Shatzel, Joseph J.

Abstract Background and Significance: Polycythemia vera (PV) is a myeloproliferative neoplasm associated with pathologic erythrocytosis, most often driven by somatic mutations in the JAK2 gene. A key treatment goal is maintaining hematocrit (HCT) below 45% to reduce thromboembolic complications. Current standard of care for patients diagnosed with PV, including phlebotomy (PHL) and cytoreductive therapies (CRT), can be burdensome, may lead to intolerable adverse effects, and often are associated with symptoms of iron deficiency. DISC-3405 is an investigational, novel, humanized immunoglobulin (Ig)G1 monoclonal antibody that targets transmembrane serine protease 6 (TMPRSS6, also known as matriptase 2) to stimulate endogenous production of hepcidin, a peptide hormone secreted by hepatocytes and the key regulator of iron homeostasis. In a randomized, placebo-controlled study in healthy volunteers (DISC-3405-101), DISC-3405 administered subcutaneously at doses between 37.5-300 mg was well-tolerated, resulted in dose-dependent pharmacokinetic (PK) profiles, significantly increased hepcidin production with corresponding reductions in serum iron levels, and reduced HCT (Liu et al, EHA 2025, PS2207). DISC-3405 is being developed as a potential treatment for patients with PV requiring HCT reduction, regardless of baseline risk or concurrent CRT. Study Design and Methods: This is a multi-center, open-label, 52-week Phase 2 study enrolling up to 20 patients with PV in the United States to assess the safety, tolerability, PK, pharmacodynamics (PD), and therapeutic effect of DISC-3405 on PV disease control as evidenced by HCT reduction and PHL requirements. After an observation period of 4-12 weeks, participants will be treated and followed for 52 weeks and dosed up to 300 mg every 2 weeks. After 52 weeks, participants can continue in an optional 2-year continuation phase where long-term safety and efficacy will continue to be assessed. The main efficacy endpoints of the study include the proportion of participants achieving therapeutic response, defined as absence of PHL eligibility; number of PHLs during the treatment period; and proportion of participants with HCT values <45% throughout the study. PHL eligibility is defined as (1) HCT ≥45% and ≥3% (absolute change) of pre-treatment values or (2) HCT >48%. Eligible participants include adults 18 or older who meet the 2022 World Health Organization diagnostic criteria for PV. Clinically acceptable laboratory values include HCT <45% prior to Day 1 (dosing) or HCT <48% if followed by a PHL within 2 weeks prior to first dose of study drug, white blood cells 4000/μL to 20,000/μL (inclusive), and platelets 100,000/μL to 1,000,000/μL (inclusive). Participants should have at least 3 PHL in 26 weeks or 5 PHL in the 52 weeks prior to screening, and at least 1 PHL within 12 weeks prior to screening. Participants receiving CRT must have been on the therapy for at least 6 months and on a stable PV treatment regimen, including hydroxyurea, interferon, or ruxolitinib, for at least 2 months. Participants treated with only PHL must have stopped CRT 6 months before screening. Key exclusion criteria include participants that require PHL at HCT levels <45%, clinically significant thrombosis within 2 months prior to study treatment, active or chronic bleeding, estimated glomerular filtration rate of <30 mL/min/1.73 m2, and history of invasive malignancies within the last 5 years, except localized cured prostate cancer and cervical cancer, or other malignancies deemed acceptable in discussion with the Sponsor. The study will enroll participants from approximately 15-20 sites in the United States. Additional details can be found at https://clinicaltrials.gov/study/NCT06985147.

