U.S. Food and Drug Administration (FDA)
Accepted for Review a Supplemental New Drug Application (sNDA) for
RECARBRIO in Hospital-Acquired or Ventilator-Associated Bacterial
Pneumonia in February 2020
Merck (NYSE: MRK), known as MSD outside the United States and
Canada, today announced results from RESTORE-IMI 2, a randomized,
controlled, double-blind Phase 3 clinical trial evaluating
RECARBRIO™ (imipenem, cilastatin, and relebactam) for the treatment
of adults with hospital-acquired or ventilator-associated bacterial
pneumonia (HABP/VABP). The results demonstrated noninferiority of
RECARBRIO compared to piperacillin and tazobactam (PIP/TAZ), the
active comparator, in the primary and key secondary endpoints of
the study, 28-day all-cause mortality and clinical response,
respectively. In February 2020, the U.S. Food and Drug
Administration (FDA) accepted for review a supplemental New Drug
Application (sNDA) for use of RECARBRIO in this patient population.
The FDA Prescription Drug User Fee Act (PDUFA) goal date is June 4,
2020. Phase 3 trial data are now available in a compendium of
presentations posted by Merck, coinciding with publication of study
abstracts by the 30th European Congress of Clinical Microbiology
& Infectious Diseases (ECCMID).
“We are pleased to post results from the RESTORE-IMI 2 clinical
trial, which further demonstrate the potential of RECARBRIO to
treat HABP/VABP due to certain susceptible Gram-negative
pathogens,” said Dr. Joan Butterton, associate vice president,
infectious disease clinical research, Merck Research Laboratories.
“These data underscore Merck’s commitment to pursuing innovative
options for those in need of novel antibiotic treatments.”
RESTORE-IMI 2 Design
RESTORE-IMI 2 was a Phase 3 multinational, randomized,
double-blind, non-inferiority trial evaluating the efficacy and
safety of RECARBRIO versus PIP/TAZ in adult patients with
HABP/VABP. In the study, 537 patients at 113 clinical trial sites
were randomized 1:1 to receive a dose of RECARBRIO (imipenem 500
mg/cilastatin 500 mg/relebactam 250 mg) or PIP/TAZ (piperacillin
4000 mg/tazobactam 500 mg), each given intravenously every six
hours for seven to 14 days. Patients in both treatment groups also
received open label empiric linezolid (600 mg) until baseline
cultures confirmed absence of methicillin-resistant Staphylococcus
aureus (MRSA). The primary endpoint was Day 28 all-cause mortality
and the key secondary endpoint was clinical response at early
follow-up (seven to 14 days after completing therapy).
RESTORE-IMI 2 Results
RECARBRIO met its primary and key secondary endpoints,
demonstrating non-inferiority compared to PIP/TAZ. For patients
treated with RECARBRIO, Day 28 all-cause mortality (primary
endpoint) was 15.9% (42/264) compared with 21.3% (57/267) in those
treated with PIP/TAZ (adjusted treatment difference: 5.3%, 95%
confidence interval [CI]: -11.9, 1.2). For patients treated with
RECARBRIO, a favorable clinical response at early follow-up (key
secondary endpoint) was observed in 60.9% (161/264) compared with
55.8% (149/267) in the PIP/TAZ group (adjusted treatment
difference: 5%, 95% CI: -3.2, 13.2).
Rates of overall adverse events (AEs) were similar between
treatment groups, with 84.9% (226/266) in the RECARBRIO arm vs.
86.6% (233/269) in the PIP/TAZ arm, reporting at least one AE. AEs
classified as drug-related by the investigator were 12% (31/266) in
the RECARBRIO arm vs. 10% (26/269) in the PIP/TAZ arm.
Additionally, therapy discontinuations due to any AE were similar
in both groups, with 6% (15/266) in the RECARBRIO arm vs. 8%
(22/269) in the PIP/TAZ arm. Therapy discontinuations due to
drug-related AEs were also similar: 2.3% (6/266) in the RECARBRIO
arm vs. 1.5% (4/269) in the PIP/TAZ arm. The most frequently
reported (>5 patients) drug-related AEs in the RECARBRIO arm
were diarrhea and elevated levels of the liver function biomarkers
alanine aminotransferase and aspartate aminotransferase (2% each
[6/266]).
