BEMNIFOSBUVIR HAS LOW POTENTIAL TO INHIBIT P-gp, BCRP, AND OATP1B1 MEDIATED TRANSPORT

Background: Bemnifosbuvir (BEM, AT-527) is a guanosine nucleotide prodrug candidate for the treatment of COVID-19 and chronic HCV. BEM was identified in vitro as an inhibitor of drug transporters P-glycoprotein, breast cancer resistant protein (BCRP) and organic anion transporting polypeptide 1B1 (OATP1B1). Ph 1 studies in healthy participants were conducted to assess the clinical implications of these results using digoxin (DIG) and rosuvastatin (ROSU) as P-gp and BCRP/ OATP1B1 index drugs, respectively. Method(s): Both studies employed a similar design with 2 groups of 14 healthy participants: Day 1/period 1, all participants received a single dose of DIG 0.25mg or ROSU 10mg alone. In period 2, participants received DIG 0.25mg or ROSU 10mg with BEM 1100mg, simultaneously (n=14) or staggered by 2h (n=14). Serial plasma samples were collected and quantitated for DIG or ROSU concentrations. Result(s): A single dose of BEM 1100mg simultaneously administered slightly increased the Cmax of DIG (78%), yet had no effect on its AUC, consistent with the transient nature of BEM plasma PK. When dosed staggered, BEM did not affect the PK of DIG. A single dose (simultaneous or staggered) of BEM 1100mg slightly increased the plasma exposure of ROSU (20%-40%). There was no effect on vital signs, ECG, and no SAEs or drug discontinuations. Conclusion(s): A single high dose of BEM 1100mg only slightly increased the plasma exposure of the P-gp and BCRP/OATP1B1 index drugs DIG and ROSU. BEM has low potential to exhibit clinical meaningful inhibition of these transporters. No dose adjustment will be needed for drugs that are sensitive substrates of P-gp or BCRP/OAT1B1 when co-administered with BEM, staggered dosing may lessen any DDI risk.

Safety and Pharmacokinetics of a Novel Double Prodrug Asc10 in Healthy Subjects

Background: ASC10 is an oral double prodrug of the active antiviral ribonucleoside analog, ASC10-A (also known as beta-d-N4-hydroxycytidine), which is a potent inhibitor of SARS-CoV-2. ASC10 is rapidly metabolized into ASC10-A in vivo after oral dosing. Here, we report the results of the first-in-human, phase 1 study to determine the safety, tolerability, and pharmacokinetics (PK) of ASC10 in healthy subjects, and to assess the food effect on the pharmacokinetics. Method(s): This study included 2 parts. Part 1 (multiple-ascending-dose) consisted of 6 cohorts (8 or 12 subjects per cohort). Eligible subjects were randomized in a 3:1 ratio to receive either twice-daily (BID) doses of 50 to 800 mg ASC10 or placebo for 5.5 days, and were then followed for 7 days for safety. In Part 2 (food effect), 12 subjects were randomized in a 1:1 ratio to either 800 mg ASC10 in the fed state followed by 800 mg in the fasted state, or vice versa, with a 7-day washout period between doses. PK blood samples were collected and measured for ASC10-A along with ASC10 and molnupiravir. Safety assessments included monitoring of adverse events (AEs), measurement of vital signs, clinical laboratory tests, and physical examinations. Result(s): ASC10-A was the major circulating metabolite ( >99.94%) in subjects after oral dosing of ASC10. ASC10-A appeared rapidly in plasma, with a median Tmax of 1.00 to 2.00 h, and declined with a geometric t1/2 of approximately 1.10 to 3.04 h. After multiple dosing for 5.5 days, both Cmax and AUC of ASC10-A increased in a dose-proportional manner from doses of 50 to 800 mg BID without accumulation. of ASC10-A in the fed state occurred slightly later, with a median of 3.99 h postdose versus 2.00 h (fasted state). However, Cmax and AUC were very similar or the same between fed and fasted states. Thus, administration of ASC10 with food is unlikely to have an effect on exposure. The incidence of AEs was similar between subjects receiving ASC10 or placebo (both 66.7%) and 95.0% of AEs were mild. There were no serious adverse events as well as no clinically significant findings in clinical laboratory, vital signs, or electrocardiography. Conclusion(s): Results of this study showed that ASC10 was well tolerated, and the increase in plasma exposure of ASC10-A was dose proportional across the range of doses tested with no accumulation and no food effect. 800 mg ASC10 BID is selected for further studies in patients infected with SARS-CoV-2.

Simulation of pharmacokinetic drug-drug interaction and dosage regimens optimization of nelfinavir and cepharanthine as a potential combination against COVID-19

The pharmacokinetic (PK) drug-drug interactions (DDIs) of nelfinavir and cepharanthine combination is limited information in human. In addition, the dosage regimen of this combination is not available for COVID-19 treatment. The objective of this study was to perform in silico simulations using GastroPlusTM software to predict physicochemical properties, PK parameters using the physiologically based pharmacokinetic (PBPK) model of healthy adults in different dosage regimens. The DDIs analysis of nelfinavir and cepharanthine combination was carried out to optimize the dosage regimens as a potential against COVID-19. The Spatial Data File (SDF) format of nelfinavir and cepharanthine structures obtained from PubChem database were used to carry out in silico predictions for physicochemical properties and PK parameters using several aspects of modules such as ADMET Predictor, Metabolism and Transporter, PBPK model. Subsequently, all data were utilized in the DDIs simulations. The dynamic simulation feature was selected to calculate and investigate the Cmax, AUC0-120, AUC0-inf, Cmax ratio, AUC0-120 ratio, and AUC0-inf ratio. The victim or nelfinavir dosage regimens were used four oral administration regimens of 500 mg and 750 mg in every 8 and 12 hours for simulations. The perpetrator or cepharanthine oral dosage regimens were used in several regimens from 10 mg to 120 mg in every 8, 12, and 24 hours. From all predicted results, the dosage regimen as a potential combination against COVID-19 was nelfinavir 500 mg every 8 hours and cepharanthine 10 mg every 12 hours.Copyright © 2023 by Faculty of Pharmacy, Mahidol University, Thailand is licensed under CC BY-NC-ND 4.0. To view a copy of this license, visit https://www.creativecommons.org/licenses/by-nc-nd/4.0/.

