pelabresib (DAK539)

Ropeginterferon alfa-2b, a novel interferon-based therapy, demonstrated durable clinical efficacy in polycythemia vera...Combination regimens involving ruxolitinib and agents such as pelabresib, selinexor, and interferon showed potential for enhanced efficacy...Its early use and personalized strategies are increasingly recognized. Real-world data and regional insights are shaping a more nuanced, globally informed approach to MPN care.

P3, N=50, Recruiting, Novartis Pharmaceuticals | Trial completion date: Jun 2029 --> Jun 2027 | Trial primary completion date: Jun 2029 --> Jun 2027

P1/2, N=336, Completed, Constellation Pharmaceuticals | Active, not recruiting --> Completed

Co-treatment with SY-5609 and ruxolitinib was synergistically lethal in HEL, SET2 and PD post-MPN-sAML cells.  A CRISPR screen in SET2 and HEL cells revealed BRD4, CBP and p300 as co-dependencies with SY-5609 treatment. Accordingly, co-treatment with SY-5609 and the BETi OTX015 or pelabresib or with the CBP/p300 inhibitor GNE-049 was synergistically lethal in MPN-sAML cells (including those exhibiting TP53 loss). Finally, in the HEL-Luc/GFP xenograft model, compared to each agent alone, co-treatment with SY-5609 and OTX015 reduced post-MPN-sAML burden and improved survival without inducing host toxicity. These findings demonstrate promising preclinical activity of the CDK7i-based combinations with BETi or HATi against advanced-MPNs, including post-MPN-sAML.

P3, N=50, Recruiting, Constellation Pharmaceuticals | Not yet recruiting --> Recruiting | Trial completion date: Jun 2024 --> Jun 2029 | Trial primary completion date: Jun 2024 --> Jun 2029

P3, N=50, Not yet recruiting, Constellation Pharmaceuticals

P3, N=430, Active, not recruiting, Constellation Pharmaceuticals | Trial completion date: Dec 2026 --> Dec 2027

P3, N=430, Active, not recruiting, Constellation Pharmaceuticals | Trial completion date: Apr 2027 --> Dec 2026

P1, N=35, Completed, Constellation Pharmaceuticals | Active, not recruiting --> Completed | Trial completion date: Nov 2023 --> Feb 2024

P1/2, N=336, Active, not recruiting, Constellation Pharmaceuticals | Trial primary completion date: Dec 2023 --> Oct 2024

This review summarizes novel and promising treatments for anemia in myelofibrosis including transforming growth factor-β inhibitors luspatercept and KER-050, JAK inhibitors momelotinib, pacritinib, and jaktinib, BET inhibitors pelabresib and ABBV-744, antifibrotic PRM-151, BCL2/BCL-XL inhibitor navitoclax, and telomerase inhibitor imetelstat. Standard approaches to treat myelofibrosis-related anemia have limited efficacy and are associated with toxicity. New drugs have shown positive results in myelofibrosis-associated anemia when used alone or in combination.

Despite the current standard of care, the JAK1/2 inhibitor (JAKi) ruxolitinib (RUX), a significant unmet need remains for patients (pts) with MF, due to lack of response or JAKi resistance... JAK2V617F mutant cell lines HEL ( TP53M113K), UKE-1 ( TP53WT), MUTZ-8 ( TP53WT), and JAK2WT ELF-153 ( TP53I251N) cells were treated with SEL alone or in combination with RUX, pacritinib (PAC), momelotinib (MMB), pelabresib (PELA), or navitoclax (NAV)... In a panel of MPN-derived cells with or without JAK2V617F, SEL showed single-agent antiproliferative activity, and synergism with other MF therapeutics at clinically achievable concentrations through regulation of XPO1, JAK/STAT signaling, and apoptosis/senescence regulators. In addition to positive Phase 1 clinical data in pts with JAKi-naïve MF who received SEL with RUX, these preclinical data support synergistic activity between SEL and other MF therapies, suggesting the potential for SEL as a backbone for novel treatment combinations for MF.