Jazz Pharmaceuticals Research Articles

8307 Molecularly Targeted Therapy in Oncogene-Driven Human Thyroid Cancer Cell Models: Assay Selection and Response Assessment

Abstract Disclosure: A.T. Yang: None. T.W. Laetsch: Consulting Fee; Self; Cellectis, Deciphera, GentiBio, Jazz Pharmaceuticals, Jumo Health, MassiveBio, Novartis Pharmaceuticals, Pyramid Biosciences, Y-mAbs Therapeutics, Advanced Microbubbles, AI Therapeutics, Bayer, Inc.. A.T. Franco: None. Background: The most common types of pediatric thyroid cancer (TC) demonstrate kinase-activating genomic alterations that are clinically inhibitor responsive – however, optimal integration of molecular therapy into practice remains uncertain. Human TC cell models can facilitate evaluation of combination therapies. However, prior studies vary from using traditional cell counts to newer reaction-based assays; we assessed whether a linear relationship between cell count and alternative assays exist for human TC cell models. Methods: Standardized curves for Cell TiterGlo (CTG; measures total ATP using luciferase-based luminescence) and NucBlue (DAPI; binds to DNA with nuclear fluorescence) were generated using TC cells seeded at escalating concentrations (5k to 300k cells/well). A linear equation was fitted to the CTG data and used to estimate cell count. DAPI counts were obtained with EVOS automation. Human TC cell lines TPC1 (RET fusion) / CUTC5 (BRAF V600E) were seeded at low (1.5k/2k) and high (3k/4k) cells per well, exposed for 3 days to 0-256 nM selpercatinib (RET inhibitor) or 0-192 nM dabrafenib (BRAF inhibitor), respectively, and response was measured using CTG and DAPI. All were measured in triplicate. Results: Standardized curves of CTG and DAPI demonstrated a 9-23% difference between known and measured cell counts. CTG was accurate within 20k-40k cells/well; DAPI showed linearity within 10k-80k cells/well. TC cells exhibited different IC50 depending on the assay and seeding concentration. Prior studies for selpercatinib and dabrafenib reported in vitro IC50 of 0.4-67 nM and 0.5-6 nM, respectively. In this study, IC50 for CTG/DAPI were closer at higher cell counts: TPC1 was 6.1 / 8.2 nM respectively; CUTC5 was 10.6 / 5.1 nM. Wells seeded at lower counts demonstrated larger inter-assay difference: IC50 for TPC1 was 10.1 / 5.9 nM respectively; CUTC5 was 38.4 / 5.9 nM. Conclusion: IC50 values varied by cell seeding concentrations and assay used, with a two to six fold difference at lower seeding and loss of linearity between luminescence measurements and cell count. This variability complicates evaluating the concordance among data from different laboratories, and in vitro and clinical response. Alternative assays intended to assess viability of inhibitor-exposed human TC cell models may require additional evaluation to ensure measured values demonstrate the expected relationship to the intended measure (ie cell number) and ultimately clinical outcome. Presentation: 6/3/2024

An Improved Algorithm for the Detection of Ventilator Associated Pneumonia

Background: Ventilator associated pneumonia (VAP) is associated with significant rates of morbidity and all-cause mortality. Active VAP surveillance can identify risk factors for which targeted preventive measures can be implemented. However, surveillance efforts are complicated by challenges associated with accurate VAP diagnosis. We aimed to improve the accuracy and automation of existing VAP diagnostic algorithms to better identify patients at risk. Methods: The study was conducted at NYU Langone Health from June 2022 through December 2023. We created a semi-automated VAP surveillance system using the Centers for Disease Control & Prevention (CDC) ventilator associated event (VAE) definition as a base framework (Figure 1). We modified this definition to include additional elements, such as having a sputum culture ordered within 48 hours of worsening oxygen status, regardless of culture result. Using this algorithm—followed by manual clinician reviews—we retrospectively assessed possible VAP cases to determine the ability of our surveillance system to correctly identify VAP. Results: Of the 123 possible VAP cases identified through our automated system, 75 (61%) were correctly diagnosed as VAP after clinical review. This reflects a rate of 1.5 infections per 1000 ventilation days across the system and 1.85 infections per 100 patients ventilated for greater than 2 days. Of the 48 remaining patients without VAP after clinical review, 25% (n=12) were characterized as having hospital-acquired pneumonia, 21% (n=10) as acute respiratory distress syndrome or infection at another site and 10% (n=5) as pulmonary embolism/infarction. Among all patients identified through this automated system (VAP and non-VAP), 53% experienced in-hospital death. Discussion: Our automated VAP surveillance algorithm identified 123 cases of potential VAP, 61% of which were consistent with a clinical diagnosis of VAP upon manual chart review. Our VAP rate of 1.5 infections per 1000 ventilation days was similar to published rates at other North American hospital systems. The high in-hospital mortality rate among these patients highlights the need for improved surveillance systems and earlier interventions to reduce the risk of VAP. There are several limitations to the CDC’s VAE definition, including its requirement of a positive microbiologic culture and focus on sputum quality. This potentially misses cases of culture-negative VAP in patients receiving antibiotics prior to sputum collection. Our goal is to continue to validate and improve our algorithm’s ability to correctly identify patients with clinical VAP, so that targeted prevention efforts can be focused upon the patients with the highest risk for poor outcomes.Disclosure: Madeline DiLorenzo: Stocks - Abbvie, Amgen Inc., Becton Dickinson, Biogen Inc., Bristol Myers and Squibb, CVS Health, Davita Inc., Elevance Health, Gilead, Henry Schein, Hologic Inc., Humana Inc., Jazz Pharmaceuticals, Laboratory Corp, Merck and Co., Quest Diagnostics, ResMed Inc., Teladoc Health, Vertex Pharmaceuticals, West Pharmaceuticals

Understanding the impact of mpox-related hospitalizations for medical versus infection control indications in New York City

