CGM097 / Novartis - LARVOL DELTA

TP53-MUTATED AML: A MULTI-OMICS APPROACH TO UNDERSTAND HETEROGENEITY AND THERAPEUTIC VULNERABILITIES (EHA 2025) - "Standard therapies, including intensive chemotherapy, allogeneic hematopoietic stem cell transplantation, and venetoclax-based regimens, offer minimal survival benefit...A single TP53-mut sample was mature, harbouring the mutation with 37% VAF, alongside a KMT2A rearrangement and GATA2 and NRAS mutations—features associated with mature AMLs.The in vitro drug sensitivity analysis identified four MDM2 inhibitors—Idasanutlin, AMG-232, NVP-CGM097, and SAR40583—as the compounds to which TP53-mut cases were most resistant among the 527 tested (11/12 TP53-mut cases exhibiting resistance (p=0.0042)... Identifying actionable vulnerabilities in poor-risk AML remains challenging. Our findings highlight TP53-mut AML's distinct biology, including its enrichment in the Primitive subtype, resistance to MDM2 inhibitors, and differential ADC target expression. While validation in larger cohorts is needed, these insights could guide tailored therapeutic strategies for this..."

Heterogeneity • IO biomarker • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Oncology • CD123 • CD33 • CD34 • CLEC12A • CXCR4 • GATA2 • HAVCR2 • IL3RA • KIT • KMT2A • NRAS • TP53

MDM2 inhibitor is potent against ER-positive breast cancer in a dual endocrine therapy and CDK4/6 inhibitor-resistant setting (LCC 2025) - "The MDM2 inhibitor, NVP-CGM097 was evaluated in vitro models of dual therapy resistant ER-positive breast cancer using flow cytometry analysis for apoptosis, senescence, and cell cycle, RNA sequencing analysis, western blots, IHC and Bcl-2 family pro-survival multiplex immunoassays...In two PDX models of combined ET and CDK4/6 inhibitor resistance, we further confirm MDM2i suppressed tumour growth and increased survival percentage by reducing cell proliferation and increasing p21 expression without inducing apoptosis. In conclusion, we demonstrate here that MDM2 inhibition has potent anti-tumour activity in the setting of ER-positive breast cancers resistant to combined endocrine therapy and CDK4/6 inhibitors."

IO biomarker • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • BCL2 • BCL2L1 • CDKN1A • ER • MCL1

An anti-GD2 aptamer-based bifunctional spherical nucleic acid nanoplatform for synergistic therapy targeting MDM2 for retinoblastoma. (PubMed, Biomed Pharmacother) - "Here, we reported on anti-GD2 and glutathione-responsive spherical nucleic acids (SNAs), loaded with siRNA and the inhibitor NVP-CGM097, which jointly blocked the oncogenic factor n in RB cells (Y79 and WERI-RB-1). In hematological analysis and hepatotoxicity assays, SNAs were safer for mice than melphalan, the favored drug for treating RB in clinical practice. Our results illustrated the potential of intravitreally injected SNAs as a precision medicine for treating RB."

Journal • Eye Cancer • Hematological Disorders • Hepatology • Oncology • Pediatrics • Retinal Disorders • Retinoblastoma • Solid Tumor

CRISPR activation screen identifies MDM2 as a modulator of proteasome inhibitor resistance in multiple myeloma (EACR 2023) - "Investigating the basis of drug resistance, particularly with regard to proteasome inhibitors (PIs), is crucial.Material and MethodsIn this study, we performed a gain of function screen using the CRISPR-based SAM system and SAM sgRNA library targeting 23,430 genes, as well as a loss of function screen with a library of 320 small-molecule inhibitors under the selective pressure of carfilzomib (CFZ).Results and DiscussionsThe Mouse Double Minute 2 homolog (MDM2) gene emerged from the genome-wide CRISPR activation screen as a potential modulator of carfilzomib (CFZ) resistance. Complementary pharmacological screening revealed that the MDM2 selective inhibitor NVP-CGM097 significantly synergized with CFZ, increasing cell death in a panel of MM cell lines independently of their p53 status. Importantly, NVP-CGM097 was also effective against primary CD138+ cells from MM patients and was able to resensitize CFZ/BTZ-resistant cell lines to PI.ConclusionOur results suggest that..."

Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology • MDM2 • SDC1 • TP53

Improving Speed and Affordability without Compromising Accuracy: Standard Binding Free-Energy Calculations Using an Enhanced Sampling Algorithm, Multiple-Time Stepping, and Hydrogen Mass Repartitioning. (PubMed, J Chem Theory Comput) - "Furthermore, we demonstrated the transferability of our method to other complexes by triplicating a 200 ns separation simulation of nine chosen protocols for the MDM2-p53:NVP-CGM097 complex...Chem. 2015, 58, 6348-6358.] Our results, based on an aggregate simulation time of 14.4 μs, allowed an optimal set of parameters to be identified, able to accelerate convergence by a factor of three without any noticeable loss of accuracy."

Journal

MDM2 inhibition as a novel therapy to overcome treatment resistance in ER-positive breast cancer (LCC 2023) - "We further examined efficacy of MDM2 inhibition in a patient-derived xenograft (PDX) model of fulvestrant-resistant and palbociclib-resistant ER+ breast cancer, and demonstrated that MDM2 inhibition with NVP-CGM097 slowed tumour growth by reducing cell proliferation and extended survival time. We conclude that MDM2 inhibition leads to potent anti-tumour activity and represents a rationadl therapeutic strategy to overcome treatment-resistance in ER+ breast cancer."

Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CDKN1A • ER

Deep Multi-Omics Profiling in Cytogenetically Poor-Risk AML (ASH 2022) - "For example, we validated TP53 WT status as a determinant of response to MDM2 inhibitors (AMG-232, idasanutlin, SAR405838 and NVP-CGM097) and we found that within the TP53-WT group of patients, good-responders have a significantly lower expression of TP53 pathway genes at diagnosis compared to non-responders. Altogether, these findings demonstrate the feasibility of simultaneously generating multi-omics data from several different platforms in AML primary samples and highlights that integrative analysis will increase our understanding of the biology of the disease and its therapeutic vulnerabilities."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ABCB1 • DEK • ETV6 • GATA2 • GNAS • KMT2A • NUP214 • PBX3

Hazardous Shortcuts in Standard Binding Free Energy Calculations. (PubMed, J Phys Chem Lett) - "Here the accuracy and convergence of the two approaches are critically compared in the case of two protein-ligand complexes (Abl kinase-SH3:p41 and MDM2-p53:NVP-CGM097) and three protein-protein complexes (pig insulin dimer, SARS-CoV-2 spike RBD:ACE2, and CheA kinase-P2:CheY)...In contrast, simulations bereft of geometrical restraints converge more poorly, yielding inconsistent results that are at variance with the experimental measurements. Furthermore, the orientational and positional time correlation functions of the protein in the unrestrained simulations decay over several microseconds, a time scale that is far longer than the typical simulation times of the geometrical route, which explains why those simulations fail to sample the relevant degrees of freedom during the separation process of the complexes."

Journal • Review • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • MDM2

Pharmacokinetic-pharmacodynamic guided optimisation of dose and schedule of CGM097, an HDM2 inhibitor, in preclinical and clinical studies. (PubMed, Br J Cancer) - P1 | "Despite delayed-onset thrombocytopenia frequently observed, the tolerability of CGM097 appears manageable. This study provided insights on dosing optimisation for next-generation HDM2 inhibitors."

Journal • PK/PD data • Preclinical • Hematological Disorders • Oncology • Solid Tumor • Thrombocytopenia • GDF15 • MDM2

Venetoclax-based rational combinations are effective in models of MYCN-amplified neuroblastoma. (PubMed, Mol Cancer Ther) - P1 | "First, MDM2 inhibitor NVP-CGM097 increases the pro-death BH3-only protein NOXA to sensitize p53-wild-type, MYCN-amplified NBs to venetoclax. Second, the MCL-1 inhibitor S63845 sensitizes MYCN-amplified NB through neutralization of MCL-1, inducing synergistic cell killing when combined with venetoclax. Lastly, the standard of care drug cocktail cyclophosphamide and topotecan reduces the apoptotic threshold of NB, thus setting the stage for robust combination efficacy with venetoclax...Venetoclax is currently being evaluated in pediatric patients in the clinic, including neuroblastoma (NCT03236857). While establishment of safety is still ongoing, the data disclosed herein indicate rational and clinically actionable combination strategies that could potentiate the activity of venetoclax in MYCN-amplified NB patients."

IO biomarker • Journal • Acute Myelogenous Leukemia • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Neuroblastoma • Oncology • Pediatrics • Solid Tumor • BCL2 • MYCN • PMAIP1

[VIRTUAL] Mdm2 inhibition synergises with endocrine therapy or cdk4/6 inhibition for the treatment of estrogen receptor-positive breast cancer (SABCS 2020) - " We used the MDM2 inhibitor NVP-CGM097 to treat in vitro and in vivo models alone and in combination with fulvestrant or palbociclib. We conclude that MDM2 inhibitors in combination with ER degraders or CDK4/6 inhibitors represent a rational strategy for treating advanced, endocrine resistant ER-positive breast cancer, operating through synergistic activation of cell cycle co-regulatory programs."

Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER

PD-1/PD-L1 blockade enhances MDM2 inhibitor activity in p53 wild-type cancers (AACR 2018) - "...From gene expression and immunohistochemical analysis of pre- and post-treatment biopsies from patients treated with the MDM2 inhibitor NVP-CGM097, we observed upregulation of immune checkpoint transcripts (PD1 and PDL1), and an increase in the number of CD8+ tumor infiltrating lymphocytes. To investigate the immunomodulatory effect of p53 in more detail, we studied murine syngeneic models treated with NVP-HDM201, a potent and selective second generation MDM2 inhibitor...The animals thatachieved complete regressions also developed long lasting anti-tumor memory against the specific tumor cells as evidenced by re-challenge experiments. Taken together, these results demonstrate that MDM2 inhibition triggered adaptive immunity which was further enhanced by blockade of PD-1/PD-L1 pathway, thereby providing a rationale for combining MDM2 inhibitors and checkpoint blocking antibodies in cancer patients with wildtype p53."

IO Biomarker • PD(L)-1 Biomarker • Oncology

The MDM2 inhibitor CGM097 synergizes with the BET inhibitor OTX015 to induce cell death in neuroblastoma cells (AACR 2018) - "This study indicates that the combination of CGM097 and OTX015 synergistically decreases viability in NB cells with wild-type p53 expression. Further in vitro and in vivo work will be necessary to elucidate the mechanisms behind this interaction and in vivo efficacy."

Neuroendocrine Tumor

[VIRTUAL] Integration of Deep Multi-Omics Profiling Veals New Insights into the Biology of Poor-Risk Acute Myeloid Leukemia (ASH 2020) - "Collectively, t(6;9) primary samples also showed a selective drug sensitivity to XPO1 (selinexor and eltanexor) and JAK inhibitors (ruxolitinib, tofacitinib and momelotinib) compared to other cytogenetic risk groups. On the other hand, a comparison of in vitro drug sensitivity data with genomic data of our entire cohort of patients demonstrated that TP53 wt AMLs (n=37) were more sensitive to all four MDM2 inhibitors (AMG-232, idasanutlin, SAR405838 and NVP-CGM097) compared to TP53 mutated cases (n=13). Comparisons of transcriptomics with the in vitro sensitivity to drugs included in early/late phase AML clinical trials, identified signatures of response associated with MDM2 and Aurora B kinase (AZD1152-HQPA) inhibitors...Functionally, group A presented with elevated HOXA10 protein expression and enhanced in vitro response to genotoxic drugs and cell cycle inhibitors when compared to group B leukemia. Conclusions : Our study demonstrates the feasibility of simultaneously..."

IO Biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD34 • FLT3 • FOXO3 • GATA2 • KIT • MLL • NUP214 • TP53

Small-molecule MDM2/X inhibitors and PROTAC degraders for cancer therapy: advances and perspectives. (PubMed, Acta Pharm Sin B) - "Numerous small-molecule MDM2 inhibitors have been reported since the release of the structure of the MDM2-P53 interaction in 1996, SAR405838, NVP-CGM097, MK-8242, RG7112, RG7388, DS-3032b, and AMG232 currently undergo clinical evaluation for cancer therapy. This review is intended to provide a comprehensive and updated overview of MDM2 inhibitors and proteolysis targeting chimera (PROTAC) degraders with a particular focus on how these inhibitors or degraders are identified from starting points, strategies employed, structure-activity relationship (SAR) studies, binding modes or co-crystal structures, biochemical data, mechanistic studies, and preclinical/clinical studies. Moreover, we briefly discuss the challenges of designing MDM2/X inhibitors for cancer therapy such as dual MDM2/X inhibition, acquired resistance and toxicity of P53 activation as well as future directions."

Journal • Review • Oncology • Targeted Protein Degradation

The MDM2 inhibitor CGM097 combined with the BET inhibitor OTX015 induces cell death and inhibits tumor growth in models of neuroblastoma. (PubMed, Cancer Med) - "This study warrants further investigation into the combination of MDM2 inhibitors and BET inhibitors for the treatment in NB."

