ZYESAMI (Aviptadil) Intermediate Population Expanded Access Protocol (SAMICARE)

5. INTRODUCTION

5.1 Executive Summary ZYESAMI (aviptadil) is a synthetic form of Vasoactive Intestinal
Polypeptide (VIP), a ubiquitous, naturally synthesized human peptide with extensively
documented anti-inflammatory, anti-cytokine cascade properties. It has been granted FDA Fast
Track Designation for treatment of Critical COVID-19 with Respiratory Failure. A phase 2/3
trial is underway that has passed its first evaluation at 30 patients for safety and
futility. This expanded access protocol is designed to offer access to investigational use of
RLF-100 to patients who do not qualify for inclusion in Protocol RLF-100-001 (NCT04311697)
either on the basis of specific medical exclusions or because there is no accessible study
site available to the prospective participant.

5.2 Definition of Critical COVID-19

In May 2020, FDA defined Critical COVID-19 to be used in clinical trials and disease staging
as follows:

Critical COVID-19

- Positive testing by standard RT-PCR assay or an equivalent test

- Evidence of Respiratory Failure based on FDA definition of: need for Endotracheal
intubation and mechanical ventilation, oxygen delivered by high-flow nasal cannula
(heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates > 20
L/min with fraction of delivered oxygen ≥ 0.5), noninvasive positive pressure
ventilation, ECMO, or clinical diagnosis of respiratory failure (i.e., clinical need for
one of the preceding therapies, but preceding therapies not able to be administered in
setting of resource limitation)

Acute Lung Injury in COVID-19 is characterized by progressive failure of corporeal
oxygenation, attributed on large part by SARS-CoV-2 infection of Alveolar Type II cells
(Mason 2020). Extensive nonclinical studies document that 70% of VIP in the body binds to
receptors on the Alveolar Type II cell, where VIP is known to block cytokine production and
upregulate production of surfactant.

Severity of COVID is associated with and graded by a progressively worsened state of
oxygenation. This is seen in the PaO2/FIO2 ratio, which reflects the status of oxygenation
for patients on high pressure oxygen and mechanical ventilation. In patients breathing room
air, disease severity is assessed by SpO2. Many patients with Critical COVID meet the
clinical definitions of Acute Respiratory Distress Syndrome (ARDS). However, there is
increasing recognition that respiratory distress in COVID-19 has different characteristics
than ARDS in the setting of bacterial sepsis and other common presentations of ARDS.

The pathologic hallmark of COVID-19 lung injury is diffuse alveolar damage, vascular
endothelium damage, and damage to the surfactant-producing type II cells which results in
loss of the integrity of the alveolar-capillary barrier, transudation of protein-rich fluid
across the barrier, pulmonary edema, and hypoxemia from intrapulmonary shunting. Typically,
patients who have progressed to Critical COVID-19 require care in an intensive care unit
(ICU). The mortality rate is approximately 50%. Deaths usually result from multisystem organ
failure rather than lung failure alone.

5.3 ZYESAMI Experimental Therapy in COVID-19

Under this protocol, patients with Critical COVID-19 will be treated with ZYESAMI (Aviptadil)
with the aim to support pulmonary alveolar function, combat the cytokine-induced
inflammation, improve blood oxygenation, and reduce mortality.

5.4 Clinical Rationale Given by intravenous infusion in appropriate concentrations, ZYESAMI
has been shown in clinical trials to have a manageable safety profile with no observed SAEs
to date that would rise to the level of a black box warning.

6. OBJECTIVES

6.1 Primary Objective The primary objective of this study is to measure the effectiveness and
safety of ZYESAMI + maximal standard of care (SOC) in treating Critical COVID-19 with
Respiratory Failure.

6.2 Secondary Objective The key secondary objective is to test the hypothesis that ZYESAMI
improves blood oxygenation as measured by SaO2.