An economic evaluation of eptinezumab for the preventive treatment of migraine in the UK, with consideration for natural history and work productivity.

BACKGROUND: Migraine is a highly prevalent neurological disease with a substantial societal burden due to lost productivity. From a societal perspective, we assessed the cost-effectiveness of eptinezumab for the preventive treatment of migraine. METHODS: An individual patient simulation of discrete competing events was developed to evaluate eptinezumab cost-effectiveness compared to best supportive care for adults in the United Kingdom with ≥ 4 migraine days per month and prior failure of ≥ 3 preventive migraine treatments. Individuals with sampled baseline characteristics were created to represent this population, which comprised dedicated episodic and chronic migraine subpopulations. Clinical efficacy, utility, and work productivity inputs were based on results from the DELIVER randomised controlled trial (NCT04418765). Timing of natural history events and treatment holidays-informed by the literature-were simulated to unmask any natural improvement of the disease unrelated to treatment. The primary outcomes were monthly migraine days, migraine-associated costs, quality-adjusted life years (QALYs), incremental cost-effectiveness ratio, and net monetary benefit, each evaluated over a 5-year time horizon from 2020. Secondary analyses explored a lifetime horizon and an alternative treatment stopping rule. RESULTS: Treatment with eptinezumab resulted in an average of 0.231 QALYs gained at a saving of £4,894 over 5 years, making eptinezumab dominant over best supportive care (i.e., better health outcomes and less costly). This result was confirmed by the probabilistic analysis and all alternative assumption scenarios under the same societal perspective. Univariate testing of inputs showed net monetary benefit was most sensitive to the number of days of productivity loss, and monthly salary. CONCLUSIONS: This economic evaluation shows that from a societal perspective, eptinezumab is a cost-effective treatment in patients with ≥ 4 migraine days per month and for whom ≥ 3 other preventive migraine treatments have failed. TRIAL REGISTRATION: N/A.

Structural equation modeling for identifying the drivers of health-related quality of life improvement experienced by patients with migraine receiving eptinezumab.

BACKGROUND: As new migraine therapies emerge, it is crucial for measures to capture the complexities of health-related quality of life (HRQoL) improvement beyond improvements in monthly migraine day (MMD) reduction. Investigations into the correlations between MMD reduction, symptom management, and HRQoL are lacking, particularly those that focus on improvements in canonical symptoms and improvement in patient-identified most-bothersome symptoms (PI-MBS), in patients treated with eptinezumab. This exploratory analysis identified efficacy measures mediating the effect of eptinezumab on HRQoL improvements in patients with migraine. METHODS: Data from the DELIVER study of patients with 2-4 prior preventive migraine treatment failures (NCT04418765) were inputted to two structural equation models describing sources of HRQoL improvement via Migraine-Specific Quality-of-Life Questionnaire (MSQ) scores. A single latent variable was defined to represent HRQoL and describe the sources of HRQoL in DELIVER. One model included all migraine symptoms while the second model included the PI-MBS as the only migraine symptom. Mediating variables capturing different aspects of efficacy included MMDs, other canonical symptoms, and PI-MBS. RESULTS: In the first model, reductions in MMDs and other canonical symptoms accounted for 35% (standardized effect size [SES] - 0.11) and 25% (SES - 0.08) of HRQoL improvement, respectively, with 41% (SES - 0.13) of improvement comprising "direct treatment effect," i.e., unexplained by mediators. In the second model, substantial HRQoL improvement with eptinezumab (86%; SES - 0.26) is due to MMD reduction (17%; SES - 0.05) and change in PI-MBS (69%; SES - 0.21). CONCLUSIONS: Improvements in HRQoL experienced by patients treated with eptinezumab can be substantially explained by its effect on migraine frequency and PI-MBS. Therefore, in addition to MMD reduction, healthcare providers should discuss PI-MBS improvements, since this may impact HRQoL. Health technology policymakers should consider implications of these findings in economic evaluation, as they point to alternative measurement of quality-adjusted life years to capture fully treatment benefits in cost-utility analyses. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT04418765 ; EudraCT (Identifier: 2019-004497-25; URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-004497-25 ).

Burden of Medication Overuse in Migraine: A Cross-sectional, Population-Based Study in Five European Countries Using the 2020 National Health and Wellness Survey (NHWS).

