^
    Contact us  to learn more about
    our Premium Content:  News alerts, weekly reports and conference planners
    DRUG:

    brigimadlin (BI 907828)

    i
    Other names: BI 907828, BI-907828, BI907828
    Company:
    Boehringer Ingelheim
    Drug class:
    MDM2-p53 antagonist
    15d
    A Study in People With Advanced Cancer to Test Whether the Amount of BI 907828 in the Blood is Influenced by Taking an OATP Inhibitor or a CYP3 Inhibitor (clinicaltrials.gov)
    P1, N=34, Active, not recruiting, Boehringer Ingelheim | Trial completion date: Aug 2025 --> Feb 2025
    Trial completion date • Metastases
    |
    TP53 (Tumor protein P53)
    |
    TP53 wild-type
    |
    brigimadlin (BI 907828) • itraconazole • rifampicin
    24d
    This Study Aims to Find the Best Dose of BI 907828 (Brigimadlin) in Patients With Different Types of Advanced Cancer (Solid Tumors) (clinicaltrials.gov)
    P1, N=267, Active, not recruiting, Boehringer Ingelheim | Recruiting --> Active, not recruiting
    Enrollment closed • Metastases
    |
    TP53 (Tumor protein P53) • MDM2 (E3 ubiquitin protein ligase)
    |
    TP53 wild-type • MDM2 amplification • TP53 amplification
    |
    brigimadlin (BI 907828)
    1m
    A Study to Test Long-term Treatment With Brigimadlin in People With Solid Tumours Who Took Part in a Previous Study With This Medicine (clinicaltrials.gov)
    P2, N=50, Not yet recruiting, Boehringer Ingelheim
    New P2 trial
    |
    brigimadlin (BI 907828)
    2ms
    Brightline-2: A Study to Test Whether Brigimadlin (BI 907828) Helps People With Cancer in the Biliary Tract, Pancreas, Lung or Bladder (clinicaltrials.gov)
    P2, N=103, Recruiting, Boehringer Ingelheim | N=155 --> 103
    Enrollment change • Metastases
    |
    TP53 (Tumor protein P53) • MDM2 (E3 ubiquitin protein ligase)
    |
    TP53 wild-type • MDM2 amplification • TP53 amplification
    |
    brigimadlin (BI 907828)
    2ms
    Discovery and Characterization of Brigimadlin, a Novel and Highly Potent MDM2-p53 Antagonist Suitable for Intermittent Dose Schedules. (PubMed, Mol Cancer Ther)
    Exploratory clinical pharmacokinetic studies (NCT03449381) showed high systemic exposure and a long plasma elimination half-life in cancer patients who received oral brigimadlin. These findings support the continued clinical evaluation of brigimadlin in patients with MDM2-amplified cancers, such as dedifferentiated liposarcoma.
    Journal
    |
    MDM2 (E3 ubiquitin protein ligase)
    |
    TP53 mutation • TP53 wild-type • MDM2 amplification + TP53 wild-type
    |
    brigimadlin (BI 907828)
    4ms
    Brightline-4: A Study to Test How Well Brigimadlin is Tolerated by People With a Type of Cancer Called Dedifferentiated Liposarcoma (clinicaltrials.gov)
    P3, N=240, Active, not recruiting, Boehringer Ingelheim | Recruiting --> Active, not recruiting
    Enrollment closed • Metastases
    |
    MDM2 (E3 ubiquitin protein ligase)
    |
    brigimadlin (BI 907828)
    4ms
    A Study to Determine How BI 907828 (Brigimadlin) is Taken up in the Tumor (Phase 0) and to Determine the Highest Dose of BI 907828 (Brigimadlin) That Could be Tolerated (Phase 1a) in Combination With Radiation Therapy in People With a Brain Tumor Called Glioblastoma (clinicaltrials.gov)
    P1, N=28, Recruiting, Boehringer Ingelheim | Trial completion date: Dec 2027 --> Dec 2026 | Trial primary completion date: Nov 2027 --> Nov 2026
    Trial completion date • Trial primary completion date • Combination therapy
    |
    TP53 (Tumor protein P53)
    |
    brigimadlin (BI 907828)
    4ms
    Brightline-3: A Study to Find Out Whether Brigimadlin in Combination With Ezabenlimab Helps People With Advanced Soft Tissue Sarcoma (clinicaltrials.gov)
    P3, N=0, Withdrawn, Boehringer Ingelheim | N=263 --> 0 | Not yet recruiting --> Withdrawn
    Enrollment change • Trial withdrawal • Combination therapy • Metastases
    |
    gemcitabine • docetaxel • brigimadlin (BI 907828) • ezabenlimab (BI 754091)
