Increased Recovery and Survival in Patients With COVID-19 Respiratory Failure Following Treatment with Aviptadil: Report #1 of the ZYESAMI COVID-19 Research Group

Youssef, J. Georges; Lee, Richard; Javitt, Jonathan C.; Lavin, Philip T.; Lenhardt, Rainer; Dj, Park; Jp, Fernandez; Morganroth, Melvin L.; Jayaweera, Dushyantha

doi:10.2139/ssrn.3830051

Cited by 3 publications

(4 citation statements)

References 25 publications

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“…Our findings support and encourage clinical trials with VIP in COVID‐19 patients, which are in progress with intravenous 38 and inhaled 39 , 40 formulations and are expected to be disclosed throughout this year. An initial release of the data, as preprint, shows an increase in survival rates and reduction of IL‐6 levels on those who received intravenous Aviptadil (VIP) 62 . Our present data may substantiate additional larger trials with VIP, an overlooked molecule associated with antiviral, anti‐inflammatory, and enhanced survival activities.…”

Section: Discussionmentioning

confidence: 99%

VIP plasma levels associate with survival in severe COVID-19 patients, correlating with protective effects in SARS-CoV-2-infected cells

Temerozo

Sacramento

Fintelman-Rodrigues

et al. 2022

Journal of Leukocyte Biology

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Infection by SARS‐CoV‐2 may elicit uncontrolled and damaging inflammatory responses. Thus, it is critical to identify compounds able to inhibit virus replication and thwart the inflammatory reaction. Here, we show that the plasma levels of the immunoregulatory neuropeptide VIP are elevated in patients with severe COVID‐19, correlating with reduced inflammatory mediators and with survival on those patients. In vitro, vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase‐activating polypeptide (PACAP), highly similar neuropeptides, decreased the SARS‐CoV‐2 RNA content in human monocytes and viral production in lung epithelial cells, also reducing cell death. Both neuropeptides inhibited the production of proinflammatory mediators in lung epithelial cells and in monocytes. VIP and PACAP prevented in monocytes the SARS‐CoV‐2‐induced activation of NF‐kB and SREBP1 and SREBP2, transcriptions factors involved in proinflammatory reactions and lipid metabolism, respectively. They also promoted CREB activation, a transcription factor with antiapoptotic activity and negative regulator of NF‐kB. Specific inhibition of NF‐kB and SREBP1/2 reproduced the anti‐inflammatory, antiviral, and cell death protection effects of VIP and PACAP. Our results support further clinical investigations of these neuropeptides against COVID‐19.

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Section: Discussionmentioning

confidence: 99%

VIP plasma levels associate with survival in severe COVID-19 patients, correlating with protective effects in SARS-CoV-2-infected cells

Temerozo

Sacramento

Fintelman-Rodrigues

et al. 2022

Journal of Leukocyte Biology

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“…Based on the effect of aviptadil in previous trials described in the introductory section, we assume that patients in the experimental group will show a 1.75-fold hazard to have a clinical improvement as compared to patients in the control group (hazard ratio (HR) = 1.75) [ 42 , 50 ]. Furthermore, based on previously published results for current standard care, we assume an overall probability of 80% for reaching the primary endpoint (clinical improvement) within 28 days ( d = 0.8) [ 56 , 57 ].…”

Section: Methods: Participants Interventions and Outcomesmentioning

confidence: 99%

“…VIP was also shown to increase surfactant production by upregulation of choline phosphate cytidylyltransferase and C-Fos protein expression in ATII cells [ 38 – 40 ]. Recent data demonstrated that plasma levels of VIP are higher in patients with severe COVID-19, compared to healthy individuals and those with mild COVID-19 [ 41 , 42 ], and that VIP can block SARS-CoV-2 virus replication in vitro [ 32 ].…”

Section: Introductionmentioning

confidence: 99%

“…Two phase II trials have been announced recently on the US National Library of Medicine platform “ClinicalTrials.gov” (COVID-AIV (NCT04311697), AVICOVID-2 (NCT04360096)), which investigate aviptadil in patients with COVID-19 in the USA. Preliminary results of the COVID-AIV trial, which has been recruiting patients with COVID-19 and respiratory failure, indicate a promising antiviral effect of the intravenous administration of aviptadil [ 42 ]. In contrast, this current trial investigates the inhaled application of aviptadil in an earlier stage of disease, in patients at increased risk for ARDS.…”

Section: Introductionmentioning

confidence: 99%

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Inhaled aviptadil for the possible treatment of COVID-19 in patients at high risk for ARDS: study protocol for a randomized, placebo-controlled, and multicenter trial

