On September 16, 2024 Ribometrix, a biotechnology company developing small molecule therapeutics that modulate RNA biology, reported the latest data from its eIF4E program at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress, taking place in Barcelona, Spain, September 13-17 (Press release, Ribometrix, SEP 16, 2024, View Source [SID1234646662]). The poster presentation reviews in vitro and in vivo studies of a small molecule eIF4E inhibitor, RBX-6610, as a potential treatment for KRASG12C mutant non-small cell lung cancer (NSCLC). Acquired resistance is observed in most patients treated with the two approved therapies for KRASG12C 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.

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"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 KRASG12C 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 KRASG12C 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 (AACR) (Free AACR Whitepaper) 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 (Free ESMO Whitepaper) 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.