POIESIS: A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Global Phase 3 Study of Navtemadlin As Add-on to Ruxolitinib in JAK Inhibitor-Naïve Patients with Myelofibrosis Who Have a Suboptimal Response to Ruxolitinib

Background: Most myelofibrosis (MF) patients treated with standard of care ruxolitinib (rux) fail to achieve an optimal response: spleen volume reduction of ≥35% (SVR35) and total symptom score reductions of ≥50% (TSS50) (Verstovsek 2012; Harrison 2012). Maximizing SVR and TSS is critical for patient care since improvements in quality of life is correlated with overall survival (OS) (Vannucchi 2015; Maffioli 2022; Mesa 2013). As such, novel approaches using combinations with rux are urgently needed to improve upon the suboptimal response to achieve better clinical outcomes for MF patients. MF is characterized by excessive production of mouse double minute 2 (MDM2), a key negative regulator of the tumor suppressor protein p53, in CD34+ progenitor cells. Navtemadlin is a potent, selective, orally available MDM2 inhibitor that restores p53 function. Preclinically, navtemadlin monotherapy drives apoptosis of TP53 wild-type (TP53WT) CD34+ MF cells through modulation of B cell lymphoma (BCL-2) family proteins, and when added to rux, synergistically increases apoptosis through the inhibition of p21-mediated cell-cycle arrest (Clevenger 2023). In the randomized, global, phase 3 study BOREAS, navtemadlin monotherapy showed clinically meaningful activity with disease-modifying potential in TP53WT MF patients who were R/R to JAKi treatment (publication pending). In a phase 1b/2 study in MF patients with a suboptimal response to rux, navtemadlin added to a stable dose of rux achieved an SVR35 and a TSS50 of 32% at Week 24, respectively (Mascarenhas 2023). In both settings (monotherapy and combination), navtemadlin demonstrated disease-modifying potential with marked reductions in bone marrow fibrosis, driver mutation allele burden, circulating CD34+ cell counts, and serum cytokine levels (Publication pending; Vachhani 2021, 2023; Mascarenhas 2023). Thus, the preclinical synergy of the combination with complementary mechanisms, robust clinical results from navtemadlin monotherapy and add-on studies, and the disease-modifying potential evidenced by prominent biomarker reductions, provide strong justification for the POIESIS study. Study Design/Methods: POIESIS (NCT06479135) isa registrational, randomized double-blind, placebo-controlled, global phase 3 study, evaluating the safety and efficacy of navtemadlin add-on vs placebo add-on to rux in JAKi-naïve MF pts who have a suboptimal response to rux. POIESIS has an innovative and unique design that aligns with MF treatment approaches adopted in routine clinical practice - treat, when necessary, with add-on therapy. The study comprises two treatment periods: the rux monotherapy (rux-mono) run-in period (~600 pts) followed by the randomized period (navtemadlin/placebo add-on to rux; N=180 pts). Eligibility criteria for the rux-mono period include: JAKi-treatment naïve pts aged ≥18 years with primary or secondary MF (WHO criteria); ECOG 0-2; intermediate- or high-risk MF per IPSS; spleen volume ≥450 cm3; TSS≥10 by MFSAF v4.0; platelets ≥100x109/L; white blood cells ≤50x109/L. After the rux-mono run-in period, spleen and TSS responders (optimal response) and rux refractory pts (primary refractory) will be discontinued from the study. Eligible TP53WT MF pts must be treated for ≥18 weeks on a stable dose of rux (≥5 mg BID) for ≥8 continuous weeks before randomization and must meet the protocol-defined suboptimal response criteria. Eligible pts will be randomized (2:1) to add-on navtemadlin (Arm 1; n=120) or add-on placebo (Arm 2; n=60). Arm 1 will receive navtemadlin 240 mg QD (Day 1-7/28-day cycle) added on to a stable dose of rux. Arm 2 will receive matching placebo added on to a stable dose of rux. During the randomized period, rux dose escalation above the stable dose of rux will not be permitted before the primary efficacy assessment. Pts will continue treatment until disease progression or unacceptable toxicity. Crossover between arms is not allowed, thus isolating navtemadlin's independent contribution to key secondary survival endpoints (leukemia-free survival, progression-free survival, and OS). Co-primary endpoints are the rates of SVR35 and TSS50 in Arm 1 vs 2, assessed 24 weeks after the start of the randomized period. Spleen imaging (MRI/CT) will be assessed by blinded central review and TSS will be assessed by MFSAF v4.0. This study is currently enrolling.