BioMarin Research Articles

530. Bamlanivimab (BAM) for SARS-CoV-2 Infection: Rates and Risk Factors for Hospitalization after Monoclonal Antibody Administration in a High-Risk Population

BackgroundIn response to the ongoing COVID-19 pandemic, an emergency use authorization (EUA) was issued for neutralizing antibody therapies including BAM. Licensing trials suggest that use of BAM reduces hospitalizations when compared with placebo (1.6% vs 6.3%). However, the real world impact of BAM is not well-described. In this study, risk factors, outcomes, and hospitalization rates among high-risk outpatients presenting with mild-to-moderate COVID-19 who received BAM were examined.MethodsThis is a single center retrospective analysis of all patients who received BAM monotherapy between 11/11/2020 and 3/16/2021. Electronic health records were reviewed for baseline demographics, EUA indications, comorbidities, and outcomes to include infusion reactions, hospitalizations, and deaths occurring within 29 days of BAM administration. Moderate COVID-19 was defined as having any infiltrate on chest imaging prior to BAM administration. Chi-squared or Fisher’s exact tests were used to compare categorical values as appropriate, and Mann-Whitney U for continuous variables. ResultsOf the 101 patients who received BAM (median age 64 years; 21% black; 4% Hispanic; 55% male), 13 were subsequently admitted. 22 patients (22%) had moderately severe disease as evidenced by abnormal imaging. Severity on presentation, number of indications for therapy, hypertension, stroke, diabetes, and number of co-morbidities were significantly associated with subsequent admission (table 1). No patients had adverse infusion reactions. Of those hospitalized, 8 (61.5%) were for COVID-19, the median duration of hospitalization was 2 days, and 4 received guideline-directed treatment for COVID-19 (table 2).Table 1. Factors Associated with Hospitalization Following Bamlanivimab (BAM) Administration Table 1. (Continued) Factors Associated with Hospitalization Following Bamlanivimab (BAM) Administration Table 2: Characteristics and Resource Utilization of Patients Hospitalized After Bamlanivimab Therapy (n=13) ConclusionIn a high-risk population, hospitalization rates were higher than those observed in clinical trials, with 8% of subjects being admitted for COVID-19. Disease severity on presentation, multiple indications for therapy, and the presence of multiple co-morbidities were all associated with subsequent admission. Reassuringly, BAM was well tolerated, and in those requiring admission, hospitalizations were short, resource utilization was low, and there were no deaths.Disclosures Benjamin L. Custer, M.D., Alexion Pharmaceuticals (Shareholder)Armata Pharmaceuticals (Shareholder)Biomarin Pharmaceutical (Shareholder)Crispr Therapeutics (Shareholder)CVS Health Corp (Shareholder)Editas Medicine (Shareholder)Gilead (Shareholder)Glaxo Smith Kline (Shareholder)Hologic Inc (Shareholder)Merck (Shareholder)Mesoblast LTD (Shareholder)Pfizer (Shareholder)Sanofi (Shareholder)Unitedhealth Group (Shareholder)Vertex Pharmaceuticals (Shareholder) Dana M. Blyth, MD, Nothing to disclose

Health insurance coverage and switching among people with hemophilia A in the United States

BACKGROUND: Hemophilia A (HA) is marked by substantial economic burden, including costs of ongoing treatment, increased monitoring, bleed events, and other health care utilization associated with managing the disease and comorbidities related to the disease. Gene therapies and other anticipated breakthrough treatments hold potential to substantially offset long-term traditional factor VIII (FVIII) prophylaxis in specific populations. Fragmentation of the US insurance system, however, may impact payers' approaches to coverage of new treatments, given concerns about patients "switching" insurance and the payer's ability to offset costs over time. OBJECTIVE: To assess insurance coverage and switching across payers among people with severe HA (SHA) using real-world data. METHODS: Adult men with SHA (FVIII measuring < 1%) in the American Thrombosis and Hemostasis Network dataset between January 2013 and September 2019 were identified. Patients' primary insurance category (ie, commercial, Medicaid, Medicare) and insurance switching over time were described. Outcomes included distribution of current primary insurance coverage by category and mean years of coverage per payer for commercially insured patients, including those with 2 or more commercial payers, and for those who switched insurance categories (eg, coverage by a commercial payer and government payer). RESULTS: Among the cohort of patients with SHA (N = 3,677), 51.9% had commercial primary insurance and 29.0% had coverage by Medicaid (including state-funded programs). The mean duration of follow-up in the database was 6.3 years for patients with at least 1 year of follow-up. Among patients who had ever been commercially insured, 74.9% had the same commercial payer for the entire follow-up period. The mean time covered by the same commercial insurance was 4.8 years. Only 7.5% of patients switched insurance categories (eg, from commercial to Medicaid). Among those who switched categories, patients averaged 3.9 years of commercial coverage, 4.0 years of Medicaid coverage, and 4.8 years of Medicare coverage during the follow-up period. CONCLUSIONS: Both commercially and government-insured patients with SHA typically maintain continuous coverage for extended periods, with limited switching between payers and insurance categories over time. These findings suggest that should breakthrough treatments be approved, payers would likely be able to realize substantial cost savings associated with avoiding long-term prophylactic therapies during the several years after treatment. DISCLOSURES: This study was funded by BioMarin Pharmaceutical Inc. Hinds, Chen, and Sammon are employees of BioMarin Pharmaceutical Inc. and own stock/stock options. Solari was an employee of BioMarin Pharmaceutical Inc. at the time of the study. Pezalla is CEO of Enlightenment Bioconsult, LLC. He, Cheng, and Recht are, or were at the time of this study, employees of American Thrombosis and Hemostasis Network (ATHN), which has received ATHNdataset licensing and other fees from BioMarin Pharmaceutical Inc. Research funding to Recht's employers has come from Bayer, BioMarin Pharmaceutical Inc., CSL Behring, Genentech, Grifols, Hema Biologics, LFB, Novo Nordisk, Octapharma, Pfizer, Sanofi, Spark, Takeda, and uniQure. Recht has also worked as a consultant for Catalyst Biosciences, CSL Behring, Genentech, Hema Biologics, Kedrion, Novo Nordisk, Pfizer, Sanofi, Takeda, and uniQure; sits on the board of directors of the Foundation for Women and Girls with Blood Disorders and of Partners in Bleeding Disorders; and is an employee of the Oregon Health & Science University. Data from this study were presented as a poster at AMCP Nexus 2021; October 18-21, 2021; Denver, CO.

