M-LIFE™ has identified 8 drugs as prospective repurposing targets to address the cytokine storm associated with severe COVID-19 cases.
NASHVILLE, TENNESSEE – M-LIFE™ has identified 8 drugs as prospective repurposing targets to address the cytokine storm associated with severe COVID-19 cases. As with M-Life’s™ prior list of repurposing targets directed at the virus, prospective cytokine candidates were identified via the Company’s proprietary algorithms. The prospects include: Losartan, Mepyramine, Midazolam, Pioglitazone, Raloxifene, Sarpogrelate, Suramin, and Surinabant.
Dr. John Panos, M-Life™ Director of Translational Discovery, said, “The most disturbing feature of severe COVID-19 infection is the cytokine storm which is a pro-inflammatory, immune response induced by the virus that often leads to acute respiratory distress syndrome (ARDS) and widespread multi-organ tissue damage. And while the fatal consequences of the cytokine storm are of immediate concern during infection, survivors may well experience long-lasting effects from multi organ tissue damage after recovery.”
The present clinical approach for addressing the cytokine storm is through treatment with a corticosteroid like dexamethasone. However, the use of corticosteroids also comes associated with risks including withdrawal and organ damage from prolonged or repeated dosing (Ref. 1).
“One alternative to corticosteroids are IL-6 targeting drugs,” Panos further explained. “IL-6 inhibitor drugs are potential pharmacotherapies for the hyper-inflammatory respiratory state associated with COVID-19. Drugs such as Tocilizumab and Remdesivir have been linked to decreased mortality rate in hospitalized COVID-19 patients (Refs. 2, 3, 4). The M-Life™ repurposing strategy was to identify other promising IL-6 targeting small molecule drugs,” he said.
The following Table shows the M-Life™ predicted drugs suitable for repurposing as IL-6 targeting. Some of the predicted repurposed drugs, like Suramin and Losartan, have been previously identified as plausible repurpose targets by M-Life™ for inhibition of viral enzymes.
Key: The Table above consists of a compilation of repurposed drugs. Column two shows the algorithm predicted efficacy, columns 3 to 7 show predictions for various toxicities, and column 8 shows the clinical experience based on two sources. The predictive values are expressed as probabilities of toxicity with a zero indicating no toxicity and 1.00 indicating 100 percent likelihood of toxicity. As mentioned previously, the hepatotoxicity algorithm is based on post-market drugs that cause acute liver failure or significant liver toxicity rather than long term steatosis and cholestasis.
Table Summary
The M-Life™ study was designed around the use of ‘benchmark drugs’ to corroborate the validity of algorithm predictions. Three benchmark drugs: Suramin, Losartan, and Pioglitazone appear in published studies affirming IL-6 inhibition characteristics (Refs. 5, 6, 7). Aside from validation of algorithm predictions, the benchmark drugs also served as a basis for comparison to other prospective repurposed drugs solely by algorithm predictions. The Suramin Benchmark is known to have high IL-6 inhibition characteristics but also elicited a number of toxicity issues according to both clinical data and M-Life™ algorithms. The Benchmark drugs Losartan and Pioglitazone had concordant clinical and algorithm scoring for both toxicity and IL-6 inhibition, while also having lower predicted toxicity than Suramin.
The objective of M-Life’s™ IL-6 targeting study was to identify new repurposing candidates that may be suitable for use as a treatment for the COVID-19 cytokine storm. The study accomplished this objective. This Study confirmed not only identified potential repurposed drugs but also confirmed the predictive ability of the M-Life™ algorithms. Losartan, Mepyramine, Midazolam, Pioglitazone, Raloxifene, Sarpogrelate, Suramin, and Surinabant all had M-Life™ algorithm predictive scoring consistent with favorable IL-6 inhibition characteristics. Curiously, Losartan, a known IL-6 inhibitor via published studies with high algorithm scoring, has not entered clinical assessment for IL-6 inhibition in COVID-19 patients.
