ABSTRACT The transition to a low-carbon economy requires a steady and secure supply of minerals, which are susceptible to international tensions. In particular, the coronavirus pandemic in 2019 and the Russia-Ukraine conflict in 2022 are two novel shocks affecting the clean energy market. Measuring the impact of increasing geopolitical risks due to these shocks on the clean energy sector is critical to the future of sustainable development. In this framework, this study uses wavelet coherence analysis and time-varying parameter VAR methods to examine the impact of geopolitical risks on the prices of aluminum, copper, lead, zinc, cobalt, and nickel from January 1992 to August 2022. The results show that mineral prices decreased during the COVID-19 period and increased after the Russia-Ukraine conflict. The results also indicate that global geopolitical risk has a moderating effect on the prices of copper, aluminum, cobalt, and zinc, while geopolitical risk associated with Russia increases the prices of all minerals except cobalt. These results imply that the problems in Russia destabilize the prices of mineral commodities used in the renewable energy market, while the global geopolitical risks do not pose serious problems. Therefore, the Russian-Ukrainian conflict should be resolved in order to use clean energy minerals more effectively.

The environmental management cycles for chemicals and climate change (EMC4 ) is a suggested conceptual framework for integrating climate change aspects into chemical risk management. The interaction of climate change and chemical risk brings together complex systems that are imperfectly understood by science. Making management decisions in this context is therefore difficult and often exacerbated by a lack of data. The consequences of poor decision-making can be significant for both environmental and human health. This article reflects on the ways in which existing chemicals management systems consider climate change and proposes the EMC4 conceptual framework, which is a tool for decision-makers operating at different spatial scales. Also presented are key questions raised by the tool to help the decision-maker identify chemical risks from climate change, management options, and, importantly, the different types of actors that are instrumental in managing that risk. Case studies showing decision-making at different spatial scales are also presented highlighting the conceptual framework's applicability to multiple scales. The United Nations Environment Programme's development of an intergovernmental Science Policy Panel on Chemicals and Waste has presented an opportunity to promote and generate research highlighting the impacts of chemicals and climate change interlinkages. Integr Environ Assess Manag 2024;20:433-453. © 2023 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

ObjectivesThe purpose of this study was to examine the number of exacerbations, counts of eosinophils, and asthma-related symptoms 1 year before and after initiating benralizumab for the treatment of severe eosinophilic asthma.MethodsPatients with prior exacerbations and newly initiating benralizumab were identified in the claims-based Healthcare Integrated Research Database. Claims were used to assess benralizumab treatment patterns, exacerbations, healthcare resource utilization, and other asthma medication used. Among a subset of patients, medical records were abstracted for Asthma Control Test (ACT) scores and asthma symptoms.ResultsThere were 506 patients meeting inclusion/exclusion criteria for claims-based analyses and 123 for medical-record analyses. The number of patients experiencing exacerbations significantly decreased from baseline to follow-up (40% reduction, McNemar’s χ2 = 204.00, p < .001). The mean number of exacerbations also decreased from 3.2 (1.5) to 1.2 (1.4) (paired t = 24.45, p < .001; Cohen’s D = 1.09). The effects were larger among patients with eosinophils ≥300 cells/µL. Among patients with an ACT available for baseline and follow-up (n = 47), there was a significant reduction in the number of patients with scores <19 (72% vs. 45%, p < .01).ConclusionsTreatment with benralizumab resulted in fewer exacerbations, reduced utilization, and improved ACT scores. This study demonstrates that benralizumab is an effective treatment option for patients with severe eosinophilic asthma.

