In this section of the coronavirus pandemic series, we discuss the current capacity of local healthcare systems and the need for effective treatment options as well as the pathogenesis of the coronavirus. Current treatment options include RNA, monoclonal antibodies (mAb), antibodies, convalescent plasma, and others. Critical stage implications such as cytokine storm and the need for immunomodulatory agents would also be discussed. Therapeutic pathways would are also compared.

1. Overview of Potential Treatment Pathways & Candidates
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Coronavirus Pandemic
Part III (B): Therapeutic Options

2. Coronavirus Pandemic Series
Part III (B): Therapeutic Options
• Healthcare systems at
critical capacity
• Critical sectors in R&D
• Antiviral therapeutics
• Known competitors
• RNA therapeutics
• Monoclonal antibodies
• Other options
• Ongoing R&D projects
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3. Part III (A) Recap: Diagnostic Technologies
Source: Worldometers.info, UN, Medium.com
The Need for
Effective
Diagnostic Tools
Accurate, rapid,
cheap point-of-care
for mass testing
Diagnostic technologies play
a critical role in identifying
patients that are COVID-19
positive.
While RT-PCR is the gold standard
in testing, there is a need for a
more cost-effective, rapid point-
of-care solution that allows local
healthcare systems to conduct
testing on a much larger scale.
Need to Test,
Isolate & Treat 80%
of Patients
As symptoms onset
(24h) to control the
spread in 1 year
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4. Healthcare System at Critical Capacity
Countries are
struggling to
flatten the curve
of infection.
Higher mortality
rates in countries
with low critical
healthcare
capacity per
capita.
Source: OECD, EDU, Forbes, Statista, Worldometer
0%
2%
4%
6%
8%
10%
12%
14%
16%
0
5
10
15
20
25
30
35
40
45
50
Turkey USA Germany Italy France Spain UK
Number of CCB-ICU per 100,000 people Mortality Rate April 6 Mortality Rate May 11
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5. Key R&D Sectors To Address COVID-19
Source: WHO R&D
A:Diagnostics
• IDENTIFICATION
• It’s critical that
local healthcare
systems can
diagnose
patients quickly &
effectively
• Asymptomatic
patients
represent a
considerable
portion of cases
B:Therapeutics
• TREATMENT
• With almost 2.6
million active
cases worldwide
(and rising),
healthcare
providers are in
desperate need
of effective
treatment
options
C:Vaccines
• PREVENTION
• Development,
production &
coverage of
vaccines is
crucial to prevent
future outbreaks
of COVID-19
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6. Pathogenesis & Severity
COVID-19 Progression from a Cell Biology Perspective

7. COVID-19 Pathogenesis & severity
Source: https://erj.ersjournals.com/content/55/4/2000607
https://ccforum.biomedcentral.com/articles/10.1186/s13054-020-02911-9
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STAGEI
Asymptomatic State
- Inhaled virus binds to
epithelial cells in the
nasal cavity & starts
replicating
- Limited immune
response
- Virus detection via
nasal swab
STAGEII
Conducting Airways
- Virus propagates &
migrates down the
respiratory tract
- Clinical manifestation,
symptoms start to show
- Increased immune
response
- Virus detection via
nasal swab, sputum &
immunology assay
STAGEIII
Progression to ARDS
- Virus reaches gas
exchange units of the
lung, infects alveolar
Type II cells
- High amounts of virus
particles released, cells
undergo apoptosis &
die
- Hypoxia, ground-
glass opacity & acute
respiratory distress
syndrome (ARDS)
1-2 days 3-7 days 8-12 days
Severity & risk of mortality increases

8. Pathogenesis Stage I: Asymptomatic State
Source: https://erj.ersjournals.com/content/55/4/2000607
The inhaled SARS-Cov-2 virus
infects epithelial cells in the
nasal cavity & starts replicating.
The immune response is limited.
While the viral burden is low, patient
is infectious. RT-PCR useful to predict
viral load and subsequent infectivity
as well as the clinical course.
Possible treatment options:
• Therapies to increase immune response
• Therapies to disrupt viral genes
ACE2 is the main receptor for SARS-CoV-2
virus causing COVID-19.
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Credit: Drug Target Review

