Myelofibrosis is a rare hematologic neoplasm categorized under myeloproliferative neoplasms, with approximately 19,350 cases in the US, according to DelveInsight. Hepcidin, a central regulator of iron homeostasis, is pathologically elevated in patients with myelofibrosis and anemia. Chronic elevations in hepcidin limit iron availability for red cell production and contribute 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. A completed healthy volunteer study demonstrated dose-dependent reductions in serum hepcidin, increases in serum iron and increasing trends in reticulocyte count, reticulocyte hemoglobin, mean corpuscular hemoglobin, total hemoglobin (Hgb), and red blood cell count. 

The presentation at the EHA 2024 Congress showcased results from the Phase Ib trial of DISC-0974 in patients with myelofibrosis and anemia. DISC-0974 was administered subcutaneously monthly for a total of 6 doses. Primary endpoints include safety and tolerability of DISC-0974. Secondary endpoints include PK/PD markers of iron regulation and hematologic parameters.

The results demonstrated that DISC-0974 was well tolerated across all dose levels assessed. Treatment with DISC-0974 led to reduced hepcidin levels and increased serum iron, which were sustained for several weeks after each dose. 

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Key findings among participants receiving 28-100 mg included the following: 

• ≥1.5 g/dL increase in hemoglobin in 68.9% of non-transfusion-dependent (nTD) participants. 

• Among those who completed the study, 62.5% of nTD participants maintained a mean hemoglobin increase of ≥1.5 g/dL above baseline for at least 12 weeks.

• One of two evaluable transfusion-dependent participants transitioned to transfusion independence by the study's end.

• Hematologic responses were observed in 6 out of 10 participants receiving concurrent JAK inhibitor therapy.

• Participants with a baseline transfusion requirement experienced at least a 50% reduction in transfusions over an 8-week period compared to baseline.

Regarding safety, common adverse events reported in two or more subjects included fatigue, anemia, diarrhea, and nausea. Grade 3 adverse events included anemia in three patients and headache in one patient, all deemed unrelated to DISC-0974. One serious adverse event of worsening hip pain was reported, also assessed as unrelated to DISC-0974.

KOL insights

“We are thrilled to see this level of hematologic activity so early during dose escalation and in a range of patient types. This is the second program in the last six months where Disc has shown proof-of-concept data in patients, and we look forward to advancing DISC-0974 deeper into development and presenting updated data from this myelofibrosis study soon.” – MD, United States.

Conclusion 

JAK inhibitors have significantly transformed myelofibrosis treatment since the approval of JAKAFI in 2011. At present, JAKAFI stands as the undisputed champion in the realm of Myelofibrosis therapeutics, reigning supreme amidst its recently approved competitors. Although existing JAK inhibitors prescribed for myelofibrosis have demonstrated considerable clinical advantages by reducing symptoms and reducing spleen enlargement, they have not exhibited definitive disease-modifying effects, leading to most patients discontinuing the medication within one to two years. Owing to these reasons, the MPN community is keen on exploring potential alternative treatments beyond JAK inhibitors that could offer additional benefits

DISC-0974, a hepcidin suppressor demonstrated acceptable safety and tolerability at all evaluated dose levels. Elevated hepcidin is an important driver of anemia in patients with MF and these data suggest that DISC-0974 has leading activity in suppressing hepcidin. Anemia responses were achieved in nTD and TD participants, regardless of concomitant JAK inhibitor use. Sustained and substantial hepcidin reduction with DISC-0974 leads to increased serum iron that precedes anemia responses. DISC-0974 longer-term follow-up is ongoing in participants with MF and anemia with 34 participants enrolled as of this data cut. The final Phase Ib data is expected in the second half of 2024. The company also plans to initiate a Phase II study in the second half of 2024 and announce its topline results in 2025.

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