MANIFEST-3

Adults ≥18 with PMF or post-PV/ET MF (ICC 2022), DIPSS int-1 to high risk, JAKi-naive, spleen ≥450 cm3, TSS ≥15, platelets ≥100, ANC ≥1, blood blasts <5%, ECOG 0–2, adequate liver function.

1. Signed informed consent must be obtained prior to participation in the study. 2. Male or female participants are at least 18 years of age at the time of signing the informed consent form (ICF). 3. Participants have a diagnosis of primary myelofibrosis (PMF) or post-polycythemia vera MF or post-essential thrombocythemia MF (Post-PV/ET MF) according to the International Consensus Classification (ICC) of Myeloid Neoplasms and Acute Leukemias 2022. 4. DIPSS risk category of intermediate-1, intermediate-2 or high-risk. 5. Spleen volume ≥ 450 cm3 by MRI or CT scan (local read sufficient if no central read available). 6. Have an average TSS of ≥15 within 7 days during screening prior to randomization, using MFSAF v4.0 (at least 4 out of 7 TSS assessments required for average calculation). 7. Platelet count ≥ 100 × 10^9/L in the absence of growth factor support (including thrombopoietin mimetics/ agonists) or platelet transfusions for the previous 4 weeks. 8. Absolute neutrophil count (ANC) ≥ 1 × 10^9/L in the absence of growth factor support (including granulocyte colony stimulating factors (G-CSF)) or granulocyte transfusions for the previous 4 weeks. 9. Participants with adequate liver function as demonstrated by the following laboratory assessments: • Total bilirubin <2x upper limit of normal (ULN). In participants with Gilbert's syndrome: total bilirubin <3x ULN and direct bilirubin <2x ULN. Any elevated bilirubin should be asymptomatic at enrollment. • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <3× ULN. For participants with elevated ALT or AST at baseline the values must be stable for 2 weeks, without evidence of biliary obstruction by imaging. • Albumin ≥ 2.5 g/dL (25 g/L) 10. Participants with an ECOG performance status score of 0, 1, or 2. 11. Blasts <5% in peripheral blood. Assessment of blasts in peripheral blood is mandatory at screening.

Prior JAK or BET inhibitor, splenectomy or recent splenic RT, prior/planned HCT, blasts ≥5% or AP/leukemic transformation, active infection, other malignancy, significant cardiac/GI/renal disease, pregnancy.

