab in patients with moderate-to-severe Crohn's Disease. Visual predictive check was used to evaluate model performance. Potential impacts of the study design on model development and evaluation of the E-R relationship in the induction and maintenance phases of treatment are discussed. Certain biases appeared difficult to overcome, and an autocorrelated residual error model was found to provide improvement.

Informative exposure-response modeling of clinical endpoints is important in drug development. There has been much recent progress in latent variable modeling of ordered categorical endpoints, including the application of indirect response (IDR) models and accounting for residual correlations between multiple categorical endpoints. This manuscript describes a framework of latent-variable-based IDR models that facilitate easy simultaneous modeling of a continuous and a categorical clinical endpoint. The model was applied to data from two phase III clinical trials of subcutaneously administered ustekinumab for the treatment of psoriatic arthritis, where Psoriasis Area and Severity Index scores and 20, 50, and 70 % improvement in the American College of Rheumatology response criteria were used as efficacy endpoints. Visual predictive check and external validation showed reasonable parameter estimation precision and model performance.

Background IL-23 expression is increased in psoriatic lesions and might regulate T H 17 T-cell counts in patients with psoriasis. Objectives We sought to test a novel IL-23–specific therapeutic agent for the treatment of psoriasis. Methods In this randomized, double-blind, placebo-controlled study the safety, tolerability, and clinical response of guselkumab, an anti–IL-23–specific mAb, were evaluated in patients with moderate-to-severe plaque psoriasis. A total of 24 patients were randomized to receive a single dose of placebo or 10, 30, 100, or 300 mg of guselkumab. Clinical response was assessed by using the Psoriasis Area and Severity Index (PASI). Additionally, histologic analysis and gene expression in skin biopsy specimens from guselkumab-treated patients were compared with those from placebo-treated patients. Results At week 12, 50% (10 mg), 60% (30 and 100 mg), and 100% (300 mg) of guselkumab-treated patients, respectively, achieved a 75% improvement in PASI scores from baseline compared with 0% of placebo-treated patients. Improvements in PASI scores were generally maintained through week 24 in all guselkumab-treated patients. The proportion of patients experiencing an adverse event was comparable between the combined guselkumab (13/20 [65.0%]) and placebo (2/4 [50.0%]) groups through week 24. Analysis of lesional and nonlesional skin biopsy specimens demonstrated decreases in epidermal thickness and T-cell and dendritic cell expression in guselkumab-treated patients compared with values seen in placebo-treated patients. At week 12, significant reductions in psoriasis gene expression and serum IL-17A levels were observed in guselkumab-treated patients. Conclusion IL-23 inhibition with a single dose of guselkumab results in clinical responses in patients with moderate-to-severe psoriasis, suggesting that neutralization of IL-23 alone is a promising therapy for psoriasis.

AIMS: To evaluate endoscopic healing in the ustekinumab (UST) induction (UNITI-1&2) & maintenance (IM-UNITI) phase 3 studies. METHODS: Substudy patients (pts) had colonoscopies at baseline (UNITI Wk0), then 8 & 52 weeks later (IM-UNITI Wk44). Video-endoscopies were centrally read by a single blinded reader for ulcerations & SES-CD. In UNITI, pts received one IV dose (UST 130mg, UST ~6mg/kg, or PBO). Pts with clinical response [CR] (CDAI drop≥100) in UNITI were re-randomized to subcutaneous (SC) PBO or UST 90mg (q12w or q8w) [primary randomized IM-UNITI population]. Non-randomized pts were added to the pooled IM-UNITI population: UST IV non-responders - SC UST 90mg, then SC UST 90mg q8w if in CR 8wks later; PBO IV non-responders - UST IV 130mg, then SC UST 90mg q12w if in CR 8wks later; PBO induction responders - PBO throughout. Pts required SES-CD ≥3 at UNITI Wk0 to be included. Primary outcome: Change in SES-CD at UNITI Wk8 (combined UST vs PBO). IM-UNITI Wk44 efficacy was evaluated for both the IM-UNITI populations. RESULTS: At wk8, UST reduced SES-CD significantly more vs PBO. Results were similar across UST doses, studies, & other endpoints (Table 1a). At IM-UNITI Wk44, in the primary randomized IM-UNITI population trends favoured UST vs PBO maintenance (especially UST 90mg q8w) but small sample sizes (UST n=46; PBO n=24) limited conclusions. In the post-hoc pooled IM-UNITI population (Table 1b), trends supporting UST maintenance were favourable, especially 90mg q8w. CONCLUSIONS: The endoscopy substudy primary endpoint was met: One IV UST dose significantly reduced SES-CD vs PBO, as early as Wk8. More pts receiving UST maintenance achieved wk44 endpoints vs PBO. These data support efficacy of UST in inducing & maintaining endoscopic healing in CD. FUNDING AGENCIES: Janssen Research & Development, LLC