Abstract Introduction Cardiovascular disease causes a quarter of all deaths in the UK, making it a top NHS priority1. One such cardiovascular disease, heart valve disease (HVD), is serious with worse outcomes than many cancers2. Yet diagnosed early, before a patient deteriorates, HVD can be treated effectively with valve replacement or repair. A large proportion of patients however are estimated to be undiagnosed or untreated each year in England (≤53% with severe symptomatic aortic stenosis, ≤41% with moderate/severe mitral valve regurgitation, ≤81% with moderate or greater tricuspid valve regurgitation)3. HVD is often detected when GPs identify a heart murmur upon cardiac auscultation. Patients are referred to echocardiography to confirm diagnosis and severity. By using digital stethoscope to perform auscultation, community pharmacists have the potential to assist with and increase the detection of HVD. Aim To determine if community pharmacists can identify undiagnosed HVD using digital auscultation with eMurmur® stethoscope artificial intelligence (AI), and compare subsequent echocardiography referrals against those from GPs. Methods A community echocardiography service and pharmacy within a single PCN were identified based on interest, capacity, and infrastructure to undergo the service evaluation (SE). Pharmacy patients aged &amp;gt;75 years, or with type 2 diabetes, angina/myocardial infarction, atrial fibrillation or high blood pressure, were invited for HVD assessment by the pharmacist. Patients with known HVD or who had an echocardiogram in the past 10 years were excluded. The pharmacist carried out digital stethoscope auscultation and where systolic murmur was detected, patients were referred to a community clinic for full compensation echocardiography. Patient demographic, comorbidity, auscultation, and echocardiography results were collected. Clinic referrals from the community pharmacy were contrasted with referrals from GP practices to compare the number of appropriate referrals over the same period. Results Community pharmacy detected murmur in 39/86 (45%) patients, who were then referred to community echocardiography (mean age 77.8 years). Echocardiography identified: 8 (21%) moderate/severe HVD, 9 (23%) mild HVD, 22 (56%) ‘normal’ or ‘trivial’ HVD. During the SE, 24 referrals were received from GP practices (mean age 65 years): 2 (8%) moderate/severe HVD, 8 (33%) mild HVD, 14 (58%) ‘normal’ or ‘trivial’ HVD. Pharmacy referred 70% more patients with non-trivial HVD than GP practices (17 vs 10 patients). Discussion/Conclusion This SE demonstrates that community pharmacists can identify undiagnosed HVD, in this case referring more patients with non-trivial HVD to echocardiography than GPs. The rapid data sharing enabled by this technology supports quick decision-making for patients with critical disease requiring immediate treatment. Pharmacists can therefore play an important role as a gateway to accessing potentially lifesaving treatment. Patients appeared comfortable attending a digital auscultation service in a community pharmacy setting. Such a proactive service may help reduce the number of people with severe HVD who go undiagnosed and untreated. Limitations of this SE include the small sample size, rendering statistical analysis inappropriate. Additionally, the analysis indicated the number of GP referrals for echocardiography but not how many patients underwent auscultation overall. Therefore we were unable to compare efficiency of murmur detection.

Introduction: Anemia is a common occurrence in patients with myelofibrosis (MF) and is associated with the need for red blood cell transfusion and poor clinical prognosis. JAK inhibitors such as ruxolitinib are used extensively to treat symptoms of MF and improve quality of life and overall survival. However, JAK inhibitors may also contribute to myelosuppression. Therapeutic interventions that allow for optimization of JAK inhibition with no concern of anemia would benefit patients with MF and potentially lower the rate of treatment discontinuation or suboptimal dosing. Recent studies have demonstrated that inhibition of ACVR1/ALK2, a bone morphogenetic protein receptor that is upstream of the transcriptional regulation of