9. A more robust innate immune
response is triggered as the
virus propagates & migrates
down the respiratory tract.
The disease is mild for 80% of
infected patients.
Possible treatment options:
• Therapies to sustain the immune response
• Therapies to disrupt viral genes
Pathogenesis Stage II: Conducting Airway Response
Level of CXCL10 (or other innate response
cytokine) from viral infected cells may be
predictive of the subsequent clinical course.
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Source: https://erj.ersjournals.com/content/55/4/2000607
Credit: STR/AFP Getty

10. Pathogenesis Stage III: Progression to ARDS
Source: https://erj.ersjournals.com/content/55/4/2000607
20% of infected patients will
progress to Stage III. The virus
reaches gas exchange units of the
lung, infects alveolar Type II cells.
High amounts of virus released, infecting
adjacent units. Subsequent cell apoptosis
& death triggers epithelial regeneration,
activating coagulation pathways.
Possible treatment options:
• Immunomodulatory therapies to acquire an
optimal immune response
• Therapies to disrupt viral genes
Aberrant wound healing may lead to more
severe scarring and fibrosis than other
forms of ARDS.
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Credit: Drug Target Review

11. Therapeutic Options
Overview, Highlights & Other Efforts

12. Current Treatment Options for COVID-19
Antibodies
Convalescent
Plasma
RNA Drugs
Monoclonal
Antibodies
Source: Various Online Research
Currently, a promising therapeutic option
that targets viral genes & proteins. It can
be used to invoke an immune response.
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mAbs can be used to neutralize the viral
infection mechanism. It can be used as
an immunomodulatory agent.

13. Antiviral Therapeutics: Concept
Source: Medical Illustration & Animation
Antiviral
Therapies
Antiviral drugs are a
class of medication used
specifically for treating
viral infections. They
work by disrupting a
specific step in the virus
life cycle.
*NOTE: They are different from
antibiotics, which is ineffective
to treat infections caused by
viruses.
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14. Therapeutic Pathways to Disrupt the virus Life-Cycle
Source: https://weekly.biotechprimer.com/covid-19-antivirals/
Virus Life Cycle Step Therapeutic Pathway
1. Attach to host cell wall & enter the
cytoplasm
Immuno-modulators (interferons) or antibodies to prevent
virions binding onto the host’s cell wall
2. Uncoating of virus protein shell or
capsid (to release genetic material
within the host cell)
Introduction of antagonistic agents to prevent viral
shedding within the host cell
3. Insertion of viral genetic material
Reverse-transcription and integrase inhibitors to prevent
viral genetic material integrating with host cell DNA
4. Replication & assembly of viral
components
RNA polymerase inhibitors block genetic replication, and
protease inhibitors prevent the building of viral
components
5. New viruses released from the host
cell to infect other host cells
Neuraminidase inhibitors (NAIs) to prevent viral
reproduction by budding from the host cell.
*Viral neuraminidases are enzymes of the influenza virus
14

15. Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7114189/
Therapeutic Option: RNA Drugs
Blocks Virus
Attachment
• Aptamers
(artificial RNA)
that detects &
binds to viral
proteins
receptors,
blocking it from
attaching onto
the host cell wall
Blocks Integration
of Viral Genes
• Antisense
oligonucleotides
(ASO): blocks
viral gene from
being expressed
after it enters &
unloads genetic
material into the
host cell
Prevents Viral
Replication
• RNA
interference
(RNAi): triggers
degradation of
viral mRNA,
preventing it
from building
viral
components
15

