TNG462 / Tango Therap - LARVOL DELTA

Tango Therapeutics Announces First Patient Dosed in Phase 1/2 Trial of TNG462 plus Revolution Medicines’ Daraxonrasib or Zoldonrasib in Patients with RAS-Mutant MTAP-deleted Pancreatic or Lung Cancer (GlobeNewswire) - "Tango Therapeutics...announced that the first patient has been dosed in the Phase 1/2 trial of TNG462 and Revolution Medicines’ daraxonrasib (RAS(ON) multi-selective inhibitor) or zoldonrasib (RAS(ON) G12D-selective inhibitor) in patients with MTAP-deleted and RAS mutant metastatic pancreatic or lung cancer....The Phase 1/2 combination trial (NCT06922591) is evaluating safety, pharmacokinetics, pharmacodynamics and antitumor activity in TNG462 in combination with daraxonrasib and TNG462 in combination with zoldonrasib in pancreatic and lung cancer patients with an MTAP deletion and a co-occurring RAS mutation. TNG462...is currently being evaluated as monotherapy in a Phase 1/2 trial, with data expected in the second half of 2025. This upcoming monotherapy data update is anticipated to provide sufficient information to inform a registrational trial in pancreatic cancer next year and advance the development plan for lung cancer."

P1/2 data • Trial status • Non Small Cell Lung Cancer • Pancreatic Cancer

MTA-Cooperative PRMT5 Inhibitors are Efficacious in MTAP-Deleted Malignant Peripheral Nerve Sheath Tumor Models. (PubMed, Clin Cancer Res) - "Clinical stage MTA-cooperative PRMT5 inhibitors TNG908 and TNG462 are efficacious in MPNST models in vitro and in vivo; therefore MTA-cooperative PRMT5 inhibitors are promising therapeutic agents for patients with MTAP-deleted MPNST."

Journal • Preclinical • Brain Cancer • Neurofibrosarcoma • Oncology • Sarcoma • Solid Tumor • CDKN2A • MTAP

S095035 as a Single Agent and in Combination in Adult Participants With Advanced or Metastatic Solid Tumors With Deletion of MTAP (clinicaltrials.gov) - P1/2 | N=308 | Recruiting | Sponsor: Servier Bio-Innovation LLC | Phase classification: P1 ➔ P1/2 | N=27 ➔ 308 | Trial completion date: May 2026 ➔ Oct 2031 | Trial primary completion date: May 2026 ➔ Oct 2031

Enrollment change • Phase classification • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Study to Evaluate the Safety, Tolerability & Efficacy of TNG462 in Combination in PDAC & NSCLC Patients (clinicaltrials.gov) - P1/2 | N=133 | Recruiting | Sponsor: Tango Therapeutics, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Thoracic Cancer

Tango Therapeutics Reports First Quarter 2025 Financial Results and Provides Business Highlights (GlobeNewswire) - "TNG462: Enrollment in dose expansion is ongoing and a clinical data update on the TNG462 Phase 1/2 trial is expected in the second half of this year. This update is anticipated to provide sufficient information to inform a registrational trial in pancreatic cancer next year and determine the next steps for the development path in NSCLC; Based on promising preclinical data, the Company is on track to initiate a combination trial with TNG462, including RAS(ON) multi-selective inhibitor, daraxonrasib, and RAS(ON) G12D-selective inhibitor, zoldonrasib (Revolution Medicines). This trial is expected to begin enrolling in the second quarter of 2025."

New trial • P1/2 data • Trial status • Non Small Cell Lung Cancer • Pancreatic Cancer

Evaluation of the impact of homozygous MTAP truncations on the clinical activity of MTA-cooperative PRMT5 inhibitors (AACR 2025) - "To benefit this large patient population, MTA-cooperative PRMT5 inhibitors, including TNG908, TNG462, and TNG456 were developed to leverage the synthetic lethal relationship between MTAP deletion and PRMT5 inhibition. Previously, we reported that homozygous loss of only the terminal exon (exon 8), an event reported to occur in only 0.5% of MTAP-deleted tumors, is insufficient for complete loss of MTAP activity in preclinical assays. Here, we report initial evidence for the clinical impact of MTAP truncations, as opposed to complete deletion, on the activity of MTA-cooperative PRMT5 inhibitors."

