MAK683 / Novartis - LARVOL DELTA

Epigenetic Modifiers MMSET and EZH2 Physically Interact and Cooperate to Support Multiple Myeloma Pathophysiology (ASH 2023) - "Furthermore, MAK-683, an allosteric inhibitor of EZH2, disrupted this interaction, but not EPZ-6438, a catalytic inhibitor of EZH2, suggesting that MMSET-EZH2 interaction may be mediated by other PRC2 factors, but is independent of the PRC2 activity. Analysis of EZH2 expression levels and t(4; 14) translocation status in 3 independent cohorts of MM patients (CoMMPass (N=674), UAMS-TT2 (N=345), Mtp-Daratumumab (N=51)) identified a worse overall survival of patients with high EZH2 expression combined with t(4; 14) chromosomal translocation than patients with only one of these genetic events...Finally, we demonstrated that disrupting EZH2-MMSET interaction with MAK-683 may be of therapeutic interest, since MAK-683 combination with conventional drugs used in MM treatment, including melphalan and Panobinostat or BRD4 inhibitors, synergized to kill MM cells. Taken together, our data identified an "EZH2High t(4; 14)+" signature in MM patients with a poor outcome who..."

Hematological Malignancies • Multiple Myeloma • Oncology • BRD4 • EZH2 • IGF1 • IL6 • KRAS • NSD2

Identification of Transcriptional Targets of NSD2 and the Underlying Regulatory Mechanism in t(4; 14) Multiple Myeloma Cells Using the Slam-Seq and d-TAG Technologies (ASH 2024) - "To test to what extent NSD2 regulation of gene transcription is dependent on its SET domain function, we reconstituted NSD2dTAG and NSD2KO cells with doxycycline-inducible wild-type NSD2 (NSD2WT) or its SET-domain mutant (NSD2Y1179A) that is null for H3K36me2 methyl transferase activity...We employed two PRC2 inhibitors, EPZ-6438 and MAK-683, targeting the EZH2 and EED subunits respectively, to determine the relative contributions of H3K36me2 and H3K27me3 to NSD2-mediated transcriptional regulation...Mechanistically, we demonstrated that the transcriptional regulation by NSD2 is critically dependent on its SET domain function. Furthermore, this is directly dependent on the antagonistic effect of H3K36me2 on H3K27me3, rather than H3K36me2 itself, suggesting that H3K36me2 deposited by NSD2 creates a chromatin landscape conductive to transcription by preventing the deposition of H3K27me3."

Hematological Malignancies • Monoclonal Gammopathy • Multiple Myeloma • Oncology • NSD2 • PHGDH • PIK3CD

Polycomb repressive complex 2 (PRC2) pathway's role in cancer cell plasticity and drug resistance. (PubMed, Funct Integr Genomics) - "Inhibitors like MAK683 and EED226 disrupt EED's ability to maintain PRC2 activity, thereby reducing H3K27me3 levels and reactivating tumor suppressor genes. Valemetostat, a dual inhibitor of both EZH2 and EED, has shown promising results in aggressive cancers like diffuse large B-cell lymphoma and small-cell lung cancer, underlining the therapeutic potential of targeting multiple PRC2 components...Tazemetostat, a selective EZH2 inhibitor, has demonstrated significant clinical efficacy in EZH2-mutant cancers, such as non-Hodgkin lymphomas and epithelioid sarcoma. However, the compensatory function of enhancer of zeste homolog 1 (EZH1) in some cancers requires dual inhibition strategies, as seen with agents like UNC1999 and Tulmimetostat, which target both EZH1 and EZH2. Given PRC2's multifaceted role in cancer biology, its inhibition represents a promising avenue for therapeutic intervention. The continued development of PRC2 inhibitors and exploration of their..."

IO biomarker • Journal • Review • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Genito-urinary Cancer • Hematological Malignancies • Lung Cancer • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Prostate Cancer • Sarcoma • Small Cell Lung Cancer • Soft Tissue Sarcoma • Solid Tumor • EZH2

A first-in-human phase 1/2 dose-escalation study of MAK683 (EED inhibitor) in patients with advanced malignancies. (PubMed, Eur J Cancer) - P1 | "Overall, MAK683 treatment was well tolerated, and clinical activity was observed in patients with advanced DLBCL and ES."

