ALBERT

Description: Introduction: Diffuse Large B-Cell Lymphoma (DLBCL) is the most common sub-type of non-Hodgkin lymphoma. Despite advances in immunochemotherapy, a significant portion of individuals with DLBCL are refractory or relapse following initial treatment and eventually succumb to the disease. Real world studies on DLBCL treatment patterns beyond first-line therapy are limited, and the health care costs associated with relapsed DLBCL are unknown. Using 100% Medicare claims data, our study set out to measure health care utilization following completion of first-line therapy for DLBCL. Methods: This retrospective study used 100% Medicare claims data (Inpatient, outpatient, Part D, SNF, HHA, Hospice, DME) to identify older adults (≥65 years) diagnosed with DLBCL (ICD9-CM diagnosis code: 200.7x) between Jan 1st 2010 - June 30th2014. Individuals were required to have prescription claims for a DLBCL chemotherapy treatment regimen 90 days pre-, or up to 1 year post-initial DLBCL claim. To limit our initial cohort selection to treatment-naïve patients, we excluded those with a DLBCL claim or prescription for a DLBCL related treatment at any time prior to the initial diagnosis date or treatment initiation date. All included patients were required to have continuous medical enrollment for 12 months before treatment initiation and receive at least one full cycle of valid DLBCL regimen. We then created our post first-line therapy study cohort by defining the end of first-line treatment by a gap of ≥60 days in therapy. Beneficiaries who initiated a second-line regimen during the follow-up period composed our relapsed group, whereas, individuals who completed first-line therapy without initiating any other chemotherapy treatment composed our non-relapse group. The index date for our health care utilization analysis was defined as the first-line treatment end date plus 60 days. Beneficiaries in both groups were required to have continuous medical benefits ≥1 year after this date or until death. Our primary outcome of health care resource utilization following first-line therapy were calculated as per patient per month and compared between our relapse and non-relapse groups using the chi-square test and t-test. Results:We identified 5,909 Medicare beneficiaries who completed first-line treatment for DLBCL, of which 1,552 had claims indicating second-line therapy during follow up (relapsed group). The mean age for the relapsed group was 77 years compared to 76 years for the non-relapse group (p=0.006). Other baseline characteristics were similar between our relapsed versus non-relapsed cohort. Compared to the non-relapse group, patients in our relapsed cohort were less likely to receive R-CHOP as first-line therapy (56.3% vs 80.5%, p

Description: INTRODUCTION: Recent large randomized controlled trials have shown that novel oral anticoagulants (NOACs) are at least as effective as warfarin for risk reduction of stroke or systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and are associated with similar or lower rates of bleeding.1,2,3,4 The study aimed to compare real-world major bleeding and stroke risk reduction and their related medical costs following initiation of apixaban compared to other oral anticoagulants (OACs) among treatment-naïve NVAF patients. METHODS: From a large national commercial and Medicare advantage insurance database, adult patients initiating apixaban, dabigatran, rivaroxaban, or warfarin (01/01/2013-12/31/2014) were identified. The OAC prescription date was designated as the index date. Patients were required to have an AF diagnosis (ICD-9-CM: 427.31) and continuous health plan enrollment for 6 months pre-index date. Patients with evidence of mitral valvular heart disease, valve replacement procedures, pregnancy, or OAC claims before the index date were excluded. Patients were classified into four cohorts based on their index prescription: apixaban, dabigatran, rivaroxaban and warfarin. Time-to- first stroke and major bleeding events, identified by the Cunningham algorithm plus additional bleeding sites, were compared using a Cox proportional hazards model. Major bleeding and stroke-related medical costs including those for recurring events were calculated per patient per month (PPPM) and compared using propensity-weighted generalized linear models. RESULTS: The study included 5,573 apixaban, 4,104 dabigatran, 13,370 rivaroxaban, and 25,978 warfarin patients. Apixaban patients had significantly higher CHA2DS2-VASc (3.6) and HAS-BLED (2.4) scores compared to dabigatran (CHA2DS2-VASc=3.3, HAS-BLED=2.2; p