INTRODUCTION: Overuse of medication to treat migraine attacks can lead to development of a new type of headache or significant worsening of pre-existing headache, known as medication overuse headache. However, data concerning the burden of medication overuse (MO) in migraine are limited. This study aimed to assess the humanistic burden of MO in individuals with migraine from five European countries. METHODS: Data are from the 2020 National Health and Wellness Survey-a cross-sectional, population-based survey conducted in France, Germany, Italy, Spain, and the UK. Data were included from adults (≥ 18 years) with a self-reported diagnosis of migraine and at least one migraine attack and one headache in the past 30 days. MO was defined as (i) use of simple analgesics/over-the-counter medications on ≥ 15 days/month; or (ii) use of migraine medication, including combination analgesics, on ≥ 10 days/month. Humanistic burden of MO was assessed using the 12-Item Short-Form Health Survey (SF-12v2), EuroQol 5-Dimensions 5-Levels (EQ-5D), Short-Form 6-Dimensions (SF-6D), and Migraine Disability Assessment (MIDAS). The association of MO with humanistic burden was evaluated using generalized linear models adjusted for potential confounders in the full migraine population and in subgroups defined by headache frequency (monthly headache days [MHDs] 1-3, 4-7, 8-14, or ≥ 15). RESULTS: Among individuals with migraine, humanistic burden (SF-12v2, SF-6D, EQ-5D, and MIDAS) was higher in individuals who reported MO (n = 431) versus no MO (n = 3554), even after adjustment for confounding variables (p < 0.001 for all measures). MIDAS and EQ-5D scores were higher in individuals with MO than without, at all levels of headache frequency. For SF-12v2 and SF-6D, differences between groups with/without MO were seen only at lower levels of headache frequency (MHD 1-3 and 4-7). CONCLUSION: Among people with migraine, those who report MO face a greater humanistic burden than those without MO, irrespective of headache frequency.

Meta-regression to explain the placebo effects in clinical trials of anti-CGRP monoclonal antibodies for migraine prevention.

Background: Commonly used methods of comparison (e.g. network meta-analyses) require common comparator(s) across trials, such as placebo in placebo-controlled trials. Recent literature indicates that route of administration differences across placebo arms of clinical trials in pain disorders may contribute to differences in placebo effect.Methods: We conducted a meta-regression on placebo data from pivotal clinical trials of anti-calcitonin gene-related peptide (anti-CGRP) monoclonal antibodies for migraine prevention to quantify the impact of route of administration, migraine type (episodic/chronic), and number of prior treatment failures on placebo reduction in monthly migraine days (MMDs) across weeks 1-12 of treatment. A systematic literature review of Embase, MEDLINE, the Cochrane Library, and grey literature conducted in June 2021 identified 14 relevant, randomized placebo-controlled trials for analysis.Results: After testing models with different covariates, a meta-regression was fitted to the extracted placebo data with the covariates of route of administration, migraine type, and proportion of patients with ≥2 prior preventive treatment failures. An intravenous route of administration for the placebo arm was a predictor for higher MMD reduction. Predictors of lower MMD reduction were migraine type (episodic migraine) and a higher proportion of patients having ≥2 failed preventive treatments.Conclusions: The efficacy of intravenous anti-CGRP monoclonal antibodies are likely underestimated, and differences in the route of administration of placebo may necessitate use of alternative methods that do not assume the presence of a common comparator when comparing anti-CGRP monoclonal antibodies in migraine prevention. Further research into the contextual effects of the placebo effect is warranted.

Comparison of indirect treatment methods in migraine prevention to address differences in mode of administration.

Aim: Indirect treatment comparisons (ITCs) are anchored on a placebo comparator, and the placebo response may vary according to drug administration route. Migraine preventive treatment studies were used to evaluate ITCs and determine whether mode of administration influences placebo response and the overall study findings. Materials & methods: Change from baseline in monthly migraine days produced by monoclonal antibody treatments (subcutaneous, intravenous) was compared using fixed-effects Bayesian network meta-analysis (NMA), network meta-regression (NMR), and unanchored simulated treatment comparison (STC). Results: NMA and NMR provide mixed, rarely differentiated results between treatments, whereas unanchored STC strongly favors eptinezumab over other preventive treatments. Conclusion: Further investigations are needed to determine which ITC best reflects the impact of mode of administration on placebo.

Estimating treatment effects on health utility scores for patients living with migraine: a post hoc analysis of the DELIVER trial.

