siremadlin (HDM201) / Novartis - LARVOL DELTA

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

Use of Combination Therapies Including the XPO1 Inhibitor Selinexor in Is a Potential Effective Therapeutic Strategy to Treat Myelofibrosis Patients (ASH 2023) - "We also evaluated the ability of SEL alone to eliminate MF CD34+ cells and in combination with other candidate drugs such as HDM201 (HDM2 antagonist), ruxolitinib (RUX), pan-BET inhibitor (JQ1) or a Bcl-2/Bcl-xL inhibitor (navitoclax). The effects of SEL combined with either RUX or an HDM2 antagonist more effectively depleted mutated MF CD34+ cells than either drug alone. The combination of SEL+HDM201 spared the reservoir of WT progenitors, and reduced JAK2 mutated progenitor cells to a great degree suggesting that this combination might be associated with less hematological toxicity and greater efficacy."

Clinical • Combination therapy • IO biomarker • Myelofibrosis • Oncology • BCL2 • BCL2L1 • CCNB1 • CD34 • CDKN1A • MYC • RB1 • TP63 • TP73 • XPO1

Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status. (PubMed, Oncol Res) - "The efficacy of the mouse double minute 2 homolog (MDM2) inhibitor (HDM201) and the Wee1 G2 checkpoint kinase (Wee1) inhibitor (adavosertib) was confirmed in both p53 wild-type (p53 WT) and p53 mutant (p53 MT) GIST cells. Our results highlight the importance of p53 status in guiding GIST treatment. p53 WT tumors respond to MDM2 inhibitors, while p53 MT tumors show greater sensitivity to Wee1 inhibitors, supporting p53 pathway targeting as a promising strategy for GIST patients."

Journal • Preclinical • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • CDK1 • CDKN1A • PDGFRA • TP53

ADORE: Platform Study of Novel Ruxolitinib Combinations in Myelofibrosis Patients (clinicaltrials.gov) - P1/2 | N=45 | Terminated | Sponsor: Novartis Pharmaceuticals | Completed ➔ Terminated; Sponsor Decision

Trial termination • Myelofibrosis

ADORE: an open platform study of ruxolitinib in combination with other novel therapies in patients with myelofibrosis. (PubMed, Blood Adv) - P1/2 | "Forty-four patients were enrolled in Part 1 of the study of ruxolitinib in combination with siremadlin, rineterkib, sabatolimab, crizanlizumab, or NIS793. Overall, available data from ADORE suggest the feasibility and benefits of combining novel agents with ruxolitinib in patients with suboptimal response to ruxolitinib alone. This trial was registered at www.clinicaltrials.gov as #NCT04097821."

Journal • Hematological Disorders • Myelofibrosis • Neutropenia • Thrombocytopenia • GDF15

Siremadlin Demonstrates Efficacy, Safety in Treatment of Patients With TP53 Wild-Type Chronic Lymphocytic Leukemia (Pharmacy Times) - "Siremadlin (HDM201; BioVision) may be an efficacious additional targeted therapy for patients with wild-type TP53 chronic lymphocytic leukemia (CLL), according to data published in Cancers....The findings showed that homozygous TP53-KO cells and B-cells with TP53 mutations had notable resistance to HDM201, whereas TP53 wild-type and heterozygous TP53-KO Nalm-6 cells were sensitive to it....In TP53 wild-type cells, siremadlin efficiently stabilized p53 and caused apoptosis; but, in TP53 mutant cells, its effectiveness was suboptimal."

Preclinical • Chronic Lymphocytic Leukemia

Targeting the MDM2-p53 Interaction with Siremadlin: A Promising Therapeutic Strategy for Treating TP53 Wild-Type Chronic Lymphocytic Leukemia. (PubMed, Cancers (Basel)) - "The results underline the importance of TP53 status in predicting treatment efficacy and highlight the potential of HDM201 as a valuable addition to explore in CLL therapy. Future research should focus on identifying additional biomarkers of response and exploring the optimal way to include HDM201 in combination therapies to improve treatment outcomes in CLL."

Journal • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • TP53

A Study of Siremadlin in Combination With Venetoclax Plus Azacitidine in Adult Participants With Acute Myeloid Leukemia (AML) Who Are Ineligible for Chemotherapy. (clinicaltrials.gov) - P1 | N=14 | Terminated | Sponsor: Novartis Pharmaceuticals | Consequently, enrollment for Part 2 did not commence. This decision was not influenced by any safety concerns.

