PHARMACOTHERAPY OF COVID-19

2021-6-12亞東紀念醫院內科加護病房

張厚台

大綱

Case Sharing , Pathology process of SARS Cov 2, clinical spectrum Pharmacologic intervention in COVID Monoclonal antibody: SARS-CoV-2 Neutralizing Antibody Antiviral agents : Remdesivir ,baricitinib Anti-inflammation agents : corticosteroid , IL-6 antagonist Anticoagulants

Potential pharmacologic strategy for COVID-19 treatment

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Dexamethasone 6mg/d

Remdesivir 200mg, st and 100 mg, qd* 5d

O2NC O2

SM O2NRM

O2 SM

35 y/o female, husband :萬華果菜市場Nasal Swab (5/22) : SARS-Cov-2 RNA (+) Lym: 738 -> 1225 D D dimer: 407CRP: 0.584, PCT:0.05LDH: 228

Risk Factors: Age >65 y/o (-) , BMI>35 (-) , immunocompromise(-), HTN (-) , DM (-)

Clinical spectrum of SARS-Cov-2 infection

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Classification Asympto-matic

Mild Moderate Severe Critical

Definition NAAT(+) S/S of COVID fever, smell(-)CXR(-)

SpO2>94% ,at RAS/S of LRI,

SpO2 <94% , at RAPaO2/FiO2 <300 mm Hg,RR >30/min, or lung infiltrates >50%.

respiratory failure, septic shock, and/or multiple organ dysfunction.

% 81% 14% 5%

Treatment (I) SARS-Cov neutralizing antibody *bamlanivimab plus etesevimabor *casirivimab plus imdevimab

DexDex +RDV (Incr. O2)RDV

DexDex +TCZ

Treatment (2) Baricitinib +RDV LMWH

NIH guideline 新型冠狀病毒（SARS-CoV-2）感染臨床處置暫行指引

Pathology process of SARS-CoV-2

ZHOU ET AL. J Med Virol. 2021; 1–11.Eur Respir J 2021; in press

Initial stage: fever , cough…highest viral load in 7 days 2nd stage: dysfunctional host inflammatoryresponse => lung inflammation and lung injury follows

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Risk of progressive to severe COVID• Older age ( ≥65 years of age) • Obesity ( BMI >25 kg/m2, or 12-17y/o: BMI ≥85th )• Pregnancy , Chronic kidney disease , Diabetes ,Immunosuppressive

disease or immunosuppressive treatment , Sickle cell disease Cardiovascular disease (including congenital heart disease) or

hypertension Chronic lung diseases (ex: COPD, asthma [moderate-to-severe],

interstitial lung disease, cystic fibrosis, and pulmonary hypertension) Neurodevelopmental disorders (for example, cerebral palsy) Having a medical-related technological dependence (ex, tracheostomy,

gastrostomy, or positive pressure ventilation [not related to COVID 19]) Defined by EUA2021/6/12 6

ZHOU ET AL. J Med Virol. 2021;1–11..2021/6/12 7

Hajjar et al. Ann. Intensive Care (2021) 11:36

Viral cycle

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SARS-COV-2 NEUTRALIZING ANTIBODY

SARS-CoV-2 neutralzing antibody

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Antibody Therapeutics, 2020, Vol. 3, No. 4 246–256Viruses 2021, 13, 628.

* Targeting spike protein* Neutralize SARS Cov 2• Cocktail strategy - Two nAb

cocktails (casirivimab1200mg/ imdevimab 1200mg and bamlanivimab700mg/etesevimab 1200 mg )

• Mild to moderate , risk (+)• Within 10 days of symptoms

onset, not hospitalized

台灣專家會議決議

Casirivimab/ imdevimab and bamlanivimab /etesevimab 具以下任一風險因子: 未使用氧氣, 且發病七天內之成人病患

風險因子: (1). 年齡> 65 y/o * 註: 因最近進量限制, 先訂75歲以上且具以下共病者

(2). 年齡> 55 y/o, 且具以下任一情形: 糖尿病、慢性腎病、心血管疾病( 含高血壓) 、慢性肺疾、BMI >30, 或其他影響免疫功能疾病

(3), 懷孕

劑量: 600mg casirivimab +600mg imdevimab ;