Relationship between Endogenous, Transgene FVIII Expression and Bleeding Events Following Valoctocogene Roxaparvovec Gene Transfer for Severe Hemophilia A: A Post-Hoc Analysis of the GENEr8-1 Phase 3 Trial

Relationship between Endogenous, Transgene FVIII Expression and Bleeding Events Following Valoctocogene Roxaparvovec Gene Transfer for Severe Hemophilia A: A Post-Hoc Analysis of the GENEr8-1 Phase 3 Trial

Health-Related Quality of Life Following Valoctocogene Roxaparvovec Gene Therapy for Severe Hemophilia A in the Phase 3 Trial GENEr8-1

Health-Related Quality of Life Following Valoctocogene Roxaparvovec Gene Therapy for Severe Hemophilia A in the Phase 3 Trial GENEr8-1

Healthcare Resource Utilization and Costs of Patients with AL Amyloidosis: An Analysis of Hospitalizations in the Premier Database

Healthcare Resource Utilization and Costs of Patients with AL Amyloidosis: An Analysis of Hospitalizations in the Premier Database

Dasatinib Treatment Patterns after Pleural Effusion Among Patients with Chronic Myeloid Leukemia

Dasatinib Treatment Patterns after Pleural Effusion Among Patients with Chronic Myeloid Leukemia

Efanesoctocog Alfa Half-Life and Clearance Are Independent of von Willebrand Factor in Severe Hemophilia A: A Post Hoc Analysis from Phase 1/2a Studies

Efanesoctocog Alfa Half-Life and Clearance Are Independent of von Willebrand Factor in Severe Hemophilia A: A Post Hoc Analysis from Phase 1/2a Studies

Thrombosis Prophylaxis with Apixaban in Patients Treated with Asparaginase

Thrombosis Prophylaxis with Apixaban in Patients Treated with Asparaginase

The Von Willebrand Disease Aging and Bleeding Correlation (VWD ABC) Study

The Von Willebrand Disease Aging and Bleeding Correlation (VWD ABC) Study

Updated Results of the Alta Study, a Phase 1/2 Study of Giroctocogene Fitelparvovec (PF-07055480/SB-525) Gene Therapy in Adults with Severe Hemophilia a

Updated Results of the Alta Study, a Phase 1/2 Study of Giroctocogene Fitelparvovec (PF-07055480/SB-525) Gene Therapy in Adults with Severe Hemophilia a

Neutrophil Extracellular Traps Promote Joint Injury in Hemophilia

▪Epidemiological evidence suggests that recurring episodes of joint-bleeding contribute to the development of hemophilic arthropathy (H) in 70-85% of hemophilia patients. Despite major advances in the treatment to prevent joint bleeding, HA continues to be a major morbidity affecting hemophilia patients and the etiological mechanism contributing to the progression of HA remains poorly understood. Recent evidence suggests that the accumulation of blood in the joints may lead to the release of erythrocyte-derived DAMPs (eDAMPs) such as heme and hemoglobin that can promote sterile inflammation, however, the innate immune pathways contributing to this pathophysiology remain unknown.In the study, we used a model of puncture-induced knee joint injury in FVIII-total knockout (F8TKO) mice and blood samples from hemophilia-A patients diagnosed with HA. Intravital multi-photon-excitation fluorescence intravital (in vivo) microscopy of injured synovium in live F8TKO or control mice was conducted to assess neutrophil-platelet aggregation and NETs generation in the knee-joint. Imaging-flow-cytometry and ELISA assays were used to estimate the number of circulating NETs in plasma of patients diagnosed with HA and mice after the knee-injury procedure. Scoring of the bleeding severity, histology, IHC and confocal imaging of joints were conducted to quantify the joint injury in mice.F8TKO but not control mice manifested knee-joint injury and severity of bleeding 5-days post knee-injury. Progression of knee-joint injury was associated with increased neutrophil accumulation and NETs shedding within the synovium of F8TKO mice. Circulating NETs were significantly abundant in the plasma of hemophilia patients diagnosed with HA and F8TKO mice following knee-injury but not plasma of control humans or mice.These findings are the first to suggest that NETs contribute to pathogenesis of HA in hemophilia. Currently, experiments are underway to identify the innate immune pathways that promote NETs shedding, leading to joint-damage in hemophilia. DisclosuresRagni: Takeda Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bioverativ (Sanofi): Membership on an entity's Board of Directors or advisory committees; BioMarin Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Alnylam (Sanofi): Membership on an entity's Board of Directors or advisory committees; University of Pittsburgh: Research Funding; Spark Therapeutics: Membership on an entity's Board of Directors or advisory committees. Sundd: CSL Behring Inc: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding.

