Achievement of the National Psoriasis Foundation treatment targets with ixekizumab: Pooled analyses from 4 clinical studies.

BACKGROUND: The National Psoriasis Foundation (NPF) published treatment targets for US patients with plaque psoriasis. However, data are lacking on how well existing therapies help achieve these goals. OBJECTIVE: To examine the ability of an interleukin 17 inhibitor, ixekizumab, in achieving these treatment targets. METHODS: Post hoc analysis was performed on pooled data from 4 phase III clinical trials assessing ixekizumab for plaque psoriasis: the UNCOVER-1, -2, and -3 trials and the IXORA-S trial. Treatment response was evaluated using the NPF-defined acceptable response (affected body surface area [BSA] of 3% or less or BSA improvement of 75% or higher at 12 weeks of treatment) and target response (BSA of 1% or less at 12 weeks and every 6 months thereafter). RESULTS: In the UNCOVER trials (n = 2701), acceptable and target response rates at week 12 were 73.9% and 51.8% with ixekizumab 80 mg every 2 weeks, 35.7% and 14.9% with etanercept 50 mg, and 3.0% and 0.6% with placebo, respectively. In the IXORA-S trial (n = 302), acceptable and target response rates at week 12 were significantly higher with ixekizumab every 2 weeks versus ustekinumab (acceptable response 68.4% vs 38.6%, P < .0001; target response 50.7% vs 24.1%, P < .0001). LIMITATIONS: Data were from controlled studies and may not reflect real-world practice. CONCLUSION: The majority of patients treated with ixekizumab in 4 phase III clinical trials achieved NPF, patient-centered treatment targets.

Treatment patterns, adherence, and persistence among psoriasis patients treated with biologics in a real-world setting, overall and by disease severity.

PURPOSE: Describe treatment patterns by disease severity among biologic-treated psoriasis patients. MATERIALS AND METHODS: We selected our study cohort in the IQVIA PharMetrics Plus adjudicated claims database linked to Electronic Health Record data from Modernizing Medicine Data Services. Patients were classified as having mild, moderate, or severe psoriasis based on a hierarchy of available severity measures. Patients were followed for 360 days to assess combination therapy, therapy switching and restarting, adherence and persistence. RESULTS: The cohort comprised 2130 biologic-treated patients (mean age: 47.6 years; 45.4% female); 447 (21%) had available disease severity measures. Compared to patients with mild (N = 282) psoriasis, more patients with moderate (N = 116) or severe (N = 49) disease used combination therapy (21.3% vs. 34.5% and 32.7%, respectively), switched therapies (12.1% vs. 19.8% and 22.4%), and discontinued biologics (18.4% vs. 27.6% and 36.7%). Mean adherence was <75% by Medication Possession Ratio (MPR) (73.9%) and Proportion of Days Covered (PDC) (70.2%). Overall, 52.2% had a mean MPR >80%. Mean persistence to biologics was 297.6 days. Persistence and adherence decreased with increasing disease severity. CONCLUSIONS: Biologic-treated psoriasis patients had inadequate adherence (i.e., MPR <80%) and modest persistence to biologics, with moderate and severe patients demonstrating lower adherence and persistence than mild patients.

Healthcare resource utilization and costs among psoriasis patients treated with biologics, overall and by disease severity.

