Publications by authors named "Nanxin Li"

86 Publications

Patient preferences and priorities for haemophilia gene therapy in the US: A discrete choice experiment.

Haemophilia 2021 Sep 26;27(5):769-782. Epub 2021 Jul 26.

uniQure Inc, Lexington, Massachusetts, USA.

Introduction: Gene therapy has shown promise in clinical trials for patients with haemophilia, but patient preference studies have focused on factor replacement treatments.

Aim: We conducted a discrete choice experiment (DCE) to investigate the relative importance and differential preferences patients provide for gene therapy attributes.

Methods: We surveyed male adults with haemophilia in the United States recruited from patient panels including the National Hemophilia Foundation Community Voices in Research platform using an online survey over 4 months in 2020/21. Participants indicated preferences for gene therapy attributes including dosing frequency/durability, effect on annual bleeding, uncertainty related to side effects, impact on daily activities, impact on mental health, and post-treatment requirements. The relative importance of each attribute was analysed overall and for subgroups based on haemophilia type and severity.

Results: A total of 183 males with haemophilia A (n = 120) or B (n = 63) were included. Half (47%) had severe haemophilia; most (75%) were White. Overall, participants gave effect on bleeding rate the greatest relative importance (31%), followed by dose frequency/durability (26%), uncertainty regarding safety issues (17%), and impact on daily activities (11%). Dose frequency/durability had the greatest importance for those with haemophilia B (35%).

Conclusion: People with haemophilia prioritised reduced bleeding and treatment burden; the former was more important in haemophilia A and the latter in haemophilia B, followed by safety and impact on daily life in this DCE of gene therapy attributes. These findings and differences can inform clinical and health policy decisions to improve health equity for people with haemophilia.
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http://dx.doi.org/10.1111/hae.14383DOI Listing
September 2021

Health care resource utilization and cost burden of hemophilia B in the United States.

Blood Adv 2021 04;5(7):1954-1962

uniQure, Inc., Lexington, MA.

Hemophilia B is a rare congenital blood disorder characterized by factor IX deficiency. Clinical profiles of hemophilia B range from mild to severe forms of the disease. The objective of this study was to characterize the economic burden associated with differing clinical profiles of hemophilia B from a US health system perspective. Using the IBM MarketScan database (June 2011-February 2019), a claims-based algorithm was developed to identify 4 distinct profiles (mild, moderate, moderate-severe, and severe) in adult males with hemophilia B based on the frequency of hemorrhage events and factor IX replacement claims. Mean annual health care resource use (HRU) and costs were statistically compared between patients with hemophilia B (N = 454) and 1:1 demographic-matched controls (N = 454), both overall and with stratification by clinical profile. Compared with matched controls, patients with hemophilia B had a significantly higher comorbidity burden (Charlson Comorbidity Index, mean ± standard deviation [SD]: 0.9 ± 1.7 vs 0.3 ± 0.9, P < .001). Across all clinical profiles, patients with hemophilia B had significantly higher HRU vs matched controls (mean ± SD: 0.3 ± 0.6 vs 0.1 ± 0.3 inpatient admissions; 0.6 ± 1.2 vs 0.2 ± 0.6 emergency department visits; 17.7 ± 22.9 vs 8.0 ± 11.0 outpatient visits; all P < .001). Annual total health care costs per patient among patients with hemophilia B were more than 25-fold higher vs matched controls (mean ± SD: $201 635 ± $411 530 vs $7879 ± $29 040, respectively, P < .001). Annual total health care costs per patient increased with increasing severity (mean ± SD: mild, $80 811 ± $284 313; moderate, $137 455 ± $222 021; moderate-severe, $251 619 ± $576 886; severe, $632 088 ± $501 270). The findings of this study highlight the substantial burden of illness associated with hemophilia B.
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http://dx.doi.org/10.1182/bloodadvances.2020003424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045501PMC
April 2021

Clinical, humanistic, and economic burden of severe hemophilia B in the United States: Results from the CHESS US and CHESS US+ population surveys.

Orphanet J Rare Dis 2021 03 20;16(1):143. Epub 2021 Mar 20.

uniQure Inc, 113 Hartwell Avenue, Lexington, MA, 02421, USA.

Background: Hemophilia B is a rare congenital bleeding disorder that has a significant negative impact on patients' functionality and health-related quality of life. The standard of care for severe hemophilia B in the United States is prophylactic factor IX replacement therapy, which incurs substantial costs for this lifelong condition. Accurate estimates of the burden of hemophilia B are important for population health management and policy decisions, but have only recently accounted for current management strategies. The 'Cost of Severe Hemophilia across the US: a Socioeconomic Survey' (CHESS US) is a cross-sectional database of medical record abstractions and physician-reported information, completed by hematologists and care providers. CHESS US+ is a complementary database of completed questionnaires from patients with hemophilia. Together, CHESS US and CHESS US+ provide contemporary, comprehensive information on the burden of severe hemophilia from the provider and patient perspectives. We used the CHESS US and CHESS US+ data to analyze the clinical, humanistic, and economic burden of hemophilia B for patients treated with factor IX prophylaxis between 2017 and 2019 in the US.

Results: We conducted analysis to assess clinical burden and direct medical costs from 44 patient records in CHESS US, and of direct non-medical costs, indirect costs, and humanistic burden (using the EQ-5D-5L) from 57 patients in CHESS US+. The mean annual bleed rate was 1.73 (standard deviation, 1.39); approximately 9% of patients experienced a bleed-related hospitalization during the 12-month study period. Nearly all patients (85%) reported chronic pain, and the mean EQ-5D-5L utility value was 0.76 (0.24). The mean annual direct medical cost was $614,886, driven by factor IX treatment (mean annual cost, $611,971). Subgroup analyses showed mean annual costs of $397,491 and $788,491 for standard and extended half-life factor IX treatment, respectively. The mean annual non-medical direct costs and indirect costs of hemophilia B were $2,371 and $6,931.

Conclusions: This analysis of patient records and patient-reported outcomes from CHESS US and CHESS US+ provides updated information on the considerable clinical, humanistic, and economic burden of hemophilia B in the US. Substantial unmet needs remain to improve patient care with sustainable population health strategies.
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http://dx.doi.org/10.1186/s13023-021-01774-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981988PMC
March 2021

Evidence of a disability paradox in patient-reported outcomes in haemophilia.

Haemophilia 2021 Mar 17;27(2):245-252. Epub 2021 Feb 17.

uniQure Inc, Lexington, MA, USA.

Introduction: People with inherited and long-term conditions such as haemophilia have been shown to adapt to their levels of disability, often reporting better quality of life (QoL) than expected from the general population (the disability paradox).

Aim: To investigate the disability paradox in people with haemophilia in the United States by examining preference differences in health state valuations versus the general population.

Methods: We conducted a discrete choice experiment including duration to capture valuations of health states based on patient-reported preferences. Participants indicated their preferences for hypothetical health states using the EQ-5D-5L, where each participant completed 15 of the 120 choice tasks. Response inconsistencies were evaluated with dominated and repeated scenarios. Conditional-logit regressions with random sampling of the general population responses were used to match the sample of patients with haemophilia. We compared model estimates and derived preferences associated with EQ-5D-5L health states.

Results: After removing respondents with response inconsistencies, 1327/2138 (62%) participants remained (177/283 haemophilia; 1150/1900 general population). Patients with haemophilia indicated higher preference value for 99% of EQ-5D-5L health states compared to the general population (when matched on age and gender). The mean health state valuation difference of 0.17 indicated a meaningful difference compared to a minimal clinically important difference threshold of 0.07. Results were consistent by haemophilia type and severity.

