Thymalfasin (Thymosin Alpha 1) to Treat COVID-19 Infection

Ta1 is a naturally occurring peptide that has been evaluated for its immunomodulatory
activities and related therapeutic potential in several conditions and diseases, including
infectious disease and cancer. ZADAXIN® brand Ta1 is a synthetic version currently approved
for use in 37 countries; in particular it is approved in China for treatment of hepatitis B
and to enhance vaccine response. Notably, Ta1 has been used clinically in pilot studies for
treatment of severe acute respiratory syndrome (SARS) and other lung infections including
acute respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disorder (COPD),
as well as infections after bone marrow transplant. Larger clinical trials have shown
significant efficacy for treatment of severe sepsis and hepatitis B, along with certain
cancers such as melanoma, hepatocellular, and lung cancer. Ta1 has also demonstrated
improvement in response to vaccines in the elderly and in patients immunocompromised by renal
disease.

Ta1 restores immune system homeostasis, by acting as multi-tasking protein depending on the
host state of inflammation or immune dysfunction (such as infectious disease and cancer). Ta1
is believed to directly enhance the immune systems' recognition of infected cells and tumors
cells, while also possibly modulating T cell activity and stimulating both innate and
adaptive immunity to clear bacteria, virus, fungi and tumor cells. Ta1 serves a unique
function in balancing pro-inflammatory and anti-inflammatory cytokine production through the
regulation of distinct Toll-like receptors (TLRs) on different dendritic cell subsets. Data
from other coronaviruses such as SARS-CoV and Middle Eastern respiratory syndrome (MERS)-CoV
indicate that infection relies on their ability to impair both innate and adaptive immunity.
During the 2003 pandemic, Ta1 was used as a prophylactic agent against SARS. Some published
reports suggest that timely administration of immune-enhancers such as Ta1 to SARS patients
was efficacious to a certain extent in controlling the development of the disease. Another
study investigated the clinical manifestations, pharmacotherapy and prognosis of 46 patients
with SARS and divided the severe cases (22 cases) into 2 groups according to administration
of Ta1 and showed that the incidence rate of pulmonary fibrosis was lower in the group with
Ta1 (2 of 14 cases) than the group without (6 out of 8 cases), i.e., 14.3% and 75.0%,
respectively.

A recent study presented a retrospective analysis of hospitalized COVID-19 patients in China,
in which those treated with Ta1 showed an improvement in lymphocyte subsets as well as a
significant reduction in mortality (from 30 to 11%, p = 0.04).

Based on post-marketing treatment experience of more than 600,000 patients, Ta1 has been well
tolerated. Ta1 has been administered to elderly subjects (up to 101 years old), children (as
young as 13 months), and immunocompromised patients. The most common adverse events (AEs) in
previous clinical trials include injection-site pain (such as burning and itching) which was
mild and lasted for less than 30 minutes, as well as fever, nausea, and flu-like symptoms
which were mild to moderate in severity. Thus, while Ta1 is one of only a few
immunomodulatory agents that have been approved for human use, it does not appear to induce
most of the side effects and toxicities commonly associated with other biological response
modifiers (BRMs) in this class, such as interferon and interleukin (IL)-2.

The primary objective of the study is to determine whether Ta1 administered daily for one
week to hospitalized COVID-19 patients with lymphocytopenia will improve time to recovery
(free of respiratory failure) compared with a similar population of patients who do not
receive Ta1. The secondary objectives are to determine whether hospitalized COVID-19 patients
with lymphocytopenia treated with Ta1 will have a milder course of infection in terms of
length of hospitalization stay, requirement (and length) for ICU stay, and requirement for
supplemental oxygen or mechanical ventilation than patients not treated with Ta1, as well as
higher chances of survival.

After screening, hospitalized patients with COVID-19 and lymphocytopenia who meet the
inclusion criteria will receive Ta1 (1.6 mg) administered subcutaneously (SC) daily for 1
week. Individuals in the control arm will be followed on the identical protocol but will not
receive daily Ta1. After the treatment period, all subjects will be followed and evaluated
for efficacy outcomes at Day 14, with follow-up visits at Days 28, 42, and 60 (by phone, if
the subject has been discharged from the hospital) to determine any AE/serious adverse event
(SAE) and mortality.