- CHMP recommends PAXLOVID™ (nirmatrelvir [PF-07321332] tablets
and ritonavir tablets) for use in adults with COVID-19
- If authorized, PAXLOVID will be the first COVID-19 oral
treatment recommended in the EU
- European Commission decision on conditional marketing
authorization expected imminently
Pfizer Inc. (NYSE: PFE) announced today that the Committee for
Medicinal Products for Human Use (CHMP) of the European Medicines
Agency (EMA) issued a positive opinion recommending the conditional
marketing authorization (CMA) of Pfizer’s PAXLOVID™ (nirmatrelvir
[PF-07321332] tablets and ritonavir tablets) for the treatment of
COVID-19 in adults who do not require supplemental oxygen and who
are at increased risk for progressing to severe COVID-19.
“This expression of confidence in PAXLOVID comes at a critical
moment as Europe addresses the ongoing challenges of the pandemic
and as infection rates are on the rise in many countries across the
globe,” said Albert Bourla, Chairman and Chief Executive Officer,
Pfizer. “We are proud to have a strong manufacturing footprint in
Europe, which will help support the production of up to 120 million
courses of PAXLOVID globally. Pending conditional marketing
authorization from the European Commission, we will continue
working closely with EU Member State governments to ensure this
important treatment can be made available to patients across Europe
as quickly as possible.”
The CHMP based its positive opinion on the scientific evidence
supporting PAXLOVID, including data from the Phase 2/3 EPIC-HR
(Evaluation of Protease
Inhibition for COVID-19 in High-Risk
Patients) trial, which enrolled non-hospitalized adults aged 18 and
older with confirmed COVID-19 who are at increased risk of
progressing to severe illness. The data showed that PAXLOVID
reduced the risk of hospitalization or death 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. The data have been submitted to a peer-reviewed
publication. Additional Phase 2/3 clinical trials are ongoing in
adults at standard risk (i.e., low risk of hospitalization or
death) of progressing to severe illness, and in those who have been
exposed to the virus through household contacts.
PAXLOVID is currently approved or authorized for emergency use
in more than 10 countries across the globe. In December, the CHMP
issued advice under Article 5(3) of Regulation 726/2004 to support
authorities of European Union (EU) Member States regarding the
potential supply and use of PAXLOVID prior to EU conditional
marketing authorization.
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 potential ability to
produce up to 120 million courses of treatment by the end of
2022.
The company has entered into agreements with multiple countries
and has initiated bilateral outreach to more than 100 countries
around the world. 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 (Mpro) inhibitor (also
known as SARS-CoV2 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 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 three clinical trials spanning a broad
spectrum of patients, including adults who have been exposed to the
virus through household contacts, as well as adults at both
standard risk and high risk of progressing to severe illness.
In July 2021, Pfizer initiated the first of these trials, known
as EPIC-HR, 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 have been submitted to a peer-reviewed
journal for publication.
In August 2021, Pfizer began the Phase 2/3 EPIC-SR
(Evaluation of Protease Inhibition for COVID-19 in Standard-Risk Patients), 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). EPIC-SR includes a cohort of vaccinated adults who have an
acute breakthrough symptomatic COVID-19 infection and who have risk
factors for severe illness. Interim data from this study have been
reported. In September, Pfizer initiated the Phase 2/3 EPIC-PEP
(Evaluation of Protease Inhibition for COVID-19 in Post-Exposure Prophylaxis) to evaluate efficacy and safety
in adults exposed to SARS-CoV-2 by a household member. These trials
are ongoing.
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 for 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). Relative risk reduction was 94% in
patients 65 years of age or older, one of the populations at
highest risk for hospitalization or death; 1.1% of patients who
received PAXLOVID were hospitalized through Day 28 (1/94
hospitalized with no deaths), compared to 16.3% of patients who
received placebo (16/98 hospitalized with 6 deaths), with high
statistical significance (p<0.0001). In the overall study
population through Day 28, no deaths were reported in patients who
received PAXLOVID as compared to 12 (1.2%) 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 499 patients.
After accounting for baseline viral load, geographic region, and
serology status, PAXLOVID reduced viral load by approximately
10-fold relative to placebo, 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, piroxicam, 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 agents: 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.
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%), and 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.
Required Reporting for Serious Adverse Events and Medication
Errors: The prescribing healthcare provider and/or the
provider’s designee are/is responsible for mandatory reporting of
all serious adverse events and medication errors potentially
related to PAXLOVID within 7 calendar days from the onset 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:
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 CPY3A 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 renal
impairment (eGFR <30 mL/min based on CKD-EPI formula) until
more data are available; the appropriate dosage for patients with
severe renal impairment has not been determined.
