–VABOMERE was associated with higher overall
cure and lower mortality versus “best available therapy” in
subjects with known or suspected carbapenem-resistant
Enterobacteriaceae (CRE)–
–VABOMERE was also associated with better
safety and significantly better overall risk-benefit than best
available therapy–
The Medicines Company (NASDAQ:MDCO) today announced that new
data from its TANGO II study of VABOMERE (meropenem and
vaborbactam) will be presented this week at IDWeek 2017 in
San Diego.
In the TANGO II study, VABOMERE was associated with a higher
clinical cure versus “best available therapy” (BAT) in patients
with a baseline organism that was carbapenem-resistant
Enterobacteriaceae (mCRE-MITT population) at both end-of-therapy
(EOT) (VABOMERE 64.3% vs. BAT 33.3%; p=0.04) and test-of-cure (TOC)
(VABOMERE 57.1% vs. BAT 26.7%; p=0.04). In immunocompromised
patients, VABOMERE was also associated with a higher clinical cure
versus BAT at EOT (VABOMERE 60% vs. BAT 12.5%; p<0.01), as well
as lower mortality.
VABOMERE was associated, across all patients, with decreased
nephrotoxicity and fewer treatment-related adverse events versus
BAT. An analyses using the composite endpoints of clinical failure
or nephrotoxicity demonstrated a risk-benefit profile favoring
VABOMERE versus BAT (32.1% VABOMERE vs 80.0% BAT (95% CI: −74.5 to
−21.2; P< 0.001)).
In July 2017, randomization in the TANGO II study was stopped
early, following a recommendation by the TANGO II Independent Data
Safety Monitoring Board (DSMB), based on an analysis of 72
patients, including 43 patients with microbiologically evaluable
carbapenem-resistant Enterobacteriaceae (CRE) infections of blood,
lung, urinary tract and abdominal organs. The DSMB recommended,
based on risk-benefit considerations, that randomization of
additional patients to the best available therapy comparator arm
should not continue.
VABOMERE was recently approved by the U.S. Food and Drug
Administration (FDA) for the treatment of adult patients with
complicated urinary tract infections (cUTI), including
pyelonephritis, caused by designated susceptible Enterobacteriaceae
– Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae
species complex. The Medicines Company plans to begin sales
and distribution of VABOMERE in the fourth quarter of 2017 and has
set a $990 price per day of therapy.
“We are excited that the TANGO II data affirm our intention to
continue the development of VABOMERE to address serious infections
due to Klebsiella pneumoniae carbapenemase (KPC)-producing CRE,”
said Tony Kingsley, President and Chief Operating Officer of The
Medicines Company. “Infections due to CRE are increasing in all
settings of care in the United States. Patients are often treated
with combination therapies of older antibiotics, many of which have
significant toxicities, most notably renal toxicity. VABOMERE was
specifically designed and developed to address this growing public
health threat. We look forward to sharing the TANGO II results with
regulatory authorities.”
Michael Dudley, PharmD, FIDSA, Senior Vice President, Head of
R&D and Co-Leader of The Medicines Company’s Infectious Disease
Business added, “CRE is considered an urgent antimicrobial
resistant threat by the U.S. Centers for Disease Control and
Prevention (CDC), and the World Health Organization (WHO) considers
new drugs for CRE to be a critical priority. VABOMERE addresses
this need by restoring the activity of meropenem by combining it
with vaborbactam, a novel, first-in-class beta lactamase inhibitor
designed to inhibit KPC enzymes that are largely responsible for
resistance to carbapenems in Enterobacteriaceae in the United
States.”
Cornelius Clancy M.D., Associate Professor in the Division of
Infectious Diseases at University of Pittsburgh and Chief of
Infectious Diseases at the VA Pittsburgh Health System summarized,
“The totality and consistency of the data from the TANGO programs,
particularly the landmark study TANGO II, are compelling. TANGO II
showed VABOMERE was associated with a higher clinical cure rate
versus BAT in difficult to treat infections and patient
populations. The microbiological and pharmacological underpinnings
of this combination product based on meropenem have been translated
into an important advance for patients and clinicians.”
