pelabresib (DAK539) / Novartis - LARVOL DELTA

Comparative Efficacy of Drug Therapies on Spleen Size and Symptom Reduction in Myelofibrosis: A Frequentist Network Meta-Analysis (SOHO 2026) - "Single-agent JAKis demonstrated variable efficacy similar to or worse than that of ruxolitinib, with an OR of 0.88 (95%CI:0.58–1.34) for momelotinib, 0.52 (95% CI, 0.05–6.05) for fedratinib, 0.35 (95% CI, 0.04–3.20) for bezacitinib, 0.17 (95% CI, 0.02–1.41) for jaktinib, and 0.16 (95% CI, 0.02–1.52) for pacritinib...Compared with BAT, pacritinib showed an OR of 3.43 (95% CI, 0.39–29.76), navtemadlin 3.26 (95% CI, 0.92–11.53), and momelotinib 3.10 (95% CI, 1.13–8.53)... In JAKi-naïve myelofibrosis, combination strategies with navitoclax or pelabresib added to ruxolitinib demonstrated the greatest spleen responses. Ruxolitinib remains similar or superior to single-agent JAKis in spleen or symptom response. In ruxolitinib-exposed patients with myelofibrosis, fedratinib, momelotinib, and pacritinib showed clinically meaningful activity compared with BAT, and fedratinib was numerically better than others."

Retrospective data • Myelofibrosis • Oncology

Pre-Clinical Efficacy of CDK7 Inhibitor-Based Combinations in Cellular Models of Advanced Myeloproliferative Neoplasms (MPN) Transformed to AML (ASH 2023) - "Treatment with JAK inhibitor (JAKi), e.g., ruxolitinib, venetoclax or hypomethylating agents alone or in combination are ineffective in improving the poor survival in MPN-sAML...Present studies demonstrate that treatment with ATP-competitive, covalent CDK7 inhibitors (CDK7i) SY-1365, and clinical grade SY-5609, dose-dependently (20 to 250 nM) increased % G1 while reducing the % of cell-cycle S phase SET2 and HEL cells...SY-5609 treatment also exerted synergistic lethality with the BETi pelabresib or BD2-selective BETi ABBV-744 or the CBP/p300 inhibitor GNE-049 in MPN-sAML cells...Additionally, compared to each drug or vehicle control, co-treatment with SY-5609 and OTX015 (30 mg/kg/day by oral gavage) reduced more MPN-sAML burden and significantly improved survival in a HEL-Luc/GFP xenograft model without inducing toxicity. These findings demonstrate promising preclinical activity of CDK7 inhibition against the cellular models of MPN-sAML, supporting the rationale to..."

Metastases • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myeloproliferative Neoplasm • Oncology • ASXL1 • AURKA • BCL2L1 • BRD4 • CALR • CASP9 • CCND1 • CD123 • CD34 • CD99 • CDK1 • CDK4 • CDK6 • CDK9 • CDKN1A • CLEC12A • HEXIM1 • IL3RA • ITGAM • JAK2 • MCL1 • MYC • PIM1 • PLK1 • RUNX1 • SRSF2 • STAT5 • TET2 • TGFB1

PELABRESIB IN COMBINATION WITH RUXOLITINIB FOR JANUS KINASE INHIBITOR-NAIVE PATIENTS WITH MYELOFIBROSIS: 72-WEEK FOLLOW-UP WITH LONG-TERM EFFICACY OUTCOMES OF THE PHASE III MANIFEST-2 STUDY (EHA 2025) - P3 | "PELA+RUX showed sustained improvements over 72 weeks in splenic response, symptoms, SVR35/TSS50 dual response, BMF, and anemia vs PBO+RUX. The safety profile for Grade ≥3 TEAEs was similar and consistent across treatment arms, with the imbalance in leukemic transformation cases decreasing over time. Survival outcomes show a trend in favor of the PELA+RUX arm."

