‣ Cohort A:

‣ 1\. Patients refractory to, relapsed or intolerant of ruxolitinib as per one of the below:

• Refractory is defined as \<30% reduction in spleen length or \<10% SVR compared to baseline having received ruxolitinib for ≥12 weeks prior to enrollment, AND on a stable dose for ≥8 weeks prior to starting investigational therapy

• Relapsed is defined as an increase in spleen volume of ≥25% by MRI/CT from nadir, or, ≥100% in palpable spleen length from a baseline of 5 to 10 cm BLCM or, ≥50% increase in spleen length from a baseline spleen length ≥10 cm BLCM

• Intolerance is defined as the development in patients treated with ruxolitinib for ≥28 days of:

‣ Red blood cell transfusion requirement of 2 units/month for 2 months

⁃ Grade 3 thrombocytopenia, anemia, hematoma, and/or hemorrhage while on ruxolitinib treatment

‣ Cohort B:

⁃ Patients who are JAK inhibitor naïve, AND:

∙ Require MF-directed treatment, AND

‣ Have measurable disease burden including one of the following:

⁃ Disease-related symptoms, determined by a MFSAF or MPN-SAF TSS of ≥10, or at least 2 symptoms with scores ≥3

• Documented splenomegaly by physical exam, with spleen palpated ≥5 cm below the left costal margin

⁃ Both Cohorts A and B:

⁃ Willing and able to provide informed consent

⁃ Age ≥18 years

⁃ Diagnosis of Overt Myelofibrosis (primary, post-ET, or post-PV) per World Health Organization (WHO) diagnostic criteria

⁃ Intermediate-1, Intermediate-2, or high-risk disease by Dynamic International Prognostic Scoring System (DIPSS)

⁃ Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

⁃ Platelet count ≥100 x 10\^9/L prior to dosing on Cycle 1 Day 1

⁃ Absolute neutrophil count ≥0.5 x 10\^9/L prior to dosing on Cycle 1 Day 1

⁃ Peripheral blast count ≤10% prior to dosing on Cycle 1 Day 1

‣ Able to swallow capsules

‣ Women of childbearing potential and fertile men must agree to use an approved method of contraception from Screening until 30 days after the last dose of bomedemstat and ruxolitinib.