COVID-19 Pills – A Long Awaited Ally for Out-Patient Therapeutics

While vaccines are the best defense to reduce severity of illness and thereby hospitalizations, the oral agents against coronavirus disease 2019 (COVID-19) that recently received emergency use authorization (EUA) from the Unites States Food and Drug Administration (U.S. FDA), block the replication of severe acute respiratory syndrome coronavirus – 2 (SARS CoV-2) when administered early in clinical course i.e., <5 days of symptom onset. These agents include nirmatrelvir-ritonavir (Paxlovid, Pfizer) and molnupiravir (Lagevrio, Merck), that received EUA on December 22 and December 23, 2021.^1–3

Nirmatrelvir is a SARS-CoV-2 main protease (Mpro) inhibitor that inhibits the early phase of viral replication. It is reportedly (Pfizer internal data – published online in ref 5) active against all clinically significant SARS CoV-2 variants including the Omicron.^4–6 The approved formulation is in combination with ritonavir, an HIV protease inhibitor which has no effect on SARS CoV-2, but increases plasma nirmatrelvir levels above the maximum effective concentration 90%, by inhibiting hepatic enzyme CYP3A.⁵ The EUA is based on an interim analysis of the evaluation of protease inhibition for COVID-19 –high-risk (EPIC-HR) phase II/III randomized double-blind and placebo controlled clinical trial (N=1219 at interim analysis) demonstrating an 89% [Paxlovid arm 5/697 (0.8%) vs placebo arm 44/682 (6.4%), p< 0.0001] and 85% [Paxlovid 6/607 (1%) vs placebo 41/612 (6.7%), p< 0.0001] relative risk reduction for hospitalization or death at 4 weeks in unvaccinated, symptomatic (at least one symptom of mild COVID-19), test positive (antigen or PCR) and non-hospitalized adult patients with a risk factor for severe disease, when administered ≤ 3 days and ≤ 5 days of symptom onset, respectively. There was a 10-fold reduction in viral load by day 5, claimed to be the strongest viral load reduction to-date for an oral pill. Reported adverse effects include dysgeusia, diarrhea, hypertension, and myalgia. The EUA is approved for adults (≥18 years of age) and the recommended dose is nirmatrelvir 300 mg (two 150 mg tablets) + ritonavir 100 mg (1 tablet), both co-packaged together. This same dose is EUA approved for pediatric age >12 years provided their weight is >40 kg, assuming to result in efficacious serum levels akin to adults. While dose reduction to nirmatrelvir 150 mg (1 tablet) + ritonavir 100 mg (1 tablet) is recommended for moderate renal impairment (eGFR ≥ 30 to <60 mL/min), use is not recommended for severe renal (eGFR <30 mL/min) or severe liver failure (Child-Pugh Class C). The recommended duration of treatment is only 5 days, but within this period serious drug-drug interactions related to CYP3A inhibition by ritonavir is possible in patients already taking other drugs that are metabolized by or inhibit CYP3A. Similarly, drugs that induce CYP3A may void Paxlovid’s efficacy.¹ Pfizer’s EPIC-HR trial is continuing to target recruitment of 3000, along with on-going enrollment for clinical trials in patients with standard risk (EPIC-SR, for unvaccinated with no risk factors or vaccinated with risk factors, available at https://clinicaltrials.gov/ct2/show/NCT05011513) and for post-exposure prophylaxis (EPIC-PEP for household contacts of COVID-19 patients, available at https://clinicaltrials.gov/ct2/show/NCT05047601).

Molnupiravir is a nucleoside analog that induces lethal mutations via RNA dependent RNA polymerase during viral replication and is also active against all SARS CoV-2 variants of clinical significance.^6–8 The EUA was based on the efficacy and safety report of the MOVe-OUT randomized double-blind and placebo controlled phase III clinical trial in unvaccinated adult outpatients with test confirmed and symptomatic mild to moderate COVID-19. ^3,9 In this trial, molnupiravir arm had 31% lower hospitalization or death by day 29 than the placebo group [48/709 (6.8%) vs 68/699 (9.7%)], whereas a risk of death alone was lower by 89% (95% CI, 14 – 99) in the molnupiravir arm (0.1% vs 1.3%). The recommended dose is 800 mg (4 capsules of 200 mg each) twice daily for 5 days. No dose adjustments are necessary for renal or liver dysfunction or failure. Use is not recommended in pregnancy because of animal data showing fetal harm. Similarly, the EUA has excluded lactating mothers and pediatric age <18 years because of possible bone or cartilage affection. Adverse effects include diarrhea, nausea, and dizziness. There were no concerns for drug interactions or potential other contra-indications in non-pregnant adults. ¹⁰ As it causes mutations, scientists and the U.S. FDA have disputing concerns regarding its potential to create a variant of concern in the future with its use. The Centers for Disease Control and Prevention (CDC) has recommended to use molnupiravir, only if other options are unavailable because of reduced efficacy.¹¹

With Omicron surging across the U.S., the widely used monoclonal antibodies (bamlanivumab-etesevimab and casirvimab-imdevimab) have become less efficacious in preventing hospitalizations. These two drugs, offer the advantage of convenient oral administration at home and have mechanisms of action that are independent of spike protein variability (i.e., pan-genotypic anti-viral activity) offering hope for those vaccinated individuals with breakthrough mild-moderate COVID-19 and have high-risk factors for severe disease, the immunocompromised hosts who have not mounted or not sustained an immune response to the vaccine and most importantly, to those yet to be (or choose not to be) vaccinated individuals with symptomatic mild-moderate COVID-19 with high-risk factors for severe COVID-19. In this last category, it is still important to recommend vaccination by educating that full vaccination offers the best preventive measure than treatment. Testing to confirm COVID-19 is equally important to be done soon after symptom onset, in order to benefit from early institution of treatment within 5 days of symptom onset, as recommended by the EUA. The national institutes of health (NIH) treatment guidelines for COVID-19 (https://www.covid19treatmentguidelines.nih.gov/therapies/statement-on-therapies-for-high-risk-nonhospitalized-patients/) and the infectious diseases society of America’s (IDSA) COVID-19 treatment guidelines (https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/) are constantly updated as clinical trials are published, to guide health care providers. Production, distribution and supply chain issues are expected to improve in the following months according to the CDC, offering a hopeful glimpse into a better and healthier 2022.¹¹ Just like any other new drug embarking on wide-spread use, only time will reveal their true and long-term impact on this resurgent pandemic.