Takeda Pharmaceutical Company Research Articles

888-P: Urinary Albumin Levels Prior to SGLT2 Inhibitors Initiation Predict Increased TIR after 12 Months in Patients with Type 1 Diabetes on Sensor-Augmented Pump Therapy

Purpose: SGLT2 inhibitors (SGLT2i) have been shown to improve glycemic control in patients with type 1 diabetes (T1D). Predictors of SGLT2i efficacy in patients with T1D on sensor-augmented pump (SAP) therapy were investigated. Methods: Patients with T1D on SAP therapy attending our hospital who were newly initiated on SGLT2i between 2019-2020 and followed for at least one year, were included in the study. Data on BMI, blood tests, and continuous glucose monitors were compared before and 12 months after SGLT2i initiation. The predictors of time in range (TIR) change (ΔTIR) were determined by multiple regression analysis. The cutoff values for predictors of ΔTIR above the median at the end of the study were determined using ROC curve analysis. Results: 17 patients (70.6% females, median age 44.0 years) were included in the analysis, except for three patients who discontinued SGLT2i due to side effects. Median BMI and eGFR decreased significantly from 25.3 kg/m2, and 79.0 ml/min/1.73m2 at baseline to 23.9 kg/m2, and 73.0 ml/min/1.73m2 (p = 0.013, p = 0.002, respectively), while total daily dose of insulin, basal-to-total insulin ratio, and urinary albumin-to-creatinine ratio (UACR) showed no significant change (40.1 vs 41.0 units [p = 0.084], 40.1 vs 38.5% [p = 0.266], 7.0 vs 2.0 mg/g [p = 0.285], respectively). HbA1c, TIR, and TAR improved significantly (8.2 vs 7.8% [p = 0.004], 53.0 vs 61.0% [p = 0.003], and 47.0 vs 36.0% [p = 0.003], respectively), while TBR showed no significant change (0.4 vs 0.8% [p = 0.309]). Predictors of increased ΔTIR were overweight and high UACR at baseline (p = 0.026) and the cutoff value for UACR that predicted ΔTIR above the median was 28.0 mg/g (AUC = 0.82 [95%CI, 0.61-1.03]; p = 0.003). Conclusion: SGLT2i improved glycemic control of patients with T1D on SAP therapy without increasing TBR. It was also suggested that patients with UACR above 28.0 mg/g could have greater impact on TIR improvement after 12 months. Disclosure Y.Suganuma: None. H.Takahashi: Speaker's Bureau; Eli Lilly Japan K.K., Boehringer Ingelheim Japan, Inc., Medtronic, Novo Nordisk. T.Ohno: None. R.Nishimura: Speaker's Bureau; Sanofi K.K., Medicure Inc., Boehringer Ingelheim Inc., Takeda Pharmaceutical Company Limited, Kissei Pharmaceutical Co., Ltd., Novartis Pharma K.K., Eli Lilly Japan K.K., Novo Nordisk, Merck & Co., Inc., Abbott Japan Co., Ltd., Astellas Pharma Inc., Teijin Pharma Limited, Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., AstraZeneca.

0583 Prevalence and Incidence of Narcolepsy in the US General Population

Abstract Introduction Narcolepsy is a sleep disorder characterized by cataplexy, hypersomnolence, sleep fragmentation and manifestations of various REM sleep abnormalities. It is a rare orphan disorder and therefore, its prevalence is almost exclusively estimated by derivate from clinical samples. Consequently, the objective of this study was to assess the prevalence of narcolepsy in an US general population representative sample. Methods The epidemiological study was carried with 15,927 individuals from 15 US States using the Sleep-Eval system. The longitudinal study was in eight of these 15 states: 12,218 subjects were interviewed by phone during the first wave and 10,931 at the second wave three years apart. Prevalence rates were calculated with the large sample while the Incidence was calculated on the subjects who participated in both interviews (N=10,931). The same interview was completed in both waves. For the purpose of this study, an algorithm was created using the answers provided for each symptom to reach a diagnosis conclusion of Narcolepsy type 1 (NT1) or Narcolepsy type 2 (NT2) according to ICSD3. Results NT1 was identified in 0.0126% (95% CI: 0.000%-0.03%) of the whole sample. Prevalence was similar between men and women. NT1 did not differ significantly by age groups although it was slightly higher in individuals younger than 35 y.o. (0.0201% (95% CI: 0.000%-0.06%)) compared to 0.016% (95% CI: 0.000% to 0.047%) in the 35 to 54 y.o. group and none in the oldest group. NT2 was observed in 0.0251% (95% CI: 0.0005%-0.0497%) of the sample. NT2 prevalence was comparable between men and women and among age groups. Overall, 66.7% of narcolepsy individuals in the sample identified by Sleep-Eval were already diagnosed as such by a physician. The incidence rate was also very low at 0.0026% per year. Conclusion Our results support the fact that narcolepsy is indeed a rare disorder affecting 37.7 individuals per 100,000 inhabitants with a relatively low incidence at 2.6 individuals per 100,000 inhabitants per year. Recognition of the disorder by a physician was relatively high in the United States with 2/3 of the cases being already diagnosed. Support (if any) Data analysis study were funded by Tris Pharma and Takeda Pharmaceutical Company.