Pharm Aco Kin Etics, Safety, and Tolerability of Upadacitinib in Children with Atopic Dermatitis

BACKGROUND: Upadacitinib is a Janus kinase inhibitor that has been approved for the treatment of adults and adolescents with moderate to severe atopic dermatitis (AD). The objective of this study was to characterize the pharmacokinetics (PK), safety, and tolerability of upadacitinib in children with severe atopic dermatitis. METHOD(S): This is an open-label, multiple-dose study. AD patients (n = 35) were enrolled into four cohorts (Cohort 1, 6 to <12 years, low dose;Cohort 2, 6 to <12 years, high dose;Cohort 3, 2 to <6 years, low dose;Cohort 4, 2 to <6 years, high dose). The low and high doses were selected based on body weight to provide comparable plasma exposure in pediatrics to 15 mg and 30 mg QD doses in adults, respectively. All patients continued on the low dose after the PK assessment on Study Day 7. Safety and exploratory efficacy parameters are assessed in the study. RESULT(S): Geometric mean Cmax and AUC over 0-24 hours at steady state were 33.1 ng/mL and 249 ng.h/mL, respectively, in Cohort 1, 95.5 ng/mL and 523 ng.h/mL, respectively, in Cohort 2, 35.2 ng/mL and 264 ng.h/mL, respectively, in Cohort 3, and 101 ng/mL and 625 ng.h/mL, respectively, in Cohort 4. Upadacitinib was generally safe and well tolerated. The most common AEs were COVID infection, headache, and abdominal discomfort. No new safety risks were identified compared to the known safety profile for upadacitinib. In the 29 subjects with available interim efficacy results at week 12, 34.5% achieved validated Investigator's Global Assessment scale for AD score of 0 or 1 and 69.0% achieved Eczema Area and Severity Index by at least 75% at Week 12 with treatment of upadacitinib. CONCLUSION(S): The findings supported the use of current dosing regimens for further investigation of upadacitinib in upcoming phase 3 clinical trials in pediatric AD patients.

Single-Dose Bioequivalence Study of Rivaroxaban-Containing Medicinal Products in Healthy Volunteers.

Therapeutically, new oral anticoagulants (NOACs) are considered to be non-inferior or superior to vitamin K antagonists (warfarin). NOACs are included in current guidelines for the treatment of various cardiovascular diseases. Rivaroxaban medicinal products have been shown to effectively fight thrombotic complications of the new coronavirus infection, COVID-19. The wide clinical use of rivaroxaban products motivates the development of generics. The aim of the study was to compare the pharmacokinetics and safety of rivaroxaban medicinal products in a single-dose bioequivalence study in healthy volunteers under fasting conditions. Material(s) and Method(s): the bioequivalence study compared single-dose oral administration of Rivaroxaban, 10 mg film-coated tablets (NovaMedica Innotech LLC, Russia), and the reference product Xarelto, 10 mg film-coated tablets (Bayer AG, Germany), in healthy volunteers under fasting conditions. The open, randomised, crossover trial included 46 healthy volunteers. Each of the medicinal products (the test product and the reference product) was administered once;blood samples were collected during the 48 h after the administration. The washout between the study periods lasted 7 days. Rivaroxaban was quantified in plasma samples of the volunteers by high performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). Result(s): no adverse events or serious adverse events were reported for the test and reference products during the study. The following pharmacokinetic parameters were obtained for Rivaroxaban and Xarelto, respectively: Cmax of 134.6 +/- 58.0 ng/mL and 139.9 +/- 49.3 ng/mL, AUC0-48 of 949.7 +/- 354.5 ngxh/mL and 967.6 +/- 319.9 ngxh/mL, AUC0- of 986.9 +/- 379.7 ngxh/mL and 1003.6 +/- 320.4 ngxh/mL, T1/2 of 8.2 +/- 3.2 h and 7.8 +/- 3.3 h. The 90% confidence intervals for the ratios of Cmax, AUC0-48, and AUC0- geometric means were 88.04-108.67%, 89.42-104.92% and 89.44-104.81%, respectively. Conclusion(s): the test product Rivaroxaban and the reference product Xarelto were found to have similar rivaroxaban pharmacokinetics and safety profiles. The study demonstrated bioequivalence of the medicinal products.Copyright © 2022 Obstetrics, Gynecology and Reproduction. All rights reserved.

Impact of Intramuscular Injection Site on Sotrovimab Pharm Aco Kin Etics

BACKGROUND: Sotrovimab, a dual-action Fc-engineered human immunoglobulin G (IgG1) mAb, binds to a conserved epitope on the SARS-CoV- 2 receptor binding domain and was developed to treat mild to moderate COVID-19. A high concentration formulation is being evaluated to offer the potential for IM administration at lower volumes and at different injection sites. METHOD(S): COSMIC (NCT05280717) is a phase 1, open-label healthy volunteer study comprising three parts. Part A is an ongoing randomized, parallel group study investigating the relative bioavailability, safety, and tolerability of two concentrations of sotrovimab administered at different injection sites. A total of 215 subjects were randomized in a 2:2:1:1 ratio into 4 treatment arms: dorsogluteal injection (62.5 mg/mL), or 100 mg/mL administered as dorsogluteal, thigh, or deltoid injection(s). PK will be evaluated for 24 weeks post-dose. RESULT(S): Preliminary PK is available from 50 participants who received a 500 mg IM dose of sotrovimab of the higher concentration (100 mg/mL). Administration into thigh or deltoid resulted in higher geometric mean Cmax and AUCD1-15 and lower inter-subject variability compared to 100 mg/mL dorsogluteal. Following gluteal, thigh, or deltoid injections, the geometric mean (%CV) Cmax was 44.8 mug/mL (63.3), 70.9 mug/mL (35.5), and 65.1 mug/mL (27.1), respectively, and the geometric mean (%CV) AUCD1-15 was 534 day*mug/mL (67.5), 814 day*mug/mL (39.7), and 782 day*mug/mL (26.3), respectively. Median Tmax was earlier following thigh (4 days) and deltoid (5.5 days) injection than gluteal (7 days) injection. CONCLUSION(S): Administration of sotrovimab into thigh or deltoid muscles may improve exposure and reduce inter-subject variability compared to gluteal IM administration. These data may inform IM injection site selection for mAbs.

