Hexner, Elizabeth O.

ABSTRACT Approximately 30% of patients with acute graft-versus-host disease (GVHD) develop steroid-refractory disease and have very poor outcomes. Ruxolitinib has become the standard of care for steroid-refractory acute GVHD, but it is unclear which patients derive benefit. The MAGIC Composite Score (MCS), an algorithm that combines clinical symptoms and biomarkers, has been validated to predict outcomes at the start of primary GVHD treatment. Here, we evaluated its performance at the initiation of second-line treatment in 278 patients. MCS stratified patients into three risk groups (MCS1-3), with the majority (88%) classified as intermediate or high risk. Increasing MCS score was associated with progressively higher 1-year non-relapse mortality (NRM) rates (16%, 41%, and 73%; p<0.001), lower 1-year survival (77%, 56%, and 24%; p<0.001), and lower complete response (CR) rates at day 28 (47%, 38%, and 20%, respectively; p<0.01). The area under the receiver operating characteristic curve (AUROC) for 1-year NRM was significantly higher with MCS compared to clinical symptoms alone (0.70 vs. 0.63; p=0.023). Among patients treated with ruxolitinib, higher MCS similarly predicted higher NRM and lower survival and CR rates. Patients classified as MCS2/3 had poor outcomes despite ruxolitinib, underscoring the need for novel therapies in this patient population. In conclusion the MCS is an accurate predictor of outcomes for patients who require second-line treatment and may be of use as an eligibility criterion for future clinical trials in this high-risk population. Key Points MAGIC Composite Scores that integrate clinical symptoms and biomarker scores predict outcomes of second-line therapy for acute GVHD more accurately than clinical symptoms alone. MCS identifies patients with high NRM despite treatment with ruxolitinib.

The Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) are a group of heterogenous hematologic malignancies characterized by the proliferation of blood cells and consist of myelofibrosis, polycythemia vera, and essential thrombocythemia. The NCCN Guidelines for MPN were developed as a result of meetings convened by a multidisciplinary panel with expertise in MPN, with the aim of providing recommendations for the comprehensive care of adults with these diseases. The panel of experts convenes at least once a year to discuss requested changes to the Guidelines and to evaluate emerging data. These Guideline Insights focus on some of the recent updates for myelofibrosis.

6501 Background: Hepcidin, a central regulator of iron homeostasis, is pathologically elevated in patients with myelofibrosis (MF) and anemia. Chronic hepcidin elevation limits iron availability for red blood cell (RBC) production and contributes to anemia onset and severity. DISC-0974 is an investigational, first-in-class, monoclonal antibody that blocks hemojuvelin, a co-receptor in the bone morphogenetic protein-signaling pathway driving hepcidin expression. Methods: RALLY-MF (NCT05320198) is an ongoing Phase 2, open-label study conducted in the US. The primary aim is to evaluate DISC-0974 efficacy in participants with MF and anemia. Secondary aims include evaluating safety, pharmacokinetics (PK), and pharmacodynamics (PD). Eligible participants are ≥18 years of age with primary or secondary MF and hemoglobin (Hgb) <10 g/dL or RBC transfusion requirement. Participants enroll into 3 cohorts based on RBC units transfused in the 84 days prior to screening: non-transfusion dependent (nTD, 0 units and Hgb <10 g/dL), low transfusion burden (TD low, 1-2 units), high transfusion burden (TD high, 3-12 units). Stable dose of concomitant Janus kinase inhibitor (JAKi) is allowed. DISC-0974 is administered subcutaneously at 50 mg monthly for up to 6 doses, with escalation to 75 mg for inadequate or lost response. Primary endpoints include major hematologic response defined as transfusion independence (TI) during any consecutive 16 weeks (TD low) or 12 weeks (TD high), or a mean Hgb increase of ≥1.5 g/dL from baseline for ≥12 weeks (nTD). Secondary endpoints include PK/PD markers of iron regulation and safety assessments. Data were summarized using descriptive statistics. Results: At data cut (16 Oct 2025), 47 participants enrolled in the nTD (n=30), TD low (n=10), and TD high (n=7) cohorts, with 53% on concomitant JAKi therapy. DISC-0974 led to sustained hepcidin reduction and iron mobilization across cohorts. DISC-0974 resulted in meaningful hematologic responses among evaluable participants: 50% of nTD participants achieved a mean Hgb increase of ≥1.5 g/dL for ≥12 weeks, 71% of TD low participants achieved TI for ≥16 weeks, and 67% of TD high participants experienced a ≥50% reduction in transfusion burden, with follow-up ongoing. Major hematologic response rates were 50% for participants on and off concomitant JAKi therapy (n=18 and n=16, respectively). DISC-0974 was associated with meaningful improvement in FACIT-Fatigue scores for nTD and TD low participants. Serious adverse events (AEs, n=9) and ≥Grade 3 AEs (n=16) were considered unrelated to DISC-0974. There were no early withdrawals due to AEs. Conclusions: DISC-0974 was well tolerated and shows a favorable safety profile. Anemia response and fatigue scores improved across patients with MF and anemia, including those receiving JAKi therapy. These data validate hepcidin reduction as a promising approach to treating anemia in MF. Clinical trial information: NCT05320198 .

