GlaxoSmithKline Employee Research Articles

Efficacy of Soticlestat Treatment by Seizure Type in Patients with Dravet Syndrome or Lennox–Gastaut Syndrome in a Phase 2, Randomized, Placebo-controlled Study (ELEKTRA) (P11-1.002)

<h3>Objective:</h3> To develop a post hoc analysis of soticlestat treatment efficacy by seizure type in patients with Dravet syndrome (DS) or Lennox–Gastaut syndrome (LGS) in ELEKTRA (NCT03650452), a phase 2, randomized, placebo-controlled study of adjunctive soticlestat (≤300 mg BID, weight-adjusted) in children aged 2–17 years with DS demonstrating ≥3 convulsive seizures/28 days, or with LGS demonstrating ≥4 drop seizures/28 days at baseline. <h3>Background:</h3> DS and LGS involve developmental delay and frequent epileptic activity. The published ELEKTRA study investigated efficacy and safety of soticlestat, a cholesterol 24-hydroxylase inhibitor, in children with DS or LGS. Primary endpoint was change in convulsive (DS) and drop (LGS) seizure frequencies. <h3>Design/Methods:</h3> Post hoc efficacy analyses determined percent change in seizure frequency from baseline, by seizure type. Patients’ caregivers recorded seizure number and type throughout the baseline and full (20-week) treatment periods, including generalized tonic–clonic, focal to bilateral tonic–clonic, focal with motor signs and atonic seizures. <h3>Results:</h3> Of 141 enrolled patients, 126 (89%) completed ELEKTRA. The modified intent-to-treat population received ≥1 doses of study drug and had ≥1 efficacy assessments (DS, n=51; LGS, n=88). Median seizure frequency changes from baseline in patients with DS receiving soticlestat (placebo): generalized tonic–clonic seizures, −27.2% [n=14] (19.5%, n=21); focal to bilateral tonic–clonic seizures, −73.9% [n=9] (8.4%, n=4). Median seizure frequency changes from baseline in patients with LGS receiving soticlestat (placebo): generalized tonic–clonic seizures, −33.4% [n=17] (−20.0%, n=11); focal seizures with motor signs, −64.3% [n=10] (−21.1%, n=7); atonic seizures, −33.9% [n=16] (−17.9%; n=13); focal to bilateral tonic–clonic seizures, −41.3% [n=6] (none observed). <h3>Conclusions:</h3> Reduced median frequency of specific seizure types was observed in patients receiving soticlestat as adjunctive therapy. Investigation of soticlestat adjunctive therapy for these seizure types in other epilepsies is warranted (phase 3 studies ongoing for DS and LGS). Study funded by Takeda Pharmaceutical Company Limited. <b>Disclosure:</b> Dr. Pathi Jagannatham has received personal compensation for serving as an employee of Takeda Pharmaceuticals. Dr. Pathi Jagannatham has received personal compensation for serving as an employee of GlaxoSmithKline. Dr. Pathi Jagannatham has stock in Takeda Pharmaceuticals. Dr. Pathi Jagannatham has stock in GlaxoSmithKline. Dr. Dlugos has received research support from NIH. The institution of Dr. Dlugos has received research support from The Epilepsy Study Consortium. Yasir Khan has nothing to disclose. Dr. Hsiao has received personal compensation for serving as an employee of Takeda Pharmaceutical Company. Dr. Hsiao has stock in Takeda Pharmaceutical Company. Dr. Benitez has received personal compensation for serving as an employee of Takeda . Mahnaz Asgharnejad, PharmD has received personal compensation for serving as an employee of Takeda Pharmaceuticals. Mahnaz Asgharnejad, PharmD has stock in GlaxoSmithKline. Mahnaz Asgharnejad, PharmD has stock in Takeda Pharmaceuticals.

Budget impact analysis of niraparib for first-line maintenance therapy in advanced ovarian cancer from a US payer perspective.

