VBS Response to COVID-19

SARS-COV-2 has infected millions of people globally and the mortality rate is estimated to be 1%.¹ In response to this public health crisis, VBS is harnessing all of our products and research to meet this urgent threat.

The most common complication of COVID-19 is sepsis and the Global Sepsis Alliance has stated that SARS-CoV-2 causes sepsis.² Sepsis is a medical emergency involving life-threatening organ dysfunction due to a dysregulated response to infection. In turn, it can lead to septic shock, pneumonitis, acute respiratory distress syndrome (ARDS), organ failure, and death. The effects of COVID-19 on the respiratory system are well-known, with most people requiring hospital admission developing pneumonia of varying severity. Similar to severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2 infection causes clusters of severe respiratory illness. However, multiple studies have shown that all other organ systems can be affected, most likely due to a combination of direct viral invasion and sepsis.^3-14 A recent study of patients hospitalized due to COVID-19 showed that 42% of survivors and 100% of non-survivors with developed sepsis.¹⁵

Since no therapy has been shown to be sufficiently effective against the SARS-CoV-2 itself, therapies to improve COVID-19 survival should include treatment for sepsis. Despite decades of research, novel therapies to facilitate precision medicine for sepsis beyond resuscitation and infectious source control remain elusive. Use of low doses of corticosteroids, such as hydrocortisone and dexamethasone, have been investigated for treating sepsis and SARS related respiraory disease and have been shown to slightly decrease the morality rate and time spent in the ICU and on the ventilator.^16-25Additionally, there is no data showing any harmful effects of using corticosteroids for COVID-19.²⁶

Our company discovered that CARSKNKDC (CAR), a synthetic cyclic peptide, selectively accumulates at sites of septic-damaged tissue and enhances the therapeutic effects of low-dose corticosteroids to improve survival rates in two animal models of sepsis. Specifically, we found that: (1) The mechanism of CAR homing is enhanced selective macropinocytosis at sites of damaged endothelium that enhance cellular uptake of co-administered drugs; (2) CAR selectively targets and penetrates sites of septic-injury in the lung, liver, and kidney, but does not home to healthy tissues; (3) co-administration of CAR with low dose corticosteroids restores glycocalyx damage and endothelial injuries in the kidney, lung, and liver to normal microscopic structure; (4) co-administration of CAR with low dose corticosteroids increases survival in LPS-septic mice to 90% compared to 30% for septic mice treated with low-dose corticosteroids alone, and 21% in untreated septic mice (Figure 1) The addition of CAR to low-dose cortiocsteroids also also significantly improves survival in a 2CLP rat model of sepsis (Figure 2).

**Figure 1: LPS sepsis survival rates with CAR + hydrocortisone (HCT) treatment.** 48 hours after LPS administration, Group CAR + Low-HCT showed the best survival rate compared with Group No Treatment (90% vs. 21%, < 0.05) and a higher survival rate than Group High HCT. There was no significant survival difference between Groups CAR alone, Low-HCT, and no treatment.

Suzuki K, Okada H, Takada C, Oda K, Yoshida T, Mann D, Komatsu M, Ogura S. Hydrocortisone Therapy with CAR peptide protects the injured endothelial glycocalyx in sepsis. Critical Care Medicine. 2016 December; 44(12):407.

**Figure 2: 2CLP Sepsis Survival with CAR peptide.** 15 male Sprague Dawley rats were tested using a 2CLP model of Sepsis and monitored for 96 hours. CAR was given at a dosage of 3 mg/kg and HCT at a dosage of 0.2 mg/kg with time points at 8, 20, 32, 44, 56, and 68 hours.

Yehya, N, Weiss, L, Mann D. Improved Survival After Surgical Sepsis in Rats Using a Novel Vascular Homing Peptide to Target Endothelial Delivery of Hydrocortisone. ATS 2020. American Thoracic Society 2020 International Conference; 2020 May; Philadelphia, PA, USA. ajrccmconference.2020.201.1_MeetingAbstracts.A7856

The cortiocosteroid dexamethasone was the first drug to show improved survival of COVID-19 patients.^27-28 Based on this data and the recent recommendation from multiple institutes including the NIH (National Institutes of Health), IDSA (Infectious Disease Society of America), SCCM (Society of Critical Care Medicine) and ESICM (European Society of Intensive Care Medicine) for low-dose corticosteroid treatment in COVID-19 patients,¹⁴ corticosteroids show strong promise as a candidate for COVID-19 treatment development.

In response to the urgent public health need for COVID-19 therapies that improve survival, VBS is fast-tracking CAR peptide as an adjuvant therapy to improve targeting of corticosteroids such as dexamethasone. Ultimately, we seek to develop a novel therapeutic solution that can be realistically implemented at the bedside to improve survival of critically ill COVID-19 patients.

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16. Ince, C. et al. THE ENDOTHELIUM IN SEPSIS. Shock 45, 259–270 (2016). Available at: https://journals.lww.com/shockjournal/Fulltext/2016/03000/The_Endothelium_in_Sepsis.5.aspx

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24. Li, H. et al. Effect of low-to-moderate-dose corticosteroids on mortality of hospitalized adolescents and adults with influenza A(H1N1)pdm09 viral pneumonia. Influenza Other Respi. Viruses 11, 345–354 (2017). Available at: https://onlinelibrary.wiley.com/doi/full/10.1111/irv.12456

25. Siemieniuk, R. A. C. et al. Corticosteroid Therapy for Patients Hospitalized With Community-Acquired Pneumonia: A Systematic Review and Meta-analysis. Ann. Intern. Med. 163, 519–528 (2015). Available at: https://www.acpjournals.org/doi/10.7326/M15-0715

25. Shang, L., Zhao, J., Hu, Y., Du, R. & Cao, B. On the use of corticosteroids for 2019-nCoV pneumonia. The Lancet vol. 395 683–684 (2020). Available at: https://www.sciencedirect.com/science/article/pii/S0140673620303615?via%3Dihub

26. Suzuki K, Okada H, Takada C, Oda K, Yoshida T, Mann D, Komatsu M, Ogura S. Hydrocortisone Therapy with CAR peptide protects the injured endothelial glycocalyx in sepsis. Critical Care Medicine. 2016 December; 44(12):407.

27. Yehya, N, Weiss, L, Mann D. Improved Survival After Surgical Sepsis in Rats Using a Novel Vascular Homing Peptide to Target Endothelial Delivery of Hydrocortisone. ATS 2020. American Thoracic Society 2020 International Conference; 2020 May; Philadelphia, PA, USA. ajrccmconference.2020.201.1_MeetingAbstracts.A7856

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