Possible drugs to fight coronavirus remdesivir

R E M D E S I V I R
R A M I B E C H A R A
Possible drugs to fight
coronavirus
4/10/2020Dr. Rami Bechara
1

Summary
2
 Remdesivir: composition and effect
 Tests on animals
 Early Success Stories in Humans
 From Compassionate Use to Clinical Trials
 Production procedure, challenges and pricing
 References

Dangerousness of SARS-CoV-2
 Easy transmission : due to spike proteins on the
virus’ surface bind exceptionally efficiently to
angiotensin-converting enzyme 2 (ACE2) on the
surfaces of human cells.
3

Importance of coronavirus drugs
 With a vaccine for COVID-19 still at least 12-18
months away, the race is on to find drug treatments
that will save lives in patients who get the virus more
severely.
4

Remdesivir
 A adenosine nucleotide analogue prodrugthat
disrupts viruses’ RNA genome, and has been in
development for a decade.
 It was originally intended as a treatment for Ebola,
before its potential in treating SARS-CoV-2
infections was identified.
 Scientists from China claim that the drug could help
with slowing symptoms down. They said it was
'highly effective' against cases of COVID-19.
 Developed by Gilead, California Biotech Company
5

Chemical information
 Molecular Formula: C27H35N6O8P
 2D presentation:
 3D presentation:
 Molecular Weight
602.6 g/mol
6

7
 White to off-white or yellow non hygroscopic solid
 Practically insoluble in water and soluble in ethanol.
 Remdesivir has six chiral centers

Past Experience
 preliminary testing in two other coronavirus
strains that caused outbreaks – SARS and MERS –
which raised confidence that it might have some
activity against this type of virus.
 Tested against many different viruses and shown
“good activity in the laboratory” against
coronaviruses
 The antiviral agent isn’t new, but it’s never been
approved for commercial use.
8

Mechanism
 It interferes with the ability of the RNA virus to reproduce
itself
  functions at a stage post virus entry, in agreement with its
putative anti-viral mechanism as a nucleotide analogue.
 Changes the total number of viral particles that can invade
different organs, particularly the lung
 It gets incorporated into nascent viral RNA, where it prevents
RNA synthesis, and in turn, further viral replication,”
 By incorporating into RNA, additional nucleotides cannot be
added, terminating RNA transcription.3
 Viruses with mutations in RNA polymerase to develop partial
resistance to remdesivir have been shown to be less infective.
9

Tissue culture studies
 Half -maximum effective concentrations (EC50s) of
0.069 for SARS -CoV and 0.074 μ M for MERS -CoV.
 Active in the submicromolar EC50 range against a
number of highly divergent coronaviruses, including
the endemic human CoVs , OC43 (HCoV -OC43) and
229E (HCoV -229E) .
  broad -spectrum anti –CoV activity
10

Test on mice
 Mouse model of SARS -CoV pathogenesis
 Prophylactic and early therapeutic administration of
remdesivir significantly reduced the lung viral load.
 Viral titers were reduced by >2 orders of magnitude on day 4
or 5 post infection .
  Remdesivir improved the clinical signs 120 of
disease and respiratory function compared to
untreated control animals
11

Test on transgenic mice
 Comparable results were obtained with MERS -CoV
in prophylactic studies carried out with a MERS -
CoV mouse transgenic model .
 There, a humanized MERS -CoV receptor (dipeptidyl
peptidase 123 4, hDPP4) was expressed and
carboxylesterase 1c (Ces1c) was deleted to improve
the pharmacokinetics of nucleotide prodrugs
12

Test in primates
 The efficacy of prophylactic and therapeutic
remdesivir treatment was recently tested in a
nonhuman primate ( rhesus macaque ) model of
MERS -CoV infection
 Prophylactic treatment initiated 24 h before
inoculation
 MERS -CoV was prevented from inducing clinical disease and
inhibited from replicating in respiratory tissues , which
prevented the formation of lung lesions.
 Similar results were obtained when therapeutic
treatment was initiated at 12 h after virus
inoculation.
13

Specificity for coronavirus
  demonstrated by propagating the virus in tissue
culture.
 After 23 passages in the presence of the drug, two
mutations were identified (F276L and V553L) in the
viral RNA -dependent RNA polymerase gene.
 These mutations increased the replication capacity of
the virus in the presence of remdesivir
 However, these amino acid changes decrease d the
viral fitness and attenuated SARS -CoV pathogenesis
in mice
14

Application to humans
 Human safety data are available for remdesivir; thus,
human trials can be initiated for testing the efficacy
of this compound against novel coronaviruses.
 Wang et al. in his communication to Nature
indicated:
 Our findings reveal that remdesivir and chloroquine are highly
effective in the control of 2019-nCoV infection in vitro.
 These compounds have been used in human patients with a
safety track record and shown to be effective against various
ailments
 We suggest that they should be assessed in human patients
suffering from the novel coronavirus disease.
15

Case of first patient treated
16
 Within 24 hours of remdesivir initiation, the patient
became afebrile, off nasal cannulae, with chest rales
resolved.
 However, the reverse transcription polymerase chain
reaction (RT-PCR) series showed downward-trending
viral loads even before remdesivir treatment.
 It therefore cannot be determined if further viral load
decrease and clinical improvement were a direct result of
remdesivir. Although promising, the outcome from a
single case cannot be generalized to a larger population.

Early “success” stories
  Diamond Princess: Of the 51 Americans hospitalized
throughout Japan with COVID-19, 14 were critically ill.
 average age of 75 years old, severe pneumonia and
were put on ventilators or ECMO machines, which are
heart lung bypass machines, in intensive care units
 Seven severe cases who qualified for the treatment were
given remdesivir intravenously once a day for 10 days —
and all of them survived.
 This however cannot be final proof remdesivir works as a
treatment for the coronavirus
17

Success Story continued
18
 79-year-old patient in Italy recovered after taking an
experimental Ebola drug remdesivir.
 Treatment started on March 7 and has taken two
negative tests after 12 days in the hospital.
 "There's only one drug right now that we think may have
real efficacy, and that's remdesivir," said Bruce Aylward,
a World Health Organization (WHO) official at a recent
press conference in China
 American case : the patient had a positive test [showing
the presence of SARS-CoV-2] right before starting the
drug. The day after the infusion of the drug, they
consistently got better. However, no proof of relation

Compassionate use
 Emergence Access to drug was provided for patients
in Europe, Japan and the United States
 Problem: IT has seen an “exponential increase” in
compassionate use requests for the drug in recent
weeks.
 Compassionate use is now limited except for
pregnant women and children aged younger than 18
years with confirmed COVID-19 and “severe
manifestations of the disease.”
19

Emergency access process
 Transition from individual compassionate use
requests to expanded access programs.
  accelerate access to remdesivir for severely ill
patients
  enable the collection of data from all participating
patients.
 Programs under rapid development with regulatory
authorities worldwide
20

Emergence access program
 Repercussions for patients
 A site signs up, the company will send them drugs to
have on hand, so when the patient signs a consent
form that’s been approved by authorities, you order
it like you would any other drug, You don’t have to
wait days
21

Passage for Clinical Trials
22
 Compassionate-use of remdesivir temporarily
stopped
 To focus supplies of the investigational antiviral for
clinical testing as a possible treatment for the
coronavirus, COVID-19.
 Goal: rapidly assess the safety and efficacy of
remdesivir as a potential treatment for COVID-19
 Enrollment in clinical trials is the primary way to
access medicine to generate critical data that inform
its appropriate use

Different Trials
23
 Results are expected for Trials in Mid-April beginning of May

Production
24
 Remdesivir is produced as a single stereoisomer.
 The active substance is manufactured as Form II or
mixtures of Form II and another crystalline form.
 The mixture of forms and Form II show similar
solubility and do not result in differences in finished
product performance.
 The active substance is dissolved before final I.V.
administration.
 Production occurs under aseptic conditions.

Production process
25
 Long, linear chemical synthesis process that must be
completed sequentially
 Several specialized chemistry steps and novel
substances with limited global availability.
 Resource- and time-intensive, with some individual
manufacturing steps taking weeks to complete.
 Intravenous administration  production requires
sterile drug product manufacturing capabilities,
which limits the number of organizations capable of
manufacturing the medicine.

Illustrated Production Process
26
 Patent protection

Preparation steps
27
 Dissolution of betadex sulfobutyl ether sodium in water
for injection,
 pH adjustment and dissolution of remdesivir,
 dilution with sufficient quantity of water for injection,
 pH adjustment,
 bioburden reduction via filtration,
 sterile filtration,
 vial filling,
 stopper insertion,
 lyophilization,
 capping.

