COVID -19

Coronaviruses

• Range from common cold to severe disease
• Four common human coronaviruses: 229E, NL63, OC43, and HKU1
• Severe Acute Respiratory Syndrome (SARS-CoV)
• Middle East Respiratory Syndrome (MERS-CoV)

Dec 2019: 27 cases of pneumonia of unknown etiology identified in Wuhan city, China

• Causative agent identified and named SARS-CoV-2
• Disease named COVID-19 by WHO
• WHO declared COVID-19 a pandemic
   

Emergency Use Authorization of Remdesivir

 

 

 

• It permits the emergency use of the unapproved product remdesivir
• Treatment of suspected or laboratory confirmed coronavirus disease 2019 (COVID-19) in adults and children hospitalized with severe disease. 

Who are patients with “severe disease” of COVID-19?

• Patients with an oxygen saturation (SpO2) ≤ 94% on room air or 
• Requiring supplemental oxygen or 
• Requiring mechanical ventilation or 
• Requiring extracorporeal membrane oxygenation (ECMO)

   

Remdesivir: Global Perspectives

• Japanese Ministry of Health, Labour and Welfare approved remdesivir as a treatment for SARS-CoV-2 infection, referencing the United States’ FDA EUA[1,2]
• The EMA human medicines committee has recommended expanding the compassionate use recommendations for remdesivir to treat patients with COVID-19 in Europe[3]    
• In addition to treatment of patients undergoing mechanical ventilation, the recommendation now includes treatment of hospitalized patients requiring supplemental oxygen, noninvasive ventilation, high-flow oxygen devices, or ECMO

 

Potential targets and postulated mechanism of action for antiviral interventions

 

Timing of Treatment in Relation to Onset of Symptoms

Adaptive COVID-19 Treatment Trial (NIAID ACTT-1): Study Design

• Multicenter, adaptive, randomized, double-blind, placebo-controlled phase III trial

NIAID ACTT-1 : Results

Preliminary results from 1059 patients

• Serious AEs: 21.1% (114/541) with remdesivir and 27.0% (141/522) with placebo
• Grade 3 or 4 adverse events occurred in 156 patients (28.8%) in the remdesivir group and in 172 in the placebo group (33.0%).

The most common adverse events in the remdesivir group were anemia or decreased hemoglobin (43 events [7.9%], as compared with 47 [9.0%] in the placebo group); acute kidney injury, decreased estimated glomerular filtration rate or creatinine clearance, or increased blood creatinine (40 events [7.4%], as compared with 38 [7.3%]); pyrexia (27 events [5.0%], as compared with 17 [3.3%]); hyperglycemia or increased blood glucose level (22 events [4.1%], as compared with 17 [3.3%]); and increased aminotransferase levels including alanine aminotransferase, aspartate aminotransferase, or both (22 events [4.1%], as compared with 31 [5.9%]). Otherwise, the incidence of adverse events was not found to be significantly different between the remdesivir group and the placebo group.

 

SIMPLE Clinical Trial: Severe COVID-19

• Multicenter, a randomized, open-label, phase 3 trial

• Primary endpoint: Clinical status assessed on day 14 on a 7-point ordinal scale
• Secondary endpoints: proportion of patients with adverse events after the first dose of remdesivir for up to 30 days after the last dose

SIMPLE Clinical Trial: Results

Clinical improvement was defined as an improvement of two or more points from baseline on a predefined 7-point scale, ranging from hospital discharge to increasing levels of oxygen support to death. Patients achieved clinical recovery if they no longer required oxygen support or were discharged from the hospital.

Oxygen Support on Day 14

Among patients receiving mechanical ventilation or ECMO at day 5, 40% (10 of 25) in the 5-day group had died by day 14, as compared with 17% (7 of 41) in the 10-day group

Compassionate Use: Severe Covid-19

 

During a median follow-up of 18 days

In addition, we evaluated the proportion of patients with clinical improvement, as defined by live discharge from a decrease of at least 2 points from baseline on a modified ordinal scale (as recommended by the WHO R&D Blueprint Group), or both

The six-point scale consists of the following categories: 1, not hospitalized; 2, hospitalized, not requiring supplemental oxygen; 3, hospitalized, requiring supplemental oxygen; 4, hospitalized, requiring nasal high-flow oxygen therapy, noninvasive mechanical ventilation, or both; 5, hospitalized, requiring invasive mechanical ventilation, ECMO, or both; and 6, death.