About RECARBRIO™ (imipenem 500 mg, cilastatin 500 mg, and
relebactam 250 mg)
RECARBRIO was initially approved by the FDA in July 2019 for the
treatment of complicated urinary tract infections (cUTI), including
pyelonephritis, and complicated intra-abdominal infections (cIAI),
caused by susceptible Gram-negative bacteria, in adults who have
limited or no alternative treatment options.
RECARBRIO is indicated in patients 18 years of age and older who
have limited or no alternative treatment options, for the treatment
of complicated urinary tract infections (cUTI), including
pyelonephritis, caused by the following susceptible Gram-negative
microorganisms: Enterobacter cloacae, Escherichia coli, Klebsiella
aerogenes, Klebsiella pneumoniae, and Pseudomonas aeruginosa.
RECARBRIO is also indicated in patients 18 years of age or older
who have limited or no alternative treatment options, for the
treatment of complicated intra-abdominal infections (cIAI) caused
by the following susceptible Gram-negative microorganisms:
Bacteroides caccae, Bacteroides fragilis, Bacteroides ovatus,
Bacteroides stercoris, Bacteroides thetaiotaomicron, Bacteroides
uniformis, Bacteroides vulgatus, Citrobacter freundii, Enterobacter
cloacae, Escherichia coli, Fusobacterium nucleatum, Klebsiella
aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae,
Parabacteroides distasonis and Pseudomonas aeruginosa.
Approval of these indications is based on limited clinical
safety and efficacy data for RECARBRIO.
To reduce the development of drug-resistant bacteria and
maintain the effectiveness of RECARBRIO and other antibacterial
drugs, RECARBRIO should be used only to treat or prevent infections
that are proven or strongly suspected to be caused by susceptible
bacteria. When culture and susceptibility information is available,
they should be considered in selecting or modifying antibacterial
therapy. In the absence of such data, local epidemiology and
susceptibility patterns may contribute to the empiric selection of
therapy.
Selected Safety Information for RECARBRIO (imipenem,
cilastatin, and relebactam)
Hypersensitivity Reactions: RECARBRIO is contraindicated
in patients with a history of known severe hypersensitivity (severe
systemic allergic reaction such as anaphylaxis) to any component of
RECARBRIO. Serious and occasionally fatal hypersensitivity
(anaphylactic) reactions have been reported in patients receiving
therapy with beta lactams. Before initiating therapy with
RECARBRIO, careful inquiry should be made concerning previous
hypersensitivity reactions to carbapenems, penicillins,
cephalosporins, other beta lactams, and other allergens. If a
hypersensitivity reaction to RECARBRIO (imipenem, cilastatin, and
relebactam) occurs, discontinue the therapy immediately.
Seizures and Other Central Nervous System (CNS) Adverse
Reactions: CNS adverse reactions, such as seizures, confusional
states, and myoclonic activity, have been reported during treatment
with imipenem/cilastatin, a component of RECARBRIO, especially when
recommended dosages of imipenem were exceeded. These have been
reported most commonly in patients with CNS disorders (e.g., brain
lesions or history of seizures) and/or compromised renal
function.
Anticonvulsant therapy should be continued in patients with
known seizure disorders. If CNS adverse reactions including
seizures occur, patients should undergo a neurological evaluation
to determine whether RECARBRIO should be discontinued.
Increased Seizure Potential Due to Interaction with Valproic
Acid: Concomitant use of RECARBRIO, with valproic acid or
divalproex sodium may increase the risk of breakthrough seizures.
Avoid concomitant use of RECARBRIO with valproic acid or divalproex
sodium or consider alternative antibacterial drugs other than
carbapenems.