Understanding the impact of mpox-related hospitalizations for medical versus infection control indications in New York City Background: New York City (NYC) accounted for 15-20% of new mpox infections at the peak of the 2022-2023 United States outbreak. Globally, 8% of mpox patients required hospitalization. We investigated the proportion of mpox hospitalizations for medical versus infection control indications at two large healthcare systems in the New York metropolitan area. Methods: We included all patients admitted to NYU Langone Health or NYC Health + Hospitals for laboratory-confirmed mpox between May 1, 2022, and April 28, 2023. We analyzed demographic information, reasons for hospitalization, length of stay, number and type of co-infections, healthcare encounters, complications, and treatments received. Results: Sixty-five patients were hospitalized for mpox, with 8 (12%) admitted primarily for infection control isolation (Table 1). Median age was 35 years (IQR=31-40), 69% were cisgender men, and 38% were Black. Those hospitalized primarily for isolation were more likely to reside in a homeless shelter (50% vs. 9%, p < 0 .01) and less likely to have a private residence (25% vs. 81%, p < 0 .01) than those hospitalized for medical indications. Those hospitalized for medical indications were more likely to have HIV (63% vs. 25%, p=0.04), secondary bacterial infections (67% vs. 25%, p=0.02), and to receive antibiotics (82% vs. 25%, p < 0 .01) (Tables 2 and 3). There was no significant difference in median cumulative length of stay per patient (p=0.69) between those hospitalized for medical versus isolation purposes. Most admissions for medical indications were for soft tissue superinfection (40%), severe pharyngitis and/or proctitis (28%) and pain management (20%). There was no significant difference in the proportion of tecovirimat receipt (65% vs. 38%, p=0.14) between those hospitalized for medical versus isolation purposes. Conclusion: Infection control isolation accounted for a significant proportion (12%) of mpox hospitalizations and was associated with a similar median length of stay per patient as hospitalization for medical indications. Our small cohort limits statistical power for comparison between groups. However, our findings argue for increased community-based isolation capacity. This may reduce unnecessary hospitalizations during future outbreaks, particularly amongst unsheltered individuals or those living in congregate settings.Disclosure: Madeline DiLorenzo: Stocks - Abbvie, Amgen Inc., Becton Dickinson, Biogen Inc., Bristol Myers and Squibb, CVS Health, Davita Inc., Elevance Health, Gilead, Henry Schein, Hologic Inc., Humana Inc., Jazz Pharmaceuticals, Laboratory Corp, Merck and Co., Quest Diagnostics, ResMed Inc., Teladoc Health, Vertex Pharmaceuticals, West Pharmaceuticals

CPX-351 and allogeneic stem cell transplant for a therapy-related acute myeloid leukemia that developed after treatment of acute promyelocytic leukemia: a case report and review of the literature

Therapy-related myeloid neoplasms (t-MNs), which develop after cytotoxic, radiation, or immunosuppressive therapy for an unrelated disease, account for 7%–8% of acute myeloid leukemia (AML). Worse outcomes and consequently shortened survival are associated with t-MNs as compared with de novo AML. Therapy-related MNs are being reported with increasing frequency in successfully treated acute promyelocytic leukemia (APL), in particular, before the introduction of all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO). Considering the high curability of APL, t-MNs represent one of the prognosis-limiting factors in this setting of leukemia. We report our experience with a patient who developed t-AML 15 years after treatment for APL. Treatment included three cycles of chemotherapy with CPX-351 (Vyxeos, Jazz Pharmaceuticals) followed, as in remission, by an allogeneic hematopoietic stem cell transplant. A review of available literature was also included.

A randomised phase II trial of temozolomide with or without cannabinoids in patients with recurrent glioblastoma (ARISTOCRAT): protocol for a multi-centre, double-blind, placebo-controlled trial

BackgroundGlioblastoma (GBM) is the most common adult malignant brain tumour, with an incidence of 5 per 100,000 per year in England. Patients with tumours showing O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation represent around 40% of newly diagnosed GBM. Relapse/tumour recurrence is inevitable. There is no agreed standard treatment for patients with GBM, therefore, it is aimed at delaying further tumour progression and maintaining health-related quality of life (HRQoL). Limited clinical trial data exist using cannabinoids in combination with temozolomide (TMZ) in this setting, but early phase data demonstrate prolonged overall survival compared to TMZ alone, with few additional side effects. Jazz Pharmaceuticals (previously GW Pharma Ltd.) have developed nabiximols (trade name Sativex®), an oromucosal spray containing a blend of cannabis plant extracts, that we aim to assess for preliminary efficacy in patients with recurrent GBM.MethodsARISTOCRAT is a phase II, multi-centre, double-blind, placebo-controlled, randomised trial to assess cannabinoids in patients with recurrent MGMT methylated GBM who are suitable for treatment with TMZ. Patients who have relapsed ≥ 3 months after completion of initial first-line treatment will be randomised 2:1 to receive either nabiximols or placebo in combination with TMZ. The primary outcome is overall survival time defined as the time in whole days from the date of randomisation to the date of death from any cause. Secondary outcomes include overall survival at 12 months, progression-free survival time, HRQoL (using patient reported outcomes from QLQ-C30, QLQ-BN20 and EQ-5D-5L questionnaires), and adverse events.DiscussionPatients with recurrent MGMT promoter methylated GBM represent a relatively good prognosis sub-group of patients with GBM. However, their median survival remains poor and, therefore, more effective treatments are needed. The phase II design of this trial was chosen, rather than phase III, due to the lack of data currently available on cannabinoid efficacy in this setting. A randomised, double-blind, placebo-controlled trial will ensure an unbiased robust evaluation of the treatment and will allow potential expansion of recruitment into a phase III trial should the emerging phase II results warrant this development.Trial registrationISRCTN: 11460478. ClinicalTrials.Gov: NCT05629702.

My voyage in the enchanted world of sleep.

In this paper, I describe my 45-year career in sleep research. I started my undergraduate studies at Tel Aviv University, where I was first introduced to the enchanted world of sleep, continued to my graduate studies with Wilse B. Webb at the University of Florida, and then to post-doctoral training with Dan Kripke at the University of California at San Diego. Then, I describe the evolution of my academic career at the Technion-Israel Institute of Technology, where I started in 1975 as an Assistant Professor and retired in 2019 as the President of the Institute. I describe the areas of research that I pursued and how the research developed, emphasizing unexpected results that guided me and my lab team in new directions. This includes my early studies on ultradian rhythms, inspired by Nathaniel Kleitman's Basic Rest Activity Cyle hypothesis, utilizing the ultrashort sleep-wake paradigm to chart the 24-hour sleep propensity function, and how these studies led us to explore the role of melatonin in sleep regulation. I also explain why we directed our attention to sleep apnea, and how clinical observations led to the provocative hypothesis that sleep apnea-typically seen as a disorder-may also play a protective role. Under the leadership of my research partner and wife, Lena, we confirmed this hypothesis. Also in this article, I describe my enthusiasm for the history of our field and, as derived from my experience as a Dean of Medicine and President of a university, I share my philosophy about the role of members of academia in society. I emphasize that none of my achievements could have been accomplished without the hard work and motivation of my students and research partners, who shared my enthusiasm and passion for the enchanted world of sleep. This paper is part of the Living Legends in Sleep Research series, which is sponsored by Idorsia Pharmaceuticals and Jazz Pharmaceuticals.