Clinical • Combination therapy • P3 data • Anemia • Fibrosis • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Myelofibrosis • Oncology • Thrombocytopenia

Preclinical Studies Demonstrating Efficacy of Tasquinimod in Models of Advanced Myeloproliferative Neoplasm (MPN) in Blastic Phase (ASH 2023) - "Additionally, our findings showed that co-treatment with TM (5 to 30 µM) and ruxolitinib (250 to 1000 nM), BET inhibitor OTX015 (50 to 250 nM) or pelabresib (CPI-0610) (100 to 500 nM), or BCL2/Bcl-xL inhibitor navitoclax induced synergistic lethality in advanced MPN-BP cells exhibiting delta synergy scores of >1.0 (by the ZIP method). In a separate experiment on the same PDX model, treatment with TM (30 mg/kg/day) also induced significantly greater survival advantage than treatment with ruxolitinib (30 mg/kg/day) or OTX015 (30 mg/kg/day) by oral gavage. These findings clearly demonstrate preclinical efficacy of TM in advanced MPN-BP cellular models and create the rationale to further interrogate the efficacy of TM alone and in combinations with current, front-line therapies for advanced MPN with excess blasts."

IO biomarker • Metastases • Preclinical • Fibrosis • Immunology • Inflammation • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • BCL2 • BCL2L1 • CALR • CCND1 • CD123 • CD33 • CD34 • CD99 • CDK6 • CDKN1A • CLEC12A • CXCR4 • IL3RA • IL6 • ITGAM • JAK2 • MPO • MYC • NLRP3 • S100A8 • S100A9 • TERT • TLR4 • TNFA

SAFETY AND EFFICACY OF PELABRESIB IN COMBINATION WITH RUXOLITINIB FOR JAK INHIBITOR TREATMENT-NAÏVE PATIENTS WITH MYELOFIBROSIS: LATEST DATA FROM THE PHASE 3 MANIFEST-2 STUDY (EHA 2024) - P3 | "PELA+RUX resulted in a significant and durable spleen response, with a trend toward reduced TSS, and improved anemia and BMF at Wk 24 vs PBO+RUX in JAKi-naïve pts with MF, addressing all 4 hallmarks of MF.Results support a potential paradigm shift to combination therapy with PELA+RUX for pts with MF. The development of pelabresib was funded in part by the Leukemia and Lymphoma Society. CH and JM contributed equally."

Clinical • Combination therapy • P3 data • Anemia • Fibrosis • Hematological Disorders • Immunology • Leukemia • Lymphoma • Myelofibrosis • Thrombocytopenia

Study of Pelabresib add-on to Ruxolitinib in Japanese Adult Patients With Myelofibrosis (clinicaltrials.gov) - P1 | N=3 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Active, not recruiting | Trial primary completion date: Nov 2026 ➔ Jul 2026

Enrollment closed • Trial primary completion date • Hematological Disorders • Myelofibrosis • Myeloproliferative Neoplasm • Thrombocytosis

BET INHIBITOR PELABRESIB (CPI-0610) COMBINED WITH RUXOLITINIB IN PATIENTS WITH MYELOFIBROSIS — JAK INHIBITOR-NAÏVE OR WITH SUBOPTIMAL RESPONSE TO RUXOLITINIB — PRELIMINARY DATA FROM THE MANIFEST STUDY (EHA 2022) - P1/2, P3 | "Conclusion Based on these interim Phase 2 data, pelabresib in combination with RUX, in both RUX treatment-naïve and -experienced pts with MF, resulted in splenic and symptom responses and BM fibrosis improvement, and appeared to be well tolerated. Based on data from MANIFEST Arm 3, the randomized, double-blind, active-control Phase 3 MANIFEST-2 study was initiated to further evaluate the safety and efficacy of pelabresib in combination with ruxolitinib in JAKi treatment-naïve pts with MF (NCT04603495)."