Conclusion: Our findings indicated the presence of a disability paradox among patients with haemophilia, who reported higher health states than the general population, suggesting the impact of haemophilia may be underestimated if general population value sets are used.
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http://dx.doi.org/10.1111/hae.14278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048516PMC
March 2021

Adult lifetime cost of hemophilia B management in the US: payer and societal perspectives from a decision analytic model.

J Med Econ 2021 Jan-Dec;24(1):363-372

American Thrombosis and Hemostasis Network, Rochester, NY, USA.

Aims: Hemophilia B (HB) is a rare congenital disorder characterized by bleeding-related complications which are managed by prophylactic or post-bleeding event ("on-demand") replacement of clotting factor IX (FIX). The standard of care for severe HB is life-long prophylaxis with standard half-life (SHL) or extended half-life (EHL) products given every 2-3 or 7-14 days, respectively. FIX treatment costs in the US have been investigated, but the lifetime costs of HB treatment have not been well characterized, particularly related to the impact of joint health deterioration and associated health resource utilization. We developed a decision-analytic model to explore outcomes, costs and underlying cost drivers associated with FIX treatment options over the lifetime of an adult with severe or moderately severe HB.

Materials And Methods: With participation from clinicians, health technology assessment specialists and patient advocates, a Markov model was constructed to estimate bleeding events and costs associated with health states including "bleed into joint", "bleed not into joint", "no bleed" and "death". Sub-models of joint health were based on 0, 1, or ≥2 areas of chronic joint damage. US third-party payer and societal perspectives were considered with a lifetime horizon; sensitivity analyses tested the robustness of primary findings.

Results: Total adult lifetime costs per patient with severe and moderately severe HB were $21,086,607 for SHL FIX prophylaxis, $22,987,483 for EHL FIX prophylaxis, and $20,971,826 for on-demand FIX treatment. For FIX prophylaxis, the cost of FIX treatment accounts for >90% of the total HB treatment costs.

Conclusions: This decision analytic model demonstrated significant economic burden associated with the current HB treatment paradigm.
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http://dx.doi.org/10.1080/13696998.2021.1891088DOI Listing
September 2021

Physical activity and bleeding outcomes among people with severe hemophilia on extended half-life or conventional recombinant factors.

Res Pract Thromb Haemost 2021 Jan 30;5(1):94-103. Epub 2020 Dec 30.

Precision Health Economics and Outcomes Research Los Angeles CA USA.

Background: Few have assessed physical activity (PA) and annual bleed rates (ABRs) among people with hemophilia on extended half-life (EHL) factors (recombinant factor VIII Fc [rFVIIIFc]/recombinant factor IX Fc [rFIXFc]) and conventional factors (recombinant factor VIII [rFVIII]/recombinant factor IX [rFIX]).

Objective: To assess changes in PA and ABR at consecutive annual visits in individuals with severe hemophilia A and B (HA/HB) on prophylactic treatment with rFVIIIFc/rFIXFc versus rFVIII/rFIX.

Patients/methods: We conducted a retrospective chart review of 344 people with severe HA/HB (ages 6-35) receiving prophylaxis with rFVIIIFc/rFIXFc (EHL factors) or rFVIII/rFIX (conventional factors) for ≥6 months in 2014-2015. Differences in changes in outcomes from 2014 to 2015 were compared across the treatment groups.

Results: Baseline characteristics and adherence to the prophylactic regimen were similar across the treatment groups. Greater increase in weekly PA frequency and duration were observed among all EHL groups, except for children treated with rFIXFc. The increase in PA frequency was greater among the children on rFVIIIFc group, adults on rFVIIIFc group, and adults on rFIXFc group by 1.2, 1.2, and 1.4 events/week, respectively, compared to their rFVIII/rFIX counterparts. The increases in PA duration were 44, 60, and 80 min/wk greater among the children on rFVIIIFc, adults on rFVIIIFc, and adults on rFIXFc groups, respectively. Larger reductions in total ABR were observed in children and adults treated with rFVIIIFc compared to rFVIII (0.4 and 0.7 fewer bleeds). Larger reductions were also observed in spontaneous ABR in adult rFVIIIFc and rFIXFc groups (0.8 and 0.3 fewer bleeds, respectively).

Conclusions: This study suggests that rFVIIIFc/FIXFc agents can positively impact PA while maintaining low ABRs.
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http://dx.doi.org/10.1002/rth2.12437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845067PMC
January 2021

Linking water environmental factors and the local watershed landscape to the chlorophyll a concentration in reservoir bays.

Sci Total Environ 2021 Mar 11;758:143617. Epub 2020 Nov 11.

College of Resources and Environment, Huazhong Agricultural University, Wuhan 430070, China. Electronic address:

The frequency of harmful algal blooms caused by eutrophication is increasing globally, posing serious threats to human health and economic development. Reservoir bays, affected by water environment and local watershed landscape, are more prone to eutrophication and algal blooms. The chlorophyll a (Chl a) concentration is an important indicator for the degree of eutrophication and algal bloom. Exploring the complex relationships between water environment and landscape background, and Chl a concentration in the reservoir bays are crucial for ensuring high-quality drinking water from reservoirs. In this study, we monitored Chl a concentrations of 66 bays in Danjiangkou Reservoir and the related water quality parameters (e.g., water temperature, turbidity, nutrients) in waterbodies of these reservoir bays in the storage and discharge periods from 2015 to 2018. Partial least squares-structural equation modeling (PLS-SEM) was used to quantify the relationship between water environmental factors and watershed landscapes, and Chl a concentrations in reservoir bays. The results showed that mean Chl a concentration was higher in storage period than that in discharge period. Two optimal PLS-SEMs explained 66.8% and 53.6% of Chl a concentration variation in the storage and discharge periods, respectively. The net effect of water chemistry on Chl a concentration was more pronounced during the discharge period (total effect = 0.61, 37% of the total effect on Chl a), while the net effect of land-use composition on Chl a concentration was more significant during the storage period (total effect = 0.57, 30% of the total effect on Chl a). The landscape pattern had significant indirect effects on Chl a concentration, especially during the discharge period (indirect effect = -0.31, 19% of the total effect on Chl a). Our results provide valuable information for managers to make rational decisions, thereby contributing to the prevention of eutrophication and algal blooms in reservoir bays.
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http://dx.doi.org/10.1016/j.scitotenv.2020.143617DOI Listing
March 2021

Patient and caregiver preferences for haemophilia A treatments: A discrete choice experiment.

Haemophilia 2020 Nov 16;26(6):e291-e299. Epub 2020 Sep 16.

Sanofi Genzyme, Bridgewater, NJ, USA.

Introduction: Long-acting products are changing the haemophilia A treatment landscape by giving patients and caregivers treatment options with varying product attributes.

Aim: A discrete choice experiment (DCE) was used to elicit treatment attribute preferences among patients with haemophilia A and caregivers of children with haemophilia A.

Materials & Methods: A survey of sociodemographics and preferences was completed by an online panel of adult patients with haemophilia A and caregivers of children (<18 years) with haemophilia A. The DCE included a series of questions in which respondents chose their preferred option from pairs of hypothetical treatment profiles with systematic variation in the levels of six attributes (safety concerns with too much clotting, bleed protection, dosing frequency, length of time the product has been approved for use, product type and joint health studies). Preference weights and relative attribute importance scores were estimated using random parameters logit models.

Results: One hundred and thirteen patients (mean age: 35.5 years) and 96 caregivers (mean age of child: 10.3 years) were included. For patients with haemophilia A, the top three attributes ranked from the most to least important were: (a) dosing frequency; (b) bleed protection; and (c) safety concerns with too much clotting. For caregivers of children with haemophilia A, the ranking was as follows: (a) safety concerns; (b) bleed protection; and (c) dosing.