Abstract Background Acute graft-versus-host disease (GVHD) is a major cause of non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT). High-dose steroids are standard first-line therapy for grade II–IV acute GVHD, whereas systemic treatment (tx) is generally not recommended for grade I. However, in practice many patients (pts) with grade I GVHD receive systemic steroids. A prior GITMO randomized trial (n=173) of grade I GVHD to either systemic steroid tx or “watch and wait” found that preemptive steroid tx reduced progression to grade II but not grade III/IV GVHD, increased serious infections, and resulted in similar chronic GVHD, NRM and survival (Bacigalupo, Haematologica 2017). In this study we analyzed real world evidence for early systemic steroid use and the potential impact of serum biomarkers in grade I GVHD. Methods We analyzed clinical data and serum samples from pts with grade I acute GVHD at 24 Mount Sinai Acute GVHD International Consortium (MAGIC) centers between 2014 and 2022 who were treated according to physician discretion. Pts were divided into a preemptive steroid tx group or a watch-and-wait group (systemic steroids administered only if progression to grade II–IV GVHD). Preemptive steroid use was treated as a time-dependent covariate and a frailty proportional hazards model with random effects was used to adjust for center effects to account for possible heterogeneity in clinical practices across transplant centers. Serum samples collected at the diagnosis of grade I GVHD were analyzed for ST2 and REG3α to calculate validated Ann Arbor (AA) scores (1, 2, 3). Results Grade I GVHD was diagnosed in 1143 pts; 591 (52%) received preemptive tx and 552 (48%) were treated by a watch-and-wait strategy. In the preemptive tx group, steroids were initiated at a median of 0 days and within 7 days for &gt;90%. The median initial dose of steroids was 1 mg/kg of prednisone or its equivalent. In the watch and wait group, only 184 pts (33%) required systemic steroids for progression to grade II-IV GVHD at a median of 14 days from grade I diagnosis. Preemptive steroid tx reduced the risk of grade II–IV acute GVHD (HR, 0.71; 95% CI, 0.56–0.89; P=0.003), but not the risk of grade III/IV acute GVHD (HR, 1.03; 95% CI, 0.69–1.52; P=0.899) or chronic GVHD (HR, 1.03; 95% CI, 0.69–1.52; P=0.899), consistent with the GITMO trial. The 12-month incidence of NRM was higher for preemptive tx vs. watch and wait (13% vs 7%, P=0.002). In multivariate analysis preemptive steroid use independently predicted an increased risk of NRM (HR, 1.63; 95% CI, 1.06–2.50; P=0.026) as did several other known risk factors (older recipient age, umbilical cord blood donor, HCT-CI ≥3, and myeloablative conditioning). Greater NRM in the preemptive tx group was driven primarily by 3-fold more infectious deaths; deaths due to uncontrolled GVHD were similar for both tx groups. The risk for relapse was unexpectedly lower in the preemptive tx group (HR 0.64; 95% CI 0.47-0.88; P=0.006) and overall survival was therefore not different between groups, but risk factors for relapse such as minimal residual disease status were not available precluding further analysis of this finding. Serum was collected in 871 (76%) pts at onset of grade I GVHD for retrospective biomarker analysis. AA scores were AA1 (80%), AA2 (15%), and AA3 (5%). AA scores were highly predictive of progression to grade III/IV GVHD (AA1 vs AA2 vs AA3: 9% vs 14% vs 44%, all P&lt;0.001) and the risk of 12-month NRM (8% vs 16% vs 39%, all P&lt;0.001); this pattern was observed in both tx groups. The negative effect of preemptive steroid tx was most pronounced in pts with grade I/AA1 GVHD who experienced 5-fold more infectious related deaths compared to pts managed with a watch and wait approach. Conclusion Treatment of grade I GVHD with systemic steroids did not reduce the incidence of grade III/IV GVHD or deaths due to uncontrolled GVHD and instead increased the risk of NRM from infections compared to pts who were treated only after GVHD progressed. Importantly, 2/3 of the watch and wait pts never needed systemic steroid tx. These findings remained robust after adjusting for multiple confounders, including center effects, and were consistent with the GITMO trial. MAGIC biomarkers at the onset of grade I GVHD predicted outcomes and a watch and wait strategy may be best for the 80% of pts with AA1 GVHD. Better treatment options are needed for the 20% of pts with grade I and AA2/3 GVHD.