Description: Hemophilia A is an X-linked bleeding disorder caused by mutations in the gene encoding the Factor VIII coagulation protein (FVIII). Bleeding episodes in patients are reduced by prophylactic therapy or treated acutely using recombinant or plasma derived FVIII. Recently, Nathwani et al demonstrated in preclinical and clinical studies sustained expression of coagulation factor IX using AAV8 technology to deliver the human gene to the liver, driven by a liver specific promoter. The same group demonstrated FVIII expression in mice and primates using a modified B-domain truncated form of FVIII delivered in an AAV8 capsid. We have made an AAV5 construct containing a B-domain deleted FVIII gene (AAV5-SQ) with a liver specific promoter and evaluated it in a double knockout mouse model of hemophilia. The double knockout mice (DKO) were created by crossing factor VIII deficient mice with RAG2 deficient mice (RAG2 KO). The RAG2 KO mice lacked the ability to mount an adaptive immune response thereby allowing sustained expression of a human protein without the development of an antibody response. Eight week old male DKOs were randomly distributed into three groups, twenty per group, and treated via a single IV injection with either vehicle, or AAV5-SQ at 2 x 1013 or 1 x 1014 vg/kg. C57BL/6J mice comprised a fourth group and were treated with vehicle via a single IV injection to demonstrate wild type bleeding times and blood loss. Bleeding times and blood loss were assessed in these mice 8 weeks post-dose, at 16 weeks of age. In addition, forty 16 week old DKO mice were randomly divided into two groups and treated with a single IV injection of rhFVIII-SQ protein (rhSQ, Xyntha®) at either 50 or 200 IU/kg. Bleeding times were assessed in these mice 30 minutes post-dose, at 16 weeks of age. Eight weeks post dosing with either AAV5-SQ or vehicle, the tail bleeding time and blood loss were measured following transection of the tip of the tail for evaluation of the functional efficacy of AAV5-SQ gene therapy. Wild-type mice receiving vehicle had a mean of 0.040 ± 0.073 g blood loss and 5.11 ± 5.61 min bleeding time. DKO mice treated with vehicle had a mean blood loss and bleeding time of 0.741 ± 0.207 g and 28.96 ± 1.40 min, respectively. Mice receiving AAV5-SQ at 2x1013 vg/kg showed significantly reduced blood loss (0.387 ± 0.384 g, p=0.0008 vs DKO+ vehicle; p=0.0003 vs WT) and bleeding time (17.12 ± 11.58 min, p=0.00005 vs DKO+ vehicle; p=0.0013 vs WT) while 1x1014 vg/kg AAV5-SQ treatment corrected blood loss and bleeding times to wild-type levels (0.104 ± 0.203 g [p=0.192 vs WT, p= 5.49x10-12 vs DKO + vehicle] and 5.58 ± 9.32 mins [p=0.847 vs WT, p= 1.75x-13 vs DKO + vehicle], respectively). The effect of AAV5-SQ treatment on blood loss and bleeding time was comparable to the effects of rhSQ. DKO mice receiving 50 IU/kg of rhSQ had a mean blood loss and bleeding time of 0.492 ± 0.297 g and 18.14 ± 9.39 min, respectively, which was not significantly different from mice receiving AAV5-SQ at 2x1013 (p=0.343 for blood loss, p=0.760 for bleeding time). DKO mice receiving 200 IU/kg of rhSQ had a mean blood loss and bleeding time of 0.134 ± 0.191 g and 4.29 ± 6.16 min, respectively, which was not significantly different from mice receiving AAV5-SQ at 1x1014 (p=0.635 for blood loss, p=0.608 for bleeding time). In a separate experiment, 4 groups of DKO mice, n=10 per group, were injected with either vehicle, AAV5-SQ at 2x1013, AAV5-SQ at 2x1014 vg/kg or rhSQ at 50 IU/kg. Blood was collected 8 weeks after AAV5-SQ treatment or 5 and 30 min after rhSQ for evaluation of plasma hFVIII-SQ protein levels and activity. Expressed hFVIII-SQ levels were measured by electrochemiluminescence assay. Factor VIII-SQ protein levels at 2x1013 vg/kg AAV5-SQwere 46.8±44.0 ng/ml and 355±166ng/ml at 2x1014 vg/kg. At 50 IU/kg of rhSQ the plasma protein levels were 79.1±11.3 ng/ml at 5 min and 44.7±16.6 ng/ml at 30min post dosing. Western blot analysis of the plasma from these mice showed the expressed protein to be similar in size to rhSQ. In summary, AAV5-SQ injected into DKO hemophilic mice resulted in a dose dependent expression of B-domain deleted FVIII protein and a corresponding correction of bleeding time and blood loss. At the highest dose tested complete correction was achieved. Similar corrections in bleeding were observed at approximately the same plasma levels of FVIII protein produced either endogenously by AAV5-SQ or following exogenous administration of B-domain deleted FVIII. Disclosures Bunting: BioMarin Pharmaceutical: Employment. Zhang:BioMarin Pharmaceutical: Employment. Xie:BioMarin Pharmaceutical: Employment. Bullens:BioMarin Pharmaceutical: Employment. Mahimkar:BioMarin Pharmaceutical: Employment. Fong:BioMarin Pharmaceutical: Employment. Sandza:BioMarin Pharmaceutical: Employment. Colosi:BioMarin Pharmaceutical: Employment. Long:BioMarin Pharmaceutical: Employment. Vehar:BioMarin Pharmaceutical: Employment. Carter:BioMarin Pharmaceutical: Employment.

