Phase 3 Randomized Double‑Blind Study of Pelabresib (DAK539) Plus Ruxolitinib vs Placebo + Ruxolitinib in JAK‑Inhibitor‑Naive Adults with Myelofibrosis

The primary objective is to evaluate the efficacy of the combination of pelabresib and ruxolitinib versus placebo plus ruxolitinib in reducing spleen volume and improving symptoms at Week 24 in Janus kinase inhibitor‑naive patients with myelofibrosis, assessed in the overall population (Total Symptom Score ≥15) and in the high‑symptom burden subgroup (Total Symptom Score ≥25). Secondary objectives include:

• Assessment of spleen volume reduction with the investigational regimen compared with control.
• Evaluation of improvement in symptoms with the investigational regimen compared with control.
• Determination of a concurrent dual response (spleen volume reduction and symptom improvement) over time.
• Investigation of the effect on hemoglobin levels and incidence of anemia.
• Evaluation of overall survival outcomes.
• Evaluation of progression‑free survival.
• Evaluation of leukemia‑free survival.
• Assessment of the incidence of leukemic transformation.
• Characterization of safety and tolerability of the combination therapy.
• Characterization of the pharmacokinetics of pelabresib when administered with ruxolitinib.
• Evaluation of the pharmacokinetic profile in participants enrolled in China and Japan.
• Assessment of the impact on patient‑reported fatigue and quality of life over time.

The trial enrolled 288 participants diagnosed with myelofibrosis, including primary myelofibrosis, post‑polycythemia vera myelofibrosis, and post‑essential thrombocythemia myelofibrosis as defined by the 2022 International Consensus Classification. Both male and female adults falling within the age categories denoted by codes 3 and 4 were eligible. Enrollment required an intermediate‑1, intermediate‑2, or high‑risk DIPSS classification, spleen volume of at least 450 cm³ by imaging, and an average total symptom score (TSS) of ≥15 measured within 7 days before randomization. Additional criteria included an ECOG performance status of 0–2, peripheral blood blasts <5%, and platelet count ≥100 × 10⁹/L without recent growth‑factor support or transfusion. Participants were selected based on these clinical and laboratory parameters and were subsequently randomized to receive either pelabresib plus ruxolitinib or placebo plus ruxolitinib.

The study is a Phase 3, randomized (1:1), double‑blind, active‑control trial evaluating oral pelabresib 175 mg plus ruxolitinib versus placebo plus ruxolitinib in adult patients with Myelofibrosis who are JAK‑inhibitor naive; the overall protocol spans from the projected recruitment start on 15 August 2026 to an estimated completion date of 29 November 2030, with each participant remaining in the trial for approximately 48 weeks of treatment and follow‑up. After informed consent, a screening visit is performed to confirm eligibility criteria, including spleen volume ≥ 450 cm³, total symptom score (TSS) ≥ 15, DIPSS risk category, ECOG status 0‑2, peripheral blood blasts < 5 % and platelet count ≥ 100 × 10⁹/L; eligible subjects then proceed to a baseline/randomization visit (Day 0) where study medication is assigned and the first dose administered. Subsequent study visits occur at weeks 2, 4, 8, 12, 24, 36, and 48, during which safety laboratory tests, adverse‑event monitoring, drug dispensation, compliance checks, and efficacy assessments (MRI/CT for spleen volume and MFSAF‑v4.0 for TSS) are conducted; imaging for spleen response is scheduled at weeks 12, 24, 36 and 48, and the final end‑of‑study visit at week 48 includes comprehensive safety and efficacy evaluations. Participants may be withdrawn early for predefined reasons such as grade ≥ 3 drug‑related toxicity, disease progression, failure to meet visit compliance, withdrawal of consent, or investigator discretion, and any early termination is documented with appropriate safety follow‑up.

The investigational product is DAK539, an oral tablet containing pelabresib monohydrate. Each tablet delivers 175 mg of the active substance. The tablet is administered by mouth once daily throughout the treatment period.

Participants assigned to the control arm receive a matching oral tablet that contains no active ingredient. This placebo is taken once daily in the same manner as DAK539 to maintain blinding.

All participants receive background therapy with ruxolitinib, supplied as Jakavi tablets of 5 mg, 10 mg, 15 mg, or 20 mg strength. The total daily dose is 25 mg, administered orally. Tablet strengths are combined as needed to achieve the target dose and are taken once daily.

Drug administration occurs each day in the morning with water. Dosing adjustments for ruxolitinib are permitted based on tolerability, using the available tablet strengths. Compliance is monitored by pill counts at each study visit and by participant‑maintained dosing diaries.

Efficacy will be evaluated using both anatomical and patient‑reported endpoints. The primary co‑endpoints are a ≥35% reduction in spleen volume reduction (SVR35) from baseline to Week 24, measured by MRI (or CT) with central radiology review, and the absolute change in total symptom score (TSS) at Week 24, assessed with the Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0).

Secondary efficacy assessments include spleen response (SVR35) at Weeks 12, 36, 48 and thereafter; time to first SVR35 response; duration of SVR35 response; symptom response defined as ≥50% reduction in TSS (TSS50) at the same time points; time to first TSS50 response; duration of TSS50 response; dual response (both SVR35 and TSS50); hemoglobin response (≥1.5 g/dL increase in mean 12‑week hemoglobin); overall survival, progression‑free survival, and leukemia‑free survival; and patient‑reported outcomes such as fatigue (PROMIS SF v1.0 Fatigue 7a) and overall quality of life (EORTC QLQ‑C30).

Imaging assessments will be performed at baseline and at each scheduled visit (Weeks 12, 24, 36, 48, and subsequent visits) using standardized MRI or CT protocols, with images interpreted by a central radiology reading center. Symptom scores will be collected via electronic case report forms employing the validated MFSAF v4.0 questionnaire at the same time points. Laboratory measurements for hemoglobin and other hematologic parameters will be obtained at each visit, and plasma concentrations of pelabresib will be sampled at predefined pharmacokinetic time points to derive Cmax, Tmax, and AUCτ. All efficacy data will be analyzed using appropriate statistical models to compare the pelabresib + ruxolitinib arm with the placebo + ruxolitinib control.