hepcidin, could reduce serum hepcidin levels in patients with MF and improve anemia (Verstovsek S et al. Lancet 2023; Oh S et al. Clin Lymphoma Myeloma Leuk 2022). Reducing levels of hepcidin, a key regulator of plasma iron levels, and restoring erythropoiesis would broadly benefit patients with MF. Based on these recent data, we developed zilurgisertib, a potent and selective ALK2 inhibitor that could be administered in combination with ruxolitinib at doses titrated to the needs of patients with MF. Methods and Results: In biochemical and cellular assays, zilurgisertib inhibited ALK2 kinase activity and SMAD1/5 phosphorylation with IC 50 values of 15 nM and 63 nM, respectively. In Huh-7 cells stimulated with BMP-6, zilurgisertib inhibited hepcidin production with an IC 50 of 20 nM, demonstrating the compound is a potent ALK2 inhibitor capable of regulating iron homeostasis via hepcidin. To assess possible off-target effects of zilurgisertib, kinome profiling at 10 μM ATP was performed at Reaction Biology (Malvern, PA) to determine the overall specificity across 356 kinases (see Figure). At 200 nM, zilurgisertib only inhibited ALK2, ALK1 (to 50%), and ALK6 (to 48%). In addition, zilurgisertib at 20 μM did not affect viability of HEK293 cells, a human cell line commonly used to assess general cell health and compound toxicity. Similarly, zilurgisertib did not affect viability of human fibroblasts or endothelial cells at concentrations up to 5 μM. To test whether the combination of ruxolitinib and zilurgisertib could suppress hepcidin and restore erythropoiesis in an in vivo mouse model of cancer-induced anemia, B16F10 cells were injected intraperitoneally, mimicking a metastatic tumor that leads to anemia 1 week after injection. In a dose-dependent manner, zilurgisertib improved hemoglobin by 2 to 3 g/dL and red blood cell counts, while reducing both liver pSMAD and circulating hepcidin levels by 50% or more compared with vehicle control. The combination of zilurgisertib with ruxolitinib had no effect on this activity, suggesting that inhibition of JAK2 does not inhibit erythropoiesis restored following ALK2 inhibition. Conclusion: Taken together, the potent and selective on-target activity of zilurgisertib suggests that ALK2 inhibition could reduce hepcidin and improve anemia, and that the combination of zilurgisertib with ruxolitinib is a rational and attractive approach to mitigate anemia in patients with MF. The combination of ruxolitinib and zilurgisertib is currently being evaluated in a phase 1 clinical trial in patients with anemia due to myeloproliferative disorders (NCT04455841).

The Janus kinase 2 ( JAK2) mutation, JAK2V617F, is the most common oncogenic driver in myeloproliferative neoplasms (MPNs), with nearly all cases of polycythemia vera (PV) and over half of primary myelofibrosis (MF) and essential thrombocythemia (ET) patients positive for the somatic mutation. Approved therapies for MPNs such as ruxolitinib, which act by directly inhibiting activity of the kinase domain (JH1) of JAK2, have demonstrated impressive clinical efficacy and safety in patients with MPNs; however, they do not address JAK2V617F allelic burden or achieve molecular remission of disease. A targeted JAK2V617F selective agent sparing wild-type (WT) JAK2 activity has potential to eliminate mutant cells, induce molecular remission, and theoretically lead to functional cure of MPNs. We report herein the preclinical development of pseudokinase (JH2)-targeting INCB160058, a first-in-class, orally bioavailable small molecule with the ability to selectively target JAK2V617F + cell populations derived from patients with JAK-mutant MPNs. Using structure- and function-guided molecular design, INCB160058 was designed to bind with picomolar affinity to the JH2 domain of JAK2V617F at the canonical ATP-binding site, with high specificity (&amp;gt;2500-fold) relative to binding at the active kinase domain (JH1) targeted by currently approved JAK inhibitors. Live cell single-molecule fluorescence microscopy showed that INCB160058 binding to JAK2V617F blocked ligand-independent thrombopoietin receptor dimerization induced by the mutation, and consequently led to loss of JH1 domain kinase activity. X-ray crystallography