    4ms
    Brightline-2: A Study to Test Whether Brigimadlin (BI 907828) Helps People With Cancer in the Biliary Tract, Pancreas, Lung or Bladder (clinicaltrials.gov)
    P2, N=155, Recruiting, Boehringer Ingelheim | Trial completion date: Mar 2027 --> Nov 2026 | Trial primary completion date: Jun 2025 --> Feb 2025
    Trial completion date • Trial primary completion date • Metastases
    |
    TP53 (Tumor protein P53) • MDM2 (E3 ubiquitin protein ligase)
    |
    brigimadlin (BI 907828)
    5ms
    A Study in People With Advanced Cancer to Test Whether the Amount of BI 907828 in the Blood is Influenced by Taking an OATP Inhibitor or a CYP3 Inhibitor (clinicaltrials.gov)
    P1, N=32, Active, not recruiting, Boehringer Ingelheim | Recruiting --> Active, not recruiting
    Enrollment closed • Metastases
    |
    TP53 (Tumor protein P53)
    |
    brigimadlin (BI 907828) • itraconazole • rifampicin
    5ms
    Treatment options for biliary tract cancer: unmet needs, new targets and opportunities from both physicians' and patients' perspectives. (PubMed, Future Oncol)
    MDM2/MDMX are important negative regulators of the tumor suppressor p53 and provide an additional target in BTC (∼5-8% of tumors are MDM2-amplified). Brigimadlin (BI 907828) is a highly potent MDM2-p53 antagonist that has shown antitumor activity in preclinical studies and promising results in early clinical trials; enrollment is ongoing in a potential registrational trial for patients with BTC.
    Review • Journal • IO biomarker
    |
    TP53 (Tumor protein P53) • MDM2 (E3 ubiquitin protein ligase)
    |
    brigimadlin (BI 907828)
    5ms
    Brightline-2: A Study to Test Whether Brigimadlin (BI 907828) Helps People With Cancer in the Biliary Tract, Pancreas, Lung or Bladder (clinicaltrials.gov)
    P2, N=155, Recruiting, Boehringer Ingelheim | Trial primary completion date: Feb 2025 --> Jun 2025
    Trial primary completion date • Metastases
    |
    TP53 (Tumor protein P53) • MDM2 (E3 ubiquitin protein ligase)
    |
    brigimadlin (BI 907828)
    6ms
    A Study in People With Advanced Cancer to Test How BI 907828 is Processed in the Body (clinicaltrials.gov)
    P1, N=13, Active, not recruiting, Boehringer Ingelheim | Recruiting --> Active, not recruiting
    Enrollment closed
    |
    brigimadlin (BI 907828)
    6ms
    A Study in Patients With Different Types of Advanced Cancer (Solid Tumors) to Test Different Doses of BI 907828 in Combination With BI 754091 (Ezabenlimab) and BI 754111 or BI 907828 in Combination With BI 754091 (Ezabenlimab) (clinicaltrials.gov)
    P1, N=119, Active, not recruiting, Boehringer Ingelheim | Recruiting --> Active, not recruiting
    Enrollment closed • Combination therapy • Metastases
    |
    TP53 (Tumor protein P53) • MDM2 (E3 ubiquitin protein ligase)
    |
    TP53 mutation • TP53 wild-type • TP53 amplification
    |
    brigimadlin (BI 907828) • ezabenlimab (BI 754091) • miptenalimab (BI 754111)
    7ms
    Brightline-3: A Study to Find Out Whether Brigimadlin in Combination With Ezabenlimab Helps People With Advanced Soft Tissue Sarcoma (clinicaltrials.gov)
    P3, N=263, Not yet recruiting, Boehringer Ingelheim
    New P3 trial • Combination therapy • Metastases
    |
    gemcitabine • docetaxel • brigimadlin (BI 907828) • ezabenlimab (BI 754091)
    7ms
    Brightline-4: A Study to Test How Well Brigimadlin is Tolerated by People With a Type of Cancer Called Dedifferentiated Liposarcoma (clinicaltrials.gov)
    P3, N=240, Recruiting, Boehringer Ingelheim | Initiation date: Mar 2023 --> Dec 2023
    Trial initiation date • Metastases
    |
    MDM2 (E3 ubiquitin protein ligase)
    |
    MDM2 amplification
    |
    brigimadlin (BI 907828)
    8ms
    Brightline-4: A Study to Test How Well Brigimadlin is Tolerated by People With a Type of Cancer Called Dedifferentiated Liposarcoma (clinicaltrials.gov)
    P3, N=240, Recruiting, Boehringer Ingelheim | Initiation date: Dec 2023 --> Mar 2023