Conclusions: Patients with haemophilia A viewed dosing as the most important driver of treatment decision-making whereas caregivers of children with haemophilia A valued safety the most.
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http://dx.doi.org/10.1111/hae.14137DOI Listing
November 2020

The scientific elucidation of medicinal materials.

Chin Med 2020 20;15:86. Epub 2020 Aug 20.

Research Center for Traditional Chinese Medicine of Lingnan (Southern China), Jinan University, Guangzhou, 510632 China.

medicinal materials (DMMs), with unique characteristics and specific ecological growing environments, are recognized as high-quality medicinal products of Chinese medicinal materials (CMMs). The quality evaluation of CMMs is fundamental for standardization. The concept and application of DMMs have a long history as described in records in ancient books and rooted in practice and experience over generations. DMM is the specific term for pure, superior medicinal herbs with the following characteristics: optimum harvest season (reflecting the appropriate developmental stage of the plant), scrupulous processing, traditional preparation technology, etc. As DMM and high-quality medicinal products are traditionally thought to be closely related, modern scientific studies that confirm the association of these products are described. This article aims to clarify the scientific elucidation of DMMs.
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http://dx.doi.org/10.1186/s13020-020-00367-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439724PMC
August 2020

Efficacy and Tolerability of Pyrazolo[1,5-]pyrimidine RET Kinase Inhibitors for the Treatment of Lung Adenocarcinoma.

ACS Med Chem Lett 2020 Apr 12;11(4):558-565. Epub 2020 Feb 12.

The Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.

RET (REarranged during Transfection) kinase gain-of-function aberrancies have been identified as potential oncogenic drivers in lung adenocarcinoma, along with several other cancer types, prompting the discovery and assessment of selective inhibitors. Internal mining and analysis of relevant kinase data informed the decision to investigate a pyrazolo[1,5-]pyrimidine scaffold, where subsequent optimization led to the identification of compound WF-47-JS03 (), a potent RET kinase inhibitor with >500-fold selectivity against KDR (Kinase insert Domain Receptor) in cellular assays. In subsequent mouse studies, compound demonstrated effective brain penetration and was found to induce strong regression of RET-driven tumor xenografts at a well-tolerated dose (10 mg/kg, po, qd). Higher doses of , however, were poorly tolerated in mice, similar to other pyrazolo[1,5-]pyrimidine compounds at or near the efficacious dose, and indicative of the narrow therapeutic windows seen with this scaffold.
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http://dx.doi.org/10.1021/acsmedchemlett.0c00015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7153282PMC
April 2020

Chromatographic fingerprints analysis and determination of seven components in Danmu preparations by HPLC-DAD/QTOF-MS.

Chin Med 2020 18;15:19. Epub 2020 Feb 18.

1College of Pharmacy, Lingnan Traditional Chinese Medicine Research Center of Jinan University, Lingnan Branch of National Engineering Research Center for Modernization of Traditional Chinese Medicine, Jinan University, Guangzhou, 510632 Guangdong China.

Background: Danmu preparations (Danmu Capsule and Danmu Syrup), which are made from stem extracts, have good clinical efficacy in acute tonsillitis, acute pharyngitis and upper respiratory tract infection. However, there is currently no reliable and systematic method to control the quality of these two Danmu preparations.

Methods: Using high-performance liquid chromatography (HPLC) coupled with diode array detection (DAD), the fingerprints of the Danmu preparations were established at 250 nm to comprehensively investigate the stability of preparation process. The chemical constituents in the Danmu preparations were separated and identified by HPLC coupled with quadrupole-time-of-flight high-definition mass spectrometry (HPLC-Q-TOF-MS). And seven major components were simultaneously determined at dual wavelengths (250 nm, 326 nm).

Results: The results of HPLC fingerprint similarity evaluation showed that the similarity values of 25 batches of Danmu preparations were more than 0.993. Twenty-three compounds, including 10 alkaloids, 6 phenolic acids, 2 iridoids, and 5 unknown compounds, were identified or tentatively characterized according to the retention times and MS/MS fragment patterns of compounds. The developed assay method of seven components was validated with acceptable linearity, precision, repeatability, stability and recovery. The contents of strictosamide belonging to alkaloids as the most abundant constituent in Danmu Capsule and Danmu Syrup were 43,681.20-99,652.49 μg/g and 1567.83-2427.25 μg/mL respectively. The contents of protocatechuic acid which were the highest in measured phenolic acids were 2633.01-7739.78 μg/g in Danmu Capsule and 192.05-448.71 μg/mL in Danmu Syrup, respectively. As an iridoid, the contents of sweroside in Danmu Capsule and Danmu Syrup were 1573.82-2789.81 μg/g and 70.32-182.81 μg/mL, respectively.

Conclusion: The established qualitative analysis method of fingerprint can be used to attain standardization, uniformity and stability of the preparation process. Meanwhile, the quantitative analysis in this study can be used as an accurate assay method for preparations.
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http://dx.doi.org/10.1186/s13020-020-00301-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027017PMC
February 2020

Cost-Effectiveness Analysis of Recombinant Factor VIII Fc-Fusion Protein (rFVIIIFc) for the Treatment of Severe Hemophilia A in Italy Incorporating Real-World Dosing and Joint Health Data.

Pharmacoecon Open 2020 Mar;4(1):133-142

Swedish Orphan Biovitrum AB (publ), 112 76, Stockholm, Sweden.

Background: Patients with severe hemophilia A (SHA) in Italy are routinely treated with standard half-life recombinant factor VIII (rFVIII) products. rFVIII Fc-fusion protein (rFVIIIFc) is an extended half-life rFVIII product that enables less frequent administration than rFVIII, which may support improved adherence. Available data indicate low breakthrough bleed rates and potentially improved long-term joint health for patients treated with rFVIIIFc prophylaxis.

Objective: This study assessed the cost effectiveness of rFVIIIFc versus rFVIII from an Italian healthcare perspective.

Methods: A Semi-Markov model was constructed to assess the lifetime costs and benefits of rFVIII and rFVIIIFc prophylaxis. rFVIII product acquisition costs from a published Italian database were included for both prophylaxis and the resolution of breakthrough bleeding. Clinical outcomes within the model were determined based on published annualized bleeding rates and literature regarding the development of target joints (TJs) as the incidence of bleeds and TJs is associated with impaired health-related quality of life. Cost effectiveness was assessed using cost per quality-adjusted life-year (QALY) gained.

Results: Compared with rFVIII, rFVIIIFc was associated with a per-patient cost saving of approximately €1.3 million and QALY gains of 0.39 over a lifetime horizon. Sensitivity analyses considering alternative efficacy, dosing, and structural assumptions each showed that rFVIIIFc dominated rFVIII (i.e., provided more QALYs at a reduced cost).

Conclusions: This cost-effectiveness analysis demonstrated that rFVIIIFc may offer a cost-effective treatment option for patients with SHA in Italy.
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http://dx.doi.org/10.1007/s41669-019-0158-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018914PMC
March 2020

Clinical burden and healthcare resource utilization among patients with chronic hypoparathyroidism, overall and by adequately vs not adequately controlled disease: a multi-country chart review.

J Med Econ 2019 Nov 17;22(11):1141-1152. Epub 2019 Jun 17.

Healthcare Practice, Analysis Group Inc , Los Angeles , CA , USA.