analysis indicates that the observed inhibition is likely driven by conformational disruption of the ⍺C helix motif at Phe 594 and Phe 595 in conjunction with a shift of the upstream region from Leu 583 to Asn 589 upon INCB160058 binding to the JH2 domain of JAK2V617F. We utilized both CD34 + human multipotent hematopoietic stem cells derived from patients with JAK2-mutant MF, engineered JAK2-mutant human hematopoietic cancer cell lines (eg, SET2 and UKE-1), and murine BA/F3 cell lines to explore the selective effects of INCB160058 on JAK2V617F compared with WT JAK2. INCB160058 treatment selectively reduced pathogenic phospho-STAT5 levels, decreased abnormal megakaryopoiesis, and suppressed colony formation only in JAK2V617F + CD34 + cells but not in CD34 + cells from healthy volunteers. Importantly, continuous exposure of mutant and WT JAK2 cells to INCB160058 in co-cultures at concentrations below IC 50 resulted in progressive elimination of JAK2V617F + cells without affecting WT cells. At the end of the testing period, the JAK2V617F-harboring population was no longer detectable in the co-culture assay. In NSG mice subcutaneously inoculated with JAK2V617F-expressing SET2 cells, INCB160058 was tolerated and exhibited significant antitumor activity. In addition, following INCB160058 treatment, a significant reduction in the engraftment of total human cells, particularly human erythroid progenitors (hCD45 − mCD45 − Ter119 − hCD71 + hCD235a +), was observed in NSGS mice xenotransplanted with JAK2V617F + CD34 + cells. Moreover, INCB160058 treatment also led to the normalization of various pathogenic cytokines, such as interleukin (IL)-6 and IL-8. Importantly, these observations were absent in NSGS mice engrafted with CD34 + cells from healthy volunteers following INCB160058 treatment, further demonstrating the selectivity of INCB160058 for JAK2V617F. In summary, our results indicate a novel mechanism of action of INCB160058, a high-affinity pseudokinase (JH2) binding inhibitor of JAK2V617F that blocks cytokine-independent activity of JAK2V617F while preserving cytokine-dependent signaling. Extended treatment with INCB160058 at low therapeutic doses results in the specific elimination of mutant JAK2V617F-harboring cells in mouse models and human cancer cells with minimal impact on WT counterparts. Clinical testing of INCB160058 may allow patients with MPNs to achieve molecular remission by eliminating cells with the main genetic aberration and afford an opportunity to overcome the disease.

Acute Lymphoblastic Leukemia (ALL) is the most common cancer in children, with a second incidence peak in adults over 60 years old. Long-term survival with currently available therapy regimens is &amp;gt;90% in children, but &amp;lt;50% in adults, reflecting differences in disease biology and tolerance of aggressive multi-agent chemotherapy regimens. While CAR-T cell therapy provides effective salvage to patients with relapsed B-cell ALL (B-ALL), outcome in relapsed T-ALL is exceptionally poor. In addition, therapy-related chronic functional impairment in pediatric ALL survivors are common. Less toxic, and more effective therapies are needed to improve ALL survival, particularly in adults, and reduce toxicity and functional impairment in all patients. There is evidence that energy restriction creates a barrier to malignant transformation as B cell precursors undergo somatic hypermutation and during T cell receptor diversification. Mutational inactivation of B-lineage transcription factors such as IKZF1 and PAX5 in B-ALL and aberrant expression of T-lineage regulators such as TLX1/3 in T-ALL disables this metabolic brake, promoting malignant transformation of B and T lymphoid precursors, respectively. Metabolism is being recognized as an attractive target in cancer therapy, but metabolic plasticity often limits the efficacy of targeting single metabolic pathways. SIRT5 is a lysine deacylase that regulates multiple metabolic pathways, including energy metabolism. We have previously reported that a subset of acute myeloid leukemia (AML) cases depends on SIRT5 as a master regulator of central energy metabolism, implicating SIRT5 as a therapy target in AML. We hypothesized that this metabolic vulnerability may extend to