Caregiver-reported outcomes with real-world use of cannabidiol in Lennox-Gastaut syndrome and Dravet syndrome from the BECOME survey

PurposePlant-derived highly purified cannabidiol (CBD) reduced the frequency of seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) and improved the overall condition of patients in placebo-controlled phase 3 clinical trials. Anecdotal reports also suggest a positive effect on nonseizure outcomes. In this study, we aimed to identify, through a caregiver survey which nonseizure outcomes were most likely to change in these patients. MethodsThe BEhavior, COgnition, and More with Epidiolex® (BECOME) was a 20-minute, cross-sectional, online survey that was developed with extensive input from caregivers, healthcare professionals, and epilepsy researchers, and was based on questions from validated measures and previously published caregiver reports. US-based caregivers (from Jazz Pharmaceuticals patient/caregiver database) of people with LGS or DS who were treated with CBD (Epidiolex®, 100 mg/mL oral solution) for ≥3 months were asked to compare the past month to the period before CBD initiation and rate their impression of changes using symmetrical Likert scales. ResultsA total of 498 caregivers (97% parents) of patients with LGS (80%) or DS (20%) completed the survey. Mean (range) age of patients was 16 (1−73) years, and 52% were male. Patients were taking a median CBD dose of 14 mg/kg/d and median 4 concomitant antiseizure medications. A large proportion of respondents reported improvements in ≥1 survey question for all nonseizure-related domains: alertness, cognition, and executive function (85%); emotional functioning (82%); language and communication (79% in nonverbal patients and 74% in verbal); activities of daily living (51%); sleep (51%); and physical functioning (46%). Respondents reported improvements in seizure-related domains, including overall seizure frequency (85%), overall seizure severity (76%), seizure-free days per week for ≥1 seizure type (67%), and seizure freedom during the past month (16%). The majority of respondents who reported reduction in seizure frequency also reported improvements in nonseizure outcomes domains (51–80%). However, improvements in nonseizure outcomes (18–56%) were also reported in patients who either had no change or worsening of seizure frequency. ConclusionsThis survey characterized and quantified caregiver impression of changes in the seizure and nonseizure outcomes in patients taking add-on CBD treatment. Overall, 93% of caregivers reported planning to continue CBD treatment, primarily because of reduced seizure burden but also because of improvements in nonseizure-related outcomes. Despite the limitations that are associated with a retrospective survey-based study design, these results support further evaluation of the effect of CBD treatment on nonseizure outcomes among patients with LGS or DS.

A Phase II Study to Evaluate the Safety and Efficacy of Defibrotide in Children with High Risk Kawasaki Disease (IND 127812)

Background: Kawasaki disease (KD) is the leading cause of acquired heart disease in children in the developed world. It is an acute, generalized vasculitis, particularly in the coronary arteries, that occurs predominantly in infants and young children (Newburger et al, 2016). The acute phase of KD produces diffuse vascular inflammation that is thought to be associated with activation of the IL-1 pathway. Endothelium, located in the innermost layer of the coronary arteries, serves as an interface between the vascular media and circulating inflammatory cells and inflammatory cytokines. The coronary artery endothelium is the first target of the inflammatory attack in the early stages of KD (Qiu et al, Frontiers Cardiovascular Medicine, 2022) (Liu et al, Molecular Cell Biochem, 2021). There are pathologic changes during an acute arteritis with neutrophilic infiltration leading to necrosis in all the vessel walls, although the usual target is the medium sized extra-parenchymal muscular arteries. Current treatment is directed at reducing inflammation with IVIG and aspirin. Usually, this leads to rapid clinical improvement. However, 10-20% of patients are IVIG resistant and require further methods of reducing inflammation (Newburger et al, 2004). These patients that are IVIG resistant, have recrudescent fevers and evidence of ongoing inflammation, with subsequent increased risk for aneurysm formation (Tremoulet et al, 2008). Furthermore, other particular patient groups have been identified as having a higher risk (HR) of coronary artery aneurysms. Boys have a higher incidence of developing KD, but even accounting for that, are at a higher risk for developing coronary artery aneurysms (Belay et al, 2006). Defibrotide is a polydisperse mixture of predominantly single-stranded oligonucleotides (90% single-stranded and 10% double-stranded) derived from porcine intestinal mucosa. Several in vivo studies indicate that defibrotide primarily targets endothelium, particularly in small vessels, and appears to reduce endothelial cell injury and stabilize endothelial function (Falanga et al, Leukemia, 2003) (Cairo et al, BJH, 2020). Defibrotide is currently approved for SOS/VOD, with renal or pulmonary dysfunction post HSCT and has been well studied in infants with SOS post HSCT (Corbacioglu et al, Lancet, 2012). We hypothesized that Defibrotide will be safe and well tolerated in HR KD patients who fail IVIG and may be effective in difficult to treat KD patients, by mitigating ongoing endothelial dysfunction. Primary Aims: To determine the safety and efficacy of defibrotide in infants with HR KD. Design/Methods: Patients with KD as defined by the American Heart Association, have HR features (Table 1), age birth - 11 years of age, PT/PTT WNL, platelet count ≥100K/mm 3, and without active bleeding, hypersensitivity to defibrotide or receiving systemic anti-coagulant therapy, were eligible. Defibrotide, generously supplied by Jazz Pharmaceuticals, was administered within 96 hours of the conclusion of IVIG at 6.25 mg/kg IV Q6H (total daily dose 25 mg/kg/day) and continued for 7 days or until the patient was discharged from hospital, whichever occurred first (IND 127812) (NCT04777422). Stopping rules included: ≥ 15% grade III-IV allergic reaction or anaphylaxis or hemorrhage. All patients were treated with current standard of care, including: IVIG, aspirin (max 5mg/kg/dose), antibiotics, and intravenous fluids. Complete blood counts, coagulation studies and echocardiogram were performed at baseline, day 10, day 21, and 6 weeks after defibrotide was first given for disease assessment. Results: We have preliminary enrolled 2 patients (mean age of 31 months, range 15 months to 4 years) with a gender ratio of M/F 1/1 (Table 2). The median dose of defibrotide per patient was 5.5 (range 1-11) and the average hospital admission length was 5.5 days (range 5-6 days). No patients demonstrated heart abnormalities on baseline echocardiogram. There were no serious adverse events (SAE) probably or directly related to defibrotide, as evaluated by investigators. One patient had a grade II epistaxis, but no patients had any SAEs. Conclusion: This preliminary data suggests defibrotide is safe in children with HR KD failing IVIG. Further patients will be required to determine the safety and preliminary efficacy of defibrotide in children with HR KD. Supported in part by a research grant from Jazz Pharmaceuticals.