To assess the real-world clinical burden and healthcare resource utilization (HRU) among patients with chronic hypoparathyroidism, overall and by adequately controlled (AC) vs not adequately controlled (NAC) disease, informed by guideline-recommended clinical management targets, including biochemistry and symptoms. In this retrospective online chart review, endocrinologists in the US, Canada, the UK, France, Germany, Italy, and Spain were randomly selected to review the medical charts of adult patients with chronic hypoparathyroidism receiving calcium and activated vitamin D. Patients' demographics, disease characteristics, symptoms, comorbidities, and hypoparathyroidism-related HRU during the 1 year before the review date were assessed. Clinical burden and HRU were compared between patients with NAC and AC hypoparathyroidism. Of 614 patients with hypoparathyroidism (AC, N = 442; NAC, N = 172), the mean age was 43.6 years, and the majority were female (61.6%), Caucasian (78.8%), and had post-surgical hypoparathyroidism (74.4%). Mean duration of hypoparathyroidism was 46.0 months. Hypoparathyroidism-related symptoms and comorbidities were reported in 59.4% and 46.7% of patients, respectively; 90.7% of patients had ≥1 hypoparathyroidism-related HRU event. More patients with NAC (57.6%) vs AC (42.5%) hypoparathyroidism experienced ≥1 comorbidity including calcium/phosphate imbalances, and brain, cardiovascular, metabolic, and renal disorders (all  < 0.01). More patients with NAC vs AC hypoparathyroidism incurred ≥1 hypoparathyroidism-related hospitalization (27.9% vs 16.3%) and emergency room visits (47.7% vs 38.5%), and patients with NAC vs AC hypoparathyroidism had a higher number of outpatient visits (3.6 vs 2.6; all  < 0.05), in the 1-year observation period. Limitations of this online chart review include possible under-estimation of disease burden, limited sample size, and the inability to rule out selection bias. Findings indicate that patients with chronic hypoparathyroidism experience substantial symptomatic and comorbid burdens resulting in frequent HRU, suggesting an unmet need, particularly in NAC disease.
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http://dx.doi.org/10.1080/13696998.2019.1624081DOI Listing
November 2019

Cost Effectiveness of Midostaurin in the Treatment of Newly Diagnosed FLT3-Mutated Acute Myeloid Leukemia in the United States.

Pharmacoeconomics 2019 02;37(2):239-253

Novartis Pharmaceuticals Corporation, 1 Health Plaza, East Hanover, NJ, 07936, USA.

Objectives: The aim of this study was to assess the cost effectiveness of midostaurin + cytarabine + daunorubicin (midostaurin arm) versus placebo + cytarabine + daunorubicin (placebo arm) in the treatment of adult patients with newly diagnosed FLT3-mutated acute myeloid leukemia (AML) who are eligible for standard cytarabine + daunorubicin chemotherapy, from a US third-party payer perspective.

Methods: A lifetime partitioned survival model with four health states (active disease, complete remission [CR], relapse, and death) was constructed. Efficacy inputs (time to CR or death, time to relapse or death, and overall survival) were estimated using data from the RATIFY trial (NCT00651261). Costs (inflated to 2016 US dollars) included treatment, drug monitoring, stem cell transplantation (SCT), adverse events costs, and medical costs associated with health states. Incremental costs per quality-adjusted life-year (QALY) and life-year (LY) gained were estimated. Deterministic (DSA) and probabilistic sensitivity analyses (and PSA) were performed to assess model robustness.

Results: In the base case, patients in the midostaurin arm incurred higher total direct costs over a lifetime compared with the placebo arm ($4,043,470 vs. $3,959,741), resulting in an incremental cost of $83,729; however, the midostaurin arm had better effectiveness, with 1.59 more LYs and 1.37 more QALYs. These led to a base-case incremental cost-effectiveness ratio (ICER) of $52,596 per LY, or $61,167 per QALY. Results were robust in the DSA. In the PSA, the probability of the midostaurin arm being cost-effective compared with the placebo arm was 65.9%, at a willingness to pay of $150,000/QALY.

Conclusions: This analysis suggests that midostaurin is a cost-effective treatment for adult patients with newly diagnosed FLT3-mutated AML, from a US third-party payer perspective.
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http://dx.doi.org/10.1007/s40273-018-0732-4DOI Listing
February 2019

Real-World Economic Outcomes During Time on Treatment Among Patients Who Initiated Sunitinib or Pazopanib as First Targeted Therapy for Advanced Renal Cell Carcinoma: A Retrospective Analysis of Medicare Claims Data.

J Manag Care Spec Pharm 2018 Jun;24(6):525-533

5 Huntsman Cancer Institute, University of Utah, Salt Lake City.

Background: The median age at renal cell carcinoma (RCC) diagnosis is 64 years. However, few studies have assessed the real-world time on treatment (TOT), health resource utilization (HRU), costs, or treatment compliance associated with targeted therapy use among patients in this age group with RCC.

Objective: To assess the HRU, costs, and compliance during TOT among Medicare patients aged ≥ 65 years with advanced RCC (aRCC) who initiated first targeted therapy with pazopanib or sunitinib.

Methods: Patients with aRCC were identified in the 100% Medicare + Part D databases administered by the Centers for Medicare & Medicaid Services. Eligible patients initiated first targeted therapy with sunitinib or pazopanib (index drug) on or after their first diagnosis of secondary neoplasm between October 19, 2009, and January 1, 2014, and were aged ≥ 65 years as of 1 year before first targeted therapy initiation (index date). Included patients were stratified into pazopanib and sunitinib cohorts based on first targeted therapy and matched 1:1 on baseline characteristics using propensity scores. TOT was defined as the time from the index date to treatment discontinuation (prescription gap > 90 days) or death. Compliance was defined as the ratio of drug supply days to TOT. Monthly all-cause costs and costs associated with RCC diagnosis (medical and pharmacy in 2015 U.S. dollars) and HRU (inpatient [admissions, readmissions, and days], outpatient, and emergency room visits) were assessed in the 1-year post-index period during TOT. Matched cohorts' TOT was compared using Kaplan-Meier analyses and univariable Cox models, and compliance, HRU, and costs were compared using Wilcoxon signed-rank tests.

Results: Of 1,711 included patients, 526 initiated pazopanib and 1,185 initiated sunitinib. Before matching, more patients in the pazopanib cohort were white, diagnosed in 2010-2014 versus 2006-2009, and had lung metastases compared with the sunitinib cohort (all P < 0.05). The pazopanib cohort also had higher mean outpatient visits and costs but lower mean total all-cause pharmacy costs, than the sunitinib cohort (all P < 0.05). After matching, the pazopanib and sunitinib cohorts had similar characteristics (mean age 75 years, 58% male, and Charlson Comorbidity Index score of 9.2 in both cohorts) and median TOT (4.8 and 4.1 months, respectively). Among the 522 matched pairs, pazopanib was associated with significantly lower total all-cause health care costs ($8,527 vs. $10,924, respectively [mean difference = $2,397]); total medical costs ($3,991 vs. $5,881, respectively, [$1,890]); and inpatient costs ($2,040 vs. $3,731, respectively, [$1,692]; all P < 0.01) compared with sunitinib. Patients receiving pazopanib had significantly fewer inpatient admissions (0.179 vs. 0.289, respectively) and days (1.063 vs. 1.904, respectively; both P < 0.01) than patients receiving sunitinib. Mean treatment compliance was lower for the pazopanib versus sunitinib cohort (0.91 vs. 0.94, respectively; P < 0.01).

Conclusions: In this retrospective analysis of Medicare patients with aRCC from a TOT perspective, first targeted therapy with pazopanib was associated with significantly lower all-cause health care costs and HRU, but lower compliance, compared with sunitinib.