A total of nine posters on VABOMERE, including comprehensive
analyses from the TANGO II study, are now available to
IDWeek registrants and will be presented on Friday, October
6th and Saturday, October 7th. The electronic versions of posters
can be accessed on The Medicines Company website at
http://www.themedicinescompany.com/investors/events.
Summaries of the key findings from poster presentations, as
detailed in the IDWeek 2017 schedule, are as follows:
1862: Clinical Outcomes of Serious Infections due to
Carbapenem-Resistant Enterobacteriaceae (CRE) in TANGO II, a Phase
3, Randomized, Multi-National, Open-Label Trial of
Meropenem-Vaborbactam (M-V) vs. Best Available Therapy (BAT)
- VABOMERE monotherapy was associated with a higher rate of
clinical cure compared to BAT at both EOT and TOC across all
infection types in the mCRE-MITT population. At EOT, clinical cure
was 64.3% for VABOMERE versus 33.3% for BAT (p=0.04). At TOC,
clinical cure was 57.1% for VABOMERE versus 26.7% for BAT
(p=0.04).
VABOMERE was associated with fewer treatment-related adverse
events (AEs) versus BAT (VABOMERE 24.4% vs. BAT 44.0%) and
decreased nephrotoxicity as evidenced by serum creatinine increase
≥0.5 mg/dL (VABOMERE 11.1% vs. BAT 24.0%). An exploratory analyses
using the composite endpoints of clinical failure or nephrotoxicity
demonstrated a risk-benefit profile favoring VABOMERE versus BAT
(32.1% VABOMERE vs 80.0% BAT (95% CI: −74.5 to −21.2; p <
0.001)).
1867: Meropenem-Vaborbactam vs. Best Available Therapy
for Carbapenem-Resistant Enterobacteriaceae Infections in TANGO II:
Primary Outcomes by Site of Infection – At EOT/TOC, VABOMERE
showed clinical cure of 50% to 58% vs. 25% to 37.5% with BAT in
mCRE-MITT patients with bacteremia. Mortality at 28 days in the
pooled patient population with bacteremia, hospital-acquired
bacterial pneumonia (HABP) or ventilator-associated bacterial
pneumonia (VABP) was 25% for VABOMERE vs. 44% for BAT (43.7%
reduction). In patients with complicated urinary tract
infections/acute pyelonephritis (cUTI/AP), the overall success at
EOT was 72.7% for VABOMERE compared to 50% for BAT; success at TOC
was 42.9% vs. 50% for VABOMERE and BAT, respectively.
1868: Meropenem-Vaborbactam vs. Best Available Therapy
for Carbapenem-Resistant Enterobacteriaceae Infections in TANGO II:
Outcomes in Immunocompromised Patients - Approximately
40% of patients with CRE in TANGO II were immunocompromised (n=18).
Treatment of these immunocompromised CRE patients with VABOMERE was
associated with higher clinical cure rate (60% vs. 12.5%; P=0.01)
and lower mortality (20% vs. 37%) than BAT. Among immunocompromised
subjects, when compared to BAT, VABOMERE was associated with fewer
AEs (84.6% vs. 100%), drug-related AEs (30.8% vs. 40.0%), serious
AEs (38.5% vs. 50.0%), discontinuations of study drug or study due
to AEs (15.4% vs. 30.0%) and renal-related AEs (7.7% vs.
40.0%).
