Pfizer Inc. announced that it has initiated a phase 2/3 study, EPIC-PEDS (Evaluation of ProteaseInhibition for COVID-19 in Paediatric Patients), to evaluate the safety, pharmacokinetics, and efficacy of Pfizer’s Paxlovid (nirmatrelvir [PF-07321332] tablets and ritonavir tablets) in non-hospitalized, symptomatic, paediatric participants with a confirmed diagnosis of Covid-19 who are at risk of progression to severe disease.
“Since the beginning of the pandemic, more than 11 million children under the age of 18 in the United States alone have tested positive for Covid-19, representing nearly 18% of reported cases and leading to more than 100,000 hospital admissions. There is a significant unmet need for outpatient treatments that can be taken by children and adolescents to help prevent progression to severe illness, including hospitalization or death,” said Mikael Dolsten, chief scientific officer and president, worldwide research, development and medical, Pfizer. “Paxlovid is already authorized or approved in many countries around the world, with more than 1.5 million treatment courses delivered thus far and 30 million expected by July to help combat this devastating disease. We are proud to expand studies of our novel Covid-19 treatment to include paediatric participants to further evaluate the safety and efficacy of this treatment in this important population.”
The phase 2/3 trial is an open-label, multi-center, single-arm study in approximately 140 paediatric participants under 18 years of age. Initial enrollment features two cohorts; Cohort 1 includes participants aged 6 to 17 weighing at least 40 kg [88 lbs], and Cohort 2 includes those aged 6 to 17 weighing more than 20 kg [44 lbs] and less than 40 kg [88 lbs].
Participants enrolled in Cohort 1 will receive Paxlovid (nirmatrelvir/ritonavir 300 mg/100 mg) orally twice daily for five days (10 doses total), the current authorized dosing for pediatric patients 12 years of age and older weighing at least 40kg.
Participants enrolled in Cohort 2 will receive Paxlovid (nirmatrelvir/ritonavir 150 mg/100 mg) orally twice daily for five days (10 doses total).
Pfizer is also working to develop an age-appropriate formulation for three additional planned cohorts of younger than 6 years old and will enroll the trial to include these younger age groups as data from Cohorts 1 and 2 and the new formulation are available.
An independent Data Monitoring Committee (DMC) will review safety data of participants in each cohort.
Data from the phase 2/3 study of non-hospitalized, high-risk adults with Covid-19 showed Paxlovid reduced risk of hospitalization or death by 89% (within three days of symptom onset) and 88% (within five days of symptom onset) from any cause compared to placebo, with no deaths observed in the treatment group. Treatment-emergent adverse events were comparable between Paxlovid (23%) and placebo (24%), most of which were mild in intensity.
The safety and effectiveness of Paxlovid have not yet been directly established in paediatric patients. Although other Paxlovid clinical trials did not include participants under the age of 18, the FDA authorized Paxlovid for emergency use in paediatric patients 12 years of age and older weighing at least 40 kg [88lbs] as pharmacokinetic-pharmacodynamic (PK/PD) modelling determined that the authorized adult dosing regimen would result in comparable blood concentration levels of Paxlovid in this population and the adults with similar body weight who were included in the EPIC-HR trial. Data from the EPIC-PEDS study will provide further support for the dose recommendations in this population, as well as potentially expand the indication to younger age groups and lower weights.
Paxlovid is currently authorized or approved in more than 50 countries across the globe.
Pfizer is committed to working toward equitable access to Paxlovid for all people, aiming to deliver safe and effective antiviral therapeutics as soon as possible and at an affordable price. During the pandemic, Pfizer will offer its oral therapy through a tiered pricing approach, pending country authorization or approval, based on the income level of each country to promote equity of access across the globe. High and upper-middle income countries will pay more than lower income countries.
Pfizer continues to invest to support the manufacturing and distribution of Paxlovid, including exploring potential contract manufacturing options. As a result of these efforts, Pfizer has raised its production projections, with the ability to produce up to 120 million courses of treatment by the end of 2022, pending global demand.
