Efgartigimod improved health-related quality of life in generalized myasthenia gravis: results from a randomized, double-blind, placebo-controlled, phase 3 study (ADAPT).

There are substantial disease and health-related quality-of-life (HRQoL) burdens for many patients with myasthenia gravis (MG), especially for those whose disease symptoms are not well controlled. HRQoL measures such as the Myasthenia Gravis Quality of Life 15-item revised (MG-QOL15r) and EuroQoL 5-Dimensions 5-Levels (EQ-5D-5L) are vital for evaluating the clinical benefit of therapeutic interventions in patients with MG, as they assess the burden of disease and the effectiveness of treatment, as perceived by patients. The phase 3 ADAPT study (NCT03669588) demonstrated that efgartigimod-a novel neonatal Fc receptor inhibitor-was well tolerated and that acetylcholine receptor antibody-positive (AChR-Ab+) participants who received efgartigimod had statistically significant improvements in MG-specific clinical scale scores. The ancillary data reported here, which cover an additional treatment cycle, show that these participants had similar significant improvements in HRQoL measures, the MG-QOL15r and EQ-5D-5L utility and visual analog scales, and that these improvements were maintained in the second treatment cycle. Positive effects on HRQoL were rapid, seen as early as the first week of treatment in both treatment cycles, and maintained for up to 4 weeks in the follow-up-only portion of treatment cycles. The pattern of improvements in HRQoL paralleled changes in immunoglobulin G level, and correlational analyses show that improvements were consistent across HRQoL measures and with clinical efficacy measures in the ADAPT study. The substantial and durable improvements in HRQoL end points in this study demonstrate the broader benefit of treatment with efgartigimod beyond relief of immediate signs and symptoms of gMG.

Patient-reported burden of myasthenia gravis: baseline results of the international prospective, observational, longitudinal real-world digital study MyRealWorld-MG.

OBJECTIVES: Myasthenia gravis (MG) is a rare, chronic, autoimmune neuromuscular disease which can affect functional and mental aspects of health and health-related quality of life (HRQoL). This study aims to obtain detailed knowledge of the impact of MG on HRQoL in a broad population from the perspective of the patient. DESIGN: Prospective, observational, digital, longitudinal real-world study. SETTING: Adult patients with MG from seven countries (USA, Japan, Germany, UK, Italy, Spain and Canada) downloaded a mobile application onto their phones and entered data about themselves and their MG. OUTCOME MEASURES: Data was collected using the following general and disease-specific patient-reported outcome measurements: EuroQol 5 Domains Health-Related Quality of Life Questionnaire (EQ-5D-5L), Myasthenia Gravis Activities of Daily Living (MG-ADL), Myasthenia Gravis Quality of Life 15-item revised scale (MG-QoL-15r), Hospital Anxiety and Depression Scale (HADS) and Health Utilities Index III (HUI3). Patients were categorised by their self-assessed Myasthenia Gravis Foundation of America (MGFA) class (I-V). RESULTS: Baseline results of 841 participants (mean age 47 years, 70% women) are reported . The distribution across the MGFA classes was: 13.9%, 31.0%, 38.1%, 15.5% and 1.6% for classes I-V. The MGFA class was a strong predictor of all aspects of HRQoL, measured with disease-specific and with generic instruments. The domains in which patients with MG most frequently mentioned problems were usual activities, anxiety and depression, tiredness, breathing and vision. The mean total MG-ADL Score was positively associated with increasing MGFA classes: 2.7, 4.4, 6.3 and 8.4 for MGFA classes I-IV. Mean baseline EQ-5D-5L utility was also associated with MGFA classes and was 0.817, 0.766, 0.648 and 0.530 for MGFA class I-IV. CONCLUSIONS: MG has a large impact on key aspects of health and HRQoL. The impact of this disease increases substantially with increasing disease severity.

Clinical efficacy comparison of avapritinib with other tyrosine kinase inhibitors in gastrointestinal stromal tumors with PDGFRA D842V mutation: a retrospective analysis of clinical trial and real-world data.