Bleeding Data across Baseline FIX Expression Levels in People with Hemophilia B: An Analysis Using the 'Factor Expression Study'

▪IntroductionComplications such as spontaneous and trauma-related bleeding events typically experienced by people with hemophilia B (PWHB) are associated with long-term joint damage and chronic pain, and burdensome treatment with intravenous factor IX administration.Gene therapy, designed to enable the endogenous production of the missing clotting factor, has potential for curative benefit in PWHB (Dolan et al, 2018). Due to its link to risk for bleeding episodes, factor expression level (FEL) is commonly used as an endpoint in hemophilia gene therapy trials. However, little data currently exist linking FEL to bleeding risk in PWHB, most notably within the mild range. As such, the aim of this analysis was to examine the relationship between annual bleed rate (ABR) data across baseline FEL in PWHB.MethodsData from adult non-inhibitor PWHB, across Europe and the United States (US) who received clotting factor on-demand (OD), were drawn from the 'Cost of HaEmophilia in adults: a Socioeconomic Survey' (CHESS) studies. The CHESS studies are retrospective, burden-of-illness studies in people with hemophilia A or B, capturing the economic and humanistic burden associated with living with hemophilia. Additional data were collected to supplement the existing CHESS studies, particularly in people with exogenous FEL in the mild and moderate range. ABR was defined as the physician-reported number of bleed events experienced by the patient in the 12 months to study capture. A generalized linear model (GLM) was used to analyze variation in ABR data across FEL, adjusting for covariates age, body mass index (BMI), and blood-borne viruses. Following this, a multivariable restricted cubic spline (RCS) GLM regression was performed to create, model, and test for the potential non-linear relationship between FEL and ABR. The RCS regression employed 3 knots, located at baseline FEL values of 1, 5, and 10, and controlled once again for age, BMI, and blood-borne viruses.ResultsA total of 407 adult non-inhibitor PWHB, receiving an OD therapy regimen and with information on ABR, were profiled. The GLM provided adequate fit for the modeling of bleed data; the average marginal effect at the mean was computed from the GLM regression outputs. After controlling for the effects of all other model covariates, the regression analysis showed a significant association between FEL and ABR; for every 1% increase in FEL, the average ABR decreased by 0.08 units (p<0.001). The results of the RCS regression found a significant non-linear relationship between FEL and ABR, ceteris paribus (p<0.001).ConclusionsThe results of this analysis found baseline FEL to be significantly associated with ABR in PWHB; as baseline FEL increased, ABR reduced. This highlights the clinical importance of new hemophilia gene therapies potentially increasing FEL to that of the mild or non-hemophilic range in terms of reducing patient burden through the better prevention of bleeding events in PWHB. DisclosuresAli: UniQure: Current Employment. Li: UniQure: Current Employment. Konkle: Pfizer, Sangamo, Sanofi, Sigilon, Spark, Takeda and Uniqure: Research Funding; BioMarin, Pfizer and Sigilon: Consultancy. O'Mahony: BioMarin Pharmaceutical Inc.: Consultancy; Freeline: Consultancy; Uniqure: Speakers Bureau. Pipe: Apcintex: Consultancy; ASC Therapeutics: Consultancy; Bayer: Consultancy; Biomarin: Consultancy, Other: Clinical trial investigator; Catalyst Biosciences: Consultancy; CSL Behring: Consultancy; HEMA Biologics: Consultancy; Freeline: Consultancy, Other: Clinical trial investigator; Novo Nordisk: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy, Other; Sangamo Therapeutics: Consultancy; Sanofi: Consultancy, Other; Takeda: Consultancy; Spark Therapeutics: Consultancy; uniQure: Consultancy, Other; Regeneron/ Intellia: Consultancy; Genventiv: Consultancy; Grifols: Consultancy; Octapharma: Consultancy; Shire: Consultancy.

Prevalence and Risk Factor for Hepatocellular Carcinoma in Individuals with Hemophilia in the Era of Direct-Acting Antiviral Agents: A National Inpatient Sample Study

