Summary
Background
The interleukin‐17 cytokine family plays a central role in psoriasis pathogenesis.
Objectives
To evaluate the efficacy and safety of brodalumab, a human anti‐interleukin‐17 ...receptor antibody, in treating patients with moderate‐to‐severe plaque psoriasis.
Methods
In this phase III, double‐blind, placebo‐controlled study (NCT01708590; AMAGINE‐1), adult patients in the U.S.A., Canada and Europe were randomized to brodalumab (140 or 210 mg) or placebo every 2 weeks (Q2W), with an additional dose at week 1, for a 12‐week induction phase. At week 12, patients receiving brodalumab who achieved static Physician's Global Assessment 0 or 1 (sPGA success) were rerandomized to the placebo or induction dose. After week 16, patients with sPGA ≥ 3 were re‐treated with the induction dose. After ≥ 12 weeks of retreatment, patients with sPGA 2 for ≥ 4 weeks or sPGA ≥ 3 were rescued with brodalumab 210 mg Q2W. At week 12, patients randomized to brodalumab with sPGA ≥ 2 or placebo received brodalumab 210 mg Q2W. Coprimary end points were the percentage of patients with ≥ 75% improvement in Psoriasis Area and Severity Index score (PASI 75) and sPGA success at week 12.
Results
There were 661 patients randomized: 220 placebo, 219 brodalumab 140 mg and 222 brodalumab 210 mg. At week 12, 60% (140 mg) and 83% (210 mg) vs. 3% (placebo) achieved PASI 75, and 54% (140 mg) and 76% (210 mg) vs. 1% (placebo) achieved sPGA success. The safety profile was considered acceptable.
Conclusions
Brodalumab therapy resulted in significant clinical benefit and an acceptable safety profile in patients with moderate‐to‐severe plaque psoriasis.
What's already known about this topic?
Anti‐interleukin (anti‐IL)‐17 receptor A and anti‐IL‐17A antibodies have been shown to be efficacious in treating patients with moderate‐to‐severe plaque psoriasis.
What does this study add?
This study further demonstrates that brodalumab therapy in patients with moderate‐to‐severe plaque psoriasis results in a high degree of complete skin clearance.
This study also further elucidates the safety profile of brodalumab.
Linked Comment: Ormerod. Br J Dermatol 2016; 175:243–244
Plain language summary available online
One of the signal failures in health technology assessment is the absence of consideration given, not only to the standards of normal science, but to those of fundamental measurement. A recent ...evidence report by the Institute for Clinical and Economic Review (ICER) is emblematic of this failure. Based on a simple linear regression model that translates aggregate scores from the ordinal Menopause-specific Quality of Life Questionnaire (MENQOL) to the ordinal EuroQol EQ-5D-5L, ICER has applied these scores to an assumption driven model simulation to produce preferences, QALYs and incremental cost-per-QALY claims for fezolinetant for moderate to severe symptoms associated with menopause. Unfortunately, the attempt to crosswalk multidimensional or multiattribute ordinal scores is mathematically impossible. The ‘created’ EQ-5D-5L preferences are, as a result, of no interest. The overall result is that the ICER modelled claims for cost-effectiveness fail the required standards for normal science and fundamental measurement. fundamental are impossible. This is unfortunate, although it might be possible to assess certain domains of the MENQOL for their approximation to an interval score with the application of the Rasch Rating Scale Model, this will not support quality of life claims. A preferred approach would be to consider an alternative latent trait for quality of life in menopause, applying Rasch Measurement Theory (RMT), to develop a polytomous instrument that has the required measurement properties. The purpose of this commentary is to point out, as a number of previous commentaries have done, that this framework for creating assumption driven simulated modelled claims has no role in decisions for product assessment, access to formulary and pricing. This commentary expands upon these previous commentaries in placing RMT is the context of a needed paradigm shift to support the evolution of objective knowledge. This is critical if we are to understand, from the individual’s perspective, not only an accurate assessment of the burden of menopause but to see this as part of an on-going research program that has to rely on fundamental measurement.
Platelets shed microRNAs (miRNAs). Plasma miRNAs change on platelet inhibition. It is unclear whether plasma miRNA levels correlate with platelet function.
To link small RNAs to platelet reactivity.
...Next-generation sequencing of small RNAs in plasma revealed 2 peaks at 22 to 23 and 32 to 33 nucleotides corresponding to miRNAs and YRNAs, respectively. Among YRNAs, predominantly, fragments of RNY4 and RNY5 were detected. Plasma miRNAs and YRNAs were measured in 125 patients with a history of acute coronary syndrome who had undergone detailed assessment of platelet function 30 days after the acute event. Using quantitative real-time polymerase chain reactions, 92 miRNAs were assessed in patients with acute coronary syndrome on different antiplatelet therapies. Key platelet-related miRNAs and YRNAs were correlated with platelet function tests. MiR-223 (rp=0.28; n=121; P=0.002), miR-126 (rp=0.22; n=121; P=0.016), and other abundant platelet miRNAs and YRNAs showed significant positive correlations with the vasodilator-stimulated phosphoprotein phosphorylation assay. YRNAs, miR-126, and miR-223 were also among the small RNAs showing the greatest dependency on platelets and strongly correlated with plasma levels of P-selectin, platelet factor 4, and platelet basic protein in the population-based Bruneck study (n=669). A single-nucleotide polymorphism that facilitates processing of pri-miR-126 to mature miR-126 accounted for a rise in circulating platelet activation markers. Inhibition of miR-126 in mice reduced platelet aggregation. MiR-126 directly and indirectly affects ADAM9 and P2Y12 receptor expression.
