pelabresib (DAK539) / Novartis - LARVOL DELTA

EFFECT OF THERAPEUTICALLY TARGETING BET BROMODOMAINS IN ENHANCING MARKERS OF MACROPHAGE PHAGOCYTOSIS AS A NOVEL IMMUNOTHERAPEUTIC STRATEGY FOR MPN (EHA 2025) - "SET-2 cells were treated for 48 hours with a Pelabresib either alone or in combination with Ruxolitinib. These findings indicate that BET inhibition remarkably alters CD47 and intracellular CALR immune signalling mechanisms in the SET-2 cell line signalling a potent prophagocytic signal. Future research will focus on examining how BET inhibition influences CD47/CALR expression ratios and importantly whether these alterations in CD47/CALR levels impact upon macrophage-mediated phagocytosis to further determine its potential as a novel approach in MPN immunotherapy."

IO biomarker • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myeloproliferative Neoplasm • Oncology • CALR • CD47

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

New Novartis data at ASCO and EHA showcase momentum of pioneering portfolio with promising pipeline (Novartis Press Release) - "Novartis will present data from 60 company or investigator sponsored abstracts that have the potential to change clinical practice, at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting and the European Hematology Association (EHA) 2025 Congress....Novartis will also highlight its US partnerships with the National Football League (NFL), Alliance for Breast Cancer Policy, and ZERO Prostate Cancer, which encourage people to make proactive decisions about their health and advance patient-centered policy solutions to help improve outcomes."

Clinical data • Castration-Resistant Prostate Cancer • Chronic Myeloid Leukemia • Diffuse Large B Cell Lymphoma • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Myelofibrosis

High-throughput screening reveals novel synergistic drug combinations for metastatic castration-resistant prostate cancer (AACR 2025) - "Metastatic castration-resistant prostate cancer (mCRPC) remains a significant clinical challenge, with patients often developing resistance to androgen receptor (AR)-axis-targeted therapies such as Abiraterone and Enzalutamide...These results guided the development of a novel triple combination therapy to simultaneously target CDK9-regulated productive RNA polymerase II phosphorylation (Enitociclib), BRD4-mediated epigenetic remodeling (Pelabresib), and pro-survival BcL-xL (Navitoclax)...These findings provide a strong rationale for clinical development of multi-drug targeted combination regimens to overcome AR-V7-driven resistance and deliver durable responses with reduced toxicity for mCRPC patients with limited treatment options. Our approach also highlights the power of HTS to unbiasedly innovate synergistic therapies while uncovering critical biological mechanisms underlying cancer drug resistance."

Metastases • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • BCL2L1 • BRD4 • CASP3 • CASP7 • CDK9

BRD4 Inhibitor Attenuates Chronic Lung Injuries in Cutaneous Lewisite Exposure Mice (ATS 2025) - "We confirmed that BRD4 inhibitor CPI-0610 is capable of inhibiting lewisite-induced chronic lung injuries. These findings support that targeting BRD4 protein provides a promising novel therapeutic strategy for the treatment of arsenic-induced chronic lung injuries."

Preclinical • Pain • Pulmonary Disease • Respiratory Diseases • BRD4

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

Managing Myelofibrosis: Matching Advances in Treatments With Clinical Unmet Needs. (PubMed, Hematol Oncol) - "The janus kinase inhibitor (JAKi) ruxolitinib has been the mainstay of treatment for over a decade...Other JAKi (pacritinib, momelotinib, jaktinib) address treatment-related cytopenia, expanding the therapeutic utility of this class of agents to patients with baseline anemia or thrombocytopenia. Novel candidates exploit multiple molecular pathways, and offer the potential to improve the management of MF-associated cytopenia (imetelstat, pelabresib, navitoclax, selinexor, luspatercept, sotatercept, elritercept, LCL161, bomedemstat) and recover bone marrow fibrosis (imetelstat, pelabresib, navitoclax and bomedemstat). It remains to be seen if these newer agents can induce any remission in MF and enable patients to come off therapy, but the future is beginning to look much brighter."

Journal • Review • Fibrosis • Hematological Disorders • Immunology • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Thrombocytopenia

Pelabresib plus ruxolitinib for JAK inhibitor-naive myelofibrosis: a randomized phase 3 trial (Nature) - P3 | N=430 | MANIFEST-2 (NCT04603495) | Sponsor: Constellation Pharmaceuticals | "The primary endpoint was met in 65.9% of patients randomized to pelabresib–ruxolitinib (n = 214) versus 35.2% to placebo–ruxolitinib (n = 216) (difference, 30.4%; 95% confidence interval (CI), 21.6, 39.3; P < 0.001). Absolute change in TSS was −15.99 versus −14.05 (difference, −1.94; 95% CI, −3.92, 0.04; P = 0.0545) and TSS50 was achieved in 52.3% versus 46.3% (difference, 6.0%; 95 CI, −3.5, 15.5) with pelabresib–ruxolitinib versus placebo–ruxolitinib. Exploratory analyses of proinflammatory cytokine amounts and bone marrow morphology showed greater improvement with the combination."