ALL. To study the function of SIRT5 in ALL, we stably expressed doxycycline (Dox)-inducible shRNAs targeting SIRT5 in ALL cell lines and primary samples. Knockdown (KD) of SIRT5 significantly inhibited growth and increased apoptosis in B-ALL and T-ALL cell lines. Similar results were seen with primary cells relapsed ALL, whereas SIRT5 KD had no effect on colony formation by normal CD34 + cord blood cells. We also injected mice with Jurkat T-ALL cells expressing Dox-inducible sh SIRT5 and luciferase. Dox-induced SIRT5 KD abrogated disease initiation and eliminated established disease (Figure 1A). To determine whether ALL cells require SIRT5 to maintain a metabolic state that is permissive to malignant transformation, we next evaluated the effect of SIRT5 disruption on energy metabolism, using Seahorse extracellular flux analysis. We found that SIRT5 deficient T-ALL cells had lower rates of both oxidative phosphorylation and glycolysis in comparison to SIRT5 wild type (WT) cells (Figure 1B). Next, to evaluate dependency of SIRT5-KD on multiple genotypes and therapy-resistant ALL, we engineered 30 ALL cell lines to stably express doxycycline sh SIRT5 representing B and T cell origin, diverse genotypes, and including drug resistant lines. We found that several B-ALL and T-ALL cell lines are highly dependent on SIRT5 for growth and survival, while others are not, showing a large range of sensitivity to SIRT5 KD. Therefore, to elucidate the potential mechanisms underlying SIRT5 dependence in ALL, we first analyzed whether SIRT5 KD differentially affects OXPHOS and glycolysis. Preliminary analysis of mitochondrial respiration upon SIRT5 KD suggested that OXPHOS and glycolysis are reduced in SIRT5-dependent cells, but not in SIRT5-independent cells upon SIRT5 KD. Finally, to determine whether Sirt5 disruption affects energy metabolism in normal hematopoietic stem cells (HSCs), we generated a tamoxifen-inducible conditional hematopoietic cell-specific Sirt5 knockout (KO) model. In preliminary experiments, we found no difference in mitochondrial respiration between normal HSCs with or without genetic absence of Sirt5, suggesting that leukemic cells, but not normal hematopoietic stem cells are dependent on Sirt5 for regulation of energy metabolism. Collectively, our results suggest that SIRT5 plays a critical oncogenic role in the development and maintenance of a subset of ALL, providing a rationale for the development of a clinical SIRT5 inhibitor. Targeting master regulators rather than single pathways may circumvent plasticity-based resistance in ALL.

Marburg virus (MARV) causes severe disease and high mortality in humans. The objective of this study was to characterize disease manifestations and pathogenesis in cynomolgus macaques exposed to MARV. The results of this natural history study may be used to identify features of MARV disease useful in defining the ideal treatment initiation time for subsequent evaluations of investigational therapeutics using this model. Twelve cynomolgus macaques were exposed to a target dose of 1000 plaque-forming units MARV by the intramuscular route, and six control animals were mock-exposed. The primary endpoint of this study was survival to Day 28 post-inoculation (PI). Anesthesia events were minimized with the use of central venous catheters for periodic blood collection, and temperature and activity were continuously monitored by telemetry. All mock-exposed animals remained healthy for the duration of the study. All 12 MARV-exposed animals (100%) became infected, developed illness, and succumbed on Days 8-10 PI. On Day 4 PI, 11 of the 12 MARV-exposed animals had statistically significant temperature elevations over baseline. Clinically observable signs of MARV disease first appeared on Day 5 PI, when 6 of the 12 animals exhibited reduced responsiveness. Ultimately, systemic inflammation, coagulopathy, and direct cytopathic effects of MARV all contributed to multiorgan dysfunction, organ failure, and death or euthanasia of all MARV-exposed animals. Manifestations of MARV disease, including fever, systemic viremia, lymphocytolysis, coagulopathy, and hepatocellular damage, could be used as triggers for initiation of treatment in future therapeutic efficacy studies.

Introduction: Cytokine release syndrome (CRS) and immune effector cell (IEC)-associated neurotoxicity syndrome (ICANS) are common adverse effects following IEC therapy. Janus kinase (JAK) pathways are important for the signaling of several cytokines involved in CRS pathogenesis. Itacitinib is a potent, selective JAK1 inhibitor with broad anti-inflammatory activity. We describe preliminary results from the randomized, placebo-controlled portion of the study evaluating itacitinib 200 mg twice daily (bid) for the prevention of CRS. Methods: This randomized, placebo-controlled portion of the phase 2 Study INCB 39110-211 (NCT04071366) enrolled patients ≥18 years old planning to receive axicabtagene ciloleucel for relapsed/refractory large B-cell lymphoma (rrLBCL) and follicular lymphoma (rrFL). Participants received oral itacitinib 200 mg bid beginning 3 days before axicabtagene ciloleucel infusion and continued itacitinib through Day 26. Protocol did not allow tocilizumab for treatment of grade 1 CRS unless CRS did not improve after 72 hours of supportive treatment. Patients who received tocilizumab for grade 1 CRS were not censored. Primary endpoint was incidence of CRS grade ≥2 by Day 14 using American Society for Transplantation and Cellular Therapy grading system. Secondary endpoints included incidence of ICANS by Day 28, duration of CRS and ICANS, and itacitinib safety. Results: 47 patients with rrLBCL were randomized to itacitinib (n=23; median age, 66 [range: 29-80] years; male, 65%) or placebo arms (n=24; median age, 64 [range: 31-79] years; male, 71%). Median (range) number of prior regimens was 2 (1-6) and 1.5 (1-4), respectively. No rrFL patients enrolled in the study. Two (8%) patients in the itacitinib arm received platelet transfusions after Day 28; no transfusions were received in the placebo group. A total of 15 (65.2%) patients in the itacitinib arm developed CRS (grade 1, n=11 [47.8%]) compared with 20 (87.0%) patients in placebo arm (grade 1, n=7 [30.4%]; Figure). No hypotension or hypoxia was observed in patients with grade 1 CRS who received tocilizumab. Grade 2 CRS was experienced by 4 (17.4%) and 13 (56.5%) patients, respectively ( P=0.003; 95% CI: 0.14-0.65). There was no grade 3 or 4 CRS in either arm. Median (range) time to any-grade CRS onset was 2 (0-8) days and 3 (0-9) days, respectively; median (range) duration of grade 2 CRS was 2 (1-8) and 2 (1-5) days. Overall, tocilizumab was used for CRS treatment in 4 (17.4%) patients in the itacitinib arm and in 15 (65.2%) patients in the placebo arm, including 2 and 6 patients, respectively, who received tocilizumab for grade 1 CRS. ICANS occurred in 3 (13%; 95% CI: 3-34) patients in the itacitinib arm and 8 (34.8%; 95% CI: 16-57) patients in the placebo arm (Figure). ICANS grade ≥2 was reported in 2 (8.6%; 95% CI: 1-28) and 5 (21.7%; 95% CI: 8-44) patients, respectively. No grade 4 ICANS occurred in either arm. Median (range) time to any-grade ICANS onset was 5 (4-9) days and 6.5 (2-11) days, respectively; median (range) duration was 2 (2-11) and 3.5 (2-13) days. Persistent grade 3 or 4 thrombocytopenia at Day 28 in the itacitinib arm was reported in 8 (38.1%; [grade 4: n=4]) patients; in the placebo arm in 4 (18.2%; [grade 4: n=0]) patients. Persistent grade 3 or 4 neutropenia at Day 28 in the itacitinib arm was reported in 7 (33.3%; [grade 4: n=3]) patients; in the placebo arm in 3 (13.6%; [grade 4: n=0]) patients. Infections grade ≥3 occurred before Day 28 in 2 (8.7%) patients in the itacitinib arm (urinary tract infection [UTI], n=2) and in 3 (12.5%) patients in the placebo arm (sepsis, n=2; UTI, n=1). There were no fatal adverse events. With a minimum follow-up of 28 days, lymphoma best overall response to axicabtagene ciloleucel showed no difference between the 2 arms. Conclusions: Results from the randomized, placebo-controlled portion of Study INCB 39110-211 have shown prophylaxis treatment with itacitinib 200 mg bid to be well tolerated and resulted in a lower rate and grade of CRS and ICANS after lymphoma treatment with axicabtagene ciloleucel. Incidence of grade 3/4 neutropenia and thrombocytopenia not resolved at Day 28 was higher with itacitinib vs placebo. Rates of severe infections were comparable in both arms. Longer follow-up data on lymphoma response will be available upon presentation. Biomarker analyses comparing the effect of itacitinib on CAR-T cells expansion and function are ongoing.