Trial termination • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • TP53

ENHANCING THERAPEUTIC EFFICACY IN SYNOVIAL SARCOMA BY TARGETING P53-MDM2 AXIS AND HDAC PATHWAYS (CTOS 2024) - "HDM201 and Panobinostat alone demonstrated modest effects on tumor growth, their combination significantly suppressed tumor progression, indicating a synergistic effect in inducing cell cycle arrest as observed through RNA-seq analysis. This study underscores the potential of targeting the p53-MDM2 interaction and HDAC pathways simultaneously to enhance apoptosis and inhibit growth in synovial sarcoma, offering promising avenues for overcoming resistance mechanisms and improving patient outcomes."

Clinical • Oncology • Sarcoma • Solid Tumor • Synovial Sarcoma • MDM2 • MDM4 • SS18

HDM201 in Combination With MBG453 or Venetoclax in Patients With Acute Myeloid Leukemia (AML) or High-risk Myelodysplastic Syndrome (MDS) (clinicaltrials.gov) - P1 | N=52 | Terminated | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Terminated; Business decision

Combination therapy • Trial termination • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • TP53

ADORE: Platform Study of Novel Ruxolitinib Combinations in Myelofibrosis Patients (clinicaltrials.gov) - P1/2 | N=45 | Completed | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Completed

Trial completion • Myelofibrosis

Siremadlin (S) and ribociclib (R) in patients (pt) with advanced well-differentiated/dedifferentiated liposarcomas (WD/DD LPS) and other molecularly selected cancers: Final analysis of the MEGAMOST "Ribociclib/HDM201" basket study (ESMO 2024) - P2 | "S + R demonstrated a manageable safety profile with encouraging efficacy in patients with advanced MDM2-CDK4 amp LPS while the results in others cancers characterized by different molecular alterations were modest."

Clinical • Late-breaking abstract • Metastases • Pan tumor • Liposarcoma • Oncology • Sarcoma • Solid Tumor • CCND1 • CCND3 • CDKN2A • RB1

Combination treatment with siremadin and ribociclib for advanced WD/DD liposarcoma with MDM2/CDK4 amplification achieved a 3-month progression-free rate of 78.9% and a median PFS of 8.3 months [ESMO 2024] [Google translation] (Nikkei) - P2 | N=455 | MegaMOST (NCT04116541) | "In patients with well-differentiated/dedifferentiated (WD/DD) advanced liposarcoma (LPS) with MDM2/CDK4 amplification, the combination of the MDM2 inhibitor siremadin, which inhibits the interaction between p53 and MDM2, and the CDK4/6 inhibitor ribociclib showed promising results, with a 3-month progression-free rate (PFR) of 78.9% and a median PFS of 8.3 months. This was revealed in the final analysis of MEGAMOST , a multicenter, open-label, phase 2 basket trial conducted by biology-driven using a sequential Bayesian adaptive design , and was reported by Mehdi Brahmi of Centre Leon Berard, France, at the European Society for Medical Oncology 2024 (ESMO 2024) held in Barcelona, ​​Spain from September 13 to 17."

P2 data • Liposarcoma • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

A Study of Siremadlin in Combination With Venetoclax Plus Azacitidine in Adult Participants With Acute Myeloid Leukemia (AML) Who Are Ineligible for Chemotherapy. (clinicaltrials.gov) - P1 | N=14 | Completed | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Completed

Combination therapy • Trial completion • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • TP53

A Study of Siremadlin in Combination With Venetoclax Plus Azacitidine in Adult Participants With Acute Myeloid Leukemia (AML) Who Are Ineligible for Chemotherapy. (clinicaltrials.gov) - P1 | N=14 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Phase classification: P1/2 ➔ P1

Combination therapy • Phase classification • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • TP53

ABCB1-mediated chemotherapeutic drug resistance is reversed by a potent p53-MDM2 inhibitor NVP-HDM201 (AACR 2024) - "According to our findings, HDM201 significantly increased the sensitivity of ABCB1-overexpressing cells to ABCB1 substrates, such as colchicine and doxorubicin...Moreover, HDM201 promoted the accumulation of paclitaxel in cell lines that overexpress ABCB1...The computational support for the cross-reactivity of this p53 inhibitor with human ABCB1 comes from docking simulation results that align with the binding conformation of HDM201 within the vast cavity of the transmembrane region of ABCB1. In conclusion, by blocking the transport function of ABCB1, HDM201 can reverse ABCB1-mediated MDR in vitro."