Excipient manufacture
28
 CycloLab Budapest: cyclodextrin technology and
manufacturer of critical excipient, Dexolve (sulfobutyl-
ether beta-cyclodextrin, SBECD) that enables remdesivir
to work.
 SBECD is combined with a wide range of active
pharmaceutical ingredients to improve their solubility or
stability.
 Remdesivir: insoluble in water, which prevents the
preparation of an injectable formulation to treat patients.
 Use of proper technology and combine the active with
this particular cyclodextrin, remdesivir gets water-
soluble, can exert its effect and fight the virus effectively

Excipient manufacture challenges
29
 Manufacture of Dexolve with a forced march and make
as much of the product in 4 weeks as in 3-4 months,
which translates to the metric ton range.
 Efforts mostly to cover the ongoing and upcoming
clinical trials.
 Should the remdesivir get approved, the needs would
definitely further increase and standardize on the long
term.
 Interesting side-branch: different cyclodextrins active
against several other, yet related viruses [including
herpes simplex virus (HSV), respiratory syncytial virus
(RSV), dengue virus, and Zika virus]

Evaluation of production steps
30
 Steam sterilization of equipment and closures
 Dry heat sterilization and depyrogenation of glass
vials.
 Acceptable limit for bioburden of the bulk solution
prior to sterile filtration. Two filters are used in
sequence. Filter integrity is tested. Media fill studies
have been performed. Vials are visually inspected.
 Overall, the manufacturing process and in process
controls are sufficiently described for use of the drug
product in clinical trials and compassionate use
programs.

Problems faced
31
 Considered in January 2020 a compound in early
development  inventory of finished product to
treat just 5,000 patients.
 Late March,  30,000 patient courses of remdesivir
on hand, assuming a 10-day course of treatment for
patients.
 New raw materials arrive  supply rapidly increase.
 Complex process impacts the ability to rapidly
produce large quantities of drug supply in an
emergency situation like the COVID-19 pandemic.

Solutions
32
 Procure a steady flow of long-lead-time raw
materials that will accelerate large-scale production
 Shorten the manufacturing timeline through process
improvements. From nine - 12 months; to six to
eight months.
 Optimize chemical synthesis processes to further
accelerate product deliveries and volumes.

Goals set by manufacturer
33
 More than 140,000 treatment courses by the end of
May 2020
 More than 500,000 treatment courses by October
2020
 More than 1 million treatment courses by December
2020
 Several million treatment courses in 2021, if
required

Capacity expansion
34
 Supplemented capacity from multiple partners
 Creation of a manufacturing network capable of
producing large volumes of remdesivir at the fastest
pace feasible.
 Geographically diverse consortium of
pharmaceutical and chemical manufacturing
companies to meet and exceed these production
goals by expanding capacity for raw materials and
production beyond what any company could do
individually.

European importation
35
 Manufacturers responsible for import and batch
release in the European Economic Area
 Manufacturing steps conducted at each facility are in
full compliance with current Good Manufacturing
Practices (cGMP) guidelines.

Price of Remdesivir
36
 Prices taken from research retailer
 News that FDA have granted
Remdesivir orphan drug
status
 Financial incentives  partial tax credit for clinical
trial expenditures, waived user fees, and eligibility
for 7 years of marketing exclusivity

Conclusion
37
 Remdesivir: One of most efficient Drugs against
Covid-19
 Applied only in hospital setting currently for urgent
cases (Compassionate use, emergency access).
Related success stories but no scientific correlation
 Start of clinical trials in many countries worldwide
for different conditions
 Manufacture process explained: Key steps identified.
Key challenges to face global pandemic were stated.

References
 https://www.pmlive.com/pharma_news/clinical_tri
al_of_gileads_coronavirus_hopeful_remdesivir_be
gins_in_uk_1334307
 https://www.healio.com/infectious-
disease/emerging-
diseases/news/online/%7B692f5047-bcf0-4072-
ab33-2062b24f137c%7D/gilead-revises-access-to-
remdesivir-for-covid-19-amid-surge-in-demand
 https://www.wbur.org/hereandnow/2020/03/30/gi
lead-experimental-coronavirus-drug
38

 https://pubchem.ncbi.nlm.nih.gov/compound/Remdesi
vir
 https://www.drugbank.ca/drugs/DB14761
 https://www.nature.com/articles/s41422-020-0282-0
 https://clinicaltrials.gov/ct2/show/NCT04292730
 http://www.gabionline.net/Generics/News/Chinese-
company-makes-copy-of-patented-coronavirus-
treatment-remdesivir
 https://www.ema.europa.eu/en/documents/other/sum
mary-compassionate-use-remdesivir-gilead_en.pdf
39

40
 https://cyclolab.hu/news/cyclolab_picks_up_the_gaunt
let_to_fight_coronavirus
 https://patentscope.wipo.int/search/en/detail.jsf;jsessio
nid=8E2676A298B21D70554470C6346E1C1E.wapp1nC?
docId=WO2016069826&tab=PCTDESCRIPTION
 https://www.npr.org/sections/health-
shots/2020/03/24/821035311/fda-grants-experimental-
coronavirus-drug-benefits-for-rare-disease-treatments
 https://ojrd.biomedcentral.com/articles/10.1186/s13023
-017-0665-6

Possible drugs to fight coronavirus remdesivir

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