BACKGROUND: This post hoc analysis aimed to estimate eptinezumab's therapeutic effect on health utilities and determined to which extent monthly migraine days (MMDs) explain changes in health utilities. RESEARCH DESIGN/METHODS: DELIVER, a randomized, double-blind, placebo-controlled phase 3b trial (NCT04418765), investigated eptinezumab efficacy and safety in patients with 2-4 prior migraine treatment failures. Regression analysis explored the relationship between utility scores and MMDs, with eptinezumab treatment as a covariate along with MMDs to identify any MMD-independent effect on utilities. Path analysis quantified eptinezumab's impact as mediated through MMD reduction. RESULTS: The base case model showed that each reduction in MMD was associated with a mean utility score increase (0.0189; 95% CI: 0.0180, 0.0198; P < 0.001). Mean utility score was generally higher for eptinezumab versus placebo, justifying addition of treatment effect to the base case model. Patients administered eptinezumab had on average 0.0562 (95% CI: 0.0382, 0.0742; P < 0.001) higher utility versus placebo when controlling for number of MMDs. From path analysis, MMD reduction resulting from eptinezumab treatment accounted for 53% additional utility gain observed in patients. CONCLUSIONS: Changes in MMDs alone inadequately captured migraine's impact on patient utility, as there was also a positive eptinezumab-driven, treatment-specific impact on utility score. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT04418765).

Patient preferences for attributes of injected or infused preventive migraine medications: Findings from a discrete choice experiment.

OBJECTIVE: To assess preferences among adults with migraine for differentiating attributes of injected or infused preventive treatment options and evaluate their importance in determining a treatment choice. BACKGROUND: Adults with migraine and health-care providers consider many factors when making treatment decisions. Injected or infused preventive migraine treatment options differ in several attributes, including mode of administration and dosing frequency, which may be preferentially selected or avoided by patients. Understanding a patient's preference is important for clinicians as they advise on various treatment options. METHODS: A total of 604 US adults diagnosed with migraine participated in an online survey that captured information on demographics, migraine history, and treatment preferences. A discrete choice experiment (DCE) was used to evaluate participants' preferences for specific attributes of injected/infused preventive migraine therapies. The DCE data were utilized to estimate attribute importance (expressed as a percentage) and identify subgroups that had different distributions of preferences. RESULTS: In the overall migraine population, mode of administration (28.8%), durability of effectiveness (27.0%), and speed of onset (25.5%) had the highest relative importance, whereas administration setting (9.9%) and dosing frequency (8.8%) had the lowest. Four distinct subgroups were identified: Group 1 (n = 128) preferred self-injection administration and durability of effectiveness; Group 2 (n = 189) expressed aversion to cranial injections; Group 3 (n = 158) prioritized rapid speed of onset; and Group 4 (n = 129) favored health-care provider administration and durability of effectiveness. CONCLUSIONS: Speed of onset, durability of effectiveness, and mode of administration are key moderators of treatment preference among US adults with migraine. Certain segments of the migraine population prioritize specific treatment attributes over others, with intravenous infusion not considered a barrier in three of four identified segments. Clinicians can best help their patients find the right medication if they understand which medication attributes are most and least important to them.

Long-Term Outcomes of Previously Treated Adult and Adolescent Patients with Severe Hemophilia A Receiving Prophylaxis with Extended Half-Life FVIII Treatments: An Economic Analysis from a United Kingdom Perspective.

BACKGROUND: The standard of care for patients with hemophilia A is prophylaxis with factor VIII (FVIII) therapies. Extended half-life (EHL) FVIII products offer a reduced infusion burden compared with standard FVIII treatments. However, comparative evidence between EHLs is lacking. OBJECTIVE: To develop a pharmacodynamic-pharmacokinetic decision model to predict comparative bleed outcomes of adolescents and adults with hemophilia A receiving treatment with various EHL FVIII therapies, capturing differences in cumulative bleeding episodes, breakthrough bleed resolution and resource costs, as well as quality-adjusted life years (QALYs). METHODS: The patient population from the pathfinder 2 Phase III clinical trial was used to understand the link between FVIII levels and annual bleeding rates (ABRs). Pharmacokinetic/pharmacodynamic modeling was subsequently applied to estimate FVIII levels for four EHL FVIII treatments (turoctocog alfa pegol [Esperoct®], rurioctocog alfa pegol [Adynovi®], efmoroctocog alfa [Elocta®], and damoctocog alfa pegol [Jivi®]) to predict comparative ABRs. FVIII consumption costs (due to prophylactic treatment and breakthrough bleed resolution) and resource costs, as well as QALYs, were subsequently estimated from a UK NHS perspective over a 70-year time horizon. RESULTS: Turoctocog alfa pegol prophylaxis resulted in 8-19% fewer cumulative bleeding episodes versus comparators in the base case scenario. Assuming parity in annual prophylaxis costs, turoctocog alfa pegol prophylaxis reduced the cost of product and resource use to resolve a breakthrough bleed by 9-25% versus comparators. Prophylaxis with turoctocog alfa pegol was also associated with the most QALYs, representing a discounted QALY gain of 0.35-1.05 compared with the other treatments. CONCLUSION: Using a pharmacodynamic-pharmacokinetic decision model, turoctocog alfa pegol prophylaxis was associated with fewer cumulative bleeds, as well as lower product and resource costs related to resolving a breakthrough bleed and most QALYs versus comparators.