Oncology • ABCB1

Combined inhibition of MDM2 and PARP lead to a synergistic anti-tumoral response in p53 wild-type rhabdomyosarcoma (AACR 2024) - "In summary, our study demonstrates, for the first time, the synergistic effect of the combination between Siremadlin and Olaparib in the inhibition of p53 wild-type RMS tumor growth in vitro and in vivo. These findings advocate for the exploration of this drug combination in clinical trials and underscore the need for further investigation in tumors sharing similar molecular features."

Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor

AMPHISARC: HDM201 and Pazopanib in Patients With P53 Wild-type Advanced/Metastatic Soft Tissue Sarcomas (clinicaltrials.gov) - P1/2 | N=58 | Recruiting | Sponsor: Centre Leon Berard | Trial completion date: Jul 2025 ➔ Jul 2026 | Trial primary completion date: Jan 2025 ➔ Jan 2026

Metastases • Trial completion date • Trial primary completion date • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • MDM2

A Study of Siremadlin in Combination With Venetoclax Plus Azacitidine in Adult Participants With Acute Myeloid Leukemia (AML) Who Are Ineligible for Chemotherapy. (clinicaltrials.gov) - P1/2 | N=14 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Nov 2026 ➔ May 2024 | Trial primary completion date: May 2025 ➔ May 2024

Combination therapy • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • TP53

A Study of Siremadlin in Combination With Venetoclax Plus Azacitidine in Adult Participants With Acute Myeloid Leukemia (AML) Who Are Ineligible for Chemotherapy. (clinicaltrials.gov) - P1/2 | N=14 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Active, not recruiting

Enrollment closed • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • TP53

A Study of Siremadlin Alone and in Combination With Donor Lymphocyte Infusion in Acute Myeloid Leukemia Post-allogeneic Stem Cell Transplant (clinicaltrials.gov) - P1/2 | N=8 | Terminated | Sponsor: Novartis Pharmaceuticals | N=38 ➔ 8 | Trial completion date: Jan 2028 ➔ Oct 2023 | Recruiting ➔ Terminated | Trial primary completion date: Jan 2027 ➔ Oct 2023; Study has been stopped following to strategic decision from the Sponsor. Not based on any safety findings or safety concerns with siremadlin.

Combination therapy • Enrollment change • Monotherapy • Trial completion date • Trial primary completion date • Trial termination • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation • HLA-B • HLA-C • HLA-DRB1 • TP53

ADORE: Platform Study of Novel Ruxolitinib Combinations in Myelofibrosis Patients (clinicaltrials.gov) - P1/2 | N=45 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Mar 2024 ➔ Jul 2024

Trial completion date • Myelofibrosis

MegaMOST: A Study Evaluating the Activity of Anti-cancer Treatments Targeting Tumor Molecular Alterations/Characteristics in Advanced / Metastatic Tumors. (clinicaltrials.gov) - P2 | N=425 | Recruiting | Sponsor: Centre Leon Berard

Metastases • Trial completion date • Trial primary completion date • Oncology • Solid Tumor • ALK • AXL • BRAF • CCND1 • CCND3 • CDK4 • CDK6 • CDKN2A • FLT1 • FLT3 • HRAS • KRAS • NF1 • NRAS • NTRK • NTRK2 • PTPN11 • RAF1 • ROS1 • SMAD4 • TYRO3

Pharmacokinetics and Safety Study of Siremadlin (HDM201) in Participants With Mild, Moderate and Severe Hepatic Impairment (clinicaltrials.gov) - P1 | N=38 | Completed | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Completed

Trial completion • Hepatology

TRAHD: Trametinib + HDM201 in CRC Patients With RAS/RAF Mutant and TP53 Wild-type Advanced/Metastatic Colorectal Cancer Mutant and TP53 Wild-type (clinicaltrials.gov) - P1 | N=12 | Completed | Sponsor: Centre Leon Berard | Recruiting ➔ Completed | N=24 ➔ 12 | Trial completion date: Dec 2024 ➔ Sep 2023

Enrollment change • Metastases • Trial completion • Trial completion date • Colorectal Cancer • Gastrointestinal Cancer • Neutropenia • Oncology • Solid Tumor • HRAS • KRAS • NRAS • TP53