- Data support that antibiotic aztreonam-avibactam (ATM-AVI) is
effective and well-tolerated in treating infections caused by
Gram-negative bacteria, with a similar safety profile to aztreonam
alone
Pfizer Inc. (NYSE: PFE) today announced positive results from
the Phase 3 program comprising the REVISIT (NCT03329092) and
ASSEMBLE (NCT03580044) studies evaluating the efficacy, safety, and
tolerability of the novel investigational antibiotic combination
aztreonam-avibactam (ATM-AVI) in treating serious bacterial
infections due to Gram-negative bacteria, including
metallo-β-lactamase (MBL)-producing multidrug-resistant pathogens
for which there are limited or no treatment options. Data support
that ATM-AVI is effective and well-tolerated, with no new safety
findings and a similar safety profile to aztreonam alone.
“We believe these data demonstrate that ATM-AVI, if approved,
could be an important treatment option for patients with
life-threatening bacterial infections that are resistant to almost
all currently available antibiotics,” said James Rusnak, Senior
Vice President and Chief Development Officer, Internal Medicine,
Anti-Infectives and Hospital, Pfizer. “We are committed to meeting
this critical need and helping to address the global health threat
of antimicrobial resistance.”
The REVISIT study compared ATM-AVI ± metronidazole (MTZ) with
meropenem (MER) ± colistin (COL) for the treatment of complicated
intra-abdominal infections (cIAI), hospital-acquired pneumonia
(HAP), and ventilator-associated pneumonia (VAP). Key results
include:
- For patients with cIAI, cure rate in the intention to treat
(ITT) analysis set was 76.4% (95% confidence interval (CI) [70.3,
81.8]) for the ATM-AVI ± MTZ treatment arm vs 74.0% (95% CI [65.0,
81.7]) for the MER ± COL treatment arm, with a treatment difference
of 2.4% (95% CI [-12.4, 19.1]). In the clinically evaluable (CE)
analysis set, cure rate was 85.1% (95% CI [79.2, 89.9]) for ATM-AVI
± MTZ versus 79.5% (95% CI [69.9, 87.1]) for MER ± COL.
- For patients with HAP/VAP, cure rate in the ITT analysis set
was 45.9% (95% CI [34.9, 57.3]) for ATM-AVI ± MTZ versus 41.7% (95%
CI [26.7, 57.9]) for MER ± COL, with a treatment difference of 4.3%
(95% CI [-25.6, 32.2]). In the CE analysis set, cure rate was 46.7%
(95% CI [32.7, 61.1]) for ATM-AVI ± MTZ vs 54.5% (95% CI [34.3,
73.7]) for MER ± COL.
- All-cause 28-day mortality rates were 4/208 (1.9%) for ATM-AVI
± MTZ versus 3/104 (2.9%) for MER ± COL in cIAI, and 8/74 (10.8%)
for ATM-AVI ± MTZ versus 7/36 (19.4%) for MER ± COL in
HAP/VAP.
- ATM-AVI ± MTZ was well-tolerated, with an overall observed
pattern of treatment-emergent adverse events (TEAEs) in line with
that described for aztreonam alone. The incidence of serious
adverse events (SAEs) was similar between treatment groups (53
[19.3%] patients in the ATM-AVI ± MTZ group and 25 [18.2%] patients
in the MER ± COL group). No patient treated with ATM-AVI ± MTZ
experienced a treatment-related SAE.
These results are further supported by the ASSEMBLE study, which
found that 5/12 (41.7%) of the ATM-AVI ± MTZ patients with
infections due to confirmed MBL-producing Gram-negative bacteria
were cured at TOC versus 0/3 (0%) of those on best available
therapy (BAT). ATM-AVI patients experienced TEAEs that were in line
with those of aztreonam alone. No patient treated with ATM-AVI
experienced a treatment-related SAE.
Antimicrobial resistance (AMR), particularly in Gram-negative
bacteria, is widely recognized as one of the biggest threats to
global health and developing new treatments for infections caused
by these bacteria has been highlighted as a critical area of need
by the World Health Organization (WHO).1 An estimated 1.27 million
deaths globally were caused by bacterial AMR in 2019 alone.2
Without solutions, a continued rise of AMR could make routine
medical procedures too risky to perform.3
“These clinical findings show that ATM-AVI, if approved, could
help provide coverage against Gram-negative bacteria without
compromising on efficacy or safety,” said Yehuda Carmeli, Head,
National Institute for Antibiotic Resistance and Infection Control,
Tel Aviv Medical Center, Tel Aviv, Israel. “These data are
particularly promising given the complexities of managing cIAI and
HAP/VAP infections in these hospitalized, critically ill patients,
and the challenges of real-world patient recruitment within this
population.”
Full results from the studies will be submitted for scientific
publication. Data from the REVISIT and ASSEMBLE studies are
expected to form the basis for planned regulatory filings in the
European Union, United Kingdom, China, and the U.S. in the second
half of 2023. Pfizer holds the global rights to commercialize
ATM-AVI outside of the U.S. and Canada, where the rights are held
by its development partner AbbVie.
These studies were sponsored by Pfizer and funded in whole or
part with federal funds from the U.S. Department of Health and
Human Services; Administration for Strategic Preparedness and
Response; Biomedical Advanced Research and Development Authority,
under OTA number HHSO100201500029C. The research leading to these
results has received support from the Innovative Medicines
Initiative Joint Undertaking under grant agreement 115620,
resources of which are composed of financial contribution from the
European Union Seventh Framework Programme (FP7/2007-2013) and
EFPIA companies in kind contribution. Additional information about
the studies can be found at www.clinicaltrials.gov under the
identifiers NCT03329092 and NCT03580044.