Journal • P1/2 data • B Cell Lymphoma • Castration-Resistant Prostate Cancer • Clear Cell Carcinoma • Diffuse Large B Cell Lymphoma • Febrile Neutropenia • Gastric Cancer • Genito-urinary Cancer • Hematological Disorders • Hematological Malignancies • Lymphoma • Nasopharyngeal Carcinoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Ovarian Cancer • Ovarian Clear Cell Cancer • Prostate Cancer • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Thrombocytopenia

A First-in-Human Phase 1/2 Dose-Escalation Study of MAK683 (EED Inhibitor) in Patients with Advanced Malignancies (Eur J Cancer) - P1/2 | N=139 | NCT02900651 | Sponsor: Novartis Pharmaceuticals | "Overall, 139 patients (clear cell carcinoma of the ovary, n=9; castration-resistant prostate cancer, n=22; diffuse large B-cell lymphoma [DLBCL], n=31; epithelioid sarcoma [ES], n=17; gastric cancer, n=37; nasopharyngeal carcinoma, n=17; SWI/SNF-mutated sarcoma, n=6) received MAK683. Median duration of exposure was 57 days (range: 4-1006). Fifteen patients experienced 22 DLTs....Median progression-free survival was 1.9 months (90% confidence interval [CI]: 1.8-2.3), and overall response rate was 5.8% (90% CI: 2.52%-11.03%). Patients with advanced DLBCL and ES had clinical activity."

P1/2 data • Castration-Resistant Prostate Cancer • Diffuse Large B Cell Lymphoma • Gastric Cancer • Nasopharyngeal Carcinoma • Ovarian Cancer • Sarcoma

Safety and Efficacy of MAK683 in Adult Patients With Advanced Malignancies (clinicaltrials.gov) - P1 | N=139 | Terminated | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Terminated; The decision of early termination was made due to business reasons, and was not based on any safety or tolerability concerns for MAK683

Metastases • Trial termination • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Head and Neck Cancer • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Prostate Cancer

PPARγ and C/EBPα enable adipocyte differentiation upon inhibition of histone methyltransferase PRC2 in malignant tumors. (PubMed, J Biol Chem) - "Furthermore, the combination of the PPARγ agonist rosiglitazone and the PRC2 inhibitor MAK683 exhibited a higher inhibition on Ki67 positivity in tumor xenograft compared to MAK683 alone. High CEBPA, PLIN1 and FABP4 levels positively correlated with favorable prognosis in sarcoma patients in TCGA cohort. Together, these findings unveil an epigenetic regulatory mechanism for PPARG and highlight the essential role of PPARγ and C/EBPα in the adipocyte differentiation of MRTs and sarcomas with a potential clinical implication."

Epigenetic controller • Journal • Oncology • Rhabdoid Tumor • Sarcoma • Solid Tumor • CEBPA • FABP4 • PPARG

Safety and Efficacy of MAK683 in Adult Patients With Advanced Malignancies (clinicaltrials.gov) - P1 | N=139 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Phase classification: P1/2 ➔ P1

Metastases • Phase classification • Diffuse Large B Cell Lymphoma • Gastrointestinal Cancer • Head and Neck Cancer • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Prostate Cancer

Safety and Efficacy of MAK683 in Adult Patients With Advanced Malignancies (clinicaltrials.gov) - P1/2 | N=139 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Sep 2023 ➔ Jul 2024 | Trial primary completion date: Sep 2023 ➔ Jul 2024

Metastases • Trial completion date • Trial primary completion date • Diffuse Large B Cell Lymphoma • Gastrointestinal Cancer • Head and Neck Cancer • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Prostate Cancer • Solid Tumor

Safety and Efficacy of MAK683 in Adult Patients With Advanced Malignancies (clinicaltrials.gov) - P1/2 | N=139 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Active, not recruiting | N=203 ➔ 139

Enrollment change • Enrollment closed • Diffuse Large B Cell Lymphoma • Head and Neck Cancer • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Prostate Cancer • Solid Tumor

Discovery of the Clinical Candidate MAK683: An EED-Directed, Allosteric, and Selective PRC2 Inhibitor for the Treatment of Advanced Malignancies. (PubMed, J Med Chem) - "Here, we report the stepwise optimization of the tool compound EED226 toward the potent and selective EED inhibitor MAK683 (compound 22) and its subsequent preclinical characterization. Based on a balanced PK/PD profile, efficacy, and mitigated risk of forming reactive metabolites, MAK683 has been selected for clinical development."

Journal • Oncology

Phase I/II Study of MAK683 in Patients with Advanced Malignancies, Including Diffuse Large B-Cell Lymphoma (ASH 2021) - "MAK683 was generally well tolerated and there were preliminary signs of activity in patients with treatment-resistant DLBCL. The use of MAK683 as a novel strategy for the inhibition of EED may have potential in relapsed/refractory DLBCL."