The company has initiated bilateral outreach to more than 100 countries around the world and has entered into agreements with multiple countries. Additionally, Pfizer has signed a voluntary license agreement with the Medicines Patent Pool (MPP) for its oral treatment to help expand access, pending country regulatory authorization or approval, in 95 low- and middle-income countries that account for approximately 53% of the world’s population.
Paxlovid is a SARS-CoV-2 main protease (Mpro) inhibitor (also known as SARS-CoV-2 3CL protease inhibitor) therapy. It was developed to be administered orally so that it can be prescribed at the first sign of infection or, pending clinical success of the rest of the EPIC development program and subject to regulatory authorization, at first awareness of an exposure – potentially helping patients avoid severe illness (which can lead to hospitalization and death) or avoid disease development following contact with a household member who contracts Covid-19. Nirmatrelvir [PF-07321332], which originated in Pfizer laboratories, is designed to block the activity of the Mpro, an enzyme that the coronavirus needs to replicate. Co-administration with a low dose of ritonavir helps slow the metabolism, or breakdown, of nirmatrelvir in order for it to remain active in the body for longer periods of time at higher concentrations to help combat the virus.
Nirmatrelvir is designed to inhibit viral replication at a stage known as proteolysis, which occurs before viral RNA replication. In preclinical studies, nirmatrelvir did not demonstrate evidence of mutagenic DNA interactions.
Current variants of concern can be resistant to treatments that work by binding to the spike protein found on the surface of the SARS-CoV-2 virus. Paxlovid, however, works intracellularly by binding to the highly conserved Mpro of the SARS-CoV-2 virus to inhibit viral replication. Nirmatrelvir has shown consistent in vitro antiviral activity against earlier and current variants of concern (i.e., Alpha, Beta, Delta, Gamma, Lambda, Mu, and Omicron).
Paxlovid is generally administered at a dose of 300 mg (two 150 mg tablets) of nirmatrelvir with one 100 mg tablet of ritonavir, given twice-daily for five days. One carton contains five blister packs of PAXLOVID, as co-packaged nirmatrelvir tablets with ritonavir tablets, providing all required doses for a full five-day treatment course.
The EPIC (Evaluation of Protease Inhibition for Covid-19) phase 2/3 development program for Paxlovid consists of four clinical trials spanning a broad spectrum of participants, including adults who have been exposed to the virus through household contacts, adults at both standard risk and high risk of progressing to severe illness, and children under the age of 18 at risk of progressing to severe disease.
In July 2021, Pfizer initiated the first of these trials, known as EPIC-HR (Evaluation of Protease Inhibition for Covid-19 in High-Risk Patients), a randomized, double-blind study of non-hospitalized adults with Covid-19, who are at high risk of progressing to severe illness. At the recommendation of an independent Data Monitoring Committee and in consultation with the US FDA, Pfizer ceased further enrollment into the study in early November 2021 due to the overwhelming efficacy demonstrated in these results. Findings from the EPIC-HR final analysis were published online in The New England Journal of Medicineon February 16, 2022.
In August 2021, Pfizer began the phase 2/3 EPIC-SR (Evaluation of Protease Inhibition for Covid-19 in Standard-Risk Patients) study to evaluate efficacy and safety in adults with a confirmed diagnosis of SARS-CoV-2 infection who are at standard risk (i.e., low risk of hospitalization or death). Interim data from this study have been reported. Pfizer is currently expanding the population of the ongoing EPIC-SR study by approximately 800 participants and expects to share results later this year.
In September 2021, Pfizer initiated the phase 2/3 EPIC-PEP (Evaluation of Protease Inhibition for Covid-19 in Post-Exposure Prophylaxis) study to evaluate efficacy and safety in adults exposed to SARS-CoV-2 by a household member. This trial is also ongoing, and Pfizer expects to share results later this year.