Real-world utilities and health-related quality-of-life data in hemophilia patients in France and the United Kingdom.

Purpose: Congenital hemophilia A and B are bleeding disorders characterized by deficiency of factors VIII and IX, respectively. This study aimed to collect health-related quality-of-life (HRQoL) and health-utility data from hemophilia patients with differing disease severity. Methods: Individuals with hemophilia aged ≥12 years living in France or the UK completed a series of questionnaires, including the EQ-5D-3L and -5L and SF-36 version 2. Association with demographic and clinical variables was explored using linear regression, and health-utility comparison was completed using Pearson and intraclass correlation coefficients. Results: A total of 122 patients in France and 62 in the UK completed the survey. The combined sample primarily consisted of hemophilia A patients, mean age of 41 years, 70% had severe hemophilia, and 56% were on long-term prophylaxis. Similar HRQoL and utility scores were observed across the French and UK samples. The presence of more than two target joints, occurrence of joint surgery, and increased joint-pain frequency were independent predictors of lower SF-36 - physical health summary scores and lower health-utility scores. No statistically significant reductions in SF-36 - mental health summary scores were observed, except for participants with target joints. Strong correlations were observed between health- utility values derived from the three instruments (r=0.69-0.79). Conclusion: Results of this study reinforce the importance of appropriate treatment to limit the physical burden and long-term joint damage associated with hemophilia. Further, utility values collected here reflect real-world data, and can serve as health-state weights in future cost-utility analyses.

Health-related quality-of-life and treatment satisfaction of individuals with hemophilia A treated with turoctocog alfa pegol (N8-GP): a new recombinant extended half-life FVIII.

BACKGROUND: Prophylactic treatment regimens lead to improvements in health-related quality-of-life (HRQoL) among individuals with hemophilia. Turoctocog alfa pegol (N8-GP) provides the benefit of extending the duration of protection from bleeding and reducing the number of injections, which is expected to impact HRQoL and treatment satisfaction (TS). AIM: To investigate the HRQoL and TS of patients with severe hemophilia A from two phase III trials evaluating the safety and efficacy of N8-GP. METHODS: HRQoL was assessed using the Haemo-QoL (reported by children and their parents) and Haem-A-QoL (reported by adults). TS was assessed using Hemo-Sat. Domain and total scores for all questionnaires ranged from 0 to 100, with lower scores indicating a better HRQoL or TS. A negative change in score indicates an improvement in HRQoL/TS. RESULTS: Mean changes in HRQoL scores were reported for 14 children aged 4-7 years, 21 children aged 8-11 years, 10 adolescents aged 13-16 years, and 163 adults (17 years and above). Mean changes in children/adolescents-reported Haemo-QoL total score were -14.0 for ages 4-7 years, -3.6 for ages 8-11 years, and -0.1 for ages 13-16 years. Mean changes in parent-reported Haemo-QoL total scores were -11.5 for 4-7 years, -8.6 for ages 8-11 years, and -4.0 for 13-16 years. Adults' mean change in Haem-A-QoL total score was -3.1 for those receiving on-demand treatment and -2.3 for those receiving prophylaxis treatment. High levels of TS with N8-GP were reported by parents of children/adolescents and the adults at the end of the trial. CONCLUSION: While most patients reported a relatively good baseline HRQoL when entering the respective trials, the HRQoL of patients was either maintained or further improved when treated with N8-GP. Adults and parents of children and adolescents reported a high level of treatment satisfaction with N8-GP.

Diabetes Management and Healthcare Resource Use When Intensifying from Basal Insulin to Basal-Bolus: A Survey of Type 2 Diabetes Patients.