▪Background: Hepatocellular carcinoma (HCC) is a major complication of chronic hepatitis C virus (HCV) infection. HCV is the leading cause of liver disease in hemophilia population and was acquired with their first transfusion. While direct-acting antiviral agents (DAAs) are effective in HCV eradication, its impact on preventing HCC remains unclear. Few data on HCC in hemophilia after DAA are available. We undertook an observational study to determine the prevalence of and risk factors for HCC in hemophilia since the introduction of DAAs.Methods: We conducted an observational study including adult male discharges in the National Inpatient Sample (NIS) database from 2016-2018. Status of hemophilia (H) and non-hemophilia (NH), HCV, HCC, and other relevant medical conditions were identified using ICD-10 codes. Analysis included NIS-provided discharge-level weights to reflect national estimates. Categorical and continuous variables were assessed by Rao-Scott Chi-Square and weighted simple linear regression, respectively. Weighted multivariable logistic regression was performed to determine HCC risk factors. Variables included were age, race, HCV, HIV, alcoholism, smoking, obesity, hyperlipidemia (HLD), non-alcoholic steatohepatitis (NASH), substance abuse, transfusion, and Charlson comorbidity index (CCI).Results: In total, 7,674,969 adult male discharges, including 3,370 with H (0.04%), were identified between 2016 and 2018. Between 2016 and 2018, the diagnosis rates of HCV were 10.06% (95%CI 8.97%-11.26%) in H vs. 1.22% (95%CI 1.19%-1.25%) in NH, and the rates of HCC were 1.07% (95%CI 0.76%-1.51%) in H vs. 0.27% (95%CI 0.26%-0.28%) in NH. The diagnosis rates of HCV and HCC were similar in 2016, 2017 and 2018, for both H and NH populations. Compared with H without HCC, H with HCC were older (58.6 vs. 50.9 years-old, p<0.001), had higher CCI (mean : 6.5 ± 0.6 vs. 2.0 ± 2.0, p<0.001), and higher prevalence of HCV (36.11% vs. 9.78%, p<0.001), HBV (11.11% vs. 0.45%, p<0.001), NASH (5.56% vs. 0.12%, p<0.001), end-stage liver disease (88.89% vs. 8.61%, p<0.001), portal hypertension (27.78% vs. 2.61%, p<0.001), and platelet transfusion (11.11% vs. 1.44%, p<0.001). The prevalence of HIV infection between H with and without HCC was similar (8.33% vs. 8.82%, p=0.919). Among these with HCC, H were more likely to be younger (58.6 vs. 64.1 years-old, p=0.001), HIV (+) (8.33% vs. 1.64%, p=0.002), and less likely to have alcoholism (11.1% vs. 33.2%, p=0.018) and HLD (2.78% vs. 20.8%, p=0.008), than NH. The rates of cirrhosis, NASH, autoimmune hepatitis, and biliary cirrhosis were similar between groups. Multivariable logistic regression analysis among H patients indicated that NASH (OR 21.6, 95%CI 4.63-100.6), HCV (OR 3.96, 95%CI 1.55-10.2), and CCI (OR 1.54, 95%CI 1.39-1.72) were significant risk factors for HCC, while HIV (OR 0.02, 95% CI 0.00-0.13) and HLD (H: OR 0.07, 95% CI 0.01-0.39) were protective.Conclusion: From 2016 to 2018, the rate of HCC did not significantly decrease in discharges with hemophilia in the NIS database. Chronic HCV infection remains a significant risk factor of HCC in hemophilia despite availability of DAA therapy. NASH and Charlson comorbidity contribute to HCC risk, while HIV and hyperlipidemia appear protective. DisclosuresRagni: Takeda Therapeutics: Membership on an entity's Board of Directors or advisory committees; BioMarin Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Bioverativ (Sanofi): Membership on an entity's Board of Directors or advisory committees; Spark Therapeutics: Membership on an entity's Board of Directors or advisory committees; Alnylam (Sanofi): Membership on an entity's Board of Directors or advisory committees; University of Pittsburgh: Research Funding.

Five-Year Outcomes of Chronic Red Blood Cell Exchange Transfusion Program for Patients with Sickle Cell Disease, the Experience of University of Nebraska Medical Center

▪Background:Red blood cell exchange (RBCX) is an effective therapy in treatment of acute and chronic complications of sickle cell disease (SCD). It involves exchanging patient's red blood cells (RBCs) with donor RBCs to significantly lower hemoglobin S concentration without subjecting the patient to the risk of iron overload. The University of Nebraska Medical Center (UNMC) established a chronic RBCX program in November 2015, which cared for patients with multiple hemoglobinopathies. In this study, we aim to evaluate some of the outcomes of patients with SCD who joined the program.Methods:This is a retrospective study based on review of medical records of patients with sickle cell disease. We reviewed the health records of patients with SCD who were enrolled in the chronic RBCX program between 11/2015-8/2020 at UNMC. We included patients with SCD, regardless of age, who underwent RBCX in the outpatient setting during the study period. Data were collected to assess if RBCX influenced the frequency of SCD crisis, emergency room visits, hospitalizations, and other sickle cell-related complications.Results:A total of 404 sessions of exchange transfusions were performed between November 2015 and August 2020 for 21 patients with SCD. The study included 9 adults (age ≥ 18 years) and 12 children with a median age of 12 years (2-31 years). During the study period, 3 adults left the program due to relocation out of state, patient's preference, or physician's decision. Table 1 summarizes the population demographic. The most common indication for enrollment in the RBCX program was recurrent sickle cell crisis (Figure 1). The mean number of emergency room visits before enrollment in the RBCX program was 22.5 visits (2-62 visits), which reduced after enrollment to 10.4 visits (0-65 visits), with a difference in mean of 12.1 visits (P=0.0021). The mean number of hospital admissions before enrollment in the RBCX program was 13.2 admissions(0-54 admissions), which also reduced to 6.7 admissions (0-50 admissions), with a significant difference in the means equal to 6. 6 admissions (P=0.0013) (Figure 2). Thirteen patients had a baseline ferritin > 500 ng/ml at enrollment; all of them had a decrease in their baseline ferritin during the study, with 4 of them achieving a new baseline < 500 ng/ml. Six patients had pre-existing antibodies at enrollment due to prior alloimmunization; however, no new alloantibodies were noticed after enrollment. The patients without preexisting antibodies were transfused with Rh and Kell matched blood. The patients with pre-existing antibodies were transfused with phenotypically matched blood. Three patients became pregnant during the study period, and their pregnancies were uncomplicated except for one patient with preeclampsia resulting in early delivery. There was no reportable death, acute chest syndrome, or stroke among the patients during the study period.ConclusionOutpatient chronic RBCX demonstrated safety and feasibility in both adults and children. It also showed promising outcomes in terms of reduction of sickle cell complications, number of emergency room visits and hospitalizations. These results can provide the basis for evaluating RBCX in a prospective study to better understand changes in quality of life and clinical outcomes of patients with SCD and limited therapeutic options. [Display omitted] DisclosuresGundabolu: Pfizer: Research Funding; Samus Therapeutics: Research Funding; BioMarin Pharmaceuticals: Consultancy; Bristol-Myers Squibb Company: Consultancy; Blueprint Medicines: Consultancy.

