Trials

Landscape analysis of therapeutics as 21st March 2020

Product type and candidate

Description

Licensed for

Licensed dose

Route of administration

Currently being trialled COVID-19?

Status of clinical development for Coronaviruses

Proposed dose for COVID-19

Status of clinical development for other relevant conditions

Re-purposed/off label

Corticosteroids

Steroid hormones

 

Various

Various

Inhaled, parenteral injectables and intravenous injectables

Yes1

Clinical trial COVID-191, clinical studies SARS2,3,

clinical studies MERS4

COVID-19 clinical trial: Methylprednisolone 40 mg q12h for 5 days

Phase III clinical trial H1N15

Chloroquine

Antimalarial agent, heme polymerase inhibitor

 

Malaria prophylaxis and treatment

Prophylaxis: 500mg chloroquine phosphate once per week. Treatment: 2.5g chloroquine phosphate over 3 days

Oral or injectable

Yes6,29

ChiCTR2000029939, ChiCTR2000029935, ChiCTR2000029899, ChiCTR2000029898, ChiCTR2000029868, ChiCTR2000029837, ChiCTR2000029826, ChiCTR2000029803, ChiCTR2000029762, ChiCTR2000029761, ChiCTR2000029760, ChiCTR2000029740, ChiCTR2000029609, ChiCTR2000029559, ChiCTR2000029542

Clinical trial COVID-196, in vitro study COVID-197,29,

In vitro studies, chloroquine was found to block COVID-19 infection at low-micromolar concentration, with a half- maximal effective concentration (EC50) of 1.13 μM and a half- cytotoxic concentration (CC50) greater than 100 μM

Gao et al 2020

Chloroquine phosphate has shown apparent efficacy and acceptable safety against COVID-19 associated pneumonia in multicenter clinical trials conducted in China. The drug is recommended to be included in the next version

COVID-19 clinical trial: hydroxychloroquine 400mg per day for 5 days

In vitro studies MERS-CoV8–10,30,
De Wilde et al 2014: Huh7 cells infected with MERS-CoV isolate EMC/2012 (MOI, 0.005) and incubated for 2 days. 50% effective concentrations [EC(50)s], 3 to 8 μM
Cong et al 2018
Primary cells – valuated in MDMs and MDDCs to determine their antiviral effect on MERS-CoV infection.

In vitro studies SARS-CoV11,12,13, 30
Keyaerts et al 2004: Vero cells, 3 days post infection viable cell quantified. IC50 of chloroquine for antiviral activity (8.8 +/- 1.2 microM) was significantly lower than its cytostatic activity; CC50 (261.3 +/- 14.5 microM), yielding a selectivity index of 30 De Wilde et al 2014: Vero E6 cells infected wuth SARS-CoV isolate Frankfurt-1 (MOI, 0.005) and incubated for 3 days. Pre and post infection effective.
Wang et al 2020
Vero E6 cells were infected with nCoV2019BetaCoV/Wuhan/WIV04/2019

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 1

Landscape analysis of therapeutics as 21st March 2020

                 

of the Guidelines for the Prevention, Diagnosis, and Treatment of Pneumonia Caused by COVID-19 issued by the National Health Commission of the People’s Republic of China for treatment of COVID-19 infection in larger populations in the future

(MOI) of 0.05. Quantification of viral copy

numbers by qRT-PCR confirmed with

visualization of virus nucleoprotein (NP)

expression through immunofluorescence

  

(EC

= 1.13 μM; CC

50 50

Barnard et al 2006

In vitro inhibition of SARS-CoV replication in African green monkey kidney cells

In vitro H-Cov OC4331

Shen et al 2016

In vivo study MERS 8

In vivo study SARS-CoV11,

Barnard et al 2006

Effect of i.p. and i.n. treatment on SARS- CoV replication in female BALB/c mice. Day 3 viral load – no effect.

In vivo study H-Cov OC4332

Keyaerts et al 2009

Pregnant mice treated – offspring protected from lethal challenge

 

chloroquine strongly inhibited HCoV-OC43

replication in vitro, with a 50% inhibitory

> 100 μM, SI > 88.50)

concentration (IC50) of 0.33 μM

                        

Ritonavir + Lopinavir (Kaletra)

Protease inhibitors

HIV infection

Adults 5 ml of oral solution (400/100mg ) twice a day

capsule oral, solution oral, tablet oral

Yes14–21

Clinical trials COVID-1914– 21,, case report COVID-1935, clinical studies SARS22, in vitro and clinical studies SARS-CoV23, in vivo studies MERS-CoV24

Retrospective cohort COVID-1934
Deng et al 2020

500mg once, twice a day, 2 weeks

Clinical trial SARS33

Chu et al 2004

41 patients given intervention (control group Ribavirin 111 patients). The patients had a decreasing viral load and rising peripheral lymphocyte count.

Retrospective matched cohort SARS22

Chan et al 2003

 

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 2

Landscape analysis of therapeutics as 21st March 2020

16 patients – 2 groups: LPV/r + Arbidol and LPV/r monotherapy.

CoV-2 could not be

The SARS-

 

detected for 12(75%) of 16

patients’ nasopharyngeal

specimens in the

combination group after

seven days, compared with

6 (35%) of 17 in the

monotherapy group (p <

0·05). After 14 days, 15

(94%) of 16 and 9 (52·9%)

of 17, respectively, SARS-

CoV-2 could not be

detected (p < 0·05).

75 patients – 2 intervention groups:

lopinavir/ritonavir as initial treatment, and

 

lopinavir/ritonavir as rescue therapy.

The

addition of lopinavir/ritonavir to a

standard treatment protocol as an initial

treatment for severe acute respiratory

syndrome appeared to be associated with

improved clinical outcome.

Ribavirin + Ritonavir + Lopinavir

Nucleoside Inhibitor + protease inhibitor

Clinical trial SARS25,26

Clinical trial: (1) lopinavir 400 mg/ritonavir 100 mg orally twice daily, plus (2) ribavirin 2.4 g orally as a loading dose followed by 1.2 g orally every 12 hours. Duration of treatement up to 10 days. Case study: ribavirin 600mg 2x day and lopinavir + ritonavir 1000mg 1x day

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 3

Landscape analysis of therapeutics as 21st March 2020

Product type and candidate

Description

Licensed for

Licensed dose

Route of administration

Currently being trialled COVID-19?

Status of clinical development for Coronaviruses

Proposed dose for COVID-19

Status of clinical development for other relevant conditions

Darunavir (with cobicistat) (Prezista® / Prezcobix® and Generic)

Antiretroviral, protease inhibitor. Used with low doses of cobicistat to increase bioavailability and half life

HIV infection

Treatment-naïve and those with no resistance associated substitutions: 800 mg taken with ritonavir 100 mg per day

Oral suspension and tablets

Yes19,27

Clinical trials COVID- 199,27

Darunavir 800 mg/Cobicistat 150 mg QD

Emtricitabine + tenofovir (Truvada)

Non-nucleoside reverse transcriptase inhibitor + nucleotide reverse transcriptase inhibitor

HIV infection

1 tablet (emtricitabine (200 mg) and tenofovir disoproxil (245 mg)) per day in those weighing at least 35kg

Oral

Yes16

Clinical trial COVID-1916

Dosage clinical trial not available

Ruxolitinib (Jakafi or Jakavi)

Myelofibrosis and polycythaemia vera treatment

Myelofibrosis and polycythaemia vera

Oral

Yes28

Clinical trial COVID-198

Dosage clinical trial not available

Baricitinib (Olumiant or Baricinix)

Inhibitor of janus kinase

Rheumatoid arthritis

4 mg per day, can be reduced to 2 mg per day when disease under control, impaired kidney function, increased risk of infections, aged >75, or taking certain other medicines.