    Trial initiation date • Metastases
    |
    MDM2 (E3 ubiquitin protein ligase)
    |
    MDM2 amplification
    |
    brigimadlin (BI 907828)
    8ms
    A Study in Patients With Different Types of Advanced Cancer (Solid Tumors) to Test Different Doses of BI 907828 in Combination With BI 754091 (Ezabenlimab) and BI 754111 or BI 907828 in Combination With BI 754091 (Ezabenlimab) (clinicaltrials.gov)
    P1, N=140, Recruiting, Boehringer Ingelheim | Phase classification: P1a/1b --> P1
    Phase classification • Combination therapy • Metastases
    |
    TP53 (Tumor protein P53) • MDM2 (E3 ubiquitin protein ligase)
    |
    TP53 mutation • TP53 wild-type • TP53 amplification
    |
    brigimadlin (BI 907828) • ezabenlimab (BI 754091) • miptenalimab (BI 754111)
    10ms
    Brightline-2: a phase IIa/IIb trial of brigimadlin (BI 907828) in advanced biliary tract cancer, pancreatic ductal adenocarcinoma or other solid tumors. (PubMed, Future Oncol)
    Brigimadlin (BI 907828) is a highly potent MDM2-p53 antagonist that has shown promising activity in preclinical and early-phase clinical studies. This manuscript describes the rationale and design of an ongoing phase IIa/IIb Brightline-2 trial evaluating brigimadlin as second-line treatment for patients with advanced/metastatic BTC, PDAC, lung adenocarcinoma, or bladder cancer.
    P2a data • Review • Journal • Metastases
    |
    TP53 (Tumor protein P53) • MDM2 (E3 ubiquitin protein ligase)
    |
    TP53 wild-type • MDM2 amplification + TP53 wild-type • TP53 amplification
    |
    brigimadlin (BI 907828)
    11ms
    Brightline-4: A Study to Test How Well Brigimadlin is Tolerated by People With a Type of Cancer Called Dedifferentiated Liposarcoma (clinicaltrials.gov)
    P3, N=240, Recruiting, Boehringer Ingelheim | Not yet recruiting --> Recruiting
    Enrollment open
    |
    MDM2 (E3 ubiquitin protein ligase)
    |
    MDM2 amplification
    |
    brigimadlin (BI 907828)
    12ms
    Brightline-2: A Study to Test Whether Brigimadlin (BI 907828) Helps People With Cancer in the Biliary Tract, Pancreas, Lung or Bladder (clinicaltrials.gov)
    P2, N=155, Recruiting, Boehringer Ingelheim | Phase classification: P2a/2b --> P2
    Phase classification
    |
    TP53 (Tumor protein P53) • MDM2 (E3 ubiquitin protein ligase)
    |
    TP53 wild-type • MDM2 amplification • TP53 amplification
    |
    brigimadlin (BI 907828)
    almost1year
    This Study Aims to Find the Best Dose of BI 907828 (Brigimadlin) in Patients With Different Types of Advanced Cancer (Solid Tumors) (clinicaltrials.gov)
    P1, N=269, Recruiting, Boehringer Ingelheim | Phase classification: P1a/1b --> P1 | N=204 --> 269
    Phase classification • Enrollment change • Metastases
    |
    TP53 (Tumor protein P53) • MDM2 (E3 ubiquitin protein ligase)
    |
    TP53 wild-type • MDM2 amplification • TP53 amplification
    |
    brigimadlin (BI 907828)
    1year
    A Study in People With Advanced Cancer to Test How BI 907828 is Processed in the Body (clinicaltrials.gov)
    P1, N=16, Recruiting, Boehringer Ingelheim | Trial primary completion date: Feb 2024 --> May 2024
    Trial primary completion date • Metastases
    |
    brigimadlin (BI 907828)
    1year
    Burning Rock and Boehringer Ingelheim Achieved a Master Service Agreement in Oncology Companion Diagnostics (GlobeNewswire)
    "Burning Rock Biotech Limited...is pleased to announce that the Company and Boehringer Ingelheim officially have signed the Master Service Agreement (MSA) in the field of oncology companion diagnostics. This agreement aims to provide Chinese patients with safer, more efficient, and precise treatment options and diagnostic methods, thereby promoting innovation and development in cancer treatment. This partnership will primarily focus on advancing the clinical trials related to Boehringer Ingelheim's MDM2-p53 antagonist, brigimadlin (BI 907828), and the development of companion diagnostic products in China."
