Pfizer Initiates Phase 2/3 Study of Novel COVID-19 Oral Treatment in Pediatric Participants

• PAXLOVID™ (nirmatrelvir [PF-07321332] tablets and ritonavir tablets) is the first oral therapy specifically designed to combat COVID-19 to be evaluated in a pediatric clinical study
• PAXLOVID is currently authorized under U.S. Food and Drug Administration (FDA) Emergency Use Authorization (EUA) in both high-risk adult and high-risk pediatric patients 12 years of age and older weighing at least 40 kg
• Clinical data from the EPIC-HR study showed PAXLOVID reduced risk of hospitalization or death from any cause by 89% (within three days of symptom onset) and 88% (within five days of symptom onset) 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.

NEW YORK–(BUSINESS WIRE)–Pfizer Inc. (NYSE: PFE) announced today that it has initiated a Phase 2/3 study, EPIC-PEDS (Evaluation of Protease Inhibition for COVID-19 in Pediatric Patients), to evaluate the safety, pharmacokinetics, and efficacy of Pfizer’s PAXLOVID™ (nirmatrelvir [PF-07321332] tablets and ritonavir tablets) in non-hospitalized, symptomatic, pediatric 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 pediatric 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 pediatric 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 pediatric patients. Although other PAXLOVID clinical trials did not include participants under the age of 18, the FDA authorized PAXLOVID for emergency use in pediatric patients 12 years of age and older weighing at least 40 kg [88lbs] as pharmacokinetic-pharmacodynamic (PK/PD) modeling 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.

Please see Full Emergency Use Authorization (EUA) Prescribing Information available at www.fda.gov and www.COVID19oralRx.com.

Our Commitment to Equitable Access

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.

About PAXLOVID™ (nirmatrelvir [PF-07321332] tablets and ritonavir tablets)

PAXLOVID is a SARS-CoV-2 main protease (M^pro) 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 M^pro, 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 M^pro 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.

About the EPIC Development Program

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 U.S. 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 Medicine on 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.

For more information on the EPIC Phase 2/3 clinical trials for PAXLOVID, visit clinicaltrials.gov.

About the EPIC-HR Final Results

In the final analysis of the primary endpoint from all patients enrolled in EPIC-HR, an 89% reduction in COVID-19-related hospitalization or death from any cause compared to placebo in patients treated within three days of symptom onset was observed, consistent with the interim analysis. In addition, a consistent safety profile was observed.

0.7% of patients who received PAXLOVID were hospitalized through Day 28 following randomization (5/697 hospitalized with no deaths), compared to 6.5% of patients who received placebo and were hospitalized or died (44/682 hospitalized with 9 subsequent deaths). The statistical significance of these results was high (p<0.0001). In a secondary endpoint, PAXLOVID reduced the risk of hospitalization or death from any cause by 88% compared to placebo in patients treated within five days of symptom onset; 0.8% of patients who received PAXLOVID were hospitalized or died through Day 28 following randomization (8/1039 hospitalized with no deaths), compared to 6.3% of patients who received placebo (66/1046 hospitalized with 12 subsequent deaths), with high statistical significance (p<0.0001). In the overall study population through Day 34, no deaths were reported in patients who received PAXLOVID as compared to 13 deaths in patients who received placebo.

In the EPIC-HR trial, in a secondary endpoint, SARS-CoV-2 viral load at baseline and Day 5 have been evaluated for 1574 patients. After accounting for baseline viral load, geographic region, and serology status, PAXLOVID reduced viral load by approximately 10-fold relative to placebo when treatment was initiated within three days of symptom onset, indicating robust activity against SARS-CoV-2 and representing the strongest viral load reduction reported to date for an oral COVID-19 agent.

Treatment-emergent adverse events were comparable between PAXLOVID (23%) and placebo (24%), most of which were mild in intensity. Fewer serious adverse events (1.6% vs. 6.6%) and discontinuation of study drug due to adverse events (2.1% vs. 4.2%) were observed in patients dosed with PAXLOVID, compared to placebo, respectively.

All other secondary endpoints for this study, which are available on clinicaltrials.gov (NCT04960202) and EudraCT (2021-002895-38), were not yet available for this review.

