Key 3 – Implement 4R standards (right patient, right drug,
right dosage, right timing)
1. Right patient
The idea of matching drugs to patients is a widely accepted paradigm in
pharmacology. This personalized medicine approach emphasizes the
numerous patient-level factors that can affect therapeutic targets, a
medication’s PK, as well as the overall burden of disease.
Patient selection is complicated by heterogeneity in the clinical
manifestations of COVID-19. About 80% of patients will only have
mild/moderate flu-like or pneumonia symptoms.8 The
majority of COVID-19 cases are self-limited and not life-threatening. A
considerable portion of patients, up to 17.9% of RT-PCR-confirmed cases
in some models,9 may be completely asymptomatic for
the entire duration of infection, though some may have objective
subclinical manifestations of disease10. However,
around 20% of patients are deemed severe cases with significant
dyspnea, hypoxia, or lung imaging findings that require supplemental
oxygen or intensive care and current estimates of COVID-19 case fatality
rates vary from 2-7%,8,11,12 though this figure
varies by location.
A number of factors contribute to the disparate manifestations of
COVID-19; the most well-studied factor is age. It has been reported in
China, Italy, South Korea and United States that elderly patients
comprised approximately 60-83% of all COVID-19
fatalities.13,14,15 A similar trend is seen with
designation of “severe” cases as well as rates of hospitalization and
ICU admission, all of which are more prevalent in older
individuals.15
Another factor is cardiovascular disease (CVD). There is a high
prevalence of CVD amongst severe COVID cases and COVID cases overall,
with death rates of individuals with CVD reportedly over four times the
overall mortality rate.11 The leading hypothesis for
this is suggested to involve SARS-COV-2’s interaction with
angiotensin-converting enzyme 2 (ACE2) and the
renin-angiotensin-aldosterone axis. Chronic respiratory disease is also
linked with severe and fatal COVID-19 cases,15potentially due to the decreased lung pulmonary reserve, dysregulated
immune system, and disrupted lung microbiome in these
patients.16,17 Diabetes is also a significant risk
factor for severe COVID-19 infection, potentially due to similar
mechanisms of immune dysregulation, alterations in ACE2 expression, and
increased processing of the SARS-COV-2 spike
protein.18 In addition, it has been suggested that
common therapies for these conditions, such as angiotensin converting
enzyme inhibitors, angiotensin receptor blockers, and immunomodulators
like inhaled steroids have an effect on COVID-19
pathophysiology.19,20,21
In designing therapeutic drug trials for COVID-19, we may have to
control for not only age, CVD, pulmonary disease, diabetes, and other
patient-level factors like immunodeficiency, but also control for the
therapies patients have been given.
2. Right Drug
Two approaches for developing scientific treatments for COVID-19 exist:
1) a “bottom-up” approach by repurposing already approved drugs or
molecules under clinical development for other indications
2) a “top-down” approach targeting at new molecules and vaccines
specifically designed for SARS-COV-2 which can be time-consuming, but
more effective and safer.
COVID-19 is caused by SARS-CoV-2 that is a single-stranded
positive-sense RNA virus.22 Since SARS-CoV-2 is a
newly discovered pathogen, no specific drugs are currently available.
Several existing drugs and new drugs that have potential therapeutic
effects are summarized in Table 1. These therapeutics are divided into 4
categories: convalescent plasma or immunoglobulins; direct-acting
antiviral agents (DAA); host cell internalization protein blockers; and
anti-inflammatory drugs.
Convalescent Plasma or immunoglobulin fractions have been used for
treatment of Ebola virus, Middle East respiratory syndrome coronavirus
(MERS-CoV), and SARS-CoV infections.23,24,25 A
clinical study of 5 critically ill patients with COVID-19 and acute
respiratory distress syndrome (ARDS) showed that administration of
convalescent plasma containing neutralizing antibodies improved some
patient’s clinical status.26 Issues associated with
this approach include donner identification, elimination of residual
SARS-CoV-2 risk, off-target immunoglobulin binding, and dose estimation.