Oral

 

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 4

Landscape analysis of therapeutics as 21st March 2020

Product type and candidate

Description

Licensed for

Licensed dose

Route of administration

Currently being trialled COVID-19?

Status of clinical development for Coronaviruses

Proposed dose for COVID-19

Status of clinical development for other relevant conditions

Sirolimus (Rapamycin, Rapamune®)

mTor inhibitor IL2, immunosuppres sant

Anti-rejection medicine in those aged >=13 who received a kidney transplant. Also used to treat LAM

Organ rejection: 6 mg given soon after the transplantation followed by 2 mg once a day S-LAM: 2 mg daily and after 10 to 20 days dose adjustment

Oral

 

In vitro studies MERS- CoV:
Kindrachuk et al. Antimicrob Agents Chemother. 2015 ;59(2):1088-99 – Huh7 cells ; Sirolimus largely retained inhibitory activity against MERS- CoV whether it was added pre- or postinfection.

Influenza: 1 mg 1xday. Severe H1N1 pneumonia: 2mg 1xday

RCT for H1N1:
Wang et al. Crit Care Med. 2014 ;42(2):313-21. RCT, 38 patients – early adjuvant
treatment with
corticosteroids and sirolimus (Rapamune 2 mg/d) was associated with improvement in outcomes, such as hypoxia, multiple organ dysfunction, virus clearance, and shortened liberation of ventilator and ventilator days.

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 5

Landscape analysis of therapeutics as 21st March 2020

Product type and candidate

Description

Licensed for

Licensed dose

Route of administration

Currently being trialled COVID – 19?

Status of clinical development for Coronaviruses

Proposed dose for COVID-19

Status of clinical development for other relevant conditions

IFN-α / PEGIFN- α

type I interferons – signaling proteins made and released by host cells in response to the presence of several viruses, that help regulate the activity of the immune system.

In vivo studies SARS-CoV:
– Haagmans et al. Nat Med. 2004;10(3):290-3 – Prophylactic positive outcome / postexposure treatment less effective. – Smits et al. PLoS Pathog. 2010; 6(2):e1000756 – reduced pathology without affecting virus replication ; pro- inflammatory gene expression significantly diminished

Clinical studies MERS:
Al Ghamdi et al. BMC Infect Dis 2016;16:174 (case series ; 8 patients) – 6/8 died.

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 6

Landscape analysis of therapeutics as 21st March 2020

IFN-α2a (Pegasys® and others PEGylated IFNα2a)

type I
interferon made by leukocytes during viral infection

Hepatitis C (with ribavirin) and hepatitis B

Pegasys is given once a week for 48 weeks for hepatitis B and once a week for between 16 and 72 weeks for hepatitis C. Adult dose is usually 180 micrograms but the children’s dose varies depending on their height and weight.

Parenteral injection, for subcutaneous use

Clinical study MERS: Arabi et al. Clin Infect Dis. 2019. pii: ciz544 (Retrospective observational study ; 349 patients) – no decrease in mortality nor faster virus RNA clearance.

MERS:
Pegylated interferon alfa-2a (Pegasys): 180 μg subcutaneously per week for 2 weeks

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 7

Landscape analysis of therapeutics as 21st March 2020

Product type and candidate

Description

Licensed for

Licensed dose

Route of administration

Currently being trialled COVID-19?

Status of clinical development for Coronaviruses

Proposed dose for COVID-19

Status of clinical development for other relevant conditions

IFN-α2b (PegIntron®, Sylatron®, IntronA®)

type I interferon made by leukocytes during viral infection

– Hepatitis C (with ribavirin) – Melanoma
– AIDS-Related Kaposi’s Sarcoma, Chronic Hepatitis C, Chronic Hepatitis B

PegIntron®: once a week. In adults, used in combination treatments at a dose of 1.5 mg per kg body weight, or on its own at 0.5 or 1.0 mg/kg. In children and adolescents, the dose is 60 mg per m2 body surface area. Treatment duration from 6 months to a year. IntronA®: 3 times per week. Dose and duration of treatment depend on the disease being treated and the response of the patient, with doses ranging from 2 to 20 million IU per square metre of body surface area.

– Parenteral injection SC – Parenteral injection SC – intramuscular, subcutaneous, intralesional, or intravenous

Yes

http://www.c hictr.org.cn/s howprojen.as px?proj=4868 4

 

Clinical trials COVID-19

Clinical study MERS: Arabi et al. Clin Infect Dis. 2019. pii: ciz544 (Retrospective observational study ; 349 patients) – no decrease in mortality nor faster virus RNA clearance.

MERS:
Pegylated interferon alfa 2b (PEG-Intron): 1.5mcg/kg subcutaneously once per week x 2

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 8

Landscape analysis of therapeutics as 21st March 2020

Product type and candidate

Description

Licensed for

Licensed dose

Route of administration

Currently being trialled COVID – 19?

Status of clinical development for Coronaviruses

Proposed dose for COVID-19

Status of clinical development for other relevant conditions

IFN-β

type I interferons – signaling proteins made and released by host cells in response to the presence of several viruses, that help regulate the activity of the immune system.

 

Clinical study MERS:
Al Ghamdi et al. BMC Infect Dis 2016;16:174 (case series ; 23 patients) – 18/23 died.

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 9

Landscape analysis of therapeutics as 21st March 2020

Product type and candidate

Description

Licensed for

Licensed dose

Route of administration

Currently being trialled COVID – 19?

Status of clinical development for Coronaviruses

Proposed dose for COVID-19

Status of clinical development for other relevant conditions

IFN-β1a (Avonex®, Plegridy® (peginterferon β1a), Rebif®, CinnoVex®)

type I
interferon made by leukocytes during viral infection

Relapsing forms of multiple sclerosis

In adults, the recommended dose of Avonex is 30 micrograms, given by injection into a muscle once a week. Plegridy treatment should start with a dose of 63 micrograms, followed by a dose of 94 micrograms after two weeks, and then 125 micrograms every two weeks thereafter. The recommended dose of Rebif is 44 micrograms given three times a week by injection under the skin. A 22-microgram dose is recommended for patients who cannot tolerate the higher dose.

IM injection SC injection

 

In vitro study SARS-CoV: Hensley et al. Emerg Infect Dis. 2004; 10(2): 317–319

Clinical study MERS:
Arabi et al. Clin Infect Dis. 2019. pii: ciz544 (Retrospective observational study ; 349 patients) – no decrease in mortality nor faster virus RNA clearance.