U.S. FDA Emergency Use Authorization Statement

PAXLOVID has not been approved, but has been authorized for emergency use by FDA under an EUA, for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct SARS CoV-2 viral testing, and who are at high-risk for progression to severe COVID-19, including hospitalization or death.

The emergency use of PAXLOVID is only authorized for the duration of the declaration that circumstances exist justifying the authorization of the emergency use of drugs and biological products during the COVID-19 pandemic under Section 564(b)(1) of the Act, 21 U.S.C. § 360bbb-3(b)(1), unless the declaration is terminated or authorization revoked sooner.

AUTHORIZED USE

The U.S. Food and Drug Administration (FDA) has issued an Emergency Use Authorization (EUA) for the emergency use of the unapproved product PAXLOVID for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death.

LIMITATIONS OF AUTHORIZED USE

• PAXLOVID is not authorized for initiation of treatment in patients requiring hospitalization due to severe or critical COVID-19
• PAXLOVID is not authorized for use as pre-exposure or post-exposure prophylaxis for prevention of COVID-19
• PAXLOVID is not authorized for use for longer than 5 consecutive days

PAXLOVID may only be prescribed for an individual patient by physicians, advanced practice registered nurses, and physician assistants that are licensed or authorized under state law to prescribe drugs in the therapeutic class to which PAXLOVID belongs (i.e., anti-infectives).

PAXLOVID is not approved for any use, including for use for the treatment of COVID-19.

PAXLOVID is authorized only for the duration of the declaration that circumstances exist justifying the authorization of the emergency use of PAXLOVID under 564(b)(1) of the Food Drug and Cosmetic Act unless the authorization is terminated or revoked sooner.

IMPORTANT SAFETY INFORMATION

PAXLOVID is contraindicated in patients with a history of clinically significant hypersensitivity reactions (eg, toxic epidermal necrolysis [TEN] or Stevens-Johnson syndrome) to its active ingredients (nirmatrelvir or ritonavir) or any other components of the product.

PAXLOVID is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious and/or life-threatening reactions:

• Alpha₁-adrenoreceptor antagonist: alfuzosin
• Analgesics: pethidine, propoxyphene
• Antianginal: ranolazine
• Antiarrhythmic: amiodarone, dronedarone, flecainide, propafenone, quinidine
• Anti-gout: colchicine
• Antipsychotics: lurasidone, pimozide, clozapine
• Ergot derivatives: dihydroergotamine, ergotamine, methylergonovine
• HMG-CoA reductase inhibitors: lovastatin, simvastatin
• PDE5 inhibitor: sildenafil (Revatio^®) when used for pulmonary arterial hypertension
• Sedative/hypnotics: triazolam, oral midazolam

PAXLOVID is contraindicated with drugs that are potent CYP3A inducers where significantly reduced nirmatrelvir or ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance. PAXLOVID cannot be started immediately after discontinuation of any of the following medications due to the delayed offset of the recently discontinued CYP3A inducer:

• Anticancer drugs: apalutamide
• Anticonvulsant: carbamazepine, phenobarbital, phenytoin
• Antimycobacterials: rifampin
• Herbal Products: St. John’s Wort (hypericum perforatum)

There are limited clinical data available for PAXLOVID. Serious and unexpected adverse events may occur that have not been previously reported with PAXLOVID use.

Risk of Serious Adverse Reactions Due to Drug Interactions: Initiation of PAXLOVID, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving PAXLOVID, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of PAXLOVID, respectively. These interactions may lead to:

• Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications
• Clinically significant adverse reactions from greater exposures of PAXLOVID
• Loss of therapeutic effect of PAXLOVID and possible development of viral resistance

Consult Table 1 of the Fact Sheet for Healthcare Providers for clinically significant drug interactions, including contraindicated drugs. Consider the potential for drug interactions prior to and during PAXLOVID therapy; review concomitant medications during PAXLOVID therapy and monitor for the adverse reactions associated with the concomitant medications.

Hypersensitivity reactions have been reported with PAXLOVID including urticaria, angioedema, dyspnea, mild skin eruptions, and pruritus. Cases of anaphylaxis, TEN, and Stevens-Johnson syndrome have also been reported with components of PAXLOVID (refer to NORVIR labeling). If signs and symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue PAXLOVID and initiate appropriate medications and/or supportive care.

