- In the EPIC-SR study of PAXLOVID™ (nirmatrelvir [PF-07321332]
tablets and ritonavir tablets), the novel primary endpoint of
self-reported, sustained alleviation of all symptoms for four
consecutive days was not met, as previously reported
- Data from standard-risk patients, both vaccinated and
unvaccinated, while not all statistically significant, are
supportive of efficacy data observed in EPIC-HR study and will be
included in upcoming NDA submission to U.S. FDA for high-risk
patients
- Pre-specified secondary endpoint resulted in a nominally
significant 62% decrease in COVID-19-related medical visits per day
across all patients, relative to placebo
- In a sub-group analysis, non-significant 57% reduction in
hospitalizations and death observed in PAXLOVID-treated vaccinated
patients with at least one risk factor for severe COVID-19
- Pfizer to cease enrollment into the EPIC-SR trial due to low
rate of hospitalization or death in the standard-risk population;
will continue to evaluate treatment in populations with high unmet
need
Pfizer Inc. (NYSE: PFE) today shared data from the Phase 2/3
EPIC-SR (Evaluation of
Protease Inhibition for COVID-19 in Standard-Risk Patients) study evaluating the use of
PAXLOVID™ (nirmatrelvir [PF-07321332] tablets and ritonavir
tablets) in patients who are at standard risk for developing severe
COVID-19. In previously reported interim analyses, the company
disclosed that the novel primary endpoint of self-reported,
sustained alleviation of all symptoms for four consecutive days was
not met, and a non-significant 70% relative risk reduction was
observed in the key secondary endpoint of hospitalization or death
(treatment arm: 3/428; placebo: 10/426). An updated analysis from
1,153 patients enrolled through December 2021 showed a
non-significant 51% relative risk reduction (treatment arm: 5/576;
placebo: 10/569). A sub-group analysis of 721 vaccinated adults
with at least one risk factor for progression to severe COVID-19
showed a non-significant 57% relative risk reduction in
hospitalization or death (treatment arm: 3/361; placebo:
7/360).
Additional analyses of secondary endpoint data showed that
treatment with PAXLOVID resulted in a nominally significant 62%
decrease in COVID-19-related medical visits per day across all
patients, relative to placebo (p=0.0228). Types of medical visits
included trips to the emergency room, urgent care, hospital
admissions, and telehealth calls, among others. This observation is
consistent with data from a secondary endpoint of the EPIC-HR1
study, which showed a 67% reduction in medical visits per day
versus placebo (p<0.0001 statistically significant). An
additional pre-specified descriptive analysis showed a 72%
reduction in the average number of days in hospital among
PAXLOVID-treated patients versus placebo in EPIC-SR. Other not
statistically significant findings included no PAXLOVID-treated
patients admitted to the intensive care unit, compared to three in
the placebo group, and no deaths in patients who received PAXLOVID
with one death in the placebo group.
“Results from our Phase 2/3 EPIC-HR and EPIC-SR studies, as well
as post-authorization experience, support the efficacy and safety
profile for PAXLOVID in the treatment of mild-to-moderate COVID-19
patients with at least one risk factor for progressing to severe
COVID-19, regardless of vaccination status,” said Albert Bourla,
Chairman and Chief Executive Officer, Pfizer. “With up to 40-50% of
people around the world estimated to be high risk, we believe there
remains a significant unmet need for treatment options to help
combat this disease, and we will continue to prioritize efforts to
advance the development of PAXLOVID.”
Treatment-emergent adverse events were comparable between
PAXLOVID (23.1%) and placebo (23.4%), most of which were mild in
intensity. Rates of serious adverse events (1.4% vs. 1.9%) and
discontinuation of study drug due to adverse events (1.7% vs. 1%)
were also comparable between PAXLOVID and placebo.