Introduction Long-distance travel is assumed to be a risk factor for venous thromboembolism (VTE). However, the available data have not clearly demonstrated the strength of this relationship, nor have they shown evidence for the role of thromboprophylaxis. Methods We performed a systematic review of the literature. We also summarized available guidelines from 5 groups. Results We found 18 studies that addressed this question. Based on the data presented in the review, we conclude that there is an association between VTE and length of travel, but this association is mild to moderate in effect size with odds ratios between 1.1 and 4. A dose-response relationship between VTE and travel time was identified, with a 26% higher risk for every 2 h of air travel ( P=0.005) starting after 4 h. The quality of evidence for both travel length and thromboprophylaxis was low. However, low-risk prophylactic measures such as graduated compression stockings were shown to be effective in VTE prevention. There is heterogeneity among the different practice guidelines. The guidelines generally concur that no prophylaxis is necessary in travelers without known thrombosis risk factors and advocate for conservative treatment such as compression stockings over pharmacologic prophylaxis. Conclusions We conclude air travel is a risk factor for VTE and that there is a dose relationship starting at 4 h. For patients with risk factors, graduated compression stockings are effective prophylaxis.

Background: Identifying individual and systemic risk factors are key to reducing cancer incidence and improving mortality. Unfortunately for hematologic malignancies, few clear-cut common cause-and-effect relationships exist. Multiple myeloma has been associated with Black race and obesity, and the lymphomas and leukemias differ in incidence with age. In order to identify potential risk factors, in this study we compared incidence and mortality rates among U.S. states for myeloma, all leukemias and lymphomas, and correlated these rates with the prevalence of several lifestyle and demographic characteristics. Methods: Data came from the following sources: cancer incidence and mortality data from 1999-2015 came from the CDC WONDER database; race and poverty prevalence from the 2015 American Community Survey; gross domestic product (GDP) data from the Bureau of Economic Analysis; median household income from the Census Bureau; and weight and physical activity data from the Behavioral Risk Factor Surveillance System survey. Spearman's rank correlation coefficient was used to compare cancer incidence/mortality and potential risk factors. Results: Myeloma incidence and mortality were more common in obese individuals (incidence, rho = 0.27, P = 0.05; mortality, 0.38, P = 0.006) and individuals identifying as Black (0.65, P < 0.001; 0.42, P = 0.002). Incidence was lower in physically active individuals. (-0.51, P < 0.001). Leukemia incidence and mortality were more common in individuals identifying as white (0.45, P = 0.001; 0.36, P = 0.009). Mortality was positively associated with obesity (0.39, P = 0.005), and negatively associated with physical activity (-0.36, P = 0.009) and median household income (-0.39, P = 0.004). Lymphoma incidence and mortality were more common in white individuals (0.38, P = 0.006; 0.40, P = 0.004). Incidence was negatively associated with state poverty percentage (-0.40, P = 0.003). Mortality was positively associated with obesity (0.35, P = 0.01), and negatively associated with a healthy weight (-0.35, P = 0.01). Discussion: This data suggests that weight and activity are modifiable risk factors for a variety of hematologic cancers, while race may be a non-modifiable risk factor. Individual and state wealth do not appear to play a large role in incidence or mortality. Although further study is needed, these results underscore the importance of maintaining a healthy weight and regular physical activity in cancer prevention. This data also confirms the higher incidence of myeloma in Black individuals and suggests lymphoma and leukemias may be more common among those identifying as white. Disclosures Shatzel: Aronora, Inc.: Consultancy.