Description: Introduction It is crucial to assess clinical benefit and bleeding risk when selecting an anticoagulant for patients with venous thromboembolism (VTE). This study examined the incidence of major bleeding and non-major bleeding and clinical predictors of major bleeding among patients with VTE in the usual clinical practice setting. Methods VTE patients aged ≥18 years were identified from the Truven Health MarketScan commercial or Medicare supplemental insurance database. Index date was defined as the first VTE diagnosis between 07/01/2006 – 12/31/2011. Patients were required to have ≥2 VTE outpatient diagnoses within a 3-week window or have 1 VTE diagnosis in an inpatient setting, have a continuous health plan enrollment for 6 months prior to the index date (baseline), and have no VTE diagnosis in the baseline period. Major bleeding was defined as any bleeding that resulted in hospitalization or blood transfusion; all other bleeds were non-major bleeding. Patients were followed until major bleeding/non-major bleeding, death, disenrollment, or end of study. Multivariate Cox regression was used to examine factors associated with major bleeding. Results Of 267,655 eligible patients, 182,972 patients were with deep vein thrombosis (DVT) only (68.4%), 69,169 with pulmonary embolism (PE) only (25.8%); and 15,514 with both (5.8%). Mean age was 61.5 years, and 53.1% were female. Mean follow-up period was 17.3 months (median=12.1). The annual incidence of major bleeding and non-major bleeding were 3.9% and 20.1%, respectively. The median time to major bleeding from index VTE diagnosis was 2.2 months. Major risk factors at baseline for major bleeding (Risk increase〉20%) were history of major bleeding (HR=10.78, 95%CI=10.30-11.28) and non-major bleeding (HR=1.61, 95%CI=1.54-1.68), chemotherapy (HR=1.27, 95%CI=1.20-1.35), age ≥65 vs.≤40 years (HR=1.27, 95%CI=1.18-1.37), alcohol abuse (HR=1.26, 95%CI=1.16-1.38), cancer (HR=1.25, 95%CI=1.19-1.31), and heart disease (HR=1.23, 95%CI=1.18-1.28) (Table). Baseline hormone therapy (HR=0.74, 95%CI=0.68-0.80) and pregnancy (HR=0.59, 95%CI=0.46-0.74) were associated with reduced risk for major bleeding. Conclusions Major and non-major bleeding were common in patients with VTE. Multiple factors, especially history of bleeding, age≥65 years, alcohol abuse, cancer and heart disease, were associated with increased risk for major bleeding. Further research needs to examine bleeding risk associated with anticoagulant therapy. Disclosures: Liu: Pfizer: Employment, Equity Ownership. Xie:StatInMed: Employment, Research Funding. Phatak:BMS: Employment, Equity Ownership. Mardekian:Pfizer: Employment, Equity Ownership. Tan:Pfizer: Employment, Equity Ownership. Baser:StatInMed: Employment, Research Funding. Ramacciotti:BMS: Employment, Equity Ownership.

