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    DRUG:

    zotatifin (eFT226)

    i
    Other names: eFT226, selective translation inhibitor, Zota
    Company:
    eFFECTOR Therap
    Drug class:
    eIF4A1 inhibitor
    Related drugs:
    5ms
    eIF4A controls translation of estrogen receptor alpha and is a therapeutic target in advanced breast cancer. (PubMed, Proc Natl Acad Sci U S A)
    In an early clinical trial (NCT04092673), the eIF4A inhibitor zotatifin was combined with either fulvestrant or fulvestrant plus CDK4 inhibitor, abemaciclib, in patients with acquired resistance to these agents. Multiple clinical responses including a handful of durable regressions were observed, with little toxicity. Thus, eIF4A inhibition could be useful for treating ER+ breast cancer resistant to other modalities.
    Journal
    |
    ER (Estrogen receptor) • CCND1 (Cyclin D1)
    |
    Verzenio (abemaciclib) • fulvestrant • zotatifin (eFT226)
    5ms
    Umbrella Trial of Subtype-Targeted Therapies in ER+/HER2- Breast Cancer (clinicaltrials.gov)
    P2, N=19, Suspended, Stanford University | Active, not recruiting --> Suspended
    Trial suspension
    |
    HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PGR (Progesterone receptor)
    |
    ER positive • HER-2 negative • HER-2 negative + ER positive
    |
    Piqray (alpelisib) • fulvestrant • zotatifin (eFT226) • Soltamox (tamoxifen citrate)
    6ms
    Targeting EIF4A1 is effective against human intrahepatic cholangiocarcinoma. (PubMed, JHEP Rep)
    Moreover, the Bcl-xl inhibitors A-1155463 and DT2216 profoundly augmented apoptotic cell death when administered in association with zotatifin. From a clinical standpoint, these results suggest that zotatifin improves patient outcomes by inhibiting iCCA growth and reducing tumor aggressiveness. Furthermore, combining zotatifin with other drugs could represent a promising therapeutic strategy for targeting iCCA.
    Journal
    |
    BCL2L1 (BCL2-like 1) • EIF4G1 (Eukaryotic translation initiation factor 4 gamma, 1)
    |
    zotatifin (eFT226) • DT2216
    6ms
    RESOLVE: Abemaciclib + Letrozole +/- Metformin, Zotatifin, or Gedatolisib in Endometrial or Low-Grade Serous Ovarian Cancer (clinicaltrials.gov)
    P2, N=180, Recruiting, Dana-Farber Cancer Institute | Active, not recruiting --> Recruiting | N=130 --> 180 | Trial completion date: Aug 2030 --> Aug 2031 | Trial primary completion date: Aug 2027 --> Aug 2028
    Enrollment open • Enrollment change • Trial completion date • Trial primary completion date
    |
    ER (Estrogen receptor)
    |
    ER positive
    |
    Verzenio (abemaciclib) • letrozole • gedatolisib (PF-05212384) • zotatifin (eFT226) • metformin • samotolisib (LY3023414)
    9ms
    Small-molecule RNA therapeutics to target prostate cancer. (PubMed, Cancer Cell)
    Remarkably, tumors treated with zotatifin become more sensitive to anti-androgen therapy and radiotherapy. Therefore, "translatome therapy" provides additional strategies to treat the deadliest cancers.
    Journal
    |
    HIF1A (Hypoxia inducible factor 1, alpha subunit)
    |
    zotatifin (eFT226)
    1year
    RESOLVE: Abemaciclib + Letrozole +/- Metformin or Zotatifin in Endometrial or Low-Grade Serous Ovarian Cancer (clinicaltrials.gov)
    P2, N=130, Active, not recruiting, Dana-Farber Cancer Institute | Recruiting --> Active, not recruiting | Trial completion date: Aug 2029 --> Aug 2030 | Trial primary completion date: Aug 2026 --> Aug 2027
    Enrollment closed • Trial completion date • Trial primary completion date • Combination therapy
    |
    ER (Estrogen receptor)
    |
    ER positive
    |
    Verzenio (abemaciclib) • letrozole • zotatifin (eFT226) • metformin • samotolisib (LY3023414)
    over1year
    Umbrella Trial Testing Integrative Subtype Targeted Therapeutics in Estrogen Receptor Positive, HER2-Negative Breast Cancer (clinicaltrials.gov)
    P2, N=19, Active, not recruiting, Stanford University | Recruiting --> Active, not recruiting | N=150 --> 19
    Enrollment closed • Enrollment change
    |
    HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PGR (Progesterone receptor)
    |
    Piqray (alpelisib) • fulvestrant • zotatifin (eFT226) • Soltamox (tamoxifen citrate)
    over1year
    RESOLVE: Abemaciclib + Letrozole +/- Metformin or Zotatifin in Endometrial or Low-Grade Serous Ovarian Cancer (clinicaltrials.gov)
    P2, N=130, Recruiting, Dana-Farber Cancer Institute | N=60 --> 130 | Trial completion date: May 2026 --> Aug 2029 | Trial primary completion date: May 2024 --> Aug 2026
    Enrollment change • Trial completion date • Trial primary completion date • Combination therapy
    |
    ER (Estrogen receptor)
    |
    Verzenio (abemaciclib) • letrozole • zotatifin (eFT226) • metformin • samotolisib (LY3023414)
    2years
    Targeting EIF4A triggers an interferon response to synergize with chemotherapy and suppress triple-negative breast cancer. (PubMed, J Clin Invest)
    Surprisingly, Zotatifin significantly synergizes with carboplatin to trigger DNA damage and an even heightened interferon response resulting in T cell-dependent tumor suppression. These studies identified a vulnerability of eIF4A in TNBC, potential pharmacodynamic biomarkers for Zotatifin, and provide a rationale for new combination regimens comprising Zotatifin and chemotherapy or immunotherapy as treatments for TNBC.
    Journal • IO biomarker
    |
    FGFR1 (Fibroblast growth factor receptor 1) • SOX4 (SRY-Box Transcription Factor 4)
    |
    carboplatin • zotatifin (eFT226)
    2years
    PROPEL: Intravenous Zotatifin in Adults With Mild or Moderate COVID-19 (clinicaltrials.gov)
    P1b, N=36, Completed, Effector Therapeutics | Active, not recruiting --> Completed
    Trial completion
    |
    zotatifin (eFT226)
    over2years
    Study of eFT226 in Subjects With Selected Advanced Solid Tumor Malignancies (clinicaltrials.gov)
    P1/2, N=30, Recruiting, Effector Therapeutics | N=228 --> 30 | Trial completion date: Sep 2023 --> Mar 2025 | Trial primary completion date: Jul 2023 --> Dec 2024
    Enrollment change • Trial completion date • Trial primary completion date
    |
    KRAS (KRAS proto-oncogene GTPase) • FGFR (Fibroblast Growth Factor Receptor) • CCND1 (Cyclin D1)
    |
    KRAS mutation • KRAS G12C • HER-2 negative • KRAS G12 • FGFR amplification
    |
    Herceptin (trastuzumab) • Verzenio (abemaciclib) • Lumakras (sotorasib) • fulvestrant • zotatifin (eFT226)