CRISPR/Cas9 Screen Identifies CPX-351 and 7+3 Regimens Response Modulators with Distinct Sensitive and Resistant Profiles

CPX-351 (dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio) is approved for newly diagnosed high-risk and secondary AML as an alternative to the widely used cytarabine and daunorubicin (7+3) regimen. Despite newly approved drugs, many AML patients still developed treatment resistance and relapse, leading to poor survival. Amid mounting research into the molecular mechanisms of AML therapies, treatment resistance remains a major concern. To overcome treatment resistance, it is necessary to examine the molecular mechanisms underlying the CPX-351 and 7+3 treatment response. We conducted custom CRISPR/Cas9 synthetic-lethal screens targeting 2440 genes (AML-relevant genes, cytarabine and daunorubicin pharmacology, and druggable genes) in six AML cell lines, profiled drug-sensitive/-resistant modulators, and identified novel targets for overcoming drug resistance in CPX-351 and 7+3 regimen. Six AML cell lines were transduced with a custom library and puromycin was selected before pool transduced cells were treated with DMSO, the IC30-IC50 of cytarabine, daunorubicin, or CPX-351 for 7 doubling-times at 500x coverage. All samples were processed with genomic DNA, sgRNAs were amplified by PCR, and Illumina NovaSeq 6000 SP 100SR sequencing was performed. The abundance of sgRNA was analyzed using MAGeCK-RRA to estimate the RRA drug response score (Drug vs. Control conditions at 7-doubling times) or RRA essential score (Control at 7-doubling time vs. Control at Day 0). Genes with an average RRA score of < -1 across six AML cell lines were defined as drug-resistant or essential genes (negative selection), whereas genes with an average RRA score of > 1 were categorized as sensitive or suppressor genes (positive selection). Next, comparisons of functional pathways with over-representation analysis were performed on resistant and sensitive genes across three drugs to determine differences in their functions. At the average RRA response score cut-off, 61, 163, and 112 were identified as drug-resistant genes, while 46, 93, and 86 were sensitive genes to cytarabine, daunorubicin, or CPX-351 (provided by Jazz Pharmaceuticals), respectively. Fig 1A showed a Venn diagram of all significant resistant and sensitive genes across all three drugs with 14 common significant genes and 73, 174, and 118 unique genes to cytarabine, daunorubicin and CPX-351, respectively, along with their essential score. Among these significant common response genes, some notable genes included ABCC1, SAMHD1 and TP53, where CRISPR knocking out screens led to depletion or enrichment of sgRNA when treated with drugs across all AML cell lines. ABCC1 is a drug-resistant gene that encodes the ATP Binding Cassette C1-mediated drug efflux transporter; therefore, knocking out the efflux transporter causing drug resistance, would increase the lethality of AML cells . Our result also showed ABCC1 isa tumor suppressor gene; because knocking out the ABCC1 gene improves cell survival and growth . SAMHD1 is another notable gene that encodes for deoxynucleoside triphosphate (dNTP) tri-phosphohydrolase that cleaves physiological dNTPs into deoxyribonucleosides and inorganic triphosphate. SAMHD1 has been shown to cause resistance in cytarabine, but there is limited evidence of its response to other drugs. In this study, we showed that SAMHD1 is a resistant gene for CPX-351 and a sensitive gene for daunorubicin, and it is a tumor suppressor gene. Lastly, TP53 is one of the significant common sensitive genes to cytarabine, daunorubicin, and CPX-351. TP53 encodes for the well-known tumor suppressor gene tumor protein 53, and mutations in TP53 have been shown to affect drug response. In this study, we demonstrated that knocking out TP53 in all AML cell lines contributed to cell survival and growth as a tumor suppressor gene and a drug-sensitive gene across the three drugs. Comparing significant resistant and sensitive genes across CPX-351, cytarabine, and daunorubicin, as shown in Fig 1B, revealed that resistant genes shared some common involvement in the cell cycle and cellular response to stress, but resistant genes for each drug displayed more distinct functional pathways. Moreover, each drug's sensitive genes revealed distinct functional enrichment pathways. Our current research is focused on identifying novel drug targets to combat drug resistance in the CPX-351 and 7+3 regimens.

A Phase II Study to Evaluate the Safety and Efficacy of Defibrotide and Changes in Plasma Biomarkers in Sickle Cell Disease-Related Acute Chest Syndrome (IND 127812)

Background: Acute Chest Syndrome (ACS) is the greatest contributor to the morbidity and mortality of Sickle Cell Disease (SCD) patients with a rate of 12.8 cases per 100 patient-years. The mortality rates of ACS are 4 times higher in adults than in children (Vichinsky et al, Blood, 1997). The root cause of ACS in SCD is related to endothelial dysfunction (Paul et al, European Journal of Hematology 2011). While existing therapies target infection, inflammation, and alveolar hypoxia, they do not address endothelial dysfunction, a major contributor to SCD associated ACS. Defibrotide is a polydisperse mixture of predominantly single stranded oligonucleotides derived from porcine intestinal mucosa. Several pre-clinical studies indicate that defibrotide primarily protects endothelium, particularly in small vessels, and reduces endothelial cell injury (Falanga et al, Leukemia, 2003) (Cairo/Cooke et al, British Journal of Haematology 2020). In a randomized phase III study, a decrease in incidence of SOS/VOD was observed in pediatric hematopoietic stem cell transplantation patients who received prophylactic defibrotide (Corbacioglu et al, Lancet, 2012). We hypothesized that Defibrotide would be safe and well tolerated in children and adolescents with SCD-associated ACS. Primary Aims: To determine the safety and efficacy of defibrotide in the treatment of patients with SCD-associated ACS. Design/Methods: Patients with SCD- (Homozygous Hemoglobin S disease, Hemoglobin SC Disease or Hemoglobin Sβ 0/+ Thalassemia) associated ACS 2 to 40 years of age were enrolled. Defibrotide, generously supplied by Jazz Pharmaceuticals, was administered at 6.25 mg/kg IV Q6H (total daily dose 25 mg/kg/day) within 24 hours of consent and continued for 7 days or until the patient was discharged from hospital (IND 127812) (NCT 03805581). All patients were treated with current standard of care, including antibiotics, analgesics, oxygen, intravenous fluids, and packed red blood cells (PRBC)/exchange transfusion. Complete blood counts and coagulation studies were performed at baseline, day 7 and day 30, while chest radiograph (CXR), CT chest angiogram (CTA), pulmonary function test, and transthoracic echocardiogram were performed at baseline and 30 days after defibrotide was first given. Blood plasma was collected from patients at baseline, day 7, day 30, and age matched SCD patients without ACS and analyzed for biomarkers of inflammation through ELISA and Luminex multiplex assays and significance was calculated using two-tailed T tests. Results: We have enrolled 20 patients (median age 9.5 years) with a gender ratio of M/F 8/12. Patients had hemoglobin SS (n=14), hemoglobin Sβ 0/+ (n=2), or hemoglobin SC (n=4). The median doses of defibrotide per patient was 18.5 (range 6-28) and the average hospital admission length was 6.1 days (range 3-13 days). There were no serious adverse events possibly, probably, or directly related to defibrotide, as judged by investigators. Two patients had a grade I/II epistaxis that did not disrupt defibrotide's course. Pulmonary infiltrate on CXR and/or CTA was the most common finding at diagnosis, detected in 18/20 study participants. Thirteen patients had fever as a presenting symptom, with an average fever duration of 2.8 days (range 1-6 days). Nine patients required O 2 supplementation, with an average duration of 4.1 days (range 2-7 days). Thirteen patients were treated with blood transfusions with a median of 1.9 units (PRBC unit was defined as 15ml/kg) transfused per patient (range, 1-5 units) and 1 patient underwent an exchange transfusion (Table 1). Soluble Intercellular Adhesion Molecule-1 (sICAM-1) was significantly elevated at the onset of ACS (p < 0.01) compared to control SCD plasma and was reduced by Day 30 after defibrotide treatment. Other markers of inflammation, including Angiopoetin-2 (Ang2), Interleukin-6 (IL-6), and Phospholipase A2-IIA (PLA2G2A) were elevated at baseline in patient plasma samples but were significantly decreased following defibrotide treatment (p < 0.05, 0.01, 0.01, respectively) (Figure 1). Conclusion: Our data suggests that defibrotide is safe and well tolerated in SCD patients with ACS. sICAM-1, Ang2, IL-6, and PLA2G2A may serve as important biomarkers in SCD associated ACS. A randomized phase II/III multi-center clinical trial will need to be conducted to further investigate efficacy of defibrotide in patients with SCD-associated ACS.