Bioequivalence Study of Generic Molnupiravir in Healthy Volunteers

Molnupiravir is one of the drugs for the etiotropic therapy of a new coronavirus infection COVID-19. It has confirmed its clinical efficacy in the treatment of patients with mild and moderate COVID-19, including those who are at high risk of progressing to severe disease. The aim of the study was to evaluate bioequivalence of the generic drug molnupiravir ALARIO-TL and the original drug Lagevrio with a single oral administration in healthy volunteers. Materials and methods. This bioequivalence study was an open, randomized, two-period crossover study. In each of the two periods, volunteers received a single dose of the test drug, or reference drug molnupiravir, in the form of capsules at the dose of 200 mg. The washout period between the doses was 3 days. To determine pharmacokinetic (PK) parameters and bioequivalence, the concentration the concentration of N-hydrozycytidine (NHC), the main molnupiravir metabolit in the blood plasma of volunteers was evaluated. The blood plasma sampling was carried out in the range from 0 to 16 hours in each of the study periods. Bioequivalence was assessed by comparing 90% confidence intervals (CIs) for the ratio of geometric means of AUC(0-16) and Cmax of the test drug and reference drugs with the established equivalence limits of 80.00 - 125.00%. Results. A total of 28 healthy male volunteers were included in the study. According to the results of the statistical analysis, after the administration of the test and reference drugs, the 90% CIs for the ratio of the geometric means of AUC (0-16) and Cmax were 96.31% - 113.64% and 91.37% - 114.8%, respectively. These intervals fit within the established limits of 80.00-125.00%, which confirms the bioequivalence of the drugs. When comparing the frequency of the individual adverse events registration, no significant differences were found out after the administration of the test and reference drugs. Conclusion. Based on the results of this study, it can be concluded that the test and reference drugs of molnupiravir are bioequivalent. In addition, the data obtained indicate that the drugs have similar safety profiles.Copyright © 2022 Volgograd State Medical University, Pyatigorsk Medical and Pharmaceutical Institute. All rights reserved.

CILTACABTAGENE AUTOLEUCEL IN LENALIDOMIDE-REFRACTORY PATIENTS WITH PROGRESSIVE MULTIPLE MYELOMA AFTER 1-3 PRIOR LINES OF THERAPY: CARTITUDE-2 BIOLOGICAL CORRELATIVE ANALYSES AND UPDATED CLINICAL DATA

Background: Cohort A of the multicohort phase 2 CARTITUDE-2 (NCT04133636) study is assessing ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell (CAR-T) therapy, in patients with multiple myeloma (MM) who received 1-3 prior lines of therapy (LOT) and were refractory to lenalidomide (len). This population is difficult to treat and has poor prognosis. Aims: To present updated results from CARTITUDE-2 Cohort A. Methods: All patients provided informed consent. Eligible patients had progressive MM after 1-3 prior LOT that included a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD). Patients were len-refractory and had no prior exposure to BCMA-targeting agents. Patients received a single cilta-cel infusion (target dose: 0.75×106 CAR+ viable T cells/kg) after lymphodepletion. Cilta-cel safety and efficacy were assessed. The primary endpoint was minimal residual disease (MRD) negativity at 10-5 by next generation sequencing. Patient management strategies were used to reduce the risk of movement and neurocognitive adverse events (MNTs). Other assessments included pharmacokinetic (PK) analyses (Cmax and Tmax of CAR+ T-cell transgene levels in blood), levels of cytokine release syndrome (CRS)-related cytokines (e.g., IL-6) over time, peak levels of cytokines by response and CRS, association of cytokine levels with immune effector cell-associated neurotoxicity syndrome (ICANS), and CAR+ T cell CD4/CD8 ratio by response, CRS, and ICANS. Results: As of January 2022 (median follow-up: 17.1 months [range: 3.3-23.1]), cilta-cel was administered to 20 patients (male: 65%;median age: 60 years [range: 38-75]). Median number of prior LOT was 2 (range: 1-3);median time since MM diagnosis was 3.5 years (range: 0.7-8.0). 95% of patients were refractory to their last LOT;40% were triple-class refractory. Overall response rate was 95%, with 90% of patients achieving ≥complete response and 95% achieving ≥very good partial response. Median time to first response was 1.0 month (range: 0.7-3.3);median time to best response was 2.6 months (range: 0.9-13.6). All MRD-evaluable patients (n=16) achieved MRD negativity at 10-5. Median duration of response was not reached. The 12-month progression-free survival rate was 75% and the 12-month event-free rate was 79%. CRS occurred in 95% of patients (grade 3/4: 10%), with a median time to onset of 7 days (range: 5-9) and median duration of 3 days (range: 2-12). 30% of patients had neurotoxicity (5 grade 1/2 and 1 grade 3/4). ICANS occurred in 3 patients (15%;all grade 1/2);1 patient had facial paralysis (grade 2). No MNTs were observed. 1 death due to COVID-19 occurred and was assessed as treatment-related by the investigator;2 deaths due to progressive disease and 1 due to sepsis (not related to treatment) also occurred. Based on preliminary PK analyses of CAR transgene by qPCR, peak expansion of CAR-T cells occurred at day 10.5 (range: 8.7-42.9);median persistence was 153.5 days (range: 57.1-336.8). Summary/Conclusion: A single cilta-cel infusion led to deepening and durable responses at this longer follow-up (median 17.1 months) in patients with MM who had 1-3 prior LOT and were len-refractory. Follow-up is ongoing. We will present updated and detailed PK, cytokine, and CAR-T subset analyses as well as clinical correlation to provide novel insights into biological correlates of efficacy and safety in this difficult-to-treat patient population, which is being further evaluated in the CARTITUDE-4 study (NCT04181827;enrollment concluded).