Long-term safety evaluations of biologics are needed to inform patient management decisions.

Several small studies suggest that the presence of the human leukocyte antigen (HLA)-Cw6 (C*06:02) allele may be a predictor of improved response to ustekinumab. This study was designed to assess the association of the HLA-C*06:02 allele with response to ustekinumab in large cohorts of patients from the phase 3 studies of ustekinumab in moderate-to-severe psoriasis. In this retrospective study, both HLA-C*06:02-positive and -negative patients demonstrated good responses to ustekinumab (86% vs. 76%, respectively, achieved at least a 75% improvement from baseline in Psoriasis Area and Severity Index [PASI 75] at week 24). A modestly higher proportion of HLA-C*06:02-positive than HLA-C*06:02-negative patients achieved PASI 75/90 responses at weeks 12 and 24. The largest response difference between the positive and negative patients (17.9%) was observed for PASI 75 (week 12), with smaller differences noted at later time points for PASI 90 (11.8% at week 24) and PASI 100 (10.2% at week 28). A differential response to ustekinumab has been confirmed in HLA-C*06:02-positive versus HLA-C*06:02-negative patients; however, this difference is modest, particularly at the higher response rate thresholds (PASI 90/100) and later time points (weeks 24/28).

Background Ongoing evaluation of biological agents in patients with moderate-to-severe psoriasis is needed to support their long-term use. Objective To evaluate long-term efficacy and safety of ustekinumab through 5 years in the PHOENIX 1 study. Methods Patients were randomized to placebo or ustekinumab (45 mg or 90 mg) at Weeks 0, 4 and every-12-weeks thereafter; placebo patients crossed-over to ustekinumab at Week 12. Clinical response through Week 244 was evaluated using the Psoriasis Area and Severity Index (PASI) in the Overall Population (i.e. patients receiving ≥ 1 dose of ustekinumab), Initial Responders (i.e. PASI 75 responders [Weeks 28/40] re-randomized at Week 40 to continue every-12-week maintenance) and Partial Responders (i.e. Results Overall, 68.7% (517/753) of ustekinumab-treated patients completed treatment through Week 244. Initial clinical responses were generally maintained through Week 244 (PASI 75: 63.4% and 72.0%; PASI 90: 39.7% and 49.0%; PASI 100: 21.6% and 26.4%) for patients receiving 45 mg and 90 mg, respectively. Similarly, PASI 75 responses were generally maintained among Initial Responders [79.1% (45 mg) and 80.8% (90 mg)] and Partial Responders [57.6% (45 mg) and 55.1% (90 mg)]. With 3104 patient-years of follow-up, rates of overall adverse events (AEs), serious AEs, serious infections, malignancies and major adverse cardiovascular events were generally consistent over time and comparable between doses. Conclusions Through 5 years of continuous treatment, ustekinumab demonstrated stable clinical response and a safety profile consistent with previous reports.