Abstract Background Hepcidin, a central regulator of iron homeostasis, is pathologically elevated in patients with myelofibrosis (MF) and anemia. Chronic hepcidin elevation limits iron availability for red blood cell production and contributes to the onset and severity of anemia, for which there is a large unmet need for safe and effective treatments. DISC-0974 is an investigational, first-in-class, monoclonal antibody that blocks hemojuvelin, a co-receptor in the bone morphogenetic protein-signaling pathway driving hepcidin expression. In studies involving healthy volunteers (Novikov, et al, J Clin Pharmacol 2024:64(8):953-962) and participants with MF (Gangat et al, Blood 2024;144(Suppl1):657), DISC-0974 dosing resulted in reduced serum hepcidin levels and increased serum iron, with a favorable safety profile. Clinically meaningful improvements in anemia were also observed: 50% of non–transfusion-dependent (nTD) participants achieved a mean hemoglobin increase of ≥1.5 g/dL for at least 12 weeks, while 80% of participants with low transfusion burden (TD low) and 40% of participants with high transfusion burden (TD high) achieved transfusion independence (TI) for ≥16 and ≥12 consecutive weeks, respectively. Aims This Phase 2, open-label, multiple-ascending dose study (NCT05320198) assesses efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) in participants with MF. Methods Participants were enrolled into 3 primary cohorts (n=30 per cohort), categorized by the units of red blood cells transfused in the 84 days prior to screening: nTD (hemoglobin &lt;10 g/dL with 0 units), TD low (1-2 units), and TD high (3-12 units transfused). Additionally, an exploratory cohort of participants receiving concomitant treatment with momelotinib or pacritinib (n=10) was included. Eligible participants were ≥18 years of age with hemoglobin &lt;10 g/dL or a transfusion requirement meeting World Health Organization diagnostic criteria for primary or secondary MF. A stable dose of concomitant hydroxyurea and/or Janus kinase (JAK) inhibitor (ruxolitinib and fedratinib for primary cohorts; momelotinib and pacritinib for exploratory cohort) was allowed. Major exclusion criteria included liver iron concentration ≥7 mg/g dry weight (TD high only) and nutritional, genetic, infectious, or autoimmune anemia. DISC-0974 was administered subcutaneously at a dose of 50 mg once monthly for a total of 6 doses. Dose escalation to 75 mg was required for inadequate or loss of response. Primary endpoints included evaluating hematologic response defined for TD low and TD high as TI during any 16- and 12-week consecutive period, respectively, and for nTD as a mean hemoglobin increase of ≥1.5 g/dL from baseline for at least 12 weeks. Secondary endpoints included PK/PD markers of iron regulation and safety assessments. Data were summarized using descriptive statistics. Results As of 01 July 2025, enrollment of the exploratory cohort of momelotinib was complete (n=10). Baseline hepcidin values in the exploratory cohort were similar (mean (SD) of 83.6 (62.8) ng/mL) to baseline hepcidin values from the DISC-0974 Phase 1b study (mean (SD) of 85.8 (71.0) ng/mL, n=35), and sustained hepcidin reduction was observed after DISC-0974 dosing. Early hematologic responses observed after 1 to 3 doses in the exploratory cohort were comparable to those reported in the Phase 1b study (Gangat et al, Blood 2024;144(Suppl1):657). Based on these initial data, the protocol was amended to allow concomitant momelotinib or pacritinib in all cohorts. Preliminary results, including baseline characteristics, PD, and hematologic responses across all cohorts, will be presented.

