Bomedemstat Yields Spleen Reduction, Symptom Improvement in Advanced Myelofibrosis

Bomedemstat (IMG-7289), an oral irreversible inhibitor of lysine-specific demethylase 1 (LSD1), demonstrated a manageable safety profile and clinical activity in patients with advanced myelofibrosis, most of whom had received a prior JAK inhibitor, according to findings from a phase 1/2 study (NCT03136185) published in Blood Advances.¹

Among patients with spleen volume data at week 24 (n = 35), 66% had any reduction from baseline in spleen volume, and 26% had a reduction of at least 20%. Mean platelet and white blood cell (WBC) counts normalized over 24 weeks, hemoglobin levels remained stable, and most symptoms improved, including fatigue.

A numerical improvement in most key symptoms was observed, especially fatigue,” lead study author Harinder Gill, MD, of the Department of Medicine at the Li Ka Shing Faculty of Medicine, The University of Hong Kong, and colleagues wrote in the publication. “Most evaluable participants [83%] exhibited improvement or stability in bone marrow fibrosis score, which may be associated with the anti-inflammatory effect of LSD1 inhibition.”

In terms of safety, 87 of 90 patients (97%) in the all-safety population experienced at least 1 any-cause adverse effect (AE), and 69% experienced at least 1 grade 3 or higher AE; the most common AEs of any grade were thrombocytopenia (48%) and dysgeusia (36%).

What was the rationale for evaluating LSD1 inhibition in myelofibrosis?

Although JAK inhibitors such as ruxolitinib (Jakafi) represent standard treatment options for patients with myelofibrosis, a large proportion of patients develop resistance or intolerance, and complete molecular remissions are rare, underscoring a need for therapies that can improve symptoms and alter disease trajectory, particularly after JAK inhibitor failure.

LSD1, also known as KDM1A, is a histone demethylase essential for the terminal differentiation of megakaryocytes and neutrophils—2 cell types that, under constitutive JAK-STAT activation, stimulate the production of growth factors and inflammatory cytokines driving bone marrow pathology, clonal evolution, and symptomatology in myelofibrosis.^1,2 LSD1 also regulates the balance between proliferation and differentiation of hematopoietic stem and progenitor cells, suggesting that its inhibition may reduce the burden of mutant cells.

Bomedemstat is an irreversible LSD1 inhibitor that, in murine models of myeloproliferative neoplasms, normalized blood counts, reduced spleen volume, decreased bone marrow fibrosis, lowered mutant allele frequency, and improved survival.¹

How was the phase 1/2 study designed?

The open-label, multicenter, phase 1/2 study evaluated the safety, tolerability, and pharmacodynamics of once-daily oral bomedemstat in patients with primary myelofibrosis per World Health Organization criteria, or post–polycythemia vera or post–essential thrombocythemia myelofibrosis per International Working Group–Myeloproliferative Neoplasms Research and Treatment criteria. Eligible patients had disease that was refractory or resistant to, inadequately controlled by, or intolerant of approved therapy, or were not candidates for available therapy; had an ECOG performance status of 0 to 2, a baseline blast count of no more than 10%, and a baseline platelet count of at least 100 × 10⁹/L; and could have a spleen of any size.

Through protocol amendments, the starting dose of bomedemstat was increased from 0.25 mg/kg to 0.5 to 0.6 mg/kg once daily, with subsequent dose adjustment to a target platelet count of 50 × 10⁹/L to 75 × 10⁹/L over a 24-week course.

The primary objectives were safety and change in spleen volume; exploratory objectives included hematologic response, patient-reported symptom burden measured with the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score, bone marrow fibrosis grade, and the frequency of mutant alleles. Between July 18, 2017, and May 24, 2021, 89 participants were enrolled at 24 centers across Australia, Germany, Hong Kong, Italy, the United Kingdom, and the United States; the data cutoff was August 26, 2022.

The median age was 68 years (range, 35-88), 52% of patients were male, and 97% had an ECOG performance status of 0 or 1. Forty-six percent had primary myelofibrosis, 33% had post–essential thrombocythemia myelofibrosis, and 21% had post–polycythemia vera myelofibrosis. By International Prognostic Scoring System criteria, 53% were classified as high risk, 40% as intermediate-2, and 7% as intermediate-1. The median spleen volume at baseline was 1354 mL (range, 99-6819). JAK2 mutations were identified in 64% of participants, CALR mutations in 24%, and MPL mutations in 7%; 43% had additional high-molecular-risk mutations. Seventy-six percent had received prior ruxolitinib or fedratinib (Inrebic), and 47% had received prior hydroxyurea.

What additional data did the efficacy analysis show?

When considered across the modified safety population (n = 89), 26% had any spleen volume reduction, and 10% had a reduction of at least 20%.

Among 35 patients with baseline and week 24 bone marrow fibrosis data, 23% had an improvement of at least 1 grade, and 60% were stable, for a total of 83% with stable or improved fibrosis; 17% worsened. No patient’s disease progressed to acute myeloid leukemia.

Among 36 participants with JAK2, CALR, or MPL mutations and follow-up genetic data at week 24, 56% had a reduction in variant allele frequency, and no new somatic mutation was detected that was not already present at baseline.

What adverse effects (AEs) were reported with bomedemstat?

The median duration of treatment was 199.5 days (range, 25-882). The most frequently occurring AEs of any grade were thrombocytopenia (48%), dysgeusia (36%), anemia (33%), and nausea (30%); grade 3 to 5 thrombocytopenia occurred in 41% of patients. Bleeding events occurred in 16% of patients; 9% experienced both thrombocytopenia and a bleeding event.

Serious AEs were reported in 49% of patients, and 26% discontinued treatment due to AEs. Three patients (3%) experienced an AE that led to death, which comprised septic shock, cerebrovascular accident, and acute respiratory failure; none were deemed related to treatment. Treatment-related AEs were reported in 79% of patients, grade 3 to 5 treatment-related AEs in 56% of patients, and serious treatment-related AEs in 14% of patients.

Bomedemstat is under continued investigation, including phase 3 studies in essential thrombocythemia (NCT06456346; NCT06079879), a phase 2 extension study (NCT05223920), and a phase 2 study in combination with ruxolitinib for myelofibrosis (NCT05569538).

References

1. Gill H, Yacoub A, Gerds AT, et al. The lysine-specific demethylase 1 (LSD1) inhibitor bomedemstat in myelofibrosis: results from a phase 1/2 study. Blood Adv. 2026;10(13):4585-4594. doi:10.1182/bloodadvances.2025018141
2. Grimm J, Bhayadia R, Gack L, Heckl D, Klusmann JH. Combining LSD1 and JAK-STAT inhibition targets Down syndrome-associated myeloid leukemia at its core. Leukemia. 2022;36(7):1926-1930. doi:10.1038/s41375-022-01603-3