Clinical • IO biomarker • Anemia • Gastrointestinal Disorder • Hematological Disorders • Immunology • Infectious Disease • Myelofibrosis • Respiratory Diseases • Thrombocytopenia • BCL2

Pelabresib (CPI-0610) Combined with Ruxolitinib for JAK Inhibitor Treatment-Naïve Patients with Myelofibrosis: Durability of Response and Safety Beyond Week 24 (ASH 2022) - P1/2, P3 | "The combination of PELA and RUX in JAKi-naïve pts with MF showed durable improvements in spleen volume, total symptom score and BM fibrosis, and was generally well tolerated. The randomized, double-blind, active-controlled Phase 3 MANIFEST-2 study is open for enrollment and evaluating the safety and efficacy of PELA in combination with RUX in JAKi treatment-naïve pts with MF (NCT04603495)."

Clinical • IO biomarker • Anemia • Hematological Disorders • Immunology • Infectious Disease • Musculoskeletal Diseases • Myelofibrosis • Orthopedics • Respiratory Diseases • Thrombocytopenia • BCL2

Identifying novel ’druggable’ targets via Npm1A-turboid fusion and mass spectrometry to overcome genetic or adaptive resistance to menin inhibitors in mtNPM1 AML (ASH 2025) - "Treatment with revumenib may also cause emergenceof hot spot mutations in menin (e.g., S160T, M327V, M327I, G331D, G331R, and T349M) exhibitingreduced affinity to MI-binding...OCI-AML3 MEN1-M327I cells were resistant toSNDX-50469, ziftomenib, and DS1594b, but sensitive to the second-generation MI, bleximenib, aspreviously reported.To identify novel 'druggable' targets in mtNpm1 AML cells either sensitive or resistant to MI, we knockedin TurboID by CRISPR/Cas9 into the C-terminus of the mtNpm1 gene in OCI-AML3 cells...When combined with a BET inhibitor (pelabresib) ora novel dual BET/HAT inhibitor (NEO2734/EP31670), both RocA and talazoparib induced synergisticlethality in the sensitive OCI-AML3 and OCI-AML2-Npm1A KI, as well as the MI-resistant (OCI-AML3-Menin-M327I or the OCI-AML3 MITR) cells...Exvivo treatment with EP31670 and RocA or talazoparib induced synergistic loss of viability in MI (SNDX-50469)-resistant, patient-derived (N = 3) mtNpm1 AML cells. In the..."

IO biomarker • Acute Myelogenous Leukemia • AURKA • CDK9 • CDKN1A • EIF4A1 • EIF4A2 • FLT3 • HOXA9 • IL7R • IRAK4 • KMT2A • MEIS1 • MEN1 • MYC • NPM1 • PLK1 • S100A8 • SF3B1 • SMARCA2 • TP53

Updated safety and efficacy data from the phase 3 MANIFEST-2 study of pelabresib in combination with ruxolitinib for JAK inhibitor treatment-naïve patients with myelofibrosis. (ASCO 2024) - P3 | "PELA+RUX significantly and durably reduced splenomegaly, with a trend toward reduced TSS, and improved anemia and BMF at Wk 24 compared with PBO+RUX in JAKi treatment-naïve pts with MF, addressing key hallmarks of MF. Resultssupport a potential paradigm shift to combination therapy for MF. CH and JM contributed equally."

Clinical • Combination therapy • P3 data • Anemia • Fibrosis • Hematological Disorders • Immunology • Leukemia • Lymphoma • Myelofibrosis • Thrombocytopenia

Trial in Progress: A Phase 3, Randomized, Double-Blind, Active-Control Study of Pelabresib (DAK539) Plus Ruxolitinib vs Placebo Plus Ruxolitinib in JAK Inhibitor-Naïve Adult Patients With Myelofibrosis (MANIFEST-3) (SOHO 2026) - P3 | "MANIFEST-3 will build on the positive findings of MANIFEST-2 (NCT04603495) by evaluating efficacy and safety of PELA+RUX vs PBO+RUX in the broad population, including patients with higher symptom burden. This population may benefit more from PELA+RUX than RUX alone, aiming to address disease biology and achieve deeper, more durable spleen responses. AE: adverse event, ePROs: electronic patient-reported outcomes, MFSAF: Myelofibrosis Symptom Assessment Form, NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells, OS: overall survival, PFS: progression-free survival, QoL: quality of life."