Of special concern is the ability to scale this approach to the level
required.
The potential targets of DAA against non-structural proteins include
RNA-dependent RNA polymerase (RdRp), coronavirus main protease (3CLpro),
and papain-like protease (PLpro). A potential target for a DAA against a
viral structural protein was the glycosylated spike (S)
protein.27 S protein mediates SARS-CoV-2 entry via
binding to angiotensin-converting enzyme 2 (ACE2) located on the surface
membrane of host cells following which host cell produced transmembrane
protease serine 2 (TMPRSS2) was involved in S protein priming that
facilitates the process of internalization.28 Thus,
both host cell membrane proteins ACE2 and TMPRSS2 have become potential
therapeutic targets. In addition, some recent studies also reported that
S protein can also bind to the host cell receptor CD14729 and the glucose regulated protein 78 (GRP78)30 that may also mediate internalization.
The protease inhibitor combination lopinavir and ritonavir (Aluvia®),
and two viral polymerase inhibitors, favipiravir and remdesivir, are
non-structural SARS-CoV-2 protein targets currently in clinical trials.
Galidesivir (BCX4430) is an adenine analogue RdRp inhibitor originally
developed for the treatment of hepatitis C virus. It is currently
undergoing safety testing in early clinical studies and is being
evaluated for its efficacy in treating yellow fever. In preclinical
studies, it exhibits activity against a variety of RNA viruses,
including SARS and MERS.
Both SARS-CoV, responsible for severe acute respiratory syndrome (SARS),
and SARS-CoV-2, responsible for COVID-19, are beta-coronaviruses (CoV)
that share a structurally similar spike glycoprotein (S) complex
surrounding the spherical viral particle that is comprised of a receptor
binding domain (RBD) S1 subunit and a membrane fusion S2
subunit.31 The S proteins of SARS-CoV-2 have about
76% homology to those of SARS-CoV and both recognize and bind to
ACE2.31
While Abidol is mainly used for the prevention and treatment of
influenza virus infections, it may disrupt the binding of S proteins to
ACE2 to prevent viral internalization and is currently in clinical
trials (see Table 1). Soluble recombinant human angiotensin converting
enzyme-2 (srhACE2) was initially proposed as a treatment for general
ARDS but its affinity for the SARS-CoV-2 spike protein could enable a
neutralization with the virus preventing the viral internalization. It
is possible for shrACE2 to treat COVID-19 through a combination of
preventing lung injury by reducing local angiotensin-II levels and
preventing lung epithelial internalization of the virus.
Nafamostat and Camostat are two TMPRSS2 inhibitors with similar
molecular structure that could block the virus internalization process.
Camostat is currently in clinical trials for COVID-19 Infection (see
Table 1).
Hydroxychloroquine (HCQ) / chloroquine (CQ) are anti-malarial drugs used
for treating Lupus and forms of arthritis. HCQ is a derivative of CQ
with therapeutic effects similar to those of CQ, but with reduced toxic
side effects. HCQ/ CQ can inhibit the in vitro replication of several
coronaviruses. Recent publications support the hypothesis that CQ can
improve the clinical outcome of patients infected by SARS-CoV-2. CQ may
interfere with ACE2 receptor glycosylation to inhibit SARS-CoV-2 binding
to target cells. It may also inhibit cleavage of S proteins by
acidifying lysosomes and may inhibit cathepsin activity. HCQ activates
CD8 + T-cells that reduces the production of pro-inflammatory cytokines32,33,34 to limit lung inflammation.