A RANDOMISED PHASE i PHARMACOKINETIC STUDY COMPARING HIGH-CONCENTRATION, LOW-VOLUME, and CITRATE-FREE SB5 (40 MG/0.4 ML) with PRIOR SB5 FORMULATION, and ADALIMUMAB BIOSIMILAR, in HEALTHY MALE SUBJECTS

Background: SB5, an adalimumab (ADL) biosimilar, was developed in a low-concentration (40 mg/0.8 mL, SB5-LC) aligned with the reference ADL product. Pharmacokinetics (PK) equivalence of SB5 and reference ADL was demonstrated in a Phase I study conducted in healthy subjects1. Equivalent efficacy and comparable safety between 40 mg/0.8 mL SB5 and 40 mg/0.8 mL reference ADL were demonstrated in a Phase III study conducted in patients with rheumatoid arthritis2. High-concentration, low-volume, citrate-free SB5 (40 mg/0.4 mL, SB5-HC) has been developed as a part of life cycle management in line with the reference ADL formulation. Objectives: To compare the PK, safety, and tolerability of the newly developed SB5-HC (40 mg/0.4 mL) to prior SB5-LC (40 mg/0.8 mL) in healthy male subjects. Methods: This study was a randomised, single-blind, two-arm, parallel group, single-dose study in healthy male subjects. Subjects were randomised in a ratio of 1:1 to receive a single dose of either SB5-HC or SB5-LC by subcutaneous injection on Day 1 and then observed for 57 days during which the PK, safety, and immunogenicity were evaluated. The serum concentration of ADL was measured using an enzyme-linked immunosorbent assay. The primary PK parameters were area under the concentration-time curve from time zero to infnity (AUCinf) and maximum serum concentration (Cmax). Equivalence for the primary PK parameters was to be concluded if the 90% confdence intervals (CIs) for the ratio of geometric least squares means (LSMeans) of the treatment groups compared were completely contained within the pre-defned equivalence margin of 0.80 to 1.25 using an analysis of variance. Results: Of 188 randomised subjects, 187 subjects were analysed as PK Analysis Set (PKS) (n=93 in SB5-HC and n=94 in SB5-LC). One subject was excluded from the PKS in SB5-HC group (major protocol deviation for not being withdrawn in the event of confrmed COVID-19). The geometric LSMeans ratios for the comparison of SB5-HC and SB5-LC for AUCinf and Cmax were 0.920 and 0.984, respectively, and the corresponding 90% CIs were within the pre-defned equivalence margin of 0.80 to 1.25 (Table 1), indicating the two treatment groups are bioequivalent. There were no deaths, serious adverse events or discontinuation of the study due to treatment-emergent adverse events (TEAEs) during the study. The proportions of subjects who experienced TEAEs were comparable between the two treatment groups (44.7% in SB5-HC vs 51.1% in SB5-LC). The most frequent TEAEs were headache (10.6% in SB5-HC vs 12.8% in SB5-LC). Conclusion: This study demonstrated PK equivalence between SB5-HC and SB5-LC in healthy subjects. Both SB5-HC and SB5-LC were generally well tolerated with similar safety profiles.

Biological correlative analyses and updated clinical data of ciltacabtagene autoleucel (cilta-cel), a BCMA-directed CAR-T cell therapy, in lenalidomide (len)-refractory patients (pts) with progressive multiple myeloma (MM) after 1-3 prior lines of therapy (LOT): CARTITUDE-2, cohort A

Background: Cohort A of the multicohort phase 2 CARTITUDE-2 (NCT04133636) study is evaluating cilta-cel safety and efficacy in pts with MM who received 1-3 prior LOT and were len-refractory - a difficult- to-treat population with poor prognosis. We present updated results. Methods: Pts had progressive MM after 1-3 prior LOT, including a PI and IMiD, were len-refractory, and had no prior exposure to BCMA-targeting agents. A single cilta-cel infusion (target dose 0.75×106 CAR+ viable T cells/kg) was given post lymphodepletion. Safety and efficacy were assessed, and the primary endpoint was MRD negativity at 10-5. Management strategies were implemented to minimize risk of movement/neurocognitive AEs (MNTs). Pharmacokinetic (PK) analyses (Cmax and Tmax of CAR+ T-cell transgene levels in blood) are being conducted, as well as analyses of levels of CRS-related cytokines (eg, IL-6) over time, peak levels of cytokines by response and CRS, association of cytokine levels with ICANS, and CAR+ T cell CD4/CD8 ratio by response, CRS, and ICANS. Results: As of January 2022 (median follow- up [MFU] 17.1 mo [range 3.3-23.1]), 20 pts (65% male;median age 60 y [range 38-75]) received cilta-cel. Pts received a median of 2 (range 1-3) prior LOT, and a median of 3.5 y (range 0.7-8.0) since MM diagnosis. 95% were refractory to last LOT, and 40% were triple-class refractory. ORR was 95%, 90% achieved CR or better, and 95% had ≥VGPR. Median times to first and best response were 1.0 mo (range 0.7-3.3) and 2.6 mo (range 0.9-13.6), respectively. 16 pts were MRDevaluable, all of whom achieved MRD negativity at 10-5. Median DOR was not reached and 12-mo event-free rate was 79%. The 12-mo PFS rate was 75%. Median time to onset of CRS was 7 d (range 5-9) and occurred in 95% of pts (gr 3/4: 10%), with median duration of 3 d (range 2-12). Neurotoxicity occurred in 30% of pts (5 gr 1/2;1 gr 3/4). 3 pts (15%) had ICANS (all gr 1/2);1 pt had gr 2 facial paralysis. No MNTs were seen. 1 death occurred due to COVID-19 (assessed as tx-related by the investigator), 2 due to progressive disease, and 1 due to sepsis (not related to tx). Preliminary PK analyses indicate that peak expansion of CAR-T cells occurred at d 10.5 (range 8.7-42.9) and median persistence was 153.5 d (range 57.1-336.8). Conclusions: At a longer MFU of 17.1 mo, a single cilta-cel infusion led to deepening and durable responses in pts with MM who had 1-3 prior LOT and were lenrefractory. Follow-up is ongoing. Updated and in-depth PK, cytokine, and CAR-T subset analyses and clinical correlation will be presented and provide novel insights into biological correlates of efficacy and safety in this pt population. This pt population is being further evaluated in the CARTITUDE-4 study (NCT04181827), which has concluded enrollment.

Updated results of a multicenter first-in-human study of BCMA/CD19 dual-targeting fast CAR-T GC012F for patients with relapsed/refractory multiple myeloma (RRMM)

Background: GC012F is a B cell maturation antigen (BCMA)/CD19 dual-targeting CAR-T developed on the novel FasT CAR-T platform with overnight manufacturing and designed to improve depth of response and efficacy. Data was presented at ASCO and EHA 2021 for initial 19 pts. We present updated data for study (NCT04236011;NCT04182581) with longer follow up and 9 additional pts treated (n = 28) in 3 different dose levels. Methods: From October 2019 to November 2021, 28 heavily pretreated RRMM pts (age 27-76) median of 5 prior lines (range 2-9) were treated on a single-arm, open label, multicenter Investigator Initiated Trial receiving a single infusion of GC012F. 89.3% (25/ 28) were high risk (HR- mSMART), 8 pts had EM disease, 3 had never achieved a CR including after transplant, 1 pts presented with plasma cell leukemia, 24/28 pts were refractory to last therapy, 3 pts primary refractory. 9/28 pts had received prior anti-CD38, 27/28 pts prior IMiDs. 26/28 pts were refractory to PI, 26/28 pts to IMiDs. After lymphodepletion over 2-3 days (30 mg/m2/d, 300mg/ m2/d Flu/Cy) GC012F was administered as single infusion at 3 dose levels: 1x105/kg (DL1) n = 2, 2x105/kg (DL2) n = 10 and 3x105/kg (DL3) n = 16. Results: As of Jan 26th 2022, 28 pts - median follow-up (f/ u) 6.3 mths (1.8-29.9) - had been evaluated for response. Overall response rate (ORR) in DL1 was 100% (2/2)- DL 2 -80% (8/10) DL 3 -93.8% (15/16) with 27 pts MRD negative by flow cytometry (sensitivity 10-4-10-6). 100% of MRD assessable pts (27/27) achieved MRD negativity. One patient out of 28 could not get assessed. At d28, 21/24 assessable patients were MRD negative (81.5%), 4/ 28 pts could not get d28 MRD assessment f/u due to COVID-19 restrictions however were assessed at a later timepoint. To date best response is MRD- sCR in 21/28 patients(75.0%) across all dose levels. Some pts after short f/u show responses that are still deepening. Cytokine Release Syndrome (CRS) was mostly low grade: gr 0 n = 3 (10.7%), gr 1-2 n = 23 (82.1%), gr 3 n = 2 (7.1%) - no gr 4/5 CRS and no ICANs were observed (Graded by ASBMT criteria). Median duration of CRS was 3 d (1-8 d). PK results showed no difference amongst dose levels DL1 to DL3. Overall, CAR-T median Tmax was 10 d (range 8-14 d), median peak copy number (Cmax) was 97009 (16,011-374,346) copies /μg DNA with long duration of persistence of up to d793 (data cut-off). CAR-T geometric mean AUC0-28 for DL1, DL2 and DL3 were 468863, 631540 and 581620 copies/μg DNA×day, respectively. Pts continue to be monitored for safety and efficacy including DOR. Conclusions: BCMA-CD19 dual FasT CAR-T GC012F continues to provide deep and durable responses with a favorable safety profile in additional RRMM pts across all dose levels demonstrating a very high MRD negativity rate including in pts refractory to anti-CD38, PI and IMIDs. GC012F is currently being studied in earlier lines of therapy as well as additional indications.

A Pharmacokinetic Modeling Approach to Evaluate the Current Dosing Recommendations for Molnupiravir, a Novel Oral SARS-CoV-2 Antiviral, in the Egyptian Population

Introduction: Molnupiravir, a prodrug of the antiviral Nhydroxycytidine (NHC), is one of the limited treatment options that has recently gained emergency use authorization for treating mild-tomoderate SARS-CoV-2 cases. While NHC is shown to follow linear pharmacokinetics with similar exposures in healthy and SARS-CoV-2 subjects, its pharmacokinetics has not been characterized in the Egyptian population. Research Question or Hypothesis: We aimed to develop a population pharmacokinetic model for NHC and evaluate through simulations the current molnupiravir dosage of 800 mg twice daily for five days in the Egyptian population. Study Design: An open label, single arm pharmacokinetic study. Methods: Twelve healthy volunteers received 800 mg molnupiravir oral dose. Model development using non-linear mixed effect modeling and internal validation using bootstrapping and visual predictive check were conducted in MonolixSuite. Simulation-based maximum concentration (Cmax) 'the safety metric' and area under the curve (AUC0-12h) 'the efficacy metric' were computed for 1000 virtual subjects. Geometric mean ratios (GMR) and 90% confidence intervals (CI) compared to previously reported values were calculated. Results: A total of 132 NHC plasma concentrations were analyzed. Six transit compartments for absorption and one-compartment with weight on apparent clearance (CL/F) and volume of distribution (Vd/F) for disposition best described NHC's pharmacokinetics. The pharmackokinetic parameters were estimated with good precision and the population estimates for mean transit time, first-order absorption rate constant, CL/F and Vd/F were 0.49 hours, 2.32 hour-1, 75.12 L/hour.70 kg and 118 L/70 kg, respectively. Geometric means of simulation-based Cmax and AUC0-12 were 3827 ng/mL (GMR = 1.05;90% CI= 0.96-1.15) and 9320 ng.hr/mL (GMR = 1.04;90% CI= 0.97-1.11), respectively. Conclusion: Population pharmacokinetic model was developed for NHC. Simulations showed that current molnupiravir dosage can achieve the therapeutic targets and dose adjustment may not be required for the Egyptian population. The developed model could be used in the future to refine molnupiravir's dosage once further therapeutic targets are identified.

Doxycycline inhibits SARS-CoV-2 replication in vitro

Introduction and Aim: We examined the effect of pre-and/or post-infection doxycycline on human nasal epithelial cell viability and SARS-CoV-2 (clinical strain IHUMI-3) replication in vitro. Materials and Methods: Human nasal epithelial cells, an in vivo SARS-CoV-2 target, were derived from healthy donor nasal epithelial stem/progenitor cells via in vitro differentiation. The cells were exposed to doxycycline at 0, 0.1, 0.5, 1, 5, 10, 50, and 100 μM before and/or after IHUMI-3 inoculation to determine the optimal inhibitory concentration. Viral replication was evaluated using quantitative reverse-transcription PCR, and doxycycline 50% cytotoxic concentration (CC50) and half-maximal effective concentration (EC50) were calculated. The peak serum concentration (Cmax) resulting from typical oral (100 or 200 mg) or intravenous (100 mg) doxycycline doses was estimated, and the Cmax/EC50 ratio was calculated as an index of potential clinical utility. Results: Doxycycline exhibited low cytotoxicity (CC50 > 100 μM) in human nasal epithelial cells and inhibited SARS-CoV-2 replication (EC50: 5.2 ± 3.3 μM) in a dose-dependent manner when administered pre-and/or post-infection. Reasonable oral or intravenous doses will help achieve effective concentrations in vivo. Conclusion: Early administration of this well-characterized, safe, and accessible drug may limit person-to-person transmission and prevent progression to severe coronavirus disease.

A Randomized, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Inhaled Ribavirin Administered Via Air-Jet Nebulizer in Healthy Volunteers

RATIONALE: Ribavirin is an inosine monophosphate dehydrogenase inhibitor. Studies suggest ribavirin aerosol could be a safe and efficacious treatment option in the fight against coronaviruses. It is currently approved for treatment of lower respiratory tract infections due to respiratory syncytial virus in pediatrics. However, treatment is long and continuous (12-18 hours per day, 3-7 days) limiting wider clinical utility. A reduction in treatment time would mean ribavirin could become a practical treatment option for SARS-CoV-2. The primary objective of this study was to evaluate the safety and pharmacokinetics (PK) of four, single-dose regimens of ribavirin aerosol in healthy volunteers. METHODS : Thirty-two subjects entered this phase Ia, randomized, doubleblinded, placebo-controlled, study. Four successive cohorts received ribavirin (active) or placebo. Cohort 1 received 50 mg/mL ribavirin/placebo (10 ml total volume);2 - 50 mg/mL ribavirin/placebo (20 ml total volume);3 - 100 mg/mL ribavirin/placebo (10 ml total volume);4 - 100 mg/mL ribavirin/placebo (20 ml total volume). All treatments were aerosolized and administered over 20 or 40 min for the 10ml and 20 ml volumes respectively. Randomization to cohorts took place on day 1, followed by intense safety monitoring and PK sampling on days 1, 2, 3 and 40. Treatment-emergent adverse events (TEAEs) were summarized by cohort and treatment group. PK parameters were analyzed using non-compartmental methods for maximal plasma concentration (Cmax), time to maximal plasma concentration (Tmax), area under the curve (AUC), and elimination half life (t1/2). RESULTS : Subjects were (mean ± SD, active vs placebo) aged 57 ± 4.5 vs 60 ± 2.5 years;83% vs 88% were female;and 75% vs 50% were Caucasian. 12.5% (3/24) and 25% (2/8) of subjects experienced at least one TEAE (2 moderate;5 mild) in active and placebo groups respectively. TEAEs were unrelated to study treatment. No clinically significant safety concerns were reported. Table I provides a summary of PK parameters. PK results were linear and well-behaved across the four single-dose regimens, demonstrating systemic exposure with minimal systemic effects. Ribavirin absorption reached Cmax within 2 hrs across all cohorts. The t1/2 was similar across all cohorts. CONCLUSIONS : Four single-dose regimens of ribavirin aerosol demonstrated systemic exposure with minimal systemic effects. These results support preliminary efficacy and safety data in COVID-19 patients and continued clinical development of ribavirin aerosol as a treatment option for SARS-CoV-2 and its variants. (Table Presented).

The Dual Phosphodiesterase (PDE) 3 and 4 Inhibitor Ensifentrine Does Not Prolong QT Interval in Healthy Volunteers

Ensifentrine (RPL554) is an investigational, first-in-class, inhaled dual inhibitor of PDE 3 and 4 with bronchodilator and anti-inflammatory actions in a single compound administered via nebulizer. This reports on the results from a phase 1, randomized, double-blind, placebo- and positivecontrolled, 4-way crossover thorough QT (TQT) study in healthy individuals. Thirty-two male and female subjects were randomized to receive a single dose of blinded ensifentrine 3mg (therapeutic dose), 9 mg (supra-therapeutic dose), and placebo via standard jet nebulizer and a single dose of oral moxifloxacin (400 mcg, open-label) in 4 separate treatment periods. 12-lead electrocardiograms (ECGs) were extracted from continuous Holter recordings pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours post-dose. ECG parameters were measured by a blinded central ECG laboratory. The primary statistical method was concentration-QTc analysis with the placebo-corrected change-from-baseline QTcF (ΔΔQTcF) as the primary endpoint. No clinically relevant effect on ΔΔQTcF was observed with either the 3mg or 9mg dose of ensifentrine. Using concentration-QTc analysis, the effect on ΔΔQTcF at the geometric mean estimated Cmax of 3 mg (546 pg/mL) and 9 mg (2342 pg/mL) ensifentrine indicated 1.4 ms (90% CI: 0.4 to 2.4) and 3.7 ms (90% CI: 0.7 to 6.7) increases vs placebo, respectively. The by-timepoint analysis showed that all upper bounds of the 90% CIs of ΔΔQTcF were below 10 ms with both doses across all timepoints. The lower bound of the 90% CI of the predicted QTc effect at the moxifloxacin mean Cmax was above 5 ms, thereby demonstrating assay sensitivity. Ensifentrine did not have a clinically meaningful effect on heart rate, PR or QRS intervals with either dose. In healthy individuals, both doses of ensifentrine were well tolerated. There were 14 (14.3%) reported AEs, including 13 treatment-emergent AEs (TEAE) of which 1 TEAE was serious (syncope) approximately 2 days post-dose in a subject who was hospitalized following the syncope event and physical injuries from a subsequent fall. The subject was positive for COVID-19 (moderate AE) at the time of hospitalization for the SAE event, and this was the only TEAE that led to study discontinuation. All AEs were mild except for syncope (severe) and COVID-19 (moderate). There were no deaths. AEs (23.3%) were more frequently reported in the ensifentrine-9mg arm. In summary, ensifentrine at the studied doses had no clinically relevant effects on studied ECG parameters.

Bioequivalence study of a new formulation of paracetamol/ibuprofen during the COVID-19 pandemic

Objective: To determine the bioequivalence of two oral formulations of paracetamol 500 mg/ibuprofen 200 mg. Tolerability of both formulations of paracetamol/ ibuprofen were evaluated descriptively. Material and/or methods: Twenty-four healthy volunteers were enrolled at this random, single-dose, crossover, two-period design, open-label, bioequivalence study. After overnight fasting, two formulations (test and reference) of paracetamol/ibuprofen (paracetamol 500 mg/ ibuprofen 200-mg film coated tablets), were administered as a single dose on two treatment days separated by a 72 h (minimum) washout period. After dosing, blood samples were drawn for a period of 12 h. Pharmacokinetic parameters were determined from plasma concentrations for both formulations. The coronavirus disease 2019 (COVID-19) pandemic was declared a public health emergency of international concern by the WHO. Extraordinary safety measures were implemented at different levels that intended to preserve the clinical trial activities as far as possible, protecting the safety and preserving the traceability while no vaccine was available. These measures, locally, consisted of: information about the importance of the measures, PCR test for COVID-19 at the screening visit (if IgG serology was positive) and PCR test at every period of admission to Trials Unit, the subject came into the Unit only after a negative result. Results: The highest effort made to assure the safety of participants led to a regular development of the study, with only two cases excluded primarily and one excluded after the first dose administration. Regarding pharmacokinetics, the results found for Paracetamol: Ln (Cmax) ng/ml Ratio 92.83% (CI90: 83.73%-102.94%);Ln (AUClast) h∗ng/ml Ratio: 96.14% (CI90: 93.24%-99.13%);for Ibuprofen: Ln (Cmax) ng/ml Ratio: 93.78% (CI90: 85.43-102.96%), Ln (AUClast) h∗ng/ml Ratio: 96.06% (CI90: 93.75%-98.42%). No drug-related safety concerns appeared. Conclusions: The clinical development of the BE clinical trial was made available by the extraordinary safety measures adopted. The pharmacokinetics results comply with the regulatory requirements for bioequivalence. No significant findings concerning safety were found.

A Novel Solution of Levothyroxine Results in Clinically Similar Maximum and Extent of Exposure Whether Taken 30 or just 15 Minutes Before a High-Fat High-Caloric Breakfast

Objective: Levothyroxine is essential for the treatment of hypothyroidism, but unfortunately its absorption when taken as a tablet has been shown to be significantly decreased with coffee or food ingestion, particularly if containing calcium or magnesium. Tablets and soft-gel formulations of levothyroxine are therefore recommended to be taken at least 30 minutes before meals, an inconvenience for patients in the morning. Tirosint-Sol® is a novel solution of levothyroxine that has been shown to result in an approximate 30 minutes faster absorption process than tablets or soft gel formulations. The objective of this trial was to investigate whether Tirosint-Sol® could be administered as late as 15 minutes before a high-fat, high-caloric meal, in comparison to 30 minutes. Methods: Thirthy-six (thirty-three completers, 24 males and 9 females) healthy volunteers participating in the randomized study took a 600 mcg Levothyroxine dose of Tirosint-Sol® after a 10-hour fast, 15 or 30 minutes before a high-fat high-caloric “FDA type” breakfast. Serum samples were taken at three different times at baseline, and at 0.5, 1, 1.5, 2.5, 3, 4, 6, 8, 10, 12, 16, 24, 48 and at 72 hours after dosing. The washout period was at least 35 days. Serum concentrations of Levothyroxine were measured using a validated LC-MS method. Results: Median tmax was unchanged between the two groups at 1.5 h. The three subjects that did not complete the trial did so because of not showing up for COVID19 testing, vomiting within 6 hours after dosing, and not finishing the breakfast. The geometric mean ratios and confidence intervals for the baseline adjusted maximum (Cmax, 85%, CI: 80-90%) and extent of exposure (AUC0-72, 92%, CI: 87-97%) were within the recognized equivalence boundaries of 80 to 125%, indicating an absence of meaningful clinical difference between dosing at 15 or 30 minutes before a meal. There were no differences in adverse events between groups. Discussion/Conclusion: The data of this randomized study indicate that the absorption profile of Tirosint-Sol® is clinically equivalent when administered 30 or 15 minutes before a high-fat high-caloric breakfast.

European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) - 37th Congress

This year's ECTRIMS brought scientists and specialists together to discuss developments in multiple sclerosis (MS), including how to define and monitor disease progression, imaging pathology, and, of course, the impact of the COVID-19 pandemic on MS patient care.

A Phase 1b Study of Blinatumomab Including Subcutaneous Administration in Relapsed / Refractory (R/R) Indolent Non Hodgkin's Lymphoma (NHL)