Description: INTRODUCTION: Chronic myeloid leukemia (CML) is a bone marrow and blood disorder accounting for 15% of adult leukemia. A shift in CML management has occurred over the past decade with the introduction of tyrosine kinase inhibitors (TKIs), changing CML status from fatal to a chronic, lifelong illness. However, an association between TKI use and cardiovascular events has been observed. This study aimed to compare major adverse cardiac events (MACE), arterial occlusive events (AOEs), and venous thrombotic events (VTEs) among CML patients in chronic phase (CP-CML) treated with different TKIs. METHODS: A retrospective observational study of adult (aged ≥18 years) CP-CML patients prescribed a TKI was conducted using the IBM® MarketScan® Research Databases from July 2012-June 2017. The index date was defined as the index drug prescription date, identified based on TKI use during the identification period (January 2013-December 2016) in hierarchical order: ponatinib, bosutinib without ponatinib, and other TKIs (imatinib, dasatinib, nilotinib) excluding ponatinib and bosutinib. Patients were required to have continuous health plan enrollment for ≥6 months pre-index date (baseline period) and at least 6 months post-index date (follow-up period). Patients with use of one or two previous TKI(s) before the index date were examined separately. Cardiovascular events occurring through the earliest of discontinuation of index TKI, switch to another TKI, or end of follow-up period using ICD-9/10-CM diagnosis codes were calculated as the number of events per 100 person-years. MACE was defined as a composite of stroke (hemorrhagic stroke and ischemic stroke), myocardial infarction, and inpatient death; AOEs included cardiovascular, cerebrovascular, and peripheral vascular events; VTEs included pulmonary embolism and deep vein thrombosis. RESULTS: After applying the selection criteria, 161 patients had one previous use of a TKI, with 50 ponatinib, 80 bosutinib and 31 other TKI patients. Mean ages were 54, 57, and 58 years for ponatinib, bosutinib, and other TKI cohorts, respectively. Most ponatinib patients initiated treatment with a dose of 45 mg (60%); most bosutinib patients initiated with a dose of 500 mg (53%) . For patients with use of one previous TKI, the average Charlson Comorbidity Index score was 1.4 for ponatinib, 1.8 for bosutinib and 0.8 for other TKI patients. Common baseline comorbid conditions by drug included anemia (ponatinib: 50%; bosutinib 31%; other TKI: 19%), hypertension (ponatinib: 32%, bosutinib: 43%, other TKI: 29%), and diabetes (ponatinib: 16%; bosutinib: 28%; other TKI: 10%). CP-CML patients were observed to have cardiovascular events prior to index TKI use, especially MACE (ponatinib: 4%, bosutinib: 16%, other TKI: 3%), and AOEs (ponatinib: 12%; bosutinib: 25%; other TKI: 19%). During the follow-up period, no significant differences were found for cardiovascular events across patients with TKI use (Table 1); the incidence of MACE was 4.7-8.3, AOEs: 25.8-33.3, and VTE: 2.3-9.1 (in 100 person-years). For those with use of two types of TKIs before the index date, 29 ponatinib, 29 bosutinib, and 4 other TKI patients were identified, with an average age of 51, 59, and 65 years, respectively. A similar trend was observed for patients with use of two prior TKIs. CONCLUSION: CP-CML patients treated with different TKIs (ponatinib, bosutinib, imatinib, dasatinib, and nilotinib) did not have different incidence of cardiovascular events (MACE, AOEs, VTEs) in this small cohort of real-world patients with ≥6-month of follow-up. The results were consistent among patients with prior use of one and two TKI types. Disclosures Levy: Takeda (Millennium Pharmaceuticals, Inc.): Consultancy. Xie:STATinMED Research: Employment. Wang:STATinMED Research: Employment. Neumann:Takeda (Millennium Pharmaceuticals, Inc.): Employment. Srivastava:Takeda (Millennium Pharmaceuticals, Inc.): Employment. Naranjo:Takeda (Millennium Pharmaceuticals, Inc.): Employment. Zhang:STATinMED Research: Employment. Dalal:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd, Cambridge, MA, USA: Employment, Equity Ownership.