MERS:
rIFN-β1a (Rebif): 44 mg subcutaneously three- times weekly

In vivo study ARDS:
– In animal model of ARDS (mice), administration of subcutaneous IFN-β 1 before bacterial challenge reduced the odds ratio for 7- day mortality by 85% – Hiruma et al. Am J Respir Cell Mol Biol.
2018;59(1):45-55.

Clinical studies ARDS: – In an open-label, nonrandomized, phase 1–2 study of intravenous IFN beta-1a (FP- 1201) in ARDS, IFN was associated with lower mortality day 28, 8% vs 32%, odds ratio 0·19 [95% CI 0·03– 0·72]; p=0·01). – Bellingan et al. Lancet Respir Med. 2014 ;2(2):98-107.

– A multicenter phase III, double-blind, randomized,
parallel-group trial (PHASE III TRIAL (INTEREST STUDY, NCT02622724) has been completed. – Bellingan et al. Trials. 2017 Nov 13;18(1):536.

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 10

Landscape analysis of therapeutics as 21st March 2020

Product type and candidate

Description

Licensed for

Licensed dose

Route of administration

Currently being trialled COVID – 19?

Status of clinical development for Coronaviruses

Proposed dose for COVID-19

Status of clinical development for other relevant conditions

IFN-β1b (Betaseron®/ Betaferon®, Extavia®)

type I
interferon made by leukocytes during viral infection

Relapsing forms of multiple sclerosis

Treatment should start with 62.5 micrograms (a quarter of the dose) every other day, increasing progressively over 19 days to reach the recommended dose of 250 micrograms given every other day.

SC injection

In vitro study SARS-CoV:
Cinatl at al. Lancet. 2003;362(9380):293-4
(Vero and Caco2 cells) – IFN-β1b > IFN-α2b or IFNγ1b

In vivo study MERS-CoV: Chan et al. J Infect Dis.
2015. 212(12):1904-13 (Betaferon® SQ) – less severe disease and lower mean viral loads in necropsied lung and extrapulmonary tissues compared with untreated animals.

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 11

Landscape analysis of therapeutics as 21st March 2020

IFN-γ (Actimmune®)

type II IFNs – immune interferon activated by Interleukin-12

Serious infections associated with Chronic Granulomatous Disease (CGD) ; severe, malignant osteopetrosis (SMO)

50 mcg/m2 for patients whose body surface area is greater than 0.5 m2 and 1.5 mcg/kg/dose for patients whose body surface area is equal to or less than 0.5 m2 three times weekly.

SC injection

 

In vivo study SARS-CoV:
Nagata et al. Am J Pathol.
2008; 172(6):1625-37 – IFN-γ treatment protected the animals from the lethal respiratory illness.

In vitro study SARS-CoV:
Cinatl at al. Lancet. 2003;362(9380):293-4
(Vero and Caco2 cells)
Sainz et al. Virology. 2004 ; 329(1):11-7 (Vero E6 cells) Spiegel et al. J Clin Virol.

2004; 30(3):211-3 (Vero
cells)
Scagnolari et al. Antivir
Ther. 2004; 9(6):1003-11
(Vero cells) – IFN-β + IFN-γ > IFN-β or IFN-γ (synergic effect) .

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 12

Landscape analysis of therapeutics as 21st March 2020

IFN + Ribavirin

Combination antiviral + proteins made and released by host cells

 

Clinical study SARS:

Zhao et al. J Med
Microbiol. 2003; 52: 715720 ( IFN-α + RBV) – Inconclusive
Clinical studies MERS:
– Al Ghamdi et al. BMC
Infect Dis 2016;16:174
(case series ; 23 patients ; IFN-α or IFN-β +/- RBV) – 18/23 died.
– Arabi et al. Clin Infect Dis.
2019. pii: ciz544 (Retrospective observational study ; 349 patients ; RBV + rIFN-α2a or rIFN-α2b or rIFN- β1a) – no decrease in mortality nor faster virus RNA clearance.
– Shalhoub et al. J
Antimicrob Chemother.
2015. 70(7):2129-32
(Retrospective Cohort Study ; 24 patients ; IFNα2a or IFN-β1a SQ + PO RBV) – The fatality rate was
85% in INF-α-2a vs 64% in INF-β-1a (p=0,24) ; Older age and comorbid conditions,
Omrani et al. Lancet Infect Dis.2014. 14(11):1090-1095. and Erratum in Lancet Infect
Dis. 2015; 211(2):13 (SQ
PEG-INF α-2a +
PO Ribavirin for 8–10 days ; Retrospective cohort study ; 44 patients) – significantly improved survival at 14 days, but not at 28 days.
Khalid et al. Antivir Ther. 2015. 20(1):87-91 (case

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 13

Landscape analysis of therapeutics as 21st March 2020

 

series ; 2 patients ; SQ PEGINF- α-2b + RBV PO
(treatment or prophylaxis)) – Complete recovery and discharge home,

– Khalid et al. Respir Care 2016;61:340–8 (case series
; 11 patients ; RBV + INF- α-
2a) – survival of all
patients,
– Al-Tawfiq et al. Int J Infect
Dis. 2014. 20:42-6 (Retrospective observational study ; 5 patients ; RBV PO for 5 days + SQ INF α-2b (1 or 2 doses)) – Late treatment administration, multiple comorbidities. All patients died.
– Tawalah et al. J Infect Dis
Ther, 2015, 3(4), pp. 1-5 (Retrospective observational
study ; 2 patients ; PEG-IFN α2a or PEG-IFN α2b + RBV) – Both
patients recovered. – Malik et al. Emerg Infect Dis 2016. 2013;22 (case report ; 1 patient ; RBN and IFN-α2a day 12 from onset) – died.
– Khalid et al. Ann Saudi
Med. 2014, 34, pp. 396400 (case series ; 6 patients ; RBV + IFN-α2b) – 3/6 died (delayed diagnosis and treatment).
In vivo study MERS-CoV:
Falzarano et al. Nat Med. 2013. 19(10):1313-7 (IFNα2b + RBV) – improved outcome.

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 14

Landscape analysis of therapeutics as 21st March 2020

IFN + Ribavirin + steroids

Combination of proteins made

 

Clinical study SARS:

Wu et al. Chin Med J (Engl)

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 15

Landscape analysis of therapeutics as 21st March 2020

Product type and candidate

Description

Licensed for

Licensed dose

Route of administration

Currently being trialled COVID-19?

Status of clinical development for Coronaviruses

Proposed dose for COVID-19

Status of clinical development for other relevant conditions

and released by host cells + antiviral + steroid hormones

2003;116(6):811-8 (IFN-α + RBV + steroids)

Clinical study MERS:
Al Ghamdi et al. BMC Infect Dis 2016;16:174 (case series ; 23 patients ; hydrocortisone + RBV + IFN-α or IFN-β) – Inconclusive.