    Licensing / partnership
    |
    brigimadlin (BI 907828)
    1year
    EMPIRE: Targeting MDMD and PD1 in Tumors With Tertiary Lymphoid Structures (clinicaltrials.gov)
    P2, N=120, Not yet recruiting, Institut Bergonié
    New P2 trial
    |
    PD-L1 (Programmed death ligand 1) • TP53 (Tumor protein P53)
    |
    TP53 wild-type
    |
    brigimadlin (BI 907828) • ezabenlimab (BI 754091)
    1year
    Delivery versus potency in treating brain tumors: BI-907828, a MDM2-p53 antagonist with limited BBB penetration but significant in vivo efficacy in glioblastoma. (PubMed, Mol Cancer Ther)
    These studies show that efficacy of BI-907828 in orthotopic models is related to high potency even though its CNS distribution is limited by BBB efflux. Therefore, a comprehensive understanding of all aspects of the "Delivery - Potency - Efficacy" relationship is warranted in drug discovery and development, especially for treatment of CNS tumors.
    Preclinical • Journal
    |
    MDM2 (E3 ubiquitin protein ligase)
    |
    TP53 wild-type
    |
    brigimadlin (BI 907828)
    1year
    Brightline-4: A Study to Test How Well Brigimadlin is Tolerated by People With a Type of Cancer Called Dedifferentiated Liposarcoma (clinicaltrials.gov)
    P3, N=240, Not yet recruiting, Boehringer Ingelheim
    New P3 trial • Metastases
    |
    MDM2 (E3 ubiquitin protein ligase)
    |
    MDM2 amplification
    |
    brigimadlin (BI 907828)
    1year
    Brightline-1: A Study to Compare BI 907828 With Doxorubicin in People With a Type of Cancer Called Dedifferentiated Liposarcoma (clinicaltrials.gov)
    P2/3, N=386, Active, not recruiting, Boehringer Ingelheim | Recruiting --> Active, not recruiting
    Enrollment closed • Metastases
    |
    MDM2 (E3 ubiquitin protein ligase)
    |
    MDM2 amplification
    |
    doxorubicin hydrochloride • brigimadlin (BI 907828)
    1year
    A Study in People With Advanced Cancer to Test Whether the Amount of BI 907828 in the Blood is Influenced by Taking an OATP Inhibitor or a CYP3 Inhibitor (clinicaltrials.gov)
    P1, N=32, Recruiting, Boehringer Ingelheim | N=16 --> 32 | Trial primary completion date: Aug 2023 --> Aug 2024
    Enrollment change • Trial primary completion date • Metastases
    |
    TP53 (Tumor protein P53)
    |
    TP53 wild-type
    |
    brigimadlin (BI 907828) • itraconazole • rifampicin
    1year
    LONGITUDINAL MUTATIONAL ANALYSIS OF TP53 IN CIRCULATING TUMOR DNA IN THE PLASMA OF PATIENTS WITH LIPOSARCOMA IN A PHASE I STUDY OF BRIGIMADLIN (BI 907828), AN MDM2-P53 ANTAGONIST (CTOS 2023)
    This mutation analysis represents one of the most robust assessments of longitudinal ctDNA by NGS for TP53 from an MDM2–p53 antagonist trial in liposarcoma. While acquired mutations in TP53 are very common, these data suggest that brigimadlin does not systematically lead to broad acquisition of resistance by inducing alterations in TP53.