P3 data • Myelofibrosis

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

MANIFEST: A Phase 2 Study of CPI-0610 with and Without Ruxolitinib in Patients with Myelofibrosis (clinicaltrials.gov) - P1/2 | N=336 | Completed | Sponsor: Constellation Pharmaceuticals | Active, not recruiting ➔ Completed

Trial completion • Acute Myelogenous Leukemia • Acute Promyelocytic Leukemia • Essential Thrombocythemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Thrombocytopenia • Thrombocytosis

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

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

A Phase 1/2 Study of Nuvisertib (TP-3654), an Investigational Selective PIM1 Kinase Inhibitor, in Combination with JAK Inhibitors Ruxolitinib or Momelotinib in Patients with Myelofibrosis (ASH 2024) - P1/2 | "Recent Phase 3 combination studies of RUX with Pelabresib (Rampal R, 2023) or Navitoclax (Pemmaraju N, 2023) in treatment naïve MF pts with platelet (PLT) count ≥100 x 109/L showed significant increase only in spleen responses; however, did not improve symptoms response, also were limited by overlapping toxicities of thrombocytopenia. For TP-3654 in combination with MMB (Arm 3), pts that have been previously treated with an approved JAK inhibitor (except MMB) for ≥12 weeks, or ≥4 weeks if JAK inhibitor therapy was complicated by a transfusion requirement of ≥4 units of RBC in 8 weeks, or Grade 3/4 AEs of thrombocytopenia, anemia, or hematoma. Combination arms are currently recruiting pts."

Clinical • Combination therapy • P1/2 data • Anemia • Fibrosis • Hematological Disorders • Hematological Malignancies • Immunology • Myelofibrosis • Oncology • Thrombocytopenia • PIM1

Updated Results from the Phase 3 Manifest-2 Study of Pelabresib in Combination with Ruxolitinib for Janus Kinase Inhibitor–Naïve Patients with Myelofibrosis (ASH 2024) - P3 | "Conclusion At Wk 48, PELA+RUX continued to show improvements in spleen volume, TSS, multiple measures of anemia, and the BM microenvironment vs PBO+RUX, impacting the four hallmarks of MF. These data suggest that PELA+RUX could lead to more profound and sustained responses in pts with MF vs PBO+RUX."

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

Novartis shutters MorphoSys sites, lays off staff (BioPharma Dive) - "Swiss pharmaceutical company Novartis plans to close MorphoSys sites in the U.S. and Germany in a 'strategic decision' that will affect 330 jobs. The move, which was first reported by the German magazine WirtschaftsWoche, stems from Novartis’ evaluation of its R&D priorities and the time needed to determine an approval path for MorphoSys’ drug pelabresib in a bone marrow cancer. 'Novartis remains committed to advancing the development of pelabresib', a spokesperson said in a statement to BioPharma Dive....The pharma revealed in third quarter earnings that it wrote down the value of the deal."

Commercial • Myelofibrosis

Pelabresib Plus Ruxolitinib Leads to Sustained Responses in JAK Inhibitor–Naive Myelofibrosis (OncLive) - P3 | N=430 | MANIFEST-2 (NCT04603495) | Sponsor: Constellation Pharmaceuticals | "Pelabresib (CPI-0610) plus ruxolitinib (Jakafi) demonstrated improvements in spleen volume, total symptom score, anemia, and the bone marrow microenvironment at week 48 vs placebo plus ruxolitinib in patients with JAK inhibitor–naive myelofibrosis, according to results from the phase 3 MANIFEST-2 study (NCT04603495). Data presented at the 2024 ASH Annual Meeting showed that at a median follow-up of 72 weeks, the primary end point of spleen volume reduction of 35% (SVR35) was maintained, with a 48-week response rate of 57.0% with pelabresib and ruxolitinib vs 37.5% with ruxolitinib plus placebo. Total symptom score (TSS) improvement of at least 50% at week 48 was 45.3% vs 39.4%, respectively. Fewer patients required red blood cell transfusions, and bone marrow fibrosis improvement of at least 1 grade was reported in 41.0% vs 15.0%, respectively."

P3 data • Myelofibrosis

Preclinical efficacy of CDK7 inhibitor-based combinations against myeloproliferative neoplasms transformed to AML. (PubMed, Blood) - "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."