Background: Blinatumomab, a bispecific T-cell engager (BiTE ®) molecule that directs cytotoxic T-cells to lyse CD19-expressing B lineage cells, has been investigated in NHL (Goebeler JCO 2016, Viardot Blood 2016, Katz ASH 2019). Here, we evaluated subcutaneous (SC) blinatumomab, which may simplify administration, improve convenience, and potentially reduce adverse events (AEs). Methods: Patients (pts;≥18 y) had indolent NHL (follicular, marginal zone, lymphoplasmacytic, mantle cell, or small lymphocytic) that was primary refractory (1+ prior line), relapsed (within 1 y of first response), or that had responded to initial therapy for ≥1 y and relapsed after 2+ lines, including an anti-CD20 monoclonal antibody. Disease must not have been irradiated and was measurable (≥1.5 cm) on PET-CT or CT. Pts had a 3-wk continuous intravenous (cIV) run-in period followed by SC dosing in 5 cohorts, a further 2 wks of cIV dosing, and the option for a second cycle of cIV dosing (Figure). The primary objective was safety and tolerability of SC blinatumomab;secondary objectives included pharmacokinetics (PK), estimating the maximum tolerated dose (MTD), ie, the highest dose at which ≤1/6 pts had a dose-limiting toxicity (DLT), and efficacy (NCT 02961881). Results: Pts (n=29) had a median (range) age of 64 (42-75) y, 55% were male, 90% Caucasian, with follicular I-IIIA (76%), marginal zone (10%), mantle cell (10%) and lymphoplasmacytic lymphoma (3%) subtypes;no pts had prior allo-hematopoietic stem cell transplant (HSCT), 38% had prior auto-HSCT. Of the 29 pts, 5 discontinued (D/C) blinatumomab due to AEs (n=3;2 cIV, 1 SC), pt request (1), and disease progression (1);no pts D/C due to COVID-19 control measures;26 pts completed the study;pts received a median (range) of 5 (3-10) doses. AEs leading to D/C in SC treatment included neurologic events of aphasia and seizure. During SC dosing, 2 DLTs occurred (aphasia, n=1;seizure, n=1 ). MTD was not reached. Five pts had grade 3 (G3) AEs (thrombocytopenia, erosive esophagitis, asthenia, device-related infection, hyperglycemia, aphasia, seizure;pts may have had >1 G3 AE);there were no G4 AEs or fatal AEs. AEs of interest included neurologic events (all, n=15;G3, n=2), infection (2;1), and cytokine release syndrome (4;0). One pt had grade 1 injection site erythema. Anti-blinatumomab antibodies have not been detected to date. Preliminary PK results were consistent across the 5 SC cohorts and 3 different dosing regimens. Following the first dose, maximum concentrations (C max) were reached after ~5-12 hours and exposures (C max and area under concentration-time curve [AUC] from 0-12 hours) increased in a dose-related manner. At steady state, exposures (AUC over the dosing interval) increased in a dose-related manner for dosing intervals of once every 12, 24, and 48 hours across cohorts. Blinatumomab bioavailability and apparent terminal elimination half-life were favorable for extending the dosing interval to once every other day and potentially longer intervals. The steady-state concentrations during both cIV infusion periods were consistent with those previously reported in NHL pts. In all pts, the overall response rate (ORR, representative of cIV, 5 wks and SC, 1wk) per Cheson criteria was 69% (evaluable, n=23: complete response [CR], 21%;partial response [PR], 48%;cycle 1 [C1], n=22: ORR, 62%;CR, 14%;PR,48%;cycle 2 [C2], n=17: 45%;17%;28%;respectively);per Lugano criteria, the ORR was 52% (n=21: CR, 24%;PR, 28%;C1, n=18: 45%;17%;28%;C2, n=12: 31%;21%;10%);for follicular lymphoma, ORR was 77% per Cheson (n=19: CR, 23%;PR, 55%) and 55% per Lugano (n=15: CR, 23%;PR, 32%). Conclusions: In pts with R/R indolent NHL, SC blinatumomab had a favorable safety profile, with the caveat that pts who could not tolerate cIV blinatumomab did not advance to SC dosing. Efficacy was comparable with that seen for cIV dosing in prior blinatumomab NHL studies. In contrast to prior blinatumomab trials, no dose dependency in efficacy or toxicity was observed because SC dosi g was administered for only 1 wk, after 3 wks of cIV;pts not tolerating cIV did not receive SC dosing. Safety/tolerability of blinatumomab SC administration over the whole cycle is currently being evaluated in a phase 1 trial of pts with R/R acute lymphoblastic leukemia (NCT 04521231). SC blinatumomab PK, including bioavailability and half-life, showed promising features, warranting further investigation. [Formula presented] Disclosures: Rossi: Astellas: Membership on an entity's Board of Directors or advisory committees;Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees;Abbvie: Membership on an entity's Board of Directors or advisory committees;Alexion: Membership on an entity's Board of Directors or advisory committees;Sanofi: Honoraria;Takeda: Membership on an entity's Board of Directors or advisory committees;Celgene: Membership on an entity's Board of Directors or advisory committees;Daiichi Sankyo: Consultancy, Honoraria;Janssen: Membership on an entity's Board of Directors or advisory committees;Jazz: Membership on an entity's Board of Directors or advisory committees;Novartis: Membership on an entity's Board of Directors or advisory committees;Pfizer: Membership on an entity's Board of Directors or advisory committees. Prince: Takeda: Consultancy, Honoraria;Amgen: Honoraria, Research Funding;Novartis: Honoraria. Tam: Janssen: Consultancy, Honoraria, Research Funding;BeiGene: Consultancy, Honoraria;AbbVie: Consultancy, Honoraria, Research Funding;Loxo: Consultancy;Roche: Consultancy, Honoraria;Novartis: Honoraria;Pharmacyclics: Honoraria. Ku: Roche: Consultancy;Genor Biopharma: Consultancy;Antegene: Consultancy. Thieblemont: Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding;Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees;Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees;Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees;Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Hospira: Research Funding;Bayer: Honoraria;Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses. Popplewell: Pfizer: Other: Travel;Hoffman La Roche: Other: Food;Novartis: Other: Travel. Wermke: Novartis, Roche, Pfizer, BMS: Consultancy, Honoraria, Research Funding. Haioun: Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company);Janssen-Cilag: Consultancy;Celgene: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company);Novartis: Honoraria;Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company);Servier/Pfizer: Honoraria;Gilead Sciences: Consultancy, Honoraria;Takeda: Consultancy;Miltenyi Biotec: Consultancy. Viardot: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees;Amgen: Membership on an entity's Board of Directors or advisory committees;Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees;Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees;F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees;University Hospital of Ulm: Current Employment. Ferreri: Pfizer: Research Funding;x Incyte: Membership on an entity's Board of Directors or advisory committees;Amgen: Research Funding;Genmab: Research Funding;BMS: Research Funding;Hutchison Medipharma: Research Funding;PletixaPharm: Membership on an entity's Board of Directors or advisory committees;Adienne: Membership on an entity's Board of Directors or advisory committees;ADC Therapeutics: Research Funding;Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding;Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding;Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding;Ospedale San Raffaele srl: Patents & Royalties;Beigene: Research Funding. Wong: Amgen: Current Employment;Amgen: Current equity holder in publicly-traded company. Kadu: IQVIA: Current Employment. Zugmaier: Amgen: Current Employment;Micromet/Amgen: Patents & Royalties: Patents 20190300609 and 20130323247 licensed;receives royalties of family members of international applications published as WO2010/052014;WO2010/052013;WO2011/051307;WO2012/055961;WO 2012/062596;WO2014/122251;and WO2015/181683;Amgen: Current equity holder in publicly-traded company. Zeng: Amgen: Current Employment, Current equity holder in publicly-traded company. Rambaldi: Celgene: Other: Travel, Accommodations, Expenses;Jazz Pharmaceuticals: Consultancy;Astellas Pharma: Consultancy;Novartis: Consultancy;Omeros: Consultancy, Honoraria;Amgen: Consultancy, Honoraria. OffLabelDisclosure: Blinatumomab is approved in the United States for administration as a continuous intravenous infusion. It has not been approved for subcutaneous administration.