A Randomized, Controlled Trial of Efficacy and Safety of Cannabidiol in Idiopathic and Diabetic Gastroparesis

Cannabis (delta-9-tetrahydrocannabinol), a nonselective cannabinoid-receptor agonist, relieves nausea and pain. Cannabidiol (CBD), a cannabinoid receptor 2 inverse agonist with central effects, also reduces gut sensation and inflammation. We compared the effects of 4 weeks of treatment with pharmaceutical CBD vs placebo in patients with idiopathic or diabetic (diabetes mellitus) gastroparesis. We performed a randomized, double-blinded, placebo-controlled study of CBD twice daily (Epidiolex escalated to 20 mg/kg/d; Jazz Pharmaceuticals, Dublin, Ireland) in patients with nonsurgical gastroparesis with delayed gastric emptying of solids (GES). Symptoms were assessed by the Gastroparesis Cardinal Symptom Index Daily Diary. After 4 weeks of treatment, we measured GES, gastric volumes, and Ensure (Abbott Laboratories, Abbott Park, IL) satiation test (1 kcal/mL, 30 mL/min) to assess volume to comfortable fullness and maximum tolerance. Patients underwent specific FAAH and CNR1 genotyping. Statistical analysis compared 2 treatments using analysis of variance including baseline measurements and body mass index as covariates. Among 44 patients (32 idiopathic, 6 diabetes mellitus type 1, and 6 diabetes mellitus type 2), 5 patients did not tolerate full-dose escalation; 3 withdrew before completing 4 weeks of treatment (2 placebo, 1 CBD); 95% completed 4 weeks of treatment and diaries. Compared with placebo, CBD reduced the total Gastroparesis Cardinal Symptom Index score (P= .008), inability to finish a normal-sized meal (P= .029), number of vomiting episodes/24 hours (P= .006), and overall symptom severity (P= .034). Patients treated with CBD had a higher volume to comfortable fullness and maximum tolerance and slower GES. FAAH rs34420 genotype significantly impacted nutrient drink ingestion. The most common adverse events reported were diarrhea (14 patients), fatigue (8 patients), headache (8 patients), and nausea (7 patients). CBD provides symptom relief in patients with gastroparesis and improves the tolerance of liquid nutrient intake, despite slowing of GES. gov NCT #03941288.

446-P: Antihyperglycemic Medication Initiation after Cardiovascular Hospitalization in Older Adults with Diabetes Increases Hypoglycemia without Improving Survival

Background: The short-term safety and long-term cardiovascular benefits of initiating new antihyperglycemic medications at hospital discharge are unclear, especially for elderly patients with acute cardiovascular disease. This study aimed to determine if initiation of a new diabetes medication is associated with differences in outcomes in this patient population. Methods: This was a population-based cohort study of individuals ≥65 years with diabetes on antihyperglycemic medication who were discharged from a hospitalization for heart failure, acute myocardial infarction, or stroke in Ontario, Canada from April 2011 to March 2019. We categorized individuals based on initiation of a new diabetes medication (initiators) within 30 days of discharge. Primary outcome was a composite of death or cardiovascular hospitalization. Secondary outcome was rate of hypoglycemia. We performed a Cox-regression on a propensity matched cohort. Results: A total of 54,117 individuals were included, with 5,129 (9.5%) initiators and 48,988 (90.5%) non-initiators. Median age was 78 years (IQR 71-84) and 56.7% were male. Matched pair analysis included 4,844 pairs of initiators and non-initiators with standardized differences of ≤0.05 for all baseline variables. Median follow-up was near 2.2 years in both groups. There were no significant differences in the hazard of the composite of death/cardiovascular hospitalization (HR 0.97, 95% CI 0.92-1.02, p=0.18) or the hazard of death (HR 0.98, 95% CI 0.93-1.04, p=0.56). There was a higher risk of hypoglycemia among initiators (113 [2.3%] vs 76 [1.6%]) within one year of follow-up (HR: 1.49, 95% CI 1.12-1.98, p=0.007). Conclusion: Starting a new antihyperglycemic medication in patients with diabetes who are discharged after hospitalization for a cardiovascular event is associated with an increased risk of hypoglycemia but does not reduce mortality or cardiovascular events. Disclosure A.Farahvash: None. A.Sivaswamy: None. H.Abdel-qadir: Other Relationship; AstraZeneca, JAZZ Pharmaceuticals. I.C.Lega: None.