SARS-CoV-2 may cause the rapid release of inflammatory cytokines
resulting in ARDS and multiple organ failure. Anti-inflammatory drugs
can relieve this response. IL-6, CCR5 and JAK kinase are potential
targets for relieving SARS-CoV-2 caused
inflammation.35 Tocilizumab
(ACTEMRA®) is a recombinant human monoclonal antibody
that specifically binds to soluble and membrane-bound IL-6 receptors
(sIL-6R and mIL-6R) and inhibits inflammatory IL-6-mediated signal
transduction. CytoDyn’s humanized CCR5 antagonist leronlimab (PRO140)
has applied for a phase II clinical trial for adult patients with mild
to moderate respiratory disease after infection with SARS-CoV-2. The JAK
kinase inhibitors baricitinib and ruxolitinib can inhibit JAK-mediated
inflammatory processes and are currently in clinical trials for COVID-19
(see Table 1).
3. Right dosage
New drug development paradigm : Dose is an important issue for
antiviral drug development requiring years of work. The process starts
at the interface between preclinical and Phase I when the first in human
dose is calculated. Under today’s model-based drug development paradigm,
this exercise is supported by translational PK-PD modelling using
available data of nonclinical PK, drug metabolism and toxicology. Phase
I dose escalation trials will then be conducted to examine safety,
tolerability and PK in reference of in vitro susceptibility and in vivo
animal data. Phase II studies will be further conducted in target
patients to achieve goals of PoC and dose ranging using biomarkers for
both efficacy such as viral load and safety. Dosage for Phase III trial
will be optimized based on a target PK/PD metric (e.g.,
Cmin,ss/EC90) and population PK of the drug. In
addition, experimental medicine studies will be conducted to study
tissue penetration, and a series of clinical pharmacology studies will
be conducted to examine intrinsic and extrinsic factors including age,
body weight, the stage of the disease, the presence of co-morbidities,
patients’ use of other medications for the purposes of adjusting dose in
special populations.
Dose estimation for repurposed drugs : Drug development for
COVID-19, thus far, is dependent on the indication extension of
existing, approved drugs. These anti-viral drugs must have been through
the full pre-clinical discovery and clinical development process with
extensive pharmacological, PK, toxicology and manufacturing work done.
It is essential that drug candidates for repurposing must have shown
efficacy for their original intended indication such that regulatory
approval is achieved or fully expected. Absent these requirements
additional exploratory development work will be required prior to
conduct of a pivotal efficacy trial for the new indication (e.g.
COVID-19).
The only information that should be needed to extend an existing drug
for use to the new indication is the characterization of its target
interaction as nothing else should change. If the new viral target
attacks a different tissue, then additional tissue distribution work may
be required.
The need to characterize an existing drug’s interaction at a different
target in the same tissue such as the RdRp for SARS-CoV-2 versus that of
another RNA virus in the lung can be done at the in vitro level.
If the EC50 value in this case is different, as it is more likely that
the drug will be less potent, then a proportional dose adjustment is a
useful approximation. In this case, a much greater effort must be made
to estimate the effect of increasing the dose for the new indication. Do
the human PK findings support a simple proportional dose adjustment? Do
the safety findings support a higher exposure level? Small differences
in potency make it likely that the drug can be used for the new
indication but larger ones may well preclude this use. This is
especially true if significant new clinical development efforts must be
made that will substantially increase the time required to get the drug
into patients. Assuming that the outcome supports repurposing the
existing drug for the new indication it still must be tested in an
adequately powered clinical trial for an appropriate patient population.
In COVID-19 drug trials, we found only two trials intended to explore
different dosage regimens, Gilead remdesivir trials examine treatment
durations of 10 days vs 5 days [NCT04292730, NCT04292899], and the
PrEP trial by Washington University School of Medicine on HCQ employ
low, mid and high dose regimens [NCT04333732]. None tried a dosage
higher than its approved level.
Clinical investigators should collaborate closely with the innovator
company to understand the PK, PD, biomarker and safety of drugs
repurposed for the new indication and propose a dosage with highest
possibility of suppressing the virus within the exposure range known to
be safe. In most cases, safety data for levels much higher the than
approved dose may be present in the development data file (i.e., single
or multiple ascending dose studies). However, there can be no
justification for pushing the clinical dose beyond the drug’s known
therapeutic window.