Abstract Changes in the clinical symptoms of acute graft-versus-host disease (GVHD) are currently used to assess treatment responses. The Mount Sinai Acute GVHD International Consortium (MAGIC) consortium has recently revealed that the integration of serum biomarkers with clinical symptoms at the onset of treatment in a MAGIC composite score (MCS) more accurately predicts treatment response and 6-month nonrelapse mortality (NRM) than clinical symptoms alone. In this study, we evaluated whether the integration of serum biomarkers and clinical symptoms on day 28 (D28) would also better predict NRM than clinical response only (CRO). We analyzed data from 1135 patients receiving systemic treatment for acute GVHD and created a fourth MCS category for patients with complete resolution of symptoms and low-risk clinical biomarkers on D28. Using a classification and regression tree model with 6-month NRM as the end point, we identified status of MCS 0 or MCS 1 at D28 as responses, which we termed the MAGIC composite response (MCR). In the validation cohort (n = 309), MCR more accurately predicted 6-month NRM than CRO (area under the curve: 0.77 vs 0.69; P = .014) and demonstrated higher negative and positive predictive values. MCR correctly reclassified both clinical nonresponders and responders: 28 of 213 clinical responders (13%) became nonresponders with fivefold higher NRM (34.3% vs 6.8%, P &lt; .001) and a larger group (29/96, 30%) of clinical nonresponders became responders with sixfold lower NRM (7.6% vs 50.7%, P &lt; .001). These findings support the use of MCR as a superior surrogate end point for long-term GVHD control and survival in future clinical trials.

Abstract Overall response (OR) that combines complete (CR) and partial responses (PR) is the conventional end point for acute graft-versus-host disease (GVHD) trials. Because PR includes heterogeneous clinical presentations, reclassifying PR could produce a better end point. Patients in the primary treatment cohort from the Japanese Society for Transplantation and Cellular Therapy (JSTCT) were randomly divided into training and validation sets. In the training set, a classification and regression tree algorithm generated day 28 refined response (RR) criteria based on symptoms at treatment and day 28. We then evaluated RR for primary and second-line treatments, using the area under the receiver operating characteristic curve (AUC) and negative predictive value (NPV) for 6-month nonrelapse mortality as performance measures. RR considered patients with grade 0/1 at day 28 without additional treatment as responders. RR for primary treatment produced higher AUCs than OR with small improvement of NPVs in both validation sets: JSTCT (AUC, 0.73 vs 0.69 [P &lt; .001]; NPV, 92.0% vs 89.6% [P &lt; .001]) and the Mount Sinai Acute GVHD International Consortium (MAGIC; AUC, 0.71 vs 0.68 [P = .032]; NPV, 90.9% vs 89.8% [P = .009]). RR for second-line treatment produced similar AUCs but much higher NPVs than OR in both validation sets of JSTCT (AUC, 0.64 vs 0.63 [P = .775]; NPV, 74.5% vs 66.0% [P &lt; .001]) and MAGIC (AUC, 0.67 vs 0.64 [P = .105]; NPV, 86.8% vs 76.1% [P = .004]). Classifying persistent but mild skin symptoms as responses and residual lower gastrointestinal GVHD as nonresponses were major drivers in improving the prognostic performance of RR. Our externally validated day 28 RR would serve as a better end point than conventional criteria in future first- and second-line treatment trials.

