pelabresib (DAK539) / Novartis - LARVOL DELTA

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

Pelabresib plus ruxolitinib for JAK inhibitor-naive myelofibrosis: a randomized phase 3 trial. (PubMed, Nat Med) - P3 | "Pelabresib in combination with ruxolitinib is well tolerated, improves signs of underlying myelofibrosis pathobiology and provides substantial clinical benefit over standard-of-care JAK inhibitor monotherapy. ClinicalTrials.gov identifier: NCT04603495 ."

Journal • P3 data • Myelofibrosis

PELABRESIB PLUS RUXOLITINIB AS BRIDGING THERAPY TO HAEMATOPOIETIC STEM CELL TRANSPLANTATION IN MYELOFIBROSIS: INSIGHTS FROM MANIFEST AND MANIFEST-2 STUDIES (EBMT 2026) - P1/2, P3 | "PELA+RUX enabled a subgroup of JAKi-naïve MF patients to undergo HSCT, demonstrating significant reductions in spleen volume and notable improvements in symptoms, indicating potential as a bridging therapy to HSCT in MF and supporting broader clinical utility."

Bone Marrow Transplantation • Myelofibrosis • Myeloproliferative Neoplasm • Transplantation

Pelabresib: “Deep and durable reduction in spleen volume (SVR35, 91.5% vs 57.6%); sustained improvements in both TSS and anemia“; Myelofibrosis (Novartis) - Q4 2025 Results

P3 data • Hematological Malignancies • Myelofibrosis • Myeloproliferative Neoplasm • Oncology

Progress of investigational bromodomain and extra-terminal domain inhibitors for myelofibrosis therapy. (PubMed, Expert Opin Investig Drugs) - "Trials assessing the efficacy of pelabresib, ABBV-744, INCB057643, BMS-986158, and OPN-2853 are detailed herein. Research into novel pan-and selective-BETis both as monotherapy and in combination with JAKis or other mechanism-based therapies are ongoing. Whether BETi therapy in MF will ultimately deliver substantial anti-clonal activity to modify disease biology and meaningfully impact clinical outcomes is yet to be determined."

Journal • Review • Fibrosis • Hematological Disorders • Immunology • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • ABL1 • BCR

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

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

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

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

MANIFEST-3: A Phase 3 Study of Pelabresib (DAK539) and Ruxolitinib in Myelofibrosis (MF) (clinicaltrials.gov) - P3 | N=460 | Not yet recruiting | Sponsor: Novartis Pharmaceuticals

New P3 trial • Hematological Disorders • Myelofibrosis • Myeloproliferative Neoplasm • Thrombocytosis

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

Study of Pelabresib add-on to Ruxolitinib in Japanese Adult Patients With Myelofibrosis (clinicaltrials.gov) - P1 | N=3 | Not yet recruiting | Sponsor: Novartis Pharmaceuticals

New P1 trial • Hematological Disorders • Myelofibrosis • Myeloproliferative Neoplasm • Thrombocytosis

A Drug-drug Interaction Study to Evaluate the Effects of Pelabresib on the Pharmacokinetics of Repaglinide, Midazolam, and Combined Oral Contraceptive in Patients With Advanced Malignancies (clinicaltrials.gov) - P1 | N=24 | Not yet recruiting | Sponsor: Novartis Pharmaceuticals

New P1 trial • Oncology

Phase 3 Study of Pelabresib (CPI-0610) in Myelofibrosis (MF) (MANIFEST-2) (clinicaltrials.gov) - P3 | N=430 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Dec 2027 ➔ Jun 2027

Trial completion date • Hematological Disorders • Myelofibrosis • Myeloproliferative Neoplasm • Thrombocytosis

Efficacy and safety of ruxolitinib-based combination therapy in the patients with myelofibrosis (MF): A systematic review and meta-analysis (ASH 2025) - "Among JAK inhibitor-naïve patients, the combination of ruxolitinib with selinexor demonstrated the highest efficacy (SVR35: 92%; TSS50: 78%), followed by ruxolitinib plus BMS-986158 (SVR35: 90%). In addition, the efficacy ofthe combination of ruxolitinib with IFNα(SVR35:70%) and pelabresib (SVR35:66%; TSS50:53%) are also acceptable. For patients with prior JAK inhibitor exposure, ruxolitinib plus siremadlin (SVR35: 45%) and ruxolitinib plus selinexor (SVR35: 38%; TSS50: 33%) showed notable activity... For JAK inhibitor-naïve patients, ruxolitinib-based combination regimens demonstrated advantages over ruxolitinib monotherapy. For patients with prior JAK inhibitor exposure, the addition of combination therapy drugs may further enhance the efficacy. Personalized treatment selection remains essential, as therapeutic efficacy is significantly influenced by prior JAK inhibitor exposure."