Journal • Neuroblastoma • Oncology • Solid Tumor • MYC • MYCN

[VIRTUAL] MDM2 inhibition in combination with endocrine therapy and CDK4/6 inhibition for the treatment of ER-positive breast cancer (COSA 2020) - "Methods : We used the MDM2 inhibitor NVP-CGM097 to treat in vitro and in vivo models alone and in combination with fulvestrant or palbociclib. Combination therapy pushes cell lines resistant to fulvestrant or palbociclib to become senescent and significantly reduces tumour growth in a fulvestrant-resistant patient-derived xenograft model. Conclusions : We conclude that MDM2 inhibitors in combination with ER degraders or CDK4/6 inhibitors represent a rational strategy for treating advanced, endocrine-resistant ER-positive breast cancer, operating through synergistic activation of cell cycle co-regulatory programmes."

Combination therapy • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • MDM2

NVP-CGM097, an HDM2 Inhibitor, Antagonizes ATP-Binding Cassette Subfamily B Member 1-Mediated Drug Resistance. (PubMed, Front Oncol) - "Docking study indicated that NVP-CGM097 tended to bind to the inhibitory site, which led to slight but critical conformational changes in the transporter and reduced the ATPase activity. Overall, our study demonstrates that NVP-CGM097 can be used in conjunction with chemotherapeutic drugs to counteract MDR and improve the antitumor responses."

Journal • CNS Disorders • Oncology • ABCB1 • ABCG2 • TP53

MDM2 inhibition in combination with endocrine therapy and CDK4/6 inhibition for the treatment of ER-positive breast cancer. (PubMed, Breast Cancer Res) - "We conclude that MDM2 inhibitors in combination with ER degraders or CDK4/6 inhibitors represent a rational strategy for treating advanced, endocrine-resistant ER-positive breast cancer, operating through synergistic activation of cell cycle co-regulatory programmes."

Combination therapy • Journal • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • MDM2

MDM2 inhibition: an important step forward in cancer therapy. (PubMed, Leukemia) - "We identified the following molecules for inclusion in this review: RG7112 (RO5045337), idasanutlin (RG7388), AMG-232 (KRT-232), APG-115, BI-907828, CGM097, siremadlin (HDM201), and milademetan (DS-3032b). Overall, targeting MDM2 is a promising treatment strategy, as evidenced by the increasing number of MDM2 inhibitors entering the clinic. Additional clinical investigation is needed to further elucidate the role of MDM2 inhibitors in the treatment of human cancers."

Journal • Review • Hematological Malignancies • Oncology • Targeted Protein Degradation

CCGM097X2101: A Phase I Dose Escalation Study of CGM097 in Adult Patients With Selected Advanced Solid Tumors (clinicaltrials.gov) - P1; N=51; Completed; Sponsor: Novartis Pharmaceuticals; Active, not recruiting ➔ Completed

Clinical • Trial completion • Oncology • Solid Tumor

Structural states of Hdm2 and HdmX: X-ray elucidation of adaptations and binding interactions for different chemical compound classes. (PubMed, ChemMedChem) - "In addition, we report the previously unpublished details of X-ray structure determinations for eight further Hdm2 complexes, including the clinical trial compounds NVP-CGM097 and NVP-HDM201. In order to make comparisons easier, we have used the same numbering for Hdm2 and HdmX. Taken together, these structural insights should prove useful for the design and optimization of further selective and/or dual Hdm2/HdmX inhibitors."

Journal • Oncology • Targeted Protein Degradation

The Mdm2 inhibitor, NVP-CGM097, in combination with the BRAF inhibitor NVP-LGX818 elicits synergistic antitumor effects in melanoma (AACR 2014) - Presentation time: Wednesday, Apr 09, 2014, 8:00 AM -12:00 PM; Abstract #5466; “...combined inhibition of Mdm2, using NVP-CGM097, and BRAF using NVP-LGX818, synergistically inhibited the viability of BRAF mutant melanoma cells in vitro and tumor growth in vivo. NVP-CGM097 caused induction of p21 and Bax, while NVP-LGX818 did not."

Preclinical • Melanoma • Oncology

CCGM097X2101: A Phase I Dose Escalation Study of CGM097 in Adult Patients With Selected Advanced Solid Tumors (clinicaltrials.gov) - P1; N=51; Active, not recruiting; Sponsor: Novartis Pharmaceuticals; Trial primary completion date: Jun 2017 ➔ Jun 2018

Trial primary completion date • Biosimilar • Oncology • Solid Tumor

CCGM097X2101: A Phase I Dose Escalation Study of CGM097 in Adult Patients With Selected Advanced Solid Tumors (clinicaltrials.gov) - P1; N=51; Active, not recruiting; Sponsor: Novartis Pharmaceuticals; Trial completion date: Dec 2019 ➔ Jul 2020; Trial primary completion date: Dec 2019 ➔ Jul 2020

Clinical • Trial completion date • Trial primary completion date