0323 Natural Evolution of Insomnia in Major Depressive Disorders

Abstract Introduction Insomnia is a fairly common sleep disturbance affecting nearly one third of the general population. Although its predictive value for major depressive disorder (MDD) has been well documented, little is known about its role in the appearance of a first episode or in the recurrence. In this study, we examine the predictive value of insomnia symptoms in the incidence and recurrence of MDD. Methods In this longitudinal study, 2 interview waves were conducted between 2002 and 2015. The initial interviews (wave 1 [W1]) were carried out with 12,218 individuals aged ≥18 years from the general population in 8 US states. At follow-up 3 years later (wave 2 [W2]), 10,931 of the initial participants agreed to be interviewed again. Data were analyzed for the individuals who participated in both interviews (N=10,931). A diagnosis of MDD was made according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria. Insomnia symptoms were defined according to DSM-5 criteria A, C, and D for insomnia disorder. Results The 12-month prevalence of MDD was 9.5% (95% CI, 9.0%-10.0%) and 12.1% (95% CI, 11.5%-12.7%) in W1 and W2, respectively. Over the course of the study, 2.6% of participants experienced recurrence of depression (95% CI, 2.3%-2.9%). After adjusting for age, gender, race, and body mass index, participant characteristics in W1 that predicted recurrent MDD in W2 included early morning awakenings (EMA) (relative risk [RR], 3.2; 95% CI, 2.3-4.4), being dissatisfied with one’s sleep (RR, 2.8; 95% CI, 2.1-3.7), nocturnal awakenings (RR, 2.4; 95% CI, 1.8-3.2), and difficulty initiating sleep (DIS) (RR, 2.0; 95% CI, 1.5-2.9). MDD incidence was predicted by DIS (RR, 3.8; 95% CI, 2.5-5.9), being dissatisfied with one’s sleep (RR, 2.1; 95% CI, 1,4-3.2), and EMA (RR, 2.0; 95% CI, 1.2-3,2) at W1. Conclusion Insomnia symptoms appear to play an important part in predicting both the development of a first depressive episode as well as the recurrence of depression. Support (if any) Data analysis study were funded by Takeda Pharmaceutical Company.

0045 Characterization of a novel narcolepsy mouse model with conditional ablation of the orexin neurons

Abstract Introduction Narcolepsy type 1 (NT1) is caused by selective loss of orexinergic neurons. Although narcolepsy typically begins in childhood or adolescence, most mouse models induce loss of the orexin peptides or orexin neurons from birth. To generate a mouse model that reflects the acquired loss of orexinergic neurons in human NT1, we produced recombinant mice expressing the human diphtheria toxin receptor (DTR) driven by the prepro-orexin promoter (orexinDTR mice). We examined whether administration of diphtheria toxin (DTX) to orexinDTR mice caused selective loss of orexinergic neurons and induced narcolepsy symptoms such as sleep-wake fragmentation and cataplexy. In addition, we investigated the effects of an orexin 2 receptor (OX2R)-selective agonist OX-201 on narcolepsy symptoms in DTX-treated orexinDTR mice. Methods We produced orexinDTR mice with the human DTR knocked into the prepro-orexin locus. To induce loss of orexinergic neurons, we intramuscularly injected DTX into heterozygous orexinDTR mice, and later counted orexin-A (OX-A) immunoreactive neurons. Moreover, we collected functional data of EEG/EMG recordings during the dark period in orexinDTR mice. Finally, we evaluated the effects of OX-201 on narcolepsy symptoms, including sleepiness and cataplexy, 6 weeks after DTX injection. Results Within 1 week after injection of DTX, the number of OX-A immunoreactive neurons was reduced to 1% of normal with no change in the number of neurons making melanin-concentrating hormone. Furthermore, orexinDTR mice treated with DTX developed severe sleep-wake fragmentation within 1 week, and very frequent cataplexy (~100 episodes/night) in the subsequent weeks. These symptoms were substantially and dose-dependently improved by administration of OX-201. Conclusion OrexinDTR mice are a useful and simple model for understanding the neurobiology of narcolepsy and evaluating new drugs to treat narcolepsy symptoms. As only one allele of the orexin-DTR is required, these mice are also convenient for crossing with other lines, enabling a variety of methods to study the orexinergic neurons. OX-201 markedly reduced narcolepsy symptoms. Although it is a tool compound unlikely to be used in patients, it further demonstrates the potential of high efficacy of OX2R agonists in treating narcolepsy. Support (if any) This work was funded by Takeda Pharmaceutical Company Limited.