1412-P: Sleep Patterns and Metabolic Syndrome Severity among African Americans in the Jackson Heart Study

Objective: To elucidate the relationship between sleep and metabolic dysfunction among African Americans, who are disproportionally affected by cardiometabolic diseases. Methods: This is a cross-sectional analysis of participants in the Jackson Heart Sleep Ancillary Study (2012-2016) who completed 7-day actigraphy and home sleep apnea studies. We used linear regression to assess the associations between metabolic syndrome (MetS) and actigraphy-derived parameters including: sleep timing, total sleep duration and regularity (night-to-night variation measured by within-individual standard deviation in sleep duration), and sleep continuity (sleep maintenance efficiency and fragmentation index). We assessed MetS severity, expressed as a validated sex- and race/ethnicity-specific z-score (MetS-Z), given the high prevalence of each of the MetS components in this cohort. Models were adjusted for age, socioeconomic factors, physical activity, smoking, alcohol use, and the presence of moderate to severe obstructive sleep apnea. Results: Among 660 participants (mean age 63 ± 11 yrs, 66% women, mean BMI 31.8 ± 6.9 kg/m2), mean sleep onset was 23:09 ± 1.4h, mid-sleep time was 2:54 ± 1.2h, total sleep duration was 6.7 ± 1.2h, median night-to-night variation was 1.2h (IQR 0.8-1.5), median sleep maintenance efficiency was 88.9% (IQR 85.6-91.4), median sleep fragmentation index was 28.5% (IQR 23.3-34) and mean MetS-Z score was 0.33 ± 1.1. In adjusted models, later mid-sleep time (β 0.09, p<0.01), increased variation in sleep duration (β 0.004, p<0.01), lower sleep maintenance efficiency (β -0.02, p=0.03), and higher sleep fragmentation index (β 0.01, p=0.02) were associated with higher MetS-Z. Conclusions: Later sleep timing, irregular sleep duration, and poor sleep continuity were associated with higher MetS severity scores among African Americans, highlighting the importance of sleep and circadian disruption as factors that influence metabolic health. Disclosure D.Duan: None. J.Jun: None. R.Ahima: None. A.Bertoni: None. S.Redline: Consultant; Eli Lilly and Company, JAZZ Pharmaceuticals, Apnimed. J.Echouffo tcheugui: None. Funding National Institutes of Health (K23DK133690)

Hypersensitivity Reactions to Native E. coli L-asparaginase in Children With Acute Lymphoblastic Leukemia Treated in Trial ALL-BFM 2000: Impact of Treatment Schedule and Type of Glucocorticoid in Induction.

Hypersensitivity Reactions to Native E. coli L-asparaginase in Children With Acute Lymphoblastic Leukemia Treated in Trial ALL-BFM 2000: Impact of Treatment Schedule and Type of Glucocorticoid in Induction.

CNS radiotherapy as bridging prior to CAR T‐cell therapy for hematologic malignancies

Introduction: Up to 80% of patients who receive CAR T-cell therapy for central nervous system lymphoma (CNSL) require bridging therapy, yet optimal regimens remain undefined. Bridging radiotherapy (BRT) is an established strategy for extracranial lymphoma that provides beneficial cytoreduction. However, BRT for CNSL (CNS-BRT) is controversial due to concerns of potential enhanced neurotoxicity. We explored the safety and response profiles for CNS-BRT prior to CAR T therapy. Methods: We identified CAR T patients with hematologic malignancy at MSKCC who received CNS-BRT, defined as treatment delivered between cell collection and infusion to targets in CNS parenchyma, leptomeninges, or epidural space. Safety was evaluated by cytokine release syndrome (CRS), immune effector associated neurotoxicity syndrome (ICANS), and immune effector cell encephalopathy (ICE) scores, as documented by primary physician. Response was evaluated within the RT field for patients with baseline measurable disease using the International Primary CNS Lymphoma Collaborative Group (IPCG), Response Assessment in Neuro-Oncology (RANO), and Response Evaluation Criteria in Lymphoma (RECIL) radiographic criteria for parenchymal, leptomeningeal, and epidural lesions, respectively. Results: 11 patients received CNS-BRT with median follow up of 10.1 months (range: 1.1–25.9). At RT, median age was 51 (25–79), median KPS was 80 (50–90), and 9/11 patients had progressive CNS disease. 8/11 patients received prior methotrexate (high dose n = 7, intrathecal n = 1) with median 39-day interval to RT (0–179). Disease was localized to the brain parenchyma (n = 6), leptomeninges (n = 2), and epidural spine (n = 3). RT targets included whole brain (n = 3), involved site (partial) brain (n = 4), and involved site spine (n = 4), with median dose 24 Gy (20–30). Patient and CAR T cell characteristics are shown in Table 1. 4/10 patients experienced ICANS (n = 1 grade (G) 1, n = 1 G2, n = 1 G3, and n = 1 G4). 8/10 patients experienced CRS (n = 2 G1, n = 5 G2, and n = 1 G3). 6/11 patients required tocilizumab and/or steroids. Patients with G3/4 ICANS had decreased baseline ICE scores of 5 and 6, respectively. Median change in lesion size prior to CAR T infusion was -43.6% (-3.1% to -74.5%) among 7 evaluable patients. Best response included 6 partial responses (PR) and 4 complete responses (CR) at median 4.2 months (0.5–10.4). There were 3 CNS treatment failures, 1 in the leptomeninges and 2 in the paraspinal/epidural space. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Cellular therapies, Radiation Therapy Conflicts of interests pertinent to the abstract. R. Shouval Other remuneration: Medexus Pharmaceuticals, Inc., MyBiotics P. B. Dahi Other remuneration: Curio Science LLC, Kite Pharmaceuticals, OncLive, Targeted Oncology R. J. Lin Consultant or advisory role: Kite, A Gilead Company M. L. Palomba Other remuneration: BeiGene, Ltd., Mustang Bio, Novartis, Synthekine, Inc. M. Perales Stock ownership: NexImmune, Omeros, Orca Biosystems, Inc. Other remuneration: ADC Therapeutics, Bristol-Myers Squibb, Cidara Therapeutics, Inc., CoImmune, Inc., Equillium, Inc., Incyte, Jazz Pharmaceuticals, Karyopharm, Kite Pharmaceuticals, Merck & Co Inc., Miltenyi Biotec Incorporated, MorphoSys AG, Novartis, Partners Therapeutics Inc., VectivBio AG, Vor Biopharma Inc. G. Salles Stock ownership: Owkin, Inc. Other remuneration: AbbVie, Aptitude Health, Bayer, BeiGene, Ltd., Bio Ascend, Bristol-Myers Squibb, Celgene, Epizyme, Everest Clinical Research Corporation, GenMab, Genentech, Gilead Pharmaceutical, Incyte, Ipsen, Janssen Pharmaceuticals, Inc., Loxo Oncology, Miltenyi Biotec Incorporated, MorphoSys AG, Nordic Nanovector ASA, Novartis, Physicians' Education Resource, RAPT Therapeutics, Regeneron Pharmaceuticals, Inc., Roche, Scientific Education Support Ltd., Takeda Millennium L. Falchi Consultant or advisory role: Genmab, Abbvie, Genentech, ADC therapeutics, Astrazeneca, Seagen, Roche Research funding: Genmab, Abbvie, Roche, Genentech Educational grants: Genmab C. Grommes Other remuneration: BTG International, Ono Pharma, Roche M. Scordo Consultant or advisory role: McKinsey & Company, Angiocrine Bioscience, Inc., Omeros Corporation, Kite – A Gilead Company Honoraria: i3Health, Medscape Research funding: Angiocrine Bioscience, Inc., and Omeros Corporation J. Yahalom Other remuneration: Convergent R.N.R Ltd. B. S. Imber Other remuneration: GT Medical Technologies, Inc.