Abstract Introduction: Though less commonly used than their anticoagulant counterparts, procoagulants have an important role in the reversal of anticoagulation. Four-factor prothrombin complex concentrate (4PCC) is now approved by the U.S. Food & Drug Administration (FDA) for the reversal of major bleeding associated with warfarin, and is often used off-label to reverse direct oral anticoagulants. Three-factor concentrate (3PCC) and off-label use of recombinant activated factor VII (rFVIIa) have filled this role in the past. Vitamin K is also used as a common antidote for warfarin-induced coagulopathy. Comparative data evaluating the safety profiles and relative thrombotic risks of the PCCs and rFVIIa is limited. In order to better evaluate their comparative safety we calculated the rate of adverse events reported to the FDA of each procoagulant. Methods: We evaluated the FDA Adverse Event Reporting System (FAERS) database, which compiles drug-related adverse events reported to the FDA from 1969 onwards, to assess the rate of adverse events reported with various procoagulants. Safety profiles were assessed using proportional reporting ratios (PRR) with the total number of reported cases as the denominator. Adverse events data for each drug (vitamin K, rFVIIa, 3PCC, 4PCC) was gathered from FAERS. Both generic and brand names were used to query the database. Adverse events data was filtered by including only events reported by healthcare professionals. Specific adverse events were chosen apriori based on hypothesized potential complications and included hemorrhagic and thrombotic complications. The PRR with 95% confidence interval was generated for each event, with a cut-off of 2 being used to identify associations. Results: As shown in Table 1 and Figure 1, rFVIIa was associated with increased reports of mortality while 4PCC was associated with ischemic stroke, and all but rFVIIa were associated with high INR. 3PCC displayed an increased association with reports of intracranial hemorrhage (ICH), although there was a low rate of reports for 3PCC. Lesser associations were found between rFVIIa and myocardial infarction (MI), 3PCC and deep-vein thrombosis (DVT), and 4PCC and DVT and ICH. In general, vitamin K had the weakest associations among adverse events. Conclusions: Our analysis found that the rate of reports of death and MI were higher with rFVIIa than other procoagulants, while reports of ischemic stroke and intracranial hemorrhage were more common with PCCs. rFVIIa has been associated with cardiovascular before, a finding reiterated by our study. There are notable limitations of this type of analysis, including the reliance on the accurate reporting of adverse events to the FDA, possibility of duplications of reports in the FAERS database, and the importance of not conflating correlation with causation as it relates to these events. The association between rFVIIa and increased death may be due to rFVIIa's history of off-label use in trauma patients and other patient groups at higher risk for mortality. While 4PCC may be the procoagulant of the present, it does not have a perfect safety profile, and further study is needed to better characterize the complications of 4PCC and ensure that it is used in such a way as to not under- or over-treat the condition. Disclosures No relevant conflicts of interest to declare.

Abstract Introduction: Direct oral anticoagulants (DOACs) are being increasingly used due to their improved safety and efficacy as compared with warfarin. However, unlike warfarin, less is known regarding long-term and large-scale side effects of DOACs. In order to better evaluate the rates of DOAC-related adverse events on a population level we examined the rate of adverse events reported to the U.S. Food & Drug Administration (FDA) for three commonly used DOACs and warfarin. Methods: We evaluated the FDA Adverse Event Reporting System (FAERS) database, which compiles drug-related adverse events reported to the FDA from 1969 onwards. The safety profiles of warfarin and three DOACs were assessed by comparing adverse events per outpatient prescription and with proportional reporting ratios (PRR). Adverse event data for each drug (warfarin, dabigatran, rivaroxaban, apixaban) was gathered from FAERS. The generic name of each drug was used, and in the case of dabigatran and warfarin, dabigatran etexilate mesylate and warfarin sodium respectively were used to query the database. Adverse events data was filtered by including only those reported by healthcare professionals in the U.S. Specific adverse events were chosen apriori based on hypothesized potential hemorrhagic and thrombotic complications. Numbers of U.S. outpatient prescriptions were gathered from the ClinCalc DrugStats database using information from the Medical Expenditure Panel Survey (MEPS). Only adverse events data from years in which there was also prescription data were included in the study. PRR with 95% confidence interval was used to compare rates of DOAC adverse events, with warfarin being excluded to avoid the new-drug effect. A PRR of 2 or greater was considered significant. Results: As shown in Table 1, warfarin had the fewest reported adverse events per prescription for all categories save elevated international normalized ratio. Rivaroxaban had the highest proportion of reported adverse events, most notably the rate for breakthrough venous thromboembolism (VTE) was higher than for other DOACs. Dabigatran had the highest reported rated of ischemic stroke. When the DOAC data was analyzed using PRR, as seen in Figure 1, less difference was observed. Reported rates of pulmonary embolism (PE) and deep-vein thrombosis (DVT) were again higher with rivaroxaban while dabigatran again showed higher than expected rates of ischemic stroke and a slightly higher risk of myocardial infarction. Apixaban did not show higher than expected rates in any category. Reported rates of mortality did not significantly differ among the drugs. Conclusion: Our analysis found that among DOACs rates of breakthrough VTE were significantly higher with rivaroxaban, and that reported rates of ischemic stroke were significantly higher with dabigatran. While no DOACs have been compared against each other in prospective trials, post-marketing reports have suggested that different safety profiles exist among DOACs, a finding reiterated by our analysis. The significantly higher rate of VTE reported with rivaroxaban as compared to other DOACs has not previously been described to the best of our knowledge and deserves further analysis. The two methods of comparing the anticoagulants - reported event rate per prescription and PRR - show slightly different results, but the adverse findings reported with rivaroxaban and dabigatran remain consistent. Limitations of this study include the reliance on the accurate reporting of adverse events and reliability of the MEPS data, possible duplications in the FAERS database, and the importance of not conflating correlation with causation as it relates to these events. Considering both event rate per prescription and PRR, apixaban seems to offer the best safety profile of DOACs according to the FAERS data. Further study is needed to better characterize the comparative safety profiles of DOACs. Disclosures No relevant conflicts of interest to declare.

