Promising opportunities in an expanding pipeline


RLF-100™ (aviptadil) is a synthetic form of Vasoactive Intestinal Peptide (VIP) consisting of 28 amino acids, which was first discovered in 1970. Although initially identified in the intestinal tract, human VIP is now known to be produced throughout the body and to be primarily concentrated in the lungs. Here VIP has shown a multimodal mechanism of action: decrease of inflammatory cytokines release leading to prevention of cytokine storm syndrome and viral replication, immunomodulating effect, vasodilating and bronchodilating effects, and prevention of surfactant depletion (surfactant coats the inside of the lungs, which can be lost during COVID-19 and lead to respiratory failure). Seventy percent of VIP in the body is bound to a less common type of cell in the lung, the alveolar type 2 cell, which is critical to the absorption of oxygen into the body. 

RLF-100™ has a 20-year history of safe use in humans in multiple human trials for sarcoidosis, idiopathic pulmonary fibrosis, asthma, pulmonary arterial hypertension, and sepsis-induced acute respiratory distress syndrome. A combination of aviptadil with phentolamine is approved for the treatment of erectile dysfunction by intra-cavernous injections in countries outside the U.S.

RLF-100™ is currently in clinical testing for acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) associated with the SARS-CoV-2 virus (COVID-19). Relief also plans to develop RLF-100™ for less severe form of COVID-19 and other acute and chronic lung diseases, including pulmonary sarcoidosis.

RLF-100™ Multimodal mechanism of action

  • Vasoactive Intestinal Peptide (VIP or RLF-100)
    • Produced throughout the body
    • Primarily concentrated in the lungs
    • 70% of VIP bound to AT2
    • Human peptide consisting of 28 amino acids
    • Exogenously applied RLF-100 accumulates in the lung with extended half-life (half-life ~19 minutes)
    • 20-year history of safety in humans
  • Binding to G protein-coupled receptors VPAC1, VPAC2 and PACAP-R1 triggers intracellular signaling
    • Highest density of receptors VPAC1 found in AT2
    • Significant modulation of the immune cell response (macrophages, CD4-T cells and tolerogenic dendritic cells) mediated by activation of the VPAC1 and VPAC2 receptors.
  • Anti-inflammatory and immunomodulatory roles → immune cells

    • Decreases pro-inflammatory cytokines (TNF-α, IL-6, INF-g, …)
    • Increase expression of IL-10 and TGF-β

    Vasodilatory and inotropic effects → vascular system

    • Decreases vascular resistance
    • Significantly increases arterial blood flow
    • Primary positive ionotropic effect on cardiac muscle

    Maintenance of bronchial system → lung

    • Upregulates the production of surfactant
    • Prevents cell death
    • VIP mice display airway hyper-responsiveness to noxious stimulus
    • Reduce replication of SARS-CoV-2 virus in AT2 and monocytes s

in Covid-19

Relief devised a swift plan of action to respond to one of the largest healthcare disasters our time by rapidly advancing RLF-100™ towards approval in COVID-19-induced lung injury. Through its multimodal mechanism of action, RLF-100™ may uniquely target the pathways attacked by the SARS-CoV-2 virus (COVID-19).

mulitmodal answer 3 2022

COVID-19-related death is primarily caused by respiratory failure. However, before this acute phase there is evidence of early viral infection of the alveolar type 2 cells. These cells are known to have angiotensin converting enzyme 2 (ACE2) receptors at high levels, which serve as the route of entry for the SARS-CoV-2 into the cells. Coronaviruses are known to replicate in alveolar type 2 cells, but not in the more numerous type 1 cells. These same type 2 alveolar cells have high concentrations of VIP receptors on their cell surfaces, giving rise to the hypothesis that VIP could specifically protect these cells from injury.

Injury to the type 2 alveolar cells is an increasingly plausible mechanism of COVID-19 disease progression (Mason 2020). These specialized cells replenish the more common type 1 cells that line the lungs. More importantly, type 2 cells manufacture surfactant that coats the lung and are essential for oxygen absorption into the body. Other than RLF-100™, no currently proposed treatments for COVID-19 specifically target these vulnerable type 2 cells.

  • Cell injury* and virus replication trigger the release of inflammatory cytokines and even so-called cytokine storms that could cause ARDS Destruction of surfactant production capability
  • Pulmonary alveolar type 2 (AT2) cells

    Pulmonary alveolar type 2 (AT2) cells

    • Manufacture surfactant that coats the lung
      and is essential for oxygen exchange
    • 70% of vasoactive intestinal peptide (VIP) bound to AT2 VIP receptors, upregulating surfactant production, protecting AT2 cells from cytokines</li
    • Promote angiotensin converting enzyme 2 (ACE2) receptors, a transmembrane protein involved in blood pressure regulation
  • SARS-CoV-2

    specifically binds to ACE2 receptors on the surface of AT2 cells that serve as the virus’ route of entry to penetrate the cell and start replication

Because of its safety profile and more cost-effective manufacturing process compared to proprietary biologics, RLF-100™ may be uniquely attractive to those focused on global countermeasures against COVID-19.

