Savage, William

Background DISC-0974 is a monoclonal antibody that targets hemojuvelin, a co-receptor to BMP-SMAD signaling that stimulates hepcidin production. In healthy volunteers, DISC-0974 has been shown to be safe and induce dose-dependent decreases in serum hepcidin and corresponding increases in serum iron and absolute reticulocyte count (JCP 2024). Serum hepcidin level is abnormally elevated in myelofibrosis (MF) and is believed to contribute to iron-restricted erythropoiesis (AJH 2013:88:312). In an ongoing phase 1/2 study in MF (NCT05320198), DISC-0974 was well tolerated and associated with marked reduction in serum hepcidin levels and improvement in anemia (Blood 2023;142/DOI 10.1182). The current investigator-initiated laboratory correlative study examined the impact of mutations and baseline cytokine levels on anemia response to DISC-0974, in non-transfusion-dependent (nTD) patients with MF. Methods The current study was conducted under an institutional review board approved minimum risk protocol that allowed retrospective collection and analysis of data from Mayo Clinic patient records (Rochester, MN, USA). Study patients were selected from the aforementioned ongoing phase 1/2 study, based on availability of information on mutations and baseline cytokine levels. Definitions of nTD and anemia response criteria were according to the revised international working group (IWG) criteria (Blood 2024; in press): i) nTD was defined as the presence of ≤2 units transfused in the 12 weeks prior to enrollment; ii) a 12-week rolling average increase of hemoglobin by ≥1.5 or 1-1.4 g/dL is required for major and minor response, respectively. Mutation and cytokine analyses were performed according to institutional standard protocols; next-generation sequencing panel included 48 genes and cytokine panel 12 inflammatory cytokines. Results A total of 21 nTD patients with MF (median age 71 years; males 62%) were considered: 15 primary and 6 secondary. Driver mutation distribution was JAK2 52%, MPL 14%, and CALR-1 33%. DIPSS risk distribution was high (10%) and intermediate-2 (90%). Baseline median (range) values were 8.0 g/dL (range 7.1-9.5) for hemoglobin, 266 (41-1221) for serum ferritin, 79 (32-130) for serum iron, 32 (13-49) for transferrin saturation, and 59 (10-913) for serum erythropoietin. Karyotype was favorable (N=18) or unfavorable (N=2). Other mutations, included ASXL1 (N=5), SF3B1 (N=4), SRSF2 (N=1), U2AF1 (N=1), and “none of the above” (N=5). Elevated cytokines at baseline included TNF (90%), IL-18 (43%), IL-2R alpha (34%), IL-6 (24%), and MCP-1 (14%). DISC-0974 dose levels were 28 mg (N=2), 50 mg (N=7), 75 mg (N=7), and 100 mg (N=5). Twelve (60%) patients were on DISC-0974 monotherapy while 9 (40%) received concomitant ruxolitinib (N=5), pacritinib (N=1), or hydroxyurea (N=3). At median follow-up of 6 months (range 2-14), one (5%) patient has discontinued DISC-0974 for lack of response. Details on drug safety are summarized in another abstract (Gangat et al. ASH 2024). Per IWG criteria, 9 (43%) patients achieved major (MR) and 3 (14%) minor responses, resulting in an overall response (OR) rate of 57%. Two additional patients have surpassed the hemoglobin threshold for major response (≥1.5 g/dL) but have not yet met IWG criteria. OR and MR rates were higher in patients receiving DISC-0974 as monotherapy (OR 75% and MR 58%) vs. combined with JAK2 inhibitor or hydroxyurea (OR 33% and MR 22%) (p=0.05 for OR and 0.09 for MR), ASXL1 wild-type (N=15; OR 67% and MR 53%) vs. mutated (N=6; OR 33% and MR 17%) (p=0.16 for OR and 0.11 for MR), no ASXL1/SRSF2/U2AF1/SF3B1 (N=5; OR 100% and MR 80%) vs. at least one mutated (N=16; OR 44% and MR 31%) (p<0.01 for OR and 0.05 for MR). OR was also higher in the presence of elevated MCP-1 (p=0.05) or elevated IL-2R alpha (p=0.05) and MR in the presence of elevated IL-2R alpha (71% vs. 29%; p=0.06). Conclusions: The current study suggests that ASXL1 mutation might attenuate but not abrogate anemia response to DISC-0974, in MF. Elevated inflammatory cytokines in MF are often associated with increased hepcidin levels (AJH 2013:88:312) and this might explain their association with a higher response rate to DISC-0974, observed in the current study. Regardless, it is important to note that these observations represent preliminary data from a subset of patients from an ongoing clinical trial.

Hepcidin, a central regulator of iron homeostasis, is pathologically elevated in patients with myelofibrosis (MF) and anemia. Chronic elevations in hepcidin contribute to the onset and severity of anemia. 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. Preclinical studies have shown that DISC-0974 suppresses hepcidin and increases serum iron. A healthy volunteer study has demonstrated dose-dependent reductions in serum hepcidin, increases in serum iron with doses up to 56 mg administered subcutaneously, and increasing trends in reticulocyte count, reticulocyte hemoglobin, mean corpuscular hemoglobin, total hemoglobin (Hgb), and red blood cell count. In this Phase 1b/2a, open-label, multiple-ascending dose study (NCT05320198), we are assessing the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of DISC-0974 in patients with MF and anemia. Eligible participants include patients over 18 years of age with intermediate-2 or higher-risk MF and anemia. MF is required to be confirmed using the World Health Organization 2016 criteria. Anemia is defined per protocol as Hgb < 10 g/dL or transfusion dependence, as defined by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT). A stable dose of hydroxyurea and/or Janus kinase (JAK) inhibitor is allowed on trial. Major exclusion criteria include: liver iron concentration ≥ 7 mg/g dry weight; splenectomy; nutritional, genetic, infectious, or autoimmune causes of anemia. Dose escalation is based on a Bayesian optimal interval design with accelerated titration. Safety Review Committee assessments gate escalation decisions. Dosing occurs monthly for a total of 6 doses. Primary endpoints include safety and tolerability assessments of adverse events (AEs), clinical laboratory assessments, vital signs, physical examinations, and electrocardiograms. Secondary endpoints include anemia response as defined by the IWG-MRT, transfusion response as defined by a decrease of 50% in transfusion requirement over any 8-week period, standard PK parameters and PD metrics including serum hepcidin-25, iron, transferrin saturation, ferritin, and hematology biomarkers. All data are summarized using descriptive statistics. Initial data show a dose-related increase in pharmacokinetic parameters. DISC-0974 treatment led to dose-dependent reductions in serum hepcidin-25 and increases in serum iron levels. There have been no serious AEs or AEs leading to study withdrawal. Most AEs were mild, transient, and unrelated to DISC-0974. As of August 1, 2023, enrollment and dose escalation are ongoing. Safety, PK, and PD data from at least the first two cohorts will be presented.