BACKGROUND: Ovarian cancer (OC) is the fifth leading cause of cancer death in women and has the highest mortality rate of gynecological cancers. Niraparib was recently approved by the FDA for the maintenance treatment of adult patients with advanced epithelial OC in complete or partial response to first-line platinum-based chemotherapy (PBC) regardless of biomarker status. OBJECTIVE: To estimate the direct economic impact on US payers of adding niraparib as a first-line maintenance therapy for patients with advanced OC. METHODS: The model considered 2 scenarios: a current scenario in which niraparib does not have regulatory approval for first-line maintenance therapy and a future scenario in which niraparib has regulatory approval for first-line maintenance therapy. The budget impact was calculated as the difference in cost between the 2 scenarios. The budget impact model (BIM) considered 2 different US health care payer perspectives: a commercial health plan and a Medicare plan. Both payer perspectives were assumed to have a hypothetical 1 million affiliates that were covered. Epidemiological data was used to estimate the eligible incident population of patients with OC. Active surveillance, bevacizumab (as a monotherapy), and olaparib (as a monotherapy restricted to patients with the breast cancer gene [BRCA] mutation) were included in the model as alternative maintenance treatment options (maintenance treatment options required 1% market share for inclusion). Cost categories considered in the BIM included diagnostic testing, treatment acquisition and administration, treatment-emergent adverse events, and subsequent therapy. Results were presented as an incremental budget impact to payers over 3 years. RESULTS: For a commercial health plan of 1 million affiliates, the estimated impact of adding niraparib as a first-line maintenance treatment option for advanced epithelial OC was calculated as $87,906, $93,106, and $87,037 for years 1, 2, and 3, respectively. The average budget impact per member per month was $0.007. For a Medicare health plan of 1 million affiliates, the estimated impact was calculated as $206,785, $219,017, and $204,739 for years 1, 2, and 3, respectively. The average budget impact per member per month was $0.018. One-way sensitivity analyses suggested that budget impact was most sensitive to the treatment duration and market share of niraparib, the non-treatment-specific data on overall survival rates, and the treatment duration of bevacizumab. Treatment of drug-specific adverse events had little impact on the budget model. CONCLUSIONS: The model estimated a minimal budget impact to both a commercial or Medicare health plan following the introduction of niraparib as a first-line maintenance therapy for patients with advanced epithelial OC who are in complete or partial response to first-line PBC regardless of biomarker status. DISCLOSURES: This study was financially supported by GlaxoSmithKline. Liu, Hawkes, Maiese, and Hurteau are employees of GlaxoSmithKline. Travers was employed by GlaxoSmithKline at the time of this study. Spalding and Walder are employees of FIECON Ltd., which was contracted by GlaxoSmithKline to develop the budget impact model used in this study.

Cost-effectiveness and budget impact of dolutegravir/lamivudine for treatment of human immunodeficiency virus (HIV-1) infection in the United States.

BACKGROUND: Dolutegravir(DTG)/lamivudine(3TC) is the first 2-drug regimen recommended as an initial treatment for people living with HIV (PLHIV). OBJECTIVE: To assess the cost-effectiveness and potential budget impact of DTG/3TC in the US healthcare setting. METHODS: A previously published hybrid decision-tree and Markov cohort state transition model was adapted to estimate the incremental costs and health outcome benefits over a patients' lifetime. DTG/3TC was compared with current standard of care in treatment naive and treatment experienced virologically suppressed PLHIV. Health states included in the model were based upon virologic response and CD4 cell count, with death as an absorbing state. Clinical data was informed by the Phase III GEMINI 1 and 2 clinical trials, a published network meta-analysis (NMA) in treatment-naive patients and the Phase III TANGO clinical trial in treatment experienced patients. Costs and utilities were informed by published data and discounted annually at a rate of 3%. A separate 5-year budget impact analysis was conducted assuming 5%-15% uptake in eligible treatment naive and 10%-30% uptake in eligible treatment experienced patients. RESULTS: In the treatment naive analyses based on GEMINI 1 and 2, DTG/3TC dominated, i.e., was less costly and more effective, than all comparators. DTG/3TC resulted in 0.083 incremental quality-adjusted life-years (QALYs) at a cost saving of $199,166 compared with the DTG + tenofovir disoproxil(TDF)/emtricitabine(FTC) comparator arm. The incremental QALY and cost savings for DTG/3TC compared with DTG/abacavir(ABC)/3TC, cobicistat-boosted darunavir(DRV/c)/tenofovir alafenamide(TAF)/FTC, and bictegravir (BIC)/TAF/FTC, based on NMA results were 0.465, 0.142, and 0.698, and $42,948, $122,846, and $44,962, respectively. In the analyses of treatment-experienced virologically suppressed patients based on TANGO, DTG/3TC offered slightly lower QALYs (-0.037) with an estimated savings of $78,730 when compared with continuation of TAF-based regimen (TBR). Sensitivity analyses demonstrated that these conclusions were relatively insensitive to alternative parameter estimates. The budget impact analysis estimated that by 5th year a total of 70,240 treatment naive patients and 1,340,480 treatment experienced patients could be eligible to be prescribed DTG/3TC. The estimated budget savings over 5 years ranged from $1.12b to $3.35b (corresponding to 27,512 to 82,536 on DTG/3TC by year 5) in the lowest and highest uptake scenarios, respectively. CONCLUSION: In conclusion, DTG/3TC with its comparable efficacy and lower drug acquisition costs, has the potential to offer significant cost savings to US healthcare payers for the initial treatment of treatment naive patients and as a treatment switching option for virologically suppressed patients. DISCLOSURES: This study was funded in full by ViiV healthcare, Brentford, UK. Medical writing to support this study was also funded in full by ViiV Healthcare, Brentford, UK. Butler, Hayward, and Jacob are employees of HEOR Ltd, the company performing this study funded by ViiV Healthcare. Anderson is an employee of GlaxoSmithKline and owns shares in the company. Punekar, Evitt, and Oglesby are employees of ViiV Healthcare and own stocks in GlaxoSmithKline.