700mg Bamlanivimab+1400mg etesevimab2021/6/12 11

ANTIVIRAL AGENTS Remdesivir

JAMA. 2020;323(18):1824-1836

virus-induced host immune system response and viral processing within target cells

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Remdesivir

GS-5734, Remdesivir inhibits viral RNA-dependent RNA polymerase, causing premature termination of RNA transcription, inhibit SARS-CoV-1 and MERS -CoV

Dosage: D1: 200mg, Loading; D2-D10 or discharge: 100mg maintenance

Remdesivir is recommended for hospitalized patients with COVID-19 disease

Remdesivir: shorter time to recovery , in the ordinal scale score at day 15 Lower mortality at D15, prevented the progression to more severe respiratory

disease

Remdesivir for the Treatment of Covid-19 — Final Report. N Engl J Med 2020;383:1813-26. DOI: 10.1056/NEJMoa2007764 14

Recommendation 10: In patients on supplemental oxygen but not on mechanical ventilation or ECMO, the IDSA panel suggests treatment with five days of remdesivir rather than 10 days of remdesivir.• Remark: In patients on mechanical ventilation or ECMO, the duration of treatment is 10 days.

Recommendation 9: In hospitalized patients with severe* COVID-19, the IDSA panel suggests remdesivir over no antiviral treatment. • Remdesivir appears to demonstrate the most benefit in those with severe COVID-19 on supplemental oxygen rather than in patients on mechanical ventilation or ECMO.

http://www.idsociety.org/COVID19guidelines

IDSA guideline1

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Remdesivir for the Treatment of Covid-19 — Final Report

The mortality rate (day 15) was 6.7% (remdesivir): 11.9% (placebo)

Median time to recovery:

10 (remdesivir) vs. 15( placebo)=> Lower mortality and Faster recovery !!

Serious adverse events were reported in 24.6% of remdesivir patients and 31.6% of placebo patients

Remdesivir for the Treatment of Covid-19 — Final Report. N Engl J Med 2020;383:1813-26.

Adaptive Covid-19 Treatment Trial (ACTT-1)

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Remdesivir for the Treatment of Covid-19 — Final Report. N Engl J Med 2020;383:1813-26. 17

International Journal of Infectious Diseases 106 (2021) 71–7774

Real world data: Symptoms onset to RDV Tx <9 days Better survival

Remdesivir for the Treatment of Covid-19 — Final Report. N Engl J Med 2020;383:1813-26.

Hospitalized+O2 NIV MV/ECMO

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55 y/o FBH:150cm, BH: 86Kg* 5/26 COV(+)* 5/30 喘* Refer from 趣淘檢疫旅館5/31, 1: 37AM 抵達ER , SpO2:74-80% at room air* 3:27AM Dexamethasone6mg, iv st* CRP: 15.1 ,RR: 45/min, SpO2 89-90% under NRM 15L/min* 6:48AM intubation * 7:30AM TCZ , 600mg , ivd* 8:45AM ICU

D4-D6

6/10 拔管

ANTI-INFLAMMATIONCorticosteroid , tocilizumab (TCZ)

ARDS

Dexamethasone

SARS-CoV-2Cytokine storm

European Journal of Pharmacology 894 (2021) 173854

IL-6 antagonist

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IDSA guideline2

Recommendation 4: Among hospitalized critically ill patients* with COVID-19, the IDSA guideline panel recommends dexamethasone rather than no dexamethasone. (Strong recommendation, Moderate certainty of evidence)

equivalent : methylprednisolone 32 mg and prednisone 40 mg *Critical illness: Patients on mechanical ventilation and extracorporeal mechanical oxygenation (ECMO). In COVID-19, the most commonly reported form of end organ dysfunction is ARDS

**Severe illness: SpO2 ≤94% on room air, including patients on supplemental oxygen.

http://www.idsociety.org/COVID19guidelines2021/6/12 22

Systemic Corticosteroids

We recommend systemic corticosteroids for COVID-19 positive patients who are critically ill or require supplemental oxygen

Dosing regimens to consider include:✔ Dexamethasone 6mg IV or PO daily x 10 days✔ Hydrocortisone 50mg IV Q8h x 10 days✔ Methylprednisolone 15mg IV BID x 10 days✔ Prednisone 40mg PO daily x 10 days