Clinical • P3 data • Essential Thrombocythemia • Hematological Malignancies • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera

MANIFEST: Pelabresib in Combination With Ruxolitinib for Janus Kinase Inhibitor Treatment-Naïve Myelofibrosis. (PubMed, J Clin Oncol) - P1/2 | "The rational combination of the BETi pelabresib and ruxolitinib in JAKi-naïve patients with myelofibrosis was well tolerated and showed durable improvements in spleen and symptom burden, with associated biomarker findings of potential disease-modifying activity."

Combination therapy • Journal • Myelofibrosis

Durable efficacy and long-term safety with pelabresib plus ruxolitinib in JAK Inhibitor–Naive myelofibrosis: 96-week Results from the Phase III MANIFEST-2 study (ASH 2025) - P3 | "Longer-term follow-up showed numerically fewer deathsand fewer progression events in the PELA+RUX arm vs the PBO+RUX arm. Overall findings suggest thatPELA+RUX provides clinically meaningful benefits vs RUX monotherapy, with potential for diseasemodification and improving survival in pts with MF."

Clinical • P3 data • Hematological Disorders • Myelofibrosis

Evaluation of the Lethal Activity and Its Mechanism of Tasquinimod in Advanced Myeloproliferative Neoplasm (MPN) in Blastic Phase (ASH 2024) - "Importantly, cotreatment with TQ (5 to 30 µM) and ruxolitinib (250 to 1000 nM), BET inhibitor OTX015 (50 to 250 nM) or pelabresib (CPI-0610) (100 to 500 nM), or BCL2/Bcl-xL inhibitor navitoclax, induced synergistic lethality in advanced MPN-BP cells, represented by delta synergy scores of >1.0 (by the ZIP method)...Co-treatment with TQ and RGFP966 (HDAC3i) induced synergistic lethality in post-MPN sAML cells...These findings demonstrate the pre-clinical efficacy of TQ and/or JAKi or BETi or with novel agents identified here in advanced MPN and MPN-AML cells. They also create the rationale to further interrogate the pre-clinical efficacy of the TQ-based combinations against cellular models of advanced MPN."

IO biomarker • Metastases • Fibrosis • Hematological Malignancies • Immunology • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • BCL2 • BCL2L1 • CALR • CCL2 • CCND1 • CD123 • CD33 • CD34 • CD99 • CDK6 • CDKN1A • CLEC12A • CXCL12 • CXCL8 • CXCR4 • HDAC3 • IL1A • IL3RA • IL6 • ITGAM • JAK2 • MPO • MYC • NLRP3 • NSD2 • S100A8 • S100A9 • TERT • TLR4 • TNFA • TP53

Closing the disease modification gap: Emerging therapies in myelofibrosis beyond JAK inhibition. (PubMed, Semin Hematol) - "We discuss BET inhibitors (pelabresib), PIM kinase inhibitors (TP-3654), telomerase inhibition (imetelstat), nuclear export inhibition (selinexor), LSD1 inhibition (bomedemstat), MDM2 antagonism (navtemadlin), mutant CALR-directed immunotherapies, and activin receptor ligand traps (elritercept). Strategies such as high-molecular-risk mutation profiling and variant allele frequency monitoring to assess disease progression and clonal burden will also be discussed. As the focus of MPN management shifts towards curative nontransplant options, a combination of improved access to clinical trials and accounting for patient-reported outcomes will be vital if we are to realize the promise of these next-generation therapies."

IO biomarker • Journal • Fibrosis • Hematological Disorders • Immunology • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Transplantation • CALR

Pelabresib in Combination with Ruxolitinib for Janus Kinase Inhibitor Treatment-Naïve Patients with Myelofibrosis: Results of the MANIFEST-2 Randomized, Double-Blind, Phase 3 Study (ASH 2023) - P1/2, P3 | "As DIPSS Int-1 pts have been excluded or underrepresented in prior randomized trials in MF, MANIFEST-2 will also provide important insights in assessing the benefits of starting treatment at an earlier stage of the disease. Primary results from the pivotal Phase 3 MANIFEST-2 trial of pela and rux versus placebo and rux in JAKi treatment-naïve pts may have the potential to influence the MF treatment paradigm and will be presented at the ASH Annual Meeting 2023."