Clinical • Oncology • CDKN2A • MTAP

TNG462, an MTA-cooperative PRMT5 inhibitor, demonstrates strong efficacy in combination with clinically relevant targeted therapies in MTAP-null preclinical models (AACR 2025) - "This supports our clinical development plans for TNG462, which include targeted combinations with two RAS(ON) inhibitors, RMC-6236 and RMC-9805 from Revolution Medicines, as well as the EGFR inhibitor osimertinib from AstraZeneca...Significant efficacy was observed in preclinical models with the combination of TNG462 and CDK4/6 inhibitors, supporting a potential development path in GBM for our next generation CNS penetrant PRMT5 inhibitor, TNG456, with abemaciclib...However, TNG462 monotherapy at a clinically relevant dose achieved comparable benefits to the combination. Collectively, these findings strongly support evaluating TNG462 in combination with other targeted therapies in clinical trials for patients with cancers that exhibit MTAP loss."

Combination therapy • Preclinical • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CDKN2A • KRAS • MAT2A • MTAP

TNG456 is a next-generation, brain-penetrant, MTA-cooperative PRMT5 inhibitor for the treatment of solid tumors with MTAP loss (AACR 2025) - "TNG908, TNG462, AMG 193, BMS-986504, and AZD3470 are clinical-stage MTA-cooperative PRMT5 inhibitors for the treatment of solid tumors with MTAP loss, though only TNG908 and AMG 193 are reported to be brain-penetrant. Oral administration of TNG456 drives dose-dependent antitumor activity including durable tumor regressions and complete responses in multiple cell line- and patient-derived xenograft models. With enhanced potency and selectivity for MTAP-null cancer cells, and strong preclinical evidence of brain-penetrance, TNG456 has the potential for broad clinical activity in MTAP-null solid tumors including gliomas and CNS metastases."

Brain Cancer • CNS Tumor • Glioma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • MTAP

Study to Evaluate the Safety, Tolerability & Efficacy of TNG462 in Combination in PDAC & NSCLC Patients (clinicaltrials.gov) - P1/2 | N=133 | Not yet recruiting | Sponsor: Tango Therapeutics, Inc.

New P1/2 trial • Hepatology • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Thoracic Cancer

Tango Therapeutics to Highlight Preclinical Data on Precision Oncology Pipeline with Five Posters at the American Association for Cancer Research (AACR) Annual Meeting 2025 (GlobeNewswire) - "Tango Therapeutics...announced that five abstracts have been accepted as poster presentations at the American Association for Cancer Research (AACR) Annual Meeting 2025....'The data we are presenting at this year’s AACR meeting highlights important preclinical analyses of our PRMT5 programs that underscore the potential of these molecules as both standalone treatments and as key combination partners in MTAP-deleted cancers, including in combination with KRAS-inhibitors'..."

Preclinical • Solid Tumor

Discovery of TNG462: A Highly Potent and Selective MTA-Cooperative PRMT5 Inhibitor to Target Cancers with MTAP Deletion. (PubMed, J Med Chem) - "We have previously described the discovery of TNG908, a brain-penetrant clinical-stage compound that selectively targets MTAP-deleted cancer cells by binding to and inhibiting PRMT5 cooperatively with MTA, which is present in elevated concentrations in MTAP-deleted cells. Herein we describe the discovery of TNG462, a more potent and selective MTA-cooperative PRMT5 inhibitor with improved DMPK properties that is selective for MTAP-deleted cancers and is currently in Phase I/II clinical trials."

Journal • Oncology • MTAP

Tango Therapeutics Reports Fourth Quarter and Full Year 2024 Financial Results and Provides Business Highlights (GlobeNewswire) - "Investigational New Drug (IND) application for TNG456, a next-generation brain-penetrant MTA-cooperative PRMT5 inhibitor, cleared by FDA. Phase 1/2 enrollment expected to begin 1H 2025; Data update from ongoing TNG462 monotherapy trial expected in 2025 with focus on pancreatic and lung cancer."

P1/2 data • Trial status • Lung Cancer • Pancreatic Cancer

TNG462-C101: Safety and Tolerability of TNG462 in Patients With MTAP-deleted Solid Tumors (clinicaltrials.gov) - P1/2 | N=225 | Recruiting | Sponsor: Tango Therapeutics, Inc. | N=159 ➔ 225

Enrollment change • Metastases • Lung Cancer • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • MTAP

Clinical collaboration with Revolution Medicines (Businesswire) - "In November 2024, the Company entered into a clinical collaboration with Revolution Medicines to evaluate the efficacy and safety of TNG462 in combination with RMC-6236, a RAS(ON) multi-selective inhibitor, and with RMC-9805, a RAS(ON) G12D-selective inhibitor. The agreement provides that Revolution Medicines will supply RMC-6236 and RMC-9805 to Tango and that Tango will be the sponsor of any combination trials. Each company will retain commercial rights to their respective compounds and the agreement is mutually non-exclusive."