Disclosures Background: Chronic graft-versus-host disease (cGVHD) is an immune-mediated complication of allogeneic hematopoietic cell transplant (alloHCT) that affects multiple organs with inflammatory and fibrotic pathology, leading to significant patient burden and mortality. Colony-stimulating factor 1 receptor (CSF-1R)-dependent monocytes and macrophages play a key role in cGVHD inflammation and fibrosis. Axatilimab (SNDX-6352) is an investigational, high-affinity anti-CSF-1R monoclonal antibody that targets monocytes and macrophages. We previously demonstrated the biological and clinical activity of axatilimab with organ-specific responses and symptom improvement in a phase 1/2 study (NCT03604692) in patients with cGVHD. Methods: This pivotal phase 2, open-label, randomized, multicenter study evaluated axatilimab at 3 different doses in alloHCT patients with recurrent or refractory cGVHD (AGAVE-201; NCT04710576). Eligible patients were randomized 1:1:1 to receive intravenous (IV) axatilimab at 0.3 mg/kg every 2 weeks (Q2W), 1 mg/kg Q2W, or 3 mg/kg every 4 weeks (Q4W). Randomization was stratified by severity of cGVHD and prior use of ibrutinib, ruxolitinib, or belumosudil. Concomitant use of corticosteroids, calcineurin inhibitors, or mammalian target of rapamycin inhibitors (sirolimus or everolimus) was allowed. Axatilimab treatment could be continued as long as there was clinical benefit as assessed by the investigator. The primary efficacy endpoint was overall response rate (ORR) in the first 6 cycles (24 weeks) as defined by the NIH 2014 consensus criteria; the efficacy boundary of the ORR is based on the lower bound of the 95% CI exceeding 30%. The key secondary endpoint was the proportion of patients reporting a clinically significant reduction of symptoms, as measured by the modified Lee Symptom Scale (mLSS) score with a threshold of ≥7 points. Safety endpoints included frequency and severity of treatment-related adverse events (TRAEs) and treatment-emergent adverse events (TEAEs). Results: A total of 241 patients were enrolled across 121 study sites and 239 (99.2%) patients were treated with axatilimab at the data cutoff of 7 April 2023. Patients were heavily pretreated with a median of 4 prior lines of therapy, including ruxolitinib (74%), belumosudil (23%), and ibrutinib (31%). Demographics and disease characteristics were balanced among the 3 dose cohorts (Table 1). ORR (95% CI) was 74% (63, 83) with 0.3 mg/kg Q2W, 67% (55, 77) with 1 mg/kg Q2W, and 50% (39, 61) with 3 mg/kg Q4W (Table 1). Median duration of response (DOR) has not been reached in any of the cohorts, with 60%, 60% and 53% of patients maintaining response at 12 months in the 0.3 mg/kg Q2W, 1 mg/kg Q2W, and 3 mg/kg Q4W dose cohorts, respectively. Clinical benefit, as measured by reduction in mLSS score, was reported in 55%, 54%, and 36% of patients in the 0.3 mg/kg Q2W, 1 mg/kg Q2W, and 3 mg/kg Q4W cohorts, respectively, in the first 6 cycles. Drug discontinuation owing to TEAEs occurred in 6% of patients with 0.3 mg/kg Q2W, 22% with 1 mg/kg Q2W, and 18% with 3 mg/kg Q4W. The most common TEAEs are summarized in Table 2. Fatal TEAEs occurred in 1.3%, 8.6%, and 7.6% of patients in the 0.3 mg/kg Q2W, 1 mg/kg Q2W, and 3 mg/kg Q4W dose cohorts, respectively. The frequency of TRAEs and grade ≥ 3 TRAEs were dose dependent, consistent with CSF-1R inhibition-mediated macrophage clearance. Most infections were mild, with 3 reported cytomegalovirus infections, including reactivations, in the higher dose cohorts. Conclusions: The AGAVE-201 pivotal trial met its primary endpoint for all doses