BACKGROUND: Avapritinib, a potent inhibitor of KIT and platelet-derived growth factor receptor A (PDGFRA) tyrosine kinases, has demonstrated unprecedented clinical activity in PDGFRA D842V-mutant gastrointestinal stromal tumors (GIST). METHODS: This retrospective analysis compared efficacy of avapritinib in patients enrolled in the NAVIGATOR phase 1 trial (NCT02508532) with the efficacy of other tyrosine kinase inhibitors (TKIs) in patients with unresectable/metastatic PDGFRA D842V-mutant GIST enrolled in a retrospective natural history study (Study 1002). The primary endpoint was overall survival (OS) from the start of reference treatment (avapritinib for NAVIGATOR patients or first-line TKI for treatment of unresectable/metastatic GIST for Study 1002 patients); the secondary endpoint was progression-free survival (PFS). Adjusted Kaplan-Meier survival curves were compared by Cox regression. RESULTS: Fifty-six (NAVIGATOR) and 19 (Study 1002) patients with PDGFRA D842V-mutant GIST were evaluated; of the 56 patients from NAVIGATOR, a subgroup of patients treated with either 300 mg (recommended phase 2 dose) or 400 mg (maximum tolerated dose) avapritinib starting dose (n = 38) were analyzed separately. Patient characteristics were adjusted for imbalances by propensity score between the study groups. Inverse probability of treatment weighting-adjusted Kaplan-Meier analysis of OS showed median OS was not reached for NAVIGATOR patients treated with any of the avapritinib doses tested and was 12.6 months for Study 1002 patients; OS rate at 6/48 months was 100%/63% in NAVIGATOR and 56%/17% in Study 1002 (P = 0.0001). In the 300/400 mg subgroup, adjusted OS rates at 6/36 months were 100%/73 and 68%/20% in Study 1002 (P = 0.0016). Adjusted median PFS was 29.5 months in NAVIGATOR and 3.4 months in Study 1002. CONCLUSIONS: In this indirect, retrospective analysis, avapritinib demonstrated more durable survival outcomes compared with other TKIs in patients with unresectable/metastatic PDGFRA D842V-mutant GIST. TRIAL REGISTRATION: The NAVIGATOR trial was registered at ClinicalTrials.gov as per July 2015, Identifier: NCT02508532 .

Cost Effectiveness of the Third-Generation Tyrosine Kinase Inhibitor (TKI) Ponatinib, vs. Second-Generation TKIs or Stem Cell Transplant, as Third-Line Treatment for Chronic-Phase Chronic Myeloid Leukemia.

BACKGROUND AND OBJECTIVES: Third-line treatment options for patients with chronic-phase chronic myeloid leukemia include tyrosine kinase inhibitors and allogeneic hematopoietic stem cell transplantation (alloHSCT). The objective of this study was to develop a Markov model with a lifetime time horizon to assess the cost effectiveness of ponatinib for third-line chronic-phase chronic myeloid leukemia vs. second-generation tyrosine kinase inhibitors (dasatinib, nilotinib, bosutinib) or alloHSCT from the public healthcare system perspective in Germany, Sweden, and Canada. METHODS: Clinical outcomes were derived from the literature, and from patient-level data (phase II PACE trial) for ponatinib. Resource use included drugs, alloHSCT, monitoring and follow-up, adverse events, and end-of-life care; costs were based on national tariffs. Quality-adjusted life-years (QALYs) were calculated using chronic myeloid leukemia health-state utilities from an international time-trade-off study. Costs and benefits were discounted at 3% per annum for Germany and Sweden, and 5% for Canada. RESULTS: Ponatinib yielded more discounted QALYs than any second-generation tyrosine kinase inhibitor/alloHSCT in all three countries, mainly owing to better response rates and longer durations of response. Incremental cost-effectiveness ratios for ponatinib vs. second-generation tyrosine kinase inhibitors were US$21,543-37,755/QALY in Germany, $24,018-38,227/QALY in Sweden, and $43,001-58,515/QALY in Canada. Ponatinib was dominant over alloHSCT in Germany, while incremental cost-effectiveness ratios for ponatinib vs. alloHSCT in Sweden and Canada were $715/QALY and $31,534/QALY, respectively. CONCLUSIONS: Ponatinib may improve outcomes (mainly because of higher response rates and longer response durations) at an acceptable cost level compared with other third-line treatment options for chronic-phase chronic myeloid leukemia in Germany, Sweden, and Canada; however, the lack of an indirect comparison is a limitation of our study.

