eIF4A

DURHAM, N.C.--( BUSINESS WIRE )-- Ribometrix , a biotechnology company developing small molecule therapeutics that modulate RNA biology, presented the latest data from its eIF4E program at the European Society for Medical Oncology (ESMO) Congress, taking place in Barcelona, Spain, September 13-17. The poster presentation reviews in vitro and in vivo studies of a small molecule eIF4E inhibitor, RBX-6610, as a potential treatment for KRAS G12C mutant non-small cell lung cancer (NSCLC). Acquired resistance is observed in most patients treated with the two approved therapies for KRAS G12C mutant NSCLC, creating a significant opportunity for a therapy that re-sensitizes tumors to KRAS inhibition. Ribometrix’s data supports RBX-6610’s ability to deliver this mechanism in combination with the approved therapies. “ In less than three years, Ribometrix has advanced its eIF4E program from concept to a lead molecule that has just completed non-GLP toxicology studies,” stated Michael Solomon, CEO of Ribometrix, Inc. “ The program is a testament to Ribometrix drug discovery capabilities, and the commitment and professionalism of the Ribometrix team. We look forward to moving this program forward into the clinic in collaboration with a partner who shares our vision of its potential to benefit patients, via its novel mechanism of action.” “ These data further evidence the broad potential of eIF4E inhibition in multiple tumor types, particularly in combination as a re-sensitizing agent. We have further validated the mechanism of action and characterized the synergistic benefit of RBX-6610, our most advanced eIF4E inhibitor,” said Jessica Sorrentino, Ph.D., SVP of Translational Medicine. “ RBX-6610 is progressing towards the clinic and we see significant promise for its inclusion with the standard-of-care for both naïve and treatment resistant NSCLC patients, especially whose tumors have KRAS mutations.” Key highlights: RBX-6610 demonstrated consistent anti-proliferative effects in KRAS G12C mutant tumor cell lines, in both treatment-naïve lines and those with acquired resistance. Additionally, the combined in vitro effects of co-treatment of RBX-6610 with KRAS inhibitors were synergistic, such that the proliferative inhibitory effects were greater than the sum of either treatment alone. Mechanistically, this was due to an induction of apoptosis, specific to co-treatment in treatment-naïve tumor cells as well as cells resistant to KRAS inhibitors. This synergistic phenotype was observed with both approved KRAS inhibitors, as well as investigational RAS inhibitors. Daily oral RBX-6610 monotherapy led to substantial tumor growth inhibition in both treatment naïve and resistant KRAS G12C NSCLC xenograft model (75% vs 71% TGI, respectively), corroborating the anti-proliferative effects seen in vitro . In combination with sotorasib, an approved KRAS inhibitor, daily oral treatment with RBX-6610 led to significant tumor regression and improved survival in both the treatment-naïve and sotorasib resistant setting (34% and 49% mean tumor regression respectively). No toxicity was observed in up to 35 days of daily oral treatment across all cohorts. In vitro data demonstrated improved selectivity of cap dependent translation inhibition by RBX-6610 relative to other translation inhibitors including zotatifin, an eIF4A inhibitor. Ribometrix continues to generate data demonstrating the multi-tumor therapeutic potential of eIF4E inhibition. Studies in melanoma and breast cancer were presented at the Society for Melanoma Research and the San Antonio Breast Cancer Symposium in 2023, and data across melanoma, colorectal, breast, and non-small cell lung cancer were presented at the American Association for Cancer Research Annual Meeting in 2024. Data have repeatedly included support for both monotherapy and combination regimens as well as the potential to re-sensitize to standard-of-care treatments. The ESMO poster is now available to view on the “ Publications ” page of Ribometrix’s website. About eIF4E Eukaryotic translation initiation factor 4E (eIF4E) is a crucial regulatory component of mRNA translation and well-documented driver of oncogenesis. Clinically, eIF4E activity is elevated in many tumor indications and it is typically associated with poor prognosis. Targeting eIF4E has the potential to enhance anti-cancer activity when given in combination with standard-of-care. Additionally, eIF4E inhibition has the potential to overcome drug resistance and re-sensitize tumors to anti-cancer therapies. Based on substantial external and in-house data, Ribometrix is developing eIF4E inhibitors as a promising combination therapy approach and treatment for treatment-resistant tumors. About Ribometrix Ribometrix is a biotechnology company pioneering a completely new class of small molecule therapeutics that modulate RNA biology to treat human diseases. Ribometrix leverages its world-leading expertise in three-dimensional RNA structural analysis to identify novel small molecules that inhibit the production of disease-associated proteins. Ribometrix is advancing multiple internal programs including one targeting the oncogenic RNA-binding protein eIF4E and one directly targeting oncogenic c-MYC mRNA, and has established collaborations with Genentech, a member of the Roche Group, and Vertex Pharmaceuticals, which leverage Ribometrix’s discovery platform. Ribometrix is headquartered in Durham, North Carolina.

