DISC-0974 Produces Meaningful Hematologic Responses in Myelofibrosis-Associated Anemia

The investigational anti-hemojuvelin monoclonal antibody DISC-0974 produced meaningful hematologic responses across all three transfusion cohorts and demonstrated a favorable safety profile in patients with myelofibrosis (MF)-associated anemia, regardless of concomitant JAK inhibitor (JAKi) therapy, according to initial efficacy data from the phase 2 RALLY-MF study presented at the 2026 ASCO Annual Meeting.¹

In the non-transfusion dependent (nTD) cohort, 55% of evaluable participants (n = 31) achieved the primary endpoint of a major hematologic response, defined as a mean Hgb increase of ≥1.5 g/dL sustained for ≥12 weeks. The overall hematologic response rate, incorporating both major and minor responses (mean Hgb increase ≥1.0 g/dL for ≥12 weeks), was 68%. Mean time to major response was 27 ± 30 days, and the duration of the longest major response through the optional continuation phase was 318 ± 235 days among 14 evaluable participants with ongoing follow-up. Hgb increases were maintained through the optional continuation phase, with major responders sustaining mean Hgb elevations of approximately 2.0-2.5 g/dL above baseline through study day 337.

In the low transfusion-dependent (TD Low) cohort, 64% of evaluable participants (n = 11) achieved the primary endpoint of transfusion independence for ≥16 weeks with a minimum Hgb of 7 g/dL. The overall response rate, including patients achieving ≥50% reduction in transfusion requirement, was 73%. Mean time to major response was 4 ± 8 days, and the duration of the longest major response through optional continuation was 345 ± 243 days among 6 evaluable participants with ongoing follow-up. Hgb increases were similarly durable through the continuation phase, with TD Low major responders achieving mean Hgb gains of approximately 3.0-3.5 g/dL above baseline.

In the high transfusion-dependent (TD High) cohort, 50% of evaluable participants (n = 8) achieved the primary endpoint of transfusion independence for ≥12 weeks with a minimum Hgb of 7 g/dL, with an overall response rate of 88%. Mean time to major response was 2 ± 1 days among 4 evaluable participants, and the duration of the longest major response through optional continuation was 239 ± 18 days among 2 evaluable participants with ongoing follow-up.

Hematologic responses were independent of concomitant JAKi therapy. Among the 50 efficacy-evaluable participants, major response rates were identical at 56% in both participants receiving concomitant JAKi (n = 25) and those not receiving concomitant JAKi (n = 25). Analysis by specific JAKi showed consistent results: ruxolitinib (major response 58%, n = 12), momelotinib (major response 50%, n = 12), and pacritinib (n = 1). Overall response rates were similarly comparable at 72% with and without JAKi, 75% with ruxolitinib, and 67% with momelotinib. Hepcidin reduction, iron mobilization, and Hgb improvement curves were superimposable across JAKi subgroups, further supporting the conclusion that DISC-0974 activity is independent of background MF-directed therapy.

Pharmacodynamic data confirmed that DISC-0974 produced sustained reductions in serum hepcidin across all three transfusion cohorts, with levels falling rapidly after the first dose and remaining near or at the lower limit of detection through study day 169. Simultaneously, serum iron levels rose substantially from baseline and were maintained throughout the treatment period and into the optional continuation phase, findings consistent with the proposed mechanism of action and confirming robust target engagement.

“DISC-0974 was safe and generally well tolerated and resulted in meaningful hematologic responses across cohorts. The treatment resulted in sustained hepcidin and serum iron in participants regardless of concomitant JAKi therapy or baseline transfusion requirement,” said lead study author Naseema Gangat, MBBS, a professor of medicine and a consultant in hematology at Mayo Clinic, Rochester, MN.

Safety and Patient-Reported Outcomes

DISC-0974 was safe and generally well tolerated across all cohorts.1 Any treatment-emergent adverse event (TEAE) was reported in 91.8% of participants overall (nTD: 94.3%; TD Low: 92.3%; TD High: 84.6%). Related TEAEs occurred in 24.6% of participants overall. Serious adverse events (SAEs) were reported in 19.7% of participants, and adverse events of special interest (AESIs), defined as AEs related to decrease in renal function including creatinine increase grade 2 or higher or acute kidney injury, occurred in 3.3% of participants overall; none of the AESIs were considered related to study drug. Grade ≥3 TEAEs occurred in 41.0% of participants overall.