AIMS: To describe healthcare resource utilization (HCRU) and costs among biologic-treated psoriasis patients in the US, overall and by disease severity. MATERIALS AND METHODS: IQVIA PharMetrics Plus administrative claims data were linked with Modernizing Medicine Data Services Electronic Health Record data and used to select adult psoriasis patients between April 1, 2010 and December 31, 2014. Eligible patients were classified by disease severity (mild, moderate, severe) using a hierarchy of available clinical measures. One-year outcomes included all-cause and psoriasis-related outpatient, emergency department, inpatient, and pharmacy HCRU and costs. RESULTS: This study identified 2,130 biologic-treated psoriasis patients: 282 (13%) had mild, 116 (5%) moderate, and 49 (2%) severe disease; 1,683 (79%) could not be classified. The mean age was 47.6 years; 45.4% were female. Relative to mild psoriasis patients, patients with moderate or severe disease had more median all-cause outpatient encounters (28.0 [mild] vs 32.0 [moderate], 36.0 [severe]), more median psoriasis-related outpatient encounters (6.0 [mild] vs 7.5 [moderate], 8.0 [severe]), and a higher proportion of overall claims for medications that were psoriasis-related (28% [mild] vs 37% [moderate], 34% [severe]). Relative to mild psoriasis patients, patients with moderate or severe disease had higher median all-cause total costs ($37.7k [mild] vs $42.3k [moderate], $49.3k [severe]), higher median psoriasis-related total costs ($32.7k [mild] vs $34.9k [moderate], $40.5k [severe]), higher median all-cause pharmacy costs ($33.9k [mild] vs $36.5k [moderate], $36.4k [severe]), and higher median psoriasis-related pharmacy costs ($32.2k [mild] vs $33.9k [moderate], $35.6k [severe]). LIMITATIONS: The assessment of psoriasis disease severity may not have necessarily coincided with the timing of biologic use. The definition of disease severity prevented the assessment of temporality, and may have introduced selection bias. CONCLUSIONS: Biologic-treated patients with moderate or severe psoriasis cost the healthcare system more than patients with mild psoriasis, primarily driven by higher pharmacy costs and more outpatient encounters.

Evaluation of sPGA × BSA as an Outcome Measure and Treatment Target for Clinical Practice.

Clinical outcome measures are becoming more important in psoriasis treatment. Reliable and standardized measures of severity feasible for clinical practice are needed. Our objective was to investigate body surface area (BSA) and the product of BSA and static Physician Global Assessment (sPGA) (ie, BSA × sPGA) as potential proxy measures for PASI scores. Data were pooled from three multicenter, randomized, double-blind, placebo-controlled, phase 3 trials of ixekizumab in patients with moderate to severe psoriasis (UNCOVER-1, -2, -3; N = 3,866). Assessments included the Psoriasis Area and Severity Index (PASI), BSA, and BSA × sPGA. Rank correlations between BSA × sPGA and PASI were stronger than between BSA and PASI (baseline, r = 0.759 vs. r = 0.707; week 12, r = 0.959 vs. r = 0.924). Week 12 concordance rates with PASI responses were as follows: for 75% reduction in PASI: BSA, 86.2%; BSA × sPGA, 93.8%; for 90% reduction in PASI: BSA, 86.9%; BSA × sPGA, 88.2%. The 75% reduction in PASI positive and negative predictive values were higher for BSA × sPGA versus BSA; for 90% reduction in PASI, positive predictive value was lower and negative predictive value was higher for BSA × sPGA versus BSA. Receiver operating characteristic curve analyses identified the most accurate percentage changes in BSA and BSA × sPGA as 66% and 83% for a 75% reduction in PASI cutoff and 84% and 94% for a 90% reduction in PASI, respectively. These results suggest that BSA and BSA × sPGA are viable tools for use as a PASI proxy by real-world practitioners and may be appropriate measurements for use in clinical practice for treat-to-target strategies.

Patient Characteristics, Health Care Resource Utilization, and Costs Associated with Treatment-Regimen Failure with Biologics in the Treatment of Psoriasis.