Commercial • Oncology

Tango Therapeutics Reports Third Quarter 2024 Financial Results and Provides Business Highlights (Businesswire) - P1/2 | N=159 | NCT05732831 | Sponsor: Tango Therapeutics, Inc. | "Data from the ongoing phase 1/2 clinical trial of TNG462, a potentially best-in-class MTA-cooperative PRMT5 inhibitor, demonstrate clinical activity across multiple tumor types, including NSCLC and pancreatic cancer. Of note, this includes an ORR of 43% in cholangiocarcinoma (n=7). Substantive durability and a good safety and tolerability profile also were observed in this ongoing trial. The next clinical update is expected in 2025. The Company plans to initiate multiple targeted and standard of care combinations with TNG462 including RAS(ON) multi-selective and RAS(ON) G12D-selective inhibitors (Revolution Medicines), osimertinib (AstraZeneca) and pembrolizumab (Merck). These studies are expected to begin enrolling in 1H 2025."

New trial • P1/2 data • Non Small Cell Lung Cancer • Pancreatic Cancer

Tango Therapeutics Reports Second Quarter 2024 Financial Results and Provides Business Highlights (Businesswire) - "Enrollment in the dose expansion portion of the TNG908 phase 1/2 clinical trial is ongoing. Expansion cohorts are being enrolled in MTAP-deleted solid tumors in glioblastoma (GBM), non-small cell lung and pancreatic cancers at 600 mg BID....The dose expansion portion of the TNG462 phase 1/2 clinical trial is ongoing....A comprehensive update of the PRMT5 program, including clinical data from the ongoing phase 1/2 clinical trials of TNG908 and TNG462, is expected in 2H 2024."

P1/2 data • Trial status • Bladder Cancer • Cholangiocarcinoma • Glioblastoma • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Sarcoma

Tango Therapeutics Reports First Quarter 2024 Financial Results and Provides Business Highlights (Businesswire) - "Dose expansion is expected to initiate in the TNG462 phase 1/2 clinical trial in 2Q 2024...A comprehensive update of the PRMT5 program, including clinical data from the ongoing phase 1/2 clinical trials of TNG908 and TNG462, is expected in 2H 2024."

P1/2 data • Trial status • Oncology • Solid Tumor

MTAP loss alters the epigenetic landscape and demonstrates superior therapeutic sensitivity to concomitant PRMT5 and PARP inhibition in cholangiocarcinoma (AACR 2024) - P1/2 | "This renders selective targeting of MTAP null tumors with agents (MRTX1719, AMG193, TNG462, TNG908) targeting MTA bound PRMT5 (PRMT5:MTA), while sparing surrounding normal MTAP wild-type (WT) tissue...To address this pressing need, we co-treated CCA cell lines with MRTX1719 and PARP inhibitor olaparib...Similar differences in proportion of splicing events were also observed in MTAP loss CCA patient derived xenografts as compared to WT models. Collectively, these data implicate MTAP to be a crucial player in modulation of the chromatin and splicing events that may drive therapeutic response to PRMT5 inhibition."

Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • MTAP

Genome-wide drug anchor screens identify CAAP1 and AKAP17A as regulators of PRMT5 inhibitor sensitivity (AACR 2024) - "CAAP1 or AKAP17A knockout in MTAP-deleted cancer cell lines sensitized the cells to PRMT5 inhibitors including the clinical stage MTA-cooperative inhibitors, TNG908 and TNG462, and the non-MTA-cooperative inhibitor, GSK3326595. S. Yoda and M. R. Tonini contributed equally."

Oncology • CDKN2A • MTAP

Evaluation of the impact of homozygous MTAP truncations on the activity and selectivity of MTA-cooperative PRMT5 inhibitors (AACR 2024) - P1/2 | "To benefit this large and diverse patient population, MTA-cooperative PRMT5 inhibitors, including TNG908 and TNG462, have been developed to leverage the synthetic lethal relationship between MTAP deletion and PRMT5 inhibition. Here, we present our initial functional genomics analysis of this important diagnostic biomarker using in vitro cDNA reconstitution approaches for MTAP activity combined with analysis of PRMT5 inhibitor sensitivity. Ultimately, these data may help refine patient enrollment on clinical trials to drive the maximum benefit for patients with MTAP-deleted cancers."