Lopinavir + Ritonavir + IFN + Ribavirin

combination of protease inhibitor + proteins made and released by host cells + antiviral

 

Clinical studies MERS:
– Spanakis et al. https://www.ncbi.nlm.nih. gov/pubmed/25288266
– Kim et al. https://www.ncbi.nlm.nih. gov/pubmed/26492219

MERS:
Spanakis et al. : oral (p.o.) lopinavir/ritonavir (400/100 mg twice daily), pegylated interferon (180 μg subcutaneously once per week for 12 days) and ribavirin (2000 mg p.o. loading dose, followed by 1200 mg p.o. every 8 h for 8 days) Kim et al.:
LPV/r (per oral, lopinavir 400 mg/ritonavir 10 mg twice per day), ribavirin (per oral, as a loading dose of 2.0 g followed by 1.2 g three times per day) and pegylated IFNα2a (subcutaneous injection,
180 μg /0.5 ml)

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 16

Landscape analysis of therapeutics as 21st March 2020

IFN-β1a + mycophenolate mofetil

combination of proteins made and released by host cells + immunosupress ant

mycophenolate mofetil (generic) is licensed for preventing organ rejection (used with ciclosporin and corticosteroids)

Dose depend on the type of organ transplant and the patient’s age and size (in adults: usually 1.0 to 1.5g twice a day)

Mycophenolate mofetil is available as capsules (250 mg) and tablets (500 mg), and can also be given as an infusion (drip into a vein).

 

Clinical study MERS:
Al Ghamdi et al. BMC Infect Dis 2016;16:174 (case series ; 23 patients ; hydrocortisone + RBV + IFN-α or IFN-β) – Inconclusive.

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 17

Landscape analysis of therapeutics as 21st March 2020

Product type and candidate

Description

Licensed for

Licensed dose

Route of administration

Currently being trialled COVID – 19?

Status of clinical development for Coronaviruses

Proposed dose for COVID-19

Status of clinical development for other relevant conditions

Lopinavir + Ritonavir + IFNβ1b

Lopinavir and ritonavir are antiretroviral protease inhibitors combination protease inhibitor and host

Lopinavir/ritona vir: tablet form (or suspension via nasogastric tube) IFN-β1b: subcutaneous injections

Clinical studies MERS: NCT02845843 (MIRACLE Trial)
(100 mg Lopinavir/100 mg Ritonavir PO q12 h for 14 days + INF- β1b 0.25 mg/ml SQ on alternative days for 14 days),

Arabi et al. Trials. 2018 ; 19(1):81 (study protocol) Arabi at al. Trials. 2020 ; 21(1):8 (statistical analysis plan)

Abbott Laboratories. Product Information: Kaletra®. https://www.accessdata.fd a.gov/drugsatfda_docs/lab el/2010/021226s030lbl.pdf .

In vivo study MERS-CoV: Chan et al. J Infect Dis. 2015. 212(12):1904-13 – Lopinavir/ritonavir and interferon-β1b, but not MMF, improved the outcome of MERS- CoVinfected common marmosets.

For MERS use was: Lopinavir /Ritonavir 400mg +100 mg / ml twice daily for 14 days and Interferon beta-1b 0.25 mg subcutaneous every alternate day for 14 days

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 18

Landscape analysis of therapeutics as 21st March 2020

Product type and candidate

Description

Licensed for

Licensed dose

Route of administration

Currently being trialled COVID-19?

Status of clinical development for Coronaviruses

Proposed dose for COVID-19

Status of clinical development for other relevant conditions

Baloxavir marboxil (Xofluza)

Antiviral (endonuclease inhibitor)

In the US licensed for acute uncomplicated influenza and in Japan for all influenza

single-dose (20mg or 40mg depending on body weight)

Oral

Yes

http://www.c hictr.org.cn/s howprojen.as px?proj=4901 3

Clinical trials COVID-19

clinical trial:
80mg on day1, 80mg on day4; and 80mg on day 7 as neccessary. No more than 3 times administration in total.

Phase II clinical trial influenza:
Hayden, F. G., Sugaya, N., Hirotsu, N., Lee, N., de Jong, M. D., Hurt, A. C., … Watanabe, A. (2018). Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents. New England Journal of Medicine, 379(10), 913–923. https://doi.org/10.1056/NEJ Moa1716197: Phase 2 trial influenza

Phase III Clinical trials influenza: https://clinicaltrials.gov/ct2/ show/NCT02954354 https://clinicaltrials.gov/ct2/ show/NCT03653364 https://clinicaltrials.gov/ct2/ show/NCT03629184 https://clinicaltrials.gov/ct2/ show/NCT03684044

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 19

Landscape analysis of therapeutics as 21st March 2020

Product type and candidate

Description

Licensed for

Licensed dose

Route of administration

Currently being trialled COVID-19?

Status of clinical development for Coronaviruses

Proposed dose for COVID-19

Status of clinical development for other relevant conditions

Licensed in country of origin for other diseases

Favipiravir (or T-705 or Avigan)

Experimental antiviral drug. Pyrazinecarbox amide derivative viral RNA polymerase inhibitor.

Influenza (licensed in Japan)

Day 1: 1600 mg twice daily Days 2 through 5: 600 mg twice daily

Oral

 

Yes http://www.c hictr.org.cn/s howprojen.as px?proj=4901 5 http://www.c hictr.org.cn/s howprojen.as px?proj=4901 3 http://www.c hictr.org.cn/s howproj.aspx ?proj=49042 =

Clinical trials COVID-19 =- ChiCTR2000029600 Trial Experimental Treatment with Favipiravir for COVID- 19: An Open-Label (unpublished). Favipiravir vs Lopinavir-Ritonavir (control arm) – Multivariable Cox regression showed that FPV was independently associated with faster viral clearance. In addition, fewer adverse reactions were found in the FPV arm than in the control arm. In this open-label nonrandomized control study, FPV. fewer adverse reactions were found in the

600 mg tid with 1600mg first loading dosage for no more than 14 days

Phase I/II and phase III Clinical trials Influenza:
Phase III completed in the
US: NCT02026349 ;

NCT02008344
Phase I / II completed, in the
US: NCT01068912 ; NCT01728753 or in China:
NCT03394209 or in Japan: JPRN-JapicCTI-142657

Used in JIKI Trial (Ebola, nonrandomized): day 0: 6000 mg; day 1 to day 9: 2400 mg/d
Dose escalation trial in preparation in France

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 20

Landscape analysis of therapeutics as 21st March 2020

FPV arm than in the control arm.

Enisamium iodide (Amizon)

Antiviral on the market in Ukraine

 

In vitro studies influenza:
Boltz, D., Peng, X., Muzzio,
M., Dash, P., Thomas, P. G., & Margitich, V. (2018). Activity of enisamium, an isonicotinic acid derivative, against influenza viruses in differentiated normal human bronchial epithelial cells. Antiviral Chemistry and Chemotherapy, 26. https://doi.org/10.1177/204 0206618811416
Cocking, D., Cinatl, J., Boltz,
D. A., Peng, X., Johnson, W., Muzzio, M., … Margitich, V. (2018). Antiviral effect of a derivative of isonicotinic acid enisamium iodide (FAV00A) against influenza virus. Acta Virologica, 62(2), 191–195. https://doi.org/10.4149/av_2 018_211

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 21

Landscape analysis of therapeutics as 21st March 2020

Product type and candidate

Description

Licensed for

Licensed dose

Route of administration

Currently being trialled COVID- 19?