BACKGROUND: Psoriasis is a chronic, incurable, and immune-mediated skin disorder that is characterized by erythematous scaly papules and plaques. Understanding of psoriasis at the molecular level has led to the development of biologic agents that target disease-specific inflammatory mediators in psoriatic lesions. Biologic agents have become important components of the psoriasis armamentarium, but some patients become refractory to these agents over time or fail to respond to subsequent biologics. OBJECTIVES: To (a) evaluate demographic and clinical characteristics of psoriasis patients who have treatment patterns suggestive of failure to a newly initiated biologic agent (treatment-regimen failures) compared with those who do not (non-treatment-regimen failures) and (b) to assess health care-related resource utilization and costs in non-treatment-regimen failures and treatment-regimen failures. METHODS: In this retrospective observational cohort study, patients were selected from the MarketScan claims database of commercially insured individuals and individuals with Medicare supplemental insurance. The index event was a newly initiated biologic agent for the treatment of psoriasis (etanercept, adalimumab, ustekinumab, or infliximab) between January 2010 and December 2011. The analysis included psoriasis patients aged ≥ 18 years with ≥ 1 prescription claim for a biologic and continuous enrollment 12 months pre- and post-index date. Patients with claims for a biologic in the pre-index period were excluded. Patients were divided into treatment-regimen-failure and non-treatment-regimen-failure groups based on their treatment patterns post-index date. The treatment-regimen-failure group included patients who switched to another biologic, discontinued the biologic without restarting, increased the dose of the biologic, or augmented treatment with a nontopical psoriasis medication during the post-index period. Between-group patient characteristics and medication use were compared using analysis of variance for continuous variables and chi-square tests for categorical variables without adjustment. Cost differences were compared using the propensity score-adjusted bin bootstrapping method. RESULTS: Overall, 2,146 patients met the enrollment criteria. The mean age was 45.1 years. Of these patients, 41.5% were considered treatment-regimen failures. Among treatment-regimen failures, 53% were females, and among non-treatment-regimen failures, 61% were male. Patients who experienced treatment-regimen failure had higher incidences of comorbid cerebrovascular disease, hypertension, chronic pulmonary disease, depression, and anxiety in the pre-index period and were more likely to use concomitant topicals (67.0% vs. 58.4%; P < 0.001), methotrexate (20.2% vs. 7.3%; P < 0.001), and cyclosporine (3.1% vs. 1.0%; P < 0.001) in the post-index period. Mean total all-cause health care costs were higher in patients with treatment-regimen failure versus non-treatment-regimen failure during the pre-index period ($8,024 vs. $6,637; P = 0.002), but patients with non-treatment-regimen failure had higher all-cause costs ($30,759 vs. $28,012; P = 0.002) and psoriasis-related costs ($25,286 vs. $19,625; P < 0.001) during the post-index period. CONCLUSIONS: The results of the current study demonstrated that psoriasis patients with treatment patterns suggestive of treatment-regimen failure on an index biologic had different characteristics and incurred higher all-cause health care costs than did patients without treatment-regimen failure during the pre-index period. This study was supported by Eli Lilly and Company. Foster, Zhu, Guo, Nikai, Malatestinic, Ojeh, and Goldblum are full-time employees and stockholders of Eli Lilly and Company. Kornberg is a full-time employee of INC Research, which was contracted by Eli Lilly to assist with medical writing. Wu has received research funding from AbbVie, Amgen, Coherus Biosciences, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Regeneron, and Sandoz; he is a consultant for AbbVie, Amgen, Celgene, Dermira, DUSA Pharmaceuticals, Eli Lilly, and Pfizer. Study concept was developed by Foster, Ojeh, Malatestinic, and Goldblum. Zhu and Guo, along with Foster, took the lead in data collection, and data interpretation was performed by Nikai, Wu, and Foster, with assistance from the other authors. The manuscript was primarily written by Kornberg, along with Foster, with assistance from the other authors. All of the authors were involved with manuscript revision.

The influence of smoking status on the pharmacokinetics and pharmacodynamics of clopidogrel and prasugrel: the PARADOX study.