The in vitro-in vivo translation of antiviral efficacy should be
considered throughout the development process. There are many
considerations when using in vitro derived EC50 or EC90 to
predict an efficacious dose in vivo . For typical drugs, the
free-drug hypothesis can be used to translate in vitro EC values
to in vivo efficacious dose based on the theory that unbound drug
in the circulation equilibrates with that at the target site under
steady-state conditions. However, differences in metabolic activity,
drug permeability or transporter expression between the model cell line
and target tissue or organ can result in prediction inaccuracy. In
addition, special attention should be paid for an anti-viral prodrug, as
its active moiety is a metabolite which only stays intracellularly
(e.g., remdesivir).36,37 An investigator using a
cultured cell model needs to convince themselves that any such
differences were characterized during the model development and can be
accounted for.
Remdesivir and CQ were found to be relatively more potent (EC50 reported
to be 0.77 and 1.13 μM, respectively) compared to ribavirin,
penciclovir, nitazoxanide, nafamostat and favipiravir against a clinical
isolate of SARS-CoV-2 in vitro.36 This study also
demonstrated that remdesivir functioned at a stage after virus entry
while CQ functioned at both entry, and at post entry stages of the
SARS-CoV-2 infection in Vero E6 cells.36 In another
study, the EC50 of HCQ is reported to be 0.72 µM.38
Remdisivir is an example of a proposed “repurposed drug” that appears
not to meet the key standard on clinical efficacy described previously.
An efficacy trial for Ebola where the drug, when combined with the
triple monoclonal antibody ZMapp, failed to show efficacy relative to
ZMapp alone.39 Remdisivir is active against SARS-CoV
and MERS-CoV replication in cell models and shows efficacy against
SARS-CoV infection in carboxylesterase 1c knockout
mice37 and MERS-CoV infection in rhesus
monkeys40.
CQ and HCQ act at both viral entry and post entry stages so that their
in vitro and in vivo translation can be complicated by major differences
in their lung to plasma concentration ratios. Both CQ and HCQ are highly
distributed to the lung in male CD albino rats41 and
HCQ42.
For srhACE2 to occupy viral S protein it must reach the interior of the
lung where the virus is located. To block infection srhACE2 must be
delivered to the site of infection in both the upper and lower
respiratory track areas by inhalation therapy in an adequate amount to
occupy S protein sites on the virus. Intravenous administration is
unlikely to block infection since there is little virus in the blood but
might serve to reduce lung injury though this was not demonstrated in
ARDS patients.
4. Right timing
Timing is important to the administration of therapy during the COVID-19
disease course. While our understanding of the natural history of severe
COVID-19 infection is incomplete, it is thought to progress from
invasion of the respiratory tract and gastrointestinal mucosa, to
dysregulation of the RAAS and immune systems, systemic spread to other
organs, and then finally cytokine storm, sepsis, and acute respiratory
distress syndrome.43
COVID-19 is best treated in its early stages when viral load is low and
host physiology is relatively unperturbed. However, this is complicated
by COVID-19’s relatively mild onset, with many patients being
asymptomatic. A study showed that virus shedding was very high during
the first week of symptoms (peak at 7.11 × 108 RNA
copies per throat swab, day 4).44 Furthermore, once
the disease has progressed to its end-stage and organ failure has
occurred, the number of specific therapies available dwindles as drivers
of pathology shift from direct viral effects to secondary systemic
dysregulation of host physiology. Given that most of the trial drugs
currently being studied act on the Sars-Cov-2 viral lifecycle, rather
than the downstream manifestations of COVID-19, these medications may
not have an effect later in illness. This can be seen in the treatment
of influenza, where the anti-viral oseltamivir is only effective if
given in the first 48 hours.45 After this period,
there are no specific therapies that have shown benefit, and supportive
care is the standard. Thus, it is important to define patients’ disease
progression in clinical trials, as certain drugs may have different
effects when given at different times.