Background Patients with psoriasis are known to have an increased number of cardiovascular (CV) risk factors and be at increased risk for CV events. Objectives We sought to describe and characterize the underdiagnosis and undertreatment of CV risk factors in patients with moderate to severe psoriasis. Methods Medical histories including diabetes, hypertension, and hyperlipidemia were obtained from 2899 patients in 3 phase III ustekinumab trials, a therapeutic anti-interleukin (IL)-12/IL-23p40 monoclonal antibody. Reported history was compared with measured fasting glucose, fasting lipids, and blood pressure. Ten-year Framingham risk scores and the proportion of patients achieving glycemic, lipid, and blood pressure targets were evaluated. Results Significant risk factors existed in patients with moderate to severe psoriasis (58.6% and 28.8% of patients had ≥2 and ≥3 established CV risk factors, respectively). Based on Framingham risk score, 18.6% of patients were at high risk and 12.3% were at intermediate risk for CV events. At baseline, a small proportion of patients with diabetes (2.3%), hypertension (9.1%), or hyperlipidemia (4.9%) were previously without a diagnosis. However, 19.1%, 21.8%, and 38.6% of patients with diabetes, hypertension, or hyperlipidemia, respectively, were untreated at baseline, and the proportion at treatment goal was not ideal (hypertension 59.6% and hyperlipidemia 69.7%), especially for diabetes (36.7%). Limitations Results are based on a clinical trial population and findings may not be generalizable to the general psoriasis population. Conclusions In this moderate to severe psoriasis population, a high prevalence of undiagnosed and undertreated CV risk factors existed, emphasizing the importance of screening patients with psoriasis for CV risk factors.

Summary Background An unmet need remains for safe and effective long-term treatments of psoriasis. Objectives To evaluate ustekinumab efficacy and safety for up to 3 years in the PHOENIX 1 trial. Methods Patients (n = 766) with moderate-to-severe psoriasis were randomized to ustekinumab 45 mg or 90 mg at weeks 0 and 4, and then every 12 weeks, or placebo at weeks 0 and 4, with crossover to ustekinumab at week 12. Ustekinumab responders [≥ 75% improvement from baseline in the Psoriasis Area and Severity Index (PASI 75) at weeks 28 and 40] were re-randomized at week 40 to continue or withdraw from treatment until psoriasis recurrence. Partial responders (week 28: PASI 50–74; week 40

Ustekinumab has been evaluated in Caucasian patients with psoriasis, but no studies have been conducted in Asian patients.To assess the efficacy and safety of ustekinumab in Taiwanese and Korean patients with moderate-to-severe psoriasis.In this 36-week, multicenter, double-blind, placebo-controlled study, 121 patients with moderate-to-severe psoriasis were randomized (1:1) to receive subcutaneous injections of ustekinumab 45mg at weeks 0, 4, 16 or placebo at weeks 0, 4 and ustekinumab 45mg at weeks 12, 16. Efficacy endpoints at week 12 included the proportion of patients achieving at least 75% improvement from baseline in Psoriasis Area and Severity Index (PASI 75; primary endpoint), proportion of patients with Physician's Global Assessment (PGA) of cleared or minimal, and change from baseline in Dermatology Life Quality Index (DLQI).At week 12, the proportion of patients achieving PASI 75 was 67.2% and 5.0% in the ustekinumab 45mg and placebo groups, respectively (p0.001). PGA of cleared or minimal was achieved by 70.5% (ustekinumab) and 8.3% (placebo; p0.001), and median DLQI changes were -11.0 and 0.0, respectively (p0.001). Efficacy was maintained through week 28 in ustekinumab-treated patients. Adverse event (AE) profiles at week 12 were similar between the ustekinumab and placebo groups: 65.6% and 70.0%, respectively, had at least one reported AE. Through week 36, no disproportionate increase in AEs was observed, with the exception of abnormal hepatic function, which was related to concomitant isoniazid treatment for latent tuberculosis. Injection-site reactions were rare and mild. No deaths, malignancies, or cardiovascular events were reported.Treatment with subcutaneous ustekinumab 45mg offers a favorable benefit/risk profile for Taiwanese and Korean patients with moderate-to-severe psoriasis. The efficacy and safety profile is consistent with the global phase III studies of ustekinumab in psoriasis.

