A paper by Dr. Michelle Ross, Senior Vice President of Public Health and Government Affairs, Cleveland BioLabs, USA

Acute Radiation Syndrome (ARS) results from exposure to high doses of radiation resulting in damage to sensitive tissues such as hematopoietic (HP), gastrointestinal (GI), and the central nervous system (CNS), such as might occur following the explosion of an improvised radiological device or nuclear weapon. There are currently no FDA-approved treatments for ARS. Society’s need for an ARS therapeutic has been recognized since the beginning of the atomic age. This grew dramatically following the September 11, 2001 terrorist attacks and the subsequent use of anthrax in a biological attack in the United States. Terrorist activities worldwide have continued in the intervening years and the possibility of chemical, biological, radiation and nuclear attacks continues to represent a threat for governments world-wide. The scale of possible casualties (number of people dead or injured) assuming central business district explosions of approximately 10kt in yield has been estimated by the U.S. government to range from approximately 150,000 (Los Angeles – population of ~4M) to 500,000 (New York City – population of ~8M). Currently prescribed pharmaceuticals to treat radiation exposure have limitations. Potassium iodide (KI) will protect after exposure to certain types of radiation and is effective against the long-term risk of cancer. Prussian Blue was approved to reduce the net exposure to certain radioactive elements, but does not protect bone marrow. Calcium and zinc diethylenetriaminepentaacetic acid (DTPA) are effective chelating agents. None of these approved agents, however, are effective in preventing or treating the medical conditions associated with ARS. The U.S. government procured filgrastim (Neupogen®), to be used off-label following lethal radiation exposure for treatment of ARS. The use of Neupogen® has limitations, requiring multiple types of supportive care with intensive medical monitoring, has a limited window of efficacy, and demonstrates variable survival efficacy.

Entolimod (previously known as CBLB502) is an engineered derivative of the Salmonella flagellin protein. Entolimod acts as an agonist of Toll-like receptor 5 (TLR5), an innate immunity receptor. Entolimod binds with high-affinity to TLR5 expressed on the surface of specific cell types and triggers activation of the NF-kappaB signaling pathway. Activation of NF-kappaB, a transcription factor that plays major roles in regulation of immunity and cellular responses to stress, leads to induction of numerous molecular factors including inhibitors of apoptosis (IAPs, Bcl2), scavengers of reactive oxygen species (SOD-2 and ferritin) and a spectrum of protective or regenerative cytokines, including G-CSF, IL-6, IL-8, and IL-102. In the context of acute high-dose total-body radiation exposure capable of inducing ARS, the combined actions of these factors result in protection and regeneration of radiosensitive tissues such as those of the hematopoietic (HP) and gastrointestinal (GI) systems.

Entolimod is currently in the pivotal stage of development as a countermeasure against death following total body irradiation. It is not feasible or ethical to test the efficacy of entolimod as a radiation
countermeasure in humans; therefore, entolimod is being developed 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 was assessed in multiple animal models. Studies in non-GLP conditions have demonstrated that a single administration of entolimod given either before or 24-48 hours after a lethal dose of total body irradiation leads to a significant improvement in animal survival. The initial proposed label for entolimod will be for administration 25 hours post radiation exposure.

A pivotal efficacy study was conducted in 179 rhesus monkeys (Macaca mulatta) that received a single intramuscular injection of placebo or 0.3-120 µg/kg entolimod at 25 hours after a 7.2 Gy (LD70/60 – a dose killing 70% of animals by day 60) dose of bilateral, total-body gamma irradiation. Survival of animals (without intensive clinical support) and blood counts were observed over 60 days after irradiation and treatment. Levels of entolimod itself and multiple biomarkers of its anti-radiation efficacy were measured in blood of irradiated and treated animals. The results of this study showed that a single injection of entolimod improved 60-day survival of lethally irradiated non-human primates 2.5fold: from 27.5% (11 out of 40) in the control group to 70-75% (14-16 out of 20) in groups treated with 10-120 µg/kg of entolimod. The trend for improved survival was highly statistically significant (P

A pivotal PK/PD study conducted in 160 non-irradiated rhesus monkeys established the dose-dependent effect of entolimod on biomarkers for efficacy in non-human primates. Clinical studies of entolimod in 150 healthy human subjects demonstrated the side effect profile of entolimod and established the dose-dependent effect of entolimod on efficacy biomarkers in humans. In these studies, and in a Phase 1 oncology study that concluded enrollment, transient decrease in blood pressure and elevation of liver enzymes were observed along with transient mild to moderate flu-like syndrome. Such effects are the most common adverse events and they are linked to up-regulation of cytokines that are also biomarkers for efficacy.

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 after a radiation disaster. A few additional
studies must be completed prior to submitting a Biological License Application (BLA) for licensure with the FDA.

A meeting was held with the FDA in July 2014 to present human dose-conversion and to discuss the intent to submit a pre-Emergency Use Application, or pre-EUA. As a result of this meeting, the FDA confirmed that entolimod’s existing efficacy and safety data and animal-to-human dose conversion are sufficient to proceed with a pre-EUA and agreed to accept a pre-EUA application for review. A pre-EUA application is being prepared for submission in the first half of 2015, using the human dose of entolimod that was determined through a proprietary dose conversion methodology, which utilizes the data from the pivotal non-human primate studies and clinical studies of entolimod in healthy volunteers. If authorized, pre-EUA status will qualify entolimod for potential use under a state of emergency. Such authorization is not equivalent to full licensure. CBLI is planning to complete development of entolimod required to submit a biologic license application, or BLA, for full FDA approval.

The Full Paper by Ross will be presented during NCT CBRNe USA Innovation Stream, taking place from April 29 to May 1.

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