16. Source: https://pubmed.ncbi.nlm.nih.gov/28262699/
https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-
update-fda-issues-emergency-use-authorization-potential-covid-19-treatment
Remdesivir was created and
developed by Gilead Sciences
to treat Ebola and Marburg
diseases.
It was later found that remdesivir
had antiviral activity (in-vitro)
against coronaviruses.
As of May 1st, FDA has issued
emergency use authorization for
the use of remdesivir to treat
COVID-19 in adults and children.
Therapeutics Highlight: Remdesivir by Gilead
Remdesivir is a nucleotide (adenosine)
analog, which inserts into the viruses' RNA
chains, causing their premature termination.
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17. Therapeutics Highlight: Avigan by Fujifilm Toyama
Source: https://weekly.biotechprimer.com/covid-19-antivirals-part-two/
https://www.cnbc.com/2020/05/04/fujifilms-flu-drug-favipiravir-sent-to-43-nations-for-covid-19-trials.html
Marketed under the brand
name Avigan, favipiravir is an
antiviral drug developed by
Fujifilm Toyama.
Like remdesivir, it targets the viral
RNA polymerase.
43 countries will be conducting
clinical trials and testing it with mild
and moderate patients. Medical
centers in Massachusetts are
evaluating the drug in a Phase 2 trial.
In an 80-day trial conducted in Shenzhen
city, favipiravir shortened the recovery time
from 11 days to 4 days in mild and moderate
COVID-19 patients.
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18. Therapeutic option: Antibodies
Source: https://www.virology.ws/2009/07/24/virus-neutralization-by-antibodies/
Antibodies can
neutralize viral
infectivity by:
• Interfering with virion
binding to cell
receptors
• Blocking uptake into
the host cell
• Prevent uncoating of
viral genes
• Aggregating virus
particles
Credit: Virology Blog
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19. Monoclonal Antibodies
Source: https://www.thestar.com.my/news/regional/2020/04/08/taiwanese-team-finds-key-antibodies-in-covid-19-patients
Monoclonal antibodies (mAbs)
are man-made proteins that
act like human antibodies in
the immune system.
They are made by identical
immune cells that are all clones of a
unique parent cell.
In the case of COVID-19, mAbs can
block the path of coronavirus from
attaching onto host cells.
A Taiwanese research team has produced
25 human mAbs: 13 strains targeting the
‘spike’ protein (S) of the coronavirus and 12
strains targeting the nucleocapsid protein
(N), the ‘shell’ of the virus.
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20. Polyclonal vs Monoclonal Antibodies
Source: https://www.creative-diagnostics.com/polyclonal-vs-monoclonal-antibodies.htm
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Polyclonal Antibodies
• Multi-epitope specificity
• Short production time and low
cost
• Highly stable
• High affinity can bind to multiple
epitopes
• Tolerant of minor changes of
antigen
• Flexibility in antigen recognition
Monoclonal Antibodies
• High specificity to one epitope
• ‘Immortal’ hybridoma cell lines
can produce unlimited quantities
of antibodies
• High consistency & homogeneity
• Minimal background noise and
cross-reactivity
• Excellent for affinity purification
• Batch–to-batch variability is
very minimal
Given the
specificity,
consistency &
minimal cross-
reactivity, mAbs
is the preferred
technology
platform.