Background: The majority of patients respond to steroid treatment for graft-vs-host disease (GVHD), but the typically high doses and prolonged courses can cause substantial morbidity. GVHD can be classified at onset into two groups with significant differences in treatment response and non-relapse mortality (NRM) by clinical criteria (Minnesota risk) but the more favorable standard risk group still experiences high rates of treatment failure and NRM [MacMillan, BBMT 2015]. We previously validated a serum biomarker-based (ST2+REG3α) risk stratification system, MAGIC algorithm probabilities (MAPs), that can stratify patients both at initiation and during treatment into risk groups for treatment response and NRM [Hartwell, JCI Insight 2017, Srinagesh, Blood Adv 2019]. GVHD that is Minnesota standard risk and has a low MAP (i.e., Ann Arbor 1) at start of treatment represents a low risk group with &gt;80% response rate to steroids and ~10% NRM [Etra, Blood 2023]. We hypothesized that serial monitoring of GVHD symptom severity and MAPs twice (days (d) 7 and 14) in patients with clinical and biomarker defined low risk GVHD could further stratify patients into clinically meaningful groups. Methods: We retrospectively determined MAPs at d7 and 14 in 450 patients with low risk GVHD who participated in a prospective, multi-center, observational trial and were treated with systemic steroids between 2015-2023. MAPs &lt;0.291 at days 7 and 14 were defined as low risk based on a previously validated threshold [Major-Monfried Blood 2018]. Clinical responses were scored as complete (CR), partial (PR), or non-response (NR) by standard criteria. Initiation of second line therapy was considered NR. Patients were categorized into three groups (A-C) based on clinical responses and MAPs at days d7 and 14. A: CR/PR by d14 and low MAP at both d7+14; B: stable or worse GVHD (NR) by d14 with low MAP at both d7 and 14; C: any response with a high MAP at d7 or 14. The endpoints were clinical response at day 28 (overall response rate, ORR=CR or PR), regardless of earlier response status, and 6-month NRM. Results: The median age of the study population was 54 years (range: 0-79); 19% of patients received PT-Cy for GVHD prophylaxis. Target organ involvement was skin ± upper GI (66%), lower GI (23%), isolated UGI (11%), and skin+liver (1%), and GVHD severity was grade I (35%), II (61%), and III (4%) at start of treatment. Patients in group A (n=310, 69%), clinical responders with low MAPs through day 14, had excellent d28 ORR (93%) and very low NRM (4%). GVHD in this group was considered ultra-low risk (ULR) and subset analyses revealed highly consistent d28 ORR and NRM, regardless of target organ severity, age (&lt;18, 18-59, &gt;60), HCT-CI score, conditioning intensity, and GVHD prophylaxis. Group B patients comprised clinical non-responders with low MAPs through day 14 (n=112, 25%); half of them responded by d28 and their NRM was low (8%), albeit double that of group A (p=0.079). Group C was small (n=28, 6%) and included both clinical responders (n=20, 4%) and clinical non-responders (n=8, 2%) who had at least one high MAP through day 14. Their d28 ORR was 54% but NRM increased four-fold (32%) and was significantly worse than patients who maintained low MAPs regardless of clinical response (p&lt;0.001). Conclusion: Serial monitoring by clinical response and biomarkers during the first two weeks of treatment identifies a small number of high risk patients whose GVHD is initially low risk (group C). This group experiences high NRM regardless of clinical response to steroid treatment and may benefit from treatment escalation. Patients with low risk GVHD who do not have an early clinical response to steroids but maintain low MAPs, (group B) have reasonably good long-term outcomes with standard treatment. Finally, serial monitoring identifies a very large subset of patients with ULR GVHD (group A) who respond exceptionally well to standard treatment and experience very low rates of 6-month NRM regardless of pre-transplant characteristics and GVHD prophylaxis. Such patients may benefit from treatment de-escalation strategies such as shorter courses of lower dose steroids, a strategy we are currently testing in a clinical trial (NCT05090384).