Disclosures: Funding for this research was provided by Novartis Pharmaceuticals. The sponsor was involved in all stages of the study's conduct and reporting. Vogelzang has been a consultant for Novartis, Amgen, Celgene, Medivation, Eisai, Exelixis, and Roche; has spoken at Novartis, Astellas, Johnson and Johnson, Pfizer, Dendreon, Bayer/Algeta, GSK, and Veridex/Janssen; and has received research support from Novartis, Bayer, Exelixis, Progenics, Bavarian Nordic, and Viamet. Pal has been a consultant for Novartis, Pfizer, Aveo, Dendreon, and Myriad and has spoken at Novartis, Pfizer and Medivation. Agarwal has been a consultant or advisor for Novartis, Pfizer, Exelixis, Cerulean Pharma, Medivation, Eisai, and Argos Therapeutics. Swallow, Peeples, Zichlin, and Meiselbach are employees of Analysis Group, which received consultancy fees from Novartis for this project. Li was an employee of Analysis Group during the conduct of this study. Ghate is an employee of Novartis and owns stock/stock options. Perez was an employee of Novartis during the conduct of this study. A synopsis of the economic outcomes was presented at the Academy of Managed Care Pharmacy Nexus 2017 in Denver, Colorado, during March 27-30, 2017. A synopsis of the clinical outcomes was presented at the 22nd ISPOR Annual International Meeting in Boston, Massachusetts, during May 20-24, 2017.
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http://dx.doi.org/10.18553/jmcp.2018.24.6.525DOI Listing
June 2018

Real-world persistence with fingolimod for the treatment of multiple sclerosis: A systematic review and meta-analysis.

J Neurol Sci 2018 05 10;388:168-174. Epub 2018 Mar 10.

Novartis Pharmaceuticals Corporation, 1 Health Plaza, East Hanover, NJ 07936, USA.

Objective: To systematically review reports of fingolimod persistence in the treatment of relapsing-remitting multiple sclerosis (RRMS) across data sources and practice settings, and to develop a consensus estimate of the 1-year real-world persistence rate.

Methods: A systematic literature review was conducted (MEDLINE, EMBASE, and abstracts from selected conferences [2013-2015]) to identify observational studies reporting 1-year fingolimod persistence among adult patients with RRMS (sample size ≥50). A random-effects meta-analysis was performed to estimate a synthesized 1-year persistence rate and to assess heterogeneity across studies.

Results: Of 527 publications identified, 25 real-world studies reporting 1-year fingolimod persistence rates were included. The studies included patients from different data sources (e.g., administrative claims, electronic medical records, or registries), used different definitions of persistence (e.g., based on prescriptions refills, patient report, or prescription orders), and spanned multiple geographic regions. Reported 1-year persistence rates ranged from 72%-100%, and exhibited statistical evidence of heterogeneity (I = 93% of the variability due to heterogeneity across studies). The consensus estimate of the 1-year persistence rate was 82% (95% confidence interval: 79%-85%).

Conclusions: Across heterogeneous study designs and patient populations found in real-world studies, the consensus 1-year fingolimod persistence rate exceeded 80%, consistent with persistence rates identified in the recently-completed trial, PREFERMS.
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http://dx.doi.org/10.1016/j.jns.2018.03.018DOI Listing
May 2018

Real-world utilization of molecular diagnostic testing and matched drug therapies in the treatment of metastatic cancers.

J Med Econ 2018 Jun 19;21(6):543-552. Epub 2018 Jan 19.

b Analysis Group, Inc. , Boston , MA , USA.

Aims: To assess the frequency of biopsies and molecular diagnostic testing (human DNA/RNA analysis), anti-cancer drug use (genomically-matched targeted therapy [GMTT], unmatched targeted therapy [UTT], endocrine therapy [ET], and chemotherapy [CT]), and medical service costs among adults with metastatic cancer.

Methods: Adults diagnosed with metastatic breast, non-small cell lung (NSCLC), colorectal, head and neck, ovarian, and uterine cancer (2010Q1-2015Q1) were identified in the OptumHealth Care Solutions claims database and followed from first metastatic diagnosis for ≥1 month and until the end of data availability. Utilization was assessed for each cancer cohort (all and patients aged ≥65 years); per-patient-per-month (PPPM) medical service costs were assessed for all patients. Testing frequency estimates were applied to Surveillance, Epidemiology, and End Results Program data to estimate the number of untested patients (2010-2014).

Results: Patients with metastatic cancer (n = 8,193; breast [n = 3,414], NSCLC [n = 2,231], colorectal [n = 1,611], head and neck [n = 511], ovarian [n = 275], and uterine [n = 151]) were 63 years old (mean), with 11.1-22.2 months of observation. Biopsy and molecular diagnostic testing frequencies ranged from 7% (uterine) to 73% (ovarian), and from 34% (head and neck) to 52% (breast), respectively. Few were treated with GMTT (breast, 11%; NSCLC, 9%; colorectal, 6%). Treatment with UTT ranged from 0.7% (uterine) to 21% (colorectal). Biopsy, diagnostic testing, and anti-cancer drug therapy were less frequent for those ≥65 years. Medical service costs (PPPM, mean) ranged from $6,618 (head and neck) to $9,940 (ovarian). The estimated number of untested new patients with metastatic cancer was 636,369 (all) and 341,397 (≥65).

Limitations: In addition to the limitations of claims analyses, diagnostic testing frequency may be under-estimated if patients underwent testing prior to study inclusion.

Conclusions: The low frequency of molecular diagnostic testing suggests there are opportunities to better inform management of patients with advanced cancer, particularly decisions to treat with GMTT.
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http://dx.doi.org/10.1080/13696998.2017.1423488DOI Listing
June 2018

Clinical and Economic Outcomes in Elderly Advanced Renal Cell Carcinoma Patients Starting Pazopanib or Sunitinib Treatment: A Retrospective Medicare Claims Analysis.

Adv Ther 2017 11 26;34(11):2452-2465. Epub 2017 Oct 26.

Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT, USA.

Introduction: Studies indicate similar survival and toxicity between pazopanib and sunitinib, but few have examined real-world outcomes among elderly patients with advanced renal cell carcinoma (RCC). The purpose of this retrospective claims analysis was to assess real-world overall survival (OS), healthcare resource utilization (HRU), and healthcare costs (both all-cause and associated with RCC diagnosis) among elderly advanced RCC patients starting pazopanib or sunitinib treatment.

Methods: Advanced RCC patients aged 65 years or older who started first-line treatment with pazopanib or sunitinib (index drug; the initiation date was the index date) were identified from the 100% Medicare database plus Part D linkage (January 1, 2006 to December 31, 2014). Patients were stratified by index drug and matched 1:1 with use of propensity scores based on baseline characteristics. OS was assessed from the index date to death and compared by Kaplan-Meier analyses and univariable Cox models; patients were censored at the end of eligibility/data. Monthly HRU and costs from an intent-to-treat perspective were compared by Wilcoxon signed-rank tests.

Results: Baseline characteristics were balanced after matching (both N = 522). Treatment with pazopanib was associated with significantly longer median OS compared with treatment with sunitinib (18.2 months vs 14.6 months, respectively; log-rank p = 0.015). Pazopanib was associated with significantly lower monthly all-cause costs compared with sunitinib ($8845 vs $10,416, respectively), as well as lower inpatient costs associated with RCC diagnosis ($1542 vs $2522), fewer monthly inpatient admissions (0.179 vs 0.262), and shorter length of inpatient stay (1.375 days vs 1.883 days; all p ≤ 0.004).

Conclusions: Among elderly Medicare patients with advanced RCC, first-line pazopanib tretament was associated with significantly longer OS, as well as lower healthcare costs and HRU, compared with first-line sunitinib treatment.
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http://dx.doi.org/10.1007/s12325-017-0628-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5702370PMC
November 2017

First-line treatment disruption among post-menopausal women with HR+/HER2- metastatic breast cancer: a retrospective US claims study.

Curr Med Res Opin 2017 12 27;33(12):2137-2143. Epub 2017 Oct 27.

d VEB HealthCare LLC , Morristown , NJ , USA.