Status of clinical development for Coronaviruses

Proposed dose for COVID-19

Status of clinical development for other relevant conditions

Arbidol (Umifenovir)

Antiviral. Russian-made small indolederivative molecule

Licensed in Russia and China for prophylaxis and treatment of influenza and other respiratory viral infections. Since 2004, ARB is patented by MasterlekTM for its medicinal use as an antiviral agent against atypical pneumonia induced by the SARS-CoV. Not approved by EMA/FDA

Yes http://www.c hictr.org.cn/s howprojen.as px?proj=4906
9
http://www.c hictr.org.cn/s howprojen.as px?proj=4906
5 https://clinica ltrials.gov/ct2 /show/NCT04 252885

Clinical trials COVID-19

In vitro study SARS-CoV: – Khamitov et al. Vopr Virusol. 2008 ;53(4):9-13 – (GMK-AH-1 cells) – Arbidol and arbidol mesylate were shown to have a direct antiviral effect in early viral replication in the cultured cells. (in Russian)

CT ChiCTR2000029592: not mentioned

CT ChiCTR2000029573: Arbidol Tablets 200mg/ time, p.o.tid.

CT NCT04252885: ordinary treatment plus a regimen of arbidol (100mg) (oral, tid, 200mg each time, taking for 7-14 days).

Review:
– Kramarev et al. Lik Sprava. 2013 Mar;(2):99-106 – The treatment of influenza and acute respiratory viral infections. (in Russian) Blaising et al. Antiviral Res. 2014 Jul;107:84-94.

Novaferon, Nova

Recombinant protein produced by DNA-shuffling of IFN-α

Licensed in China hepatitis B

Atomization inhalation

Yes http://www.c hictr.org.cn/s howproj.aspx ?proj=49065 http://www.c hictr.org.cn/s howprojen.as px?proj=4880 9

Clinical trials COVID-19

20g/ time, atomized inhalation (in one trial, in combination with Arbidol tid.Arbidol Tablets 200mg/ time, p.o.tid)

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 22

Landscape analysis of therapeutics as 21st March 2020

Product type and candidate

Description

Licensed for

Licensed dose

Route of administration

Currently being trialled COVID – 19?

Status of clinical development for Coronaviruses

Proposed dose for COVID-19

Status of clinical development for other relevant conditions

Licensed but removed from the market for commercial reasons

IFN alfacon-1 + corticosteroids (Infergen®, Advaferon® – Discontinued Drugs)

Synthetic recombinant type-I interferon (IFN) developed by comparing the amino acid sequences of several natural IFN-alpha subtypes

Hepatitis C, Chronic (withdrawn from use in the European Union)

Injection

Clinical study SARS:
Loutfy et al. JAMA 2003;290(24):3222-8 (case series ; 22 patients) – improved outcome, but higher doses of steroids received, so it is difficult to determine whether or not the beneficial effects were due to the interferon alfacon 1 .

Phase 2/Phase 3/Observational

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 23

Landscape analysis of therapeutics as 21st March 2020

Convalescent plasma

Human polyclonal

NA

NA

IV

Clinical studies SARS: Cheng, Y. et al. (2005). Use of convalescent plasma therapy in SARS patients in Hong Kong. European

Journal of Clinical
Microbiology and
Infectious Diseases, 24(1), 44–46. – > non-randomised treatment of 80 SARS pts with convalescent plasma. Soo, Y. O. Y. et al. (2004). Retrospective comparison of convalescent plasma with continuing high-dose methylprednisolone treatment in SARS
patients. Clinical
Microbiology and
Infection, 10(7), 676–678.

Clinical trials influenza:
Hung, I. F. N. et al. (2013). Hyperimmune IV immunoglobulin treatment: A multicenter double- blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection. Chest, 144(2), 464–473. -> randomisation of 35 patients
with influenza infection to hyperimmune IV immunoglobulin vs normal IV immunoglobulin. Hung, I. F. N. et al. (2011). Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1)
2009 virus infection. Clinical Infectious Diseases, 52(4), 447– 456. -> prospective cohort study where convalescent plasma was given to 20 critically ill H1N1pdm09 patients

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 24

Landscape analysis of therapeutics as 21st March 2020

Continued..

 

non-randomised retrospective 19 SARS patients treated with convalescent plasma vs
21pulsed methylprednisolone
. Wong, V. et al. (2003). Treatment of severe acute respiratory syndrome with convalescent plasma. In Hong Kong Med J (Vol. 9) > Case report of SARS patient receiving convalescent plasma (+ribavirin and corticosteroids)

Yeh, K. M. et al. (2005). Experience of using convalescent plasma for
severe acute respiratory
syndrome among healthcare workers in a Taiwan hospital. Journal of Antimicrobial

Chemotherapy, 56(5), 919–
922. -> 3 SARS infected
patients treated with convalescent plasma

Zhou, X. et al. (2003). [Epidemiologic features, clinical diagnosis and therapy of first cluster of patients with severe acute respiratory syndrome in Beijing area]. Zhonghua Yi

Xue Za Zhi, 83(12), 1018– 1022. -> 1 SARS patient treated with convalescent
Plasma
Systematic review SARS studies:

Mair-Jenkins, J. et al. (2015). The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: A systematic review and exploratory meta-analysis. Journal of

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 25

Landscape analysis of therapeutics as 21st March 2020

 

Infectious Diseases, 211(1), 80–90. ->

systematic

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 26

Landscape analysis of therapeutics as 21st March 2020

Continued..

 

review and exploratory meta- analysis of convalescent plasma treatment for SARS and severe influenza

Protocol clinical study MERS:
Arabi, Y. et al. (2015). Feasibility, safety, clinical, and laboratory effects of convalescent plasma therapy for patients with Middle East respiratory syndrome coronavirus infection: a study protocol. SpringerPlus, 4(1), 1–8. -> protocol for convalescent plasma study in MERS

Clinical studies MERS:
Ko, J. H. et al. (2018).
Challenges of convalescent plasma infusion therapy in Middle East respiratory coronavirus infection: A single centre experience. Antiviral Therapy, 23(7), 617–622. -> 3 patients received convalescent plasma. Neutralisation activity assessed. van Doremalen, N. et al. (2017). Efficacy of antibody-based therapies against Middle East respiratory syndrome coronavirus (MERS-CoV) in common marmosets.
Antiviral Research, 143, 30–37.->

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 27

Landscape analysis of therapeutics as 21st March 2020

Continued..

 

MERS infected marmosets treated with high titre hyperimmune plasma vs mAb m336.

Arabi, Y. M., et al. (2016). Feasibility of using convalescent plasma immunotherapy for MERSCoV infection, Saudi Arabia. Emerging
Infectious Diseases, 22(9), 1554–1561. -> feasibility of collecting convalescent plasma from MERS survivors Chun, S., et al. (2016). Possible transfusionrelated acute lung injury following convalescent plasma transfusion in a patient with middle east respiratory syndrome.

