zotatifin (eFT226) / SJP Biotec, eFFECTOR Therap - LARVOL DELTA

Phase 1/2 dose expansion study evaluating first-in-class eIF4A inhibitor zotatifin in patients with ER+ metastatic breast cancer. (ASCO 2023) - P1/2 | "In dose expansion cohorts of heavily pre-treated metastatic breast cancer pts, eIF4A inhibitor zotatifin showed evidence of anti-tumor activity in combination with fulvestrant and abemaciclib and had a favorable safety profile consisting of primarily grade 1/2 adverse events. Clinical trial information: NCT04092673."

Clinical • Metastases • P1/2 data • Breast Cancer • Constipation • Gastroenterology • Gastrointestinal Disorder • HER2 Breast Cancer • Oncology • Solid Tumor • CCND1 • EIF4A1 • HER-2 • KRAS

Modeling Risk Group 4 virus infection and antiviral treatment in microfluidic lung organ-on-chips in maximum containment laboratories. (PubMed, bioRxiv) - "We reproduced the known anti-NiV activity of remdesivir and evaluated that of another potential antiviral, zotatifin. Our results pave the way for similar applications of advanced microphysiological systems for modeling infections caused by high-consequence viruses."

Journal • Infectious Disease • Respiratory Diseases

Zotatifin And EIF4A Platinum Helix Inhibition In Resistant AdvancedTNBC (clinicaltrials.gov) - P1 | N=24 | Not yet recruiting | Sponsor: M.D. Anderson Cancer Center

New P1 trial • Breast Cancer • Inflammatory Breast Cancer • Triple Negative Breast Cancer • HER-2

Study of eFT226 in Subjects With Selected Advanced Solid Tumor Malignancies (clinicaltrials.gov) - P1/2 | N=198 | Recruiting | Sponsor: Effector Therapeutics | N=45 ➔ 198 | Trial primary completion date: Dec 2022 ➔ Jul 2023

Enrollment change • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • FGFR • KRAS

Study of eFT226 in Subjects With Selected Advanced Solid Tumor Malignancies (clinicaltrials.gov) - P1/2 | N=30 | Recruiting | Sponsor: 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 • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CCND1 • FGFR • KRAS

Co-Targeting Nuclear Export and Translation Initiation Uncovers a Therapeutic Vulnerability in Lethal Prostate Cancer. (PubMed, bioRxiv) - "Unbiased combinatorial screening reveals co-inhibition of nuclear export and translation initiation as a vulnerability in metastatic castration-resistant prostate cancer. Dual targeting of XPO1 and EIF4A1 drives synergistic collapse of oncogenic protein networks, including AR/AR-V7 signaling, to overcome key resistance mechanisms and induce potent antitumor responses across heterogeneous models. Notably, these effects are achieved at substantially reduced doses using clinically tractable agents, defining a mechanistically grounded therapeutic strategy poised for rapid clinical translation."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • EIF4A1 • XPO1

mTORC1-eIF4A1 dependent translational regulation of oncogenic fatty acid desaturases (AACR 2026) - "Extending these findings in vivo, zotatifin treatment in a Tsc2+/- kidney tumor mouse model, where loss of Tsc2 hyperactivates mTORC1, reduced tumor burden, decreased desaturase expression, and increased lipid peroxidation. Together, these data establish a direct link between translational control and fatty acid desaturation in cancer cells, and support eIF4A1-targeted strategies to simultaneously suppress two oncogenic fatty acid desaturases in mTORC1-hyperactive tumors."

Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • EIF4A1 • FADS2 • SCD

Design and evaluation of mRNA translation inhibitors for use as antibody drug conjugate payloads (AACR 2026) - "Inhibitors of eIF4A (e.g., silvestrol, zotatifin, and other rocaglates) block translation of select mRNAs that contain a high degree of secondary structure (e.g. mRNAs encoding MYC, KRAS, and CDK4/6, among others), resulting in inhibition of cell proliferation and induction of apoptosis...In vitro, trastuzumab ADCs showed potent antigen-dependent activity in HER2-expressing cell lines and bystander activity in mixed co-cultures of HER2+ and HER2- cells... Novel eIF4A ADCs constructed using hydrophilic drug linkers demonstrated potent and target-specific in vitro cytotoxicity. Promising in vivo efficacy was observed across multiple tumor associated targets, however the observed toxicity level in both mice and rats suggests a potentially lower than anticipated preclinical therapeutic window."