Due to a very low rate of hospitalization or death observed in
the standard-risk patient population, Pfizer has decided to cease
enrollment into EPIC-SR and include available data in this month’s
planned New Drug Application (NDA) submission to the U.S. Food and
Drug Administration (FDA) to support the use of PAXLOVID in
appropriate individuals at high risk of progression to severe
illness.2 The company will focus efforts on generating further data
on PAXLOVID in vulnerable populations, including longer treatment
durations in immunocompromised individuals, as well as exploring
other clinical development opportunities, such as its potential use
in hospitalized patients with severe disease.
The results from these additional analyses are not expected to
impact Pfizer’s full-year 2022 revenue guidance. Analyses of the
data are ongoing, and final results will be made available via
publication or presentation.
PAXLOVID is currently approved or authorized for conditional or
emergency use in more than 65 countries across the globe to treat
high-risk COVID-19 patients. Available safety data for PAXLOVID
have been generally consistent in more than 3,500 PAXLOVID-treated
participants across the EPIC-HR, EPIC-SR and EPIC-PEP3 studies, as
well as in reported post-authorization safety experience.
Please see Full Emergency Use Authorization (EUA) Prescribing
Information available at www.fda.gov and www.COVID19oralRx.com.
About PAXLOVID™ (nirmatrelvir [PF-07321332] tablets and
ritonavir tablets) 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, potentially helping
patients avoid severe illness (which can lead to hospitalization
and death). 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 the following variants: Alpha,
Beta, Delta, Gamma, Lambda, Mu, and Omicron BA.1.
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 Phase 2/3 EPIC-SR Study The study initially
enrolled 1,153 standard-risk individuals who had (1) a confirmed
diagnosis of SARS-CoV-2 infection within five days prior to
randomization, (2) onset of symptoms within five days of
randomization, and (3) at least one characteristic or underlying
medical condition associated with an increased risk of developing
severe illness from COVID-19 and were fully vaccinated against
COVID-19 OR no characteristics associated with risk of severe
COVID-19 and were unvaccinated. Following the Emergency Use
Authorization of PAXLOVID for individuals at high risk of
progression to severe COVID-19, the protocol was amended to exclude
high-risk individuals and allow enrollment of patients without risk
factors for progression to severe COVID-19 who were either
unvaccinated, or whose last COVID-19 vaccination occurred more than
12 months from enrollment. Data from patients enrolled following
this protocol amendment are not yet available.
Each patient was randomized (1:1) to receive PAXLOVID or placebo
orally twice daily for five days.
Additional secondary endpoints for this study will be released
in the coming months and submitted to a peer-reviewed publication.
Additional information is available on clinicaltrials.gov
(NCT05011513).
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. Drugs listed in Table 1 are a guide and not considered a
comprehensive list of all possible drugs that may interact with
PAXLOVID. 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 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
release is as of June 14, 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 release contains forward-looking information about Pfizer’s
efforts to combat COVID-19 and PAXLOVID (including qualitative
assessments of available data, potential benefits, expectations for
clinical trials, the anticipated timing of data readouts,
regulatory submissions, regulatory approvals or authorizations, a
planned new drug application submission in the U.S. for appropriate
individuals at high risk of progression to severe illness, revenue
guidance, potential in high-risk COVID-19 patients, and plans to
focus efforts on generating further data on PAXLOVID in vulnerable
populations as well as exploring other clinical development
opportunities), 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 data discussed in this release),
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;
uncertainties regarding the commercial impact of the results of the
EPIC-SR and EPIC-PEP trials; 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 (including a potential new drug
application submission for PAXLOVID in the U.S. for appropriate
individuals at high risk of progression to severe illness) 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 a
potential new drug application submission for PAXLOVID in the U.S.
for appropriate individuals at high risk of progression to severe
illness 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 which may lead to reduced revenues or excess
inventory; 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, 2021 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.
1 EPIC-HR (Evaluation of
Protease Inhibition for COVID-19 in High-Risk
Patients) 2 To learn more about who may be at high risk of
progression to severe COVID-19, visit the Centers for Disease
Control and Prevention or World Health Organization. 3 EPIC-PEP
(Evaluation of Protease Inhibition for COVID-19 in Post-Exposure Prophylaxis)
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