Annals of Laboratory Medicine, Vol. 36, pp. 393– 395. -> possible acute lung injury following convalescent plasma transfusion in MERS patient

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 28

Landscape analysis of therapeutics as 21st March 2020

GS-5734/ Remdesivir

Nucleoside Inhibitor

NA

NA

IV

Yes https://clinica ltrials.gov/ct2 /show/NCT04 252664?cond =COVID19&draw=2& rank=1 https://clinica ltrials.gov/ct2 /show/NCT04 257656?term =remdesivir& draw=2&rank

=1

In vitro COVID-19:

Wang, M., et al. (2020).

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (COVID-19) in vitro. Cell Research.

Holshue, M. L. et al. (2020).

First Case of 2019 Novel Coronavirus in the United States. New England Journal of Medicine, NEJMoa2001191. -> 1 COVID-19 patient

In vivo MERS-CoV:

de Wit, E. et al. (2020).

Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proceedings of the
National Academy of Sciences, 201922083. -> Efficacy against MERS in monkeys
Sheahan, T. P. et al. (2020). Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nature Communications,
11(1). -> study in MERSCoV infected mice
Jordan, R. et al. (2017). Broad-spectrum
Investigational Agent GS5734 for the Treatment of Ebola, MERS Coronavirus and Other Pathogenic Viral Infections with

 

CT NCT04252664: 200 mg loading dose on day 1 is given, followed by 100 mg iv once-daily maintenance doses for 9 days.

CT NCT04257656: 200 mg loading dose on day 1 is given, followed by 100 mg iv once-daily maintenance doses for 9 days.

Clinical trials Ebola:
Phase II: https://clinicaltrials.gov/ct2/ show/NCT02818582,

Phase III: https://clinicaltrials.gov/ct2/ show/NCT03719586

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 29

Landscape analysis of therapeutics as 21st March 2020

High Outbreak Potential. Open Forum Infectious Diseases, 4(suppl_1), S737–S737. -> mice infected with MERSCoV

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 30

Landscape analysis of therapeutics as 21st March 2020

In vivo and in vitro SARSCoV and MERS:
Agostini, M. L. et al.. (2018a). Coronavirus Susceptibility to the Antiviral Remdesivir (GS5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease. MBio, 9(2). -> human airway epithelial cells and animal

model findings SARS and MERS
Sheahan, T. P. et al. (2017). Broad-spectrum antiviral GS- 5734 inhibits both epidemic and zoonotic coronaviruses. Science Translational Medicine, 9(396). -> in human airway epithelial cultures and animal model findings

SARS and MERS

In vitro coronaviruses:

Brown, A. J. et al. (2019).

Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase. Antiviral Research, 169. -> in vitro inhibition of coronaviruses

  

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 31

Landscape analysis of therapeutics as 21st March 2020

Product type and candidate

Description

Licensed for

Licensed dose

Route of administration

Currently being trialled COVID – 19?

Status of clinical development for Coronaviruses

Proposed dose for COVID- 19

Status of clinical development for other relevant conditions

Alferon® (IFN- α-n3)

natural, human interferon alpha protein

NA

NA

Parenteral injection of oral

 

Clinical trial SARS:
Alferon® LDO – NCT00215826 (Phase 2) –
No results posted Phase 2 – randomized dose-ranging study to evaluate the safety and activity of orally administered low dose IFNα- n3 as an antiviral and immunomodulator in asymptomatic subjects with recent exposure to a person with severe acute respiratory syndrome (SARS) or possible SARS.

NO RESULTS POSTED

In vivo study SARS-CoV:

Barnard at al. Antivir Chem Chemother.2006;17(5):275- 84 – Alferon® did not reduce virus lung titres in the

SARS- CoV mouse model most probably because of the well- known species barrier between human IFN- α and the mouse IFN type 1 receptor.

 

In Phase II CT NCT00215826 SARS 650 IU vs. 1300 IU trialled

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 32

Landscape analysis of therapeutics as 21st March 2020

IFN-β1a solution for inhalation (SNG001)

IFN-β is a naturally occurring protein which orchestrates the body’s antiviral defences IFN-β1a (SNG001) is a pH neutral and contains the excipient methionine, an amino acid native to the airways.

NA

NA

Inhalation. The delivery device (iNeb by Philips) used to date is a breath actuated mesh nebuliser

 

Unpublished data assessing IFN-β1a activity agaisnt MERS virus, generated by Heinrich Feldmann and Darryl Falzarano at NIH/NIAID in 2014

Asthma phase II trial:

Djukanović et al. Am J Respir Crit Care Med. 2014.190(2) :145-54 ;
NCT01126177

Asthma: Phase II trials (SG005 and INEXAS) in asthma, conducted by Synairgen (NCT01126177) and AstraZeneca respectively, suggest that SNG001 boosts antiviral responses in the lungs, has a beneficial effect on lung function and, in more difficult to treat patients, improves asthma control during cold infections. However, the unexpectedly low exacerbation rate (<10%) in the INEXAS trial population suggests that the economic viability of the drug in an asthma indication would be limited. (https://www.synairgen.com /programmes/ifn-%CE%B2- in-copd/)

COPD phase II trial: NCT03570359 (Phase II) ; https://www.synairgen.com/ programmes/ifn-%CE%B2- incopd/
COPD: Phase II Randomised, Double-blind, Placebocontrolled Study (SG015) – ongoing (https://clinicaltrials.gov/ct2/ show/NCT03570359?term=N

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 33

Landscape analysis of therapeutics as 21st March 2020

 

CT03570359&draw=2&rank= 1)

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 34

Landscape analysis of therapeutics as 21st March 2020

Product type and candidate

Description

Licensed for

Licensed dose

Route of administration

Currently being trialled COVID-19?

Status of clinical development for Coronaviruses

Proposed dose for COVID-19

Status of clinical development for other relevant conditions

Part 1 Safety, Part 2 Efficacy and safety

pegylated IFNλ1a

type III IFN

NA

NA

SC injection

Eiger BioPharmaceuticals have some initial in vitro and in vivo data with coronas.

Influenza:
Sun et al. IFN-λ: A new spotlight in innate immunity against influenza virus infection. Protein Cell. 2018 Oct; 9(10): 832–837. Klinkhammer et al. IFN-λ prevents influenza virus spread from the upper airways to the lungs and limits virus transmission. eLife. 2018; 7: e33354.

multiple Phase 2 and 3 Clinical trials mostly for hepatitis viruses: https://clinicaltrials.gov/ct2/r esults?cond=&term=interfer on+lambda&cntry=&state=& city=&dist=

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 35

Landscape analysis of therapeutics as 21st March 2020

Polyclonal human antiMERS CoV Abs

SAB 301

SAB-301 is a purified human Immune globulin G (hIgG)polyclonal antibody designed to bind to the MERSCoV spike (S) protein.
The hIgG is purified from the plasma of immunized transchromoso mic (Tc) bovines that were immunized with a recombinant spike protein produced in insect cells.