0049 Orexin 2 receptor agonist activates pre-Bötzinger complex neurons, phrenic motoneurons and the diaphragm in rodents

Abstract Introduction Neurons in the pre-Bötzinger complex are critical for the generation of inspiratory rhythm and regulation of activity of phrenic motoneurons, which control the activity of the diaphragm. Dysregulation of this neuronal network and resulting dysfunction of the diaphragm is associated with central sleep apnea (CSA). Orexins by stimulating both orexin 1 receptor (OX1R) and/or orexin 2 receptor (OX2R) can activate these neurons and the diaphragm. In this study, we assessed effects of OX2R-selective agonists on the activity of neurons in the pre-Bötzinger complex, phrenic motoneurons, and the diaphragm. Methods OX2R-selective agonists danavorexton (TAK-925) and OX-201 (a tool compound with longer plasma half-life than danavorexton in rodents) were used. OX2R and OX1R agonistic activities were examined by calcium mobilization assay in hOX2R/CHO-K1 cells and hOX1R/CHO-K1 cells, respectively. Activity of neurons in the pre-Bötzinger complex and phrenic motoneurons was investigated by electrophysiological recording in rat tissues. Activity of the diaphragm was evaluated by electromyogram recording in anesthetized rats. Respiratory activity was evaluated by whole-body plethysmography recording in mice. Results Danavorexton and OX-201 showed potent OX2R agonistic activity with 50% effective concentration (EC50) values of 5.5 nM and 8.0 nM, respectively. Danavorexton and OX-201 had >5,000-fold and 1,000-fold OX2R selectivity over OX1R, respectively. In in vitro electrophysiological analyses, danavorexton and OX-201 increased the burst frequency of neurons in the pre-Bötzinger complex (EC50: 300 nM and 760 nM, respectively) and phrenic motoneurons (EC50: 1.6 µM and not determined, respectively). Intravenous administration of OX-201 at 1 and 3 mg/kg increased burst frequency of the diaphragm in anesthetized rats and oral administration at 3 mg/kg increased respiratory activity in conscious mice. Conclusion OX2R-selective agonists may enhance respiratory function via activation of the diaphragm through stimulation of neurons in the pre-Bötzinger complex and phrenic motoneurons. OX2R agonists may have therapeutic potential in patients with CSA if enhancement of respiratory function by OX2R agonists can be observed at non-arousal concentrations. Further preclinical and clinical studies are worth conducting in patients with CSA. Support (if any) This work was conducted by Takeda Pharmaceutical Company Limited.

0048 Orexin 2 receptor agonist activates pre-Bötzinger complex neurons, hypoglossal motoneurons and the genioglossus muscle in rodents

Abstract Introduction Neurons in the pre-Bötzinger complex are critical for the generation of inspiratory rhythm and control the activity of the genioglossus muscle via activation of hypoglossal motoneurons. Activation of the genioglossus muscle causes anterior movement of the tongue and widens the upper airway. As obstructive sleep apnea (OSA) is associated with obstruction of the upper airway, activation of this neuronal pathway may be a novel therapeutic approach. Orexins have been shown to activate these neurons by stimulation of both orexin 1 receptor (OX1R) and/or orexin 2 receptor (OX2R). In this study, we assessed effects of OX2R-selective agonists on activity of neurons in the pre-Bötzinger complex, hypoglossal motoneurons, and the genioglossus muscle. Methods OX2R-selective agonists danavorexton (TAK-925) and OX-201 (a tool compound with longer plasma half-life than danavorexton in rodents) were used. Arousal effects were investigated by electroencephalogram/electromyogram recording in C57BL/6J mice and OX2R knockout mice. Activity of neurons in the pre-Bötzinger complex and hypoglossal motoneurons was investigated by electrophysiological recording in rat tissues. Activity of the genioglossus muscle was evaluated by electromyogram recording in anesthetized rats. Results Oral administration of OX-201 increased wakefulness time during sleep phase in C57BL6J mice but not in OX2R knockout mice. In in vitro electrophysiological analyses, danavorexton, and OX-201 increased the burst frequency of neurons in the pre-Bötzinger complex (EC50: 300 nM and 760 nM, respectively) and hypoglossal motoneurons (EC50: 610 nM and 260 nM, respectively). Intravenous administration of OX-201 at 1 mg/kg increased burst amplitude of the genioglossus muscle in anesthetized rats. Conclusion OX2R-selective agonists may enhance the respiratory function via activation of the genioglossus muscle through stimulation of neurons in the pre-Bötzinger complex and hypoglossal motoneurons. OX2R agonists may have therapeutic potential in patients with OSA if enhancement of respiratory function by OX2R agonists can be observed at non-arousal concentrations. Further preclinical and clinical studies are worth conducting in patients with OSA. Support (if any) This work was conducted by Takeda Pharmaceutical Company Limited.