M-Life™ Algorithms Point Lower Toxicity and Better Efficacy Options
M-Life’s™ President and CEO Ted Moskal said, “The results of our IL-6 drug repurposing study indicated that there are a number of additional prospects for repurposing beyond those being presently used. These IL-6 inhibitor candidates augment our previous work that identified repurposed drugs that directly target the virus. The three pillars for the treatment and control of COVID-19 are preventative vaccines, cytokine-controlling treatments and antivirals; M-Life™ has addressed two of these pillars. We’re hopeful that our work may benefit clinical efforts to identify suitable treatment alternatives. Additionally, our algorithms have identified new molecular motifs useful for the design of new prospective drugs. Based on this, M-Life™ has designed new molecules that have both the potential for serving as highly effective treatments for COVID-19, and more broadly, as antivirals for the treatment of influenza. And although it’s quite early in the design process, our algorithms are producing high predicted efficacy AND low toxicity scores, making them much better prospective drugs compared to the existing alternatives.”
The Company has further research underway relative to possible off-target effects, both toxicity and side effects, for repurposed drugs and plans on sharing additional information in the near future.
About M-Life™
M-Life™ is a life sciences, molecule discovery company focusing on the development of new drugs, agricultural and diagnostics related chemicals. Whether a new antibiotic, non-opiate analgesic or environmentally friendly herbicide, the Company aims to address gaps in the present life sciences markets making life better. To learn more about M-Life™, please visit us at www.m-lifesciences.com.
M-Life™ Cautionary Statement
This press release contains statements relative to predicted performance using proprietary algorithms. The actual performance of these drugs in treating COVID-19 cannot be fully assessed until their usefulness has been determined via treatment of the illness. The Company plans on sharing additional information relative to possible off-target effects associated with the list of repurposed drugs herein in the near future.
References:
1. https://pubchem.ncbi.nlm.nih.gov/compound/Dexamethasone#section=Safety-and-Hazards
2. Effective treatment of severe COVID-19 patients with tocilizumab, Xiaoling Xu, Mingfeng Han, Tiantian Li, Wei Sun, Dongsheng Wang, Binqing Fu, Yonggang Zhou, Xiaohu Zheng, Yun Yang, Xiuyong Li, Xiaohua Zhang, Aijun Pan, Haiming Wei. Proceedings of the National Academy of Sciences May 2020, 117 (20) 10970-10975; DOI: 10.1073/pnas.2005615117
3. Klopfenstein, T., Zayet, S., Lohse, A., Balblanc, J. C., Badie, J., Royer, P. Y., Toko, L., Mezher, C., Kadiane-Oussou, N. J., Bossert, M., Bozgan, A. M., Charpentier, A., Roux, M. F., Contreras, R., Mazurier, I., Dussert, P., Gendrin, V., Conrozier, T., & the Hospital Tocilizumab multidisciplinary team (2020). Tocilizumab therapy reduced intensive care unit admissions and/or mortality in COVID-19 patients. Medecine et maladies infectieuses, 50(5), 397–400. https://doi.org/10.1016/j.medmal.2020.05.001
4. https://www.gilead.com/news-and-press/press-room/press-releases/2020/7/gilead-presentsadditional-data-on-investigational-antiviral-remdesivir-for-the-treatment-of-covid-19
5. Rei-Tsang Shiao, Susan B. McLeskey, Samira Y. Khera, Amy Wolfson & Carl E. Freter (1996) Mechanisms of Inhibition of IL-6-Mediated Immunoglobulin Secretion by Dexamethasone and Suramin in Human Lymphoid and Myeloma Cell Lines1, Leukemia & Lymphoma, 21:3-4, 293-303, DOI: 10.3109/10428199209067610
6. Heimfarth, L., Serafini, M. R., Martins-Filho, P. R., Quintans, J., & Quintans-Júnior, L. J. (2020). Drug repurposing and cytokine management in response to COVID-19: A review. International immunopharmacology, 88, 106947. Advance online publication. https://doi.org/10.1016/j.intimp.2020.106947
7. Zhang, W. Y., Schwartz, E. A., Permana, P. A., & Reaven, P. D. (2008). Pioglitazone inhibits the expression of inflammatory cytokines from both monocytes and lymphocytes in patients with impaired glucose tolerance. Arteriosclerosis, thrombosis, and vascular biology, 28(12), 23122318.