Poster 1874: Assessment of MIC Increases with
Meropenem-Vaborbactam and Ceftazidime-Avibactam in TANGO II (a
Phase 3 Study of the Treatment of CRE Infections). The
objective of this study was to examine the minimum inhibitory
concentration (MIC) increases with meropenem-vaborbactam and
ceftazidime-avibactam in patients with KPC-producing CRE enrolled
in the TANGO II trial that were treated with these agents. One
patient treated with VABOMERE had a fourfold change in MIC detected
in a post-treatment bacterial isolate; this change remained in the
susceptible range for VABOMERE (MIC ≤ 4 ug/ml). One of four
patients treated with ceftazidime-avibactam monotherapy as BAT had
a 256-fold change in MIC that became resistant to
ceftazidime-avibactam (MIC > 128 ug/ml), with mutations in the
KPC enzyme similar to those recently reported by other
investigators.
Poster 1835: Meropenem-Vaborbactam Pharmacokinetics in
Subjects with Chronic Renal Impairment, Including Hemodialysis.
Meropenem and vaborbactam pharmacokinetics were determined
following a single dose to subjects with varying degrees of renal
impairment, including patients undergoing hemodialysis. The changes
in the pharmacokinetics of meropenem and vaborbactam were similar
for patients with mild to severe renal impairment, with the
relationship between drug clearance and estimated glomerular
filtration rate (eGFR) for meropenem and vaborbactam were similar,
allowing for dosage reduction in renal impairment having a similar
proportional reduction for each component. Hemodialysis removes
both meropenem and vaborbactam from plasma, and thus a maintenance
dose of VABOMERE is required after a dialysis session.
Poster 1852: Meropenem-Vaborbactam
Pharmacokinetic-Pharmacodynamic (PK-PD) Target Attainment Analyses
as Support for Dose Selection in Patients with Normal Renal
Function and Varying Degrees of Renal Impairment. Dosage
regimens of VABOMERE in FDA-approved labeling for patients with
normal renal function and varying levels of renal impairment were
evaluated in a simulation study to determine if plasma exposures of
meropenem and vaborbactam would achieve PK-PD targets for efficacy
derived from nonclinical models of infection. Plasma
pharmacokinetics using a population PK model derived from data from
the Phase I and Phase III studies were used. The results show that
over 90% of patients achieve target exposures of both drugs for
KPC-producing Enterobacteriaceae with VABOMERE MICs up to 8
ug/ml.
Poster 1879: Meropenem-Vaborbactam: Outcomes in Subjects with
Renal Impairment in Phase 3 Studies TANGO I and II. The
efficacy of some recently approved beta-lactamase inhibitor
combinations has been noted to decrease in patients with moderate
renal impairment. This poster examined safety and efficacy in
subsets of patients with renal impairment treated with VABOMERE in
the TANGO I and TANGO II studies. In TANGO I and II, 11.5% and
20.9% of patients had a baseline creatinine clearance of less than
50 ml/min, respectively. In TANGO I, overall success in patients
with creatinine clearance < 50 ml/min at the end of IV treatment
was 100% in VABOMERE treated patients compared to 90.9% for
piperacillin-tazobactam; these values in patients with a creatinine
clearance > 50 ml/min were 98.2% vs. 94.3% for VABOMERE and
piperacillin/tazobactam, respectively. In TANGO II, the clinical
cure at EOT in patients in the mCRE-mMITT population with renal
impairment (creatinine clearance < 50 ml/min) was 40% vs. 25%
for VABOMERE and piperacillin/tazobactam, respectively.
Poster 1234: Activity of Meropenem-Vaborbactam Against
Enterobacteriaceae Isolates Carrying bla-KPC Collected
Worldwide. Over 34,000 clinical isolates of Enterobacteriaceae
collected during 2014-2016 from the worldwide SENTRY surveillance
were tested for susceptibility to VABOMERE. KPC- producing isolates
were detected in 17 countries and the incidence ranged from 0.1% to
11.3% of all Enterobacteriaceae, depending on the country.
Meropenem-vaborbactam inhibited 98.6% of isolates at FDA-approved
breakpoints (MIC <= 4 ug/ml), with an MIC50/90 of 0.12/1
ug/ml.
Poster 1866: Meropenem-Vaborbactam (VABOMERE) vs.