Global Coagulation Potentials and Breakthrough Bleeds in Emicizumab-Treated Hemophilia a Patients Were Similar to Mild Hemophilia a Patients

Emicizumab prophylaxis dramatically reduces bleeding events in severe patients with hemophilia A (PwHA) with and without FVIII inhibitors. Recently, some real-world experiences on PwHA with emicizumab prophylaxis have been reported. The effectiveness of emicizumab could be attributed to an earlier report that the coagulant potential in emicizumab at clinical dosage appeared to correspond to 10-15 IU/dL of factor VIII activity (FVIII:C) (Muto, JTH 2014), indicating that emicizumab enables to transform severe PwHA to mild PwHA. However, the comparison of coagulation potential and bleeding characteristics in PwHA receiving emicizumab (Emi-PwHA) and mild PwHA (PwMHA) remains to be investigated. Here, we examined the clinical and laboratory characteristics in Emi-PwHA and PwMHA. Clinical data of bleeding episodes and coagulation potentials were collected from 64 Emi-PwHA and 15 PwMHA (median FVIII:C 13 IU/dL [IQR 8.5-17.0]). Comprehensive coagulation function was evaluated using Ca 2+-triggered rotational thromboelastometry (ROTEM) and/or ellagic acid/tissue factor-triggered clot waveform analysis (CWA). Furthermore, we compared the features of breakthrough bleeds in two groups.We first compared with the clinical characteristics and coagulation function between the Emi-PwHA with and without the experience of breakthrough bleeds. The age, treatment period, annual bleeding rates (ABR), the percentage of inhibitor-positive, and prophylaxis regimen were not significantly different between both groups. There was no significant difference in ROTEM and CWA-based coagulation potential between Emi-PwHA with and without breakthrough bleeds (median; CT+CFT 1,703s [IQR 1,547-1,849] and 1,837s [IQR 1,671-2,216], Ad|min1| 4.92 [IQR 4.63-5.27] and 4.78 [IQR 4.4-5.11], respectively).We examined clinical data and ROTEM-based coagulation function between the Emi-PwHA and PwMHA. The age in PwMHA (median 25 years [IQR 20-49]) was older than that in Emi-PwHA (median 13 years [IQR 6-25]; p=0.004). The ABR and coagulation function in Emi-PwHA (median; ABR 0 [IQR 0-0.4], CT+CFT 1,795s [IQR 1,659-2,135]) were not significantly different from that in PwMHA (median; ABR 0.3 [IQR 0-0.49], CT+CFT 2,077s [IQR 1,627-2,449]), suggesting that the global coagulation potential in Emi-PwHA was equivalent to that in PwMHA.We next investigated bleeding features in Emi-PwHA (19 cases) and PwMHA (12 cases). Bleeding patterns of them were similar and divided into 3 groups; spontaneous, early post-traumatic (bleeding associated with trauma within 1-2 days) and late post-traumatic (bleeding involved with trauma within 1-2 weeks). Emi-PwHA experienced spontaneous (5/19), early post-traumatic (14/19) and late post-traumatic (3/19) bleedings, and PwMHA experienced spontaneous (4/12), early post-traumatic (7/12) and late post-traumatic (5/12) bleedings. Some patients of them had both spontaneous and early post-traumatic bleeding or both early and late post-traumatic bleeding. The majority of their bleedings was trauma-induced.Severe bleeding symptoms such as muscle bleeds, hemarthrosis or fracture in Emi-PwHA were required FVIII (total 60-200 IU/kg) and hospitalization for 3-5 days. In contrast, those severe breakthrough bleedings in PwMHA were required higher doses of FVIII (total 140-705 IU/kg) and hospitalization for 1-2 weeks. Although the coagulation potential in Emi-PwHA was similar to that in PwMHA, the treatment period and hospitalization for breakthrough bleeds in PwMHA appeared to be longer than those in Emi-PwHA. We speculated that this discrepancy might be due to the difference of physical activities or preventive managements for bleeding because Emi-PwHA was originally severe PwHA.In conclusion, the coagulation potential and bleeding characteristics in Emi-PwHA appeared to be similar to PwMHA, suggesting that emicizumab-mediated coagulation potential reflected the mild type in clinical severity. DisclosuresNakajima: Chugai Pharmaceutical Co., Ltd.: Research Funding; Takeda Pharmaceutical company: Research Funding. Mizumachi: Chugai Pharmaceutical Co., Ltd.: Research Funding. Shimonishi: CSL Bering: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding. Furukawa: Chugai Pharmaceutical Co., Ltd.: Research Funding. Ogiwara: Chugai Pharmaceutical Co., Ltd.: Research Funding. Takeyama: Chugai Pharmaceutical Co., Ltd.: Research Funding. Shima: Fujimoto Seiyaku: Consultancy, Speakers Bureau; Sanofi S.A.: Speakers Bureau; BioMarin Pharmaceutical Inc.: Membership on an entity's Board of Directors or advisory committees; Bayer AG: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk A/S: Honoraria, Speakers Bureau; Takeda: Research Funding; CSL Behring: Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd.: Membership on an entity's Board of Directors or advisory committees; Chugai Pharmaceutical Co., Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Inventor of patents related to anti-FIXa/FX bispecific antibodies, Research Funding, Speakers Bureau. Nogami: Chugai Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding, Speakers Bureau; CSL Behring: Honoraria, Research Funding, Speakers Bureau; Novo Nordisk A/S: Honoraria, Research Funding, Speakers Bureau; Bayer AG: Honoraria, Research Funding, Speakers Bureau; Sanofi S.A.: Honoraria, Research Funding, Speakers Bureau; KM Biologics Co., Ltd.: Honoraria, Research Funding, Speakers Bureau.