Objective: This study assessed disruption of first-line treatments initiated after the approval of the first CDK 4/6 inhibitor, palbociclib, among post-menopausal women with HR+/HER2- metastatic breast cancer (mBC) in the US.

Methods: Post-menopausal women with HR+/HER2- mBC who initiated first-line endocrine therapy or chemotherapy (index therapy) between February 3, 2015 (palbociclib approval date) and February 29, 2016 (end of data) were identified from the Symphony Source Lx database. Patients were required to have continuous quarterly activity (defined as ≥1 pharmacy or medical claim) for 12 months prior to and 1 month after the initiation of the index therapy (index date). Treatment disruption was defined as a treatment gap of ≥60 days or adding an agent after the original therapy. Kaplan-Meier analyses were conducted to estimate treatment disruption rates during the 6 months following the index date. Patients without treatment disruption were censored at the end of continuous quarterly activity or end of data.

Results: A total of 8,160 and 2,153 eligible patients initiated endocrine therapy or chemotherapy as their first-line mBC treatment, with a median follow-up of 6.7 and 7.6 months, respectively. The three most prevalent metastatic sites were bone (28.1-42.2%), liver (8.8-17.3%), and lung (8.6-9.5%). Overall, 37.7% (n = 3,074) of patients receiving endocrine therapy and 86.1% (n = 1,852) of patients receiving chemotherapy encountered treatment disruption at 6 months (log-rank test p < .05).

Conclusions: Treatment disruption rates of first-line therapies were sub-optimal among post-menopausal women with HR+/HER2- mBC, primarily driven by chemotherapy users. New therapies or interventions are needed to reduce treatment disruption in this patient population.
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http://dx.doi.org/10.1080/03007995.2017.1390447DOI Listing
December 2017

Real-world Effectiveness of Biologic Disease-modifying Antirheumatic Drugs for the Treatment of Rheumatoid Arthritis After Etanercept Discontinuation in the United Kingdom, France, and Germany.

Clin Ther 2017 Aug 17;39(8):1618-1627. Epub 2017 Jul 17.

AbbVie Inc, North Chicago, Illinois. Electronic address:

Purpose: The purpose of this study was to assess the real-world effectiveness of patients with rheumatoid arthritis (RA) who discontinued etanercept treatment and subsequently received another tumor necrosis factor α (TNF-α) inhibitor or a non-TNF-α biologic in the United Kingdom, France, and Germany.

Methods: Medical record data of patients with RA were collected from a panel of rheumatologists in the United Kingdom, France, and Germany. Patients were required to have a diagnosis of RA, be ≥18 years old, and have initiated use of another TNF-α inhibitor (adalimumab, certolizumab pegol, golimumab, or infliximab) or a non-TNF-α biologic (abatacept or tocilizumab) between January 2014 and May 2015 after discontinuing use of etanercept. Reasons for discontinuing use of etanercept and selecting a second biologic disease-modifying antirheumatic drug (DMARD) were described. Study outcomes included European League Against Rheumatism (EULAR) response and change in Clinical Disease Activity Index (CDAI) score. The study outcomes were compared among treatment groups (ie, TNF-α inhibitors and non-TNF-α biologics) using descriptive and multivariable-adjusted analyses. As a secondary analysis, the study outcomes were also descriptively compared between each of the TNF-α inhibitors. Because adalimumab is one of the most commonly used TNF-α inhibitor to treat RA, a secondary analysis was conducted to compare the outcomes among adalimumab, other TNF-α inhibitors, and non-TNF-α inhibitors.

Findings: Patient characteristics before initiating treatment with a second DMARD were similar across treatment groups (all TNF-α inhibitors [n = 296] and non-TNF-α biologics [n = 276]). The most common reasons for discontinuing etanercept treatment were inadequate response, adverse effects, and patient preference. After etanercept, TNF-α inhibitors overall were associated with a significantly lower EULAR good response rate (56.0% vs. 64.4%, P < 0.05) and smaller CDAI score change (-6.3 vs -7.3, P = .06) relative to non-TNF-α biologics. However, the proportion of patients achieving an EULAR good response was numerically higher for adalimumab versus other TNF-α inhibitors (61.1% vs 51.6%, P = 0.11) and comparable versus non-TNF-α biologics (61.1% vs 64.4%, P = 0.52). Adalimumab was also associated with a CDAI score change significantly greater than that of other TNF-α inhibitors (-7.1 vs -5.8, P < 0.05) and comparable to that of non-TNF-α biologics (-7.1 vs -7.3, P = 0.79). The results were consistent in the multivariable-adjusted analysis and secondary analysis.

Implications: In this retrospective analysis of patients with RA in the United Kingdom, France, and Germany, after discontinuation of etanercept treatment, TNF-α inhibitors as a class were overall less effective as second biologic DMARDs relative to non-TNF-α biologics; however, adalimumab was more or as effective as other TNF-α inhibitors and non-TNF-α biologics.
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http://dx.doi.org/10.1016/j.clinthera.2017.06.009DOI Listing
August 2017

Real-world palbociclib dosing patterns and implications for drug costs in the treatment of HR+/HER2- metastatic breast cancer.

Expert Opin Pharmacother 2017 Aug 19;18(12):1167-1178. Epub 2017 Jul 19.

d Novartis Pharmaceuticals Corporation , East Hanover , NJ , USA.

Background: This study described real-world palbociclib dosing patterns and associated impacts on treatment costs for HR+/HER2- metastatic breast cancer (mBC) in the US.

Methods: Postmenopausal women with HR+/HER2- mBC who initiated palbociclib-based therapy (initiation date = index date) between 02/03/2015 (palbociclib approval) and 02/29/2016, and continuous quarterly activity 1 year before and 6 months after the index date, were identified in the Symphony Health Solutions database. Rates of 1) dose reduction (≥25 mg dose decrease/daily), and 2) reduction or interruption (>60 day gap in continuous drug supply) were assessed using Kaplan-Meier analyses. Drug wastage cost was estimated based on overlapping days between two prescription fills: the last original dose fill and the first reduced dose fill.

Results: 1,242 patients initiated palbociclib-based therapy (mean age = 62.7 years, median follow-up = 8.7 months). During the 12-month post-index period, across the first four lines, dose reduction rates were 31.9-33.7% and dose reduction/interruption rates were 63.5-80.9%. A total of 411 (33.1%) patients changed dose, among whom 128 (31.1%) experienced prescription fill overlap (average = 11.1 days). Mean potential drug wastage cost among patients with fill overlap was $5,471.

Conclusions: Most patients receiving palbociclib experienced dose reduction or interruption early in treatment; the associated drug wastage may lead to considerable costs.
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http://dx.doi.org/10.1080/14656566.2017.1351947DOI Listing
August 2017

Combined ALK and MDM2 inhibition increases antitumor activity and overcomes resistance in human mutant neuroblastoma cell lines and xenograft models.

Elife 2017 04 20;6. Epub 2017 Apr 20.

Disease Area Oncology, Novartis Institutes for BioMedical Research, Cambridge, United States.

The efficacy of ALK inhibitors in patients with -mutant neuroblastoma is limited, highlighting the need to improve their effectiveness in these patients. To this end, we sought to develop a combination strategy to enhance the antitumor activity of ALK inhibitor monotherapy in human neuroblastoma cell lines and xenograft models expressing activated ALK. Herein, we report that combined inhibition of ALK and MDM2 induced a complementary set of anti-proliferative and pro-apoptotic proteins. Consequently, this combination treatment synergistically inhibited proliferation of wild-type neuroblastoma cells harboring amplification or mutations in vitro, and resulted in complete and durable responses in neuroblastoma xenografts derived from these cells. We further demonstrate that concurrent inhibition of MDM2 and ALK was able to overcome ceritinib resistance conferred by MYCN upregulation in vitro and in vivo. Together, combined inhibition of ALK and MDM2 may provide an effective treatment for wild-type neuroblastoma with aberrations.
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http://dx.doi.org/10.7554/eLife.17137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435462PMC
April 2017

A Risk Score for Fluconazole Failure among Patients with Candidemia.