OBJECTIVES: The goal of this study was to evaluate the effect of smoking on the pharmacokinetics and pharmacodynamics (PD) of clopidogrel and prasugrel therapy. BACKGROUND: Major randomized trial data demonstrated that nonsmokers experience less or no benefit from clopidogrel treatment compared with smokers (i.e., the "smokers' paradox"). METHODS: PARADOX was a prospective, randomized, double-blind, double-dummy, placebo-controlled, crossover study of objectively assessed nonsmokers (n = 56) and smokers (n = 54) with stable coronary artery disease receiving aspirin therapy. Patients were randomized to receive clopidogrel (75 mg daily) or prasugrel (10 mg daily) for 10 days and crossed over after a 14-day washout. PD was assessed by using VerifyNow P2Y12 and vasodilator-stimulated phosphoprotein phosphorylation assays. Clopidogrel and prasugrel metabolite levels, cytochrome P450 1A2 activity, CYP2C19 genotype, and safety parameters were determined. RESULTS: During clopidogrel therapy, device-reported inhibition of platelet aggregation (IPA) trended lower in nonsmokers than smokers (least squares mean treatment difference ± SE: 7.7 ± 4.1%; p = 0.062). Device-reported IPA was significantly lower in clopidogrel-treated smokers than prasugrel-treated smokers (least squares mean treatment difference: 31.8 ± 3.4%; p < 0.0001). During clopidogrel therapy, calculated IPA was lower and P2Y12 reaction units and vasodilator-stimulated phosphoprotein phosphorylation and platelet reactivity index were higher in nonsmokers than in smokers (p = 0.043, p = 0.005, and p = 0.042, respectively). Greater antiplatelet effects were present after prasugrel treatment regardless of smoking status (p < 0.001 for all comparisons). CONCLUSIONS: PARADOX demonstrated lower clopidogrel active metabolite exposure and PD effects of clopidogrel in nonsmokers relative to smokers. Prasugrel was associated with greater active metabolite exposure and PD effects than clopidogrel regardless of smoking status. The poorer antiplatelet response in clopidogrel-treated nonsmokers may provide an explanation for the smokers' paradox. (The Influence of Smoking Status on Prasugrel and Clopidogrel Treated Subjects Taking Aspirin and Having Stable Coronary Artery Disease; NCT01260584).

Decrease in high on-treatment platelet reactivity (HPR) prevalence on switching from clopidogrel to prasugrel: insights from the switching anti-platelet (SWAP) study.

The prevalence of high platelet reactivity (HPR) in patients who have switched from clopidogrel to prasugrel during maintenance phase after an acute coronary syndrome (ACS) event is unknown. Therefore, the effect of switching from clopidogrel to prasugrel on the prevalence of HPR was evaluated. This analysis from the previously reported SWAP (SWitching Anti Platelet) study assessed HPR at baseline, 2 and 24 hours, and seven days after switching from clopidogrel to prasugrel maintenance dose (MD), with or without a prasugrel loading dose (LD) using four definitions: maximum platelet aggregation (MPA) >65% (primary endpoint), MPA >50%, P2Y12 reaction units (PRU) >235, and platelet reactivity index (PRI) ≥ 50%. A total of 95 patients were available for analysis; 56 patients provided DNA for genetic assessments of cytochrome P450 (CYP) 2C19. There were 26 (27.4%) patients with HPR at the end of the clopidogrel run-in (defined as MPA >65%). The HPR prevalence varied by each definition and ranged from 19% (PRU >235) to 68% (PRI ≥ 50 %). A significantly higher HPR prevalence was observed during clopidogrel versus the combined prasugrel therapy groups at seven days as measured by MPA >65% (21.2% vs. 4.5%, p<0.05), PRU >235 (18.8% vs. 0%, p=0.001), and PRI ≥ 50 % (66.7% vs. 7.9%, p<0.0001). There was a significantly higher percentage of subjects carrying at least one reduced function allele with HPR measured by MPA >65% (p=0.02) or PRU >235 (p=0.05) than non-carriers with HPR. Switching ACS patients during maintenance clopidogrel therapy to prasugrel with or without an LD is associated with a reduced HPR prevalence and may provide an alternative strategy to treat patients with HPR, independent of CYP2C19 genotype.

A pharmacodynamic comparison of prasugrel vs. high-dose clopidogrel in patients with type 2 diabetes mellitus and coronary artery disease: results of the Optimizing anti-Platelet Therapy In diabetes MellitUS (OPTIMUS)-3 Trial.