Clinical • P1/2 data • Anemia • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Thrombocytopenia

Pharmacokinetic and pharmacodynamic activity evaluation of MAK683, a selective oral embryonic ectoderm development (EED) inhibitor, in adults with advanced malignancies in a first-in-human study. (ASCO 2022) - P1/2 | "MAK683 has a PK profile supportive of QD or BID dosing in patients with advanced malignancies. Analysis of H3K27me3 in blood monocytes and tumor biopsy confirm the in vivo pharmacodynamic activity of MAK683."

Clinical • P1 data • PK/PD data • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

HJM-353: A potent, selective and orally bioavailable EED inhibitor with robust anti-tumor activities (ESMO 2022) - "Recently EZH2 inhibitor Tazemetostat has been approved by FDA for the treatment of advanced epithelioid sarcoma and follicular lymphoma...In addition, HJM-353 caused tumor stasis as MAK683 did in a xKATO-III gastric xenograft model. Conclusions In summary, HJM-353 is a potent, selective and orally bioavailable EED inhibitor with robust anti-tumor activities. We are developing HJM-353 for the treatment of hematological malignancies and solid tumors and expect to file an IND in the second half of 2022."

Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Gastric Cancer • Gastrointestinal Cancer • Hematological Malignancies • Lymphoma • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • EZH2 • SUZ12

Safety and Efficacy of MAK683 in Adult Patients With Advanced Malignancies (clinicaltrials.gov) - P1/2 | N=203 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Nov 2022 ➔ Sep 2023 | Trial primary completion date: Oct 2022 ➔ Sep 2023

Trial completion date • Trial primary completion date • Diffuse Large B Cell Lymphoma • Head and Neck Cancer • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Prostate Cancer • Solid Tumor

[VIRTUAL] Phase I/II study of MAK683 in patients (pts) with advanced malignancies including epithelioid sarcoma (ESMO 2021) - P1/2 | "MAK683 was generally well-tolerated and there were preliminary signs of activity in pts with advanced epithelioid sarcoma."

Clinical • P1/2 data • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

Induction of senescence-associated secretory phenotype underlies the therapeutic efficacy of PRC2 inhibition in cancer. (PubMed, Cell Death Dis) - "The genes potential regulated by PRC2 in neuroblastoma samples exhibited significant enrichment of ECM and senescence associated inflammation, supporting the clinical relevance of our results. Altogether, our results unravel the pharmacological mechanism of PRC2 inhibitors and propose a combination strategy for MAK683 and other PRC2 drugs."

Journal • Immunology • Inflammation • Neuroblastoma • Oncology • Solid Tumor • ARID1A • CDKN2A • GBP1 • MMP2 • SMARCB1

Safety and Efficacy of MAK683 in Adult Patients With Advanced Malignancies (clinicaltrials.gov) - P1/2; N=203; Recruiting; Sponsor: Novartis Pharmaceuticals; Trial completion date: Aug 2022 ➔ Nov 2022

Clinical • Trial completion date • Diffuse Large B Cell Lymphoma • Head and Neck Cancer • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Prostate Cancer • Solid Tumor

Preclinical Pharmacokinetics and Metabolism of MAK683, a Clinical Stage Selective Oral Embryonic Ectoderm Development (EED) Inhibitor for Cancer Treatment. (PubMed, Xenobiotica) - "In addition, in-vivo biotransformation was also conducted in bile-duct cannulated (BDC) rat. The metabolism in BDC rat was similar to these observed the in vitro hepatocytes."

Journal • PK/PD data • Preclinical • Cholangiocarcinoma • Oncology • Solid Tumor

Safety and Efficacy of MAK683 in Adult Patients With Advanced Malignancies (clinicaltrials.gov) - P1/2; N=203; Recruiting; Sponsor: Novartis Pharmaceuticals; Trial completion date: Jan 2021 ➔ Aug 2022; Trial primary completion date: Jan 2021 ➔ Aug 2022

Clinical • Trial completion date • Trial primary completion date • Diffuse Large B Cell Lymphoma • Head and Neck Cancer • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Prostate Cancer • Solid Tumor

Safety and Efficacy of MAK683 in Adult Patients With Advanced Malignancies (clinicaltrials.gov) - P1/2; N=203; Recruiting; Sponsor: Novartis Pharmaceuticals; Trial primary completion date: Aug 2019 ➔ Jan 2021

Trial primary completion date

Safety and Efficacy of MAK683 in Adult Patients With Advanced Malignancies (clinicaltrials.gov) - P1/2; N=203; Recruiting; Sponsor: Novartis Pharmaceuticals; N=113 ➔ 203

Enrollment change