Part of the next steps include looking for strategic alternatives for eFFECTOR’s development programs. It’s the end of an era—eFFECTOR Therapeutics’ era to be exact. The oncology biotech has laid off staff as it plans to wind down, according to a June 24 company release. This includes eFFECTOR CEO Stephen Worland, Ph.D.; Chief Financial Officer Michael Byrnes; and Chief Medical Officer Douglas Warner, M.D., who all stopped serving in their positions at the end of last week. The company expects to spend about $600,000 by June 30 in one-time charges and cash expenditures tied to the workforce reduction, according to Securities and Exchange Commission documents. In the meantime, the board of directors has tapped Craig Jalbert to lead as eFFECTOR’s CEO, president, treasurer, secretary and sole board member. Jalbert is a principal from the accounting firm Verdolino & Lowey, P.C., and has more than three decades of experience helping companies wind down.  Part of the next steps include looking for strategic alternatives for eFFECTOR’s development programs. The biotech’s lead asset is zotatifin, a selective eIF4A inhibitor being tested out in several mid-stage trials for solid tumors. In April, the company's other wholly-owned asset, tomivosertib, failed to improve progression-free survival in a phase 2b trial of patients with non-small cell lung cancer (NSCLC). Based on all the data available in the primary analysis, the company said it didn't see an obvious path forward for continuing development of the asset in frontline NSCLC. eFFECTOR also had a partnership with Big Pharma Pfizer for a preclinical asset dubbed eIF4Ei, which is also designed to tackle solid tumors. The $507 million biobucks deal was struck back in 2019 when Pfizer paid out $15 million up front in an exclusive licensing agreement to develop small-molecule inhibitors of eukaryotic initiation factor 4E (eIF4E) with eFFECTOR. The biotech was founded in 2012 based on research from the University of California, San Francisco labs of Davide Ruggero, Ph.D., and Kevan Shokat, Ph.D. eFFECTOR plans to ask to be delisted from the Nasdaq. Since announcing the planned shuttering, the biotech’s stock plummeted 77% from $1.17 per share at market close Friday to 29 cents this morning at opening.

SOLANA BEACH, Calif. and REDWOOD CITY, Calif., May 20, 2024 (GLOBE NEWSWIRE) -- eFFECTOR Therapeutics, Inc. (NASDAQ: EFTR), a leader in the development of selective translation regulator inhibitors (STRIs) for the treatment of cancer, today announced a collaboration to conduct an investigator-sponsored trial (IST) evaluating zotatifin in combination with abemaciclib and letrozole in patients with estrogen receptor-positive (ER+) endometrial cancer and low grade serous ovarian cancer at the Dana-Farber Cancer Institute (DFCI) under the direction of Panagiotis Konstantinopoulos, M.D., Ph.D., Director of Translational Research and attending oncologist in the Division of Gynecologic Oncology at DFCI, and an Associate Professor of Medicine at Harvard Medical School. “Endometrial cancer is the most prevalent cancer affecting the female reproductive organs in the United States,” said Dr. Konstantinopoulos. “While early detection offers hope for successful treatment, patients with recurrent or metastatic disease have limited treatment options. Recent studies of the abemaciclib and letrozole combo in ER+ endometrial cancer patients have shown promising activity, however, most patients either fail to respond or eventually develop resistance to CDK4/6 inhibition, a critical aspect of treatment. Similarly, low grade serous ovarian cancer has shown sensitivity to combined treatment with aromatase inhibitors and CDK4/6 inhibition, but responding patients eventually develop disease progression. By targeting eIF4A, which subsequently downregulates the key factors implicated in CDK4/6 inhibition resistance, we believe that integrating zotatifin with abemaciclib and letrozole treatment regimen represents a compelling strategy for combating recurrent endometrial cancer and low grade serous ovarian cancer.” Doug Warner, M.D., chief medical officer of eFFECTOR Therapeutics added, “We are thrilled to embark on this investigator-sponsored Phase 2 trial in collaboration with Dr. Konstantinopoulos and his team at the DFCI. This trial represents a significant step forward in our collective efforts to address the complexities of endometrial cancer and low grade serous ovarian cancer. By exploring the potential of zotatifin as a combination treatment and its unique mechanism of action, we aim to redefine the treatment landscape and improve outcomes for these patients. With this comprehensive approach which simultaneously targets tumor cell cycle progression while reducing estrogen levels, we hope to overcome resistance mechanisms and enhance treatment efficacy which we believe could be applied in various malignancies beyond breast and endometrial cancers. In parallel, we continue to advance development of zotatifin in ER+ metastatic breast cancer and anticipate determination of the Phase 2 dose (RP2D) of zotatifin in combination with fulvestrant and abemaciclib, in the second half of 2024.” About Zotatifin Zotatifin is a potent and sequence-selective small molecule inhibitor of the RNA helicase eIF4A that is designed to suppress the overproduction of cell cycle proteins and oncogenes, including Cyclins D and E, CDKs 4 and 6, ERα, KRAS, HER2, and other RTKs. Zotatifin is currently being evaluated in a Phase 2a expansion cohort in combination with fulvestrant and abemaciclib in ER+ breast cancer. Efficacy data presented at 2023 ASCO and SABCS showed a 26% response rate and mPFS of 7.4 months as a triplet in heavily pretreated patients. About eFFECTOR Therapeutics eFFECTOR is a clinical-stage biopharmaceutical company pioneering the development of a new class of oncology drugs referred to as STRIs. eFFECTOR’s STRI product candidates target the eIF4F complex and its activating kinase, mitogen-activated protein kinase interacting kinase (MNK). The eIF4F complex is a central node where two of the most frequently mutated signaling pathways in cancer, the PI3K-AKT and RAS-MEK pathways, converge to activate the translation of select mRNA into proteins that are frequent culprits in key disease-driving processes. Each of eFFECTOR’s product candidates is designed to act on a single protein that drives the expression of a network of functionally related proteins, including oncoproteins and immunosuppressive proteins in T cells, that together control tumor growth, survival, and immune evasion. Zotatifin, eFFECTOR’s inhibitor of eIF4A, is currently being evaluated in a Phase 2a expansion cohort in combination with fulvestrant and abemaciclib in ER+ breast cancer and in Phase 2 IST in combination with abemaciclib and letrozole in ER+ endometrial cancer. Tomivosertib, eFFECTOR’s MNK inhibitor, is currently being evaluated in an investigator-sponsored trial in AML. eFFECTOR has a global collaboration with Pfizer to develop inhibitors of a third target, eIF4E. Forward-Looking StatementseFFECTOR cautions you that statements contained in this press release regarding matters that are not historical facts are forward-looking statements. The forward-looking statements are based on our current beliefs and expectations and include, but are not limited to: the future clinical development of our product candidates, including expectations on enrollment and the timing of reporting data from ongoing clinical trials; the potential therapeutic benefits of our product candidates; and the timing and potential benefits of the IST evaluating zotatifin in combination with abemaciclib and letrozole in patients with ER+ endometrial cancer and low grade serous ovarian cancer. Actual results may differ from those set forth in this press release due to the risks and uncertainties inherent in our business, including, without limitation: potential delays in the commencement, enrollment and completion of clinical trials, including the IST conducted by DFCI; the success of our clinical trials and preclinical studies for our product candidates is uncertain; we are dependent on DFCI to conduct the IST trial and we may not realize any benefits from the collaboration with DFCI; our dependence on third parties in connection with product manufacturing, research and preclinical and clinical testing; the results of preclinical studies and early clinical trials are not necessarily predictive of future results; regulatory developments in the United States and foreign countries; unexpected adverse side effects or inadequate efficacy of our product candidates that may limit their development, regulatory approval and/or commercialization, or may result in recalls or product liability claims; and other risks described in our prior filings with the Securities and Exchange Commission. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and we undertake no obligation to update such statements to reflect events that occur or circumstances that exist after the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement, which is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Contacts: Investors: Christopher M. CalabreseManaging DirectorLifeSci Advisors917-680-5608ccalabrese@lifesciadvisors.com Kevin GardnerManaging DirectorLifeSci Advisors617-283-2856kgardner@lifesciadvisors.com Media: Michael Fitzhugh Vice President, Chief of Media StrategyLifeSci Communicationsmfitzhugh@lifescicomms.com