Entolimod (CBLB502) Biodefense
Entolimod is in development as a countermeasure against death following total body irradiation. Acute radiation syndrome (ARS) results from damage to hematopoietic, gastrointestinal, and other tissues due to high levels of radiation exposure, such as might occur following the explosion of a nuclear weapon. There are currently no FDA-approved treatments for ARS.
Entolimod is a recombinant protein that acts as an agonist of toll-like receptor 5 (TLR5), an innate immunity receptor. Entolimod activation of TLR5 triggers NF-kB signaling, mobilizing an innate immune response that drives expression of numerous genes, including inhibitors of apoptosis, scavengers of reactive oxygen species, and a spectrum of protective or regenerative cytokines.
It is not feasible or ethical to test the efficacy of entolimod as a radiation countermeasure in humans; therefore, we are developing entolimod under the FDA’s Animal Rule guidance. The FDA established the Animal Rule in 2002 to permit the approval of certain drugs and biologics that are intended to reduce or prevent serious or life-threatening conditions based on evidence of safety from trial in healthy subjects and effectiveness from appropriate animal studies when human efficacy studies are not possible.
The efficacy of entolimod as a radiation countermeasure has been assessed in animal models. These studies demonstrate that a single administration of entolimod given either before or after lethal total body irradiation leads to a significant improvement in animal survival. We have shown that entolimod reduces radiation damage to both hematopoietic and gastrointestinal tissues and improves tissue regeneration.
Our clinical studies of entolimod in 150 healthy human subjects have demonstrated the safety profile of entolimod and established the dose-dependent effect of entolimod on efficacy biomarkers in humans. In these studies, a transient mild to moderate flu-like syndrome was observed along with transient decreases in blood pressure and elevation of liver enzymes. Such effects are the most common adverse events and are consistent with increases in cytokines that are the expected consequences of entolimod administration.
We continue to discuss requirements for submission of a Biologics License Application (BLA) for entolimod with the FDA. In addition, a pre-Emergency Use Authorization, or pre-EUA dossier for entolimod has been submitted to the FDA for review. Pre-EUA is the regulatory path through which the FDA determines that certain unapproved medical products may be used in an emergency when there are no adequate, approved, and available alternatives. Products with pre-EUA status can be purchased by the US government for stockpiling in the event of a disaster. The FDA granted entolimod both Fast Track and Orphan Drug status for reducing the risk of death following a potentially lethal dose of total body irradiation during or after a radiation disaster.
A Phase 1 study of entolimod in patients with advanced solid tumors at Roswell Park Cancer Institute has been completed. A second Phase 1 study of entolimod in patients with advanced cancer is currently ongoing in the Russian Federation to expand upon clinical observations made at the higher dose levels in the Roswell Park study and to gather further statistics on immune response to administrations of entolimod.
A Phase 2, single-blind, randomized, placebo-controlled clinical study of the safety and tolerability of entolimod as a neo-adjuvant therapy in treatment-naïve patients with primary colorectal cancer who are recommended for surgery was initiated in the Russian Federation.