Clinical development in COVID-19:


RLF-100™ is in late-stage clinical testing in the U.S. for the treatment of respiratory deficiency due to COVID-19.

In March 2021, Relief’s partner NeuroRx reported top-line 60-day results from the U.S. Phase 2b/3 clinical trial (NCT04311697, COVID-AIV) evaluating RLF-100 IV in critical COVID-19 patients with respiratory failure1. According to NeuroRx, across all patients and sites, RLF-100 met the primary endpoint for successful recovery from respiratory failure at days 28 and 60 and also demonstrated a meaningful benefit in survival after controlling for ventilation status and treatment site. On the basis of these findings, NeuroRx plans to apply to the U.S. Food and Drug Administration (FDA) for Emergency Use Authorization (EUA) and subsequently plans to submit a New Drug Application with the FDA. Once the EUA application is submitted and the FDA makes a decision, Relief will decide on the best path forward for the development of RLF-100 IV in Europe and other territories once the full dataset from this study and the FDA decision on the EUA become available.

A Phase 2b/3 study of inhaled RLF-100™ for the treatment of moderate to severe COVID-19 patients (NCT04360096, AVICOVID-2)2, was initiated by NeuroRx in February 2021. According to, study completion is estimated in September 2021.  

In January 2021, NeuroRx and Quantum Leap Healthcare Collaborative ("Quantum Leap") signed a Clinical Trial Participation Agreement for the inclusion of inhaled RLF-100™ in the I-SPY COVID-19 Clinical Trial. Quantum Leap is the sponsor of the I-SPY COVID-19 Trial (NCT04488081)3, a platform trial that is assessing multiple drugs in the U.S. for the treatment of patients with Critical COVID-19 who are hospitalized or in intensive care units. RLF-100™ will be included as one of the first drugs targeting respiratory failure in critically ill COVID-19 patients. According to, study completion is estimated to be in November 2022.

In April 2021, RLF-100 IV was identified by the U.S. National Institutes of Health (NIH) as one of two drugs selected for inclusion in a phase 3 multicenter clinical trial that will include sites in the United States and multiple other countries. The trial, designated as TESICO (Therapeutics for Severely Ill Inpatients with COVID-19, NCT048437614), is funded by the U.S. government COVID-19 Therapeutics Response and sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). According to, study completion is estimated to be in April 2023.


Relief is currently preparing a European phase 2b/3 study with RLF-100 IV in COVID-19-induced ARDS patients. Once a decision is made by the U.S. FDA regarding the EUA application submitted by partner, NeuroRx, Inc., Relief will determine the best path forward for the development of RLF-100 IV in Europe and other territories. Relief continues to see the potential value of RLF-100 to help patients with COVID-19-induced lung injury and hopes that, should the FDA grant EUA for RLF-100, this could expedite the clinical assessment of RLF-100™ in Europe.

In April 2021, Relief announced that a phase 2 trial evaluating the inhaled formulation of RLF-100™ for the prevention of COVID-19-related ARDS. The study, Inhaled Aviptadil for the Prevention of COVID-19 Related ARDS, NCT045363505, is a randomized, double-blind, placebo-controlled phase 2 investigator-sponsored trial being conducted at several clinical sites in Switzerland. It is estimated that the study will take approximately 6-12 months to complete, depending on the progression of the ongoing COVID-19 pandemic.


Since July 2020, severe COVID-19 patients in the U.S. have been treated with intravenous RLF-100™ under FDA Emergency Use Investigational New Drug (IND) authorization and an Expanded Access Protocol (NCT04453839, SAMICARE6) authorization for the treatment of respiratory failure in COVID-19. By granting RLF-100™ Expanded Access Protocol to partner company NeuroRx, the FDA made a potentially lifesaving drug immediately available to critically ill patients who have no other available treatment option. The Expanded Access Protocol was designed to treat patients whose co-morbidities excluded them from enrollment in the U.S. phase 2b/3 trial of RLF-100™ IV in severe COVID-19 patients. Data from the first 21 patients in the Expanded Access Protocol showed promising results, according to NeuroRX, which warranted further study. The data demonstrated that some critically ill patients with COVID-19 experienced substantial clinical improvement when treated with RLF-100™.

RLF-100™ additional opportunities:

Beyond COVID-19, Relief’s objective is to establish RLF-100™ as the standard of care for Intensive Care Units (ICUs) in acute as well as chronic contexts to prevent and resolve respiratory failure and its complications.

Since RLF-100™’s mechanism of action is not restricted to the protection of AT2 cells, beneficial effects could extend to some other types of ALI. Preclinical and pilot clinical data in sepsis-induced ALI support this view. These programs are likely to be viewed as risk-mitigated, should RLF-100™ be shown to be safe and effective in treating COVID-19-induced ALI.