Clinical • Combination therapy • P3 data • Anemia • Fibrosis • Hematological Disorders • Immunology • Myelofibrosis • Myeloproliferative Neoplasm • Thrombocytosis

PELABRESIB (CPI-0610) MONOTHERAPY IN PATIENTS WITH HIGH-RISK ESSENTIAL THROMBOCYTHEMIA REFRACTORY OR INTOLERANT TO HYDROXYUREA: PRELIMINARY RESULTS FROM MANIFEST STUDY (EHA 2023) - P1/2 | "Preliminary results from Arm 4 of the MANIFEST study suggest potential clinical benefit with PELA monotherapy in pts with HR ET refractory or intolerant to HU as supported by hematologic responses and symptom improvement. Safety data suggest a tolerable and manageable safety profile. Mutation data and other pharmacodynamic analyses indicate potential biomarker changes after PELA monotherapy."

Clinical • Monotherapy • Cardiovascular • Essential Thrombocythemia • Hematological Disorders • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Thrombocytopenia • Thrombocytosis • BDNF • CALR • CXCL8 • DKK1 • JAK2 • MMP1 • MMP9 • TIMP3

A Drug-drug Interaction Study to Assess the Effect of Phenytoin and Itraconazole on the Pharmacokinetics of Pelabresib in Healthy Participants (clinicaltrials.gov) - P1 | N=30 | Recruiting | Sponsor: Novartis Pharmaceuticals | Not yet recruiting ➔ Recruiting

Enrollment open

PELABRESIB MONOTHERAPY IN MYELOFIBROSIS AFTER JANUS KINASE INHIBITOR FAILURE: RESULTS FROM ARM 1 OF THE OPEN-LABEL, PHASE 2 MANIFEST STUDY (EHA 2026) - P1/2 | "Summary/Conclusion PELA monotherapy demonstrated clinically meaningful single-agent activity and manageable safety profile in advanced MF patients, with improvements across MF hallmarks of splenomegaly, symptoms, anemia, and BMF. These results support the biological and clinical activity of PELA in this difficult-to-treat patient population and the continued development of PELA in MF."

Clinical • Monotherapy • P2 data • Fibrosis • Hematological Disorders • Immunology • Myelofibrosis • Myeloproliferative Neoplasm • Polycythemia Vera • Thrombocytopenia • Thrombocytosis

ASXL1 mutations in AML are associated with a distinct epigenetic state that results in vulnerabilities to epigenetic-targeted agents (AACR 2025) - "Notably, compared to parental cells, OCIAML3 ASXL1 Y591* cells exhibited reduced sensitivity to standard anti-AML, chemotherapeutic agents, including cytarabine, etoposide and daunorubicin. Our findings confirm the previously published discovery that the presence of mtASXL1 confers an increased sensitivity to BETi inhibitors, e.g., pelabresib or birabresib...Importantly, in the NSG mice engrafted with OCIAML3 ASXL1 Y591*, monotherapy with NEO2734, pelabresib or SEL120 significantly reduced AML burden. Collectively these findings highlight previously uncharacterized biologic effects of the presence of mtASXL1 and support the rationale for further evaluating AML therapies incorporating BETi, HAT-BETi or mediator-kinase inhibitor."