Cross-sectional analysis of open payments for physicians at designated hemophilia centers in the US (2018–2020)

IntroductionPhysicians who treat hemophilia, and especially directors at hemophilia centers, are in a position to be unduly influenced by payments from pharmaceutical companies who make costly hemophilia drugs. It is from this perspective that we analyzed payments made to physicians at hemophilia centers in the US, focusing on center directors. Materials and methodsIn a cross-sectional analysis we searched the CDC's Hemophilia Treatment Center Directory for physicians (2022) and then abstracted general payments for physicians on Open Payments (2018–2020) and calculated one-year average payments. We searched academic websites to determine physician role (hemophilia center director, non-director, or non-center director). ResultsThere were 420 physicians in the hemophilia physician directory – 270 physicians/professors, 103 directors of hemophilia centers, and 47 other directors. Directors of hemophilia centers had higher median one-year general payments, compared to other directors and physician/professors ($4910 vs $79 vs $87, respectively; p < 0.0001). Takeda Pharmaceutical Company Limited, F-Hoffmann La Roche Ltd./Genentech, and Novo Nordisk have the largest hemophilia drug market share and were the three companies with the most payments to physicians. ConclusionsHigh payments, especially among individuals who have responsibility over the success of hemophilia centers and clinics, may result in competition with the interest of the patients at these centers and clinics.

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

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

Frequency of anti-IgLON5 disease in patients who meet the clinical diagnostic criteria for progressive supranuclear palsy/corticobasal syndrome (S22.010)

<h3>Objective:</h3> To confirm the prevalence of anti-immunoglobulin-like cell adhesion molecule 5 (IgLON5) disease in patients who fulfill the diagnostic criteria for progressive supranuclear palsy (PSP) or corticobasal syndrome (CBS). <h3>Background:</h3> Anti-IgLON5 disease can present symptoms that mimic PSP and CBS, including vertical supranuclear gaze palsy and parkinsonism. Some patients who are diagnosed with PSP or CBS are expected to have anti-IgLON5 antibodies; however, the frequency of such patients remains unknown. <h3>Design/Methods:</h3> We included 360 subjects enrolled in the Japanese Longitudinal Biomarker Study in PSP and Corticobasal Degeneration (JALPAC). We noted the age and sex of each patient and evaluated their diagnosis using diagnostic criteria for each subtype of PSP (PSP with Richardson’s syndrome [PSP-RS], PSP with parkinsonism [PSP-P], PSP-pure akinesia with gait freezing [PSP-PAGF], and PSP with cerebellar ataxia [PSP-C]), and using the revised Cambridge criteria and Armstrong criteria for CBS. In patients who fulfilled any diagnostic criteria, we then tested serum anti-IgLON5 antibodies via a cell-based assay. <h3>Results:</h3> Of 360 subjects in JALPAC, 223 fulfilled at least one of the diagnostic criteria for possible or probable PSP/CBS. The median age of these 223 patients was 73 (range 51–88) years; 123 (55%) were male. The numbers of patients who met each set of criteria were as follows: PSP-RS, 52; PSP-PAGF, 6; PSP-C, 2; CBS, 117; PSP-RS and CBS, 37; PSP-PAGF and CBS, 4; PSP-RS and PSP-PAGF, 1; PSP-RS and PSP-P, 1; PSP-P and CBS, 1; PSP-RS, PSP-PAGF, and CBS, 1; and PSP-RS, PSP-C, and CBS, 1. All 223 patients were negative for anti-IgLON5 antibodies. <h3>Conclusions:</h3> Anti-IgLON5 disease is likely absent or extremely rare in patients who meet the diagnostic criteria for PSP/CBS and have typical clinical presentations. Atypical symptoms such as sleep disturbance, dysautonomia, and respiratory failure may be crucial clinical features of anti-IgLON5 disease with PSP-/CBS-like presentations. <b>Disclosure:</b> Yoya Ono has nothing to disclose. Akira Takekoshi has nothing to disclose. Dr. Yoshikura has nothing to disclose. Dr. Takigawa has nothing to disclose. Ikuko Aiba has nothing to disclose. Ritsuko Hanajima has nothing to disclose. Dr. Kowa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for DAIICHI SANKYO COMPANY, LIMITED. Dr. Kowa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Eli Lilly Japan K.K.. Dr. Kowa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Otsuka Pharmaceutical Co., Ltd.. Dr. Kowa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Amgen Inc.. Dr. Kowa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Takeda Pharmaceutical Company Limited.. Dr. Kowa has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Kyowa Kirin Co., Ltd.. Dr. Kowa has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Chugai Pharmaceutical Co., Ltd.. Dr. Kowa has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for ONO PHARMACEUTICAL CO., LTD.. Dr. Kanazawa has nothing to disclose. Dr. ?? has nothing to disclose. Aya Tokumaru has nothing to disclose. Dr. Morita has nothing to disclose. Dr. Hasegawa has nothing to disclose. Kenji Nakashima has nothing to disclose. Dr. Ikeuchi has nothing to disclose. Dr. Kimura has nothing to disclose. Dr. Shimohata has nothing to disclose.