Background Endpoints for GVHD treatment trials use early response (i.e, day (D)28 of treatment) as a surrogate for long term survival. Overall response (OR) that combines complete (CR) and partial responses (PR) at day (D) 28 is the conventional endpoint for primary acute GVHD trials because of similar survival outcomes between CR and PR. D28 OR ignores symptom severity at baseline and D28, however, and the PR category encompasses a wide range of responses from minimal improvement to near complete resolution of symptoms. D28 OR is the only endpoint currently approved by the FDA for efficacy, but it has not been re-evaluated as an endpoint for primary treatment (1L) in fifteen years and little is known regarding the prognostic value of D28 OR as an endpoint for second line treatment (2L) of GVHD. We hypothesized that refinement of the current D28 OR criteria, particularly through recategorization of PR in the GI tract, the main driver of nonrelapse mortality (NRM), would more accurately reflect disease control and better predict survival outcomes than current D28 response. Methods The Japanese Society for Transplantation and Cellular Therapy (JSTCT) collaborated with the Mount Sinai Acute GVHD International Consortium (MAGIC) to develop and validate D28 refined response (RR) criteria for 1L and 2L treatment (tx) in patients with Grades II-IV acute GVHD. To maximize the correlation between treatment success (i.e, response) with long term survival, our primary measured metric was the negative predictive value (NPV). We first randomly divided the 1L tx cohort of JSTCT into the training (n=2341) and validation sets (n=1156). In the training set we used a classification and regression tree (CART) algorithm to generate RR criteria that predicted 6-month (mo) NRM based on symptoms both at tx onset and D28. We then compared the two D28 response endpoints (RR vs OR) as surrogates for 6-mo NRM in two validation sets of both 1L tx (JSTCT: n=1156; MAGIC: n=1141) and 2L tx (JSTCT: n=510; MAGIC: n=196). Results The CART algorithm defined a RR as GVHD Grades 0/I at D28 without additional tx; all other D28 grades were considered refined nonresponses. As expected, RR successfully stratified the risk of 6-mo NRM in both 1L tx validation sets (JSTCT: 8% vs 38%, p&lt;0.01; MAGIC: 9% vs 37%, p&lt;0.01). We defined a discordant nonresponse as a nonresponse by RR criteria but a response by OR criteria, which accounted for the majority (~75%) of differences between RR and OR. 6-mo NRM in discordant nonresponders was four fold higher than in responders (JSTCT: 35%; MAGIC: 30%). The large majority (&gt;80%) of discordant nonresponders had persistent GI GVHD at D28. Because the proportion of discordant nonresponders was small (&lt;7% of the total population) in the 1L setting, the improvements of an already high NPV were small (JSTCT: 93% vs 91%; MAGIC: 91% vs 90%). In the 2L tx validation sets, RR also stratified the risk of 6-mo NRM (JSTCT: 26% vs 56%, p&lt;0.01; MAGIC: 13% vs 55%, p&lt;0.01). At the time of 2L tx, the discordant nonresponders are more common and half of the discordant nonresponders experienced 6-mo NRM (JSTCT: 45%; MAGIC: 59%); as a result, RR achieved much higher NPVs than OR (JSTCT: 75% vs 66%; MAGIC: 87% vs 76%). Deaths in responders from acute GVHD (vs. other causes such as infection) were more frequent in OR than RR in both 2L tx validation sets (JSTCT: 41% vs 20%; MAGIC: 41% vs 13%) and 1L tx validation sets (JSTCT: 25% vs 18%; MAGIC: 32% vs 29%). D28 RR is superior to OR because it more accurately reflects control of serious GVHD in four independent validation cohorts, particularly in patients with GI disease. Conclusion We conclude that RR is a more accurate endpoint than OR in patients with grade II-IV GVHD primarily because it classifies persistent GI GVHD at D28 as a non-response instead of a response, which correlates with 6-mo NRM and achieves a higher NPV. This validated RR metric can serve as a better endpoint than OR in assessing treatment efficacy in both primary treatment trials that enrich for high risk GVHD, e.g. GI involvement, and second line treatment trials.