Poor Outcomes of Older Adults with Acute Promyelocytic Leukemia (APL) Regardless of Insurance Types

IntroductionPrior studies report multiple factors, including insurance status, as significant barriers to healthcare access in the United States. Barriers to healthcare access may lead to worse outcomes in APL, which requires timely diagnosis and prompt treatment. We performed a large database analysis to examine the effects of insurance type and other factors on one-month mortality and overall survival (OS) in patients ≥65 years of age with APL.MethodsWe aimed to compare one-month mortality and OS of patients on private insurance with patients on non-private insurance, which included Medicare, Medicaid, and other government insurance. Patients ≥65 years of age who were diagnosed with APL between 2004-2015 were identified from the National Cancer Database (NCDB). Multiple regression analysis was used to evaluate the effects of insurance type on the probability of one-month mortality. The Kaplan-Meier method estimated overall survival (OS), which was defined as the time from APL diagnosis to last contact or death from any cause. We used Cox regression model to determine the effects of insurance type on mortality risk adjusting for the other covariates of interest.ResultsWe analyzed a total of 1520 patients- either private (12%) or non-private (88%), which included Medicare (85%), Medicaid (2%), and other government insurance (1%). Among total patients, 60% were 65-74 years of age, 46% were female, 87% were white, 84% had Charlson-Deyo comorbidity index (CCI) of 0 or 1, and 52% were treated at academic centers.One-month mortality was 18% for patients with private insurance and 23% for patients with non-private insurance. In a multivariate regression analysis, insurance type did not affect one-month mortality (Table 1). One-month mortality was higher for older patients; patients ≥75 years of age were more likely to die at one month compared to patients 65-74 years (Odds ratio [OR] 1.98, 95% confidence interval [CI] 1.53-2.57, p<0.0001). Compared to patients with CCI of 0, patients with CCI of 1 (OR 1.91, 95% CI 1.43-2.55, p<0.0001), CCI 2 (OR 1.68, 95% CI 1.10-2.56, p=0.01), and CCI ≥3 (OR 2.88, 95% CI 1.75-4.73, p<0.0001) had worse one-month mortality. One-month mortality was higher for patients treated at comprehensive community cancer center compared to those treated at academic cancer center.Median follow-up for surviving patients was 4.5 years (0.03-13.72). Three-year OS was 56% for private insurance and 50% for non-private insurance (Table 2, Figure 1). In Cox proportional hazard model, there was no statistically significant difference in OS based on insurance type. (Table 3). OS did decrease with increasing age. Compared to patients 65-74 years of age, the likelihood of death was higher for patients ≥75 years (Hazard ratio [HR] 1.80, 95% CI 1.57-2.07, p><0.001). OS decreased with increasing comorbidities: HR 1.31 (95% CI 1.12-1.54, p=0.0007) for CCI 1, HR 1.60 (95% CI 1.28-1.99, p<0.0001) for CCI 2, and HR 1.80 (95% CI 1.37-2.37, p<0.0001) for CCI ≥3 compared to patients with CCI of 0. OS was lower for patients treated at comprehensive community cancer center compared to those treated at academic cancer center. Higher income status and diagnosis after 2009 were associated with improved OS.ConclusionIn our large database analysis, while insurance types were not associated with mortality in patients ≥65 years of age with APL, one-month mortality (about 20%) still remains high and only half of older adults are alive at 3 years. Our study highlights a significant effect of increasing age on mortality even among older adults, with approximately 2-fold higher risk of mortality among patients ≥75 years versus those 65-74 years. Other factors associated with higher mortality included treatment outside of academic centers and lower income status. Unlike younger adults, APL in older adults still has significant unmet need. [Display omitted] DisclosuresGundabolu: Bristol-Myers Squibb Company: Consultancy; Blueprint Medicines: Consultancy; Pfizer: Research Funding; Samus Therapeutics: Research Funding; BioMarin Pharmaceuticals: Consultancy. Bhatt: Servier Pharmaceuticals LLC: Consultancy; Partnership for health analytic research, LLC: Consultancy; Abbvie: Consultancy, Research Funding; Jazz: Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Research Funding; Tolero Pharmaceuticals, Inc: Research Funding; National Marrow Donor Program: Research Funding; Abbvie: Consultancy, Research Funding; Genentech: Consultancy; Rigel: Consultancy.