Acute Myelogenous Leukemia • Hematological Malignancies • Oncology • ASXL1 • AURKA • BAP1 • CDK9 • E2F1 • EP300 • FZD5 • HOXA9 • MEIS1 • MYC • PLK1 • SPI1 • TCF7L2

A Drug-drug Interaction Study to Assess the Effect of Phenytoin and Itraconazole on the Pharmacokinetics of Pelabresib in Healthy Participants (clinicaltrials.gov) - P1 | N=30 | Not yet recruiting | Sponsor: Novartis Pharmaceuticals

New P1 trial

ASXL1 Mutations in AML Are Associated with a Distinct Epigenetic State Which Highlights Vulnerabilities to Specific Epigenetic-Targeted Agents (ASH 2024) - "Notably, compared to parental cells, OCIAML3 ASXL1 Y591* cells exhibited reduced sensitivity to standard anti-AML chemotherapeutic agents, including cytarabine, etoposide and daunorubicin...Our findings also demonstrate and confirm that mtASXL1-expressing AML cells exhibited increased sensitivity to BETi (pelabresib or birabresib)...Importantly, in the NSG mice engrafted with luciferized OCIAML3 ASXL1 Y591*, monotherapy with NEO2734 (5 mg/kg QD), pelabresib (30 mg/kg QD) or SEL120-34A (40 mg/kg QD), compared to vehicle control, significantly reduced AML burden. Collectively these findings highlight previously uncharacterized biologic effects of the presence of mtASXL1 and support the rationale for further evaluating AML therapies incorporating BETi, HAT-BETi or inhibitor of mediator kinase."

Acute Myelogenous Leukemia • Hematological Malignancies • Immunology • Oncology • Targeted Protein Degradation • ASXL1 • AURKA • BAP1 • BRD4 • CD14 • CDK9 • E2F1 • FZD5 • HOXA9 • MEIS1 • MYC • NDUFA2 • PLK1 • SPI1 • TCF7L2

ASXL1 Mutations in AML Are Associated With a Distinct Epigenetic State That Results in Vulnerabilities to Epigenetic-Targeted Agents (SOHO 2025) - " Notably, compared with parental cells, OCIAML3 ASXL1 Y591* cells exhibited reduced sensitivity to chemotherapeutic agents, including cytarabine, etoposide, and daunorubicin. In contrast, mtASXL1-expressing AML cells exhibited increased sensitivity to bromodomain and extraterminal inhibitors (BETi; pelabresib or birabresib)... These findings highlight that rationally targeted agents including NEO2734, pelabresib, and SEL120 or their combinations can potentially exert significant anti-AML efficacy against AML cells with mtASXL1."

Acute Myelogenous Leukemia • Hematological Malignancies • Oncology • ASXL1 • BAP1 • BCL9L • DVL1 • HOXA9 • MEIS1 • MYC • SPI1 • TCF7L2 • WNT5B • WNT7B

Integrated Multi-Omics and Interactome Analysis of CDK8 Inhibition Reveals Erythroid Differentiation Programs and Therapeutic Synergy with BET Blockade in AML. (PubMed, Cells) - "CDK8, a kinase component of the Mediator complex, regulates oncogenic transcription, and the selective CDK8/CDK19 inhibitor RVU120 (Romaciclib) targets AML cells with CD34+/pSTAT5-high LSC-like characteristics; however, the epigenetic and transcriptional consequences of CDK8 blockade and actionable combinatorial strategies remain incompletely defined. CDK8 combined with Pelabresib acted synergistically in MOLM-16 cells and two of three PDX models. These findings identify CDK8 as a transcriptional node of LSC-associated programs and provide a mechanistic rationale for combined CDK8-BET inhibition in molecularly defined AML subsets, which will require validation in functional LSC assays and primary specimens."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BRD3 • CD34 • CD38 • CDK9 • RUVBL1 • STAT5

Emerging agents and regimens for myeloproliferative neoplasms: updates from ASH 2025 Annual Meeting. (PubMed, Exp Hematol Oncol) - "At ASH 2025 Annual Meeting, multiple investigational strategies aimed to address these limitations, including clone-directed targeting (INCA033989), phlebotomy-sparing physiologic therapy (rusfertide), and epigenetic disease-modifying combinations (pelabresib). We summarized the latest updates on these emerging agents and regimens for MPNs from the 2025 ASH Annual Meeting."

Journal • Genetic Disorders • Hematological Disorders • Myeloproliferative Neoplasm • Oncology