TNG348 / Tango Therap, Medivir - LARVOL DELTA

VRN19: A novel USP1 Inhibitor with anti-tumor efficacy and favorable safety profile (AACR 2025) - "In the BRCA1-mutated CDX model (MDA-MB-436) and PDX with resistance to PARP inhibitors, VRN19 demonstrated synergistic effect with PARP inhibitors, particularly with olaparib, and showed efficacy comparable to KSQ-4279 without toxicity. In a 2-week toxicity study in rats, administration of 300 mg/kg VRN19 showed no significant changes in anemia markers, such as RBC, Hb, and reticulocytes, nor hepatotoxicity indicators like GGT and bilirubin. However, administration of 300 mg/kg KSQ-4279 significantly elevated anemia-related markers and GGT levels, consistent with the adverse events observed in clinical trials with KSQ-4279.In conclusion, VRN19 is a promising novel USP1 inhibitor with favorable safety and improved therapeutic outcomes."

Clinical • Late-breaking abstract • Oncology • BRCA • BRCA1 • BRCA2 • USP1

Discovery of TNG-6132, a potent, selective, and orally bioavailable USP1 inhibitor. (PubMed, Bioorg Med Chem Lett) - "This inhibitory effect translates into in vitro cellular viability defects in a BRCA1-mutant breast cancer cell line, as well as an in vivo pharmacodynamic (PD) response and tumor growth suppression in a mouse xenograft efficacy model. Additionally, we report an X-ray co-crystal structure of TNG-6132 (18) bound in the USP1-UAF1 complex, a result that furthered our understanding of the role played by key elements of the pharmacophore of this chemotype as well as its mechanism of inhibition of USP1."

Journal • Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • BRCA1 • BRCA2 • USP1

Characterization of TNG348: a selective, allosteric USP1 inhibitor that synergizes with PARP inhibitors in tumors with homologous recombination deficiency. (PubMed, Mol Cancer Ther) - P1/2 | "Importantly, our data in human cancer models further show that the addition of TNG348 to PARPi treatment can overcome acquired PARPi resistance in vivo. While the clinical development of TNG348 has been discontinued due to unexpected liver toxicity in patients (NCT06065059), the present data provides preclinical and mechanistic support for the continued exploration of USP1 as a drug target for the treatment of patients with BRCA1/2 mutant or HRD cancers."

Journal • Hepatology • Oncology • Targeted Protein Degradation • BRCA1 • BRCA2 • HRD • PCNA • USP1

Study to Evaluate TNG348 Alone and With a PARP Inhibitor in Patients With BRCA 1/2 Mutant or HRD+ Solid Tumors (clinicaltrials.gov) - P1/2 | N=7 | Terminated | Sponsor: Tango Therapeutics, Inc. | N=140 ➔ 7 | Trial completion date: Jun 2026 ➔ May 2024 | Recruiting ➔ Terminated | Trial primary completion date: Dec 2025 ➔ May 2024; Terminated due to safety

Combination therapy • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Breast Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Hepatology • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Solid Tumor • BRCA • BRCA1 • BRCA2

Tango Therapeutics Announces Discontinuation of TNG348 Program (Businesswire) - P1/2 | N=140 | NCT06065059 | Sponsor: Tango Therapeutics, Inc. | "Tango Therapeutics, Inc...today announced that it will discontinue development of its TNG348 program....TNG348 was being studied in a phase 1/2 clinical trial evaluating safety, pharmacokinetics, pharmacodynamics and efficacy as a single agent and in combination with olaparib, a PARP inhibitor, in patients with BRCA1/2-mutant and other HRD+ (homologous recombination deficient) cancers. Grade 3/4 liver function abnormalities were observed in patients remaining on study longer than eight weeks, leading to the decision to terminate the program."