About the Aztreonam-Avibactam (ATM-AVI) Phase 3 Development
Program
The Phase 3 development program for ATM-AVI is comprised of two
studies: REVISIT and ASSEMBLE. These studies were not designed for
inferential testing of efficacy, but do provide randomized,
assessor-blinded descriptive efficacy data and contribute to the
safety database. This streamlined development approach for ATM-AVI
has been confirmed by the European Medicines Agency (EMA) and the
U.S. Food and Drug Administration (FDA).
REVISIT is a Phase 3, prospective, randomized, multicenter, open
label, central assessor blinded, parallel group comparative study
conducted with 422 hospitalized adult patients across 81 locations
in 20 countries. The study was to determine the efficacy, safety,
and tolerability of ATM-AVI ± MTZ versus MER ± COL in the treatment
of hospitalized adults with cIAI or nosocomial pneumonia including
HAP and VAP, in regions with endemic or emerging carbapenem
resistance, and where MBL-producing multidrug-resistant pathogens
are suspected.
ASSEMBLE is a Phase 3, prospective, randomized, multicenter,
open-label, parallel group comparator study conducted with 15 adult
patients across 12 locations in 9 countries. The study was to
determine the efficacy, safety, and tolerability of ATM-AVI versus
BAT in the treatment of hospitalized adults with infections
confirmed due to MBL-producing Gram-negative bacteria.
About Aztreonam-Avibactam (ATM-AVI)
Aztreonam-avibactam (ATM-AVI) is an investigational treatment
for infections caused by Gram-negative bacteria with limited
treatment options.4,5,6 It combines aztreonam, a monobactam
β-lactam, with avibactam, a recent broad-spectrum β-lactamase
inhibitor.5,6 Metallo-β-lactamases (MBLs) are a class of
β-lactamase enzymes which are not inhibited by current β-lactamase
inhibitors and hydrolyze nearly all β-lactam antibiotics, the
exception being monobactams such as aztreonam. However, monobactams
are degraded by other β-lactamases that are frequently co-produced
with MBLs, limiting the clinical usefulness of aztreonam
monotherapy.
The combination of aztreonam with avibactam restores aztreonam’s
activity against bacteria that co-produce MBLs and other
β-lactamases and, if approved, could offer a much-needed safe and
effective treatment option against multidrug-resistant
Gram-negative bacteria.5
ATM-AVI is being jointly developed with AbbVie. Pfizer holds the
global rights to commercialize this investigative therapy outside
of the U.S. and Canada, where the rights are held by AbbVie.
Development of ATM-AVI is also supported by public-private
partnerships between Pfizer and the Biomedical Advanced Research
and Development Authority (BARDA), and between Pfizer and the
European Union's Innovative Medicines Initiative (IMI) – a
partnership between the European Union and the European
pharmaceutical industry, under a project called COMBACTE-CARE
(Combating Bacterial Resistance in Europe – Carbapenem Resistance).
The COMBACTE-CARE consortium is a unique public-private
collaboration that unites the knowledge and capabilities of leading
drug resistant bacterial infection experts and is supported by the
COMBACTE clinical and laboratory networks.
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
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Disclosure Notice
The information contained in this release is as of June 1, 2023.
Pfizer assumes no obligation to update forward-looking statements
contained in this release as the result of new information or
future events or developments.
This release contains forward-looking information about an
investigational antibiotic, aztreonam-avibactam (ATM-AVI), and
planned regulatory filings, including its potential benefits, that
involves 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 our clinical trials,
regulatory submission dates, regulatory approval dates and/or
launch dates, as well as the possibility of unfavorable new
clinical data and further analyses of existing clinical data; the
risk that clinical trial data are subject to differing
interpretations and assessments by regulatory authorities; whether
regulatory authorities will be satisfied with the design of and
results from our clinical studies; whether and when any drug
applications may be filed in any jurisdictions for ATM-AVI; whether
and when regulatory authorities in any such jurisdictions where
applications may be filed or pending may approve such applications,
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 ATM-AVI will be commercially successful;
decisions by regulatory authorities impacting labeling,
manufacturing processes, safety and/or other matters that could
affect the availability or commercial potential of ATM-AVI; the
impact of COVID-19 on our 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, 2022 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 Tacconelli E, Carrara E, Savoldi A, et al. Discovery,
research, and development of new antibiotics: the WHO priority list
of antibiotic-resistant bacteria and tuberculosis. Lancet Infect
Dis. 2018;18(3):318-327. 2 Antimicrobial Resistance Collaborators.
Global burden of bacterial antimicrobial resistance in 2019: a
systematic analysis. Lancet. 2022;399(10325):629-655. 3 World
Health Organization. Antibiotic resistance factsheet. July 2020.
Available at:
https://www.who.int/news-room/fact-sheets/detail/antibiotic-resistance.
Last accessed May 2023. 4 Sader et al. Aztreonam/avibactam activity
against clinical isolates of Enterobacterales collected in Europe,
Asia and Latin America in 2019. J Antimicrob Chemother.
2021;76:659-666. 5 Rossolini et al. In vitro activity of
aztreonam/avibactam against isolates of Enterobacterales collected
globally from ATLAS in 2019. J Global Antimicrob Resist.
2022;30:214-221 6 Cornely OA, Cisneros JM, Torre-Cisneros J, et al.
Pharmacokinetics and safety of aztreonam/avibactam for the
treatment of complicated intra-abdominal infections in hospitalized
adults: results from the REJUVENATE study. J Antimicrob Chemother
2020;75:618–27.
Label: Research and Pipeline
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