studied. Axatilimabtreatment of refractory cGVHD in heavily pretreated patients resulted in robust clinical activity and durable responses in all 3 dose cohorts, with the highest ORR and least toxicity at the 0.3 mg/kg Q2W dose. Adverse events consisted primarily of transient laboratory abnormalities and other on-target effects known to be associated with CSF-1R block. Wolff: Novartis: Honoraria, Research Funding; Mallickrodt: Honoraria; Incyte: Honoraria; Sanofi: Honoraria; Behring: Honoraria; Takeda: Honoraria; Gilead: Honoraria. Cutler:Sanofi: Consultancy; Ruth L. Kirschstein Postdoctoral Individual National Research Service Award: Research Funding; Allovir: Other: Data Safety Monitoring Board (DSMB); Pluristem Therapeutics: Other: DSMB; InhibRx: Consultancy; Astellas: Consultancy; Rigel: Consultancy; Oxford Immune Algorithmics: Membership on an entity’s Board of Directors or advisory committees; Cimeio: Membership on an entity’s Board of Directors or advisory committees. Lee:Amgen, AstraZeneca, Incyte, Kadmon, Pfizer, Syndax: Research Funding; Novartis: Other: Steering Committee member; Janssen: Other: Study medication provider; Equillium, Kadmon, Mallinckrodt: Consultancy. Pusic:Incyte: Honoraria; Syndax: Honoraria. White:Novartis: Honoraria. Hamadani:Kite, a Gilead Company: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Caribou: Consultancy; BeiGene: Speakers Bureau; Gamida Cell: Consultancy; Incyte: Consultancy; Genmab: Consultancy; Kadmon: Consultancy; Legend Biotech: Consultancy; MorphoSys: Consultancy; Novartis: Consultancy; SeaGen: Consultancy; Astra Zeneca: Speakers Bureau; BeiGene: Speakers Bureau; Sanofi Genzyme: Speakers Bureau; Astellas: Research Funding; Spectrum Pharmaceuticals: Research Funding; Takeda: Research Funding; Genentech: Honoraria; Myeloid Therapeutics: Honoraria; Bristol Myers Squibb: Consultancy; Genmab: Consultancy; CRISPR: Consultancy; Omeros: Consultancy; Abbvie: Consultancy; ADC therapeutics: Consultancy, Honoraria, Research Funding, Speakers Bureau. Salhotra:Gilead: Research Funding; Kura Oncology: Research Funding; OrcaBio: Research Funding; Jazz Pharma: Research Funding; Rigel Pharma: Research Funding; Sobi: Membership on an entity’s Board of Directors or advisory committees; Sanofi: Speakers Bureau; BMS: Research Funding. Choe:Opna: Other: Receipt of equipment, materials, drugs to institution, Research Funding; Incyte: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Other: Receipt of equipment, materials, drugs to institution; MJH Life Sciences: Honoraria; Actinium Pharmaceuticals: Other: Support for attending meetings and/or travel; NIH National Cancer Institute: Research Funding. Kwon:Kite-Gilead: Consultancy, Speakers Bureau; Jazz: Speakers Bureau; Pfizer: Speakers Bureau. Bermúdez:Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Pfitzer: Consultancy, Speakers Bureau. Radojcic:Syndax: Current Employment, Current equity holder in publicly-traded company. O’Toole:Syndax: Current Employment, Current equity holder in publicly-traded company. Tian:Incyte: Current Employment, Current holder of stock options in a privately-held company. Ordentlich:Syndax: Current Employment, Current equity holder in publicly-traded company, Patents &amp; Royalties: Patents assigned to Syndax Pharmaceuticals. DeFilipp:Incyte: Consultancy, Honoraria, Research Funding; Regimmune: Research Funding; Taiho Oncology: Research Funding; Sanofi: Consultancy; MorphoSys: Consultancy, Honoraria; Inhibrx: Consultancy; PharmaBiome AG: Consultancy; Ono Pharmaceuticals: Consultancy. Kitko:Horizon: Membership on an entity’s Board of Directors or advisory committees. Figure 1