Piperacillin-Tazobactam in TANGO I (a Phase 3, Randomized,
Double-blind Trial): Outcomes by Baseline MIC in Adults with cUTI
or AP. This poster examined the relation between MIC to
VABOMERE or piperacillin/tazobactam to determine if the MIC or
non-susceptibility to piperacillin/tazobactam was associated with
clinical cure or microbial eradication in TANGO-1. Microbial
eradication at end of intravenous treatment (EOIVT) in patients
treated with piperacillin/tazobactam who had a non-susceptible
Enterobacteriaceae at baseline was 26/30 (86.7%) vs. 116/124
(93.5%) in those with a susceptible organism (P>0.1). There was
no relation between piperacillin/tazobactam or VABOMERE MIC and
clinical cure of microbial eradication.
About VABOMERE™
VABOMERE™ (meropenem and vaborbactam) is indicated for the
treatment of patients 18 years of age and older with complicated
urinary tract infections (cUTI), including pyelonephritis caused by
the following susceptible microorganisms: Escherichia coli,
Klebsiella pneumoniae, and Enterobacter cloacae species
complex.
To reduce the development of drug-resistant bacteria and
maintain the effectiveness of VABOMERE and other antibacterial
drugs, VABOMERE should be used only to treat or prevent infections
that are proven or strongly suspected to be caused by susceptible
bacteria.
IMPORTANT SAFETY INFORMATION
Contraindications
VABOMERE is contraindicated in patients with known
hypersensitivity to any components of VABOMERE (meropenem and
vaborbactam), or to other drugs in the same class or in patients
who have demonstrated anaphylactic reactions to beta-lactam
antibacterial drugs.
Warnings and Precautions
- Hypersensitivity reactions were
reported in patients treated with VABOMERE in the clinical trials.
Serious and occasionally fatal hypersensitivity (anaphylactic)
reactions and serious skin reactions have been reported in patients
receiving therapy with beta-lactam antibacterial drugs. There have
been reports of individuals with a history of penicillin
hypersensitivity who have experienced severe hypersensitivity
reactions when treated with another beta-lactam antibacterial drug.
If an allergic reaction to VABOMERE occurs, discontinue the drug
immediately.
- Seizures and other adverse Central
Nervous System (CNS) experiences have been reported during
treatment with meropenem, which is a component of VABOMERE. Close
adherence to the recommended dosage regimens is urged, especially
in patients with known factors that predispose to convulsive
activity.
- Clostridium difficile-associated
diarrhea (CDAD) has been reported with use of nearly all
antibacterial agents, including VABOMERE, 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.
- The concomitant use of VABOMERE and
valproic acid or divalproex sodium is generally not recommended.
Case reports in the literature have shown that co-administration of
carbapenems, including meropenem, to patients receiving valproic
acid or divalproex sodium results in a reduction in valproic acid
concentrations. The valproic acid concentrations may drop below the
therapeutic range as a result of this interaction, therefore
increasing the risk of breakthrough seizures. If administration of
VABOMERE is necessary, consider supplemental anticonvulsant
therapy.
- In patients with renal impairment,
thrombocytopenia has been observed in patients treated with
meropenem, but no clinical bleeding has been reported.
- Alert patients receiving VABOMERE on an
outpatient basis regarding adverse reactions such as seizures,
delirium, headaches and/or paresthesias that could interfere with
mental alertness and/or cause motor impairment.
- Prescribing VABOMERE in the absence of
a proven or strongly suspected bacterial infection is unlikely to
provide benefit to the patient and increases the risk of
drug-resistant bacteria.
- As with other antibacterial drugs,
prolonged use of VABOMERE may result in overgrowth of
nonsusceptible organisms.
Adverse Reactions
The most frequently reported adverse reactions occurring in ≥3%
of patients treated with VABOMERE were headache, phlebitis/infusion
site reactions, and diarrhea.
Please see www.vabomere.com for the full prescribing
information.