Background Ustekinumab, a human anti-interleukin-12/23 monoclonal antibody, has been shown to effectively treat moderate-to-severe psoriasis which significantly affects health-related quality of life (HRQoL), including patients’ sexual lives. Objectives The aim of this study was to determine if sexual difficulties associated with psoriasis are related to disease severity and whether sexual difficulties improve with skin disease during ustekinumab treatment. Methods In phase III PHOENIX 1 and 2 trials, psoriasis patients were randomized to ustekinumab (n = 1334) at weeks 0 and 4 and q12 weeks thereafter or placebo (n = 662) at weeks 0 and 4 with crossover to ustekinumab at week 12. Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI) were used to assess psoriasis severity and patient-reported HRQoL respectively. Based on DLQI Question #9, impaired sexual function was defined as ‘very much’ or ‘a lot’ of sexual difficulties. Results At baseline, mean DLQI was 12.0, indicating a very large negative effect on patients’ lives. Impaired sexual function was reported by 22.6% (women = 27.1%; men = 20.8%) and was significantly associated with increased psoriasis severity. At week 12, ustekinumab-treated patients had a greater mean improvement in DLQI (−9.13 vs. −0.53 with placebo, P

To compare the cost per responder of ustekinumab with etanercept based on data from the active comparator ACCEPT trial.In ACCEPT, patients received ustekinumab 45 mg (n = 209) or 90 mg (n = 347) at weeks 0 and 4 or etanercept 50 mg (n = 347) twice weekly for 12 weeks. The proportions of patients achieving ≥75% improvement in the Psoriasis Area and Severity Index [PASI 75] were determined at week 12. The cost per PASI 75 responder was determined for week 16, a time coinciding with treatment coverage of both drugs and accounting for the different dosing intervals. Costs for 16 weeks of therapy were based on the Wholesale Acquisition Cost (WAC) in the United States. The analysis used weight-based efficacy results for ustekinumab (45 mg for patients ≤ 100 kg; 90 mg for patients100 kg) and overall efficacy for etanercept, consistent with the approved dosages.A total of 28% of patients weighed100 kg. The PASI 75 response rates at week 12 were 72.2% for the ustekinumab 45 mg group in patients ≤ 100 kg, 65.0% for the ustekinumab 90 mg group in patients100 kg, and 56.8% for the etanercept group. At week 16, the cost per responder was $17,842 for ustekinumab and $20,077 for etanercept.The cost per responder was lower for ustekinumab than for etanercept through 16 weeks in psoriasis patients.

To assess the effect of ustekinumab on productivity and work limitations among 1230 psoriasis patients treated with ustekinumab 45 mg or 90 mg or placebo during the Phase III PHOENIX 2 trial.The self-administered Work Limitations Questionnaire (WLQ) was used to determine the on-the-job limitations at baseline and weeks 12 and 24. Productivity was assessed using a Visual Analog Scale (VAS), and the number of work days missed due to psoriasis was recorded.At baseline, work limitations and productivity were similar across treatment groups. At week 12, improvement in productivity VAS scores was significantly (p0.001) higher in the 45 mg (72.6%) and 90 mg (71.4%) ustekinumab groups versus placebo (no change), and the proportion of patients who missed work days was significantly lower (2.0% for each ustekinumab group vs 8.3% for placebo; p0.001). Mean improvements from baseline to week 12 were greater with ustekinumab than with placebo for WLQ domains, including time management (6.6/9.1 vs -0.7), mental-interpersonal (7.8/7.5 vs -1.1), and output demands (6.8/7.0 vs -1.1) (p0.001 for ustekinumab 45 mg/90 mg vs placebo). Improvements were maintained through week 24.Ustekinumab 45 mg or 90 mg significantly increased productivity, reduced work days missed, and improved work limitations compared with placebo in patients with moderate-to-severe psoriasis.