Description: Background: Despite an increasing incidence of multiple myeloma (MM) with advancing age and life expectancy, there are few real-world claims-based analyses describing treatment patterns and healthcare costs associated with use of novel treatments.1,2 This study aimed to assess treatment patterns and healthcare costs among newly-diagnosed MM patients using the US Medicare database. Methods: This retrospective study identified adult patients with ≥2 claims for MM (International Classification of Diseases, 9th Revision, Clinical Modification code: 203.0x) 30 days apart and ≥1 treatment during the identification period (01JAN2011-30JUN2014) from the 100% Medicare dataset. Medicare dataset contains medical and pharmacy claims submitted by healthcare providers, facilities and pharmacy. It includes comprehensive demographic information for beneficiaries and a longitudinal picture of their healthcare utilizations and costs .The initial course of therapy (COT1) date was the index date and included all treatments prescribed within 60 days of this date. Patients were required to have continuous enrollment for 12 months pre- and ≥6 months post-index date unless the patient died in 180-day gap, or dose increase from maintenance to relapse therapy. Steroids (dexamethasone/prednisone [d]) were assumed to be included regardless of whether or not they were observed during the study period; this did not impact the ongoing COT. Treatment patterns and healthcare costs during the follow-up period were compared among those initiating lenalidomide (R) with bortezomib (V) ± steroids (RVd) and cyclophosphamide (Cy) with bortezomib (bor) ± steroids (CyBorD). Time-to-next treatment (TTNT) was defined as the duration from initiation of COT1 plus any treatment gaps until the initiation of COT2. Kaplan Meier (KM), Cox regression analyses and a generalized linear model (GLM) were performed to evaluate TTNT, assess the impact of various predictors on TTNT, and estimate the 12-month per patient per month (PPPM) total healthcare costs respectively among patients initiating RVd and CyBorD. Results:After accounting for the patient selection criteria, 9.9% (n=345) of patients initiated RVd and 5.0% (n=175) initiated CyBorD as COT1. CyBorD-treated patients were significantly older (76.1 vs. 74.2 years, p=0.0009) with a higher age-adjusted Charlson Comorbidity Index score (9.5 vs 8.8, p=0.0119). The overall mean duration of COT1 was significantly longer among patients treated with RVd vs CyBorD (13.2 vs 8.5 months, p

Description: Background: Despite a relatively higher incidence in the veteran population, there are few real-world claims-based analyses to describe Multiple Myeloma (MM) treatment patterns among this patient population (Landgren O, Blood, 2006). This study aimed to assess treatment patterns among newly diagnosed MM (ndMM) patients using the US Veteran Health Administration (VHA) data. Methods: This retrospective study identified adult patients with ≥2 claims for MM (ICD-9-CM code: 203.0x) 30 days apart and ≥1 treatment during identification period (1OCT2011-31MAR2015) from the VHA dataset. The initial course of therapy (COT1) date was the index date and included all treatments prescribed within 60 days of this date. Patients were required to have continuous enrollment for 12 months pre- and ≥6 months post-index date unless patients died within 6 months (follow up period), ≥1 full cycle of therapy with a valid COT1 regimen, no evidence of prior MM diagnosis or treatment (including autologous stem cell transplant (ASCT)), and no evidence of ASCT in the follow up period. A subsequent COT (COT2) was defined as the earliest occurrence of: the addition of a new drug or switch in regimen after the first 60 days, restart of a previous regimen after 〉180-day gap, or a dose increase from maintenance to relapse therapy. Dexamethasone/prednisone[d] which were assumed to be included regardless of whether or not they were observed during the study period did not impact the ongoing COT. Treatment patterns during the follow-up period were initially examined among patients treated with novel (lenalidomide [R] and/or bortezomib [V] with or without chemotherapy agents) and non-novel therapies (≥1 chemotherapy agent, steroid monotherapy) and then compared among those initiating Rd and Vd. Time to next treatment (TTNT) was defined as the duration from initiation of COT1 plus any gaps before COT2. Kaplan Meier and Cox regression analyses were performed to evaluate TTNT and assess the impact of various predictors on TTNT among patients initiating Rd and Vd. Results: Of 1,183 patients that met the inclusion criteria, 55.4% (n=655) were treated with novel therapies and 44.6% (n=528) with non-novel therapies. Among patients treated with novel therapy, the majority initiated Rd (47.8%; n=313) as COT1 followed by Vd (31.2%; n=204), Vd with cyclophosphamide (11.5%; n=75), RVd (6.6%; n=43), Vd with a chemotherapy agent (2.4%; n=16) and Rd with a chemotherapy agent (0.6%; n=4).Rd initiators were significantly older (75.1 vs 70.6 years, p=0.0002) and a higher percentage was white (69.7% vs 47.0%; p