No dosage adjustment of PAXLOVID is needed for patients with
either mild (Child-Pugh Class A) or moderate (Child-Pugh Class B)
hepatic impairment. No pharmacokinetic or safety data are available
regarding the use of nirmatrelvir or ritonavir in subjects with
severe hepatic impairment (Child-Pugh Class C); therefore,
PAXLOVID is not recommended for use in patients with severe
hepatic impairment.
About Pfizer: Breakthroughs That Change Patients’
Lives
At Pfizer, we apply science and our global resources to bring
therapies to people that extend and significantly improve their
lives. We strive to set the standard for quality, safety and value
in the discovery, development and manufacture of health care
products, including innovative medicines and vaccines. Every day,
Pfizer colleagues work across developed and emerging markets to
advance wellness, prevention, treatments and cures that challenge
the most feared diseases of our time. Consistent with our
responsibility as one of the world's premier innovative
biopharmaceutical companies, we collaborate with health care
providers, governments and local communities to support and expand
access to reliable, affordable health care around the world. For
more than 170 years, we have worked to make a difference for all
who rely on us. We routinely post information that may be important
to investors on our website at www.Pfizer.com. In addition, to
learn more, please visit us on www.Pfizer.com and follow us on
Twitter at @Pfizer and @Pfizer News, LinkedIn, YouTube and like us
on Facebook at Facebook.com/Pfizer.
Disclosure Notice
The information contained in this statement is as of January 27,
2022. Pfizer assumes no obligation to update forward-looking
statements contained in this statement as the result of new
information or future events or developments.
This statement contains forward-looking information about
Pfizer’s efforts to combat COVID-19 and PAXLOVID (including a
potential CMA in the EU, qualitative assessments of available data,
potential benefits, expectations for clinical trials, advanced
purchase agreements and an agreement with MPP, efforts toward
equitable access, the anticipated timing of data readouts,
regulatory submissions, regulatory approvals or authorizations,
potential to maintain antiviral activity against variants, planned
investment and anticipated manufacturing, distribution and supply),
involving substantial risks and uncertainties that could cause
actual results to differ materially from those expressed or implied
by such statements. Risks and uncertainties include, among other
things, the uncertainties inherent in research and development,
including the ability to meet anticipated clinical endpoints,
commencement and/or completion dates for clinical trials,
regulatory submission dates, regulatory approval dates and/or
launch dates, as well as risks associated with preclinical and
clinical data, including the possibility of unfavorable new
preclinical, clinical or safety data and further analyses of
existing preclinical, clinical or safety data, including the risk
that final results from EPIC-SR could differ from the interim data;
the ability to produce comparable clinical or other results
including efficacy, safety and tolerability profile observed to
date, in additional studies or in larger, more diverse populations
following commercialization; the ability of PAXLOVID to maintain
efficacy against emerging virus variants; the risk that serious and
unexpected adverse events may occur that have not been previously
reported with PAXLOVID use; the risk that preclinical and clinical
trial data are subject to differing interpretations and
assessments, including during the peer review/publication process,
in the scientific community generally, and by regulatory
authorities; whether regulatory authorities will be satisfied with
the design of and results from these and any future preclinical and
clinical studies; whether and when any drug applications or
submissions to request emergency use or conditional marketing
authorization for any potential indications for PAXLOVID may be
filed in particular jurisdictions and if obtained, whether or when
such emergency use authorization or licenses will expire or
terminate; whether and when regulatory authorities in any
jurisdictions may approve any applications or submissions for
PAXLOVID that may be pending or filed (including the application
for conditional marketing authorization pending in the EU, a
potential new drug application submission in the U.S. and
submissions in other jurisdictions), which will depend on myriad
factors, including making a determination as to whether the
product’s benefits outweigh its known risks and determination of
the product’s efficacy and, if approved, whether it will be
commercially successful; decisions by regulatory authorities
impacting labeling or marketing, manufacturing processes, safety
and/or other matters that could affect the availability or
commercial potential of PAXLOVID, including development of products
or therapies by other companies; risks related to the availability
of raw materials for PAXLOVID; the risk that we may not be able to
create or scale up manufacturing capacity on a timely basis or
maintain access to logistics or supply channels commensurate with
global demand, which would negatively impact our ability to supply
the estimated numbers of courses of PAXLOVID within the projected
time periods; whether and when additional purchase agreements will
be reached; the risk that demand for any products may be reduced or
no longer exist; uncertainties regarding the impact of COVID-19 on
Pfizer’s business, operations and financial results; and
competitive developments.
A further description of risks and uncertainties can be found in
Pfizer’s Annual Report on Form 10-K for the fiscal year ended
December 31, 2020 and in its subsequent reports on Form 10-Q,
including in the sections thereof captioned “Risk Factors” and
“Forward-Looking Information and Factors That May Affect Future
Results”, as well as in its subsequent reports on Form 8-K, all of
which are filed with the U.S. Securities and Exchange Commission
and available at www.sec.gov and www.pfizer.com.
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