)23

Dexamethasone in Hospitalized Patients with Covid-19 — N Engl J Med 2021;384:693-704

1. IMV at randomization 2. Age-adjusted

mortality reduction :12.3%

29.3% vs 41.4%22.9% vs. 25.7% (p<0.001) 23.3% vs. 26.2%

Age-adjusted mortality reduction : 4.2%

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Dexamethasone in Hospitalized Patients with Covid-19 — N Engl J Med 2021;384:693-7042021/6/12 25

JAMA. 2020;324(13):1330-1341

Prospective meta-analysis that pooled data from 7 randomized clinical trials that evaluated the efficacy of corticosteroids in 1703 critically ill patients with COVID-19There were 222 deaths randomized to corticosteroids (n=678) and 425 deaths randomized to usual care or placebo (n=1025) (odds ratio 0.66, 95% CI 0.53-0.82, p<0.001)A class effect of steroids (odds ratio 0.70, 95% CI 0.48-1.01,p=0.053)

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JAMA. 2020;324(13):1330-1341

Dexmethasone Hydrocortisone Methylprednisolone

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Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19. JAMA. 2020;324(13):1330-1341. 2021/6/12 28

IL-6 antagonists

IL-6: recombinant humanized monoclonal antibody, directed against both the soluble and the membrane bound IL-6 receptor,

Acute-phase response, released in response to infection, stimulates inflammatory pathways

Tocilizumab and sarilumab Treatment of Rheumatic arthritis and cytokine release syndrome

associated with CAR-T cell therapy Dosage: by BW, infusion>1hr , 2nd dose: 12-24hrs later Harms: risk of infections , 亦容易引起HBV reactivation

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~This article was published on February 25, 2021, at NEJM.org.

• Tocilizumab (TCZ): 353 8mg/kg/d

• Sarilumab (SAR) :48400mg

• Standard care (402)(Control)

• COVID-19 pts , < 24 hrsof organ support in ICU

21d OSFD- OR: 1.65

Improved 90d survival

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• 14 April 2020 and 24 January 2021 2022 TCZ: 2094 usual care 562 pts (14%) IMV, 1686 (41% ) noninvasive resp support

* Median CRP: 143 mg/L, 82% with corticosteroid * 28-d mortality : TCZ: Usual care (UC) =29% vs. 33% ((rate ratio 0·86, p=0.007 )* Discharge from hospital : TCZ: UC= 54% vs. 47% ( rate ratio 1·22 , p<0·0001 )• Receipt of IMV: 33% vs. 38% (RR: 0.85, p=0.0005)=> In COVID+ hypoxia+systemic inflammation , TCZ improved survival

this version posted February 11, 2021. ; https://doi.org/10.1101/2021.02.11.21249258doi: medRxiv preprint 2021/6/12 31

28-d mortality this version posted February 11, 2021. https://doi.org/10.1101/2021.02.11.21249258doi: medRxiv preprint

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reduced the likelihood of progression to MV

N Engl J Med 2021;384:20-30.

* For critical COVID-19 pneumonia , under HFNC or high level O2 flow ** Early after intubation

*IDSA Recommendation 7: progressive severe* or critical** COVID-19 who have elevated markers of systemic inflammation, the IDSA guideline panel suggests tocilizumab in addition to standard of care (i.e., steroids)**In the largest trial on the treatment of tocilizumab, criterion for systemic inflammation was defined as CRP ≥75 mg/L.

*ERS:- The patients most likely to benefit are those:o in the first 24 hours after receiving non-invasive or invasive

ventilatory support patients receiving supplementary oxygen and who are progressing despite corticosteroid treatment or who are considered at high risk of future requirement for ventilatory support.