AIMS: Patients with diabetes mellitus (DM) have increased platelet reactivity and reduced platelet response to clopidogrel compared with patients without DM. Prasugrel, a more potent antiplatelet agent, is associated with greater reductions in ischaemic events compared with clopidogrel, particularly in patients with DM. The aim of this study was to perform serial pharmacodynamic assessments of prasugrel with high-dose clopidogrel in patients with DM. METHODS AND RESULTS: Optimizing anti-Platelet Therapy In diabetes MellitUS (OPTIMUS)-3 was a prospective, randomized, double-blind, crossover study in patients with type 2 DM and coronary artery disease (CAD). Patients (n= 35) were randomly assigned to either prasugrel 60 mg loading dose (LD)/10 mg maintenance dose (MD) or clopidogrel 600 mg LD/150 mg MD over two 1-week treatment periods separated by a 2-week washout period. Platelet function was assessed by VerifyNow® P2Y12 assay, light transmission aggregometry, and vasodilator-stimulated phosphoprotein phosphorylation at 0, 1, 4, and 24 h and 7 days. Greater platelet inhibition by VerifyNow® P2Y12 was achieved by prasugrel compared with clopidogrel at 4 h post-LD (least squares mean, 89.3 vs. 27.7%, P< 0.0001; primary endpoint). The difference in platelet inhibition between prasugrel and clopidogrel was significant from 1 h through 7 days (P < 0.0001). Similar results were obtained using all other platelet function measures. Prasugrel resulted in fewer poor responders at all time points irrespective of definition used. CONCLUSION: In patients with type 2 DM and CAD, standard-dose prasugrel is associated with greater platelet inhibition and better response profiles during both the loading and maintenance periods when compared with double-dose clopidogrel.

Increased platelet inhibition after switching from maintenance clopidogrel to prasugrel in patients with acute coronary syndromes: results of the SWAP (SWitching Anti Platelet) study.

OBJECTIVES: The objective was to evaluate the pharmacodynamic response of switching patients on maintenance phase clopidogrel therapy after an acute coronary syndrome (ACS) to prasugrel. BACKGROUND: Prasugrel P2Y(12) receptor blockade is associated with greater pharmacodynamic platelet inhibition and reduction of ischemic complications compared with that of clopidogrel in ACS patients undergoing percutaneous coronary intervention. The pharmacodynamic effects of switching patients during maintenance phase clopidogrel therapy after an ACS event to prasugrel are unknown. METHODS: The SWAP (SWitching Anti Platelet) study was a phase 2, multicenter, randomized, double-blind, double-dummy, active-control trial. After a run-in of daily open-label clopidogrel 75 mg with aspirin therapy for 10 to 14 days, patients were randomly assigned to 1 of the following 3 treatments: placebo loading dose (LD)/clopidogrel 75 mg maintenance dose (MD), placebo LD/prasugrel 10 mg MD, or prasugrel 60 mg LD/10 mg MD. Platelet function was evaluated at 2 h, 24 h, 7 days, and 14 days using light transmittance aggregometry, VerifyNow P2Y(12) assay, and vasodilator-stimulated phosphoprotein phosphorylation. RESULTS: A total of 139 patients were randomized, of whom 100 were eligible for analysis. Maximum adenosine diphosphate-induced platelet aggregation (20 µM) by light transmittance aggregometry at 1 week (primary end point) was lower after prasugrel MD compared with clopidogrel MD (41.1% vs. 55.0%, p < 0.0001), and was also lower in the prasugrel LD+MD group compared with clopidogrel MD (41.0% vs. 55.0%, p < 0.0001). At 2 h, a prasugrel LD resulted in higher platelet inhibition compared with the other regimens. Similar results were found using light transmittance aggregometry with 5 µM adenosine diphosphate, VerifyNow P2Y(12), and vasodilator-stimulated phosphoprotein phosphorylation assays. CONCLUSIONS: For patients receiving maintenance clopidogrel therapy after an ACS event, switching from clopidogrel to prasugrel is associated with a further reduction in platelet function by 1 week using prasugrel MD or within 2 h with the administration of a prasugrel LD. (A Pharmacodynamic Comparison of Prasugrel [LY640315] Versus Clopidogrel in Subjects With Acute Coronary Syndrome Who Are Receiving Clopidogrel [SWAP]; NCT00356135).