Description: INTRODUCTION: Chronic myeloid leukemia (CML) is a bone marrow and blood disorder accounting for 15% of adult leukemia. Tyrosine kinase inhibitors (TKIs) have been the standard of care for CML treatment. However, an association between TKI use and cardiovascular events has been observed. Ponatinib and bosutinib are introduced to provide more options for patients who failed their first-line treatment. The incidence of major adverse cardiac events (MACEs), arterial occlusive events (AOEs), and venous occlusive events (VOEs) were assessed among CML patients who were prescribed ponatinib vs bosutinib. METHODS: A retrospective observational study was conducted among adult CML patients aged ≥18 years with use of 1 or 2 prior TKIs who were prescribed bosutinib or ponatinib. Study patients were selected from the IBM® MarketScan® Research database from July 2012-June 2017. The index date was defined as the index drug prescription date, identified based on TKI use during the identification period (January 2013-December 2016) in a hierarchical order based on the sequence of treatment lines: ponatinib and bosutinib without ponatinib. Continuous health plan enrollment for ≥6 months pre-index date (baseline period) and at least 6 months post-index date (follow-up period) was required. Cardiovascular (CV) events (MACEs, AOEs, VOEs) using ICD-9/10-CM diagnosis codes occurring through the earliest of index TKI discontinuation, switch to another TKI, or end of follow-up period, were calculated as the number of events per 100 person-years (PYs). Inverse probability of treatment weighting (IPTW) was applied to adjust for differences in baseline characteristics between the treatment cohorts. Kaplan-Meier (KM) and Cox proportional hazard model analyses were conducted on the adjusted sample to examine any difference in CV event risk. RESULTS: After applying the selection criteria, 79 and 109 patients were included in the ponatinib and bosutinib cohorts, respectively. Mean ages were 53 years (ponatinib cohort) and 58 years (bosutinib cohort). The average Charlson Comorbidity Index (CCI) scores - defined by categorizing comorbidities using diagnosis codes - were 1.23 for ponatinib and 1.81 for the bosutinib cohort. Common baseline comorbid conditions included anemia (ponatinib: 49%; bosutinib 34%), hypertension (ponatinib: 33%, bosutinib: 46%), and diabetes (ponatinib: 15%; bosutinib: 29%). Some patients were observed to have CV events, specifically MACEs (ponatinib 8%; bosutinib 16%) and AOEs (ponatinib 15%; bosutinib 28%), before index ponatinib or bosutinib use. In the follow-up period, ponatinib patients were associated with a similar incidence of MACEs (14.70 vs 10.46 per 100 PYs; p=0.464), AOEs (29.56 vs 34.50 per 100 PYs; p=0.632), and VOEs (36.21 vs 34.70 per 100 PYs; p=0.890) compared to bosutinib patients. After applying IPTW, similar risks of the CV events (MACE, AOEs, VTEs) were observed in the KM analysis (Figure 1) expressed as time to CV event. After adjusting for additional confounders using Cox models, compared to those with bosutinib use, ponatinib patients were associated with similar rate of MACEs (Hazard Ratio [HR]: 1.02; 95% CI: 0.34, 3.01), AOEs (HR: 0.90; 95% CI: 0.43, 1.85), and VOEs (HR: 0.92; 95% CI: 0.44, 1.94). CONCLUSION: Among CML patients treated with ponatinib or bosutinib in second or third line, similar risks of cardiovascular events (MACE, AOEs, VTEs) were observed in the follow-up in this study in a community setting. Figure 1 Disclosures Levy: Takeda (Millennium Pharmaceuticals): Consultancy. Xie:STATinMED Research: Other: I am a paid employee of STATinMED Research which is a paid consultant to Takeda Pharmaceutical Corporation. . Wang:STATinMED Research: Other: I am a paid employee of STATinMED Research which is a paid consultant to Takeda Pharmaceutical Company. . Neumann:Millennium Pharmaceuticals (Takeda): Employment, Other: I am a paid employee of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd. Srivastava:Millennium Pharmaceuticals (Takeda): Other: I am a paid employee of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd. Naranjo:Millennium Pharmaceuticals (Takeda): Other: I am a paid employee of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd. Xu:Millennium Pharmaceuticals (Takeda): Other: I am a paid employee of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd. Zhang:STATinMED Research: Other: I am a paid employee of STATinMED Research which is a paid consultant to Takeda Pharmaceutical Corporation.. Dalal:Millennium Pharmaceuticals (Takeda): Other: I am a paid employee of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd.