Takeda Development Center Americas Research Articles

Recombinant ADAMTS13 in Congenital Thrombotic Thrombocytopenic Purpura

BackgroundCongenital thrombotic thrombocytopenic purpura (TTP) results from severe hereditary deficiency of ADAMTS13. The efficacy and safety of recombinant ADAMTS13 and standard therapy (plasma-derived products) administered as routine prophylaxis or on-demand treatment in patients with congenital TTP is not known.MethodsIn this phase 3, open-label, crossover trial, we randomly assigned patients in a 1:1 ratio to two 6-month periods of prophylaxis with recombinant ADAMTS13 (40 IU per kilogram of body weight, administered intravenously) or standard therapy, followed by the alternate treatment; thereafter, all the patients received recombinant ADAMTS13 for an additional 6 months. The trigger for this interim analysis was trial completion by at least 30 patients. The primary outcome was acute TTP events. Manifestations of TTP, safety, and pharmacokinetics were assessed. Patients who had an acute TTP event could receive on-demand treatment.ResultsA total of 48 patients underwent randomization; 32 completed the trial. No acute TTP event occurred during prophylaxis with recombinant ADAMTS13, whereas 1 patient had an acute TTP event during prophylaxis with standard therapy (mean annualized event rate, 0.05). Thrombocytopenia was the most frequent TTP manifestation (annualized event rate, 0.74 with recombinant ADAMTS13 and 1.73 with standard therapy). Adverse events occurred in 71% of the patients with recombinant ADAMTS13 and in 84% with standard therapy. Adverse events that were considered by investigators to be related to the trial drug occurred in 9% of the patients with recombinant ADAMTS13 and in 48% with standard therapy. Trial-drug interruption or discontinuation due to adverse events occurred in no patients with recombinant ADAMTS13 and in 8 patients with standard therapy. No neutralizing antibodies developed during recombinant ADAMTS13 treatment. The mean maximum ADAMTS13 activity after recombinant ADAMTS13 treatment was 101%, as compared with 19% after standard therapy.ConclusionsDuring prophylaxis with recombinant ADAMTS13 in patients with congenital TTP, ADAMTS13 activity reached approximately 100% of normal levels, adverse events were generally mild or moderate in severity, and TTP events and manifestations were rare. (Funded by Takeda Development Center Americas and Baxalta Innovations; ClinicalTrials.gov number, NCT03393975.)

Real-World Usage of Hyaluronidase-Facilitated Subcutaneous Immunoglobulin 10% in Patients with Multiple Myeloma Diagnosed with Secondary Immunodeficiency Disease

Introduction: In patients with mature B-cell malignancies such as multiple myeloma (MM), both the underlying disease and immunosuppressive therapy can result in patients developing secondary immunodeficiency disease (SID). SID often manifests in severe, recurrent, or persistent infections that can impair a patient's quality of life and are a major cause of morbidity and mortality in patients with MM, thereby resulting in significant clinical and socioeconomic burden. The use of immunoglobulin (Ig) replacement therapy is well established for the treatment of hypogammaglobulinemia in patients with primary immunodeficiency disease (PIDD). Hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) 10% is a dual-vial unit of IgG 10% and recombinant human hyaluronidase (rHuPH20). fSCIG 10% is approved in the USA for the treatment of adults and children aged 2 years or older with PIDD, and in the EU for adults and children of any age with PIDD or SID. fSCIG 10% is not fully integrated into standard of care for patients with SID in many countries, in part owing to comparatively less familiarity of hematologists and oncologists with the evidence supporting the use of fSCIG 10% than for intravenous IgG therapy in patients with SID. Therefore, the HyMMy study (NCT05879757) aims to generate real-world evidence to gain a better understanding of patterns of fSCIG 10% use and outcomes in patients with MM and SID. Methods: HyMMy is a prospective, noninterventional, observational study that will be conducted at 30 centers in Europe and South America. It is planned for 100 patients to be enrolled and observed over a 12-month follow-up period. The overall duration of the study will be 38 months. Patients will be eligible for inclusion if they are aged 18 years or older, have a diagnosis of MM, and fulfill the diagnosis criteria for SID: patient suffers from severe, recurrent, or persistent infection despite appropriate anti-infective treatment, and has proven specific antibody failure or a serum IgG trough level of less than 4 g/L (excluding paraprotein). Patients may enter the study after being diagnosed with SID and no more than 30 days after fSCIG 10% treatment initiation, or with no more than 2 doses of fSCIG 10% already infused ( Figure). Patients newly starting fSCIG 10% have a 30-day window from enrollment to inclusion. Patients will be excluded if they have PIDD, have received Ig treatment or prophylaxis within 3 months of enrollment, have an ongoing serious infection requiring intravenous antimicrobial therapy, have a history of malignancy other than MM within 3 years of enrollment, or have had major surgery within 2 weeks of enrollment. The primary endpoint is to characterize the real-world infusion parameters of fSCIG 10% administration (dosing and administration characteristics; treatment interval; infusion volume, sites, rate, and duration; training visits; and fSCIG 10% discontinuation, interruption, or switch to other treatment). Secondary endpoints will examine the disease course and clinical management of MM (including overall survival and healthcare resource utilization) in patients treated with fSCIG 10%. The exploratory endpoints include: burden of infection; infection rate, type, duration, and severity; patient-reported outcomes pertaining to health-related quality of life, collected via questionnaire at the patients' visit; and overall physician assessment of fSCIG 10% utilization, tolerability, and effectiveness, as measured by a 5-point Likert scale questionnaire. Results: Patient recruitment started in June 2023. Interim analysis is planned after enrollment of the first 50 patients, and the estimated end of the study is 2026. Conclusions: HyMMy is the first prospective, observational study that focuses on the assessment of fSCIG 10% utilization patterns in adults with MM diagnosed with SID. The study will help to improve understanding of the treatment patterns and options available for patients with SID and hematologic malignancies, in particular MM. Takeda Development Center Americas, Inc. funded this study. Takeda Pharmaceuticals International AG funded writing support.

Recombinant ADAMTS13 for the Treatment of Acute TTP Events in Patients with Congenital Thrombotic Thrombocytopenic Purpura: Results from the Phase 3 Randomized, Controlled, Crossover Study and the Phase 3b Continuation Study

Background Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare, life-threatening thrombotic microangiopathy caused by an inherited deficiency of the enzyme ADAMTS13. An ongoing phase 3 study (NCT03393975) and phase 3b continuation study (NCT04683003) are investigating the safety and efficacy of recombinant ADAMTS13 (rADAMTS13; TAK-755; Takeda Development Center Americas, Inc., Lexington, MA, USA) for prophylaxis and on-demand treatment of acute events in patients with cTTP. Aims To assess the efficacy and safety of rADAMTS13 for the treatment of acute TTP events and long-term prophylaxis in patients with severe cTTP. Methods The phase 3 prospective, randomized, controlled, open-label, multicenter, crossover study (NCT03393975) is open to enroll patients 0-70 years old with severe cTTP (ADAMTS13 activity <10%). Upon completion of the phase 3 study, patients could enroll into the phase 3b prospective, open-label, multicenter, single treatment arm continuation study (NCT04683003). In the phase 3 study, patients were randomized 1:1 at enrollment to receive prophylaxis with either rADAMTS13 or standard of care (SoC). SoC was determined by the treating physician and could include fresh frozen plasma, pooled solvent/detergent-treated plasma, or factor VIII/von Willebrand factor concentrates. Patients in the phase 3b continuation study received open-label rADAMTS13 treatment. In both studies, patients could be enrolled and receive treatment on demand for acute TTP events. Per protocol, rADAMTS13 was to be administered at 40 IU/kg on Day 1, 20 IU/kg on Day 2 and 15 IU/kg daily from Day 3 onwards until 2 days after resolution of the acute event (defined as platelet count either ≥150,000/μL or within 25% of baseline; and elevation of LDH levels ≤1.5× of baseline or ≤1.5× the upper limit of normal). Data are presented from a pre-planned interim analysis (data cutoff: August 12, 2022) and focus on the treatment of acute TTP events in both studies. Results At the time of the data cutoff, 8 acute TTP events were reported in 7 patients ( Table), all of whom were ≥18 years old. None of the events occurred while the patient was receiving rADAMTS13 prophylaxis. Six events occurred in 5 patients (median age: 20.0 years; sex: 3 male, 2 female) who received on-demand treatment in the phase 3 study; 2 of these patients were randomized to receive rADAMTS13 and 3 to receive SoC. One event also occurred in the phase 3 study while the patient was receiving prophylaxis with SoC. One event occurred in the screening period prior to the patient starting rADAMTS13 prophylaxis in the phase 3b continuation study; this event was treated with rADAMTS13. Platelet counts observed during the first 3 days of treatment for all 8 acute TTP events are shown in the Figure. Prior to study treatment, on Day 0, the mean platelet counts were similar between the rADAMTS13 and SoC cohorts. Over the first 3 treatment days, the mean platelet count increased more than ~5-fold with rADAMTS13, and ~3-fold with SoC. All three acute TTP events treated with rADAMTS13 resolved without requiring the administration of any other treatment containing ADAMTS13. Based on pharmacokinetics (PK) data available in 5 patients (3 received treatment with rADAMTS13 and 2 with SoC), the post-infusion ADAMTS13 activity levels ~1 hour after administration were between 80% to 270% of normal with rADAMTS13 and between 10% to 48% with SoC. These observed ADAMTS13 activity levels were as expected based on the linear PK observed following single dose PK assessments in the phase 3 study. Of the 4 patients who received SoC for the treatment of an acute TTP event, 2 experienced a mild treatment-emergent adverse event (TEAE) that was considered related to the SoC (nausea and pruritis). Of the 3 patients who received rADAMTS13, 1 patient experienced 3 mild TEAEs (feeling hot, nausea, and thrombocytosis) that were considered related to rADAMTS13. No serious TEAEs related to rADAMTS13 were reported and no neutralizing antibodies against ADAMTS13 were observed. Conclusions The resolution of acute TTP events and an improvement in platelet count in patients with cTTP following treatment with rADAMTS13 was closely related to higher ADAMTS13 activity exposure. No serious TEAEs related to rADAMTS13 were reported.

Population Pharmacokinetics and Exposure-Response Analyses to Demonstrate the Link of Causality between ADAMTS13 and the Clinical Effects of Recombinant ADAMTS13 Compared to Plasma-Based Therapies

Background: Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare, life-threatening deficiency of ADAMTS13. TTP clinical manifestations include thrombocytopenia and microangiopathic hemolytic anemia (MAHA) but incomplete understanding of their relationship to ADAMTS13 exposure is a challenge for assessing the impact of ADAMTS13 supplementation. Integrated population pharmacokinetics (PopPK) analysis and exposure-response modeling were conducted to support the clinical benefit assessment of recombinant ADAMTS13 (rADAMTS13; Takeda Development Center Americas, Inc., Lexington, MA, USA) in patients with cTTP. Aims: To characterize ADAMTS13 activity following intravenous (IV) administration of rADAMTS13 or plasma-based therapies (PBT) in patients with cTTP, to identify sources of variability, and to evaluate the relationship between ADAMTS13 activity and the probability of isolated TTP manifestations. Methods:The PopPK analysis included data from phase 1 (NCT02216084), pivotal phase 3 (NCT03393975), and phase 3b continuation (NCT04683003) studies of rADAMTS13. Exposure-response analyses included data from NCT03393975 where patients received rADAMTS13 or PBT in prophylaxis treatment period 1 and crossed over to the opposite treatment in period 2. PBT consisted of fresh frozen plasma, solvent/detergent-treated plasma or factor VIII/von Willebrand factor concentrates. A covariate analysis was conducted to identify sources and assess the significance of variability on the PK of ADAMTS13 activity. Exposure-response models were developed to assess the relationship between the average ADAMTS13 plasma activity for a given dosing interval (C ave) and the count of isolated TTP manifestations: thrombocytopenia (platelet count decreased ≥25% of baseline or a platelet count <150,000/µL) or MAHA (increased lactate dehydrogenase >1.5 × of baseline or >1.5 × upper limit of normal). Cox proportional hazard modeling using recurring events was performed to demonstrate the treatment effect of rADAMTS13 over PBT, and explain carry-over prophylactic effects. Repeated time to event was performed using longitudinal data from all periods to demonstrate ADAMTS13-dependent reduction in the hazard of thrombocytopenia. Results: A 2-compartment PK model with linear elimination adequately characterized the time profiles of ADAMTS13 activity following body-weight-based IV administration of rADAMTS13 or PBT (N=65 patients). Following body-weight-based dosing, dosing interval (once per week [Q1W] vs every 2 weeks [Q2W]) and treatment type (rADAMTS13 vs PBT) were the only significant extrinsic factors found with an impact on ADAMTS13 PK. ADAMTS13 C ave was associated with a significant reduction of the thrombocytopenia hazard in an activity-dependent manner (Figure). Exposure-response model simulations suggested that >95% of patients treated with rADAMTS13 are predicted to have plasma C ave ADAMTS13 >0.13 IU/mL (equivalent to 13% activity), with high (>70%) protection against thrombocytopenia regardless of dosing intervals (Q2W or Q1W) and age. In contrast, a similar level of protection against thrombocytopenia is expected in only ~10% of patients treated with PBT (Table). Similarly, a significant exposure-response relationship was identified between ADAMTS13 C ave and MAHA.In treatment period 1, rADAMTS13 was associated with a higher probability of zero counts of thrombocytopenia versus PBT from week 2 onwards. Patients switching from rADAMTS13 to PBT in period 2 initially had a slightly higher probability of having zero counts of thrombocytopenia than patients switching from PBT to rADAMTS13, suggesting that treatment with rADAMTS13 led to a carry-over prophylactic effect maintained for some time after treatment cessation. Conclusions: Besides body-weight-based dosing, no additional dose adjustments of rADAMTS13 are needed in the cTTP patient population. A consistent and significant ADAMTS13 activity-response relationship was identified in which rADAMTS13 reduced the hazard of objective laboratory based TTP manifestations (thrombocytopenia and MAHA) in an activity-dependent manner. Overall, these findings suggest that rADAMTS13 at 40 IU/kg Q2W or Q1W offers a favorable prophylactic treatment effect over PBT that is attributable to higher ADAMTS13 activity.

Safety and Pharmacokinetics of Recombinant ADAMTS13 in Patients with Sickle Cell Disease: A Phase 1 Randomized, Double-Blind, Placebo-Controlled Study

Background Sickle cell disease (SCD) is an autosomal recessive hemoglobinopathy associated with chronic hemolysis and vaso-occlusive crises (VOCs). Despite the use of treatments such as hydroxyurea, many patients continue to experience VOCs. There is emerging evidence implicating the dysregulation of the von Willebrand factor (VWF)-ADAMTS13 axis in the pathophysiology of VOCs. The size and platelet-binding activity of ultra-large VWF multimers is regulated by the VWF-cleaving metalloprotease ADAMTS13; therefore, the administration of recombinant ADAMTS13 (rADAMTS13), particularly during VOCs, may be therapeutically beneficial in patients with SCD. Here, we present findings from a phase 1 study (NCT03997760) investigating the safety and pharmacokinetics (PK) of three doses of rADAMTS13 (TAK-755; Takeda Development Center Americas, Inc., Lexington, MA, USA) in patients with SCD. Aims To assess the safety, tolerability, and PK of 40 IU/kg, 80 IU/kg, and 160 IU/kg rADAMTS13 in patients with SCD at baseline health. Methods This phase 1, randomized, double-blind, placebo-controlled, multicenter, ascending single dose study (NCT03997760) enrolled patients aged between 18 and 65 years with a documented history of HbSS or HbSβ o thalassemia. Concurrent treatment with a stable dose of hydroxyurea was permitted. Patients were at baseline health: those diagnosed with acute VOC in the 21 days prior to dose administration were excluded. Patients who had received a blood transfusion within 30 days of screening were also excluded. Patients were randomized 3:1 to receive a single intravenous infusion of either rADAMTS13 or placebo in three sequential dose cohorts: cohort 1, 40 IU/kg; cohort 2, 80 IU/kg; cohort 3, 160 IU/kg. Patients were followed for 28 days post-infusion. Each dose cohort was opened sequentially following a review of safety data by a dose escalation committee. Primary safety endpoints included treatment-emergent adverse events (TEAEs), serious TEAEs, and the incidence of neutralizing antibodies against ADAMTS13. Secondary endpoints included an assessment of PK, comprising the maximum concentration (C max) and the area under the concentration-time curve (AUC) from zero (pre-dose) to 72 hours post-dose (AUC 0-72) estimated from ADAMTS13 antigen and activity levels, among other parameters. Results Five patients received placebo and 14 patients received a single dose of rADAMTS13 (cohort 1, n=4; cohort 2, n=6; cohort 3, n=4). The median age (range) of patients who received placebo was 36.0 (20-43) years and 2 (40.0%) were male. Median age (range) of patients who received rADAMTS13 was 38.5 (23-50) years and 9 (64.3%) were male. TEAEs were reported in 2 (40.0%) patients who received placebo and 8 (57.1%) patients who received rADAMTS13. TEAEs considered related to rADAMTS13 were reported in 4 patients (28.6%; Table). One serious TEAE (sickle cell anemia with crisis) not considered related to rADAMTS13 was reported in a patient who received 40 IU/kg rADAMTS13. No bleeding-related TEAEs were reported during the study and no TEAEs led to study discontinuation or death. No anti-ADAMTS13 neutralizing antibodies were detected within 28 days following rADAMTS13 administration. For the PK assessment, mean (standard deviation [SD]) baseline ADAMTS13 antigen was 0.68 (0.16) μg/mL, and rADAMTS13 demonstrated a dose-proportional increase in ADAMTS13 antigen level ( Figure). For cohorts 1, 2, and 3, respectively, baseline-adjusted ADAMTS13 antigen mean C max was 0.51 μg/mL (n=4), 1.07 μg/mL (n=5), and 2.08 μg/mL (n=4), and mean AUC 0-72 was 18.21 h*μg/mL (n=3), 43.01 h*μg/mL (n=5), and 74.51 h*μg/mL (n=4). Mean (SD) baseline ADAMTS13 activity was 1.06 (0.31) IU/mL. For cohorts 1, 2 and 3, respectively, mean C max for baseline-adjusted ADAMTS13 activity was 0.94 IU/mL (n=4), 2.09 IU/mL (n=5), and 3.08 IU/mL (n=4). Conclusions No safety signals or dose-limiting toxicities, such as bleeding events, were observed for the three evaluated doses of rADAMTS13 up to 160 IU/kg, and no rADAMTS13-related serious TEAEs were reported. No anti-ADAMTS13 neutralizing antibodies were detected during the study. rADAMTS13 demonstrated a dose-proportional increase in ADAMTS13 antigen levels, which is consistent with linear PK. Findings from this study support the further investigation of rADAMTS13 as a potential therapeutic option for patients with SCD.

Quantitative System Pharmacology Modeling of the Effect of Recombinant ADAMTS13 on Platelets in Patients with Congenital Thrombotic Thrombocytopenic Purpura

Background: Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare, thrombotic microangiopathy due to an inherited deficiency of the von Willebrand factor (VWF)-cleaving protease, ADAMTS13.Accumulation of ultra-large VWF multimers increases blood clot formation in small blood vessels, leading to a low platelet count (thrombocytopenia). Treatment of cTTP consists of ADAMTS13 replacement with infusions of plasma-based therapies (PBT). Recombinant ADAMTS13 (rADAMTS13; Takeda Development Center Americas, Inc., Lexington, MA, USA) is in development for patients with cTTP.The ultra-rare nature of cTTP limits the sample size for a formally powered study to assess the impact of ADAMTS13 supplementation on efficacy outcome. This study was a proof-of-principle that model-based clinical trial simulations can be used to supplement clinical trial data in ultra-rare indications. Aims: To calibrate and validate a quantitative system pharmacology (QSP) model describing a mechanistic relationship between ADAMTS13, VWF and platelet numbers in patients with cTTP who received long-term prophylaxis with rADAMTS13 or PBT (fresh frozen or solvent/detergent treated plasma). In addition, to evaluate the treatment benefits of rADAMTS13 versus PBT using clinical trial simulations in virtual patients with cTTP as a supplement to the cTTP phase 3 study (NCT03393975) data. Methods: A QSP model was built using i) in vitro enzyme kinetic data and preclinical experimental data following administration of recombinant VWF and rADAMTS13 in ADAMTS13 knockout (KO) mice, and ii) data from the literature including platelet count and VWF activity from healthy human and untreated patients with cTTP. These data were used to calibrate the parameters corresponding to interactions between ADAMTS13 activity, VWF activity, and platelets. The model was validated against literature data from patients with cTTP treated with PBT and with data from a phase 2 study of patients with immune-mediated TTP treated with rADAMTS13 (NCT03922308). The model was then calibrated to longitudinal platelet data from the cTTP phase 3 study, in which patients with cTTP received prophylaxis for 6 months with PBT (exposure equivalent to ~10 IU/kg ADAMTS13 in the form of 10-20 mL/kg doses) and rADAMTS13 (40 IU/kg) either once every week (Q1W) or once every 2 weeks (Q2W) dosing intervals . The model was used to provide 1-year clinical trial simulations of isolated thrombocytopenia occurrences in a population of 1,000 virtual patients, phenotype-matched to patients in the cTTP phase 3 study. Results:Virtual clinical trial simulations using the QSP model suggested that rADAMTS13 administered over 1 year with a Q1W or Q2W schedule results in significantly fewer patients experiencing occurrences of thrombocytopenia (platelet count threshold of <150 x 10 9/L) compared to patients treated with PBT (hazard ratio [HR] relative to Q2W PBT: Q1W PBT, HR = 0.62; Q2W rADAMTS13, HR = 0.47; Q1W rADAMTS13, HR = 0.18). The treatment difference between rADAMTS13 and PBT was even more pronounced when a thrombocytopenia threshold of <100 x 10 9/L was used (Figure and Table). Simulations also predicted a prophylactic carry-over effect on platelets, with approximately 20 days taken to reach 90% of the long-term average platelet count when switching from rADAMTS13 to PBT or from PBT to rADAMTS13. A correlation analysis for a Q2W dosing of rADAMTS13 demonstrated that ADAMTS13 trough activity (C trough, Spearman ρ = 0.96) and time with ADAMTS13 activity above 10% (Spearman ρ = 0.93) showed stronger correlations with increased platelet count than the maximum plasma ADAMTS13 activity level (C max, Spearman ρ = 0.68). A correlation analysis for a Q1W dosing frequency produced similar results.Mean time above 10% ADAMTS13 activity was higher following rADAMTS13 versus PBT administration (5.2 vs 1.7 days). Conclusions: This model-based virtual clinical trial simulation predicts that dosing with rADAMTS13 would provide >50% reduction in the HR of thrombocytopenia occurrences over PBT. Patients may also have a higher level of protection for 2-3 weeks when switching from rADAMTS13 to PBT. These findings supplement the assessment of clinical benefit of rADAMTS13 in the cTTP phase 3 study and show that increased ADAMTS13 activity following rADAMTS13 administration is likely to reduce occurrences of thrombocytopenia in cTTP.

Comparison of health care costs and resource utilization for commonly used proteasome inhibitor-immunomodulatory drug-based triplet regimens for the management of patients with relapsed/refractory multiple myeloma in the United States.

BACKGROUND: Economic differences among currently available proteasome inhibitors (PI)-based lenalidomide-dexamethasone (Rd)-backbone triplet regimens-ixazomib (I), bortezomib (V), and carfilzomib (K) plus Rd-remain poorly understood. OBJECTIVE: To assess health care resource utilization (HCRU) and health care costs of patients with relapsed/refractory multiple myeloma (RRMM) in the United States treated with IRd, VRd, and KRd. METHODS: This retrospective longitudinal cohort study using IQVIA PharMetrics Plus adjudicated claims US data (January 1, 2015, to September 30, 2020) included adult patients with all available data who initiated IRd, VRd, or KRd in second line of therapy or later (LOT2+) on or after September 1, 2015. The index date was the treatment initiation date for each LOT (multiple LOTs per patient were included) and the baseline was 6 months pre-index. MM-related and all-cause HCRU/costs were assessed during follow-up and reported per patient per month (PPPM; 2020 US Dollars). For MM-related costs only, treatment administration costs were excluded from outpatient (OP) costs and instead summed with pharmacy costs. HCRU/costs were compared between treatment groups using generalized linear models (GLMs). Cost variables were compared using 2-part models and GLM with log transformation and γ distribution. Inverse probability of treatment weighting (IPTW) adjusted for imbalance of baseline confounders across treatment groups. RESULTS: The study included 511 patients contributing 542 LOTs (IRd: n = 153; VRd: n = 262; KRd: n = 127). Before IPTW, mean observed time spent on therapy was 8.5, 9.3, and 7.3 months for the IRd, VRd, and KRd cohorts, respectively. During follow-up and after IPTW, IRd and VRd were associated with significantly fewer OP visits vs KRd. Post-IPTW comparisons of MM-related costs for IRd vs KRd yielded lower OP costs for IRd (mean diff. PPPM: -$3,428; P < 0.001), contributing to lower total medical costs (-$3,813; P < 0.001) and total health care cost savings with IRd vs KRd (-$5,813; P = 0.001). MM-related OP costs were lower for VRd (mean diff. PPPM: -$3,543; P < 0.001) than KRd, reducing its total MM-related medical costs (-$3,997; P = 0.002), leading to total MM-related health care cost savings with VRd vs KRd (-$12,357; P < 0.001). All-cause cost comparisons yielded similar results (total health care cost savings for IRd and VRd vs KRd: -$6,371 and -$13,629, respectively; all P < 0.001). CONCLUSIONS: From the US insurance-payer perspective, patients treated with IRd and VRd had significant medical cost savings vs KRd due to lower OP costs when excluding treatment administration costs. The differential economic impacts of PI-Rd regimens in this study may help to inform treatment decisions for patients with MM. DISCLOSURES: This study and article were supported by Takeda Development Center Americas, Inc. Dr Sanchez has no conflicts to declare. Dr Chari has the following relationships: Research Support/Principal Investigator: Amgen, Array Biopharma, Celgene, Glaxo Smith Klein, Janssen, Millenium/Takeda, Novartis Pharmaceuticals, Oncoceutics, Pharmacyclics, Seattle Genetics; Consultant: Amgen, Bristol-Myers Squibb, Celgene, Millenium/Takeda, Janssen, Karyopharm; Scientific Advisory Board: Amgen, Celgene, Millenium/Takeda, Janssen, Karyopharm, Sanofi, Seattle Genetics. Drs Cherepanov, Huang, Dabora, and Noga are current employees of Takeda, while Drs Stull and Young are ex-employees of Takeda; Drs Cherepanov and Huang also own stocks in Takeda. Dr DerSarkissian, Ms Cheng, Ms Zhang, Mr Banatwala, and Dr Duh are employees of Analysis Group, Inc. (AG), a consulting firm that received funding from Takeda to conduct this study. Ms Pi was an employee of AG at the time of the study. Dr Ailawadhi has the following relationships to declare: Research Support and Consulting for BMS, GSK, and Janssen; Research Support from AbbVie, Arch Oncology, Cellectar, Medimmune, Pharmacyclics, and Xencor; Consulting for Beigene, Oncopeptides, Regeneron, Sanofi, and Takeda.

Oral Orexin Receptor 2 Agonist in Narcolepsy Type 1

BackgroundNarcolepsy type 1 is caused by severe loss or lack of brain orexin neuropeptides.MethodsWe conducted a phase 2, randomized, placebo-controlled trial of TAK-994, an oral orexin receptor 2–selective agonist, in patients with narcolepsy type 1. Patients with confirmed narcolepsy type 1 according to clinical criteria were randomly assigned to receive twice-daily oral TAK-994 (30 mg, 90 mg, or 180 mg) or placebo. The primary end point was the mean change from baseline to week 8 in average sleep latency (the time it takes to fall asleep) on the Maintenance of Wakefulness Test (range, 0 to 40 minutes; normal ability to stay awake, ≥20 minutes). Secondary end points included the change in the Epworth Sleepiness Scale (ESS) score (range, 0 to 24, with higher scores indicating greater daytime sleepiness; normal, <10) and the weekly cataplexy rate.ResultsOf the 73 patients, 17 received TAK-994 at a dose of 30 mg twice daily, 20 received 90 mg twice daily, 19 received 180 mg twice daily, and 17 received placebo. The phase 2 trial and an extension trial were terminated early owing to hepatic adverse events. Primary end-point data were available for 41 patients (56%); the main reason for missing data was early trial termination. Least-squares mean changes to week 8 in average sleep latency on the MWT were 23.9 minutes in the 30-mg group, 27.4 minutes in the 90-mg group, 32.6 minutes in the 180-mg group, and −2.5 minutes in the placebo group (difference vs. placebo, 26.4 minutes in the 30-mg group, 29.9 minutes in the 90-mg group, and 35.0 minutes the 180-mg group; P<0.001 for all comparisons). Least-squares mean changes to week 8 in the ESS score were −12.2 in the 30-mg group, −13.5 in the 90-mg group, −15.1 in the 180-mg group, and −2.1 in the placebo group (difference vs. placebo, −10.1 in the 30-mg group, −11.4 in the 90-mg group, and −13.0 in the 180-mg group). Weekly incidences of cataplexy at week 8 were 0.27 in the 30-mg group, 1.14 in the 90-mg group, 0.88 in the 180-mg group, and 5.83 in the placebo group (rate ratio vs. placebo, 0.05 in the 30-mg group, 0.20 in the 90-mg group, and 0.15 in the 180-mg group). A total of 44 of 56 patients (79%) receiving TAK-994 had adverse events, most commonly urinary urgency or frequency. Clinically important elevations in liver-enzyme levels occurred in 5 patients, and drug-induced liver injury meeting Hy’s law criteria occurred in 3 patients.ConclusionsIn a phase 2 trial involving patients with narcolepsy type 1, an orexin receptor 2 agonist resulted in greater improvements on measures of sleepiness and cataplexy than placebo over a period of 8 weeks but was associated with hepatotoxic effects. (Funded by Takeda Development Center Americas; TAK-994-1501 and TAK-994-1504 ClinicalTrials.gov numbers, NCT04096560 and NCT04820842.)

RETROSPECTIVE STUDY OF BURDEN OF INFECTION IN PATIENTS WITH AND WITHOUT SECONDARY IMMUNODEFICIENCY DISEASE FOLLOWING DIAGNOSIS OF CHRONIC LYMPHOCYTIC LEUKAEMIA

Introduction: Patients with lymphoid malignancies such as chronic lymphocytic leukaemia (CLL)/small lymphocytic lymphoma (SLL) are at risk of developing secondary immunodeficiency disease (SID), which can lead to increased susceptibility to severe, recurrent or persistent infections. This study evaluated burden of infection in patients with and without SID following diagnosis of CLL/SLL. Methods: This observational, retrospective cohort study was conducted using anonymized data from the Optum-Humedica database in the USA (1-Oct-15–10-Mar-20). Patients with SID (SID cohort) and without SID (no-SID cohort) were identified 1-Apr-16–10-Mar-19 (selection window). The definition of SID included International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) hypogammaglobulinaemia (HGG) codes, low immunoglobulin G (IgG) levels (<5.0 g/L) and signs/symptoms of SID. The SID index date was the earliest occurrence of an ICD-10-CM HGG code or record of low IgG levels. In patients without SID, the index date was randomly assigned to replicate the distribution of index dates in the SID cohort. CLL/SLL diagnosis and baseline characteristics were identified during a 6-month pre-index period. Included patients were aged ≥18 years with a confirmed diagnosis of CLL/SLL. Infection-related outcomes and overall survival were assessed in patients with ≥12-month and ≥3 months follow-up post-index date, respectively. Results: Of patients with CLL/SLL, 502 and 3928 with and without SID, respectively, were included (SID vs no-SID: mean [standard deviation; SD] age 70.6 [9.7] vs. 71.6 [10.5] years; 59.2% vs 57.7% male). At 12-month follow-up, a larger proportion of patients with SID had ≥1 infection than those without SID (SID: 70.1%; no-SID: 30.4%; p < 0.001). Compared with the no-SID cohort, in the SID cohort there was also a higher number of infections (SID vs no-SID: mean [SD]: 8.4 [12.7] vs. 4.1 [5.4]; p < 0.001), proportion of patients with ≥1 SBI (SID: 39.8%; no-SID: 9.2%; p < 0.001) and proportion of patients with ≥1 infection-associated hospitalization (SID: 27.7%; no-SID: 5.8%; p < 0.001). The most common type of infection was bacterial (SID: 63.7%; no-SID: 24.9%); in those patients who experienced an SBI, the most frequently reported infection was bacterial pneumonia. To assess overall survival, 646 and 4719 patients with and without SID, respectively, were included. Overall survival at 24 months was lower in the SID cohort (77.3%) than the no-SID cohort (87.2%). Conclusions: Patients with CLL/SLL who subsequently developed SID had a greater burden of infection than patients who did not develop SID. Increasing understanding of this burden of infection may help to improve outcomes in this population Encore Abstract—previously submitted to EHA 2023 The research was funded by: Takeda Development Center Americas, Inc. Writing support was funded by: Takeda Pharmaceuticals International AG. Keywords: cancer health disparities, chronic lymphocytic leukemia (CLL), indolent non-Hodgkin lymphoma Conflicts of interests pertinent to the abstract M. S. Davids Consultant or advisory role AbbVie, Adaptive Biotechnologies, Aptitude Health, BeiGene, Bioascend, Celgene, Curio Science, Eli Lilly, Janssen, Merck, Research to Practice and Takeda Other remuneration: Grant support (paid to his institution): Bristol Myers Squibb, Secura Bio and Surface Oncology; grant support (paid to his institution) and consulting fees: Ascentage Pharma, AstraZeneca, Bristol Myers Squibb, Genentech, MEI Pharma, Pharmacyclics and TG Therapeutics. J. Richter Consultant or advisory role Adaptive Biotechnologies, AstraZeneca, Bristol Myers Squibb, Celgene, Janssen, Karyopharm Therapeutics, Oncopeptides, Sanofi, Secura Bio, Takeda and X4 Pharmaceuticals. Honoraria: Bristol Myers Squibb and Janssen C. Anderson-Smits Employment or leadership position: Takeda Development Center Americas, Inc. Stock ownership: Takeda M. Kamieniak Employment or leadership position: Takeda Development Center Americas, Inc. Stock ownership: Takeda K. Ren Employment or leadership position: Takeda Development Center Americas, Inc. Stock ownership: Takeda D. Shah Employment or leadership position: Takeda Development Center Americas, Inc. Stock ownership: Takeda C. Siffel Employment or leadership position: Takeda Development Center Americas, Inc. Stock ownership: Takeda

REAL‐WORLD OUTCOMES OF INTRAVENOUS IMMUNOGLOBULIN FOR HYPOGAMMAGLOBULINEMIA AFTER CHIMERIC ANTIGEN RECEPTOR T‐CELL THERAPY IN PATIENTS WITH DIFFUSE LARGE B‐CELL LYMPHOMA

Introduction: Chimeric antigen receptor T-cell (CAR-T) therapy is a treatment for patients with diffuse large B-cell lymphoma (DLBCL) and is associated with toxicities, including hypogammaglobulinemia (HGG). Intravenous immunoglobulin (IVIG) is often used to manage HGG and prevent recurrent infections after CAR-T therapy, but more real-world evidence is needed to support this. Aim: To describe the real-world incidence of HGG and the effectiveness of IVIG after CAR-T therapy in patients with DLBCL. Methods: This observational cohort study used de-identified data from the nationwide (US-based) electronic health record (EHR)-derived Flatiron Health database. Patients were aged ≥18 years, diagnosed with DLBCL, had ≥2 visits in the Flatiron network on/after 1-Jan-11 and had received CAR-T therapy (tisagenlecleucel or axicabtagene ciloleucel) in any treatment line after 1-Jan-18. Baseline characteristics were identified in the 60 days prior to the index date (date of first CAR-T therapy administration). Outcomes, including HGG, were measured from index date until patient death or end of data availability (cut-off: 30-Apr-21). In this ad-hoc analysis, the primary objectives were to evaluate HGG incidence and IVIG use in patients with DLBCL who received CAR-T therapy. Exploratory objectives were to describe overall survival (OS) and progression-free survival (PFS) by IVIG treatment. Proportions and medians were used for patient characteristics. The Kaplan–Meier method was used for clinical outcomes. Results: Overall, 91 patients were included. During follow-up, 14 patients (15.4%) developed HGG, of which six cases were ‘directly attributed’ and one case ‘possibly attributed’ to CAR-T therapy; attribution was not documented for seven patients. Among these 14 patients, eight received treatment for HGG and six had no documented record of treatment. In total, 14/91 patients received IVIG (IVIG cohort). The IVIG cohort was younger (median [range] age 59 [32–67] vs 63 [28–83] years), had more females (50.0% vs 37.7%), had more patients with an Eastern Cooperative Oncology Group score of 2 (14.3% vs 6.5%) and was more frequently treated in a community setting (64.3% vs 49.4%) than the non-IVIG cohort. In the IVIG and non-IVIG cohorts, median (95% confidence interval [CI]) OS was not reached (NR; 5.6–NR) and 18.3 (9.1–NR) months, respectively and median (95% CI) PFS was NR (2.3–NR) and 3.0 (2.7–7.4) months, respectively. Conclusions: In this real-world study, half of the 14 HGG cases in patients with DLBCL were directly/possibly attributed to CAR-T therapy. This may be an underestimate because HGG is primarily assessed using laboratory data but here it was identified using EHRs. Despite a small sample size, the hypothesis-generating analyses of IVIG effectiveness and management outcomes support further evaluation of IVIG for the treatment of HGG in patients with DLBCL after CAR-T therapy. The research was funded by: Takeda Development Center Americas, Inc. Writing support was funded by: Takeda Pharmaceuticals International AG. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Immunotherapy Conflicts of interests pertinent to the abstract D. S. Chun Employment or leadership position: Takeda Development Center Americas, Inc. Stock ownership: Takeda Y. Yin Employment or leadership position: Takeda Development Center Americas, Inc. Stock ownership: Takeda C. Anderson-Smits Employment or leadership position: Takeda Development Center Americas, Inc. Stock ownership: Takeda

A Phase I Randomized Trial of Once-Daily Versus Twice-Daily Recombinant Human Parathyroid Hormone (1-84) for Hypoparathyroidism.

Recombinant human parathyroid hormone (1-84), rhPTH(1-84), is an approved adjunctive treatment to oral calcium and active vitamin D for adult patients with hypoparathyroidism; however, there is limited information on the effect of twice daily (BID) dosing of rhPTH(1-84). This was a phase I, open-label, randomized, crossover, multicenter study conducted in adult patients with chronic hypoparathyroidism. The primary objective was to assess the pharmacokinetic profile and pharmacodynamic effects of 1 day of treatment with rhPTH(1-84) administered subcutaneously at 25 μg BID, 50 μg BID, and 100 μg once daily (QD) with or without supplemental oral calcium. Safety and tolerability were evaluated as secondary objectives. In total, 33 patients with chronic hypoparathyroidism completed the study. Treatment with rhPTH(1-84), both BID and QD, over the short-term maintained serum calcium, lowered serum phosphorus, decreased urinary calcium excretion, and increased urinary phosphorus excretion. The decrease in urinary calcium excretion was numerically greater for BID than QD. Generally, baseline-adjusted pharmacokinetic parameters including area under the curve and maximum observed concentration increased with increasing rhPTH(1-84) dose, although this effect was not dose proportional. No new safety findings were observed. Our study revealed no differences thought to be clinically meaningful in pharmacokinetic or pharmacodynamic parameters with BID versus QD rhPTH(1-84) dosing. Future long-term studies are warranted to further elucidate the effects of alternative dosing strategies. © 2023 Takeda Development Center Americas, Inc and The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Tolerability and safety of facilitated subcutaneous immunoglobulin 20% in healthy adults: a phase 1 open-label study

IntroductionFacilitated subcutaneous immunoglobulin 20% (fSCIG 20%) is human immunoglobulin G (IgG) 20% administered subcutaneously with recombinant human hyaluronidase (rHuPH20). rHuPH20 depolymerizes hyaluronan in subcutaneous tissue, which transiently allows for higher IgG administration volumes. This study assessed the tolerability and safety of fSCIG 20% at various infusion rates and infusion volumes in healthy adults. MethodsThis Phase 1, single-dose, open-label, three-arm study (NCT05059977) included healthy adults aged 19–50 years with a body mass index of 18.0–30.0 kg/m2, and was conducted at one US center. After screening, participants were assigned to one of the three treatment arms (TAs) and dosed sequentially. Participants received fSCIG 20% at a single dose of 0.4 g/kg (TA 1 with in-line warming) or 1 g/kg (TA 2 with in-line warming; TA 3 without warming) on day 1 of a 4-day treatment period. After dosing, participants were followed-up for up to 12 (± 1) weeks. ResultsIn total, 24 participants were enrolled (mean [standard deviation] age 39 [7.3] years; 54.2% male) with eight per treatment arm. All but one participant completed the study. All participants had tolerable fSCIG 20% infusions and achieved the target maximum tolerable infusion rate (300 mL/hour/site). The maximum fSCIG 20% volume per site was 300 mL (achieved by 5 and 7 participants in TAs 2 and 3, respectively). No infusions were stopped or interrupted owing to a treatment-emergent adverse event (TEAE). All participants experienced TEAEs: 107 TEAEs were reported (102 local, 5 systemic), of which 105 TEAEs were related to fSCIG 20% (25, 34 and 46 TEAEs in TAs 1, 2 and 3, respectively). No TEAEs were severe, serious or led to study discontinuation. One TEAE in one participant was of special interest (TA 1; catheter leakage). The most frequent TEAEs were infusion site-related (erythema, swelling, pruritis and pain; all reported by > 50% of participants overall). ConclusionsfSCIG 20% was well tolerated with a favorable safety profile at infusion rates up to 300 mL/hour/site in healthy adults. In-line warming had no substantial impact on tolerability or safety. Takeda Development Center Americas, Inc. funded this study. Takeda Pharmaceuticals International AG funded writing support.

Efficacy and safety of hyaluronidase-facilitated subcutaneous immunoglobulin 10% in US pediatric patients with primary immunodeficiency disease

IntroductionThis study assessed the efficacy and safety of facilitated subcutaneous immunoglobulin (fSCIG; immunoglobulin G [IgG] 10% and recombinant human hyaluronidase [rHuPH20]) in US pediatric patients with primary immunodeficiency disease (PIDD). MethodsThis phase 3, open-label, prospective study (NCT03277313) was conducted at 17 centers in the US. Patients were eligible for enrollment if they were aged 2 to <16 years, diagnosed with PIDD requiring immunoglobulin replacement therapy and had received a consistent IgG dose for ≥3 months prior to screening. Patients received fSCIG 10% using a dose ramp-up over ≤6 weeks (Epoch 1) followed by fSCIG 10% treatment every 3 or 4 weeks for ≤3 years (Epoch 2). The primary endpoint, rate of acute serious bacterial infections (ASBIs), was compared with the regulatory-defined threshold (< 1.0 ASBIs per patient-year). ResultsFinal data were provided by 44 patients for Epoch 1 (mean age [range] 9.0 [3–15] years, 59.1% male) and 43 patients for Epoch 2; 34 patients completed the study. Two ASBIs (both bacterial pneumonia) were reported in the same patient. The mean rate of ASBIs (0.04 events/patient-year [99% upper confidence interval: 0.20]) was significantly lower than the regulatory-defined threshold. The mean rate of all infections was 3.12 events/patient-year. Stable mean serum trough IgG levels were maintained during Epoch 2 (10.4, 9.2, and 9.2 g/L at Months 0, 6 and 12, respectively). Excluding infections, 336 fSCIG-related treatment-emergent adverse events (TEAEs) were reported in 34 patients (Epochs 1 and 2 combined); most were mild (247 events in 32 patients) and two TEAEs in two patients were severe (celiac disease flare and headache). One serious TEAE of tonsillar hypertrophy was considered unrelated to fSCIG 10%. One patient developed anti-rHuPH20 binding antibodies (titer ≥160) without neutralizing anti-rHuPH20 antibodies. At end of Epoch 2, the majority of patients stated that they would choose to continue fSCIG 10%. ConclusionsfSCIG 10% effectively prevented ASBIs in US pediatric patients with PIDD with a safety profile consistent with previous clinical studies. Takeda Development Center Americas, Inc. and Baxalta funded this study. Takeda Pharmaceuticals International AG funded writing support.

Facilitated subcutaneous immunoglobulin 10% at a target dose of 0.4 g/kg/infusion is well tolerated with accelerated or no dose ramp-up in healthy participants

IntroductionTransitioning to recombinant human hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) infusions from intravenous immunoglobulin therapies in primary immunodeficiency disease (PID) is implemented using a gradual dose ramp-up schedule, whereby infusion volumes are increased over a number of weeks to achieve the target dose level (TDL). This study investigated the tolerability and safety of fSCIG 10% at a TDL of 0.4 g/kg/infusion (i.e. 4 mL/kg/infusion) with accelerated and no dose ramp-up schedules in comparison with conventional dose ramp-up. MethodsThis was a phase 1, open-label, single-center trial (NCT04578535). This analysis compared three fSCIG 10% treatment arms at a TDL of 0.4 g/kg/infusion: (i) conventional dose ramp-up from 0.1 g/kg/infusion at Week 1 increasing to the TDL at Week 8; (ii) accelerated dose ramp-up from 0.2 g/kg/infusion at Week 1 increasing to the TDL at Week 5; (iii) the TDL administered without dose ramp-up. Participants were healthy adults aged 19–50 years. The primary endpoint was the tolerability of fSCIG 10% infusions, assessed as the proportion of participants who completed all initiated infusions without interruptions, stoppages or reductions in infusion rate due to treatment-emergent adverse events (TEAEs). Safety was assessed as a secondary endpoint. ResultsTwenty-four participants (mean [standard deviation] age 35.3 [8.6] years; 62.5% female) were assigned equally to the three treatment arms. All participants completed all initiated infusions except for one participant who experienced a headache resulting in an infusion rate reduction in the conventional dose ramp-up arm. All participants experienced local TEAEs, including infusion site swelling, erythema, pain and pruritus. Systemic TEAEs were experienced by 1/8 (12.5%), 2/8 (25.0%) and 2/8 (25.0%) participants in the conventional, accelerated and no dose ramp-up arms, respectively. All TEAEs were mild in severity. ConclusionsfSCIG 10% at a target dose of 0.4 g/kg/infusion showed a favorable safety and tolerability profile in healthy adults, with comparable tolerability and safety outcomes between the dose ramp-up treatment arms. Accelerated and no dose ramp-up schedules could be considered as potential alternatives to conventional dose ramp-up.Takeda Development Center Americas, Inc. funded this study. Takeda Pharmaceuticals International AG funded writing support.