About TANGO II
TANGO II is a multi-center, randomized, open-label Phase III
clinical trial of VABOMERE versus “best available therapy” in
patients with serious infections (cUTI, bacteremia, HABP/VABP, and
complicated intraabdominal infections) suspected or documented to
be caused by CRE. Patients with CRE were randomized to receive
either VABOMERE monotherapy or the “best available therapy” for up
to 14 days. Patients randomized to the best available therapy arm
of the trial were given antimicrobial therapy often consisting of
two to four drugs used in combination; this treatment was selected
for each patient by the investigator based on available clinical
laboratory and other patient data, and thus represents the current
standard of care used for the treatment of CRE infections.
In July 2017, randomization in the trial was stopped early,
following a recommendation by the TANGO II DSMB, based on an
analysis of 72 patients, including 43 patients with
microbiologically evaluable CRE infections of blood, lung, urinary
tract and abdominal organs. Of the 72 patients enrolled in the
TANGO II study, 28 were treated with VABOMERE and 15 with BAT. The
most common pathogen was Klebsiella pneumoniae (86%). The DSMB
recommended, based on risk-benefit considerations, that
randomization of additional patients to the best available therapy
comparator arm should not continue. The Company plans to enroll
patients into an amended, single-arm study protocol for treatment
with VABOMERE at selected study sites.
About Carbapenem-Resistant Enterobacteriaceae (CRE)
Enterobacteriaceae comprise a family of gram-negative bacteria
that includes Klebsiella sp., E. coli, Enterobacter sp. and others.
This group of bacteria collectively are largely responsible for
hospital-acquired infections due to gram-negative bacteria.
Enterobacteriaceae have become increasingly resistant to the widely
used beta-lactam class of antibiotics due to production of enzymes
known as beta-lactamases that degrade these antibiotics. The
worldwide dissemination of newer beta-lactamases known as
carbapenemases has been responsible for resistance to the
carbapenem and other classes of antibiotics. In the United States,
the Klebsiella pneumoniae carbapenemase (KPC) enzyme is responsible
for over 90% of carbapenemase mediated resistance in CRE. The
Company estimates, based on data derived from public sources and
internal research, that there are over 60,000 patients with CRE
infections annually in the United States.
Patients at risk for CRE infections include those with prior
colonization, the institutionalized elderly, immunocompromised
patients, mechanically ventilated patients, use of prior
antibiotics, and those with multiple underlying comorbidities.
Infections due to CRE are associated with high antibiotic failure
rates, high mortality (up to 50%), and high cost to hospitals,
third party payers, and society (which could range from
$10,000-$84,000 per episode).
Due to the paucity of antibiotics with activity against CRE
pathogens, clinicians are often forced to treat CRE infections,
such as cUTIs, with combinations of antibiotics that had been
sparingly used over the past two decades.
In light of the poor outcomes associated with CRE infections and
the critical role of carbapenem antibiotics for treatment of
resistant gram negative infections, CRE is considered an urgent
antimicrobial resistance threat by the United States CDC, and the
WHO recently designated development of new drugs for CRE to be a
critical priority.
About The Infectious Disease Business
The Medicines Company Infectious Disease Business (MDCO IDC) is
committed to bringing life-saving antimicrobial products to
patients with the most serious drug-resistant infections –
infections caused by “super bugs” which are no longer treatable
with available antibiotics. MDCO IDC encompasses basic research and
drug discovery focused on bacterial mechanisms of drug resistance;
drug development focused on the most threatening bacterial
diseases; and a distribution and commercial infrastructure that
serves the leading hospitals and healthcare facilities in the
United States. MDCO IDC recently received approval for VABOMERE for
the treatment of complicated urinary tract infections in adults
caused by designated susceptible Enterobacteriaceae, including
those resistant to currently available carbapenems. MDCO IDC has a
leading pipeline of novel agents directed towards existing and
emerging multidrug-resistant bacteria.