ADC • Oncology • CDK4 • EIF4A1 • EIF4A2 • HER-2 • KRAS • LY6E • PTK7

Pharmacological inhibition of eIF4A1 suppresses leukemogenesis via specifically rewiring amino acid biosynthesis (AACR 2026) - "Overall, our findings identify eIF4A1 as a key regulator of AML pathogenesis and metabolic homeostasis. Targeting eIF4A1, particularly with Zotatifin, represents a promising therapeutic strategy for AML."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • EIF4A1 • EIF4E • EIF4G1 • PHGDH • YBX1

Broad-spectrum antiviral activity of the synthetic rocaglate zotatifin against Mayaro virus and other viruses. (PubMed, Front Cell Infect Microbiol) - "Zotatifin demonstrated superior tolerability compared to rocaglamide A and CR-1-31-B. Mechanistically, Zotatifin down-regulated viral protein synthesis for all viruses tested, and RT-qPCR analysis revealed activation of the type I interferon pathway in treated cells. Collectively, these results demonstrate that zotatifin exhibits broad-spectrum antiviral activity against five virus families, through different molecular mechanisms, supporting its potential therapeutic use as a pan-antiviral drug in humans."

Journal • Chikungunya • Infectious Disease • Influenza • Respiratory Diseases • EIF4A1 • EIF4A2

Targeting eIF4F-mediated translation to reduce T cell exhaustion and enhance PD-1 blockade efficacy in melanoma (AACR 2025) - "These experiments were performed with and without inhibition of the eIF4F-dependent translation using three different inhibitors of the eIF4A helicase (eIF4A-i: silvestrol, EFT226 and RBX0901)... Our findings unveil a previously unrecognized role of eIF4F in orchestrating the translational regulation of key proteins driving T cell exhaustion. This study is the first to demonstrate that targeting eIF4F with eIF4A inhibitors not only downregulates exhaustion markers but also synergistically enhances the efficacy of anti-PD-1 therapy across multiple models, including human TILs and murine cancer systems. This novel insight underscores the immense therapeutic potential of combining eIF4A inhibitors with ICIs to overcome resistance mechanisms and reinvigorate anti-tumor immunity."

Clinical • IO biomarker • Colon Cancer • Colorectal Cancer • Melanoma • Oncology • Solid Tumor • CD8 • EIF4A1 • EIF4A2 • EIF4E • EIF4G1 • HAVCR2 • LAG3 • STAT1

Proteomic characterization of intrahepatic cholangiocarcinoma identifies risk-stratifying subgroups and EIF4A1 as a therapeutic target. (PubMed, Nat Commun) - "The translation regulator EIF4A1, enriched in ICCs of both clusters, emerges as a therapeutic target, as its inhibition with eFT226 significantly reduces tumor growth in an ICC PDX model. Proteomic analyses of various PDX models also emphasize the critical role of tumor-stroma interactions in ICC. Overall, this study establishes two prognostic proteomic clusters, validates their relevance across datasets, and highlights EIF4A1 inhibition as a potential therapeutic strategy."

Biomarker • Journal • Biliary Cancer • Cholangiocarcinoma • Oncology • Solid Tumor • EIF4A1

Synergistic targeting of eIF4A-mediated translation initiation and apoptosis in acute myeloid leukemia. (PubMed, Blood Neoplasia) - "Using 3 in vivo xenograft models derived from patients with relapsed/refractory AML, the combination significantly suppressed the tumor burden and prolonged survival. These results support eIF4A-mediated protein translation as a therapeutic target in AML and highlight the potential of zotatifin and venetoclax in relapsed/refractory disease."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • EIF4A1 • EIF4A2 • MCL1 • STAT5

Umbrella Trial of Subtype-Targeted Therapies in ER+/HER2- Breast Cancer (clinicaltrials.gov) - P2 | N=19 | Completed | Sponsor: Jennifer Lee Caswell-Jin | Suspended ➔ Completed

Trial completion • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PGR

Targeting eIF4A unleashes type I IFN immunity in triple-negative breast cancer (SABCS 2025) - "Targeting eIF4A with the first-in-class inhibitor zotatifin remodels tumor translatome, suppresses TNBC growth, and synergizes with carboplatin in syngeneic mouse models. These data define the mechanistic basis of eIF4A-targeted therapy, linking translational inhibition to innate immune activation, and provide a biomarker framework to guide future clinical trials combining zotatifin with chemotherapy in TNBC."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • EIF4A1 • EIF4A2 • IFIH1 • IFNAR1 • IFNB1

Novel EIF4A1 inhibitors with anti‐tumor activity (ASH 2025) - "Zotatifin, a novel eIF4A inhibitor currentlyin Phase I/II trials, has aimed to overcome these limitations...The discovery of RBF197 and RBF208 represents a significant advance inthe field, providing new RocA-independent inhibitors with a unique mechanism of action and potent anti-tumor activity in both in vitro and in vivo models. These novel inhibitors pave the way for future bench tobedside research, offering a promising strategy to target dysregulated translation in cancer, with thepotential to expand therapeutic options for patients with DLBCL and other malignancies characterized byaberrant eIF4A1 activity/expression."