Development and validation of a drug adherence index for COPD.

BACKGROUND: Inhaled medications are the mainstay of treatment for chronic obstructive pulmonary disease (COPD). Despite their importance, adherence to these medications is low. Low adherence is linked to increased exacerbation rates, mortality rates, health care utilization, and, ultimately, increased costs. A drug adherence index (DAI) is a predictive modeling tool that identifies patients most likely to change adherence status so that they can be targeted for support programs. Optum has previously developed DAI tools for diabetes, hypertension, and high cholesterol. In this study, a COPD-specific DAI was developed. This DAI tool could be used to better target medication adherence support in patients with COPD, aiming to increase adherence. OBJECTIVES: To develop a COPD-specific DAI using (a) enrollment, medical, and pharmacy variables and (b) only enrollment and pharmacy variables for potential application to pharmacy benefit managers and pharmacy plans. METHODS: This was a retrospective observational study using health care claims among Medicare Advantage with Part D beneficiaries with COPD in the United States. Potential predictors of adherence were measured during a 1-year baseline period. The adherence outcome was measured during a subsequent 1-year at-risk period. Adherence to long-acting bronchodilators was defined as a proportion of days covered (PDC) ≥80%. Nonadherence was defined as a PDC of <80%. Patients were stratified according to their adherence status at baseline, and logistic regression models were developed separately for each set of patients. Separate models were also developed using enrollment, medical, and pharmacy variables (primary objective) or using enrollment and pharmacy variables only (secondary objective). RESULTS: A total of 61,507 patients met all inclusion and exclusion criteria. For the primary objective, at baseline, 31,142 patients were adherent and 30,365 patients were nonadherent. The final DAI model used to predict future nonadherence included 30 covariates, with 7 predictors from medical claims. The validated model c-statistic was 0.752. The final DAI model used to predict future adherence included 29 covariates; only 4 predictors were from medical claims. The validated model c-statistic was 0.691. Findings were similar for the secondary objective using only enrollment and pharmacy variables. CONCLUSIONS: This DAI was developed and validated specifically to predict future adherence status to long-acting bronchodilator medications among patients with COPD. The DAI models performed better for predicting nonadherence than predicting adherence. Both organizations with medical and pharmacy data and organizations with only pharmacy data could utilize the DAI tool to target patients for adherence programs, as results were similar with and without the use of medical variables. DISCLOSURES: This study was sponsored and funded by GlaxoSmithKline (HO-16-17938). The study sponsor participated in the conception and design of the study, analysis and interpretation of the data, and drafting and critical revision of the report and approved submission of the manuscript. All authors had access to the results of the analyses, reviewed and edited the manuscript, approved the final draft, and were involved in the decision to submit the manuscript for publication. The data contained in the Optum database contain proprietary elements owned by Optum and, therefore, cannot be broadly disclosed or made publicly available at this time. The disclosure of these data to third parties assumes certain data security and privacy protocols are in place and that the third party has executed a license agreement that includes restrictive agreements governing the use of the data. Bengtson, Buikema, and Bankcroft are employees at Optum, and Schilling is a former employee of Optum; their employment was not contingent on this work. Optum was funded by GlaxoSmithKline to conduct the study. Stanford was an employee of GlaxoSmithKline at the time of this study and holds stock in GlaxoSmithKline.

Estimating HIV Management and Comorbidity Costs Among Aging HIV Patients in the United States: A Systematic Review.

As life expectancy of patients infected with human immunodeficiency virus (HIV) approaches that of the general population, the composition of HIV management costs is likely to change. To (a) review treatment and disease management costs in HIV, including costs of adverse events (AEs) related to antiretroviral therapy (ART) and long-term toxicities, and (b) explore the evolving cost drivers. A targeted literature review between January 2012 and November 2017 was conducted using PubMed and major conferences. Articles reporting U.S. costs of HIV management, acquired immunodeficiency syndrome (AIDS)-defining events, end of life care, and ART-associated comorbidities such as cardiovascular disease (CVD), chronic kidney disease (CKD), and osteoporosis were included. All costs were inflated to 2017 U.S. dollars. A Markov model-based analysis was conducted to estimate the effect of increased life expectancy on costs associated with HIV treatment and management. 22 studies describing HIV costs in the United States were identified, comprising 16 cost-effectiveness analysis studies, 5 retrospective analyses of health care utilization, and 1 cost analysis in a resource-limited setting. Management costs per patient per month, including routine care costs (on/off ART), non-HIV medication, opportunistic infection prophylaxis, inpatient utilization, outpatient utilization, and emergency department utilization were reported as CD4+ cell-based health state costs ranging from $1,192 for patients with CD4 > 500 cells/mm3 to $2,873 for patients with CD4 < 50 cells/mm3. Event costs for AEs ranged from $0 for headache, pain, vomiting, and lipodystrophy to $31,545 for myocardial infarction. The mean monthly per-patient costs for CVD management, CKD management, and osteoporosis were $5,898, $6,108, and $4,365, respectively. Improvements in life expectancy, approaching that of the general population in 2018, are projected to increase ART-related and AE costs by 35.4% and comorbidity costs by 175.8% compared with estimated costs with HIV life expectancy observed in 1996. This study identified and summarized holistic cost estimates appropriate for use within U.S. HIV cost-effectiveness analyses and demonstrates an increasing contribution of comorbidity outcomes, primarily associated with aging in addition to long-term treatment with ART, not typically evaluated in contemporary HIV cost-effectiveness analyses. This analysis was sponsored by ViiV Healthcare, which had no role in the analyses and interpretation of study results. Ward, Sugrue, Hayward, and McEwan are employees of HEOR Ltd, which received funding from ViiV Healthcare to conduct this study. Anderson is an employee of GlaxoSmithKline and holds shares in the company. Punekar and Oglesby are employees of ViiV Healthcare and hold shares in GlaxoSmithKline. Lopes was employed by ViiV Healthcare at the time of the study and holds shares in GlaxoSmithKline.

The Early Impact of COVID-19 on Mental Health and Community Physical Health Services and Their Patients’ Mortality in Cambridgeshire and Peterborough, UK

BACKGROUND: COVID-19 has affected social interaction and healthcare worldwide.METHODS: We examined changes in presentations and referrals to the primary provider of mental health and community health services in Cambridgeshire and Peterborough, UK, plus service activity and deaths. We conducted interrupted time series analyses with respect to the UK “lockdown”. We examined changes in standardized mortality ratio for those with and without severe mental illness (SMI).OUTCOMES: Referrals and presentations to nearly all mental and physical health services dropped at lockdown, with evidence for changes in both supply (service provision) and demand (help-seeking). This was followed by an increase in demand for some services. This pattern was seen for all major forms of presentation to liaison psychiatry services, except for psychosis/mania and eating disorders, for which there was no evidence of change. Inpatient numbers fell, but new detentions under the Mental Health Act were unchanged. Many services shifted from face-to-face to remote contacts. Excess mortality, primarily in the over-70s, lagged slightly behind confirmed numbers of COVID-19 cases. There was a much greater increase in mortality for patients with SMI, which was not explained by ethnicity.INTERPRETATION: COVID-19 has been associated with a system-wide drop in the use of mental health services, with some subsequent return in activity. This may reflect a genuine reduction of need or a lack of help-seeking and pent-up demand. There has been a disproportionate increase in death among those with SMI during the pandemic.FUNDING: UK Medical Research Council and National Institute of Health Research.DECLARATION OF INTERESTS:  Several authors (PBJ, BRU, AM, ETB, ESO, JBD, CFH, FJT, RNC) are CPFT clinicians involved in delivering some of the services discussed here and two (BRU, FJT) are clinical directors and therefore involved in managing them.  PBJ is a scientific advisory board member for Johnson & Johnson and Recordati.  BRU is clinical director of the Windsor Unit at Fulbourn Hospital (CPFT), which delivers clinical trials in dementia/mild cognitive impairment for academic and commercial organisations without personal benefit, and is the clinical lead for dementia for the NIHR Clinical Research Network (CRN) in the East of England. His salary is part-funded by the NIHR CRN. He has been principal investigator on trials for Axovant, Lilly, and EIP Pharma; his institution has benefited from payment for research carried out but he has not personally received any money. His wife is the lead for mental health for Suffolk Clinical Commissioning Group.  AM’s salary is part-funded by the Anna Freud National Centre for Children and Families, a mental health charity.  ETB is a scientific advisory board member for Sosei Hepares, and was a half-time employee of GlaxoSmithKline until May 2019.  RNC consults for Campden Instruments Ltd and receives royalties from Cambridge University Press, Cambridge Enterprise, and Routledge.  SC, SB, EFO, JBD, CFH, FJT, JDA, MPS, and JRL have nothing else to disclose.ETHICS APPROVAL STATEMENT: De-identified data was extracted from CPFT clinical records by CPFT’s Information & Performance team and via the CPFT Research Database (NHS research ethics 17/EE/0442). The study was conducted under UK National Health Service Research Ethics approval (ref. 17/EE/0442).

Preapproval Information Exchange: Perspectives of U.S. Population Health Decision Makers on Preferences for Early Engagement with Investigational Therapies.