21. Therapeutics Highlight: DARPin® by Molecular Partners
Source: https://www.molecularpartners.com/molecular-partners-confirms-ultra-potent-
inhibition-of-sars-cov-2-live-virus-by-anti-covid-19-darpin-candidates/
DARPin® is a new class of
custom-built (antibody
mimetic) protein therapeutics
that targets live, replicating
coronavirus SARS-CoV-2 in
COVID-19 patients.
Claimed to have robust antiviral
activity, Molecular Partners claim
that only small amounts of these
candidates are required for
therapeutic effect.
DARPin® candidates can simultaneously target
the virus in different key areas and neutralize
the virus via multiple mechanisms.
Credit: Molecular Partners
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22. Source: https://weekly.biotechprimer.com/covid-19-antivirals-part-two/
The idea is that when a
patient survives a coronavirus
infection, his/her blood
becomes filled with antibody
proteins that can help other
patients fight the virus.
Scientists think this could be an
effective treatment for patients
hospitalized with COVID-19 or
those who are at high risk of
exposure, like healthcare workers.
Other Therapeutic Options: Convalescent Plasma
Plasma, or serum, is the yellowish liquid
component of our blood. This portion of blood
is filled with antibody proteins.
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23. Convalescent Plasma Explained
Source: https://www.sciencedirect.com/science/article/pii/S1568997220301166
Credit: Manuel Rojas, Yhojan Rodríguez, Diana M.Monsalve, et. al.
The plasma of COVID-19 survivors contain specific antibodies and immune
agents, making it a viable treatment option for COVID-19 patients.
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24. Source: https://weekly.biotechprimer.com/covid-19-antivirals/
Other Therapeutic Options: Hydroxychloroquine (HCQ)
Chloroquine is an anti-malaria
pill that’s been around since
1949. In 2005, it was reported to be
an effective antiviral against the
original SARS coronavirus.
Preliminary reports by University at
Albany states that it doesn't work
for very sick patients.
Meanwhile, the University of
Minnesota is sponsoring a trial on
3,000 patients, estimated to
complete on May 12, 2020.
FDA recently warned about the dangers of
hydroxychloroquine, citing serious heart
issues, including death.
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25. Stage III Implications: Cytokine Storm
25 Source: https://erj.ersjournals.com/content/55/4/2000607
https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30216-2/fulltext
Credit: European Society of Cardiology
Activation of coagulation pathways during
immune response results in overproduction
of proinflammatory cytokines (such as IL-6
and IL-1β) leading to multi-organ injury or
failure, and eventually death.
Immunomodulatory treatment is critical to
achieving the right level of immune response.
Direct oral anticoagulants (antithrombin &
antifactor Xa) might be able to reduce
microthrombosis (obstruction in blood
vessels), lung injury, and associated poor
outcomes.

26. Therapeutics Highlight: Actemra® by Roche
Source: http://www.pmlive.com/pharma_news/fda_approves_roches_actemra_covid-19_trial_1329887
https://www.nst.com.my/education/2020/04/583940/um-leads-clinical-trials-tocilizumab-covid-19-treatment
Roche is currently running Phase
III clinical trials of Actemra® /
RoActemra® (tocilizumab), a
humanized mAb.
Tocilizumab can be regarded as an
immunomodulatory agent, as it can
interrupt cytokine release syndrome
(CRS).
In Malaysia, clinical trials involving
300 Covid-19 patients is underway
at the Universiti Malaya Medical
Centre (UMMC), together with 3
other public hospitals.
Actemra could interrupt the process of CRS,
a serious inflammatory response that can
lead to multi-organ failure and death.
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27. Therapeutic Options Compared
27
RNA mAb Antibody C. Plasma
*Specificity
(determines overall effectiveness)
++ + ± -
Duration of therapy + ± +
-
(vary based on
donor plasma)
Cost of R&D
(- means higher cost, + is lower)
- ± + ++
Cost of production
(production capacity & time,
- means higher cost, + is lower)
++ ±
+
(dependent on live
animal)
-
(dependent on
donor supply)
Versatility - ± + +
Stage of disease
(mild, severe and/or critical)
severe
critical
mild
severe
mild
mild
severe
critical
Source: Various Online Research

28. RNA, 8
Others, 68
Antibody, 13
mAb, 28
Diagnostics
112
Vaccines
61
Ongoing R&D Projects
Source: Various Online Research as of Mid-April 2020
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Antiviral
Therapeutics
To date, about 40.3%
of ongoing R&D
projects are focused
on developing
therapies for patients
with COVID-19.
Therapeutics
117

29. • Immunomodulatory agents combined with antiviral drugs
could provide the best clinical outcome.
• Previously known drugs are repurposed to treat the more
critical-stage patients; some of these drugs show increased
efficacy.
• Trials are ongoing for various antiviral therapies ranging from
RNA, mAbs to convalescent plasma. Newer technologies such
as nucleotides and mAb-based therapies are being explored
in an early stage.
Conclusion
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30. By xeraya capital
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