https://www.cash.ch/sites/default/files/public/documents/forum/2020/07/preprints202007.0178.v1.pdf
Brief Report: Rapid clinical recovery from Critical COVID-19 with Respiratory Failure in a lung
transplant patient treated with intravenous Vasoactive Intestinal Peptide.
Jihad Georges Youssef, MD1
Faisal Zahiruddin, D.O.2
Mukhtar Al-Saadi, M.D.
2
Simon Yau, M.D. 3
Ahmad Goodarzi, M.D. 3
Howard J. Huang, M.D. 3
Jonathan C. Javitt, MD, MPH 4,5
Author Affiliations:
1. Houston Methodist Pulmonary Transplant Center, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, Texas, USA
2. Department of Academic Pulmonology, Houston Methodist Hospital, Houston, Texas
3. Houston Methodist Pulmonary Transplant Center, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, Texas, USA
4. NeuroRx, Inc. Wilmington, DE
5. Johns Hopkins University, Baltimore, MD
Keywords
Vasoactive Intestinal Peptide, VIP, SARS-CoV-2, COVID-19, Acute Respiratory Distress Syndrome, ARDS, Acute
Lung Injury, ALI, surfactant, Alveolar Type II
Correspondence to: jjavitt@neurorxpharma.com
Disclosure: Author JCJ is employed by a pharmaceutical company that is currently conducting clinical trials of RLF100 in patients with COVID-19 and has a financial interest in the outcome of those clinical trials. Author JGY has
received funding as an investigator for RLF-100 through his institution.
Summary: RLF-100 (Aviptadil), a synthetic form of Vasoactive Intestinal Peptide (VIP) has been granted Fast Track
Designation by the US FDA for the treatment of Critical COVID-19 with Respiratory Failure. We describe the
clinical course of the first patient treated with this investigational medication in an open label manner -- a 54 year old
patient suffering antibody-mediated rejection of his double lung transplant who contracted COVID-19 with
respiratory failure refractory to all currently available therapies. He received three infusions of RLF-100 under an
FDA-approved emergency use IND. Within 24 hours of the third infusion, substantial improvement in oxygen
saturation and radiographic improvement in characteristic COVID-19 pneumonitis was noted. He was discharged
from intensive care at that point and returned home at 1 week on room air.
Background
RLF-100 (Aviptadil), a synthetic form of human Vasoactive Intestinal Peptide (VIP) has been awarded FDA Fast
Track Designation for the treatment of Critical COVID-19 with Respiratory Failure and has entered clinical trials in
the United States and internationally. Since its discovery in 1970 by Said and Mutt1 VIP has been shown to protect the
lung against a broad array of caustic, immune, and infectious injuries2,3,4,5
through its binding to the VPAC1 receptor
of the Alveolar Type II cell. This is the same cell to which the SARS-CoV-2 virus binds via the ACE2 receptor6
. VIP
has previously demonstrated effectiveness in the treatment of ARDS related to sepsis7
, sarcoid8
, and pulmonary
hypertension9
,
10
.
Concurrent with the award of Fast Track designation, the US FDA requested that the sponsor make RLF-100
available under emergency use IND. We report rapid and unexpected radiographic and clinical improvement in a 54
year old man with PCR+ Critical COVID-19 in the setting of antibody mediated rejection (AMR) and
immunosuppressive therapy following double lung transplantation. Because of this co-morbid condition, the patient
did not meet the enrollment criteria for NCT04311697, and was offered open label access to RLF-100 under an
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 9 July 2020 doi:10.20944/preprints202007.0178.v1
© 2020 by the author(s). Distributed under a Creative Commons CC BY license.
Youssef JG et al. VIP in lung transplant patient with COVID-19 P a g e | 2
emergency use IND approved by the US FDA on a named-patient basis under the NeuroRx, Inc. expanded access
program (www.clinicaltrials.gov NCT04453839).
Clinical Report
One year prior to presentation, the patient underwent a double lung transplant secondary to rheumatoid arthritisrelated interstitial lung disease and pulmonary hypertension. A week prior to presentation, he was treated for
subclinical AMR with plasmapheresis, intravenous immunoglobulin and belatacept. 2 days later, he presented to the
emergency room with headache fever of 103 and productive cough. His nasopharyngeal swab resulted positive for
COVID; he received supportive inpatient care, remained stable without increase in O2 requirement, and was
discharged home 3 days later.
After several days, he returned to the emergency room with worsening shortness of breath, fever and hypoxemia.
His oxygen requirement continued to increase and was admitted to the intensive care unit for further care. Respiratory
failure was evident with SaO2 90% on high flow nasal O2 30 L/min and FiO2 50%. Patient received Tocilizumab for
signs of cytokine release syndrome (CRS) without apparent benefit. Ferritin level was 1189 ng/ml, interleukin-6
126pg/mL LDH 447 U/L and CRP level was 20.07 mg/dL. Awake prone therapy was not tolerated and was associated
with worsening dypsnea. He was not a candidate for Remdesivir due to chronic kidney disease. Convalescent plasma
was not available. Patient also received anticoagulation.