Pulmonary sarcoidosis

An open label proof-of-concept trial (Avisarco II) in 20 patients with pulmonary sarcoidosis demonstrated clinically significant suppression of inflammatory processes in the lung, as well as amelioration of dry cough and of exertional dyspnea (shortness of breath). It was found that RLF-100™ significantly restored immune tolerance by promoting regulatory T-lymphocytes, improved CD4/CD8 ratio and normalized TNF-α production. Improvements could also be seen in sarcoidosis-relevant biomarkers. RLF-100™ showed very good safety and compliance, indicating that the drug could potentially suppress sarcoidosis-associated cough with limited side effects. Additional development of RLF-100™ in pulmonary sarcoidosis is planned in the second half of 2021.


Scientific References


Relief signed a collaboration and license agreement with Acer Therapeutics for ACER-001 in March 2021.

ACER-001 is a proprietary powder formulation of sodium phenylbutyrate (NaPB). The formulation is designed to be both taste-masked and immediate release. ACER-001 is being developed using a microencapsulation process for the treatment of various inborn errors of metabolism, including Urea Cycle Disorders (UCDs) and Maple Syrup Urine Disease (MSUD). ACER-001 microparticles consist of a core center, a layer of active drug, and a taste-masking coating that quickly dissolves in the stomach to avoid a bitter taste while still allowing for rapid systemic absorption. ACER-001’s taste-masked formulation is designed to improve palatability of NaPB and could make it a compelling alternative to existing NaPB-based treatments, as the unpleasant taste associated with NaPB is cited as a major impediment to patient compliance with those treatments.


UCDs are a group of disorders caused by genetic mutations that result in a deficiency in any one of the six enzymes that catalyze the urea cycle, which can lead to an excess accumulation of ammonia in the bloodstream, a condition known as hyperammonemia. Acute hyperammonemia can cause lethargy, somnolence, coma, and multi-organ failure. Chronic hyperammonemia can lead to headaches, confusion, lethargy, failure to thrive, behavioral changes and learning and cognitive deficits. Common symptoms of both acute and chronic hyperammonemia also include seizures and psychiatric symptoms.

The current treatment of UCDs consists of dietary management to limit ammonia production in conjunction with medications that provide alternative pathways for the removal of ammonia from the bloodstream. Some patients may also require individual branched-chain amino acid supplementation.

Current medical treatments for UCDs include nitrogen scavengers, RAVICTI® and BUPHENYL®, in which the active pharmaceutical ingredients are glycerol phenylbutyrate (GPB) and sodium phenylbutyrate (NaPB), respectively. Their role is to provide an alternative way to excrete excessive nitrogen. According to a 2016 study by Shchelochkov et al., published in Molecular Genetics and Metabolism Reports, while nitrogen scavenging medications have been shown to be effective in helping to manage ammonia levels in some patients with UCDs, non-compliance with treatment is common. Reasons referenced for non-compliance associated with some available medications include unpleasant taste, the frequency with which medication must be taken, the number of pills, and the high cost of the medication.


MSUD is a rare inherited disorder caused by defects in the mitochondrial branched-chain ketoacid dehydrogenase complex, which results in elevated blood levels of the branched-chain amino acids (BCAA), leucine, valine and isoleucine, as well as the associated branched-chain ketoacids (BCKA) in a patient’s blood. Left untreated, this can result in neurological damage, mental disability, coma or death.

There are currently no approved pharmacologic therapies in the U.S. or the European Union for MSUD. Treatment of MSUD consists primarily of a severely restricted diet to limit the intake of BCAA, with aggressive medical interventions when blood levels of BCAA or BCKA become elevated.

NaPB is approved for people with UCDs to control their ammonia levels in conjunction with a restricted diet. People with UCDs who are treated with NaPB have been found to have a BCAA deficiency, despite adequate dietary protein intake. Based on this clinical observation, NaPB is being explored as a treatment to lower BCAA and their corresponding BCKA in patients with MSUD.

Acer has been granted orphan drug designation by the FDA for the MSUD indication.



Acer has indicated that it will begin clinical studies evaluating ACER-001 in MSUD. Based on positive data, an NDA under the 505(b)(2) pathway for ACER-001 in the treatment of this disease would then be submitted to the U.S. FDA.

* RAVICTI® and BUPHENYL® are registered trademarks owned by or licensed to Horizon Therapeutics plc.

Scientific References

  1. Ah Mew N, et al. Urea cycle disorders overview. Gene Reviews. Seattle, Washington: University of Washington, Seattle; 1993.
  2. Häberle J, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet Journal of Rare Diseases. 2012;7(32).
  3. Shchelochkov OA, et al. Barriers to drug adherence in the treatment of urea cycle disorders: Assessment of patient, caregiver and provider perspectives. Mol Genet Metab. 2016;8:43-47. 
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