 

NA

NA

IV

 

Group sequential design with multiple interim analyses to determine futility or efficacy. -Hospitalized adults with MERS CoV infection
-Single 50mg/kg infusion of SAB-301 vs. placebo control

-Being considered by KSA KAIMARC
– P.I. Dr. Yaseen Arabi, M.D.

Product type and candidate

Description

Licensed for

Licensed dose

Route of administration

 

Currently being trialled COVID-19?

 

Status of clinical development for Coronaviruses

Proposed dose for COVID-19

Status of clinical development for other relevant conditions

Phase 1

Camostat

TMPRSS-2 inhibitor – see citation

NA

NA

Oral

 

NA

Role of TMPRSS2: https://www.ncbi.nlm.nih. gov/pubmed/30849247

Chronic pancreatitis: https://www.ncbi.nlm.nih.go v/pmc/articles/PMC6694471 /

Sab-301

Polyclonal anti MERS-CoV (likely MERSspecific, but possible to crossreact)

NA

NA

IV

 

NA

Clinical trial Phase 1 MERS: https://clinicaltrials.gov/ct 2/show/NCT02788188

In vivo study MERS-CoV: https://www.ncbi.nlm.nih. gov/pubmed/26888429

1 to 2 doses at 50 mg/kg

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 36

Landscape analysis of therapeutics as 21st March 2020

BCX4430

Nucleoside Inhibitor

NA

NA

IV and IM formulations

NA

Clinical trial Phase 1 Ebola Virus Disease: https://clinicaltrials.gov/ct2/ show/NCT02319772

Clinical trial Phase 1 Yellow Fever: https://clinicaltrials.gov/ct2/ show/NCT03891420

Clinical trial Phase 1 Marburg Virus Disease: https://clinicaltrials.gov/ct2/ show/NCT03800173

     

Relacatib (SB462795)

NA

NA

 

NA

Pers comm Pauline Williamns:
We can confirm that as well as Cathepsin-K activity, it does have good activity against CathepsinL. It has completed a first time in human study in healthy post-menopausal women, and the preclinical and clinical profile would support further studies in humans. We are collating the relevant documentation on the asset.

 

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 37

Landscape analysis of therapeutics as 21st March 2020

REGN3048 and REGN3051 Antibody Cocktail

Biological: REGN3048 REGN3048 is a fully monoclonal antibody (mAbs) which binds to the S protein of MERS-CoV. Biological: REGN3051 REGN3051 is a fully human monoclonal antibody (mAb) which binds to the S protein of MERS-CoV. It can reduce virus titers and ameliorate MERS-CoV- induced lung pathology when given post infection.

NA

NA

 

NA

Clinical trial Phase I MERS: https://clinicaltrials.gov/ct 2/show/NCT03301090

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 38

Landscape analysis of therapeutics as 21st March 2020

Product type and candidate

Description

Licensed for

Licensed dose

Route of administration

Currently being trialled COVID-19?

Status of clinical development for Coronaviruses

Proposed dose for COVID-19

Status of clinical development for other relevant conditions

Polyclonal Human Abs anti-Mers

NA

NA

NA

Polyclonal human antiMERS CoV Abs

SAB 301

SAB-301 is a purified human immune
globulin G (hIgG) polyclonal antibody designed to specifically bind to the MERSCoV spike (S) protein, a component of the virion membrane that is responsible for binding of the virus to the host cell. The hIgG is purified from the plasma of immunized transchromoso mic (Tc) bovines that were immunized with a recombinant spike protein produced in insect cells. SAB-301 is purified hIgG in
a sterile liquid formulated in 10 mM glutamic acid monosodium salt, 262 mM Dsorbitol, 0.05

mg/mL Tween
80, pH 5.5. The drug product
will be administered intravenously and will be diluted in saline per the clinical protocol.

NA

NA

NA

RCT, double blinded, single dose scalation phase II, >14 years- 160 subjects

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 39

Landscape analysis of therapeutics as 21st March 2020

Product type and candidate

Description

Licensed for

Licensed dose

Route of administration

Currently being trialled COVID-19?

Status of clinical development for Coronaviruses

Proposed dose for COVID-19

Status of clinical development for other relevant conditions

Pre-clinical

Lycorine

Inhibits cell division, antineoplastic, antiviral

NA

NA

NA

NA

Shen 2019 JV 93:e0002319

UDA

Lectin

NA

NA

NA

NA

In vivo and in vitro influenza: https://www.ncbi.nlm.nih. gov/pmc/articles/PMC321 6401/

SSYA10-001

SARS/MERS nsp13 Helicase inhibitor

NA

NA

NA

NA

In vitro MERS-CoV and MHV: https://www.ncbi.nlm.nih. gov/pmc/articles/PMC413 6041/

Hiltonol PolyIC:LC

Host

NA

NA

intranasal doses

NA

In vivo SARS-CoV: https://www.ncbi.nlm.nih. gov/pubmed/27956136

RTD-1 peptide

Immunomodula tor

NA

NA

intranasal doses

NA

In vivo SARS-CoV: https://www.ncbi.nlm.nih. gov/pubmed/19710146

NHC (EIDD1931)

β-D-N4 hydroxycytidine , ribonulcoside analogue, inhibit viral replication

NA

NA

NA

NA

In vitro MERS-CoV and MERS-CoV https://jvi.asm.org/content /93/24/e01348-19.long

rHu-IFN-α B/D

NA

NA

NA

NA

In vivo SARS-CoV: https://www.ncbi.nlm.nih. gov/pubmed/17176632

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 40

Landscape analysis of therapeutics as 21st March 2020

Product type and candidate

Description

Licensed for

Licensed dose

Route of administration

Currently being trialled COVID-19?

Status of clinical development for Coronaviruses

Proposed dose for COVID- 19

Status of clinical development for other relevant conditions

Asterivir

Highly sulfonated chemicals attached to a U.S. FDA– approved Cyclodextrin scaffold

NA

NA

NA

NA

https://www.ncbi.nlm.nih. gov/pubmed/29251725 https://advances.sciencem ag.org/content/6/5/eaax9 318

The macromolecules are broad- spectrum, biocompatible, and virucidal at micromolar concentrations in vitro against many viruses [including herpes simplex virus (HSV), respiratory syncytial virus (RSV), dengue virus, and Zika virus]. They are effective ex vivo against both laboratory and clinical strains of RSV and HSV-2 in respiratory and vaginal tissue culture models, respectively. Additionally, they are effective when administrated in mice before intravaginal HSV-2 inoculation.