Preapproval information exchange (PIE) is the communication of clinical and health care economic information (HCEI) on therapies in development between U.S. population health decision makers (PHDMs) and drug manufacturers before regulatory approval. Early access to HCEI can help PHDMs plan budgets, inform formulary coverage decisions, and accelerate policy development to improve patient access to innovative health technologies. While recent FDA guidelines and proposed legislation aim to clarify definitions and execution of PIE, the level of U.S. PHDMs' awareness and preferences for early engagement with investigational therapies is unclear. To (a) assess U.S. PHDMs' current knowledge and perceptions of PIE and (b) identify their preferences for PIE, in order to shape future development of related guidelines and policy. An expert panel of 5 U.S. PHDMs representing national and regional payers from integrated health plans, pharmacy benefit management, and specialty pharmacy organizations participated in a 2-round modified Delphi process. A targeted literature review of PIE was used to develop a web-based survey administered to the panel. Survey responses were grouped by consensus, with ≥ 80% agreement or disagreement as the threshold in round 1. In round 2, content experts moderated an inperson meeting where panelists deliberated and then revoted on round 1 nonconsensus topics. In the round 1 survey, the panelists reached consensus on 35 of 54 (65%) multiple-choice questions. In the round 2 face-to-face discussion, 19 nonconsensus questions were debated. One question was removed due to duplication, and consensus was achieved on 16 additional questions, with 2 items of nonconsensus remaining. Overall, consensus was achieved on 51 of 53 topics (96%). There was full consensus by the panelists that PIE should encompass new molecular entities and new indications of marketed therapies. Panelists completely agreed on the need for a legislative "safe harbor" for PIE. Four of five panelists reported that the value of PIE was high to PHDMs, and they expressed a strong preference for peer-to-peer conversations with manufacturers' medical or outcomes liaisons for PIE. The main topic of nonconsensus was the optimal timing of PIE. This panel of U.S. PHDMs achieved consensus on the value of PIE to proactively budget, make informed formulary decisions, and develop pharmaceutical policy to facilitate patient access to new therapies. The PHDM panel's preferences for PIE should be considered in legislative discussions and planning for future PIE by PHDMs and manufacturers. The full contribution of PIE to improving the U.S. health system can best be realized under a safe harbor that allows U.S. PHDM and manufacturer experts to engage in robust scientific and economic discourse. Additional research and broad stakeholder engagement is needed to advance the development of formal U.S. PIE guidelines. This study was funded by GlaxoSmithKline (GSK). Brixner, Oderda, and Biskupiak are principals of Millcreek Outcomes Group, a consultancy that received funding from GSK to conduct this study. Marciniak and Woodward are employees of GSK and own stock in GSK. Seifter was employed by GSK at the time of this study. Neumann served as external health policy advisor for this study and has consulted or served on advisory boards with Merck, Bayer, Pacira, Novo Nordisk, Amgen, Abbvie, Boston Health Economics, Vertex, Precision Health Economics, the Congressional Budget Office, CEA Registry Sponsors, Axovant, Veritech, Janssen, Parateck, Avexis, GSK, Celegene, Bluebird, Roche, Sage, Sarepta, Biogen, and Ipsen. Neumann also reports grants from Amgen, Lundbeck, Gates, NPC, Alzheimer's Association, and NIH.

Economic Burden of Illness Among Patients with Severe Asthma in a Managed Care Setting.