Benefits and risks of ponatinib versus bosutinib following treatment failure of two prior tyrosine kinase inhibitors in patients with chronic phase chronic myeloid leukemia: a matching-adjusted indirect comparison.

OBJECTIVE: Comparing the benefit-risk profiles of ponatinib vs. bosutinib in third-line (3L) treatment of chronic phase chronic myeloid leukemia (CP-CML) is challenging because their pivotal trials lacked comparator arms. To characterize the overall benefit-risk profile in 3L CP-CML patients treated with bosutinib vs. ponatinib, a matching-adjusted indirect comparison (MAIC) was performed to compare efficacy outcomes and treatment duration after adjusting for trial subjects' baseline characteristics, and tolerability was assessed with an unadjusted comparison of study-drug discontinuation. METHODS: The MAIC was performed using published data from the pivotal bosutinib trial and the most recent individual-patient-level data on file from the pivotal ponatinib trial. RESULTS: Responses were more frequent and durable with ponatinib (n = 70 MAIC-adjusted) than with bosutinib (n = 119) - complete cytogenetic response (CCyR): 61% vs. 26%; Kaplan-Meier estimate of maintaining CCyR at 4 years: 89% vs. 54%. Median treatment duration was longer with ponatinib than with bosutinib: 38.4 vs. 8.6 months. Only 9% of ponatinib patients (n = 97 unadjusted) vs. 42% of bosutinib patients discontinued due to death, disease progression or unsatisfactory response; 19% vs. 24% discontinued due to adverse events. CONCLUSIONS: Based on these surrogate measures of patient benefit-risk profiles, ponatinib appears to provide a net overall benefit vs. bosutinib in 3L CP-CML.

Cost per responder analysis in patients with secondary hyperparathyroidism on dialysis treated with cinacalcet.

BACKGROUND: Growing financial pressure on US dialysis providers requires economic efficiency considerations. The objective of this study was to examine short-term economic efficiencies of a cinacalcet-based treatment approach for secondary hyperparathyroidism. METHODS: This study retrospectively assessed cost per biochemical response of the OPTIMA trial. OPTIMA was conducted in end-stage renal disease patients to compare biochemical control in patients receiving cinacalcet in addition to vitamin D sterols and phosphate binders vs patients receiving vitamin D sterol and phosphate binders alone. It explored three laboratory measurement response definitions from baseline to week 23: (1) decreases in parathyroid hormone (PTH) ≥30%; (2) PTH ≤ 300 pg/ml; and (3) PTH ≤ 300 pg/mL, calcium <9.5 mg/dL and phosphorus <5.5 mg/dL. Medication use and costs were measured to calculate average costs and incremental cost per responder. Stratification by lower and higher baseline PTH assessed cost per response by disease severity. RESULTS: There were 38-77% more responders with cinacalcet vs control, depending on response definition. Mean (SD) per patient total medication costs were $5423 ($3698) for cinacalcet and $2633 ($2334) for control, leading to a mean difference of $2790 over 23 weeks. When response was defined as a decrease in PTH ≥ 30% from baseline, the average cost per responder was $11,266 for control vs $7027 for cinacalcet. The incremental cost per incremental responder ranged from $5186-$9168. Across all response measures, cost per responder was lower in patients with lower baseline PTH. CONCLUSIONS: Representing a more efficient allocation of economic resources over the short-term, cinacalcet-based treatment algorithm led to a lower cost per biochemical response, particularly in patients with lower disease severity, vs vitamin D sterols and phosphate binders alone. These findings should be interpreted alongside the study limitation of converting international trial-based medication utilization into US costs.