Targeting Sumoylation with Subasumstat (TAK-981), a Selective Inhibitor of SUMO-Activating Enzyme (SAE), Induces Mitochondrial Dysfunction in Preclinical Models of Non-Hodgkin Lymphoma (NHL)

SUMOylation is a post-translational modification which leads to covalent attachment of small ubiquitin-like modifiers (SUMO) proteins to lysine residues of a target protein. SUMOylation is essential for the regulation of genomic integrity, gene expression and intracellular signaling. Many tumors exhibit deregulation of SUMOylation pathway. Subasumstat, (TAK-981), a novel selective inhibitor of SUMO-activating enzyme (SAEi), has entered early phase II clinical trials. Here we studied SAEi in pre-clinical models of B-cell non-Hodgkin's lymphoma (NHL). TAK-981 was provided by Takeda Development Center Americas, Inc. (Lexington, MA). Diffuse large B-cell lymphoma (DLBCL) cell lines (OCI-LY3, VAL, U-2932, SU-DHL10), and primary mantle cell lymphoma (MCL) cells were assayed for survival, mitochondrial function, and metabolic phenotype. In vivo experiments were performed using DLBCL cell line xenografts and MCL PDX models. Treatment with TAK-981 restricted growth of DLBCL cell lines with an IC50~10 nM. SAEi led to rapid (within 2 h) protein desumoylation in a dose dependent manner, prominently in the ~90 kDa region. TAK-981 induced pronounced double strand DNA breaks in DLBCL cells (comet assay) and cell cycle arrest (propidium iodine). RNA-Seq and ATAC-Seq analysis of TAK-981-treated DLBCL cells revealed upregulation of the DNA damage, NF-κB, and OXPHOS signaling pathways. We noted that in addition to cytoplasmic proteins, mitochondrial proteins were heavily de-SUMOylated upon treatment of NHL cells with TAK-981. In vitro exposure to TAK-981 resulted in mitochondrial membrane depolarization, loss of mitochondrial integrity (by electron microscopy) and a change of mitochondrial dynamics as assessed by expression of mitochondrial proteins (eg, Drp1). Seahorse respirometry analysis revealed dramatic downmodulation of OXPHOS following SAEi. Furthermore, metabolomic profiling of DLBCL cells treated with TAK-981 showed downmodulation of TCA substrates, while glycolysis substrates remained unchanged. The mitochondrial disruption observed following TAK-981 treatment was accompanied by rapid accumulation of reactive oxygen species, a mechanism that has been previously shown to lead to DNA damage in cancer cells. Consistent with cell line data, exposure of primary MCL cells to TAK-981 in stromal conditions (CD40L- or BAFF expressing stroma) induced apoptosis and reduced OXPHOS. Next, we conducted genome-wide CRISPR-Cas9 loss-of-function library screens and identified that loss of genes in the NFκB, TP53, DNA damage and centromere/telomere gene pathways contributed to resistance to SAEi in DLBCL cells. By means of genetic knockout we demonstrated that TP53 and its transcriptional target BAX contributed to TAK-981-induced G2 arrest and apoptosis, further implicating mitochondrial dysfunction in sensitivity to SAEi. For in vivo experiments, we used DLBCL xenografts. OCI-LY3 and U-2932 cells were inoculated subcutaneously in NSG mice. Once tumors reached 100 mm3, mice received 10 twice-weekly IV doses of 7.5 mg/kg TAK-981 (over 5 weeks), leading to resolution of flank tumors and improved survival compared with control. Finally, we used an MCL PDX model where MCL cells were inoculated intravenously. Once cells became detectable in the blood, mice were treated as above. Treatment with TAK-981 resulted in delayed tumor expansion in blood and spleen and extended animal survival. TAK-981-exposed splenocytes exhibited a reduction of maximal respiration by Seahorse analysis. Conclusions. Pharmacologic SAEi with TAK-981 demonstrated pre-clinical activity in NHL models in vitro and in vivo, accompanied by DNA damage, mitochondrial dysfunction, and metabolic reprogramming.

P16.38: Healthcare Resource Utilization in Transplant Recipients With Cytomegalovirus Infection Refractory to Prior Treatment With/Without Resistance Receiving Maribavir Versus Investigatorassigned Therapy: Exploratory Analysis of the Phase 3 SOLSTICE Trial

Introduction: Increased healthcare resource utilization (HCRU) has been associated with cytomegalovirus (CMV) infection following transplantation, in particular in patients (pts) requiring >1 antiviral course. In the Phase 3 SOLSTICE study (NCT02931539), maribavir (MBV) was superior to investigator-assigned therapy (IAT; val/ganciclovir, foscarnet, cidofovir) for CMV clearance at Wk 8 and clearance plus symptom control Wk 8 maintained through Wk 16 in transplant recipients with refractory CMV infection with/without resistance (R/R). This exploratory analysis of SOLSTICE evaluated HCRU for the MBV and IAT arms. Methods: Transplant recipients with CMV R/R to prior treatment (failure to achieve >1log10 decrease in CMV DNA after ≥14 days, with/without genotyped resistance) were randomized 2:1 to MBV 400 mg BID or IAT for 8 wks with 12 wks of follow-up. After ≥3 wks of treatment, pts in the IAT arm with pre-specified criteria could enter a MBV rescue arm (8 wks’ MBV treatment, 12 wks’ follow-up). Data on hospital admissions were collected at each study visit and analyzed by treatment during the treatment and follow-up phases. Analyses included the number of pts with ≥1 hospitalization and length of hospital stay (LOS). Hospitalization rates and LOS (per person/year) were estimated using negative binomial models adjusting for exposure time. Adjusted incidence rates (IR), 95% CIs, IR ratios (IRR) and percent reduction in IRRs were calculated. Supplementary analyses described hospitalizations and LOS for the rescue arm and individual IAT groups. Results: In total, 352 pts were randomized (MBV: 235; IAT: 117), of whom 22 (18.8%) entered the MBV rescue arm. While on treatment, pts on MBV versus IAT had reductions of 34.8% in hospitalizations (p=0.021) and 53.8% in LOS (p=0.029; Table). Hospitalization rates were lower during the follow-up than treatment phase, with no differences between treatments in the follow-up (off-treatment) period (Table). The hospitalization rate in the IAT group pre-rescue with MBV (IR=6.98; 95% CI: 4.06, 12.03) was 2.54 times higher (IRR=2.54; 95% CI: 1.28, 5.04; p=0.008) than on or after rescue with MBV (IR=2.75; 95% CI: 1.81, 4.18); increased LOS pre-rescue was also noted (IRR=2.25; 95% CI: 0.72, 7.01) but not statistically significant. In the IAT arm, foscarnet pts tended to have higher hospitalizations (5.5 admissions/person/year) and longer LOS (51.7 days/person/year) during the treatment phase compared with patients on val/ganciclovir or maribavir (Figure). Conclusion: Results from this analysis quantify the HCRU experience of pts requiring treatment for post-transplant CMV. Hospitalizations and LOS were lower for pts on MBV than IAT. Pts who received MBV rescue reported lower hospitalization rates on or after rescue than pre-rescue. Reducing hospitalizations is critical for alleviating disease burden to healthcare systems. TCT2022 encore; DOI pending This study was funded by Takeda Development Center Americas, Inc. Writing and editing support was provided by Caudex (UK), funded by Takeda Development Center Americas, Inc.