Boesing

Abig²,

Brändle

et al. 2022

Trials

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Background Despite the fast establishment of new therapeutic agents in the management of COVID-19 and large-scale vaccination campaigns since the beginning of the SARS-CoV-2 pandemic in early 2020, severe disease courses still represent a threat, especially to patients with risk factors. This indicates the need for alternative strategies to prevent respiratory complications like acute respiratory distress syndrome (ARDS) associated with COVID-19. Aviptadil, a synthetic form of human vasoactive intestinal peptide, might be beneficial for COVID-19 patients at high risk of developing ARDS because of its ability to influence the regulation of exaggerated pro-inflammatory proteins and orchestrate the lung homeostasis. Aviptadil has recently been shown to considerably improve the prognosis of ARDS in COVID-19 when applied intravenously. An inhaled application of aviptadil has the advantages of achieving a higher concentration in the lung tissue, fast onset of activity, avoiding the hepatic first-pass metabolism, and the reduction of adverse effects. The overall objective of this project is to assess the efficacy and safety of inhaled aviptadil in patients hospitalized for COVID-19 at high risk of developing ARDS. Methods This multicenter, placebo-controlled, double-blinded, randomized trial with 132 adult patients hospitalized for COVID-19 and at high risk for ARDS (adapted early acute lung injury score ≥ 2 points) is conducted in five public hospitals in Europe. Key exclusion criteria are mechanical ventilation at baseline, need for intensive care at baseline, and severe hemodynamic instability. Patients are randomly allocated to either inhale 67 μg aviptadil or normal saline (three times a day for 10 days), in addition to standard care, stratified by center. The primary endpoint is time from hospitalization to clinical improvement, defined as either hospital discharge, or improvement of at least two levels on the nine-level scale for clinical status suggested by the World Health Organization. Discussion Treatment strategies for COVID-19 are still limited. In the context of upcoming new variants of SARS-CoV-2 and possible inefficacy of the available vaccines and antibody therapies, the investigation of alternative therapy options plays a crucial role in decreasing associated mortality and improving prognosis. Due to its unique immunomodulating properties also targeting the SARS-CoV-2 pathways, inhaled aviptadil may have the potential to prevent ARDS in COVID-19. Trial registration ClinicalTrials.gov, NCT04536350. Registered 02 September 2020.

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VIP plasma levels associate with survival in severe COVID-19 patients, correlating with protective effects in SARS-CoV-2-infected cells

Temerozo

Sacramento

Fintelman-Rodrigues

et al. 2020

Preprint

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Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of coronavirus disease 2019 (COVID-19), may elicit uncontrolled and damaging inflammatory reactions, due to an excessive immune response and dysregulated production of cytokines and chemokines. Thus, it is critical to identify compounds able to inhibit virus replication and thwart the excessive inflammatory reaction and tissue lesions secondary to SARS-CoV-2 infection. Here, we show that the neuropeptides VIP and PACAP, molecules endowed with immunoregulatory properties, were able to inhibit SARS-CoV-2 RNA synthesis/replication in human monocytes and viral production in lung epithelial cells. VIP and PACAP protected these cells from virus-induced cytopathicity, reduced the production of proinflammmatory mediators, and prevented the SARS-CoV-2-induced NF-kB activation, which is critically involved in the production of inflammatory mediators. Both neuropeptides promoted CREB activation in infected monocytes, a transcription factor with antiapoptotic activity and also a negative regulator of NF-kB. As a possible host response to control patient inflammation, we identified that VIP levels were elevated in plasma from patients with severe forms of COVID-19, correlating with the inflammatory marker CRP and survival on those patients. Since a synthetic form of VIP is clinically approved in Europe and under two clinical trials for patients with COVID-19, our results provide the scientific evidence to further support clinical investigation of these neuropeptides against COVID-19.

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Increased Recovery and Survival in Patients With COVID-19 Respiratory Failure Following Treatment with Aviptadil: Report #1 of the ZYESAMI COVID-19 Research Group

Cited by 3 publications

References 25 publications

VIP plasma levels associate with survival in severe COVID-19 patients, correlating with protective effects in SARS-CoV-2-infected cells

VIP plasma levels associate with survival in severe COVID-19 patients, correlating with protective effects in SARS-CoV-2-infected cells

Inhaled aviptadil for the possible treatment of COVID-19 in patients at high risk for ARDS: study protocol for a randomized, placebo-controlled, and multicenter trial

VIP plasma levels associate with survival in severe COVID-19 patients, correlating with protective effects in SARS-CoV-2-infected cells

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