Clostridium difficile-Associated Diarrhea (CDAD):
Clostridium difficile-associated diarrhea (CDAD) has been reported
with use of nearly all antibacterial agents, including
imipenem/cilastatin plus relebactam, and may range in severity from
mild diarrhea to fatal colitis. Careful medical history is
necessary since CDAD has been reported to occur over two months
after the administration of antibacterial agents. If CDAD is
suspected or confirmed, ongoing antibacterial drug use not directed
against C. difficile may need to be discontinued.
Development of Drug-Resistant Bacteria: Prescribing
RECARBRIO in the absence of a proven or strongly suspected
bacterial infection or prophylactic indication is unlikely to
provide benefit to the patient and increases the risk of the
development of drug-resistant bacteria.
Adverse Reactions: The most frequently reported adverse
reactions occurring in ≥2% of patients treated with RECARBRIO were
diarrhea (6%), nausea (6%), headache (4%), vomiting (3%), alanine
aminotransferase increased (3%), aspartate aminotransferase
increased (3%), phlebitis/infusion site reactions (2%), pyrexia
(2%), and hypertension (2%).
Merck’s Commitment to Infectious Diseases
For more than 100 years, Merck has contributed to the discovery
and development of novel medicines and vaccines to combat
infectious diseases. In addition to a combined portfolio of
vaccines and antibacterial, antiviral and antifungal medicines,
Merck has multiple programs that span discovery through late-stage
development. To learn more about Merck’s infectious diseases
pipeline, visit www.merck.com.
About Merck
For more than 125 years, Merck, known as MSD outside of the
United States and Canada, has been inventing for life, bringing
forward medicines and vaccines for many of the world’s most
challenging diseases in pursuit of our mission to save and improve
lives. We demonstrate our commitment to patients and population
health by increasing access to health care through far-reaching
policies, programs and partnerships. Today, Merck continues to be
at the forefront of research to prevent and treat diseases that
threaten people and animals – including cancer, infectious diseases
such as HIV and Ebola, and emerging animal diseases – as we aspire
to be the premier research-intensive biopharmaceutical company in
the world. For more information, visit www.merck.com and connect
with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.
Forward-Looking Statement of Merck & Co., Inc.,
Kenilworth, N.J., USA
This news release of Merck & Co., Inc., Kenilworth, N.J.,
USA (the “company”) includes “forward-looking statements” within
the meaning of the safe harbor provisions of the U.S. Private
Securities Litigation Reform Act of 1995. These statements are
based upon the current beliefs and expectations of the company’s
management and are subject to significant risks and uncertainties.
There can be no guarantees with respect to pipeline products that
the products will receive the necessary regulatory approvals or
that they will prove to be commercially successful. If underlying
assumptions prove inaccurate or risks or uncertainties materialize,
actual results may differ materially from those set forth in the
forward-looking statements.
Risks and uncertainties include but are not limited to, general
industry conditions and competition; general economic factors,
including interest rate and currency exchange rate fluctuations;
the impact of the recent global outbreak of novel coronavirus
disease (COVID-19); the impact of pharmaceutical industry
regulation and health care legislation in the United States and
internationally; global trends toward health care cost containment;
technological advances, new products and patents attained by
competitors; challenges inherent in new product development,
including obtaining regulatory approval; the company’s ability to
accurately predict future market conditions; manufacturing
difficulties or delays; financial instability of international
economies and sovereign risk; dependence on the effectiveness of
the company’s patents and other protections for innovative
products; and the exposure to litigation, including patent
litigation, and/or regulatory actions.
The company undertakes no obligation to publicly update any
forward-looking statement, whether as a result of new information,
future events or otherwise. Additional factors that could cause
results to differ materially from those described in the
forward-looking statements can be found in the company’s 2019
Annual Report on Form 10-K and the company’s other filings with the
Securities and Exchange Commission (SEC) available at the SEC’s
Internet site (www.sec.gov).
Please see Prescribing Information for RECARBRIO (imipenem,
cilastatin, and relebactam) for injection (1.25 g) at
https://www.merck.com/product/usa/pi_circulars/r/recarbrio/recarbrio_pi.pdf
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