INTRODUCTION: Currently, there is limited knowledge about the experiences and challenges type 2 diabetes (T2D) patients face when intensifying from basal insulin to more complex regimens. The purpose of this study was to examine the experiences of adults with T2D who have been intensified to a basal-bolus insulin regimen, including challenges related to intensification, medication adherence issues, non-persistence, and healthcare resource use related to intensification. METHODS: A web-based survey of adults diagnosed with T2D and currently treated with basal insulin was conducted in the UK and the USA. The analysis sample was restricted to respondents with current/recent basal-bolus treatment (n = 398) and divided into three analysis groups: (1) "basal-bolus adherent" (current basal-bolus treatment with at least 90% adherence); (2) "basal-bolus non-adherent" (current basal-bolus treatment with less than 80% adherence); and (3) "stopped bolus" (discontinued bolus in past 12 months). RESULTS: Basal-bolus non-adherent respondents reported fewer discussions with their healthcare providers (HCPs) before starting bolus and more frequent difficulties with and worries about taking bolus insulin compared to basal-bolus adherent and stopped bolus groups. The most frequently reported reasons for discontinuing bolus were related to the complicated nature of regimen, including too complicated to calculate bolus doses (25.7%), too complicated to regulate food in relation to bolus (20.7%), and too complicated to keep track of taking two different insulins (18.6%). Respondents who stopped bolus reported more frequent HCP visits related to diabetes compared to the basal-bolus adherent and basal-bolus non-adherent groups. CONCLUSION: Results suggest that the complicated nature of basal-bolus therapy contributes to the difficulties that T2D patients have with the regimen and to non-persistence. Physician and patient education may help patients address these treatment challenges to improve basal-bolus adherence and persistence, which could reduce healthcare resource use and costs. Less complex regimens may be appropriate for patients with persistent treatment difficulties. FUNDING: Novo Nordisk A/S.

The management of type 2 diabetes with fixed-ratio combination insulin degludec/liraglutide (IDegLira) versus basal-bolus therapy (insulin glargine U100 plus insulin aspart): A short-term cost-effectiveness analysis in the UK setting.

AIM: To evaluate the cost-effectiveness of IDegLira versus basal-bolus therapy (BBT) with insulin glargine U100 plus up to 4 times daily insulin aspart for the management of type 2 diabetes in the UK. METHODS: A Microsoft Excel model was used to evaluate the cost-utility of IDegLira versus BBT over a 1-year time horizon. Clinical input data were taken from the treat-to-target DUAL VII trial, conducted in patients unable to achieve adequate glycaemic control (HbA1c <7.0%) with basal insulin, with IDegLira associated with lower rates of hypoglycaemia and reduced body mass index (BMI) in comparison with BBT, with similar HbA1c reductions. Costs (expressed in GBP) and event-related disutilities were taken from published sources. Extensive sensitivity analyses were performed. RESULTS: IDegLira was associated with an improvement of 0.05 quality-adjusted life years (QALYs) versus BBT, due to reductions in non-severe hypoglycaemic episodes and BMI with IDegLira. Costs were higher with IDegLira by GBP 303 per patient, leading to an incremental cost-effectiveness ratio (ICER) of GBP 5924 per QALY gained for IDegLira versus BBT. ICERs remained below GBP 20 000 per QALY gained across a range of sensitivity analyses. CONCLUSIONS: IDegLira is a cost-effective alternative to BBT with insulin glargine U100 plus insulin aspart, providing equivalent glycaemic control with a simpler treatment regimen for patients with type 2 diabetes inadequately controlled on basal insulin in the UK.

Systematic review: treatment pattern and clinical effectiveness and safety of pharmaceutical therapies for Crohn's disease in Europe.

BACKGROUND: Although many clinical trials have been conducted in treatments of Crohn's disease (CD), whether the trial results were representative of daily practice needs to be supported by studies conducted in real-world settings. AIM: This study aims to identify how CD is treated and what are the clinical effectiveness and safety of the pharmaceutical therapies of CD in real-world settings. METHODS: A systematic literature review was conducted based on Medline®, Embase®, and Cochrane. All publications were assessed for title/abstract and full-text according to a predefined study protocol. Data were extracted and reported. RESULTS: A total of 1,998 publications were identified. Fifty studies including six publications reporting treatment pattern and 44 studies reporting clinical effectiveness and safety of pharmaceutical therapies in CD management in Europe were included. 5-Aminosalicylic acid and corticosteroids were reported to be used among 14%-74% of CD patients. Immunomodulators were used by 14%-25% and 29%-31% of CD patients as an initial and follow-up treatment, respectively. Biological therapies were used by 25%-33% of CD patients. A trend toward an increasing use of immunomodulators and biological therapies in Europe has been reported in recent years. Approximately 50% of patients achieved remission on immunomodulator or biologic treatment, although a relapse rate of up to 23% has been reported. CONCLUSION: There is a trend of treatment shift to immunomodulators and biologics in CD management. Clinical effectiveness of immunomodulators and biologics has been demonstrated, though with a lack of sustainability of the effectiveness.