Oncology • CDKN2A • MTAP

Tango Therapeutics Reports Fourth Quarter and Full Year 2023 Financial Results and Provides Business Highlights (Businesswire) - "The U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation (ODD) to TNG462 in December 2023 for the treatment of soft tissue sarcomas....Dose escalation is ongoing in the TNG462 phase 1/2 clinical trial in patients with MTAP-deleted solid tumors except GBM, as TNG462 is not brain penetrant in preclinical models....TNG462 has the same mechanism of action as TNG908, but with enhanced potency and selectivity in MTAP-deleted cell lines and patient-derived xenografts. In preclinical studies, TNG462 is 45X selective for MTAP-deleted cancer cells versus normal cells and ~30X more potent than TNG908."

Orphan drug • Preclinical • Trial status • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

MTA-cooperative PRMT5 inhibitors are efficacious in MTAP-deleted malignant peripheral nerve sheath tumor models (SNO 2023) - P1/2 | " The proliferation effects of MTA-cooperative PRMT5 inhibitors, TNG908 or TNG462, and a SAM-cooperative PRMT5 inhibitor, GSK3326595, on MTAP-deleted and MTAP-intact MPNST cell lines were determined using CellTiter-Glo (CTG) assays. The clinical stage MTA-cooperative PRMT5 inhibitors TNG908 (NCT05275478) and TNG462 (NCT05732831) are efficacious in MPNST models in vitro and in vivo and are therefore promising therapeutic agents for patients with MTAP-deleted MPNST."

Preclinical • Brain Cancer • Neurofibrosarcoma • Oncology • Sarcoma • Solid Tumor • CDKN2A • MTAP

Tango Therapeutics Announces $80 million Private Placement Financing (GlobeNewswire) - "Tango Therapeutics, Inc...has agreed to sell approximately 15.5 million shares of its common stock ('Common Stock') (or pre-funded warrants ('Pre-Funded Warrants') in lieu thereof) to a select group of institutional and accredited healthcare specialist investors in a private investment in public equity (PIPE) financing, at a per share price of $5.15....The financing is expected to close on Friday, August 11, 2023, subject to customary closing conditions. Gross proceeds from the private placement are anticipated to be approximately $80 million, before deducting any offering-related expenses....Proceeds from the financing are expected to enable rapid expansion across multiple tumor types for the TNG908 and TNG462 PRMT5 programs, as well as maintain funding through proof-of-concept for each of its clinical-stage programs as the Company awaits clinical data."

Financing • Biliary Cancer • Biliary Tract Cancer • Brain Cancer • Cholangiocarcinoma • CNS Tumor • Gastrointestinal Cancer • Glioblastoma • Glioma • Lung Cancer • Lung Non-Small Cell Squamous Cancer • Lung Non-Squamous Non-Small Cell Cancer • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Squamous Cell Carcinoma • Thoracic Cancer

Tango Therapeutics Announces First Patient Dosed in TNG462 Phase 1/2 Trial in Patients With MTAP-deleted Solid Tumors (GlobeNewswire) - "Tango Therapeutics...announced that the first patient has been dosed in the phase 1/2 trial of TNG462 in patients with MTAP-deleted solid tumors....The TNG462 phase 1/2 clinical trial will evaluate the safety, pharmacokinetics, pharmacodynamics and efficacy of TNG462 in solid tumors with MTAP deletions."

Trial status • Oncology • Solid Tumor

Discovery of TNG462, a highly potent and selective MTA-cooperative PRMT5 inhibitor that is synthetic lethal for MTAP deleted cancers (ACS-Fall 2023) - "By binding to and inhibiting PRMT5 cooperatively with MTA, TNG462 leverages the synthetic lethal relationship between MTAP deletion and PRMT5 to selectively kill MTAP-deleted cells with a mean 45-fold selectivity over MTAP-proficient cells. Herein we report on the discovery of TNG462, a potential best-in-class, potent, and selective MTA-cooperative PRMT5 inhibitor for the treatment of MTAP-deleted cancer."

Synthetic lethality • Oncology • Solid Tumor • MTAP • PRMT5