Feasibility Assessment of Facilitated Subcutaneous Immunoglobulin 1.0 G/Kg with Abbreviated Dose Ramp-Up and without Ramp-Up: A Phase 1 Tolerability and Safety Study in Healthy Adults (P6-4.003)

<h3>Objective:</h3> To assess the feasibility of infusions of facilitated subcutaneous immunoglobulin (fSCIG; immunoglobulin infusion with recombinant human hyaluronidase) at a 1.0g/kg target dose via an abbreviated dose ramp-up or no ramp-up versus conventional ramp-up in healthy participants, based on tolerability and safety outcomes. <h3>Background:</h3> When transitioning from intravenous to facilitated subcutaneous dosing, dose ramp-up is used to incrementally increase infusion volumes to achieve target doses, acclimating patients to high-volume infusions. <h3>Design/Methods:</h3> This phase 1, open-label, single-center trial enrolled healthy adults aged 19–50 years (NCT04578535). Participants were assigned into three fSCIG arms (each with a 1.0g/kg target dose): (1) conventional dose ramp-up (0.25g/kg [Week 1] to 1.0g/kg [Week 8]), (2) abbreviated dose ramp-up (0.50g/kg [Week 1] to 1.0g/kg [Week 5]), or (3) 1.0g/kg without ramp-up. fSCIG tolerability (primary endpoint) was assessed as the proportion of participants completing all initiated infusions without interruptions or infusion rate reduction owing to treatment-emergent adverse events (TEAEs). Safety endpoints included the rates of TEAEs per person-year. <h3>Results:</h3> Overall, 27 participants were enrolled (mean age 34.9 years); with 8, 9, and 10 participants in the conventional, abbreviated, and no ramp-up arms, respectively. Participants completed all initiated infusions. No discontinuations due to TEAEs occurred but discontinuations were proportionally highest in the no ramp-up group. In total, 69.7, 74.0 and 99.7 TEAEs occurred per person-year in the conventional, abbreviated and no ramp-up arms, respectively. No serious or severe TEAEs occurred. <h3>Conclusions:</h3> fSCIG was well-tolerated in healthy adults with or without dose ramp-up at a 1.0 g/kg target dose, but the higher proportion of discontinuations in the no ramp-up arm may provide indirect evidence of better tolerability with ramp-up. The feasibility of abbreviated ramp-up was demonstrated by the lower TEAE rates seen in the dose ramp-up arms. Therefore, administration schedules can be individualized according to physician discretion based on tolerability. <b>Disclosure:</b> Zhaoyang Li has received personal compensation for serving as an employee of Takeda. Andras Nagy has nothing to disclose. Mr. Khaskhely has nothing to disclose. Mr. Lindner has received personal compensation for serving as an employee of Takeda. Mr. Lindner has stock in Takeda. Kimberly Duff has nothing to disclose. Dr. Garcia has received personal compensation for serving as an employee of Takeda Pharmaceutical Company Limited. Dr. Garcia has stock in Takeda Pharmaceutical Company Limited. Dr. AY has received personal compensation for serving as an employee of Takeda. Dr. Rondon has nothing to disclose. Prof. Yel has received personal compensation for serving as an employee of Takeda. Prof. Yel has stock in Takeda. Prof. Yel has received publishing royalties from a publication relating to health care.

Response to van Dyck, O'Dell, & Mecca letter to the editor regarding Andrews etal. (2019).

Response to van Dyck, O'Dell, & Mecca letter to the editor regarding Andrews etal. (2019).

Report of the first seven agents in the I-SPY COVID trial: a phase 2, open label, adaptive platform randomised controlled trial

An urgent need exists to rapidly screen potential therapeutics for severe COVID-19 or other emerging pathogens associated with high morbidity and mortality. Using an adaptive platform design created to rapidly evaluate investigational agents, hospitalised patients with severe COVID-19 requiring ≥6L/min oxygen were randomised to either a backbone regimen of dexamethasone and remdesivir alone (controls) or backbone plus one open-label investigational agent. Patients were enrolled to the arms described between July 30, 2020 and June 11, 2021 in 20 medical centres in the United States. The platform contained up to four potentially available investigational agents and controls available for randomisation during a single time-period. The two primary endpoints were time-to-recovery (<6L/min oxygen for two consecutive days) and mortality. Data were evaluated biweekly in comparison to pre-specified criteria for graduation (i.e., likely efficacy), futility, and safety, with an adaptive sample size of 40-125 individuals per agent and a Bayesian analytical approach. Criteria were designed to achieve rapid screening of agents and to identify large benefit signals. Concurrently enrolled controls were used for all analyses. https://clinicaltrials.gov/ct2/show/NCT04488081. The first 7 agents evaluated were cenicriviroc (CCR2/5 antagonist; n=92), icatibant (bradykinin antagonist; n=96), apremilast (PDE4 inhibitor; n=67), celecoxib/famotidine (COX2/histamine blockade; n=30), IC14 (anti-CD14; n=67), dornase alfa (inhaled DNase; n=39) and razuprotafib (Tie2 agonist; n=22). Razuprotafib was dropped from the trial due to feasibility issues. In the modified intention-to-treat analyses, no agent met pre-specified efficacy/graduation endpoints with posterior probabilities for the hazard ratios [HRs] for recovery ≤1.5 between 0.99 and 1.00. The data monitoring committee stopped Celecoxib/Famotidine for potential harm (median posterior HR for recovery 0.5, 95% credible interval [CrI] 0.28-0.90; median posterior HR for death 1.67, 95% CrI 0.79-3.58). None of the first 7 agents to enter the trial met the prespecified criteria for a large efficacy signal. Celecoxib/Famotidine was stopped early for potential harm. Adaptive platform trials may provide a useful approach to rapidly screen multiple agents during a pandemic. Quantum Leap Healthcare Collaborative is the trial sponsor. Funding for this trial has come from: the COVID R&D Consortium, Allergan, Amgen Inc., Takeda Pharmaceutical Company, Implicit Bioscience, Johnson & Johnson, Pfizer Inc., Roche/Genentech, Apotex Inc., FAST Grant from Emergent Venture George Mason University, The DoD Defense Threat Reduction Agency (DTRA), The Department of Health and Human ServicesBiomedical Advanced Research and Development Authority (BARDA), and The Grove Foundation. Effort sponsored by the U.S. Government under Other Transaction number W15QKN-16-9-1002 between the MCDC, and the Government.

