pelabresib (DAK539) / Novartis - LARVOL DELTA

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

Pelabresib Plus Ruxolitinib Combination Therapy in JAK Inhibitor-Naïve Patients With Myelofibrosis in the Phase 3 MANIFEST-2 Study: Preliminary Evidence of Bone Marrow Recovery (SOHO 2024) - P3 | "Pelabresib may enhance clinical responses to ruxolitinib by further reducing JAK2 VAF levels and decreasing NF-κB–regulated cytokines. The latter was associated with clinical responses. Pelabresib+ruxolitinib improved the bone marrow microenvironment."

Clinical • Combination therapy • P3 data • Myelofibrosis • Oncology • 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 (SOHO 2024) - P3 | "Pelabresib+ruxolitinib significantly reduced splenomegaly, with numerically smaller TSS at W24, and improved anemia at W24 and W48 compared with placebo+ruxolitinib in JAKi-naïve patients with myelofibrosis, addressing key hallmarks of myelofibrosis. Results support a potential paradigm shift to combination therapy for myelofibrosis."

Clinical • Combination therapy • P3 data • Myelofibrosis • Oncology

Is Pelabresib + Ruxolitinib the Paradigm-Shifting Combo Therapy for Myelofibrosis? (Physician’s Weekly) - P3 | N=430 | MANIFEST-2 (NCT04603495) | Sponsor: Constellation Pharmaceuticals | "The phase 3 MANIFEST-2 study (NCT04603495) evaluated pelabresib, an investigational bromodomain and extra-terminal domain (BET) protein inhibitor, in combination with JAK inhibitor ruxolitinib for treating MF....The primary endpoint was a 35% spleen volume reduction (SVR35) at week 24....At week 24, 65.9 % and 35.2 % of the participants in the pelabresib arm and placebo arm, respectively, achieved the primary endpoint (P<0.001). Dr. Rampal shared that the mean absolute change in total symptom score at week 24 was -15.99 in the pelabresib and -14.05 in the placebo arm, reflecting a numerical benefit for the pelabresib arm (P=0.055)."

P3 data • Hematological Malignancies • Myelofibrosis • Oncology

USEFULNESS OF THE OPTICAL METHOD FOR PLATELET COUNT IN PATIENTS WITH MYELOFIBROSIS AND INFLUENCE OF THROMBOCYTOPENIA IN THERAPEUTIC MANAGEMENT (EHA 2024) - "Concerning treatment, 44% (11/25) of patients received JAK inhibitors (Ruxolitinib, Fedratinib, Momelotinib orRuxolitinib plus Pelabresib) and 55% of them (6/11) needed dose adjustments due to thrombocytopenia. Platelet counts by the optical method are usually higher than with the impedance technology. The agreementof the optical method with the FRM is better for patients with MF and thrombocytopenia. Thus, this methodcould be more accurate in this subgroup of subjects."

Clinical • Hematological Disorders • Hematological Malignancies • Myelofibrosis • Oncology • Thrombocytopenia

PROMISE: INVESTIGATION INTO THE COMBINATION OF PLX2853 WITH RUXOLITINIB IN PATIENTS WITH INTERMEDIATE-2 OR HIGH RISK MYELOFIBROSIS NOT RECEIVING AN ADEQUATE RESPONSE WITH RUXOLITINIB ALONE (EHA 2024) - "The MANIFEST study looked at pelabresib (a BETi) in combination with ruxolitinib and foundthis combination was well tolerated with evidence of symptom improvement in patients, further supporting thisarea of research (7). PROMise has to date recruited 17 patients across the study, with four TSC meetings having taken place. Theinvestigators are looking to extend recruitment beyond the current end date of April-2024."

Clinical • Bone Marrow Transplantation • Fibrosis • Hematological Disorders • Hematological Malignancies • Immunology • Myelofibrosis • Oncology • Transplantation

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

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

PELABRESIB PLUS RUXOLITINIB COMBINATION THERAPY IN JAK2 INHIBITOR-NAÏVE PATIENTS WITH MYELOFIBROSIS IN THE MANIFEST-2 STUDY: PRELIMINARY EVIDENCE OF BONE MARROW RECOVERY (EHA 2024) - P3 | "Results from pts treated with PELA+RUX in MANIFEST-2 indicate a potential for PELA to enhance clinicalresponses to RUX by further reducing mutational burden and decreasing inflammation, which was associatedwith SVR35 and TSS50 responses. Additionally, PELA+RUX resulted in improvement of the BMmicroenvironment as evidenced by a reduction in fibrosis, a decrease of MK density, and maturation of EPCsassociated with amelioration of anemia. Consistent with previous findings, correlation between improvement inBM microenvironment and clinical outcome suggests that PELA+RUX could lead to more profound and durableclinical responses in pts with MF."

Clinical • Combination therapy • Tumor mutational burden • Anemia • Fibrosis • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Lymphoma • Myelofibrosis • Oncology • ITGB3 • JAK2 • TFRC • TMB

CDK8/19 INHIBITION: A PROMISING THERAPEUTIC STRATEGY IN MYELOPROLIFERATIVE NEOPLASMS (EHA 2024) - "Background: Ruxolitinib (RUX; JAK1/2 inhibitor), among other JAK inhibitors, has demonstrated important clinical benefits inmyeloproliferative neoplasms (MPNs) by mitigating aberrant activation of the JAK-STAT pathway...Synergywas also observed when RVU120 was combined with pelabresib (BETinhibitor)... Analysis of the effects from combinations of RVU120 with other drug candidates in vitro has revealedpotentially new therapeutic options for MPN patients. In vivo data further supports CDK8 inhibition as apotential novel therapeutic strategy in MPNs. Additional mechanistic work will potentially elucidate diseasemechanisms and therapeutic action independent of JAK-STAT attenuation."

Hematological Disorders • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera