This is an open-label, single-arm, Phase 2 interventional study designed to evaluate the safety and efficacy of Bomedemstat (IMG-7289) when added to Momelotinib in patients with Myelofibrosis (MF) who exhibit a suboptimal response to Momelotinib alone or who present with baseline cytopenias and do not achieve adequate improvement after 12 weeks of Momelotinib monotherapy.

The study consists of three phases:

1. Screening Phase (up to 28 days)
2. Momelotinib Monotherapy Phase - Weeks 0-12
3. Combination Treatment Phase (Momelotinib + Bomedemstat) - Weeks 12-24
4. Post-Treatment Follow-up Phase (30 days post last dose + long-term survival follow-up) All patients will continue on Momelotinib throughout the study unless toxicity or safety considerations necessitate modification.

Myelofibrosis is a disease with heterogeneous driver pathways involving JAK-STAT activation, inflammatory cytokine signaling, and aberrant megakaryopoiesis. Momelotinib targets JAK1/JAK2 and ACVR1, improving anemia and splenomegaly. However, a proportion of patients fail to achieve adequate spleen, symptom, or hematologic improvement.

Bomedemstat, an irreversible LSD1 inhibitor, may:

• Modify megakaryocyte function
• Reduce fibrosis
• Improve cytokine dysregulation
• Impact stem/progenitor dynamics Sequential introduction of Bomedemstat at Week 12 allows assessment of Momelotinib's initial stabilizing effect and evaluates whether LSD1 inhibition can rescue suboptimal responders without compromising hematologic tolerability.

STUDY DURATION

• Screening: Up to 28 days
• Momelotinib monotherapy: Weeks 0-12
• Bomedemstat + Momelotinib combination: Weeks 12-24
• Primary endpoint assessment: Week 24
• Safety follow-up: 30 days post last dose
• Long-term follow-up: Every 12 weeks for up to 12 months Total participation duration per patient: Approximately 14-16 months

NUMBER OF PARTICIPANTS Approximately 40 participants will be enrolled across multiple international sites. This sample size provides adequate precision for estimation of the primary endpoint (SVR35) and is consistent with exploratory Phase 2 combination studies.

INVESTIGATIONAL PLAN OVERVIEW

1. Screening Procedures

   o Informed consent

   o Medical history, physical exam

   • Hematology, chemistry, thyroid function
   • Bone marrow biopsy (if unavailable within 6 months)
   • Spleen volume imaging (MRI or CT)
   • MPN-SAF Total Symptom Score
   • ECG, urinalysis
   • Eligibility confirmation

2. Intervention Procedures Weeks 0-12

   o Momelotinib 200 mg QD alone

   o Hematologic monitoring

   • Week 12 response assessment Weeks 12-24
   • Bomedemstat 50 mg QD added
   • Titration per MF-specific rules (standard tables retained verbatim)
   • Weekly CBCs during first 4 weeks of combination
   • MRI/CT at Week 24

3. Follow-Up Procedures o 30-day safety follow-up

   o Every 12-week long-term survival and disease progression follow-up

   STUDY SCHEMA (REQUIRED BY THE FIRST FILE) Screening (≤ 28 days)

   ↓ Momelotinib Alone (Weeks 0-12)

   • Week 12 Response Assessment If Suboptimal → Add Bomedemstat 50 mg QD

   Combination Phase (Weeks 12-24) ↓ Week 24 Primary Endpoint Assessment ↓ Safety Follow-Up (30 days post last dose)

   ↓ Long-Term Follow-Up (q12 weeks for 12 months)

Inclusion Criteria:

• 1. Male or female participants ≥18 years of age on the day of signing informed consent.

  2. Histologically confirmed diagnosis of:

  • Primary Myelofibrosis (PMF), or
  • Secondary MF following Polycythaemia Vera (post-PV MF), or
  • Secondary MF following Essential Thrombocythaemia (post-ET MF) (as defined by WHO 2022 criteria) 3. Disease risk category:
  • Intermediate-2 or High-risk MF according to DIPSS. 4. Cohort assignment (Investigator-defined; permitted insertion):

Cohort 1 - Momelotinib-Experienced:

• Receiving Momelotinib 200 mg QD for ≥12 weeks prior to Week 12 assessment
• Demonstrates suboptimal response at Week 12 (definition below)

Cohort 2 - Cytopenic MF:

• Baseline Hb <10 g/dL and/or platelets <100 × 10⁹/L
• Starting Momelotinib at Week 0
• Demonstrates suboptimal response at Week 12

Exclusion Criteria:

5.2.1 Medical Conditions

• Known hypersensitivity to Bomedemstat or MAOIs
• Clinically significant GI conditions affecting absorption
• Increased bleeding risk
• Hereditary bleeding disorders
• Active or chronic bleeding within 8 weeks
• Autoimmune bleeding disorders
• Uncontrolled comorbidities
• Active secondary malignancies (with exceptions)
• HBV/HCV/HIV status not meeting template criteria
• Receipt of prohibited medications within 14 days (All text unchanged.)

5.2.2 Prohibited Prior Therapies

• Prior treatment with Bomedemstat or other LSD1 inhibitors
• MAOIs or strong CYP3A4 modifiers
• All hematopoietic growth factors (G-CSF, GM-CSF, EPO, TPO mimetics)
• Investigational treatments within 4 weeks

Investigator addition permitted:

• Prior treatment with Momelotinib is allowed for Cohort 1 (required)
• Prior treatment with Momelotinib is allowed for Cohort 2 (not required)
• Prior exposure to other JAK inhibitors (e.g., ruxolitinib, fedratinib) is allowed unless associated with severe toxicity

5.2.3 Prohibited During Study (Verbatim text from first file retained)

• MAOIs
• Strong inhibitors/inducers of CYP3A4
• Anticoagulants/antiplatelets/NSAIDs when platelets <100 ×10⁹/L

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