Overall safety summary

• Graded elevations in ALT and AST have been observed ,the mechanism of these elevations is unknown 
• Patients should have appropriate clinical and laboratory monitoring to aid in early detection of any potential adverse events.

Remdesivir - Mechanism of action

Remdesivir triphosphate acts as an analog of adenosine triphosphate (ATP) and competes with the natural ATP substrate for incorporation into nascent RNA chains by the SARS-CoV-2 RNA-dependent RNA polymerase, which results in delayed chain termination during replication of the viral RNA.

 

Remdesivir: How supplied

Dosage

Recommended Dosage in Adult Patients 

The recommended dosage in adults is a single loading dose of remdesivir 200 mg on Day 1 followed by once-daily maintenance doses of remdesivir 100 mg from Day 2 via IV infusion. 

Recommended Dosage in Pediatric Patients*

For pediatric patients weighing 3.5 kg to less than 40 kg, use remdesivir for injection, 100 mg, lyophilized powder only

 

 

Administration

Storage

• Lyophilized Powder : Store remdesivir for injection, 100 mg, vials below 30°C until required for use.
• Reconstituted solution : After reconstitution, vials can be stored up to 4 hours at room temperature (20°C to 25°C [68°F to 77°F]) prior to administration or 24 hours at refrigerated temperature (2°C to 8°C [36°F to 46°F]).
• Diluted Infusion Solution : Store diluted remdesivir solution for infusion up to 4 hours at room temperature (20°C to 25°C [68°F to 77°F]) or 24 hours at refrigerated temperature (2°C to 8°C [36°F to 46°F]).

Warnings and Precautions

• Increased Risk of Transaminase Elevations 
• Transaminase elevations have also been reported in patients with COVID-19 who received remdesivir in clinical trials. 
• As transaminase elevations have been reported as a component of COVID-19, including in patients receiving placebo in clinical trials of remdesivir, discerning the contribution of remdesivir to transaminase elevations in this patient population is challenging.
• Hepatic laboratory testing should be performed in all patients prior to starting remdesivir and daily while receiving remdesivir. 
• Remdesivir should not be initiated in patients with ALT greater than or equal to 5 times the upper limit of normal at baseline. 
• Remdesivir should be discontinued in patients who develop: 
           - ALT greater than or equal to 5 times the upper limit of normal during treatment with remdesivir. Remdesivir may be restarted when ALT is less             than 5 times the upper limit of normal. OR
           - ALT elevation accompanied by signs or symptoms of liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or INR. 
• Risk of Reduced Antiviral Activity When Coadministered with Chloroquine or Hydroxychloroquine
• Coadministration of remdesivir and chloroquine phosphate or hydroxychloroquine sulfate is not recommended based on in vitro data demonstrating an antagonistic effect of chloroquine on the intracellular metabolic activation and antiviral activity of remdesivir

Drug Interactions

• In vitro, remdesivir is a substrate for drug metabolizing enzymes CYP2C8, CYP2D6, and CYP3A4, and is a substrate for Organic Anion Transporting Polypeptides 1B1 (OATP1B1) and P-glycoprotein (P-gp) transporters. In vitro, remdesivir is an inhibitor of CYP3A4, OATP1B1, OATP1B3, BSEP, MRP4, and NTCP. The clinical relevance of these in vitro assessments has not been established.

Summary

• Remdesivir: EUA by US FDA for the treatment of suspected or laboratory confirmed coronavirus disease 2019 (COVID-19) in adults and children hospitalized with severe disease
• Patients on remdesivir recovered 30 % faster as compared to placebo, with a trend towards survival benefit
• 5 days’ treatment is adequate for subgroups shown so far to respond to remdesivir
• Pending further trial results in critical illness, 10 days if mechanical ventilation, ECMO
• Overall, well tolerated