    Clinical • P1 data • Circulating tumor DNA
    |
    TP53 (Tumor protein P53)
    |
    TP53 mutation • TP53 wild-type • TP53 R175H • TP53 R248Q • TP53 R273H
    |
    brigimadlin (BI 907828)
    over1year
    The MDM2-p53 antagonist BI 907828 in patients with advanced or metastatic solid tumors: results of a phase Ia, first-in-human, dose-escalation study. (PubMed, Cancer Discov)
    As evidence of target engagement, time- and dose-dependent increases in GDF-15 levels were seen. Preliminary efficacy was encouraging (11.1% overall response and 74.1% disease control rates), particularly in well-differentiated or dedifferentiated liposarcoma patients (100% and 75% disease control rates, respectively).
    P1 data • Journal • Metastases
    |
    MDM2 (E3 ubiquitin protein ligase) • GDF15 (Growth differentiation factor 15)
    |
    brigimadlin (BI 907828)
    over1year
    MDM2 Inhibition in the Treatment of Glioblastoma: From Concept to Clinical Investigation. (PubMed, Biomedicines)
    While some MDM2 inhibitors have progressed to early phase clinical trials in GBM, their efficacy, alone and in combination, is yet to be confirmed. In this article, we present an overview of MDM2 inhibitors currently under preclinical and clinical investigation, with a specific focus on the drugs being assessed in ongoing clinical trials for GBM patients.
    Review • Journal
    |
    TP53 wild-type
    |
    navtemadlin (KRT-232) • idasanutlin (RG7388) • brigimadlin (BI 907828) • ALRN-6924
    over1year
    A phase I dose-escalation and expansion study evaluating the safety and efficacy of the MDM2–p53 antagonist brigimadlin (BI 907828) in patients (pts) with solid tumours (ESMO 2023)
    Conclusions BI 907828 demonstrated antitumour activity and a manageable safety profile in pts with advanced solid tumours, including those with BTC; dose expansion is ongoing. BI 907828 is being further assessed in pts with BTC in the phase IIa/IIb open-label Brightline-2 trial (NCT05512377).
    Clinical • P1 data
    |
    MDM2 (E3 ubiquitin protein ligase)
    |
    TP53 wild-type • MDM2 amplification + TP53 wild-type
    |
    brigimadlin (BI 907828)
    over1year
    New targeted treatments for advanced sarcomas. (PubMed, Curr Opin Oncol)
    Molecular-guided precision medicine holds a bright future in bringing more active treatments for advanced sarcoma patients.
    Journal • IO biomarker • Metastases
    |
    MDM2 (E3 ubiquitin protein ligase) • XPO1 (Exportin 1) • SS18 (SS18 Subunit Of BAF Chromatin Remodeling Complex)
    |
    CDK4 amplification • MDM2 overexpression • MDM2 amplification + CDK4 amplification • SS18-SSX fusion
    |
    imatinib • Xpovio (selinexor) • Tazverik (tazemetostat) • milademetan (RAIN-32) • Fyarro (nanoparticle albumin-bound rapamycin) • brigimadlin (BI 907828)
    over1year
    Brightline-1: phase II/III trial of the MDM2-p53 antagonist BI 907828 versus doxorubicin in patients with advanced DDLPS. (PubMed, Future Oncol)
    BI 907828 has shown promising activity in preclinical studies and in a phase Ia/Ib study in patients with solid tumors, particularly those with DDLPS. This manuscript describes the rationale and design of an ongoing multicenter, randomized, phase II/III trial (Brightline-1; NCT05218499) evaluating BI 907828 versus doxorubicin as first-line treatment for advanced DDLPS.
    P2/3 data • Review • Journal • Metastases
    |
    MDM2 (E3 ubiquitin protein ligase)
    |
    doxorubicin hydrochloride • brigimadlin (BI 907828)
    over1year
    Brightline-2: A phase IIa/IIb, open-label trial of the MDM2–p53 antagonist BI 907828 in patients with advanced MDM2-amplified, TP53 wild-type biliary tract cancer, pancreatic ductal adenocarcinoma, or other selected solid tumours (ESMO-GI 2023)
    Currently, ten patients with BTC had received BI 907828 ± ezabenlimab (an immune checkpoint inhibitor). The final primary analysis will be performed after all treated patients have been followed for ≥12 weeks, or until study discontinuation. As of February 2023, 16 patients have been enrolled.Clinical trial identification: NCT05512377.Editorial acknowledgement: Medical writing assistance, funded by Boehringer Ingelheim, was provided by Jim Sinclair, PhD, of Ashfield MedComms, an Inizio Company, during the preparation of this abstract.Legal entity responsible for the study: Boehringer Ingelheim.