Is there an association between elevated or low serum levels of phosphorus, parathyroid hormone, and calcium and mortality in patients with end stage renal disease? A meta-analysis.

BACKGROUND: Biochemical markers of altered mineral metabolism have been associated with increased mortality in end stage renal disease patients. Several studies have demonstrated non-linear (U-shaped or J-shaped) associations between these minerals and mortality, though many researchers have assumed linear relationships in their statistical modeling. This analysis synthesizes the non-linear relationships across studies. METHODS: We updated a prior systematic review through 2010. Studies included adults receiving dialysis and reported categorical data for calcium, phosphorus, and/or parathyroid hormone (PTH) together with all-cause mortality. We performed 2 separate meta-analyses to compare higher-than-referent levels vs referent and lower-than-referent levels vs referent levels. RESULTS: A literature review showed that when a linear relationship between the minerals and mortality was assumed, the estimated associations were more likely to be smaller or non-significant compared to non-linear models. In the meta-analyses, higher-than-referent levels of phosphorus (4 studies, RR = 1.20, 95% CI = 1.15-1.25), calcium (3 studies, RR = 1.10, 95% CI = 1.05-1.14), and PTH (5 studies, RR = 1.11, 95% CI = 1.07-1.16) were significantly associated with increased mortality. Although no significant associations between relatively low phosphorus or PTH and mortality were observed, a protective effect was observed for lower-than-referent calcium (RR = 0.86, 95% CI = 0.83-0.89). CONCLUSIONS: Higher-than-referent levels of PTH, calcium, and phosphorus in dialysis patients were associated with increased mortality risk in a selection of observational studies suitable for meta-analysis of non-linear relationships. Findings were less consistent for lower-than-referent values. Future analyses should incorporate the non-linear relationships between the minerals and mortality to obtain accurate effect estimates.

Impact of mineral and bone disorder on healthcare resource use and associated costs in the European Fresenius medical care dialysis population: a retrospective cohort study.

BACKGROUND: Secondary hyperparathyroidism (SHPT) is associated with mortality in patients with chronic kidney disease (CKD), but the economic consequences of SHPT have not been adequately studied in the European population. We assessed the relationship between SHPT parameters (intact parathyroid hormone [iPTH], calcium, and phosphate) and hospitalisations, medication use, and associated costs among CKD patients in Europe. METHODS: The analysis of this retrospective cohort study used records of randomly selected patients who underwent haemodialysis between January 1, 2005 and December 31, 2006 at participating European Fresenius Medical Care facilities in 10 countries. Patients had ≥ 1 iPTH value recorded, and ≥ 1 month of follow-up after a 3-month baseline period during which SHPT parameters were assessed. Time at risk was post-baseline until death, successful renal transplantation, loss to follow-up, or the end of follow-up. Outcomes included cost per patient-month, rates of hospitalisations (cardiovascular disease [CVD], fractures, and parathyroidectomy [PTX]), and use of SHPT-, diabetes-, and CVD-related medications. National costs were applied to hospitalisations and medication use. Generalised linear models compared costs across strata of iPTH, total calcium, and phosphate, adjusting for baseline covariates. RESULTS: There were 6369 patients included in the analysis. Mean ± SD person-time at risk was 13.1 ± 6.4 months. Patients with iPTH > 600 pg/mL had a higher hospitalisation rate than those with lower iPTH. Hospitalisation rates varied little across calcium and phosphate levels. SHPT-related medication use varied with iPTH, calcium, and phosphate. After adjusting for demographic and clinical variables, patients with baseline iPTH > 600 pg/mL had 41% (95% CI: 25%, 59%) higher monthly total healthcare costs compared with those with iPTH in the K/DOQI target range (150-300 pg/mL). Patients with baseline phosphate and total calcium levels above target ranges (1.13-1.78 mmol/L and 2.10-2.37 mmol/L, respectively) had 38% (95% CI: 27%, 50%) and 8% (95% CI: 0%, 17%) higher adjusted monthly costs, respectively. Adjusted costs were 25% (95% CI: 18%, 32%) lower among patients with baseline phosphate levels below the target range. Results were consistent in sensitivity analyses. CONCLUSIONS: These data suggest that elevated SHPT parameters increase the economic burden of CKD in Europe.