A Healthy Volunteer-Derived, Factor VIII-Neutralized, Acquired Hemophilia a-Mimetic Plasma Produces Similar Pharmacodynamic Responses of Emicizumab to Those in Patients with Congenital Hemophilia a with or without Inhibitors

A Healthy Volunteer-Derived, Factor VIII-Neutralized, Acquired Hemophilia a-Mimetic Plasma Produces Similar Pharmacodynamic Responses of Emicizumab to Those in Patients with Congenital Hemophilia a with or without Inhibitors

Association of Insurance Types and Survival in Acute Promyelocytic Leukemia (APL)

IntroductionHealth insurance, or lack thereof, is a significant barrier to health care access in the United States. Patients without insurance or with inadequate coverage are more likely to delay or forego treatment, even with acute illness or significant symptoms, leading to worse health outcomes. We aimed to analyze if insurance types impacted one-month mortality and overall survival (OS) in younger patients with APL.MethodsWe utilized National Cancer Database to identify patients <65 years who were diagnosed with APL between 2004-2015. We used multiple logistic regression analysis to evaluate the effects of insurance type on the probability of one-month mortality. OS was estimated by the Kaplan-Meier method. A full Cox regression model was used to determine the effects of insurance types on mortality.ResultsA total of 5380 patients were included. Median age was 44 years (0-64), 50% were female, 93% had Charlson-Deyo comorbidity index (CCI) of 0 or 1, and 58% were treated at academic centers. Insurance types included private (67%), Medicaid or other government insurance (19%), Medicare (7%) or uninsured (6%). Patients with Medicare were older and had increased comorbidities. Lower percent of patients with Medicare (23%) or Medicaid/Other government insurance (21%), compared to those with private insurance (56%) or uninsured patients (63%) were treated at academic centers.One-month mortality was higher for patients with Medicare (16%) or uninsured patients (14%), compared to those with Medicaid/Other government (8%) or private insurance (7%).Patients with Medicare (Odds ratio [OR] 1.69, 95% confidence interval [CI] 1.23-2.32, p=0.001) or uninsured patients (OR 2.23, 95% CI 1.56-3.18, p<0.0001) had worse one-month mortality compared to those with private insurance (Table 1). One-month mortality worsened with increasing comorbidities (OR 2.31 for CCI 1, OR 4.44 for CCI 2, and OR 7.02 for CCI ≥3 compared to patients with CCI of 0, p<0.0001). Female patients and patients traveling <6 miles to the treatment center had lower one-month mortality.Median follow-up for surviving patients was 5.4 years (0.008-13.9). Three-year OS was 89% for private insurance, 81% for Medicaid/Other government insurance, 63% for Medicare, and 80% for uninsured patients (Table 2, Figure 1). Patients with Medicaid/Other government insurance (hazard ratio [HR] 1.39, 95% CI 1.19-1.63 p<0.0001), and Medicare (HR 1.88, 95% CI 1.57-2.24, p<0.0001) were associated with worse OS compared to patients with private insurance (Table 3). Compared to patients ≤18 years of age, the likelihood of death was worse for patients 41-64 years (HR 0.68, 95% CI 1.47-4.90, p=0.001). OS worsened with increasing comorbidities (HR 1.71 for CCI 1, HR 2.33 for CCI 2, and HR 3.48 for CCI ≥3 compared to patients with CCI of 1, p<0.0001). Male gender (p=0.0002) was associated with decreased OS.ConclusionIn one of the largest database analyses, we identified insurance status as a significant factor affecting one-month mortality and OS in APL. Our results revealed a higher one-month mortality but similar longer-term OS in uninsured patients compared to patients with private insurance, which may reflect poor access to healthcare necessary for prompt diagnosis and timely initial treatment; similar longer-term OS may reflect a higher proportion of younger patients with less comorbidities in uninsured group. Patients with Medicaid/Other government or Medicare insurance had worse OS compared to private insurance. The reasons for worse OS may be multifactorial including problems with access to quality leukemia care or drug coverage, or the effects of other differences in the patient population including income and in case of Medicare patients, older age and comorbidity burden. Our results raise concern for healthcare disparities based on insurance types and highlight challenges associated with improving OS in patients with Medicaid, Medicare, or no insurance, which comprise a significant proportion of patients with APL. [Display omitted] DisclosuresGundabolu: Samus Therapeutics: Research Funding; Pfizer: Research Funding; BioMarin Pharmaceuticals: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Company: Consultancy. Bhatt: Genentech: Consultancy; Abbvie: Consultancy, Research Funding; National Marrow Donor Program: Research Funding; Tolero Pharmaceuticals, Inc: Research Funding; Pfizer: Research Funding; Incyte: Consultancy, Research Funding; Jazz: Research Funding; Abbvie: Consultancy, Research Funding; Partnership for health analytic research, LLC: Consultancy; Servier Pharmaceuticals LLC: Consultancy; Rigel: Consultancy.