Efficacy of combination lurbinectedin (LURBI) + doxorubicin (DOX) from the phase 1B soft-tissue sarcoma (STS) lead-in to a randomized phase 2 trial in leiomyosarcoma (LMS).

11507 Background: Single agent or combination chemotherapy, typically Dox- or gemcitabine-based, are standard 1st- and 2nd-line therapies in patients (pts) with metastatic LMS; however, objective response rates (ORR), progression-free, and overall survival (PFS/OS) remain inadequate. Lurbi (PharmaMar S.A. / Jazz Pharmaceuticals) binds to DNA inhibiting transcription and inducing double strand breaks leading to apoptosis and delaying S/G2 progression. In a prior pilot study, we showed Lurbi+Dox is well-tolerated, with signs of activity, particularly in LMS. We designed this phase 1b to optimize dosing to lead into a randomized (1:1) phase 2 trial of Dox+/-Lurbi in anthracycline-naïve LMS. Herein we provide updated efficacy and tolerability data for this Phase 1b cohort. Methods: Pts > 18 yrs with locally advanced/metastatic, unresectable non-GIST STS (Phase 1b only) w/o prior anthracycline or Lurbi/trabectedin, ECOG PS < 3, RECIST 1.1 measurable, and normal organ function were eligible. The phase 1b followed a 3+3 design. Dosing included fixed Lurbi (3.2 mg/m2 d1) with two Dox dose levels (DL; DL1: 25 mg/m2 d1; DL2 25 mg/m2 d1+8). All pts received GCSF prophylaxis. Tumor assessments were every 2 cycles. DL1 was chosen as RP2D and the phase 2 trial began accrual in Aug 2022 aiming to enroll 50 LMS pts randomized 1:1 (stratified by uterine LMS [uLMS]] v. other LMS) with PFS as primary endpoint. Pts progressing on Dox are allowed to cross to Lurbi monotherapy. Results: 10 patients were enrolled in Phase 1b. Histologies included 5 LMS (4 uLMS) and 1 each of myxofibrosarcoma (myxFS), undifferentiated pleomorphic sarcoma (UPS), dedifferentiated liposarcoma (DDLPS), endometrial stromal sarcoma (ESS), and solitary fibrous tumor (SFT). With a median follow-up of 344 days, 5/10 pts remain on treatment with median PFS of 357 days (95%CI 175-ND). 6 pts demonstrated partial response (PR; 5 confirmed), 3 with stable disease (SD), and 1 with progressive disease (PD, Table). Median time to PR was 81 days (range 46-207). Duration of response was over 132 days in all responders with 3 still on treatment. Treatment-related AEs were typical for Dox/Lurbi, including nausea, fatigue, and reversible LFT elevations/cytopenias. Updated safety and response data will be provided at the time of the meeting. Conclusions: Lurbi+Dox is well-tolerated with efficacy in STS including 6/10 pts achieving PR, 9/10 pts staying on treatment for >120d, and 6/10 pts >200d. The randomized phase 2 study is currently enrolling. Clinical trial information: NCT05099666 . [Table: see text]

0611 Treatment Satisfaction and Preferences in People With Narcolepsy Transitioning From Sodium Oxybate to Lower-Sodium Oxybate

Abstract Introduction Lower-sodium oxybate (LXB; Xywav®), which contains the same active moiety as higher-sodium oxybate (SXB; Xyrem®) but with 92% less sodium, is approved by the US Food and Drug Administration (FDA) for treating cataplexy or excessive daytime sleepiness in patients ≥7 years of age with narcolepsy. LXB is recognized as clinically superior to SXB in narcolepsy by the US FDA due to lower chronic sodium exposure; however, real-world data describing patient preferences and satisfaction are lacking. Methods Transition Experience of persons with Narcolepsy taking Oxybate in the Real-world (TENOR; NCT04803786) was a patient-centric, prospective, observational, noninterventional, virtual-format study of US adults with narcolepsy (type 1 or 2) transitioning from SXB to LXB within the previous/upcoming 7 days. Longitudinal data collected during transition and for 21 weeks thereafter included responses to the Ease of Switching Medications Scale (EOSMS), Forced Preference Questionnaire (FPQ), and Treatment Satisfaction Questionnaire for Medication-version II (TSQM-vII). Results The mean (standard deviation [SD]) age of the 85 participants (narcolepsy type 1, n=45; narcolepsy type 2, n=40) was 40.3 (13.0) years; most were female (73%) and White (87%). Mean (SD) time on current SXB regimen was 57.8 (52.1) months. Nearly all participants took SXB (82/85, 96%) twice nightly prior to transition and LXB (82/84, 98%) twice nightly after transition. Most participants (61/73, 84%) reported that switching from SXB to LXB was “extremely easy, not difficult at all” or “easy” on the EOSMS, and most (59/73, 81%) preferred LXB to SXB on the FPQ. Among participants who preferred LXB, lower sodium content (56/59, 95%) and fewer cardiovascular issues (27/59, 46%) were cited as the most common reasons. There were minimal mean (SD) changes in TSQM-vII scores for global satisfaction (1.1 [18.6]), satisfaction with effectiveness (1.0 [16.8]), side effects (4.1 [23.7]), or convenience (−3.9 [15.2]) after transitioning from SXB to LXB. Conclusion Overall, most participants indicated that switching from SXB to LXB was “easy” or “extremely easy.” Most participants preferred LXB to SXB, primarily because of its lower sodium content. Satisfaction with oxybate treatment was maintained following transition to LXB. Support (if any) Jazz Pharmaceuticals

0592 Efficacy of Lower-Sodium Oxybate by Baseline Sleep Inertia in a Phase 3 Clinical Study in Patients With Idiopathic Hypersomnia

