Repurposing Pharmaceuticals Previously Approved by Regulatory Agencies to Medically Counter Injuries Arising Either Early or Late Following Radiation Exposure

Abstract

The increasing risks of radiological or nuclear attacks or associated accidents have served to renew interest in developing radiation medical countermeasures. The development of prospective countermeasures and the subsequent gain of Food and Drug Administration (FDA) approval are invariably time consuming and expensive processes, especially in terms of generating essential human data. Due to the limited resources for drug development and the need for expedited drug approval, drug developers have turned, in part, to the strategy of repurposing agents for which safety and clinical data are already available. Approval of drugs that are already in clinical use for one indication and are being repurposed for another indication is inherently faster and more cost effective than for new agents that lack regulatory approval of any sort. There are four known growth factors which have been repurposed in the recent past as radiomitigators following the FDA Animal Rule: Neupogen, Neulasta, Leukine, and Nplate. These four drugs were in clinic for several decades for other indications and were repurposed. A large number of additional agents approved by various regulatory authorities for given indications are currently under investigation for dual use for acute radiation syndrome or for delayed pathological effects of acute radiation exposure. The process of drug repurposing, however, is not without its own set of challenges and limitations.

Nuclear and Radiological Emergencies: Biological Effects, Countermeasures and Biodosimetry

“…In this technical sense, ideal radiomitigators ought to be anti-inflammatory, enhance antioxidant defenses, have antimutagenic properties, upregulate the DNA repair mechanisms, activate mitotic processes, cell growth and differentiation to promote the regeneration of damaged tissues, and forestall or reduce ARS and CRS. At present, no molecule under study meets all these prerequisites, but there are a large number of choices [ 54 , 233 , 234 ], which may be combined, for quick administration to affected individuals. For such situations, we may recommend the following:…”

“…The bone marrow recovery has been highlighted by the FDA, and in fact, some radioprotectants have been approved act in this sense, i.e., Filgrastim (a recombinant DNA type of the physiological G-CSF), Pegfilgrastim (a PEGlylated type of the previous), Sargramostim (a recombinant granulocyte-macrophage colony-stimulating factor, GM-CSF) and recently (2021) romiplostim (a Fc-peptide fusion protein that activates the thrombopoietin receptor) [ 54 , 234 , 254 ]. G-CSF and pegylated G-CSF promote proliferation, differentiation and maturation, and enhance blood neutrophil recovery and the survival rate.…”

“…In a randomized controlled trial in patients exposed to 14 Gy TBI (9 equal fractions for 3 days) captopril mitigated renal nephropathy—increasing survival but not significantly [ 312 ], although a subsequent study by the same authors indicated significant differences in survival were attributable to radiomitigating effects on the respiratory system [ 313 ]. Captopril has been shown to be a better mitigator than lisinopril, enalapril, or ramipril [ 234 ], but a large prospective study in lung cancer patients treated with captopril and radiotherapy was halted due to insufficient accrual [ 302 ]. However, a recent meta-analysis seems to evidence that the use of ACEi decreased the incidence of symptomatic radiation-induced pneumonitis in lung cancer patients, especially in those older than 70 years, while those treated with angiotensin receptor blockers had a slight (non-significant) trend towards developing pneumonitis [ 314 ].…”

Development of radiation countermeasure agents for acute radiation syndromes

“…In addition to the aforementioned cytokines, some other cytokines have shown to exert protective effects against IR injury. 49 For example, palifermin, a recombinant keratinocyte growth factor (truncated N-terminal), can prevent or reverse IR-induced mucositis, 50 and radioprotective effects have been demonstrated for several bioengineered erythropoietin analogs, such as darbepoetin alfa, epoetin alfa, Epogen, interleukin-3, interleukin-11, and thrombopoietin. [51][52][53][54][55][56][57] Medical advancements that have led to reductions in adverse effects after radiotherapy as well as radiation-induced bystander effects have also aided in the development of mitigation strategies, for example, the activation of tissue repair mechanisms via growth factors and cytokines; prevention of side effects by prebiotics and probiotics; and a reduction in inflammation by bevacizumab, cyclooxygenase inhibitors, angiotensin-converting enzyme inhibitors, and statins.…”

“…[63][64][65][66][67] Some agents that have been approved for other indications are being investigated for possible use in the treatment of radiation syndrome; expanding the indications of such agents could lead to an expansion of their clinical use. 49 Over the course of more than 20 years, Silverlon antimicrobial dressings have been approved for a diverse range of indications; the primary indications are the treatment of acute dermal wounds and thermal burns (first-and second degree), although Silverlon is now being repurposed for the treatment of radiation exposure. 68 Similarly, the original indication for Mozobil (AMD3100 or plerixafor) was the treatment of human immunodeficiency virus, and it is now also being used to treat radiation-induced injury.…”