Despite intensive pharmacotherapy, a considerable number of patients with severe asthma have inadequate disease control. Patients with severe asthma who experience exacerbations consume significant health care resources. To assess health care resource utilization and associated costs among patients with persistent severe asthma who experienced exacerbations compared with patients with persistent but nonsevere asthma. This retrospective analysis of a national administrative claims database identified patients aged ≥ 12 years who had at least 1 medical claim with an asthma diagnosis in 2012 and had continuous medical and pharmacy coverage under a commercial or Medicare Advantage plan from January 1, 2012, to December 31, 2013. Patients were assigned to 1 of 2 mutually exclusive cohorts-persistent asthma (PA) or severe asthma (SA)-according to an established algorithm based on asthma-related health care resource use and pharmacy claims for controller medication. SA patients were required to meet PA criteria and also have evidence of ≥2 asthma exacerbations in 2012. Asthma-related health care resource utilization and costs were computed from asthma medication use (rescue and controller therapy) and medical claims with an asthma diagnosis in the primary position in 2012 and 2013. Adherence to controller therapy was assessed over 365 days by using the proportion of days covered (PDC), starting with the first claim for controller therapy in 2012. Differences between the PA and SA cohorts were analyzed by t-test for continuous variables and chi-square test for categorical variables. Asthma-related costs in 2013 were also analyzed using a generalized linear model with a gamma distribution and log link, adjusted for patient demographics (age, gender, region, and insurance type) and Quan-Charlson comorbidity score. A total of 65,359 patients were included: 63,597 (97.3%) PA patients and 1,762 SA patients (2.7%). Compared with the PA cohort, the SA cohort was older (mean age = 50.8 years vs. 46.5 years, P < 0.001) and had higher mean comorbidity score (1.47 vs. 1.31, P< 0.001). The mean count of all asthma medications fills was 2.2-fold (2012) and 2.1-fold (2013) higher in the SA cohort, compared with the PA cohort (P< 0.001). Mean PDC for all oral and inhaled controller therapy was also higher in the SA cohort compared with the PA cohort (0.80 vs. 0.65, P< 0.001). SA patients had a significantly greater mean count of asthma-related hospitalizations, emergency room visits, and ambulatory visits in 2012 and 2013 (P< 0.001). Unadjusted mean annual asthma-related costs in the SA versus PA cohorts were $6,496 versus $2,739 (P < 0.001) in 2012 and $5,174 versus $1,775 (P< 0.001) in 2013. Higher asthma-related costs were driven by greater mean annual asthma medication costs in 2012 ($4,545 vs. $1,738, P< 0.001) and 2013 ($4,068 vs. $1,348, P< 0.001). Adjusted mean annual asthma-related costs in 2013 were $3,336 greater (cost ratio=2.878, P< 0.001) in the SA cohort, and adjusted mean annual asthma medication costs were $2,672 higher (cost ratio=2.982, P< 0.001) in the SA cohort. Patients with SA who experienced 2 or more exacerbations had 2.1-fold greater use of controller medications across both study years and were more adherent to controller therapy than patients with PA. Despite more intensive pharmacotherapy, SA patients incurred 2.9-fold higher adjusted asthma-related costs and 3-fold higher adjusted asthma medication costs than PA patients. Patients with SA consistently demonstrated a higher rate of health care utilization. Funding for this study (HO-14-14443) was provided by GlaxoSmithKline (GSK). All listed authors meet the criteria for authorship set forth by the International Committee for Medical Journal Editors. Albers, Forshag, and Yancey are employees of GSK and hold stock in GSK. Dalal, Nagar, and Ortega were employees of GSK at the time this research was conducted. Chastek and Korrer are employees of Optum, which received consulting fees from GSK for research related to this study. Study concept and design were contributed by Chastek, Nagar, and Dalal. Korrer took the lead in data collection, along with Chastek, and data interpretation was performed by Chastek, Ortega, Forshag, and Dalal. The manuscript was written by Chastek and Dalal and revised by Albers and Yancy, assisted by the other authors.

Dose-Response Relationship Between Long-Term Systemic Corticosteroid Use and Related Complications in Patients with Severe Asthma.

Systemic corticosteroids are a leading cause of drug-related complications, yet little has been done to quantify the dose-response relationship between systemic corticosteroid exposure and complications in patients with severe asthma. To (a) evaluate the risk of developing systemic corticosteroid-related complications by corticosteroid exposure in severe asthma and (b) quantify the associated health care resource utilization and costs. This is a retrospective study using administrative claims data from a large commercial database between 2003 and 2014. Multivariate generalized estimating equation models were used to compare corticosteroid-related complications in patients continuously exposed to at least 5 mg of prednisone or equivalent for ≥ 6 months with a 1:1 ratio of propensity score-matched patients with asthma who did not use corticosteroids. A total of 12,697 corticosteroid users and as many matched nonusers were identified. The odds of developing associated complications increased significantly in a dose-dependent manner with systemic corticosteroid exposure: odds ratios were 2.50, 2.95, and 3.32 (P values <0.05) for low (defined as < 5 mg/day), medium (≥ 5-10 mg/day), and high (>10 mg/day) exposure, respectively, relative to no exposure. Health care resource utilization increased significantly with levels of systemic corticosteroid exposure. Hence, incidence rate ratios for inpatient visits with low, medium, and high exposure relative to none were estimated to be 1.86, 2.40, and 3.37, respectively (P < 0.05). A significant dose-response relationship was found between the long-term use of systemic corticosteroids and the risk of developing systemic corticosteroid-related complications in patients with severe asthma, resulting in increased burden and costs on the health care system that intensified with systemic corticosteroid exposure. Funding for this study was provided by GlaxoSmithKline, Study number H0-15-15930, to Analysis Group for the conduct of this study. Lefebvre, Duh, and Gozalo are employees of Analysis Group, a contract research organization that has received research grants from GlaxoSmithKline. Robitaille was employed by Analysis Group at the time of this study. Yancey, Forshag, Lin, and Albers are employees of GlaxoSmithKline and own company stock. Dalal and Ortega were employed by GlaxoSmithKline at the time of this study. Lefebvre had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Additionally, all listed authors meet the criteria for authorship set forth by the International Committee for Medical Journal Editors. Study concept and design were contributed by Dalal, Duh, Albers, Yancey, Ortega, Forshag, and Lefebvre. Data acquisition was by Dalal, Gozalo, Robitaille, Forshag, and Lefebvre and was analyzed and interpreted by Dalal, Gozalo, Robitaille, Albers, Yancey, Ortega, Forshag, and Lefebvre. The manuscript was drafted and approved by Dalal, Duh, Gozalo, Robitaille, Albers, Yancey, Ortega, Forshag, Lin, and Lefebvre.