Guidelines about IL-6 antagonists

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NIH guideline (2021-3-5) Tocilizumab ( 8 mg/kg of actual body weight, up to 800 mg) in

combination with dexamethasone (6 mg daily for up to 10 days) in rapid respiratory decompensation due to COVID-19

Ex: (ICU) within the prior 24 hours and who require invasive mechanical ventilation, or high-flow nasal canula (HFNC) oxygen (>0.4 FiO2/30 L/min of oxygen flow)

(not in an ICU) with rapidly increasing oxygen needs who require NIV or HFNC and have significantly increased markers of inflammation (CRP>75mg/L)

Suggestion for IL-6 antagonists2

~ REMAP-CAP preliminary report2021/6/12 34

Baricitinib

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1. selective, efficient and safe janus kinase 1 (JAK1) and 2 (JAK2) inhibitor approved for usage in rheumatoid arthritis treatment2. inhibits the intracellular signaling pathway of cytokines implicated in severe COVID-19, including IL-2, IL-6,IL-10, IFN-, and granulocyte-macrophage colony-stimulating factor (GM-CSF)3. inhibition of both AP2-associated protein kinase 1 (AAK1) and cyclin G-associated kinase (GAK). Thus, preventing endocytosis and reducing viral assembly 4. Combined with RDV

Anticoagulant treatment in COVID-19

SARS-CoV-2 induced complement hyperactivation, endothelial dysfunction and cytokine storm have a prothrombotic effect.

COVID 19 patients develop a pro-coagulative state directly related to disease severity.

In COVID 19 critical patients, thrombotic lesions in pulmunarymicrovessels have a prevalence twice higher than critical non-COVID 19 patients. Prevalence of PE among COVID 19 in ICU : 20% Anticoagulant treatment is associated with lower in-hospital

mortality.

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Journal of Thrombosis and Thrombolysis (2021) 51:642–648CCM 2021 online

Anticoagulants in COVID 19-proposed algorithm

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Journal of Thrombosis and Thrombolysis (2021) 51:642–648

* D dimer: 6 times the upper limit of normal

* ISTH score: PLT, D dimer, PT, fibrinogen

Better results inin patients with

respiratory failure requiring invasive

ventilation.

Disease Severity Recommendations

NIH guidelines

Rapid resp decompendations: TCZ (8mg/kg)+ Dexamethasone (6mg/d)* 10 d

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Take home message

Pharmacotherapy strategy in different severity and different stages of COVID-19 illness Mild to moderate but high risk : casirivimab/ imdevimab,

bamlanivimab/etesevimab Severe illness : O2 needed to maintain SpO2>94% , hospitalization Remdesivir : organ support D1: 200mg, Loading; D2-D10 or discharge: 100mg maintenance

Critical illness: COVID-19 +end organ damage (ARDS, etc ) Dexamethasone iv/oral , 6mg/day *10 days +/- remdesivir Dexamethasone iv/oral + / followed by Tocilizumab addition

Rapid respiratory decompensation: 新的O2 setting 24 小時內+ CRP>75mg/L Dexamethasone *10 days + Tocilizumab (IL-6 antagonist) 8mg/d*1-2 doses

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THANKS FOR YOUR ATTENTION

Therapy Recommendations Recommendation Quality of evidence

Corticosteroids

The panel recommends offeringtreatment with corticosteroids forpatients with COVID-19 requiringoxygen, non-invasive ventilation or invasive mechanical ventilation

Strong Moderate

IL-6 receptorantagonistmonoclonalantibody

The panel suggests offering IL-6receptor antagonist monoclonalantibody therapy to hospitalized patients with COVID-19 requiring oxygen or ventilatory support

Conditional Low

Remdesivir No recommendation is maderegarding the use of remdesivir inpatients hospitalised with COVID-19 and not requiring invasive mechanical ventilationThe panel suggests not to offerremdesivir to patients hospitalisedwith COVID-19 infection who require invasive mechanical ventilation

None

Conditional

Moderate

Moderate

A European Respiratory Society living guideline. Eur Respir J 2021; in press2021/6/12 42

ICU admission criteria

14% developed a severe form of the disease => hospitalization, 5% were critical => ICU admission

Severe: respiratory rates ≥ 30 breaths/min oxygen saturation ≤ 93%, lung infiltrates > 50% at high risk for clinical deterioration and critical illness => ARDS

在hospitalization中有 25% 需要 ICU admission , ICU admission中60-70% 為acute hypoxemic respiratory failure

Risk factors for ARDS: Age>65y/o, T>39C, Lab data abn ( lymphocytopenia, neutrophilia, hepato-renal failure,

inflammatory marker , coagulation abn )Hajjar et al. Ann. Intensive Care (2021) 11:36

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