AbstractAlthough anticoagulation without hemorrhage is a primary aim, this vision has remained as yet out of reach. Even despite the superior safety profile of the direct oral anticoagulants, hemorrhage remains a major risk of anticoagulation. Selective inhibition of the contact pathway of coagulation, specifically coagulation factor XI (FXI) and/or factor XII (FXII), has now substantial epidemiologic and preclinical data supporting the notion that these factors contribute to pathologic thrombosis and are yet primarily dispensable for in vivo hemostasis. In this way, targeting FXI and FXII may revolutionize the future anticoagulation landscape. Several drugs are under development for this purpose, including: ISIS 416858, a FXI antisense oligonucleotide which impairs hepatic synthesis of FXI; MAA868, a monoclonal antibody that binds the procoagulant enzymatic site of both zymogen and activated FXI (FXIa); BAY 1213790, a monoclonal antibody that binds the procoagulant enzymatic site of FXIa only; and AB023, a monoclonal antibody that inhibits activated FXII-mediated activation of FXI, along with two small molecules in clinical trials. Each of these drugs have demonstrated favorable safety profiles in their phases 1 and 2 studies to date, with preclinical data also supporting efficacy of abrogating thrombosis in various animal models. Other benefits of some of these drugs include once-monthly dosing and safety in patients with renal or hepatic impairment, while others offer quickly metabolized parenteral options, thus providing more convenient and widely available anticoagulation options. Though still far from the marketplace, drugs targeting FXI and FXII have the potential to usher in a new era of anticoagulation therapy.

AbstractIntroductionDirect oral anticoagulants (DOACs) are being increasingly used. However, unlike warfarin, less is known regarding their long‐term side effects. To better evaluate the rates of DOAC‐related adverse events (AEs) on a population level, we examined AEs reported to the FDA for three commonly used DOACs and warfarin.MethodsWe evaluated the FDA Adverse Event Reporting System (FAERS) database, which compiles reported drug‐related AEs from 1969 onwards. The safety profiles of the included drugs were assessed by comparing AEs per outpatient prescription and with proportional reporting ratios (PRR).ResultsRivaroxaban had the highest proportion of reported AEs. Most notably the rate for breakthrough venous thromboembolism (VTE) was higher than other DOACs. Dabigatran had the highest reported rates of ischemic stroke. When the DOAC data were analyzed using PRR, reported rates of VTE were again higher with rivaroxaban while dabigatran again showed slightly higher than expected rates of ischemic stroke. Apixaban did not show higher than expected rates in any category.ConclusionOur analysis found rates of reported breakthrough VTE were significantly higher with rivaroxaban, while apixaban had no higher than expected rates of any studied AEs.