GD27

Human mAbs/ Fab-RBD

NA

NA

NA

NA

In vivo MERS-CoV: https://www.ncbi.nlm.nih. gov/pubmed/30091015

Gd33

Human mAbs/ Fab-RBD

NA

NA

NA

NA

In vitro MERS-CoV: https://academic.oup.com /jid/article/218/8/1249/50 17222

MCA1

Human mAbs/ Fab-RBD

NA

NA

NA

NA

In vivo MERS-CoV: https://www.ncbi.nlm.nih. gov/pubmed/28472421

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 41

Landscape analysis of therapeutics as 21st March 2020

JC57-14

Macaque mAbs/ Fab-RBD

NA

NA

NA

NA

In vitro MERS-CoV: https://www.ncbi.nlm.nih. gov/pubmed/29514901

MERS-4

Human mAbs/ Fab-RBD

NA

NA

NA

NA

In vitro MERS-CoV: https://www.ncbi.nlm.nih. gov/pubmed/29996104

Product type and candidate

Description

Licensed for

Licensed dose

Route of administration

Currently being trialled COVID-19?

Status of clinical development for Coronaviruses

Proposed dose for COVID- 19

Status of clinical development for other relevant conditions

CDC2-C2

Human mAbs/ Fab-RBD

NA

NA

NA

NA

In vitro MERS-CoV: https://www.ncbi.nlm.nih. gov/pubmed/29514901

VHH-83,

Dromedary VHHs

NA

NA

NA

NA

In vitro MERS-CoV: https://www.ncbi.nlm.nih. gov/pubmed/30101189

HCAb-83

Dromedary VHHs

NA

NA

NA

NA

CVHHs

Dromedary VHHs

NA

NA

NA

NA

NbMs10

Llama VHHs

NA

NA

NA

NA

In vitro and in vivo MERSCoV: https://www.ncbi.nlm.nih. gov/pubmed/29950421

NbM10-Fc

Llama VHHs

NA

NA

NA

NA

LCA60

Human survivor, RBD

NA

NA

NA

NA

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 42

Landscape analysis of therapeutics as 21st March 2020

Unnamed

New unpublished panel of human mAbs against SARS derived from a human survivor of the 2003 SARS outbreak in Hong Kong. The mAbs bind a

variety of sites including RBD,
NTD, and stem.

NA

NA

NA

NA

unpublished

S3.1

human mAb

NA

NA

NA

NA

In vivo and in vitro SARSCoV: https://www.ncbi.nlm.nih. gov/pubmed/15247913

S230.15

human mAb

NA

NA

NA

NA

In vivo and in vitro SARSCoV: https://www.ncbi.nlm.nih. gov/pubmed/17620608

Product type and candidate

Description

Licensed for

Licensed dose

Route of administration

 

Currently being trialled COVID-19?

Status of clinical development for Coronaviruses

Proposed dose for COVID-19

Status of clinical development for other relevant

conditions

m396

human mAb

NA

NA

NA

NA

In vitro SARS-CoV: https://www.ncbi.nlm.nih. gov/pubmed/?term=Struct ure+of+severe+acute+respi ratory+syndrome+coronavi rus+receptorbinding+domain+complexe d+with+neutralizing+antib ody

mAb F26G18 (Chimeric)

chimeric human mouse mAb

NA

NA

NA

NA

In vitro SARS-CoV: https://www.ncbi.nlm.nih. gov/pubmed/20168090

mAb F26G19

chimeric human mouse mAb

NA

NA

NA

 

NA

In vitro SARS-CoV: https://www.ncbi.nlm.nih. gov/pubmed/20168090

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 43

Landscape analysis of therapeutics as 21st March 2020

                  

Unnamed

purified mAbs to SARS

NA

NA

NA

NA

unpublished

                        

80R

human mAb

NA

NA

NA

NA

In vitro SARS-CoV: Rani et al 2012;

 

doi: 10.1128/JVI.00233-12

                   

80R

human mAb

NA

NA

NA

NA

In vitro SARS-CoV: https://www.ncbi.nlm.nih. gov/pubmed/14983044

                    

CR3014

human mAb

NA

NA

NA

NA

In vitro SARS-CoV: https://www.ncbi.nlm.nih. gov/pubmed/15650189

                         

CR3022

human mAb

NA

NA

NA

NA

In vitro SARS-CoV: https://www.ncbi.nlm.nih. gov/pubmed/15650189

                    

CR3022

NA

NA

NA

NA

                        

B1

human mAb

NA

NA

NA

NA

In vitro and in vivo SARSCoV: https://www.ncbi.nlm.nih. gov/pubmed/15939399

   

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 44

Landscape analysis of therapeutics as 21st March 2020

Product type and candidate

Description

Licensed for

Licensed dose

Route of administration

Currently being trialled COVID-19?

Status of clinical development for Coronaviruses

Proposed dose for COVID-19

Status of clinical development for other relevant conditions

201

human mAb

NA

NA

NA

NA

In vivo SARS-CoV: https://www.ncbi.nlm.nih. gov/pubmed/?term=Devel opment+and+characterizat ion+of+a+severe+acute+re spiratory+syndromeassociated+coronavir usneutralizing+human+mono clonal+antibody+that+prov ides+effective+immunopro phylaxis+in+mice

68

human mAb

NA

NA

NA

NA

In vivo SARS-CoV: https://www.ncbi.nlm.nih. gov/pubmed/?term=Devel opment+and+characterizat ion+of+a+severe+acute+re spiratory+syndromeassociated+coronavir usneutralizing+human+mono clonal+antibody+that+prov ides+effective+immunopro phylaxis+in+mice

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 45

Landscape analysis of therapeutics as 21st March 2020

Unnamed

Located frozen stock of other ~10 SARS specific mAb. These mAbs were identified together with mAb 201, with binding activities with various S protein domains. They are working on preparing these mAbs for testing.

NA

NA

NA

NA

unpublished

Unnamed

NA

NA

NA

NA

Product type and candidate

Description

Licensed for

Licensed dose

Route of administration

Currently being trialled COVID-19?

Status of clinical development for Coronaviruses

Proposed dose for COVID-19

Status of clinical development for other relevant conditions

Unnamed

working on nCoV Tx – no more information at the moment

NA

NA

NA

NA

DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 46

Landscape analysis of therapeutics as 21st March 2020

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DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 47

Landscape analysis of therapeutics as 21st March 2020

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DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 48

Landscape analysis of therapeutics as 21st March 2020

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findings.Thorax 2004;59:252-256
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of Infection. 2020: DOI: https://doi.org/10.1016/j.jinf.2020.03.002

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DISCLAIMER: These landscape documents have been prepared by the World Health Organization (WHO) for information purposes only concerning the 2019-2020 global of the novel coronavirus. Inclusion of any particular product or entity in any of these landscape documents does not constitute, and shall not be deemed or construed as, any approval or endorsement by WHO of such product or entity (or any of its businesses or activities). While WHO takes reasonable steps to verify the accuracy of the information presented in these landscape documents, WHO does not make any (and hereby disclaims all) representations and warranties regarding the accuracy, completeness, fitness for a particular purpose (including any of the aforementioned purposes), quality, safety, efficacy, merchantability and/or non- infringement of any information provided in these landscape documents and/or of any of the products referenced therein. WHO also disclaims any and all liability or responsibility whatsoever for any death, disability, injury, suffering, loss, damage or other prejudice of any kind that may arise from or in connection with the procurement, distribution or use of any product included in any of these landscape documents. 49

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