Background Hepcidin, a central regulator of iron homeostasis, is pathologically elevated in patients with myelofibrosis (MF) and anemia. Chronic hepcidin elevation limits iron availability for red blood cell production and contributes to onset and severity of anemia, for which there is a large unmet need for safe and effective treatments. DISC-0974 is an investigational, first-in-class, monoclonal antibody that blocks hemojuvelin, a co-receptor in the bone morphogenetic protein-signaling pathway driving hepcidin expression. A completed healthy volunteer study demonstrated serum hepcidin reductions, serum iron increases, and increasing trends in hematologic parameters, with no safety signal identified. Aims This Phase 1b/2, open-label, multiple-ascending dose study (NCT05320198) assessed safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and initial efficacy of DISC0974 in patients with MF and anemia. Methods Eligible participants were ≥18 years of age with intermediate-2 or high-risk MF and anemia. Anemia was defined as baseline hemoglobin (Hgb) &lt;10 g/dL with or without intermittent transfusion requirement (non-transfusion dependent [nTD]) or transfusion dependent (TD), as defined by the IWG-MRT. A stable dose of concomitant hydroxyurea and/or Janus kinase (JAK) inhibitor was allowed. Major exclusion criteria included liver iron concentration ≥7 mg/g dry weight and nutritional, genetic, infectious, or autoimmune anemia. Dose escalation was based on a Bayesian optimal interval design with accelerated titration. DISC-0974 was administered subcutaneously monthly for 6 doses. Primary endpoints included evaluating DISC-0974 safety and tolerability. Secondary endpoints included PK/PD markers of iron regulation and hematologic parameters. Hematologic response was defined for TD as transfusion independence (TI) during any 12-week consecutive period and for nTD as ≥1.5 g/dL Hgb increase from baseline at any time point. Durability was evaluated as mean Hgb ≥1.5 g/dL above baseline during any 12-week period. Data were summarized using descriptive statistics. Results At the time of data cut, 34 participants were enrolled at 5 dose levels: 14 mg (n=1), 28 mg (n=7), 50 mg (n=12), 75 mg (n=8), and 100 mg (n=6). Treatment with DISC-0974 resulted in meaningful and sustained hepcidin reductions with mean change from baseline (mean 88.2 ng/mL; range [8.7, 374.7]) reaching over 80% across treated participants. This corresponded to iron mobilization at all dose levels. Efficacy Hematologic responses were evaluated in participants dosed at 28 to 100 mg. Responses were achieved independent of baseline transferrin saturation (TSAT) values. Initial hematologic responses in nTD participants were observed around the time of administration of the second dose, with a rise in absolute reticulocyte count preceding responses. Mean erythropoietin values decreased from baseline (mean 68.2 mIU/mL; range [13.2, 1815]) in participants treated at 50 to 100 mg. Hemoglobin responses were achieved in 69% (20/29) of nTD participants; 60% of nTD participants (9/15) achieved a durable response. TSAT values above normal range (50%) were observed in all participants with a durable response. One of two evaluable TD participants achieved TI at the end of study. All evaluable participants with a baseline transfusion requirement (n=8) had ≥50% reduction in transfusions over a rolling 8-week window compared to baseline. Hematologic response was observed in 6 of 10 participants with concomitant JAK inhibitor therapy. Safety One adverse event (AE), diarrhea, was at least possibly related to DISC-0974 and reported in ≥2 participants. Grade 3 AEs included headache reported in 1 participant treated at 28 mg (not related to DISC-0974) and Grade 3 anemia reported in 2 participants treated at 28 mg and 4 participants treated at 50 mg (1 at 50 mg was deemed related to DISC-0974; all others were deemed not related). One serious AE of Grade 2 arthralgia was reported and deemed not related to DISC-0974. Summary/Conclusions DISC-0974 demonstrated acceptable safety and tolerability at all evaluated dose levels. Hematologic responses were achieved in nTD and TD participants, regardless of concomitant JAK inhibitor use. Sustained hepcidin reduction with DISC-0974 led to increased serum iron that preceded hematological response. Additional Phase 1b data, including longer follow-up, will be presented.