Conditional approval of remdesivir (Veklury®) for COVID-19 infection in Singapore
On 10 June 2020, HSA granted a conditional approval for remdesivir (Veklury®, Gilead Sciences Singapore Pte Ltd) for the treatment of COVID-19 patients in Singapore. The data on the efficacy and safety of remdesivir submitted for registration to HSA was limited. However, given the urgent public health need during the COVID-19 pandemic, HSA expedited the review for remdesivir and has required data from ongoing manufacturing and clinical studies to be submitted by the company post-approval to ensure the continued efficacy and safety of the product.
Indication of remdesivir (Veklury®) with the conditional approval
Remdesivir (Veklury®) is indicated for the treatment of COVID-19 infection caused by SARS-CoV-2 in adult patients with oxygen saturation of ≤ 94% (room air), or those requiring oxygen inhalation, under invasive mechanical ventilation (IMV), or under extracorporeal membrane oxygenation (ECMO). The approved treatment regimen is 200 mg IV injection on Day 1 of treatment, followed by 100 mg IV injection once daily from Day 2 up to Day 10. The optimal duration of treatment of remdesivir has not been established. As a guide, the total duration of treatment is up to ten days in patients under IMV or ECMO, up to five days in patients who are not under IMV or ECMO, and up to ten days if these patients do not improve. As no studies in children and pregnant women were presented to HSA, no recommendation for use were made in these special populations.
HSA’s scientific considerations for efficacy and safety of remdesivir (Veklury®) in COVID-19 patients
The conditional approval of remdesivir (Veklury®) was based on preliminary clinical data from two Phase 3 trials, i.e. the U.S. National Institute of Allergy and Infectious Diseases’ Adaptive COVID-19 Treatment Trial (NIAID-ACTT1)1 and Gilead’s SIMPLE-severe trial, 2 and an abbreviated manufacturing data set. Singapore had participated in both clinical trials and had enrolled around 100 patients.
The efficacy of remdesivir was based primarily on the results from the NIAID-ACTT1 trial which showed a faster time to recovery compared to placebo (11 days vs. 15 days), and a higher recovery rate of 32% (Rate ratio: 1.32, 95% CI: 1.12–1.55, p<0.001). The results did not show a statistically significant survival benefit, although the death rate was numerically lower with remdesivir treatment compared to placebo (5.9% vs. 10.4%, Hazards ratio (HR): 0.70, 95% CI: 0.47–1.04, p=0.059).
The observed favourable results were driven primarily by the higher recovery rate in patients who had oxygen saturation of ≤ 94% (room air) and required oxygen supplementation. In patients with very severe disease such as those who required IMV or ECMO, there was no significant difference between remdesivir and placebo. Nonetheless, preliminary results from the SIMPLE-severe trial suggested that patients who progressed to requiring IMV or ECMO may have a lower death rate with a 10-day course of remdesivir compared to a 5-day course (17% vs. 40%). This observation was inconclusive as it was based on an exploratory analysis in a very small number of patients and was not statistically powered.
In the absence of adequate data in this subgroup of severely ill patients who required IMV or ECMO, the appropriate use of remdesivir must be carefully assessed and considered only when the benefit clearly outweighs the risk.
The safety analysis comprised data from more than 1,000 patients who had received at least one dose of remdesivir. The clinical studies1,2 excluded patients with elevated liver enzymes or impaired renal functions at baseline, as measured by aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels > 5 times upper limit of normal, estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 or serum creatinine clearance < 50 ml/min. The adverse events (AEs) of clinical interest reported with remdesivir included liver enzyme elevation, renal-related AEs (acute kidney injury, increased serum creatinine, decreased glomerular filtration), infusion-related reactions (hypotension, nausea, vomiting), respiratory failure, prothrombin time prolongation, and thrombocytopenia.
Given the limited experience with remdesivir, healthcare professionals should consider appropriate clinical and laboratory monitoring, which includes liver, renal and blood tests to allow early detection of any abnormalities or potential AEs.
Restrictions on the use of remdesivir (Veklury®)
Taking into consideration the limited data on its efficacy and safety, the use of remdesivir has been restricted to Infectious Diseases (ID) physicians. Notwithstanding the approved indications for remdesivir, healthcare professionals should refer to the interim treatment guideline for remdesivir published by the National Centre for Infectious Disease (NCID) for clinical recommendations on the use of remdesivir.3
A Dear Healthcare Professional Letter (DHCPL) was issued to ID physicians on 10 June 2020. Healthcare professionals may access the DHCPL by using their professional log in access to MOH Alert via their respective healthcare professional board or councils’ websites.
HSA will continue to evaluate the situation, monitor the benefit-risk profile of remdesivir and provide updates to healthcare professionals as necessary. Healthcare professionals are required to report any suspected serious adverse events observed with the use of remdesivir to the Vigilance and Compliance Branch. Your reports are important to help us better understand the benefit-risk profile of remdesivir and will contribute significantly to patient safety.
- Beigel JH, Tomashek KM, Dodd LE, et al., (2020) Remdesivir for the treatment of COVID-19 – Preliminary Report. N Engl J Med May 22, 2020
- Goldman JD, David C.B. Lye, David S. Hui, et al., (2020) Remdesivir for 5 or 10 days in Patients with Severe COVID-19. N Engl J Med May 27, 2020
- NCID Interim Treatment Guidelines for COVID-19 (Version 3.0, dated 6 July 2020). https://www.ncid.sg/Health-Professionals/Diseases-and-Conditions/Pages/COVID-19.aspx