A cost-utility analysis of cinacalcet in secondary hyperparathyroidism in five European countries.

BACKGROUND AND OBJECTIVE: A probabilistic patient-level Markov model was previously developed to simulate lifetime clinical and economic outcomes of cinacalcet treatment in secondary hyperparathyroidism (SHPT) patients using local data from Italy. The present study extends the application of the model to four other European countries - Spain, Portugal, Switzerland and the Czech Republic - in order to assess the consistency of results. METHODS: Cinacalcet influences the levels of parathyroid hormone, serum calcium and phosphorous. Our simulation was based on data from the OPTIMA (Open-Label, Randomized Study Using Cinacalcet to Improve Achievement of KDOQI Targets in Patients with End-Stage Renal Disease) randomized controlled trial and from published correlations between bone-metabolism parameters, mortality and morbidity (cardiovascular [CV] events, fractures and parathyroidectomy). Local epidemiological and cost data for dialysis, drugs and event management were incorporated into the model. The simulation horizon was patient lifetime; standard treatment for SHPT (vitamin D sterols and phosphate binders) and cinacalcet plus standard treatment were compared. Effectiveness was measured in terms of life expectancy (LE) and quality-adjusted life expectancy (QALE). Health utility indexes derived from published literature took into account dialysis, CV events and fractures. RESULTS: The simulated mean LE extension in patients receiving cinacalcet was 1.20 life-years (LY) in Italy, 1.10 LY in Spain, 1.18 LY in Portugal, 1.10 LY in the Czech Republic and 1.40 LY in Switzerland. QALE increase was 0.89, 0.82, 0.89, 0.80 and 1.01 QALY in the same countries, respectively. The incremental cost-effectiveness ratio (ICER) result was €23,500/LY and €31,600/QALY in Italy, €21,800/LY and €29,300/QALY in Spain, €23,700/LY and €31,200/QALY in Portugal, €29,700/LY and €40,800/QALY in the Czech Republic and €24,700/LY and €34,200/QALY in Switzerland. Including dialysis costs as a part of the total costing doubled the ICER, from a minimum of €42,800/LY in Spain to a maximum of €82,800/LY in Switzerland and in the range from €57,500/QALY (Spain) to €114,700/QALY (Switzerland). CONCLUSION: Taking into consideration the limited clinical, epidemiological and health economics data available, cinacalcet treatment showed a relatively good cost-effectiveness profile in all the countries analysed, despite the differences in their healthcare systems and economic wealth.

Economic evaluation of cinacalcet in the treatment of secondary hyperparathyroidism in Italy.