Antimicrob Agents Chemother 2017 05 24;61(5). Epub 2017 Apr 24.

Analysis Group, Inc., Boston, Massachusetts, USA.

This study aimed to develop a prediction model to identify patients with candidemia who were at high risk of failing fluconazole treatment. Adult patients in the United States with candidemia who received fluconazole during hospitalization were selected from the Cerner Health Facts Hospital Database (04/2004 to 03/2013). Fluconazole failure was defined as switching/adding another antifungal, positive culture ≥10 days after fluconazole initiation, or death during hospitalization. Patients were randomized into modeling and validation samples. Using the modeling sample, a regression analysis of least absolute shrinkage and selection operator was used to select risk predictors of fluconazole failure (demographics, species, initiation of fluconazole before positive culture and after admission, and comorbidities, procedures, and treatments during the 6 months before admission and fluconazole initiation). The prediction model was evaluated using the validation sample. We found that of 987 identified patients (average age of 61 years, 51% male, 72% Caucasian), 49% failed and 51% did not fail fluconazole treatment. Of those who failed, 70% switched or added another antifungal, 21% had a second positive test, and 42% died during hospitalization. Nine risk factors were included in the prediction model: days to start fluconazole after admission, or infection, hematological malignancy, venous thromboembolism (VTE), enteral nutrition, use of nonoperative intubation/irrigation, and other antifungal use. All but VTE were associated with a higher risk of failure. The model's c-statistic was 0.65, with a Hosmer-Lemeshow test value of 0.23. In summary, this prediction model identified patients with a high risk of fluconazole failure, illustrating the potential value and feasibility of personalizing candidemia treatment.
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http://dx.doi.org/10.1128/AAC.02091-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5404593PMC
May 2017

Patterns of care among patients receiving sequential targeted therapies for advanced renal cell carcinoma: A retrospective chart review in the USA.

Int J Urol 2017 04 2;24(4):272-278. Epub 2017 Mar 2.

US Oncology Research, Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada, USA.

Objectives: To assess real-world treatment patterns of targeted therapies after failure of first-line tyrosine kinase inhibitors in patients with advanced renal cell carcinoma.

Methods: A large, retrospective review of medical charts of patients with advanced renal cell carcinoma in the USA was carried out. Descriptive statistics were used to summarize physicians' and patients' characteristics, treatment sequences, and reasons for treatment choices. P-values were calculated using χ -tests for categorical variables and Wilcoxon rank-sum tests for continuous variables. A descriptive comparison was carried out between current results and those of a previous treatment pattern study conducted in 2012 to identify changes in treatment patterns over time.

Results: Sunitinib and everolimus remained the most commonly-used first and second targeted therapies, respectively. Among patients who continued to a third targeted therapy, everolimus and axitinib were the most commonly-used treatments after second targeted therapy with a tyrosine kinase inhibitor and a mammalian target of rapamycin inhibitor, respectively. The use of pazopanib as first targeted therapy, and of axitinib and sorafenib as second targeted therapies, increased over time. Efficacy, treatment guidelines and a different mechanism of action were the main reasons given by physicians for choosing among second targeted therapies after failure of a first tyrosine kinase inhibitor.

Conclusions: The results of the present study document patterns of care during a period of rapid and ongoing therapeutic advancement in advanced renal cell carcinoma. Sequencing of therapies warrants ongoing analysis in light of new agents entering the advanced renal cell carcinoma treatment landscape.
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http://dx.doi.org/10.1111/iju.13314DOI Listing
April 2017

Real-World Survival Outcomes and Prognostic Factors Among Patients Receiving First Targeted Therapy for Advanced Renal Cell Carcinoma: A SEER-Medicare Database Analysis.

Clin Genitourin Cancer 2017 08 5;15(4):e573-e582. Epub 2017 Jan 5.

US Oncology Research, Comprehensive Centers of Nevada, Las Vegas, NV.

Background: The real-world survival outcomes and prognostic factors among patients receiving first-line targeted therapy for advanced renal cell carcinoma (aRCC) are not well known.

Patients And Methods: Adult patients diagnosed with RCC and treated with first-line targeted therapy were identified from the Surveillance, Epidemiology, and End Results-Medicare database (January 1, 1993 to December 31, 2012). The patients were grouped into early (2006-2009) or late (2010-2012) targeted therapy era cohorts by the year of the first-line targeted therapy initiation. Overall survival (OS) was measured from first-line targeted therapy initiation and compared between the 2 cohorts using Kaplan-Meier analyses. The prognostic factors for OS were assessed using a multivariable-adjusted Cox model.

Results: A total of 604 and 641 aRCC patients (mean age, 68 years; ∼60% male in both cohorts) initiated first-line targeted therapy during the early and late targeted therapy eras, respectively. OS was significantly longer in the late than in the early targeted therapy era. Higher tumor grades (hazard ratio [HR], 1.61; 95% confidence interval [CI], 1.31-2.00) and lung (HR, 1.27; 95% CI, 1.06-1.53), bone (HR, 1.37; 95% CI, 1.13-1.66), and liver (HR, 1.42; 95% CI, 1.10-1.84) metastases were associated with significantly shorter OS. Previous nephrectomy (HR, 0.55; 95% CI, 0.42-0.72) and pazopanib as first-line targeted therapy relative to sorafenib (HR, 0.56; 95% CI, 0.37-0.85) or sunitinib (HR, 0.65; 95% CI, 0.44-0.95) were associated with significantly longer OS.

Conclusion: The results of these real-world analyses suggest progress in aRCC management and identified positive (nephrectomy, pazopanib vs. sunitinib or sorafenib) and negative (higher tumor grade and lung, bone, or liver metastasis) prognostic factors among patients receiving first-line targeted therapy.
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http://dx.doi.org/10.1016/j.clgc.2016.12.005DOI Listing
August 2017

Dual and Inhibition Demonstrates Synergy against Neuroblastoma.

Clin Cancer Res 2017 Jun 16;23(11):2856-2868. Epub 2016 Dec 16.

Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Anaplastic lymphoma kinase () is the most frequently mutated oncogene in the pediatric cancer neuroblastoma. We performed an screen for synergistic drug combinations that target neuroblastomas with mutations in to determine whether drug combinations could enhance antitumor efficacy. We screened combinations of eight molecularly targeted agents against 17 comprehensively characterized human neuroblastoma-derived cell lines. We investigated the combination of ceritinib and ribociclib on proliferation, cell cycle, viability, caspase activation, and the cyclin D/CDK4/CDK6/RB and pALK signaling networks in cell lines with representative ALK status. We performed trials in CB17 SCID mice bearing conventional and patient-derived xenograft models comparing ceritinib alone, ribociclib alone, and the combination, with plasma pharmacokinetics to evaluate for drug-drug interactions. The combination of ribociclib, a dual inhibitor of cyclin-dependent kinase (CDK) 4 and 6, and the ALK inhibitor ceritinib demonstrated higher cytotoxicity ( = 0.008) and synergy scores ( = 0.006) in cell lines with mutations as compared with cell lines lacking mutations or alterations in Compared with either drug alone, combination therapy enhanced growth inhibition, cell-cycle arrest, and caspase-independent cell death. Combination therapy achieved complete regressions in neuroblastoma xenografts with -F1174L and F1245C resistance mutations and prevented the emergence of resistance. Murine ribociclib and ceritinib plasma concentrations were unaltered by combination therapy. This preclinical combination drug screen with validation has provided the rationale for a first-in-children trial of combination ceritinib and ribociclib in a molecularly selected pediatric population. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-1114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5457336PMC
June 2017

Nilotinib versus dasatinib as second-line therapy in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase who are resistant or intolerant to imatinib: a cost-effectiveness analysis based on real-world data.