Intravenous Aviptadil was offered to the patient and following his agreement Institutional IRB and FDA
emergency authorization IND were obtained. He received 3 12 hour infusions of intravenous RLF-100 (Aviptadil) at
ascending doses of 50/100/150 pmol/kg/hr. This treatment was associated with progressive improvement in blood
oxygenation and radiologic appearance of pneumonitis on chest X-Ray and chest CT (figure 1). Neither the patient
nor the clinical staff identified any adverse effects of treatment. He was discharged from the ICU 24 hours following
the third infusion and discharged to home on room air 5 days following the 3rd infusion.
Figure 1: Radiographic Appearance and blood oxygen saturation before and after treatment. Note the areas of
consolidation and pneumonitis particularly in the right lung that are substantially resolved after treatment with concomitant
Before Infusion 24- hours post 3rd
infusion
Portable Chest X-Ray
Scout CT
Chest CT
PaO2:FiO2 146 285.19
SaO2 98 95
FiO2 HFLNC 30 L/min, FiO2 50% 2 L/min
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 9 July 2020 doi:10.20944/preprints202007.0178.v1
Youssef JG et al. VIP in lung transplant patient with COVID-19 P a g e | 3
increase in lung volume.
Discussion
To our knowledge, this is the first reported case of VIP being used to treat a patient with Critical COVID-19, with
rapid clinical improvement in clinical parameters and radiographic features. Similar observations were recently
reported in a patient with checkpoint inhibitor pneumonitis.
11
The SARS-CoV-2 virus specifically attacks Alveolar Type II cells and does not enter the Type I pneumocyte.
12
Loss
of ATII cells reduces the lung’s oxygenation capacity, particularly because the ATII cell is responsible for the
production and recycling of surfactant in a addition to its other roles in supporting the pulmonary epithelium.6
VIP may have been particularly beneficial in the setting of AMR following lung transplantation based on prior
reports that VIP preserves the function of lung allografts.
13,14
VIP is a potent anti-cytokine in the lung that provides
key defense against numerous forms of acute lung injury. Although named (or mis-named) for the tissue in which it
was first isolated, VIP is produced by neuroendocrine cells throughout the body and by T-lymphocytes, Blymphocytes, and macrophages. VIP is highly localized in the lung but is a widely distributed immunomodulator with
protective effects in heart, thyroid gland, kidney, immune system, urinary tract and genital organs.15
Early COVID-19 lung injury is characterized by a remarkable degree of hypoxia in the absence of overwhelming
pneumonia, suggesting a primary injury to the pulmonary gas-exchange mechanism. VIP is the body’s primary
defense against cytokine injury in the lung and elsewhere. Unlike synthetic anti-cytokines, such as anti-IL6 drugs,
VIP is shown to have a specific role in preserving surfactant production in the lung and in protecting type 2 alveolar
cells.
16,17,18 Accordingly, VIP and longer acting modifications of VIP have been proposed in the past as respiratory
therapeutics
19
.
The SARS-CoV-2 virus is known to enter cells via binding to ACE2 receptors on the cell surface and those receptors
are predominantly found on the Alveolar type II (ATII) cells. Moreover, VIP receptors are preferentially expressed on
ATII cells and VIP is shown to prevent their apoptosis in models of lung injury.20 Li demonstrated in rat lung explants
that VIP increased the incorporation of methyl-choline into phosphatidylcholine -- the major component of the
pulmonary surfactants -- by enhancing the activity of the enzyme choline-phosphate cytidylyltransferase16
. VIP
upregulates C-Fos protein expression in cultured type II alveolar cells, which is instrumental in promoting synthesis
of pulmonary surfactant phospholipids17 and induces surfactant protein A expression in ATII cells through activation
of PKC/c-Fos pathway.
Conclusion:
The rapid clinical improvement seen in this first patient treated with intravenous RLF-100 (aviptadil), is consistent
with the theory that VIP protects the ATII cell, blocks cytokine storm, and improves oxygenation in a lung that is
under attack. This highly specific role of VIP in the lung may be key to combating the lethal effects of SARS-CoV-2
infection. A randomized prospective trial is underway, which will attempt to demonstrate that intravenous RLF-100
improves survival, oxygenation, and clinical course of Critical COVID-19 with respiratory failure.
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 9 July 2020 doi:10.20944/preprints202007.0178.v1
Youssef JG et al. VIP in lung transplant patient with COVID-19 P a g e | 4
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Peptide Inhaled Agonists: Potential Role in Respiratory Therapeutics. Hippokratia 2013;17(1):12-16
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adenylate cyclase-activating polypeptide attenuate the cigarette smoke extract-induced apoptotic death of rat
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