Discontinued • P1/2 data • Oncology • Solid Tumor

Tango Therapeutics Reports First Quarter 2024 Financial Results and Provides Business Highlights (Businesswire) - "Single agent dose escalation is ongoing in the TNG348 phase 1/2 clinical trial evaluating the safety, pharmacokinetics, pharmacodynamics and efficacy of TNG348 as a single agent and in combination with olaparib, a PARP inhibitor, in patients with BRCA1/2-mutant and other HRD+ (homologous recombination deficient) cancers....Single agent dose escalation pharmacokinetic, pharmacodynamic, safety and tolerability data are favorable and support the opening of the combination cohort with olaparib in 2Q 2024."

P1/2 data • PK/PD data • Breast Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Solid Tumor

TNG348 is synergistic with PARP inhibitors in tumor models with elevated replication stress (AACR 2024) - "We previously showed that the anti-tumor activity of USP1 inhibition results from disruption of the translesion synthesis DNA damage tolerance pathway, a mechanism of action that is functionally distinct from base excision repair targeted by PARPi...For example, overexpression of oncogenes known to induce replication stress sensitized to the TNG348 and PARPi combination both in vitro and in vivo. These data indicate that cancer-specific elevated DNA replication stress could contribute to tumor sensitivity to TNG348 and provide additional patient stratification strategies and opportunities for indication expansion."

Preclinical • Oncology • BRCA1 • BRCA2 • DRD • HRD • USP1

Tango Therapeutics Reports Fourth Quarter and Full Year 2023 Financial Results and Provides Business Highlights (Businesswire) - "Upcoming Milestones: Clinical data from the ongoing TNG908 phase 1/2 trial are expected in 2024....In March 2024, an oral presentation of the discovery and preclinical characterization of TNG348 will be presented at the ACS Spring Meeting, supporting the further development and ongoing phase 1/2 clinical trial of TNG348 as a single agent and in combination with olaparib....In April 2024, seven posters will be presented highlighting preclinical data from the Company’s clinical-stage precision oncology pipeline and synthetic lethality discovery platform. Ayushi Patel, Ph.D. from NYU Langone Health will present a minisymposium based on a Tango-NYU collaboration to study TNG260 in STK11 mutant non-small cell lung cancer in preclinical models."

P1/2 data • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Tango Therapeutics Reports Fourth Quarter and Full Year 2023 Financial Results and Provides Business Highlights (Businesswire) - "Dose escalation is ongoing in the TNG260 phase 1/2 clinical trial evaluating the safety, pharmacokinetics, pharmacodynamics and efficacy of TNG260 in combination with pembrolizumab in patients with locally advanced or metastatic solid tumors with an STK11 loss-of-function mutation. To date, the preliminary safety, tolerability and pharmacokinetics profiles are favorable....Dose escalation is ongoing in the TNG348 phase 1/2 clinical trial evaluating the safety, pharmacokinetics, pharmacodynamics and efficacy of TNG348 as a single agent and in combination with olaparib, a PARP inhibitor, in patients with BRCA1/2-mutant and other HRD+ (homologous recombination deficient) cancers."

Trial status • Oncology • Solid Tumor

Discovery of TNG348, a selective and potent inhibitor of USP1 for treatment of BRCA1, BRCA2-mutant and other HRD+ cancers (ACS-Sp 2024) - "Biochemical and cellular viability studies, along with cryo-EM structural information, confirm TNG348 is an allosteric USP1 inhibitor and its role in anti-tumor activity. TNG348 is being evaluated as a single agent and in combination with PARP1i in BRCA1/2 mutant or HRD+ cancers. Herein we report on the discovery of TNG348, an orally active, potent, and selective inhibitor of USP1."

Oncology • Targeted Protein Degradation • BRCA1 • BRCA2 • HRD • USP1

Tango Therapeutics to Highlight Preclinical Data on Precision Oncology Pipeline at the American Association for Cancer Research (AACR) Annual Meeting 2024 (GlobeNewswire) - "Tango Therapeutics, Inc...today announced that one abstract has been selected for an oral minisymposium and seven abstracts have been accepted as poster presentations at the American Association for Cancer Research (AACR) Annual Meeting 2024, taking place April 5-10, 2024, in San Diego, California."

Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Tango Therapeutics Announces First Patient Dosed in Phase 1/2 Trial of TNG348 in Patients with BRCA1/2-Mutant and Other HRD+ Cancers (GlobeNewswire) - "Tango Therapeutics, Inc...announced that the first patient has been dosed in the phase 1/2 trial evaluating TNG348 as a single agent and in combination with olaparib, a PARP inhibitor, in patients with BRCA1/2-mutant or other HRD+ (homologous recombination deficient) cancers....The U.S. FDA granted TNG348 Fast Track designation in September 2023."

Fast track designation • Trial status • Breast Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Solid Tumor • BRCA1 • BRCA2

Study to Evaluate TNG348 Alone and With a PARP Inhibitor in Patients With BRCA 1/2 Mutant or HRD+ Solid Tumors (clinicaltrials.gov) - P1/2 | N=140 | Recruiting | Sponsor: Tango Therapeutics, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Breast Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Hepatology • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Solid Tumor • BRCA • BRCA1 • BRCA2

Tango Therapeutics Reports Third Quarter 2023 Financial Results and Provides Business Highlights (GlobeNewswire) - "Upcoming Milestones: TNG348 phase 1/2 clinical trial initiation expected 1H 2024. Additional data from the ongoing TNG908 clinical trial expected 2024....Society for NeuroOncology (SNO) 28th Annual Meeting, November 15-19, 2023, Vancouver, Canada: In November 2023, preclinical data will be presented in two poster presentations supporting the development of PRMT5 inhibitors in MTAP-deleted glioblastoma and malignant peripheral nerve sheath tumors....In November 2023, Tango scientists presented preclinical data highlighting the potential of TNG260 in STK11-mutant cancers. Preclinically, TNG260 combined with anti-PD1 therapy drives tumor regression in STK11-deficient models that are resistant to anti-PD1 monotherapy."

P1/2 data • Preclinical • Trial status • Breast Cancer • Genito-urinary Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Prostate Cancer • Solid Tumor

Study to Evaluate TNG348 Alone and With a PARP Inhibitor in Patients With BRCA 1/2 Mutant or HRD+ Solid Tumors (clinicaltrials.gov) - P1/2 | N=140 | Not yet recruiting | Sponsor: Tango Therapeutics, Inc.

Combination therapy • New P1/2 trial • Breast Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Hepatology • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Solid Tumor • BRCA • BRCA1 • BRCA2 • PCNA

TNG348, a selective USP1 inhibitor, shows strong preclinical combination activity with PARP inhibitors and other agents targeting DNA repair. (AACR-NCI-EORTC 2023) - No abstract available

Preclinical • Oncology • USP1

Medivir’s Partner Tango Therapeutics received FDA clearance to start the TNG348 phase 1/2 clinical study (PRNewswire) - "Preclinical data has shown synergistic effect with PARP inhibitors in PARP naïve models and that TNG348 is active in models with resistance to PARP inhibitors. These data suggest that TNG348 may benefit patients both as single agent or in combination with PARP inhibitors."

IND • New P1/2 trial • Preclinical • Breast Cancer • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer

Tango Therapeutics to Highlight Preclinical Data on Precision Oncology Pipeline at AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics (GlobeNewswire) - "Tango Therapeutics, Inc...announced that five abstracts have been selected for poster presentations at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, taking place from October 11-15, 2023 in Boston, Massachusetts."