Abstract Introduction Idiopathic hypersomnia is a debilitating neurologic sleep disorder. Sleep inertia (difficulty awakening) is a common symptom that can significantly impair functioning and quality of life. This post hoc analysis evaluated response to lower-sodium oxybate (LXB; Xywav®) by baseline sleep inertia in a phase 3 trial (NCT03533114). Methods Eligible participants began LXB treatment with an open-label treatment titration and optimization period (10–14 weeks), followed by a 2-week stable-dose period (SDP). Participants were randomized to placebo or continued LXB treatment during a 2-week, double-blind, randomized withdrawal period (DBRWP). Using the visual analog scale for sleep inertia (VAS-SI), participants rated their difficulty awakening during baseline, SDP, and DBRWP on a 100-mm line with anchors at 0 (very easy) and 100 (very difficult). VAS-SI terciles comprised score segments of < 44 (group A), ≥44 to < 70 (group B), and ≥70 (group C). Efficacy assessments included the Epworth Sleepiness Scale (ESS), Idiopathic Hypersomnia Severity Scale (IHSS), Clinical Global Impression of Severity (CGIs), and Patient Global Impression of Change (PGIc). Results Participants (A, n=34; B, n=33; C, n=32) were a mean (SD) 40.7 (13.5) years of age and primarily female (74%). At baseline, participants with the highest VAS-SI scores had numerically higher mean (SD) ESS (A=16.0 [3.1], B=15.6 [2.6], C=17.1 [2.4]) and IHSS (A=26.7 [7.7], B=34.5 [5.9], C=36.3 [5.5]) scores. Participants with the highest baseline sleep inertia were more frequently rated severely ill on the CGIs (A=17.6%, B=12.1%, C=34.4%). Baseline total sleep time trended higher with increasing VAS-SI scores. From baseline to end of SDP, mean (SD) scores decreased (improved) on the ESS (A=−9.9 [5.1], B=−9.8 [3.5], C=−10.0 [5.1]) and IHSS (A=−14.1 [9.9], B=−19.0 [9.0], C=−18.1 [9.9]), regardless of baseline sleep inertia; nearly all (99%) participants reported improvement on the PGIc. Mean (SD) VAS-SI scores decreased by 9.3 (11.9), 31.5 (14.8), and 42.8 (22.9) in groups A, B, and C, respectively, at end of SDP. Spearman correlation coefficients for VAS-SI and IHSS items assessing sleep inertia were moderate (≥0.3) to strong (≥0.6). Conclusion Participants with higher baseline sleep inertia generally had greater baseline disease burden. LXB treatment was efficacious across subgroups regardless of baseline sleep inertia. Support (if any) Jazz Pharmaceuticals.

0614 Characterizing Sleep in Early-Morning Shift Workers at Risk for Shift Work Disorder

Abstract Introduction Shift work is increasingly common in our 24/7 society and can cause sleep disturbances and excessive sleepiness. Roughly 10-43% of shift workers are diagnosed with shift work disorder (SWD), characterized by excessive sleepiness accompanied by reduced sleep duration and/or insomnia. While more individuals work early morning shifts (shift start 3-6AM) compared to overnight shifts, few studies have investigated this population. The aim of this study was to characterize sleep in a population of early-morning shift workers. Methods We characterized sleep in early-morning shift workers (18-65yrs) from New England who were screened for a clinical trial of a wake-promoting agent. Pre-screening consisted of the Epworth Sleepiness Scale (ESS) and a Shift Work Disorder Questionnaire (SWD); screening consisted of the Pittsburg Sleep Quality Index Questionnaire Questionnaire (PSQI) ; a physical exam including an ECG, CBC, urinalysis, and comprehensive metabolic panel; a home sleep test (HST), a Monitored Wakefulness Test (MWT); a physician evaluation of their excessive sleepiness (Clinical Global Impression [CGI]); and a self-evaluation regarding how sleepiness affected their everyday life (Patient Global Impression [PGI]). Only data from consented individuals who met the initial inclusion criteria of being high risk for SWD were included in the analysis. Results 158 early-morning shift workers met the pre-screening criteria and began the screening process. Most worked in retail, healthcare, maintenance, or transportation, and worked five shifts (65%) and 40+ hours (72%) per week, with a duration of 8.8±1.9 hours. 41 were screened out for abnormal findings on the PE, ECG, or screening blood/urine tests; 26 were screened out for previously un-diagnosed OSA or PLMD; 4 were ineligible for other reasons; 7 were excluded after their MWT due to long sleep latency, 20 were lost to follow-up/withdrew and 60 completed screening and met inclusion criteria. Their average (±sd) age was 37±11 years, 45% women, PSQI score 7.5±2.7, sleep duration 5.6±1.0, ESS=16.3±3.1, CGI=4.2±0.9, PGI=3.6±1.1. Conclusion Early-morning shift workers at an increased risk for SWD report short and disturbed sleep, excessive sleepiness, and a negative impact of sleepiness on their quality of life. Many have undiagnosed OSA and PLMD. Support (if any) Axsome Therapeutics, Jazz Pharmaceuticals, Brigham and Women’s Hospital Center for Clinical Investigation.

0588 DNS and Sleep-Dependent Memory Consolidation in Pediatric Narcolepsy Type 1

Abstract Introduction Disrupted nighttime sleep (DNS) is common in narcolepsy type 1 (NT1), yet its impact on cognitive function is unknown. Given known associations between sleep-dependent memory consolidation and N2 sleep spindles, we hypothesized that NT1 impairs memory consolidation, due to fragmented N2 sleep and altered N2 sleep spindles in the NT1 group. Methods In this case-control study, we trained n=23 NT1 participants [mean age 15.8 years (3.2)] and n=28 healthy control (HC) patients [13.6 years (3.7)] to criterion on a spatial declarative memory task before a nocturnal in-lab polysomnogram and then gave them a cued recall test upon awakening in the morning. NT1 participants could take SSRI/SNRI medication for cataplexy but were weaned off wake-promoting medications and excluded if on an oxybate. We extracted wake and sleep stage bout numbers from sleep and N2 spindle characteristics from the polysomnogram and conducted linear regression with memory consolidation results across groups. Results Adjusting for age, NT1 participants had longer sleep duration than HC, more N1%, lower N3%, higher Wake/N1 Index, as well as more bouts per hour of Wake, N1, N2, REM than controls (p’s < 0.04). Compared to HC, NT1 subjects had similar N2 spindle density, amplitude, and sigma power, but shorter duration of N2 spindles (p=0.009). More NT1 participants could not meet performance criterion on the initial learning task and required an easier memory task vs. HC (p=0.02) despite being older than HC. NT1 participants showed a trend for impaired memory consolidation vs. HC across a night of sleep after adjusting for age, gender, and total sleep time (p=0.07). Across groups, shorter N2 spindle duration (p=0.02) but not increased N2 bout number was associated with worse sleep-dependent memory consolidation. Conclusion Compared to controls, NT1 participants showed encoding difficulties but only a trend difference in memory consolidation despite greater sleep fragmentation. NT1 participants had briefer N2 sleep spindles and overall, these shorter N2 spindles were associated with greater memory consolidation deficits. Future sleep therapeutic studies are needed to determine if sleep-dependent memory consolidation can be improved to address daytime cognitive problems in NT1 patients. Support (if any) Jazz Pharmaceuticals and National Institutes of Health grant 5K23NS104267-2