Levels of platelet-related plasma miRNAs and YRNAs correlate with platelet function tests in patients with acute coronary syndrome and platelet activation markers in the general population. Alterations in miR-126 affect platelet reactivity.
The purpose of this commentary is to focus on the downside of assumption-driven simulation modeling, the potential creation of a multitude of competing models, the mathematically impossible quality ...adjusted life year (QALY) and the failure to observe the axioms of fundamental measurement in mapping ordinal EQ-5D-5L preferences from the ordinal Quantitative Myasthenia Gravis (QMG) score. A second aspect of this commentary is to propose standards that should be set for the creation and evaluation of value claims in health technology assessment, in particular need fulfillment quality of life (QoL), that meet the demarcation test to distinguish science from non-science. The result is that the present ICER pricing claims for eculizumab and efgartigimod in myasthenia gravis should not be applied without consideration of more relevant evidence.
Background
Available literature on psoriasis and psoriatic arthritis (PsA) demonstrates a tremendous burden of disease and suggests underdiagnosis and undertreatment.
Objective
To obtain real‐world ...physician perspectives on the impact of psoriasis and PsA and its treatment on patients' daily lives, including perceptions of, and satisfaction with, current therapies.
Methods
The Multinational Assessment of Psoriasis and Psoriatic Arthritis (MAPP) surveyed dermatologists (n = 391) and rheumatologists (n = 390) in North America (Canada and the United States) and Europe (France, Germany, Italy, Spain and United Kingdom).
Results
Dermatologists classified 20.3% and 25.7% of their patients as having severe psoriasis and severe PsA respectively; rheumatologists indicated that 48.4% of their PsA patients had active disease. Of the psoriasis patients complaining of joint pain, only 33.0% had a diagnosis of PsA. An impact on daily activities or social/emotional well‐being was recognized by 57.2% to 79.3% of physicians. In patients with moderate‐to‐severe psoriasis, dermatologists reported 74.9% were receiving topical therapy, 19.5% conventional oral therapy and 19.6% biologics. Dermatologists and rheumatologists reported similar rates of topical (≈45%) and biologic (≈30%) therapy utilization for their PsA patients; conventional oral therapy was more often prescribed by rheumatologists (63.4%) vs. dermatologists (35.2%). Reasons for not initiating or maintaining systemic therapies were related to concerns about long‐term safety, tolerability, efficacy and costs (biologics).
Conclusion
Physicians in North America and Europe caring for patients with psoriasis and PsA acknowledge unmet treatment needs, largely concerning long‐term safety/tolerability and efficacy of currently available therapies; evidence suggests underdiagnosis of PsA and undertreatment of psoriasis among dermatologists.
Summary
Background
Certolizumab pegol (CZP) is an Fc‐free, PEGylated anti‐tumour necrosis factor biologic.
Objectives
To report 3‐year safety data from three phase III trials of CZP in adults with ...plaque psoriasis.
Methods
Data were pooled from CIMPASI‐1 (NCT02326298), CIMPASI‐2 (NCT02326272) and CIMPACT (NCT02346240). Included patients had moderate‐to‐severe plaque psoriasis of ≥ 6 months’ duration; had been randomized to CZP 200 mg every 2 weeks (Q2W) (400 mg at weeks 0, 2 and 4) or CZP 400 mg Q2W; and had received at least one dose of CZP with up to 144 weeks of exposure. Treatment‐emergent adverse events (TEAEs) were classified using MedDRA v18·1. Reported incidence rates (IRs) are incidence of new cases per 100 patient‐years (PY).
Results
Over 144 weeks, 995 patients received at least one dose of CZP (exposure: 2231·3 PY); 731 and 728 received at least one dose of CZP 200 mg Q2W (1211·4 PY) and/or 400 mg Q2W (1019·9 PY), respectively. The IR 95% confidence interval (CI) of TEAEs was 144·9 (135·3–155·0) for all patients, 134·1 (123·2–145·7) for CZP 200 mg Q2W and 158·3 (145·5–171·9) for CZP 400 mg Q2W. The IR (95% CI) of serious TEAEs for all patients was 7·5 (6·4–8·8); the IRs were 6·7 (5·2–8·3) and 8·7 (6·9–10·8) for CZP 200 mg and 400 mg Q2W, respectively. Overall, 3·2% of patients reported serious infections (2·2% within each of the CZP 200 and 400 mg Q2W groups). Overall, there was one case of active tuberculosis, 16 malignancies in 14 patients and seven deaths (two considered treatment‐related). The cumulative IR of TEAEs did not increase over time.