The most common TEAEs occurring in more than 10% of participants overall were muscle spasms (21.3%), diarrhea (16.4%), fatigue (16.4%), anemia (14.8%), headache (14.8%), dizziness (13.1%), urinary tract infection (13.1%), fall (13.1%), hypertension (11.5%), back pain (11.5%), nausea (11.5%), abdominal pain (11.5%), and constipation (11.5%). Among related TEAEs occurring in 2 or more participants overall, diarrhea (n = 5) was the most frequent; none of the related TEAEs were considered serious. SAEs and grade ≥3 AEs occurring in more than one participant included hypotension (n = 2) and cellulitis (n = 2).

Grade ≥3 AEs and non-serious AEs occurring in more than one participant included anemia (n = 7), lymphocyte count decreased (n = 3), and platelet count decreased (n = 2). One participant in the nTD cohort withdrew from the study due to unrelated adverse events of nephrolithiasis (SAE), chronic kidney disease (SAE/AESI), worsening of an existing preexisting condition, and Clostridium colitis.

Patient-reported outcomes also improved in association with Hgb increases. Among nTD and TD Low major responders, clinically significant improvements in FACIT-Fatigue scores, defined as a change of ≥3 points, were observed and sustained through study day 169. FACIT-Fatigue improvement and Hgb change were significantly correlated at end of study (r = 0.49; P = .0120). The MPN Symptom Assessment Form Total Symptom Score 50% reduction (MPN-SAF TSS50) at end of study was achieved by 50% of nTD and TD Low major responders. Patient Global Impression of Severity (PGIS) improvement was also correlated with Hgb change at end of study (r = -0.76; P = .0004), providing meaningful evidence that hemoglobin improvements translate into patient-perceived benefit.

Study Design and Patient Characteristics

RALLY-MF (NCT05320198) is an ongoing phase 2, single-arm, multicenter study enrolling approximately 90 patients with primary, post-essential thrombocythemia, or post-polycythemia vera MF and anemia across three cohorts: nTD (n approximately 30), TD Low (n approximately 30), and TD High (n approximately 30), inclusive of 12 Phase 1b participants dosed at 50 mg.

Eligible patients were adults aged ≥18 years with anemia defined by cohort-specific criteria: nTD as baseline Hgb <10 g/dL on ≥3 assessments over 84 days prior to screening without RBC transfusion; TD Low as 1 to 2 packed RBC (PRBC) units over 84 days prior to screening; and TD High as 3 to 12 PRBC units over 84 days prior to screening. Concomitant stable JAKi or hydroxyurea use was permitted. Patients with anemia due to infection, bleeding, or iron or vitamin B12 deficiency were excluded.

Following a 28-day screening period, all participants received DISC-0974 50 mg subcutaneously every 28 days for 6 cycles, with dose escalation to 75 mg at day 57 for participants with insufficient response. After the treatment period, participants entered a 28-day follow-up period with an optional continuation phase. A total of 61 participants had been treated as of the data cutoff of April 27, 2026, including data through the March 20, 2026 visit. Of the 61 participants treated, 50 (82.0%) were evaluable for efficacy analysis. Overall, 75% of participants who completed the study proceeded to the optional continuation phase.

The median age of enrolled participants was 71.0 years (range, 31-87), and 54.1% were male. The majority were White (88.5%). Approximately 52.5% were receiving concomitant JAKi therapy, most commonly ruxolitinib (24.6%) and momelotinib (24.6%). The majority (83.6%) had DIPSS intermediate-2 risk disease. JAK2 mutation was present in 44.3%. Median baseline hepcidin was 66.0 ng/mL (range, 9.8-227.3) and baseline hemoglobin median was 8.4 g/dL overall. The study is ongoing, with continued follow-up for the nTD cohort and ongoing enrollment for the TD cohorts.

The investigators acknowledge that the single-arm design without a control group is a study limitation.

REFERENCE

1. Gangat N, Tefferi A, Bose P, et al. RALLY-MF: initial efficacy of a phase 2 study of DISC-0974, an anti-hemojuvelin antibody, to treat anemia in myelofibrosis. Presented at: 2026 ASCO Annual Meeting; May 29-June 2, 2026; Chicago, IL. Abstract 6501.