In addition to the development and approval of VABOMERE, MDCO
IDC has, since 2014, successfully received approval for and
launched two antibiotics against serious infections: ORBACTIV®
(oritavancin) for the treatment of acute bacterial skin and
skin-structure infections in adults, caused by designated
pathogens, including methicillin-resistant Staphylococcus aureus,
and a new formulation of MINOCIN® (minocycline) for Injection,
which is among the few FDA-approved agents for the treatment of
infections due to Acinetobacter spp., a pathogen classified by the
CDC to be a serious antimicrobial resistance threat. For more
information on these products, including their respective important
safety information and package inserts, please see www.orbactiv.com
and www.minociniv.com.
About BARDA
In February 2014, The Medicines Company Infectious Disease
Business was awarded a cost-sharing contract by the Biomedical
Advanced Research and Development Authority (BARDA), a division of
the Office of the Assistant Secretary for Preparedness and Response
within the U.S. Department of Health and Human Services (HHS), of
which $55.8 million in federal funds have been obligated to date to
support the development of VABOMERE.
In September 2016, The Medicines Company entered into a new
strategic partnership with BARDA that will provide the Company with
the potential for up to $132 million to support the development of
new antibiotics to fight drug-resistant, gram-negative infections
(HHSO100201600026C). The partnership was established under HHS’s
Other Transactional Authority (OTA), and is a distinctive,
flexible, portfolio-based approach to funding drug development. The
Medicines Company was awarded $32 million in initial funding, and
up to an additional $100 million (pending the availability of
funding) over approximately five years, if all options to extend
the partnership are exercised by BARDA and The Medicines Company.
The initial $32 million award supports further development of
VABOMERE as well as advancement of the Company’s early stage
pipeline. Funding provided under any subsequent options exercised
by BARDA and The Medicines Company, will also support the
advancement of antibiotics in MDCO IDC’s portfolio of new
antibiotic drug candidates targeting drug resistant bacteria.
About The Medicines Company
The Medicines Company is a biopharmaceutical company driven by
an overriding purpose – to save lives, alleviate suffering and
contribute to the economics of healthcare. The Company’s mission is
to create transformational solutions to address the most pressing
healthcare needs facing patients, physicians and providers in
serious infectious disease care and cardiovascular care. The
Company is headquartered in Parsippany, New Jersey, with a global
innovation center in California.
Forward-Looking Statements
Statements contained in this press release that are not purely
historical may be deemed to be forward-looking statements for
purposes of the safe harbor provisions under The Private Securities
Litigation Reform Act of 1995. Without limiting the foregoing, the
words "believes," "anticipates," "expects," “potential,” and
similar expressions are intended to identify forward-looking
statements. These forward-looking statements involve known and
unknown risks and uncertainties that may cause the Company's actual
results, levels of activity, performance or achievements to be
materially different from those expressed or implied by these
forward-looking statements. Important factors that may cause or
contribute to such differences include whether clinical trials will
advance on a timely basis, or at all, or succeed in achieving their
specified endpoints; whether physicians, patients and other key
decision makers will accept clinical trial results; whether the
Company will make regulatory submissions on a timely basis, or at
all; whether the Company’s regulatory submissions will receive
approvals from regulatory agencies on a timely basis, or at all;
and such other factors as are set forth in the risk factors
detailed from time to time in the Company's periodic reports and
registration statements filed with the Securities and Exchange
Commission, including, without limitation, the risk factors
detailed in the Company's Quarterly Report on Form 10-Q filed with
the Securities and Exchange Commission on August 9, 2017, which are
incorporated herein by reference. The Company specifically
disclaims any obligation to update these forward-looking
statements.
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version on businesswire.com: http://www.businesswire.com/news/home/20171005005377/en/
The Medicines CompanyMediaMeg Langan, 973-290-6319Vice
Presidentmargaret.langan@themedco.comorInvestorsKrishna Gorti, M.D.,
973-290-6122Vice President, Investor
Relationskrishna.gorti@themedco.com
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