1. Prior splenectomy at any time or splenic irradiation in the previous 6 months. 2. Prior hematopoietic cell transplant, or participant anticipated to receive a hematopoietic cell transplant within 24 weeks from the date of randomization. 3. Blasts ≥ 5% in bone marrow if results available at screening or history of accelerated phase or leukemic transformation. 4. Evidence of active Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection. Participants whose disease is controlled under antiviral therapy should not be excluded. Participants with current or previous positive serology [isolated anti-HBs antibody in IgG will usually signify prior vaccination] results must have negative polymerase chain reaction results. See Section 10.3 for details on Hepatitis testing. 5. Active serious infections of bacterial, fungal, parasitic, or viral origin. Tuberculosis risk assessment (evaluation of risk factors for tuberculosis) is required for all participants and appropriate testing for tuberculosis is to be performed in line with national guidance (e.g., in participants at higher risk, or in all participants if required per local regulations). Participants with latent tuberculosis infection can be considered for inclusion if they have received a full course of treatment prior to screening (e.g., short-course, rifamycin-based 3- or 4-month regimens, or isoniazid-based 6- or 9-month regimens for latent tuberculosis infection treatment) and have no evidence of active disease. 6. Known HIV infection not controlled by standard therapy and/or with known history of opportunistic infection. For countries where HIV status is mandatory (including the United Kingdom), HIV status will be tested during screening and the treatment period in accordance with local guidelines. Participants with HIV may only be enrolled if their antiretroviral therapy is permitted per protocol and all of the following conditions are met: HIV viral RNA is undetectable, immune function is adequate (including CD4 T-cell count ≥350 cells/ microliter), no history of an AIDS-defining opportunistic infection during the past 12 months, and participant has been on a stable retroviral regimen for at least 4 weeks prior to enrolment, with no planned changes. In participants with HIV, monitoring of viral load and CD4 T-cell count during the study is recommended per standard guidance. 7. History of a malignancy (other than MF, PV or ET) except for adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate-specific antigen for ≥ 1 year prior to randomization, adequately treated Stage 1 or 2 cancer currently in complete remission, or any other cancer that has been in complete remission for ≥ 3 years. 8. History or current diagnosis of ECG or other cardiac abnormalities indicating significant risk of safety for participants such as: • Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker • History of familial long QT syndrome or known family history of Torsades de Pointes 9. Participants who have a gastrointestinal tumor, impaired GI function or GI disease, or significant resection of stomach or other portion of the GI tract, that could significantly alter absorption, including any unresolved nausea, vomiting, or diarrhea. 10. Severely impaired renal function defined by: Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 using the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation 11. Any other severe and/ or uncontrolled condition including progressive multifocal leuko-encephalopathy (PML) which, in the opinion of the investigator, could compromise participation in the study or is likely to interfere with the successful collection of the measurements required for the study. 12. Received any approved or investigational agent for the treatment of MF within 14 days of first dose of study treatment or within 5 half-lives of the approved or investigational agent, whichever is longer. NOTE: Hydroxyurea and anagrelide are permitted up to 24 hours prior to start of study treatment. 13. Had prior treatment with any JAK inhibitor or BET inhibitor. 14. Had systemic anti-cancer treatment, with the exception of hormonal therapy, less than 14 days (or 5 half-lives, whichever is longer) before the first dose of study treatment. NOTE: Hydroxyurea and anagrelide are permitted up to 24 hours prior to start of study treatment. 15. Had hematopoietic growth factor (myeloid growth factors, erythropoiesis stimulating agents, thrombopoietin mimetics/ agonists), erythroid maturation agents, or androgenic steroids less than 4 weeks before the first dose of study treatment. 16. Require immunosuppressive agents with systemic activity or systemic corticosteroids of >10 mg QD prednisolone or equivalent within 4 weeks before the first dose of study treatment. Participants who received topical, nasal, intra-articular, inhaled, and other forms of corticosteroids without systemic activity are eligible. 17. Participants who require treatment with moderate or strong CYP3A inducers or strong CYP3A inhibitors that cannot be stopped for 14 days prior to starting study treatment and for the duration of treatment. 18. Participants who require treatment with fluconazole doses greater than 200 mg daily. 19. Had live vaccination within 30 days prior to the first dose of study treatment. 20. Contraindication or hypersensitivity to any drug or metabolites from similar class as study treatment or to any excipients of the study treatment formulation. 21. Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant from menarche until becoming post-menopausal, unless they have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or bilateral salpingectomy at least six weeks before taking study treatment. In the case of oophorectomy alone, the reproductive status of the woman needs to have been confirmed by follow-up hormone level assessment. Women are considered post-menopausal if they have had 12 months of natural (spontaneous) amenorrhea without an alternative medical cause. WOCBP are excluded unless they are using highly effective methods of contraception (failure rate < 1% per year) while taking study treatment and for at least 184 days (which comprises relevant systemic exposure [5 half-lives; 4 days] plus a minimum of 1 folliculogenesis cycle [180 days]) after the last dose of study treatment. In addition, female participants must not donate eggs for the time period specified above. Highly effective contraception methods include: • Total abstinence (when this is in line with the preferred and usual lifestyle of the participant). Note that periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. • Bilateral tubal occlusion, bilateral tubal ligation (at least six weeks before taking study treatment). • Sterilization (vasectomy) of male partner(s) of the female participant at least 6 months prior to screening provided partner(s) has(have) received medical confirmation of surgical success. • Use of hormonal contraception methods: - Combined (estrogen and progestogen containing) hormonal contraception* associated with inhibition of ovulation; oral, intravaginal or transdermal. - Progestogen-only hormonal contraception* (associated with inhibition of ovulation): oral, injectable or implantable. - Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) *Pelabresib has the potential to reduce the exposure and possible the efficacy of hormonal contraceptives. An alternative contraceptive that is not affected by enzyme inducers (e.g., IUD, IUS) or additional nonhormonal contraception (barrier method, preferably male condom) must be used. If local regulations are more stringent than the contraception methods listed above, local regulations apply and will be described in the ICF. 22. Sexually active males unwilling to use a condom during intercourse while taking study treatment and for at least 94 days (which comprises relevant systemic exposure [5 half-lives; 4 days] plus a minimum of 1 sperm cycle [90 days]) after the last dose of study treatment. A condom is required for all sexually active male participants to prevent them from fathering a child AND/OR to prevent delivery of study treatment via seminal fluid to their partner. In addition, male participants must not donate sperm for the time period specified above. 23. Pregnant or nursing (breastfeeding) females. 24. Participants who are unwilling or unable to comply with this study protocol or study requirements.