Background Patients with psoriasis tend to be overweight, and the efficacy of fixed-dose biologics may be compromised by high body weight. Objective We sought to determine whether the optimal dose of ustekinumab is affected by weight in patients with psoriasis. Methods Patients were randomized in two phase III trials (PHOENIX 1 and 2) to receive 45 mg or 90 mg of ustekinumab every 12 weeks (n = 1331) or placebo with crossover to ustekinumab at week 12 (n = 665). Efficacy and serum ustekinumab concentrations were to be evaluated by 10-kg increments of body weight at week 28 (steady-state trough level). Results Mean baseline weight was 93.9 and 91.0 kg in PHOENIX 1 and 2, respectively. Based on the analyses by 10-kg increments, a cutoff of 100 kg was determined to best differentiate the dose response. The proportion of patients with at least 75% improvement from baseline in Psoriasis Area and Severity Index score was 74.2% for 90 mg and 54.6% for 45 mg in heavier patients (>100 kg), but the proportion with a response of at least 75% improvement from baseline in Psoriasis Area and Severity Index score was similar between doses (80.8% vs 76.9%) in lighter patients (≤100 kg). Serum ustekinumab concentrations were also affected by weight, with lower serum concentrations observed in heavier patients at each dose. Safety was not affected by weight. Limitations Low numbers of patients at the extremes of body weight may limit the analyses of these subgroups. Conclusion Results of weight-based analyses of clinical and pharmacokinetic data indicate that fixed dosing of ustekinumab based on weight is appropriate for the treatment of patients with psoriasis.

Background Ustekinumab has demonstrated significant efficacy and favorable safety in patients with moderate to severe psoriasis. Objective Characterization of patients achieving marked clinical responses (Psoriasis Area and Severity Index [PASI] 90 or Physician's Global Assessment [PGA] of cleared) in two double-blind, placebo-controlled, phase III studies. Methods PHOENIX 1 (n=766) and PHOENIX 2 (n=1,230) patients were randomized to receive placebo or ustekinumab 45 or 90 mg at weeks 0 and 4, then every 12 weeks. At week 12, placebo patients crossed over to ustekinumab. Marked responses, defined as PASI 90 or PGA of cleared, are reported. Results A significantly higher proportion of ustekinumab-treated patients in PHOENIX 1 (39.9%) and PHOENIX 2 (47.0%) achieved marked responses at week 12, compared with placebo-treated patients (pConclusion Significant proportions of ustekinumab-treated patients with moderate to severe psoriasis achieved marked clinical responses through week 28. Ustekinumab had a favorable risk-benefit profile through up to 18 months of follow-up.

The use of chromium-containing dietary supplements is widespread among patients with type 2 diabetes. Chromium's effects in patients at high risk for developing diabetes, especially those with metabolic syndrome, is unknown. The objective of this study was to determine the effects of chromium picolinate (CrPic) on glucose metabolism in patients with metabolic syndrome.A double-blind, placebo-controlled, randomized trial was conducted at a U.S. academic medical center. Sixty three patients with National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III)-defined metabolic syndrome were included. The primary end point was a change in the insulin sensitivity index derived from a frequently sampled intravenous glucose tolerance test. Prespecified secondary end points included changes in other measurements of glucose metabolism, oxidative stress, fasting serum lipids, and high sensitivity C-reactive protein.After 16 weeks of CrPic treatment, there was no significant change in insulin sensitivity index between groups (P = 0.14). However, CrPic increased acute insulin response to glucose (P 0.02). CrPic had no significant effect on other measures of glucose metabolism, body weight, serum lipids, or measures of inflammation and oxidative stress.CrPic at 1000 microg/day does not improve key features of the metabolic syndrome in obese nondiabetic patients.