Combination therapy • Retrospective data • Review • Chronic Eosinophilic Leukemia • Fibrosis • Hematological Disorders • Immunology • Myelofibrosis • Myeloproliferative Neoplasm • Neutropenia • Thrombocytopenia • IFNA1

The combination of ruxolitinib and the CDK4/6 inhibitor abemaciclib demonstrates safety and efficacy in previously treated myelofibrosis patients: Results of A phase I study (ASH 2025) - P1 | "Prior treatments included RUX plus pelabresib/placebo (n=3),hypomethylating agents (n=2), hydroxyurea (n=2), stem cell transplant (n=1). Combination therapy with RUX and the CDK 4/6 inhibitor ABE is safe and has encouragingobjective evidence of efficacy among pts with advanced, previously treated MF, confirming preclinicalhypotheses. These data nominate combined JAK and CDK4/6 inhibitor strategies for future investigationin JAK-STAT driven diseases. The combination of RUX and ABE will now advance to a phase II study inpreviously treated MF patients."

Clinical • P1 data • Breast Cancer • Fibrosis • Immunology • Myelofibrosis • Neutropenia • Solid Tumor • Thrombocytopenia • CALR • CDC25A • GNRP • JAK2

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

MANIFEST-2: 96-Week Data of Pelabresib Plus Ruxolitinib in JAK Inhibitor–Naive Myelofibrosis (OncoDaily) - "SVR35 at week 96: PELA+RUX: 91.5%; PBO+RUX: 57.6%. Kaplan–Meier curves for duration of spleen response showed an early separation between arms that remained throughout the 96-week follow-up. In the intent-to-treat population: Median duration of spleen response was not reached with PELA+RUX versus 138.3 weeks with PBO+RUX."

P3 data • Myelofibrosis

MODULE 4: Future Directions in the Management of MF (ASH 2024) - "This program is supported by educational grants from CTI BioPharma, a Sobi Company, Geron Corporation, GSK, Incyte Corporation and Karyopharm Therapeutics.Mechanism of antitumor activity of navitoclax and biological rationale for its evaluation for MF Available efficacy and safety findings from the Phase III TRANSFORM-1 study of navitoclax in combination with ruxolitinib versus ruxolitinib alone for patients with previously untreated MF Potential role of navitoclax in the up-front setting and ongoing evaluation for relapsed/refractory (R/R) disease in the Phase III TRANSFORM-2 study Rationale for the evaluation of BET inhibitors for MF; updated findings from the Phase III MANIFEST-2 study combining pelabresib to ruxolitinib for JAK inhibitor-naïve disease Scientific justification for the evaluation of selinexor for MF; early efficacy and safety findings with selinexor as monotherapy and in combination with ruxolitinib Ongoing evaluation of the combination of..."

Myelofibrosis • Oncology

Activity of Selinexor As a Single Agent and Synergistic Activity with Approved/Investigational Myelofibrosis Therapies in Vitro (ASH 2023) - "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..."

IO biomarker • Preclinical • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Targeted Protein Degradation • CALR • CCND1 • CDKN1A • MCL1

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

Novartis will present data from over 70 abstracts, including investigator-initiated trials at the 67th American Society of Hematology (ASH) Annual Meeting & Exposition and 2025 San Antonio Breast Cancer Symposium (SABCS). (Novartis Press Release) - "Scemblix data across clinical and real-world settings offer new evidence informing CML care amid evolving patient needs; 96-week pelabresib Phase III data represent longest follow-up of first-line myelofibrosis patients in randomized combination trial; Kisqali NATALEE and MONALEESA data add to evidence of long-term benefits for early and metastatic breast cancer patients."

Clinical data • Chronic Myeloid Leukemia • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Myelofibrosis