Evaluation of Safety, Tolerability, Pharmacokinetics and Efficacy of Dabrafenib, a Braf Inhibitor, in Japanese Patients with Braf V600 Mutation-Positive Advanced Solid Tumors: a Phase I Study

ABSTRACT Aim: Dabrafenib, a potent and selective BRAF inhibitor, has demonstrated clinical significance for BRAF V600 mutation-positive metastatic melanoma and has been approved in the US and EU. However, there is less clinical experience of treatment with dabrafenib in the Japanese population. Therefore, this study has been designed and conducted to evaluate safety, tolerability, pharmacokinetics (PK) and efficacy of dabrafenib in Japanese patients with BRAF V600 mutation-positive advanced solid tumors as the first clinical trial. Methods: Patients with BRAF V600 mutation-positive advanced solid tumors refractory to standard therapies were enrolled. Dose escalation was performed according to a standard 3 + 3 design. Dabrafenib was given twice a day (BID), which started 7 days after a single dose administration for a single-dose PK analysis. Antitumor activity was evaluated based on RECIST version 1.1. This study was registered at www.clinicaltrials.gov as NCT01582997. Results: Twelve patients (11 melanoma and 1 papillary thyroid cancer) with BRAF V600E mutation received dabrafenib at doses of 75 mg (n = 3), 100 mg (n = 3), or 150 mg (n = 6). The median duration of treatment was approximately 39 weeks. No dose-limiting toxicities were observed in these three dose cohorts. The most common adverse events (AEs) included alopecia, leucopenia, pyrexia and arthralgia. Most AEs were reported as grade 1 or 2. Squamous-cell carcinoma or keratoacanthoma, which is a well-documented BRAF inhibitor class toxicity, was not observed in this study. Preliminary PK results showed no obvious ethnic difference. Partial responses were confirmed in 7 patients (58.3%), 6 melanoma patients and 1 papillary thyroid cancer patient. The data also suggested dabrafenib had an antitumor activity in Japanese patients with BRAF V600 mutation-positive melanoma as well as papillary thyroid cancer. Conclusions: Compared with the data published for the caucasian population, dabrafenib exhibited comparable tolerability, safety and PK profiles in Japanese patients at the dose of 150 mg BID. This dose also gave a suggestive outcome for the potential efficacy to the Japanese population. Disclosure: A. Suzuki: A. Suzuki is an employee of GlaxoSmithKline K.K; A. Mukaiyama: A. Mukaiyama is an employee of GlaxoSmithKline K.K. All other authors have declared no conflicts of interest.

Phase 1 Study Evaluating Safety and Tolerability of Medi4736, an Anti-Programmed Cell Death Ligand-1 (Pd-L1) Antibody, in Combination with Dabrafenib and Trametinib or Trametinib Alone in Patients with Unresectable or Metastatic Melanoma

ABSTRACT Background: Targeted treatments have significantly improved outcomes in patients (pts) with metastatic melanoma (MM). The combination of dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor, provides high response rates in BRAF mutation-positive melanoma (BRAF V600E/K melanoma). Trametinib has also shown clinical activity in BRAF wild-type (WT) melanoma. The addition of an immunomodulator may further improve clinical outcomes in metastatic melanoma pts. MEDI4736 is a human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD-80 and is associated with a low frequency of anti-drug antibodies, showed durable clinical activity in a Phase 1 study of pts with solid tumors including melanoma. MEDI4736 is being evaluated in combination with dabrafenib/trametinib or trametinib alone in BRAF mutation-positive or BRAF mutation-negative melanoma. Trial design: This global multicenter, open-label Phase 1b study (NCT02027961) is enrolling adults with unresectable or MM and ECOG performance status 0–1 into 3 cohorts. In cohort A, BRAF-V600E/K melanoma pts receive dabrafenib orally (PO) twice daily, trametinib PO once daily (QD) and MEDI4736 intravenously (IV) every 2 wks (q2w), given concomitantly followed by continued dabrafenib/trametinib until progressive disease (PD). In cohorts B and C, BRAF mutation-negative (BRAF-WT) pts receive trametinib PO QD and MEDI4736 IV q2w according to 2 different treatment schedules,until PD. Primary objectives are determination of maximum tolerated dose (dose-limiting toxicity) and safety profile (adverse events, laboratory evaluations, physical exams, echocardiograms/electrocardiograms) of MEDI4736 in combination with dabrafenib/trametinib or trametinib alone. Secondary objectives include antitumor activity (objective response based on RECIST, duration of response, PFS, and overall survival), pharmacokinetic profile, and immunogenicity of the combination. Exploratory objectives include biomarkers, patient-reported outcomes, and tumor growth parameters. Recruitment is ongoing (target: 69 pts). This abstract was accepted and previously presented at the 2014 ASCO Annual Meeting Chicago, June 2014 (TPS9108). Disclosure: M.S. Gordon and D. Lawrence: MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; J. Lutzky: Medimmune/Astra-Zeneca: clinical trial support. Genentech, BMS, Prometheus: both clinical trial support and speaker bureau. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; M. Butler: Financial support from MedImmune to cover the costs of conducting sponsored clinical studies of Medi4736. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; P.A. Ascierto: Consultancy/research funding/honoraria: BMS, Roche-Genentech, Merck Sharp & Dohme, GSK, Ventana, and Novartis. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; B. Hug: Employee of GlaxoSmithKline. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; A. Blake-Haskins, A. Di Pietro, X. Li and P.B. Robbins: Employee of MedImmune and owns stock/stock options in AstraZeneca; A. Ribas: Consultant/funding/stock options Amgen Daiichi-Sankyo GSK Genentech-Roche Merck Novartis Pierre-Favre Kite Pharma Flexus. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest.