J Med Econ 2017 Apr 2;20(4):328-336. Epub 2016 Dec 2.

c Novartis Pharmaceuticals Corporation , East Hanover , NJ , USA.

Objective: To evaluate the cost-effectiveness of second-line nilotinib vs dasatinib among patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) who are resistant or intolerant to imatinib, from a US third-party perspective.

Methods: A lifetime partitioned survival model was developed to compare the costs and effectiveness of nilotinib vs dasatinib, which included four health states: CP on treatment, CP post-discontinuation, progressive disease (accelerated phase [AP] or blast crisis [BC]), and death. Time on treatment, progression-free survival, and overall survival of nilotinib and dasatinib were estimated using real-world comparative effectiveness data. Parametric survival models were used to extrapolate outcomes beyond the study period. Drug treatment costs, medical costs, and adverse event costs were obtained from the literature and publicly available databases. Utilities of health states were derived from the literature. Incremental cost-effectiveness ratios, including incremental cost per life-year (LY) gained and incremental cost per quality-adjusted life-year (QALY) gained, were estimated comparing nilotinib and dasatinib. Deterministic sensitivity analyses were performed by varying patient characteristics, cost, and utility inputs.

Results: Over a lifetime horizon, nilotinib-treated patients were associated with 11.7 LYs, 9.1 QALYs, and a total cost of $1,409,466, while dasatinib-treated patients were associated with 9.5 LYs, 7.3 QALYs, and a total cost of $1,422,122. In comparison with dasatinib, nilotinib was associated with better health outcomes (by 2.2 LYs and 1.9 QALYs) and lower total costs (by $12,655). Deterministic sensitivity analysis results showed consistent findings in most scenarios.

Limitations: In the absence of long-term real-world data, the lifetime projection could not be validated.

Conclusions: Compared with dasatinib, second-line nilotinib was associated with better life expectancy, better quality-of-life, and lower costs among patients with Ph+ CML-CP who were resistant or intolerant to imatinib.
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http://dx.doi.org/10.1080/13696998.2016.1261032DOI Listing
April 2017

Matching-adjusted indirect comparisons of efficacy of BAY 81-8973 vs two recombinant factor VIII for the prophylactic treatment of severe hemophilia A.

J Blood Med 2016 4;7:129-37. Epub 2016 Jul 4.

Analysis Group, Inc., New York, NY, USA.

Background: No head-to-head trials comparing recombinant factor VIII (rFVIII) products currently exist. This was a matching-adjusted indirect comparison (MAIC) study of efficacy of BAY 81-8973 with antihemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM) and turoctocog alfa for the prophylaxis of severe hemophilia A.

Methods: A systematic literature review was conducted to identify trials of rAHF-PFM and turoctocog alfa. Comparisons were conducted using BAY 81-8973 individual patient data (IPD) from LEOPOLD trials and published data from rAHF-PFM and turoctocog alfa trials. Differences in outcome reporting were reconciled using transformation of BAY 81-8973 IPD. Patients in pooled LEOPOLD trials were weighted to match baseline characteristics for rAHF-PFM or turoctocog alfa trials using MAICs. After matching, annualized bleed rates (ABRs) were compared using weighted t-tests.

Results: Two rAHF-PFM trials and one turoctocog alfa trial were identified. In these trials, rFVIIIs were dosed thrice weekly or every other day; in LEOPOLD trials, BAY 81-8973 was dosed twice- or thrice weekly. Three MAICs were conducted because the two rAHF-PFM trials calculated ABRs differently, matching for age, race, and weight (turoctocog alfa only). BAY 81-8973 had similar ABR of all bleeds vs rAHF-PFM (two trials: 4.8 vs 6.3, 1.9 vs 1.8 [square root transform]) and lower ABR of spontaneous bleeds and trauma bleeds (2.6 vs 4.1, 2.1 vs 4.7; both P<0.05). BAY 81-8973 showed lower ABR of all bleeds and spontaneous bleeds vs turoctocog alfa (4.3 vs 6.5, 2.8 vs 4.3; both P<0.05) and similar ABR of trauma bleeds (1.5 vs 1.6). In subgroup analysis, twice-weekly BAY 81-8973 had similar ABRs of all bleeds, spontaneous bleeds, and trauma bleeds compared to rAHF-PFM and turoctocog alfa.

Conclusion: This indirect comparison found that prophylaxis with BAY 81-8973, even including the lower frequency of two times a week and lower factor VIII consumption, has efficacy comparable to rAHF-PFM and turoctocog alfa, which were dosed thrice weekly or every other day. The use of IPD enabled adjustments for differences in calculation of ABRs and population characteristics between trials.
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http://dx.doi.org/10.2147/JBM.S104074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4938137PMC
July 2016

Real-World Analysis of Medical Costs and Healthcare Resource Utilization in Elderly Women with HR+/HER2- Metastatic Breast Cancer Receiving Everolimus-Based Therapy or Chemotherapy.

Adv Ther 2016 06 23;33(6):983-97. Epub 2016 May 23.

Analysis Group, Inc., Montreal, QC, Canada.

Introduction: The objective of this study was to analyze medical costs and healthcare resource utilization (HRU) associated with everolimus-based therapy or chemotherapy among elderly women with hormone-receptor-positive, human-epidermal-growth-factor-receptor-2-negative (HR+/HER2-) metastatic breast cancer (mBC).

Methods: Elderly women (≥65 years) with HR+/HER2- mBC who failed a non-steroidal-aromatase-inhibitor and subsequently began a new line of treatment with everolimus-based therapy or chemotherapy for mBC (index therapy) during July 20, 2012 to March 31, 2014 were identified from two large commercial claims databases. All-cause, BC-, and adverse event (AE)-related medical costs (2014 USD), and all-cause and AE-related HRU per patient per month (PPPM) were compared between patients treated with everolimus-based therapy and chemotherapy across their first four lines of therapy for mBC. Adjusted costs and HRU differences were estimated by pooling all lines and using multivariable models adjusted for differences in patient characteristics.

Results: In total, 925 elderly patients (mean age approximately 73 years) with HR+/HER2- mBC met the inclusion criteria; 230 received everolimus-based therapy (240 lines) and 737 received chemotherapy (939 lines). Compared with chemotherapy, everolimus-based therapy was associated with significantly lower total all-cause PPPM medical services costs (adjusted mean difference: $4007), driven by lower inpatient ($1994) and outpatient ($1402) costs; lower BC-related medical services costs ($3129), driven by both BC-related inpatient ($1883) and outpatient costs ($913); and lower AE-related medical services costs ($1873; all P < 0.01). Additionally, compared to patients treated with chemotherapy, patients treated with everolimus-based therapy had fewer all-cause outpatient visits (adjusted incidence rate ratio = 0.69), BC-related outpatient visits (0.66), other-medical-service visits (0.65), and AE-related HRU (0.59), which was driven by significantly fewer AE-related outpatient visits (0.56; all P < 0.01). Subgroup analyses comparing medical costs of everolimus-based therapy with capecitabine monotherapy showed consistent results overall.

Conclusion: This retrospective claims database analysis of elderly women with HR+/HER2- mBC in the United States showed that everolimus-based therapy was associated with significantly lower all-cause, BC-related, and AE-related medical services costs and less use of healthcare resources compared with chemotherapy.

Funding: Novartis.
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http://dx.doi.org/10.1007/s12325-016-0328-3DOI Listing
June 2016
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