Juvenile idiopathic arthritis in children and adolescents with atopic dermatitis: A Finnish nationwide registry study

Juvenile idiopathic arthritis in children and adolescents with atopic dermatitis: A Finnish nationwide registry study

Particulates are everywhere, but are they harmful in cell and gene therapies?

Cell and gene therapies (CGTs) are a broad class of revolutionary new treatment modalities with enormous potential to impact multiple intractable diseases. In recent years, the sector has reached a breakthrough point, with unprecedented approvals of cell- and gene-based treatments such as adipose-derived mesenchymal stromal cells (Alofisel, manufactured by Takeda Pharma A/S), chimeric antigen receptor T-cell therapies (e.g., Yescarta, Kite Pharma) and gene therapies (e.g., Luxturna, Spark Therapeutics) and lipid nanoparticle (LNP) vaccines against severe acute respiratory syndrome coronavirus 2 virus (Spikevax by Moderna and Comirnaty by Pfizer-BioNTech).

The cost-effectiveness of brigatinib in adult patients with ALK inhibitor-naive ALK-positive non-small cell lung cancer from a US perspective.

BACKGROUND: The discovery of specific oncogenic drivers in non-small cell lung cancer (NSCLC) has led to the development of highly targeted anaplastic lymphoma kinase tyrosine kinase inhibitors (ALKis). Brigatinib is a next-generation ALKi associated with prolonged progression-free survival in patients with ALKi-naive ALK+ NSCLC. OBJECTIVE: To estimate the cost-effectiveness of brigatinib compared with crizotinib and alectinib in patients with ALKi-naive ALK+ NSCLC, from a US payer perspective. METHODS: A lifetime area under the curve-partitioned survival model with 4 health states was used to evaluate the relative cost-effectiveness of brigatinib in the ALKi-naive ALK+ NSCLC setting. Brigatinib was compared with crizotinib within a cost-effectiveness framework and compared with alectinib in a cost-comparison framework, where all efficacy outcomes were assumed equal. The efficacy of brigatinib and crizotinib was informed by the ALTA-1L trial, and an indirect treatment comparison was performed to inform the efficacy of brigatinib vs alectinib owing to a lack of head-to-head data. Costs were derived from public sources. The main outcomes of the model were total costs, quality-adjusted life-years (QALYs), life-years, and incremental cost-effectiveness ratios. Univariate and probabilistic sensitivity analyses, in addition to multiple scenario analyses, were conducted to assess the robustness of the model outcomes. RESULTS: The improved outcomes observed in ALTA-1L translated into QALY gains (+0.97) in the comparison of brigatinib vs crizotinib. The superior efficacy profile was associated with increased time on treatment with brigatinib, which drove the increase in costs vs crizotinib (+$210,519). The resulting base-case incremental cost-effectiveness ratio was $217,607/QALY gained. Compared with alectinib, brigatinib was associated with a cost difference of -$8,546. Sensitivity analysis suggested that extrapolation of overall survival, the assumptions relating to time on treatment, and subsequent therapy costs were the most influential determinants of results. Probabilistic sensitivity analysis suggested brigatinib had the highest probability of being cost-effective beyond willingness-to-pay thresholds of $236,000 per QALY vs crizotinib and alectinib. CONCLUSIONS: At list prices and under base-case assumptions in the current analysis, brigatinib was associated with cost-savings vs alectinib, and QALY gains but at higher costs vs crizotinib. Additional research into the real-world efficacy of ALKis is warranted to further understand the comparative cost-effectiveness of these therapies. DISCLOSURES: Ms Cranmer and Ms Kearns are employees of Takeda UK Ltd. Dr Young is a former employee of Takeda Pharmaceuticals America, Inc. Dr Humphries is an employee of Takeda Pharmaceuticals U.S.A., Inc. Mr Trueman is an employee of Source Health Economics, the consultancy company that provided health economic and writing services. This work was funded by ARIAD Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Work by Source Health Economics was funded by ARIAD Pharmaceuticals, Inc. Professional medical writing assistance was provided by Phillipa White, of Source Health Economics, and funded by ARIAD Pharmaceuticals, Inc.

