A Phase 3 Randomized Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734*) in Participants with Severe COVID-19

In December 2019, a series of pneumonia cases of unknown cause emerged in
Wuhan, Hubei, China. Sequencing analysis from the patients* respiratory tract
samples indicated a novel coronavirus (CoV), which was named COVID-19. As of 23
February 2020, more than 78,000 confirmed cases have been identified in Wuhan,
other provinces in China, and in multiple countries outside China {World Health
Organisation (WHO) 2020}.

More than 2400 deaths associated with COVID-19 have been reported, making
COVID-19 a major health emergency. Antiviral drugs that are being evaluated as
potential treatments for COVID-19 include lopinavir/ritonavir (LPV/RTV; used in
the treatment of HIV infection) and remdesivir (RDV, GS-5734*). In a study of
Severe Acute Respiratory Syndrome (SARS), a significant reduction in acute
respiratory distress syndrome/mortality was observed in 41 patients treated
with the combination of LPV/RTV, compared with 111 patients receiving
monotherapy ribavirin (2.4% vs 28.8%, p = 0.001). However, the use of
historical control data does not allow for a reliable estimation of efficacy.
Additionally, LPV/RTV has multiple known adverse reactions such as prolonged QT
interval,severe gastrointestinal reactions, abnormal blood glucose,
pancreatitis, hepatic impairment, and elevated blood lipids. It has multiple
drug-to-drug interactions with many commonly used drugs in clinical practice;
thus, its clinical safety is not determined. Remdesivir shows potent in vitro
activity against the human pathogenic CoVs Middle East Respiratory Syndrome
(MERS)-CoV and SARS-CoV in multiple relevant human cell types. In a mouse model
of MERS-CoV infection, both prophylactic and therapeutic RDV significantly
improved pulmonary function and reduce lung viral loads and severe lung
pathology compared with vehicle control animals. In contrast, prophylactic
LPV/RTV + interferon-beta (LPV/RTV-IFNb) slightly reduced viral loads without
impacting other disease parameters. Therapeutic LPV/RTV-IFNbimproves pulmonary
function but did not reduce virus replication or severe lung pathology {Sheahan
2020}.

The evaluation of the safety and potential efficacy of RDV in people with
COVID-19 is urgently needed.

The primary objective of this study is as follows:
-To evaluate the efficacy of 2 remdesivir (RDV) regimens with respect to
clinical status assessed by a 7-point ordinal scale on Day 14

The secondary objective of this study is as follows:
- To evaluate the safety and tolerability of RDV

This is a Phase 3 randomized, open-labeled, multi-center study of RDV therapy
in participants with severe COVID-19.
The study will be conducted in two parts.
In Part A, approximately 400 participants who meet all eligibility criteria and
who are not mechanically ventilated may be randomized in a 1:1 ratio into one
of the following treatment groups:
Treatment Group 1: continued standard of care therapy together with IV RDV 200
mg on Day 1 followed by IV RDV 100 mg on Days 2, 3, 4, and 5
Treatment Group 2: continued standard of care therapy together with IV RDV 200
mg on Day 1 followed by IV RDV 100 mg on Days 2, 3, 4, 5, 6, 7, 8, 9, and 10.

Part B will enroll participants on mechanical ventilation and, after enrollment
to Part A is complete, any additional participants. In Part B, up to an
additional approximately 2000 participants who meet all of the eligibility
criteria will be enrolled, based on whether they are mechanically
ventilated at enrollment, to receive:
Mechanically Ventilated Treatment Group: continued standard of care therapy
together with IV RDV 200 mg on Day 1 followed by IV RDV 100 mg on Days 2, 3, 4,
5, 6, 7, 8, 9, and 10
Extension Treatment Group: continued standard of care therapy together with IV
RDV 200 mg on Day 1 followed by IV RDV 100 mg on Days 2, 3, 4, 5, 6, 7, 8, 9,
and 10
Enrollment in the mechanically ventilated treatment group will be capped at
approximately 500 participants.
If the 5-day dosing regimen used in Treatment Group 1 of Part A is selected for
Part B, all participants in the Extension Treatment Group and all new
participants will be reassigned to receive treatment for a total of 5 days.
National and local regulatory authorities will be informed.
Participants in Part A of the study will be the primary efficacy population.
Participants enrolled in Part B will have data reported descriptively at study
completion.

Remdesivir
Treatment Group 1:continued standard of care therapy together with IV RDV 200
mg on Day 1 followed by IV RDV 100mg on Days 2, 3, 4, and 5 Treatment Group
2:continued standard of care therapy together with IV RDV 200 mg on Day 1
followed by IV RDV 100mg on Days 2, 3, 4, 5, 6, 7, 8, 9, and 10

A pertinent specific risk for participantsin this study is the potential for
transient,Grade * 2, treatment-emergent elevations in alanine aminotransferase
(ALT) and aspartate aminotransferase (AST), which were observed after multiple
daily RDV administrations in Studies GS-US-399-1954 and GS-US-399-5505.

To date in human studies, no serious adverse events (SAEs)have occurred in
healthy individuals who have received at least 1 dose of RDV. Remdesivir has
been tested in healthy volunteers as a single ascending dose over a dose range
of 3 to 225 mg and in a multi-dose study of 150 mg for up to 14 days and at 200
mg loading dose followed by 100 mg for a total of 10 days. In nonclinical
animal studies, toxicity findings were consistent with dose-dependent and
reversible kidney injury and dysfunction. The clinical significance of the
nephrotoxicity noted in animal species is unknown.The etiology of reversible
kidney injury observed in rats is consistent with the ability of rat renal
organic anion transporters (OATs), but not human OATs, to efficiently interact
with blood metabolites of RDV, particularly GS-704277. This effect may lead to
proportionally higher intracellular accumulation of drug metabolites in renal
rat tubules, leading to kidney injury.

The 200 mg loading dose with 8 g of sulfobutylether *-cyclodextrin sodium
(SBECD) on Day 1 will be followed by 100 mg of RDV each day for 4 or 9 days
with 4 g of SBECD, which is within the range of daily SBECD administration
considered safe in humans. A total of 250mg/kg/day of SBECD is considered safe
by the European Medicines Agency and is therefore safe for all adults with
weight over 32 kg. The 100 mg dose prepared in 0.9% saline will be hypertonic
relative to human serum osmolality but approaches the normal physiological
osmolar range for humans. The RDV regimen consisting of a loading dose of 200
mg followed by RDV 100 mg daily for up to 9 days is not anticipated to pose a
safety risk to participants enrolled in this study.

There are currently no data available on the interaction of RDV and other
investigational agents. Administering RDV concurrent with other investigational
anti-CoV agents may lead to antagonism or synergy or have no effect.

The risk mitigation strategy for this study includes restriction of the study
population to those without a history of significant renal or hepatic disease:
- Exclusion of participants with ALT > 5 ULN *
- Exclusion of participants with an estimated glomerular filtration rate (eGFR)
<50mL/min *
- Exclusion of coadministration of other investigational agents against
COVID-19 * Serum chemistry assessments, including liver function testing, will
be closely monitored during the study period.

There are currently no investigational agents with demonstratedclinical
efficacy or approved treatments for COVID-19. The timely evaluation of a safe
and effective antiviral agent that works by directly and selectively blocking
the virus replication and is broadly efficacious against COVID-19addresses a
serious unmet medical need. In consideration of the information included in
this protocol, the overall risks to participants are outweighed by the
potential benefits of RDV experimental therapy for the treatment of COVID-19.
The benefit-risk balance for this study is considered positive.