    Clinical • P2a data • Metastases
    |
    TP53 (Tumor protein P53) • MDM2 (E3 ubiquitin protein ligase)
    |
    TP53 wild-type • MDM2 amplification • MDM2 amplification + TP53 wild-type • TP53 amplification
    |
    brigimadlin (BI 907828) • ezabenlimab (BI 754091)
    over1year
    Brightline-2: A Study to Test Whether Brigimadlin (BI 907828) Helps People With Cancer in the Biliary Tract, Pancreas, Lung or Bladder (clinicaltrials.gov)
    P2a/2b, N=155, Recruiting, Boehringer Ingelheim | Trial completion date: Nov 2026 --> Mar 2027
    Trial completion date
    |
    TP53 (Tumor protein P53) • MDM2 (E3 ubiquitin protein ligase)
    |
    TP53 wild-type • MDM2 amplification • TP53 amplification
    |
    brigimadlin (BI 907828)
    over1year
    Longitudinal mutational analysis of TP53 in plasma circulating tumor DNA (ctDNA) in patients (pts) with solid tumors in a phase I study of BI 907828, an MDM2–p53 antagonist. (ASCO 2023)
    This mutation analysis represents one of the most comprehensive assessments of longitudinal ctDNA by NGS for TP53 from a clinical trial of an MDM2–p53 antagonist. Preliminary data suggest that BI 907828 does not systematically lead to broad acquisition of resistance by inducing alterations in TP53. Clinical trial information: NCT03449381.
    Clinical • P1 data • Circulating tumor DNA
    |
    TP53 (Tumor protein P53)
    |
    TP53 mutation • TP53 wild-type • TP53 R175H • TP53 R248Q
    |
    brigimadlin (BI 907828)
    over1year
    A Study in People With Advanced Cancer to Test Whether the Amount of BI 907828 in the Blood is Influenced by Taking an OATP Inhibitor or a CYP3 Inhibitor (clinicaltrials.gov)
    P1, N=16, Recruiting, Boehringer Ingelheim | Trial completion date: Jun 2024 --> Jun 2025
    Trial completion date • Metastases
    |
    TP53 (Tumor protein P53)
    |
    TP53 wild-type
    |
    brigimadlin (BI 907828) • itraconazole • rifampicin
    over1year
    Brightline-1: A Study to Compare BI 907828 With Doxorubicin in People With a Type of Cancer Called Dedifferentiated Liposarcoma (clinicaltrials.gov)
    P2/3, N=390, Recruiting, Boehringer Ingelheim | N=300 --> 390
    Enrollment change • Metastases
    |
    MDM2 (E3 ubiquitin protein ligase)
    |
    MDM2 amplification
    |
    doxorubicin hydrochloride • brigimadlin (BI 907828)
    almost2years
    Foundation Medicine Announces Global Collaboration with Boehringer Ingelheim to Advance Biliary Tract Cancer Care (Foundation Medicine Press Release)
    "Foundation Medicine, Inc...announced a global collaboration with Boehringer Ingelheim to develop the company’s tissue-based comprehensive genomic profiling test, FoundationOne®CDx, as a companion diagnostic for Boehringer Ingelheim’s investigational MDM2-p53 antagonist, BI 907828, in the United States, Japan and European Union."
    Licensing / partnership
    |
    FoundationOne® CDx
    |
    brigimadlin (BI 907828)
    almost2years
    Brightline-2: A Study to Test Whether BI 907828 Helps People With Cancer in the Biliary Tract, Pancreas, Lung or Bladder (clinicaltrials.gov)
    P2a/2b, N=130, Recruiting, Boehringer Ingelheim | N=100 --> 130
    Enrollment change • Metastases
    |
    TP53 (Tumor protein P53) • MDM2 (E3 ubiquitin protein ligase)
    |
    TP53 wild-type • MDM2 amplification • TP53 amplification
    |
    brigimadlin (BI 907828)