NTD Drug Discovery Booster, Achievements and Next Steps

The Neglected Tropical Disease (NTD) Drug Discovery Booster is a collaborative project in early small molecule drug discovery running since 2015 between Drugs for Neglected Diseases initiative (DNDi) and pharmaceutical partners across the globe, including Astellas Pharma Ltd., Eisai Co., Ltd., Shionogi & Co., Ltd. and Takeda Pharmaceutical Company Ltd. in Japan, along with AbbVie Inc., Merck KGaA, AstraZeneca plc and Celgene Corporation. The Booster engages these partners to share both their experience with in silico screening as well as their proprietary chemical libraries to further develop new starting points for NTDs such as visceral leishmaniasis and Chagas disease. This collaborative approach allows DNDi to access new chemical space and elaborate the structure activity relationships (SAR) around phenotypic screening hits against the causative parasites of these diseases (Trypanosoma cruzi, Leishmania donovani and infantum) as well as access new starting points via innovative scaffold hops proposed by the partners. Since 2015 the Booster has probed over 20 new starting point "hits" for these diseases, successfully converting over half into new series for further exploitation. These series were developed further in partnership with the booster collaborators to enable in vivo proof of concept studies, with series from the booster progressing into lead optimization. Our efforts in the NTD Discovery Booster have demonstrated clear advantages of this precompetitive sharing mechanism and the synergistic value of exploring multiple proprietary compound libraries in parallel. The most advanced of these Booster projects is projected to deliver a preclinical candidate for leishmaniasis within the next 2 years.

Partnership Activity for Neglected Tropical Diseases

Delivering new medicines to patients suffering from Neglected Tropical Diseases (NTD) is a major challenge. There are various hurdles to be overcome, such as the large number of patients in a large number of different regions, the lack of marketability, and resistance to medicines. Takeda Pharmaceutical Company Limited (Takeda) is following a corporate mission of "striving towards better health for patients worldwide though leading innovation in medicine". These guiding principles lead to the values of Integrity, Fairness, Honesty and Perseverance that make up what we call "Takeda-ism". As part of its contribution to R&D for NTDs, Takeda collaborates with global Product Development Partnerships (PDPs). In this symposium, the "Drug Discovery Booster" project to accelerate and expand discovery of new drugs for Leishmaniasis and Chagas disease with Drugs for Neglected Diseases initiative (DNDi) and other pharmaceutical companies is introduced. Proprietary compound libraries and the drug discovery expertise of various partners was applied to this new drug discovery approach. An overview of our research projects in malaria, tuberculosis, and NTD is also presented. In addition to these, Takeda's Access to Medicines (ATM) strategy and activities are introduced. Lastly, we discuss a new open innovation model which is accelerated by partnership with a variety of organizations and how Takeda achieves its sustainable development goal (SDG) targets.

1439-P: Association between Sleep Duration, Bedtime, and Hyperglycemia or Overweight/Obesity among Japanese Children

In adults, short sleep duration and late bedtime were associated with hyperglycemia and obesity, but these relationships in children are little known. We evaluated the association of bedtime and sleep duration with overweight/obesity or hyperglycemia in children by sex, considering the effects of diet, physical activity, and screen time. A cross-sectional study was conducted for 1139 Japanese children (553 boys) aged 10-y. Overweight was as defined by the International Obesity Task Force. Cutoff value for hyperglycemia was HbA1c ≥5.6%. Variables associated with hyperglycemia or overweight were based on logistic regression analysis. Multivariate logistic regression analysis showed that compared with an early bedtime (˜21:59) and long sleep duration (weekdays ≥8.67 h, weekends ≥9 h) , short sleep duration (weekdays &amp;lt;8.67 h, weekends &amp;lt;9 h) was associated with overweight in boys but not late bedtimes (22:00˜) . The significant association seen disappeared in girls when adjusted for screen time. For hyperglycemia, in both sexes wake time and sleep duration on weekends were significant in univariate analysis, but not in multivariate analysis adjusted for diet and physical activity. In Japanese boys, short sleep duration was significantly associated with overweight. Sleep ≥8.67 on weekdays and ≥9 h on weekends may be essential to prevent overweight. Table. Adjusted odds ratios for overweight Disclosure H. Shiozaki: None. K. Fujihara: None. M.H. Yamada: None. T. Osawa: None. M. Kitazawa: None. M. Yamamoto: None. T. Sato: None. T. Yamada: None. H. Sone: Research Support; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Company Limited. Funding Patient Centered Outcomes Research Institute

92-OR: Persistence of Impaired Awareness of Hypoglycemia, Severe Hypoglycemic Events, and Suboptimal Glycemic Control Despite Advanced Diabetes Technologies

