Acute radiation syndrome (ARS)
Development and Regulatory status
Sep 18: Cleveland Biolabs states that once biocomparability results are available, they will continue with the pre-EUA US application. They will also consider the most appropriate timing for resubmission of the MAA in the European Union. The company also announced that it intends to pursue the BLA pathway for full approval of the drug in the US .
Sep 18: MAA withdrawal was owing to vendors inability to furnish entolimod for conduction of analytical analyses of a formulation biocomparability study, and subsequent incapability of the company to submit a complete response to EMA in the mandated timeframe. However, the review status with the FDA remains unaffected, as the review by the US FDA of the pre-emergency use authorization application does not take place on strict timelines .
Sep 18: CHMP confirm the withdrawal of the MAA, and note that they will publish further information ´soon´ .
Aug 18: the company announces that it will withdraw the Marketing Authorisation Application (MAA) submitted to the EMA, due to third-party delays in providing the analytical data for the bio-comparability study requested by the EMA. As a result, they cannot provide a complete response to the questions raised in the timeframe required by the EMA review. They are working with the company involved to resolve the issues, and will consider the most appropriate timing for re-submission. The separate pre-EUA application to the FDA is unaffected, as this does not take place on strict timelines .
Mar 18: ClevelandBiolabs announce that they have received Day 120 review questions from the EMA. These focus mainly on the comparability between the formulation used in earlier safety and efficacy studies and the formulation proposed for commercialisation; other questions included validation of various aspects of manufacturing, the animal-to-human dose-conversion strategy, and the human safety database. The company intend to respond by 31st August .
Oct 17: Filed in EU via the centralised procedure .
Apr 17: EMA accepts a paediatric investigation plan (PIP) submitted by Cleveland BioLabs. The company is evaluating steps required to file a MAA for entolimod as a medical radiation countermeasure, and as a prelude to filing an MAA, the EMA requires an agreement between the agency and the sponsor on the PIP .
Jan 16: Granted orphan drug status in the EU for treatment of ARS .
Jun 15: Cleveland submits a pre-emergency use authorisation (pre-EUA) application of entolimod to the US FDA, seeking approval for reducing the risk of death following exposure to radiation .
Dec 10: Granted orphan drug status in US for prevention of death following a potentially lethal dose of total body irradiation during or after a radiation disaster .
Jul 10: Granted fast track status in the US .
Trial or other data
Nov 17: 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. Entolimod reduces radiation damage to both hematopoietic and gastrointestinal tissues and improves tissue regeneration. 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 .
Nov 17: It is not feasible or ethical to test the efficacy of entolimod as a radiation countermeasure in humans; therefore, Cleveland Biolabs is developing entolimod under the FDA 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 .