BACKGROUND: Imbalanced levels of parathyroid hormone (PTH), serum calcium (Ca) and phosphorous (P) are associated with an increased risk of cardiovascular (CV) death and fracture in dialysis patients with secondary hyperparathyroidism (SHPT). The calcimimetic agent cinacalcet can attenuate the mineral and hormonal imbalances characteristic of SHPT and may improve outcomes in such patients. Here we describe a cost-utility analysis of cinacalcet for SHPT in dialysis patients in Italy. METHODS: We developed a probabilistic Markov model to simulate the effect of cinacalcet on Ca, P and PTH levels in dialysis patients with SHPT, based on data from a European, multicentre, open-label study. The model then correlated these levels with mortality and morbidity (CV events, fractures and parathyroidectomies) using data from the literature, and incorporated Italian data for dialysis, drugs and management of events according to the national cost structure. The simulation horizon was patient lifetime; simulated treatment alternatives were standard treatment (mainly vitamin D sterols and phosphate binders) and cinacalcet + standard treatment. A 3.5% discount rate was applied to life expectancy (LE), quality-adjusted life-expectancy (QALE), costs and times below the upper ranges (time in range [TiR]) recommended by the National Kidney Foundation - Kidney Disease Outcomes Quality initiative for PTH, Ca, P and Ca × P. Utilities were derived from the published literature and took into account dialysis and the impairment of quality of life due to the occurrence of CV events and fractures. Costs were evaluated in year 2009 values from the perspective of the Italian National Healthcare System. RESULTS: Baseline results were calculated with 10,000 iterations. Compared with standard treatment alone, addition of cinacalcet was associated with a mean (SD) increase in TiR of 5.26 (6.59), 3.63 (6.87), 1.70 (6.66) and 2.68 (5.55) discounted patient-years for PTH, Ca and P, respectively, and combined PTH, Ca, P and Ca × P. Cinacalcet increased LE by 1.20 (3.75) life-years (LYs) and QALE by 0.89 (2.59) QALYs. When including the cost for dialysis, the incremental cost-effectiveness ratio (ICER) was €50,012 per LY and €67,361 per QALY, while, if dialysis costs were not included, the ICER was €23,473 per LY and €31,616 per QALY. CONCLUSIONS: The results suggest that cinacalcet treatment could be considered cost effective for treatment of SHPT in the Italian healthcare setting, but further investigations are needed to confirm these findings.

Cost-effectiveness of pegfilgrastim versus six days of filgrastim for preventing febrile neutropenia in breast cancer patients.

AIMS AND BACKGROUND: Febrile neutropenia (FN) is a major complication of chemotherapy and is associated with substantial morbidity, mortality and costs. The aim of this study was to evaluate the cost-effectiveness of primary prophylaxis with, pegfilgrastim versus six-day filgrastim in preventing FN in Italian patients with early-stage breast cancer receiving adjuvant chemotherapy associated with a > or = 20% FN risk. METHODS: The pharmacoeconomic evaluation was based on a decision-analytic model taking into account the possible consequences of FN (e.g., death and reduction/delay of chemotherapy dose). Parameters included in the model were relative risk of FN with pegfilgrastim versus six-day filgrastim; direct costs (drug purchase and FN-related hospitalizations); relative risk of relative dose intensity < 85% with pegfilgrastim versus filgrastim; impact on long-term survival due to relative dose intensity < 85%; and impact of age on FN and relative dose intensity < 85%. RESULTS: Under base-case assumptions, pegfilgrastim was cost-effective compared to six-day filgrastim in Italy. The estimated cost, life expectancy and quality-adjusted life years per person for pegfilgrastim were Euro 3078, 16.47 years, and 15.32; the corresponding figures for six-day filgrastim were Euro 3033, 16.35 years, and 15.22. The corresponding incremental cost-effectiveness ratio with pegfilgrastim was Euro 409 per life-year gained and Euro 429 per quality-adjusted life year gained. One-way sensitivity analyses showed that the results were most sensitive to the relative risk of FN for 6-day filgrastim versus pegfilgrastim. The results were moderately sensitive to the cost of pegfilgrastim and filgrastim, cost of drug administration, cost of FN hospitalization, and number of chemotherapy cycles. Pegfilgrastim remained cost-effective, with an incremental cost-effectiveness ratio well below the accepted limit of Euro 50,000 per life year gained in all one-way sensitivity analyses. A two-way sensitivity analysis on cost of drugs showed a range of pegfilgrastim dominance over six-day filgrastim. CONCLUSIONS: At the current official price in Italy, primary prophylaxis with pegfilgrastim improved health outcomes with a very limited cost increase for the National Health Service payer. Even when very low prices of filgrastim and high prices of pegfilgrastim were considered in the model, the resulting incremental cost-effectiveness ratio remained well within the acceptable cost-effectiveness limit of Euro 50,000/quality-adjusted life year.