Trials of continuous glucose monitors (CGMs) and hybrid closed-loop systems (HCLS) demonstrate improvements in glycemia with reductions in hypoglycemia in T1D, but there is limited real-world data on how these technologies impact the prevalence of impaired awareness of hypoglycemia (IAH) , severe hypoglycemic events (SHEs) , and glycemic control. We conducted a one-time online survey of adults with T1D in the T1D Exchange Registry and online communities. Self-reported medical histories (insulin delivery method, HbA1c, IAH, SHEs) and CGM data were collected. 2044 patients (mean age 43 y, mean T1D duration 26 y, 72% female, 95% White) completed the survey. Most reported using CGMs (92%) ; 953 also used HCLS. Mean HbA1c was 6.89%; 41.5% had an HbA1C of ≥7%; 30.7% reported IAH; 19.8% had ≥1 SHE in the prior year; 12.0% had ≥2 SHEs in the prior year; 9.6% had IAH + ≥1 SHE; and 6.6% had IAH + ≥2 SHEs (Table) . Rates of SHEs and IAH + SHEs were lower in CGM users and CGM + HCLS users than in non-CGM users; however, among CGM + HCLS users, 16.6% reported ≥1 SHE, 8.7% ≥2 SHEs, 7.8% IAH + ≥1 SHE, and 4.7% IAH + ≥2 SHEs. Also, 35.6% of CGM + HCLS users had an HbA1C of ≥7%. In a patient cohort with high rates of technology adoption, rates of SHEs and IAH remained high, with a significant proportion of patients not achieving targeted glycemic control, indicating the need for novel T1D treatments. Disclosure J. Pettus: Advisory Panel; Lilly, MannKind Corporation, Novo Nordisk, Sanofi. Consultant; Carmot Therapeutics, Inc., Diasome. L. Titievsky: Employee; Intercept Pharmaceuticals, Inc., Pfizer Inc., Vertex Pharmaceuticals Incorporated. Stock/Shareholder; Intercept Pharmaceuticals, Inc., Pfizer Inc., Vertex Pharmaceuticals Incorporated. K. Hagan: Employee; Vertex Pharmaceuticals Incorporated. T. Liu: Employee; Takeda Pharmaceutical Company Limited, Vertex Pharmaceuticals Incorporated. Stock/Shareholder; Seattle Genetics, Inc. K. Chandarana: Employee; Vertex Pharmaceuticals Incorporated. J.L. Gaglia: Advisory Panel; Dompé, Regeneron Pharmaceuticals Inc. Consultant; Vertex Pharmaceuticals Incorporated. Research Support; Avotres Inc., Dompé, Janssen Research &amp; Development, LLC, Provention Bio, Inc. Stock/Shareholder; Vertex Pharmaceuticals Incorporated. W. Wolf: None. J. Bispham: Employee; PPD Inc., T1D Exchange. K.S.M. Chapman: None. D. Finan: None. J. Sherr: Advisory Panel; Bigfoot Biomedical, Inc., Cecelia Health, Insulet Corporation, Medtronic, Vertex Pharmaceuticals Incorporated. Consultant; Insulet Corporation, Lexicon Pharmaceuticals, Inc. Research Support; Dexcom, Inc., Insulet Corporation, Jaeb Center for Health Research, JDRF, Medtronic, National Institute of Diabetes and Digestive and Kidney Diseases. Speaker's Bureau; Lilly Diabetes.

886-P: Development and Validation of the Diabetes Outcome Model for the U.S. (DOMUS)

Purpose: The purpose of this study is to develop a diabetes outcomes model for the US (DOMUS) using a multi-ethnic, real-world-data cohort of newly diagnosed Type II diabetics that can predict outcomes for a U.S. multi-ethnic type 2 diabetes population. Methods: The Kaiser Permanente Northern California (KPNC) Diabetes Registry, which is a well-described epidemiologic cohort with up to 13 years of follow-up from EMR and claims, were used to identify over 150,000 newly diagnosed diabetes patients between 2005-2016 with up to 13-year follow-up. The DOMUS model integrates separate, but interdependent risk equations to predict events for each of the micro and macro-vascular events, hypoglycemia, dementia, depression, and death, and predictive models for eight biomarker levels. Model accounted for static demographic factors (e.g., race) , neighborhood deprivation, and dynamic factors, such as age, duration of diabetes, fifteen-possible glucose -lowering treatment combinations, biomarker levels, and history of diabetes-related events. Moreover, the models explicitly allow for a legacy effect (average A1c in the first year after diagnosis) for all outcomes. Results: Data were randomly split into 75,000, 18,750, and 18,750 patients to perform estimation, out-of-sample calibration, and validation respectively. Model predictions in the validation sample closely aligned with the observed longitudinal trajectory of biomarkers and outcomes. Moreover, we examine the model performance within by age, race/ethnicity, and sex and found excellent predictive performance within subgroups. Conclusion: The DOMUS Model is able to simulate event histories and biomarker trajectories that closely match observed outcomes in a real-world, multi-ethnic population of newly diagnosed diabetics. DOMUS has the potential to carry out many complex analyses that examine the effectiveness and cost-effectiveness of new medications, value of diabetes prevention, and serve as decision support tools in health care settings. Disclosure A.N.Winn: Consultant; Takeda Pharmaceutical Company Limited. E.Huang: Advisory Panel; Twin Health, Stock/Shareholder; AbbVie Inc. P.Clarke: None. A.J.Karter: Research Support; Dexcom, Inc. W.Wan: n/a. D.R.Miller: None. M.Franco: None. A.Deckard: None. N.Laiteerapong: None.