Conclusions
No new safety signals were identified compared with previously reported data. Risk did not increase with longer or higher CZP exposure.
What is already known about this topic?
Certolizumab pegol is an Fc‐free, PEGylated, anti‐tumour necrosis factor biologic approved for adults with moderate‐to‐severe plaque psoriasis.
Safety data from phase III trials in plaque psoriasis have found the incidence of adverse events to be generally similar over 16 weeks of treatment between the evaluated certolizumab pegol doses 200 mg and 400 mg every 2 weeks and placebo.
Additionally, the safety profile was in line with the class over 48 weeks.
What does this study add?
Plaque psoriasis is a chronic disease for which patients require lifetime management; long‐term safety data are important to understand the benefits and risks of prolonged treatment.
Here, 3‐year data from a pooled analysis of three phase III trials of certolizumab pegol in plaque psoriasis are presented, representing 2231·3 patient‐years of exposure.
No new safety signals were identified and the risk of treatment‐emergent adverse events did not increase with longer or higher certolizumab pegol exposure.
This commentary proposes that Rasch Measurement Theory (RMT) is an innovative method for assessments of patient-centric therapy response in hemophilia A and B, as they are in other disease states or ...target patient populations. RMT is a necessary and sufficient approach to moving from ordinal observations to interval measurement, which has arithmetic properties. This applies across the board in hemophilia and other disease states for clinical value claims, patient centric or subjective value claims as well as those for anticipated drug utilization and other medical care resources. The purpose of this commentary is to point out limitations regarding current methods for making claims regarding hemophilia response and to propose a new start in hemophilia studies to identify core claims that meet required measurement standards. This applies to both the development of new patient reported outcome instruments as well as the evaluation of existing instruments, with a focus on polytomous instruments and their sub-domains, to evaluate their possible application as measures that approximate RMT requirements.
Fundamental measurement is the basis for a rational assessment of patient reported outcome (PRO) value claims; both as response to therapy and the submission of credible and evaluable value claims to ...formulary committees and other health system decision makers. It is important to emphasize the importance of creating interval and ratio scales as opposed to nominal and ordinal scales to support value claims; a recognition that follows from acceptance of conjoint simultaneous measurement and the contribution of Rasch or modern measurement theory (RMT). Failure to appreciate the role of RMT has led thousands of researchers simply to apply numerals to events, inappropriately applying the techniques of classical statistical analysis, with the result that all that is produced are ordinal PRO scores. Instead, we should be aiming for interval and ratio scores based on a comprehensible latent trait and the application of the Rasch model. The purpose of this brief commentary is to review the measurement properties of PRO value claims for mavacamten (Camzyos; Bristol Myers Squibb) in symptomatic hypertrophic cardiomyopathy (SHCM) and to judge whether they have any validity when judged against the requirements of modern measurement theory. The assessment includes both the recent evidence report by the Institute for Clinical and Economic Review (ICER) for mavacamten as well as pivotal randomized trial (RCT) value claims that combine clinical endpoints with PROs that fail the standards of fundamental evidence. These include the Kansas City Cardiomyopathy Questionnaire (KCCQ), the New York Heart Association (NYHA) functional classification and the EuroQuol EQ-5D-5L multiattribute health related quality of life (HRQoL) preference instrument. The review concludes that apart from purely clinical claims based on the various pivotal trials, there are no PRO claims for mavacamten in SHCM that meet the required measurement standards.
Proposals for a patient centered core impact set (PC-CIS) are of little relevance to formulary and health system decisions, let alone patients and providers, unless the elements included in the data ...set meet the standards of normal science and fundamental measurement. Adhering to these standards will have the effect of focusing on the adequacy of proposed core impact measures, with a filter in place to accept only those that meet the standards not only of the physical sciences but also mainstream economics. and health economics. Fortunately, we are well aware of what the criteria for acceptance and rejection of the core impacts within disease states should be in terms of their required attributes and their relevance for supporting evaluable value claims, notably for patient reported outcomes, Rasch or modern measurement theory. Care must be taken to delineate the core impact elements: separately identifying those that are purely clinical from core patient centric impacts, which is turn should be separated from impacts defined in terms of drug utilization and resource utilization. The purpose of this brief commentary is to set out the required standards for core impact patient-centric value claims and the framework for evaluating those claims. The critical issue for patient-centered core impacts is to recognize the constraints imposed by the standards of fundamental measurement for target patient populations within disease areas; unless these constraints are recognized we will fail. The leads to the role of Rasch or modern measurement theory calibration as the framework for patient centric measures of latent traits or attributes. From these perspectives PC-CIS is premature; until we have agreed standards for measurement for the impact or outcomes for clinical, patient-centric and resource utilization as a core set of disease specific instruments, it seems pointless to push forward to a wider scope when the present evidentiary foundation is so weak.
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