Outcomes of Patients with Budd-Chiari Syndrome and Factors Predicting the Need for TIPS & Liver Transplantation - a Single-Center Long-Term Experience

Background: Budd-Chiari Syndrome (BCS) is a complex thrombotic disorder caused due to obstruction of hepatic venous outflow involving anywhere from small hepatic venules to the entrance of inferior vena cava into the right atrium. This leads to venous stasis and ischemic injury of hepatic parenchyma and sinusoids, with the risk of liver failure. The prognosis of patients with BCS had improved significantly with long-term anticoagulation and measures like Trans-Jugular-Intrahepatic-Porto-Systemic shunt (TIPS) and liver transplantation. We report the outcomes of patients who follow in our hematology practice and describe the factors predicting the need for TIPS/Liver Transplant.Methods: After appropriate Investigational Review Board permission, we identified patients with a history of BCS following in our thrombosis clinical practice from the year 2010 onwards. We evaluated their laboratory, demographic, anticoagulation data, Model of End-stage Liver Disease (MELD) score, Child-Pugh (CP) score at diagnosis or when earliest available, and other relevant clinical information as outlined. Descriptive statistics with medians, quartiles, frequencies, and percentages are reported. Further, we compared the two categories of patients who needed TIPS/Liver transplants versus those who did not. SAS version 9.4 was used for analysis. For continuous variables, a univariate nonparametric Mann-Whitney test was used. The Fisher's Exact Test was used to associate each variable with the need for TIPS/Liver Transplant.Results: Our study included 23 patients with baseline characteristics, including median age of 36 years (11-59 years), 91% whites, 61% females, 44% smokers, 61% obese(median BMI 29.9 kg/m 2), 6 of 14 women on oral contraceptive pills, 22% with thrombosis history, 17% with stroke history, median hemoglobin 13.4 gm/dL(8.9-20 gm/dL), white blood cell count 9,400/L (3,050-31,500/L), platelet count 294,000/L(14,000-767,000/L), serum creatinine 0.87 mg/L (0.55-2.52 mg/dL), total protein 6.3 gm/dL (5.2-8.8 gm/dL), Bilirubin 2.1 mg/dL(0.1-20.2 mg/dL), Aspartate Aminotransferase (AST) 61 U/L(16-1037 U/L), Alanine Aminotransferase (ALT) 43U/L(18-1694 U/L), MELD score 15 (range 7-38), CP score 9 (5-14), 74% with cirrhosis, 82% with ascites at one point, 57% with myeloproliferative neoplasm (MPN), 4.3% with Paroxysmal Nocturnal Hemoglobinuria (PNH), 17% with Antiphospholipid antibodies positive (APS), 13% had positive antinuclear antibodies, 35% needed TIPS and 44% required liver transplantation. 57% with Janus Kinase (JAK2) V617F mutation (1 patient with a low variant allele frequency of 1%), 1 patient (4.3%) had Calreticulin (CALR) mutation positive MPN, 91% remained on long-term anticoagulation with 40% using warfarin, 35% apixaban, 9% Enoxaparin or Rivaroxaban for long-term anticoagulation, 13% developed heparin-induced thrombocytopenia (HIT). 8.7% had developed BCS after Ad26.COV2.S vaccine to prevent SARS-CoV-2 infection. Excluding the patients with missing variables, 5 of 12 had Protein C deficiency, 3 or 10 had Protein S deficiency, 8 of 20 with Antithrombin (AT) deficiency, 4 of 14 with heterozygous factor V Leiden mutation, 0 of 10 with prothrombin gene mutation, 1 of 13 with hyper-homocysteinemia. 35% had gastrointestinal bleeding though 65% of patients had evidence of varices by endoscopy. When the group needing TIPS/Liver transplant/died is compared to those who did not, they had higher bilirubin, MELD, PC score, AT deficiency, cirrhosis, ascites, and JAK2 mutation (p-value significant: Table 1). With a median follow-up of 90 months, overall survival was not statistically significant between the two groups (Figure 1). Two patients (8.7%) died out of a total of 23.Conclusions: Our data indicate that in patients with BCS, neoplasms (61%), particularly MPN (57%), are very commonly diagnosed. Compared to the historical data in patients with BCS with dismal prognosis (60-80% six-month mortality rate), the overall survival had significantly improved, likely due to supportive measures like TIPS/Liver transplant and long-term anticoagulation. Outside the established variables like CP and MELD, lower antithrombin activity and positive JAK2 mutation status also predicted a higher TIPS/Liver transplant need. [Display omitted] DisclosuresBhatt: Partnership for health analytic research, LLC: Consultancy; Abbvie: Consultancy, Research Funding; Jazz: Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Research Funding; Tolero Pharmaceuticals, Inc: Research Funding; National Marrow Donor Program: Research Funding; Abbvie: Consultancy, Research Funding; Genentech: Consultancy; Servier Pharmaceuticals LLC: Consultancy; Rigel: Consultancy. Gundabolu: BioMarin Pharmaceuticals: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Company: Consultancy; Pfizer: Research Funding; Samus Therapeutics: Research Funding.

Vosoritide: First Approval.

Vosoritide (VOXZOGO®) is a modified recombinant human C-type natriuretic peptide (CNP) analogue, being developed by BioMarin Pharmaceutical for the treatment of achondroplasia. Achondroplasia is caused by a gain-of-function mutation in the fibroblast growth factor receptor 3 gene (FGFR3), which is a negative regulator of bone growth. Vosoritide acts to restore chondrogenesis through its binding to natriuretic peptide receptor B (NPR-B), resulting in the inhibition of downstream signalling pathways of the overactive FGFR3 gene. Vosoritide was approved in August 2021 in the EU for the treatment of achondroplasia in patients aged ≥2 years whose epiphyses are not closed; the diagnosis of achondroplasia should be confirmed by appropriate genetic testing. The drug is also under regulatory review in the USA for the treatment of achondroplasia and clinical development is underway in several countries. This article summarizes the milestones in the development of vosoritide leading to this first approval for achondroplasia in patients aged ≥2 years whose epiphyses are not closed.