IO biomarker • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • CCND1 • EIF4A1 • EIF4A2 • MYC

Enhanced Ferroptosis Induction Susceptibility in Diffuse Large B-Cell Lymphoma through Rocaglate-Mediated Translation Inhibition (ASH 2023) - "Additionally, we quantified reduced glutathione (GSH) levels, reactive oxygen species (ROS) levels, and synergy with ferroptosis inducers (e.g., erastin, RSL3) to elucidate the mechanism of rocaglates in enhancing susceptibility to the ferroptosis pathway...Correspondingly, there was strong synergy between the clinical rocaglate zotatifin and different ferroptosis inducers (Bliss δ synergy score > 10) and antagonism with ferroptosis inhibitors (Bliss δ synergy score < -10)... In conclusion, rocaglate-induced stress upregulates multiple ferroptosis suppressors, suggesting that cap-dependent translation disruption triggers a protective response against ferroptosis. Strikingly, these factors did not protect DLBCL tumors from ferroptosis inducers, which synergized remarkably with rocaglates, yielding promising new combination drug strategies. The proteomic basis for ferroptosis sensitization by rocaglate therapy remains under active investigation."

B Cell Lymphoma • Brain Cancer • CNS Tumor • Diffuse Large B Cell Lymphoma • Glioblastoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • Targeted Protein Degradation • ATF2 • GPX4 • MYSM1 • NRF1 • SDHB • SLC3A2 • TNFA

Translational Disruption of NRF2 By Zotatifin Enhances Sensitivity to Ferroptosis and CAR-T Cells in Diffuse Large B-Cell Lymphoma (ASH 2024) - "We observed strong synergy, however, between zotatifin and various ferroptosis inducers, including erastin, RSL3, dimethyl formamide (DMF), sulfasalazine (SASP), ML385, and the pharmacokinetically optimized compound imidazole ketone erastin (IKE), while the anti-ferroptotic antioxidant N-acetyl cysteine (NAC) was antagonistic. These results advocate for clinical strategies to enhance investigational ferroptosis inducers and approved CAR-T cells. Further optimization of these regimens holds potential to enhance therapeutic efficacy and overcome resistance mechanisms in DLBCL treatment."

CAR T-Cell Therapy • IO biomarker • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • EIF4A1 • EIF4A2 • IFNG • NFE2L2 • SLC3A2

Blocking NRF2 Translation by Inhibition of Cap-Dependent Initiation Sensitizes Lymphoma Cells to Ferroptosis and CAR T-cell Immunotherapy. (PubMed, Cancer Res) - "In vivo, combining zotatifin with the optimized ferroptosis inducer imidazole ketone erastin significantly reduced tumor burden in DLBCL patient-derived xenografts. Treatment with zotatifin in combination with chimeric antigen receptor (CAR) T cells, a vital treatment modality for DLBCL patients, revealed that zotatifin pre-exposure sensitized DLBCL tumors to CD19-directed CAR T cells in vitro and extended survival of CAR T-cell treated immunocompetent mice bearing syngeneic DLBCL tumors in vivo. Overall, eIF4A1 inhibition-induced translational disruption provides opportunities to leverage the therapeutic impacts of ferroptosis inducers, including cytotoxic immunotherapies."

Journal • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Rheumatology • EIF4A1

eIF4A controls translation of estrogen receptor alpha and is a therapeutic target in advanced breast cancer. (PubMed, Proc Natl Acad Sci U S A) - P1/2 | "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 • Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CCND1 • EIF4A1 • EIF4A2 • EIF4E • ER

Umbrella Trial of Subtype-Targeted Therapies in ER+/HER2- Breast Cancer (clinicaltrials.gov) - P2 | N=19 | Suspended | Sponsor: Stanford University | Active, not recruiting ➔ Suspended

Trial suspension • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PGR

RESOLVE: Abemaciclib + Letrozole +/- Metformin, Zotatifin, or Gedatolisib in Endometrial or Low-Grade Serous Ovarian Cancer (clinicaltrials.gov) - P2 | N=180 | Recruiting | Sponsor: 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 change • Enrollment open • P53WT • Trial completion date • Trial primary completion date • Endometrial Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • ER

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 • Biliary Cancer • Cholangiocarcinoma • Liver Cancer • Oncology • Solid Tumor • BCL2L1 • CAFs • EIF4A1 • EIF4E • EIF4G1

Anticancer effects of zotatifin are mediated by RNA structure remodelling. (PubMed, Nat Rev Mol Cell Biol) - No abstract available

Journal • Oncology

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 • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • EIF4A1 • EIF4A2 • HIF1A