Episode 44. Keeping Up With COVID-19: Revisiting Remdesivir with Theora Canonica, Pharm D

Series Title: Keeping Up With COVID-19

Part 2:  Revisiting Remdesivir

1. Situation (Jimmy)
   • .We are over a year into this pandemic and we have only one FDA approved medication for the treatment of COVID-19: Remdesivir.
   • The purpose of this episode is to briefly review the role of Remdesivir in the treatment of COVID with a focus on real-world application in the post-EUA era.
2. Background
   • MOA: remdesivir is a monophosphoramidate nucleoside pro-drug of adenosine analog. It works by inhibiting viral replication by competing with endogenous nucleotides for incorporation into replicating viral RNA via RNA dependent RNA polymerase. Binding promotes premature termination of RNA transcription which halts viral replication.
   • Remdesivir history
     • Originally developed in response to the 2014-2016 Ebola outbreak in West Africa
     • First EUA approval on 5/1/2020 for use in hospitalized patients with severe COVID-19 disease. EUA was later revised on 8/28/2020 to expand use, no longer limited to patients with severe disease
     • FDA approval for treatment of hospitalized patients with ,COVID-19 was granted on 10/22/2020 for adult and pediatric patients (at least 12 years old and weighing at least 40 kg). 
3. Summary of Key Remdesivir Trials
   • ACTT
     • Shorter median time to recover 8 vs 11 days for patient with severe COVID (SpO2 < 94%); failed to show mortality benefit or improvement in time to recovery for mechanically ventilated/ ECMO
   • Wang Y et al. Lancet 2020
     • Remdesivir demonstrated trend towards faster clinical improvement (18 vs 23 days) in patients with severe COVID when initiated within 10 days of symptom onset
   • Spinner CD et al. JAMA 2020
     • Five days of remdesivir demonstrated significant improvement in clinical status on day 11 vs standard of care (SOC). 
     • No difference in clinical status with 10 days of remdesivir vs SOC
   • Goldman JD et al. NEJM 2020
     • Demonstrated similar time to clinical improvement for patients that received a 5 day course of remdesivir compared to those that received 10 days. (10 vs 11 days)
4. IDSA and NIH Guidelines both recommend the use of remdesivir in hospitalized patients
   1. IDSA Guidelines (as of 6/30/21): Suggest use when SpO2 < 94% on room air. 
   2. NIH Guidelines (as of 6/30/21): Suggest use in patients requiring increased supplemental oxygen from baseline including high-flow or non-invasive O2. 
5. Major End Points  (Oscar)
   1. Real world evaluation of Remdesivir use: UF Health Central Florida
      • Medication use evaluation of remdesivir utilization
      • Mostly evaluated patients after EUA expansion and FDA approval (hospitalized, not exclusive to severe disease)
      • Stratified groups for analysis based on SPO2 above or below 94% and supplemental O2 requirements (total of 100 patients)
      • ~80% of participants exceeded 65 years old (median age 73 years old). By definition these patients are at high risk of progressing to severe COVID-19 disease based on advanced age alone.
      • Key findings: Remdesivir didn’t make an impact on clinical improvement by day 5 regardless of SpO2. This study reinforces the IDSA’s stance on advocating against remdesivir use when SpO2 exceeds 94%. However, even when remdesivir was given along with SOC treatment (95% received steroids), 54.2% of patients with an SpO2 < 94% expired and the use of remdesivir did not demonstrate clinical improvement with 5 days of treatment.
   2. Remdesivir use in patients with eGFR < 30 mL/min
      • Per the package insert, is remdesivir is not recommended in patients with eGFR < 30 mL/min 
      • There is PK data to suggest active metabolites may accumulate in the setting of renal impairment. This may be augmented by sulfobutylether-beta-cyclodextrin sodium (SBECD) which is present in the IV formulation and can also accumulate in the setting of renal impairment.
      • There are some data that exists now that suggest a lack of clinically significant SCr elevation/ LFT rising with sort term use (5-10 days) but there are no formal studies.
      • Gilead is currently enrolling for a PK study to assess this 
6. Summary
   1. Remdesivir is the only FDA approved medication for the treatment of COVID-19 infection.
   2. Remdesivir should be considered for use in hospitalized patients, particularly those with SpO2 < 94% on room air or require an increase in supplemental oxygen from baseline 
   3. In real-world practice, 5 days of remdesivir did not appear to make a difference with regards to clinical improvement in patients with advanced age, regardless of SpO2 saturation.
   4. At this time, there is a lack of robust data to support the safe use of remdesivir in patient with an eGFR less than 30 mL/min.

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