Journal • Preclinical • Acute Myelogenous Leukemia • Myeloproliferative Neoplasm • Oncology • BCL2L1 • BRD4 • CASP3 • CASP9 • CCND1 • CDK4 • CDK6 • CDKN1A • ITGAM • MYC • PIM1 • TP53

Novartis highlights new 96-week results from Phase III Scemblix ASC4FIRST trial at ASH and late-breaking analysis from Phase III Kisqali NATALEE trial at SABCS (GlobeNewswire) - "Novartis will present data from more than 65 abstracts, including investigator-initiated trials at the 66th American Society of Hematology (ASH) Annual Meeting & Exposition and the 2024 San Antonio Breast Cancer Symposium (SABCS)....Longer-term 96-week results from Scemblix ASC4FIRST Phase III study in first-line Ph+ CML-CP to be presented following recent FDA approval based on 48-week data. Late-breaking Kisqali 4-year analysis on distant disease-free survival in key subgroups with HR+/HER2- early breast cancer from Phase III NATALEE trial also to be presented."

Clinical data • Late-breaking abstract • P3 data • Diffuse Large B Cell Lymphoma • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Myelofibrosis

An Extension Study for Patients Previously Enrolled in Studies with Pelabresib (clinicaltrials.gov) - P3 | N=50 | Recruiting | Sponsor: Constellation Pharmaceuticals | Not yet recruiting ➔ Recruiting | Trial completion date: Jun 2024 ➔ Jun 2029 | Trial primary completion date: Jun 2024 ➔ Jun 2029

Enrollment open • Trial completion date • Trial primary completion date • Hematological Disorders • Hematological Malignancies • Oncology • Solid Tumor

Novartis' $2.9B MorphoSys bet stumbles as safety signal delays filing by years (FierceBiotech) - "Novartis’ 2.7 billion euro ($2.9 billion) gamble on MorphoSys has hit turbulence. Months after buying the biotech, Novartis has revealed a safety signal that could set back plans to seek approval for the jewel of the acquisition by a couple of years...The Swiss drugmaker acquired MorphoSys earlier this year, making its move in the wake of the biotech’s phase 3 readout on the myelofibrosis drug candidate pelabresib. MorphoSys linked the BET inhibitor to a reduction in spleen volume but failed to show a significant effect on symptoms, causing one hit and one miss on key endpoints...Novartis now has the 48-week data and has pushed back its plans to seek approval....Novartis said it will keep tracking patients and assess the need for additional studies to support approval."

Commercial • Trial status • Hematological Malignancies • Myelofibrosis • Myeloproliferative Neoplasm • Oncology

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..."

Oncology

Safety and efficacy of pelabresib in combination with ruxolitinib for JAK inhibitor treatment-naive patients with myelofibrosis: Latest data from the phase 3 MANIFEST-2 study (DGHO 2024) - P3 | "PELA+RUX significantly reduced splenomegaly, with a trend toward reduced TSS at W24, and improved anemia at W24 and W48 compared with PBO+RUX in JAKi-naïve pts with MF, addressing key hallmarks of MF. Results support a potential paradigm shift to combination therapy for MF."

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

Pelabresib Plus Ruxolitinib Combination Therapy in JAK Inhibitor-Naive Patients with Myelofibrosis in the Phase 3 MANIFEST-2 Study: Evidence of Bone Marrow Regeneration (DGHO 2024) - P3 | "Results from the MANIFEST-2 study indicate a potential for PELA to enhance clinical responses to RUX by further reducing JAK2 VAF levels and decreasing NF-κB–regulated CKs. The latter was associated with SVR35 and TSS50 responses. PELA+RUX resulted in improvement of the BM microenvironment."

Clinical • Combination therapy • P3 data • Anemia • Fibrosis • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Lymphoma • Myelofibrosis • Oncology • ITGB3 • JAK2 • TFRC

PELABRESIB PLUS RUXOLITINIB COMBINATION THERAPY IN JAK INHIBITOR-NAÏVE PATIENTS WITH MYELOFIBROSIS IN THE PHASE 3 MANIFEST-2 STUDY: PRELIMINARY TRANSLATIONAL EVIDENCE OF BONE MARROW RECOVERY (SIE 2024) - P3 | "This correlation suggests that PELA+RUX could lead to more profound and durable clinical responses in pts with MF. The development of pelabresib was funded in part by the Leukemia and Lymphoma Society."

Clinical • Combination therapy • P3 data • Anemia • Fibrosis • Hematological Disorders • Immunology • Leukemia • Lymphoma • Myelofibrosis • ITGB3 • JAK2 • TFRC

SAFETY AND EFFICACY OF PELABRESIB IN COMBINATION WITH RUXOLITINIB FOR JAK INHIBITOR-NAÏVE PATIENTS WITH MYELOFIBROSIS: LATEST DATA FROM THE PHASE 3 MANIFEST-2 STUDY (SIE 2024) - P3 | "Results support a potential paradigm shift to combination therapy for MF. The development of pelabresib was funded in part by the Leukemia and Lymphoma Society."

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