Hepatotoxicity: Hepatic transaminase elevations, clinical hepatitis, and jaundice have occurred in patients receiving ritonavir. Therefore, caution should be exercised when administering PAXLOVID to patients with pre-existing liver diseases, liver enzyme abnormalities, or hepatitis.

Because nirmatrelvir is co-administered with ritonavir, there may be a risk of HIV-1 developing resistance to HIV protease inhibitors in individuals with uncontrolled or undiagnosed HIV-1 infection.

Adverse events in the PAXLOVID group (≥1%) that occurred at a greater frequency (≥5 subject difference) than in the placebo group were dysgeusia (6% and <1%, respectively), diarrhea (3% and 2%), hypertension (1% and <1%), and myalgia (1% and <1%). The proportions of subjects who discontinued treatment due to an adverse event were 2% in the PAXLOVID group and 4% in the placebo group.

The following adverse reactions have been identified during post-authorization use of PAXLOVID. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders: Hypersensitivity reactions

Required Reporting for Serious Adverse Events and Medication Errors: The prescribing healthcare provider and/or the provider’s designee is/are responsible for mandatory reporting of all serious adverse events and medication errors potentially related to PAXLOVID within 7 calendar days from the healthcare provider’s awareness of the event.

Submit adverse event and medication error reports to FDA MedWatch using one of the following methods:

• Online: https://www.fda.gov/medwatch/report.htm
• Complete and submit a postage-paid FDA Form 3500 and returning by mail/fax
• Call 1-800-FDA-1088 to request a reporting form

In addition, please provide a copy of all FDA MedWatch forms to: http://www.pfizersafetyreporting.com/ or by fax (1-866-635-8337) or phone (1-800-438-1985).

PAXLOVID is an inhibitor of CYP3A and may increase plasma concentrations of drugs that are primarily metabolized by CYP3A. Co-administration of PAXLOVID with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring.

Nirmatrelvir and ritonavir are CYP3A substrates; therefore, drugs that induce CYP3A may decrease nirmatrelvir and ritonavir plasma concentrations and reduce PAXLOVID therapeutic effect.

Pregnancy: There are no available human data on the use of nirmatrelvir during pregnancy to evaluate for a drug‑associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Published observational studies on ritonavir use in pregnant women have not identified an increase in the risk of major birth defects. Published studies with ritonavir are insufficient to identify a drug‑associated risk of miscarriage. There are maternal and fetal risks associated with untreated COVID-19 in pregnancy.

Lactation: There are no available data on the presence of nirmatrelvir in human or animal milk, the effects on the breastfed infant, or the effects on milk production. A transient decrease in body weight was observed in the nursing offspring of rats administered nirmatrelvir. Limited published data reports that ritonavir is present in human milk. There is no information on the effects of ritonavir on the breastfed infant or the effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for PAXLOVID and any potential adverse effects on the breastfed infant from PAXLOVID or from the underlying maternal condition. Breastfeeding individuals with COVID‑19 should follow practices according to clinical guidelines to avoid exposing the infant to COVID‑19.

Contraception: Use of ritonavir may reduce the efficacy of combined hormonal contraceptives. Advise patients using combined hormonal contraceptives to use an effective alternative contraceptive method or an additional barrier method of contraception.

Pediatrics: PAXLOVID is not authorized for use in pediatric patients younger than 12 years of age or weighing less than 40 kg. The safety and effectiveness of PAXLOVID have not been established in pediatric patients. The authorized adult dosing regimen is expected to result in comparable serum exposures of nirmatrelvir and ritonavir in patients 12 years of age and older and weighing at least 40 kg as observed in adults, and adults with similar body weight were included in the trial EPIC-HR.

Systemic exposure of nirmatrelvir increases in renally impaired patients with increase in the severity of renal impairment. No dosage adjustment is needed in patients with mild renal impairment. In patients with moderate renal impairment (eGFR ≥30 to <60 mL/min), reduce the dose of PAXLOVID to 150 mg nirmatrelvir and 100 mg ritonavir twice daily for 5 days. Prescriptions should specify the numeric dose of each active ingredient within PAXLOVID. Providers should counsel patients about renal dosing instructions. PAXLOVID is not recommended in patients with severe re

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