Preclinical • Oncology • Solid Tumor

Cancer-specific AI identifies multi-modal biomarkers of therapeutic response for 1,951 drugs including TNG348, a highly selective USP1 inhibitor. (AACR-NCI-EORTC 2023) - No abstract available

Biomarker • Oncology • USP1

Tango Therapeutics Announces FDA Clearance of Investigational New Drug Application for TNG348, a Novel USP1 Inhibitor for the Treatment of BRCA1/2-mutant and Other HRD+ Cancers (GlobeNewswire) - "Tango Therapeutics, Inc...announced that the U.S. Food and Drug Administration (FDA) has cleared the Company’s Investigational New Drug (IND) application for TNG348, a novel inhibitor of USP1 (ubiquitin-specific protease 1), for the treatment of BRCA1/2 mutant and other HRD+ (homologous recombination deficient) cancers. 'FDA clearance to start the TNG348 phase 1/2 clinical study is an important step in the development of a novel treatment with the potential to treat a substantial number of ovarian, prostate and breast cancers. We plan to initiate the TNG348 clinical trial in the first half of 2024'..."

IND • New P1/2 trial • Breast Cancer • Genito-urinary Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Prostate Cancer • Solid Tumor

Tango Therapeutics Reports Second Quarter 2023 Financial Results and Provides Business Highlights (GlobeNewswire) - "Upcoming Milestones: TNG348 Investigational New Drug (IND) filing expected mid-2023. Additional data from the ongoing TNG908 clinical trial expected 2024."

P1/2 data • Oncology • Solid Tumor

Tango Therapeutics Reports First Quarter 2023 Financial Results and Provides Business Highlights (GlobeNewswire) - "Upcoming Milestones: First patient dose in the TNG462 phase 1/2 clinical trial expected mid-2023. TNG348 IND filing expected mid-2023. TNG260 phase 1/2 clinical trial initiation expected 2H 2023. Additional data from the ongoing TNG908 clinical trial expected 2024."

IND • New P1/2 trial • P1/2 data • Trial status • Brain Cancer • CNS Tumor • Oncology • Solid Tumor

Characterization of the clinical development candidate TNG348 as a potent and selective inhibitor of USP1 for the treatment of BRCA1/2mut cancers (AACR 2023) - "Furthermore, TNG348 activity extends beyond BRCA1/2mut models with PARP inhibitor (PARPi) sensitivity and oncogene-induced replication stress being additional features correlating with USP1 inhibitor sensitivity based on cell line panel and CRISPR screening results. We show that TNG348 induces cell death through a pathway that is distinct from PARPi and TNG348 demonstrates robust synergy when combined with first- or second-generation PARPi. The clinical development plan intends to evaluate TNG348 in patients with BRCA1/2 mutations as single agent and in combination with PARP1i in patients naïve to PARPi and with prior PARPi treatment history."

Clinical • Oncology • Ovarian Cancer • Solid Tumor • BRCA1 • BRCA2 • USP1

Tango Therapeutics Presents Preclinical Data on Precision Oncology Programs at the American Association of Cancer Research 2023 Annual Meeting (GlobeNewswire) - "Tango Therapeutics...announced highlights from presentations at the American Association for Cancer Research (AACR) 2023 Annual Meeting....Abstract #: 4970:...TNG462 causes deep tumor regressions across multiple histologies in preclinical patient and cell line derived xenograft models. TNG462 is synergistic with multiple targeted therapeutics including KRAS, EGFR, and MAT2A inhibitors, in MTAP-deleted xenograft models....Abstract #: 4968:...TNG348 has single agent activity and strong PARPi synergy in multiple BRCA1/2 mutant breast and ovarian cancer mouse models as well as other BRCA1/2 wild type HRD+ models."

Preclinical • Breast Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • BRCA1 • BRCA2 • EGFR • KRAS • MAT2A

Tango Therapeutics Reports Fourth Quarter and Full Year 2022 Financial Results and Provides Business Highlights (GlobeNewswire) - "Upcoming Milestones: An update from the ongoing dose escalation trial for TNG908 focused on proof-of-mechanism is on track for the second quarter of 2023. The IND filing for TNG260 is on track for the first half of 2023. The initiation of the Phase 1/2 clinical trial for TNG462 is on track for mid-2023. The IND filing for TNG348 is on track for mid-2023."

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