Retraction Note: Crucial role of interleukin-7 in T helper type 17 survival and expansion in autoimmune disease

The above manuscript was authored by scientists from the GlaxoSmithKline (GSK) Research and Development Center in Shanghai, China, and a researcher from Baylor Medical College who later became a GSK employee. Following anonymous reports of inaccuracies in this study, GSK conducted an investigation into these allegations.

LBA27_PR - Phase II Three-Arm Randomised Study of the Braf Inhibitor (BRAFI) Dabrafenib Alone vs Combination with Mek1/2 Inhibitor (MEKI) Trametinib in Pts with Braf V600 Mutation-Positive Metastatic Melanoma (MM)

ABSTRACT Introduction Dabrafenib (D) combined with trametinib (T) shows enhanced activity in BRAF V600-mutated cancer cell lines and xenograft models compared with either drug alone. Preclinically, D + T delays resistance and prevents BRAFi-induced proliferative skin lesions. Safety and efficacy of D + T, were evaluated in a four-part Phase 1–2 study. Safety and efficacy from Part C, the randomised study of D + T vs D are presented. Methods BRAFV600E/K mutation-positive, MM, BRAFi and MEKi treatment-naive pts (≥ 18 yrs; ECOG PS Results Pt (n = 162) baseline characteristics were balanced across the three arms. Investigator assessed median PFS for 150/2 was 9.4 mo v 5.8 for D mono (HR 0.39, 95% CI 0.25–0.62; p Conclusions D + T provided a statistically significant and clinically meaningful improvement in PFS, RR and DoR compared to D mono in pts with BRAF V600 mutation-positive MM. The data is consistent to Part B reported with D + T. Increased incidence and severity of pyrexia and lower incidence of hyperproliferative skin lesions are observed with D + T compared to D mono. Phase 3 studies are ongoing. Disclosure G.V. Long: Has participated in advisory boards for GlaxoSmithKline, Bristol Myers Squibb and Roche. Has received research funding and honoraria from Roche. J.A. Sosman: Has received research funding from GlaxoSmithKline. J.S. Weber: Has participated in advisory boards for, and has received honoraria from, GlaxoSmithKline. K.T. Flaherty: Has acted as a data safety monitoring board member and consultant (compensated) for, and has received research funding from GlaxoSmithKline. J.R. Infante: Has participated in an advisory board for GlaxoSmithKline. O. Hamid: Has acted as a consultant (uncompensated) for GlaxoSmithKline. Has received research funding from Bristol Myers Squibb. L. Schuchter: Has participated in advisory boards for Merck and has received research funding from GlaxoSmithKline, Merck and Genentech. J.S. Cebon: Has participated in GlaxoSmithKline advisory boards, and has received research funding and honoraria from GlaxoSmithKline. I. Puzanov: Has acted as a paid consultant to GlaxoSmithKline. A.P. Algazi: Has received research funding from GlaxoSmithKline. K. Lewis: Has received research funding from GlaxoSmithKline. W. Hwu: Has acted as a compensated consultant for Merck. Has received research funding from Bristol Myers Squibb. R.F. Kefford: Has participated in an advisory board for GlaxoSmithKline. P. Sun: Is a GlaxoSmithKline employee (Statistician) and owns GlaxoSmithKline stocks and shares. S.M. Little: Is a GlaxoSmithKline employee (Clinical Development Manager) and owns GlaxoSmithKline stocks and shares. R. Gonzalez: Has acted as a consultant to, and has received research funding from, GlaxoSmithKline. K. Patel: Is a GlaxoSmithKline employee (Director, Oncology Clinical Development) and owns GlaxoSmithKline stocks and shares. K.B. Kim: Has received research funding from GlaxoSmithKline. All other authors have declared no conflicts of interest.

Correction: A Genome-Wide Investigation of SNPs and CNVs in Schizophrenia

The authors declare the following competing interest, which should have been declared at the time of publication. Pamela L. St. Jean, Pierandrea Muglia, and Clyde Francks are full-time employees of GlaxoSmithKline, a pharmaceutical company that is developing treatments for schizophrenia and that has filed patent applications for SNPs related to schizophrenia (United States Patent Applications 20080176239 and 20080176240, and International Application No.: PCT/EP2008/050477).