Clinical Summary: 

• Design/Population: The phase 2 RALLY-MF study evaluated selcodebart, a first-in-class hemojuvelin-targeted monoclonal antibody, in patients with myelofibrosis and anemia across non-transfusion dependent, low transfusion burden, and high transfusion burden cohorts. 
• Key Outcomes: Selcodebart produced early and durable anemia responses across transfusion cohorts, with responses observed regardless of concomitant JAK inhibitor therapy. Hematologic improvements correlated with reductions in hepcidin, increased iron mobilization, and improvements in patient-reported fatigue and symptom outcomes.
• Clinical Relevance: These findings support hepcidin inhibition as a novel anemia-directed strategy in myelofibrosis and provide the rationale for further evaluation of selcodebart as monotherapy and in combination with JAK inhibitors. 

Naseema Gangat, MBBS, Mayo Clinic, Rochester, Minnesota, discusses results from the phase 2 RALLY-MF trial evaluating selcodebart, a first-in-class monoclonal antibody targeting hemojuvelin, for the treatment of anemia in patients with myelofibrosis. 

Dr Gangat reviews early and durable anemia responses observed across patients with varying transfusion requirements, including those receiving concomitant JAK inhibitor therapy, as well as improvements in fatigue and myelofibrosis-related symptoms. She also discusses the mechanism of hepcidin inhibition, including reductions in hepcidin and increased iron mobilization, and how these findings support further development of selcodebart as a novel anemia-directed therapy in myelofibrosis.

Transcript: 

My name is Naseema Gangat, I'm a professor of medicine with the division of hematology at the Mayo Clinic in Rochester, Minnesota. Today I will be discussing the RALLY-MF study, which is a phase 2 study of DISC-0974, also known as selcodebart, for the treatment of anemia in patients with myelofibrosis (MF). 

Selcodebart was able to produce meaningful hematological responses in patients with myelofibrosis, regardless of baseline transfusion requirement or concomitant JAK inhibitor therapy. These improvements in hemoglobin correlated with improved patient-related outcomes and the drug was found to be safe and well tolerated in patients with myelofibrosis.

Anemia in myelofibrosis is a continued unmet need. The mechanism of anemia is felt to be multifactorial with contributions from ineffective erythropoiesis, decreased production from a fibrotic marrow, splenic sequestration, chronic inflammation related increased hepcidin levels, and treatment effects such as the use of JAK inhibitors, particularly ruxilotinib.

Hepcidin appears to be a key player of anemia in patients with myelofibrosis. It has been shown in earlier studies that hepcidin levels are 12 times elevated in MF patients compared to controls, and the degree of hepcidin elevation correlates with the severity of anemia. 

Currently, there are no FDA approved treatments specifically to treat anemia in patients with myelofibrosis, hence there is a need to develop newer therapies. 

DISC-0974 or selcodebart, is a monoclonal antibody directed against hemojuvelin. Hemojuvelin is an important player because it is a core receptor for the bone morphogenic protein 6 and the BMP6 SMAT signaling pathways involved in hepcidin production. By inhibiting hemojuvelin, we are able to reduce hepcidin production and by doing that, we're able to increase iron mobilization and increase intestinal absorption of iron as well– that makes iron available for erythropoiesis and alleviates anemia.

This is a phase 2 study, which is an open-label study, with 3 dosing cohorts. Patients are required to be anemic, anemia is defined by hemoglobin below 10 grams per deciliter over the past 84 days prior to screening. [There was a] non-transfusion dependent cohort in which patients did not receive any transfusions in the past 84 days [and] there are transfusion dependent cohorts which are stratified into low transfusion needs and high transfusion needs. The low transfusion needs are 1 to 2 units in the last 84 days and high transfusion burden is 3 to 12 units in the last 84 days. 

The drug is administered as a subcutaneous injection, 50 mg every 28 days for a total of 6 cycles with the option to continue in the context of a response. The main eligibility criteria were transferrin saturation below 75% and adequate iron stores with ferritin above 50, since this is an ion mobilizing agent.

The primary efficacy analyses were based on anemia response, determined by different parameters based on the cohort. For non-transfusion requiring patients, a mean hemoglobin increase of at least 1.5 gram per deciliter persisting for 12 weeks constitutes a major anemia response and a 1-gram increase would be a minor anemia response. For the transfusion dependent patients, transfusion independence was the primary end point. For low transfusion need patients, transfusion independence demonstrated for 16 weeks or longer with a minimum hemoglobin of 7 grams per deciliter and for the high transfusion requiring patients, transfusion independence for 12 weeks with a minimum hemoglobin of 7 grams per deciliter. The minor responses constituted 50% reduction in transfusions.

For the non-transfusion dependent cohort, 55% of the patients achieved a major anemia response. These responses occurred early in the treatment within 1 to 2 months and persisted throughout the continuation phase, with patients receiving study drug 2 plus years and longer.

Similarly for the low transfusion dependent cohort, 64% achieved a major anemia response. Responses occurred early and persisted in the continuation phase. 

For the high TD cohort, 50% of the patients achieved a main anemia response. These responses also correlated with improved patient-related outcomes, particularly improved FAST fatigue scores and the MPN SAF scores, suggesting that we were providing meaningful benefit to the patients. 

In terms of pharmacokinetics, we were able to show reduced hepcidin levels amongst all patient cohorts, increased iron mobilization, and increased hemoglobin.

With respect to whether responses were different based on JAK inhibitor use, the majority of patients were receiving either ruxolitinib or momelotinib and half of the cohort was on concomitant JAK inhibitor therapy. The major anemia responses were no different for patients whether they were receiving JAK inhibitor or whether they were not receiving JAK inhibitors. Amongst the different JAK inhibitors, there was no significant difference in response rate.

The drug was found to be very well tolerated, 25% of the patients had treatment emergent AEs and they were all mild events. The most common AEs that stood out were muscle spasms and diarrhea, which were self-limiting in the patients.

In conclusion, DISC-0974, selcodebart, is a first in class monoclonal antibody directed against hemojuvelin. It is able to reduce hepcidin levels, improve iron mobilization, and improve hemoglobin levels in anemic patients with myelofibrosis. 

Going by transfusion requirements, both non-transfusion requiring and transfusion dependent patients achieved major anemia responses in almost 60% of the patients, and these responses held true regardless of concomitant JAK inhibitor use. 

These data set the stage for further evaluation of selcodebart in patients with myelofibrosis to determine if there is a benefit over currently available therapies. Just to put the context of these results, anemia and myelofibrosis is typically treated with conventional agents. Erythropoiesis stimulating agents are not specifically FDA approved, but they're often used when erythropoietin levels are suboptimal such as AVID200. Then there is luspatercept, which is a TGF-β ligand tract, which is approved for MDSRS and in clinical trials for myelofibrosis, which is often used in the off-label setting.

There are androgens such as danazol, the IMiDs, and momelotinib is a JAK inhibitor which is FDA approved for treatment of myelofibrosis patients with anemia, but it is not specifically an anemia directed drug. Keeping this in mind, DISC-0974, selcodebart, is the first drug which actually targets hepcidin production, which appears to be a significant component of the anemia and myelofibrosis patients.

The results that are seen at this point are encouraging and set the stage for its use both as monotherapy and in combination with JAK inhibitors or other approved therapies for myelofibrosis. Thank you very much for your attention.

Source:

Gangat N, Tefferi A, Hexner E, 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 the SOHO Annual Meeting; September 9-12, 2026; Houston, Texas. Abstract MPN-120.