638P Burden of infection in patients with multiple myeloma and secondary immunodeficiencies: A retrospective cohort study

This study aimed to provide insights into the burden of infection in patients with multiple myeloma (MM) with or without secondary immunodeficiencies (SID). In this retrospective cohort study, data were extracted from the Optum-Humedica electronic record database during the period 01-Oct-2015 to 10-Mar-2020, which included a 6-month pre-index period (PIP) and 12-month follow-up following patient identification. Patients aged ≥18 years with a confirmed diagnosis of MM in the PIP were included in the analysis and stratified into two cohorts: those with (SID cohort) and those without SID (no-SID cohort). If a patient had SID or primary immunodeficiencies in the PIP, they were excluded. The first occurrence of a hypogammaglobulinemia ICD-10 code, or a low (<5.0 g/L) serum Immunoglobulin G level was defined as the SID index date. Of patients with MM, 870 with SID and 3768 without SID were included (mean age: 66.5 and 68.7 years; males: 54.3% and 53.6%; respectively). At 12-month follow-up, significantly more patients in the SID cohort experienced ≥1 infection than the no-SID cohort (58.9% vs 32.1%, p<0.001). A similar pattern was observed for mean number of infections, patients experiencing ≥1 severe bacterial infection or ≥1 infection-associated hospitalization (Table). The most common infection in both cohorts was bacterial: SID, mean (standard deviation [SD]) number of bacterial infections 6.83 (8.04) and no-SID, 4.73 (6.57), p<0.001. Kaplan–Meier analysis showed overall survival (OS) at 24 months was lower in the SID cohort (74.9% of patients alive) than the no-SID cohort (81.8%).Table: 638POutcome measures at 12 monthsSID n=870No-SID n=3768p value SID vs no-SIDNumber of infections, mean (SD)7.07 (9.23)4.58 (6.45)<0.001Patients with ≥1 severe bacterial infection,a n (%)276 (31.7)510 (13.5)<0.001Patients with ≥1 hospitalization associated with any infection, n (%)231 (26.6)350 (9.3)<0.001Number of hospitalizations, mean (SD)6.55 (8.65)5.47 (6.90)0.11Length of hospital stay, mean (SD), days13.02 (34.95)9.69 (26.88)0.22aDefined using ICD-10 codes for bacteremia or sepsis, bacterial meningitis, osteomyelitis/septic arthritis, bacterial pneumonia and visceral abscess. Open table in a new tab aDefined using ICD-10 codes for bacteremia or sepsis, bacterial meningitis, osteomyelitis/septic arthritis, bacterial pneumonia and visceral abscess. Patients with MM and SID have a substantially higher burden of infection and healthcare resource use, and lower OS than those without SID. Understanding this burden will allow for earlier targeted treatment of individuals at risk of SID. Study/medical writing support funder: Takeda Development Center Americas, Inc.

The Icatibant Outcome Survey: 10 years of experience with icatibant for patients with hereditary angioedema.

In patients with hereditary angioedema (HAE), bradykinin causes swelling episodes by activating bradykinin B2 receptors. Icatibant, a selective bradykinin B2 receptor antagonist, is approved for on-demand treatment of HAE attacks. The Icatibant Outcome Survey (IOS; NCT01034969) is an ongoing observational registry initiated in 2009 to monitor the effectiveness/safety of icatibant in routine clinical practice. As of March 2019, 549 patients with HAE type 1 or 2 from the IOS registry had been treated of 5995 total attacks. This article reviews data published from IOS over time which have demonstrated that the effectiveness of icatibant in a real-world setting is comparable to efficacy in clinical trials; one dose is effective for the majority of attacks; early treatment (facilitated by self-administration) leads to faster resolution and shorter attack duration; effectiveness/safety of icatibant has been shown across a broad range of patient subgroups, including children/adolescents and patients with HAE with normal C1 inhibitor levels; and tolerability has been demonstrated in patients aged ≥65 years. Additionally, this review highlights how IOS data have provided valuable insights into patients' diagnostic journeys and treatment behaviours across individual countries. Such findings have helped to inform clinical strategies and guidelines to optimise HAE management and limit disease burden. This research was sponsored by Takeda Development Center Americas, Inc. Takeda Development Center Americas, Inc., provided funding to Excel Medical Affairs for support in writing and editing this manuscript.

Overall Survival with Brentuximab Vedotin in Stage III or IV Hodgkin’s Lymphoma

BackgroundFive-year follow-up in a trial involving patients with previously untreated stage III or IV classic Hodgkin’s lymphoma showed long-term progression-free survival benefits with first-line therapy with brentuximab vedotin, a CD30-directed antibody–drug conjugate, plus doxorubicin, vinblastine, and dacarbazine (A+AVD), as compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). A planned interim analysis indicated a potential benefit with regard to overall survival; data from a median of 6 years of follow-up are now available.MethodsWe randomly assigned patients in a 1:1 ratio to receive up to six cycles of A+AVD or ABVD. The primary end point, modified progression-free survival, has been reported previously. The key secondary end point was overall survival in the intention-to-treat population. Safety was also assessed.ResultsA total of 664 patients were assigned to receive A+AVD and 670 to receive ABVD. At a median follow-up of 73.0 months, 39 patients in the A+AVD group and 64 in the ABVD group had died (hazard ratio, 0.59; 95% confidence interval [CI], 0.40 to 0.88; P=0.009). The 6-year overall survival estimates were 93.9% (95% CI, 91.6 to 95.5) in the A+AVD group and 89.4% (95% CI, 86.6 to 91.7) in the ABVD group. Progression-free survival was longer with A+AVD than with ABVD (hazard ratio for disease progression or death, 0.68; 95% CI, 0.53 to 0.86). Fewer patients in the A+AVD group than in the ABVD group received subsequent therapy, including transplantation, and fewer second cancers were reported with A+AVD (in 23 vs. 32 patients). Primary prophylaxis with granulocyte colony-stimulating factor was recommended after an increased incidence of febrile neutropenia was observed with A+AVD. More patients had peripheral neuropathy with A+AVD than with ABVD, but most patients in the two groups had resolution or amelioration of the event by the last follow-up.ConclusionsPatients who received A+AVD for the treatment of stage III or IV Hodgkin’s lymphoma had a survival advantage over those who received ABVD. (Funded by Takeda Development Center Americas and Seagen; ECHELON-1 ClinicalTrials.gov number, NCT01712490; EudraCT number, 2011-005450-60.)

Observational study evaluating wait time and clinical outcomes in patients (pts) with diffuse large B-cell lymphoma (DLBCL) who received chimeric antigen receptor (CAR) T-cell therapy (T-CT).

e19577 Background: 5-year survival rates for DLBCL pts in the first-line setting range from 60% to 70%. Up to 50% of pts become refractory to or relapse (r/r) after treatment. Autologous CAR T-CT has shown efficacy in r/r DLBCL in ≥2 lines of treatment but faces significant challenges with cell collection and manufacturing that may delay pt treatment. This study assessed the impact of wait time for CAR T-CT (time between apheresis and CAR T-CT administration) on progression-free survival (PFS) in DLBCL pts. Methods: Data from pts in the electronic health record-derived de-identified US-based Flatiron Health database, who had a DLBCL diagnosis after Jan 1, 2011, and a documented CAR T-CT administration date, were included. Pts missing a documented apheresis date were excluded. Demographic and clinical characteristics were assessed within 6 months (mos) prior to index date (CAR T-CT administration). Pts were followed from index date to the first of pt death or end of data availability. Given no established clinically relevant cut points, short wait time was defined as &lt; median time between apheresis and index date. Long wait time was defined as ≥ median time. 3-, 6-, and 12-mo PFS probabilities (95% confidence intervals [CIs]) by wait time were reported. Results: 91 DLBCL pts received CAR T-CT; 78 had a documented apheresis date. Median time from apheresis to index date was 37 days (interquartile range: 25, 116). 55% of pts experienced longer wait times (≥37 days). 45% experienced shorter times (&lt;37 days). Pts were mostly white (80%–84%), male (57%–65%), and older (median: 60–67 years), with similar median follow-up time from index (4.0–4.7 mos). More pts with short wait times had stage 4 disease than those with long wait times (51% vs 28%). 71% of pts with shorter wait times received axicabtagene ciloleucel. Among those with long wait times, 72% received tisaggenlecleucel. More pts with long wait times received bridging therapy (66% vs 74%). Pts with short wait times had a higher 3-mo PFS probability than pts with long wait times. The 6- and 12-mo PFS probabilities were lower in those with shorter wait times (Table). No statistical comparisons were made due to small sample size. Conclusions: This real-world study showed no meaningful differences in PFS between wait times in DLBCL pts in the United States. Results from this study show evidence of channeling bias which is an important consideration for evaluating real-world data to construct external control arms. Future studies are needed to further evaluate the impact of delayed treatment in pts with r/r DLBCL. Funding: Takeda Development Center Americas, Inc.[Table: see text]