|The Medicines Company Announces FDA Approval of VABOMERE™ (meropenem and vaborbactam)|
–Accelerated approval for the treatment of adult patients with complicated urinary tract infections, including pyelonephritis–
–First carbapenem-based combination product – combination of meropenem with a new class of beta-lactamase inhibitor–
–Addresses pathogens designated by the CDC as urgent and serious antimicrobial resistance threats, and pathogens cited by the WHO as a critical need for new antibiotics–
–VABOMERE expected to be available in the fourth quarter of 2017–
VABOMERE addresses gram-negative bacteria that produce beta-lactamase
enzymes that have spread in
“We are grateful to the
The primary assessment was performed in the microbiologic modified intent-to-treat (mMITT) patient population, and was defined as overall success of clinical outcome (cure or improvement) and microbiologic outcome of eradication (baseline bacterial pathogen reduced to < 104 CFU/ml). Overall success was observed in 183/186 patients (98.4%) in the meropenem-vaborbactam group and in 165/175 patients (94.3%) in the piperacillin-tazobactam group – a difference of 4.1% (95% CI: 0.3% to 8.8%). The most common adverse events for VABOMERE included headache, infusion site reactions and diarrhea.
Data from the TANGO clinical program, including data from TANGO-2, a
multi-center, randomized, open-label clinical trial of VABOMERE versus
“best available therapy” in subjects with known or suspected
carbapenem-resistant Enterobacteriaceae (CRE), will be presented at
IDWeek 2017, to be held
We expect that VABOMERE will be available in the fourth quarter of 2017.
About VABOMERE™ (meropenem and vaborbactam) for Injection
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.
Highlights of Prescribing Information
Dosage and Administration
The recommended dosage of VABOMERE is 4 grams (meropenem 2 grams and vaborbactam 2 grams) administered every 8 hours by intravenous (IV) infusion over 3 hours in patients 18 years of age and older with an estimated glomerular filtration rate (eGFR) greater than or equal to 50 mL/min/1.73m2. The duration of treatment is for up to 14 days.
Dosage Adjustments in Patients with Renal Impairment
Dosage adjustment is recommended in patients with renal impairment who have an eGFR less than 50 mL/min/1.73m2. The recommended dosage of VABOMERE in patients with varying degrees of renal function is presented in Table 1 (below). For patients with changing renal function, monitor serum creatinine concentrations and eGFR at least daily and adjust the dosage of VABOMERE accordingly.
Meropenem and vaborbactam are removed by hemodialysis. For patients maintained on hemodialysis, administer VABOMERE after a hemodialysis session.
Table 1: Dosage of VABOMERE in Patients with Renal Impairment
Mechanism of Action
The meropenem component of VABOMERE is a penem antibacterial drug. The bactericidal action of meropenem results from the inhibition of cell wall synthesis. Meropenem penetrates the cell wall of most gram-positive and gram-negative bacteria to bind penicillin-binding protein (PBP) targets. Meropenem is stable to hydrolysis by most beta-lactamases, including penicillinases and cephalosporinases produced by gram-negative and gram-positive bacteria, with the exception of carbapenem hydrolyzing beta-lactamases.
The vaborbactam component of VABOMERE is a non-suicidal beta-lactamase inhibitor that protects meropenem from degradation by certain serine beta-lactamases such as Klebsiella pneumoniae carbapenemase (KPC). Vaborbactam does not have any antibacterial activity. Vaborbactam does not decrease the activity of meropenem against meropenem-susceptible organisms.
Mechanisms of beta-lactam resistance may include the production of beta-lactamases, modification of PBPs by gene acquisition or target alteration, up-regulation of efflux pumps, and loss of outer membrane porin. VABOMERE may not have activity against gram-negative bacteria that have porin mutations combined with overexpression of efflux pumps.
Clinical isolates may produce multiple beta-lactamases, express varying levels of betalactamases, or have amino acid sequence variations, and other resistance mechanisms that have not been identified.
Culture and susceptibility information and local epidemiology should be considered in selecting or modifying antibacterial therapy.
VABOMERE demonstrated in vitro activity against Enterobacteriaceae in the presence of some beta-lactamases and extended-spectrum beta-lactamases (ESBLs) of the following groups: KPC, SME, TEM, SHV, CTX-M, CMY, and ACT. VABOMERE is not active against bacteria that produce metallo-beta lactamases or oxacillinases with carbapenemase activity.
In the Phase 3 cUTI trial with VABOMERE, some isolates of E. coli, K. pneumoniae, E. cloacae, C. freundii, P. mirabilis, P. stuartii that produced beta-lactamases, were susceptible to VABOMERE (minimum inhibitory concentration ≤4 mcg /mL). These isolates produced one or more beta-lactamases of the following enzyme groups: OXA (non-carbapenemases), KPC, CTX-M, TEM, SHV, CMY, and ACT.
Some beta-lactamases were also produced by an isolate of K. pneumoniae that was not susceptible to VABOMERE (minimum inhibitory concentration ≥32 mcg/mL). This isolate produced beta-lactamases of the following enzyme groups: CTX-M, TEM, SHV, and OXA.
No cross-resistance with other classes of antimicrobials has been identified. Some isolates resistant to carbapenems (including meropenem) and to cephalosporins may be susceptible to VABOMERE.
Interaction with Other Antimicrobials
In vitro synergy studies have not demonstrated antagonism between VABOMERE and levofloxacin, tigecycline, polymyxin, amikacin, vancomycin, azithromycin, daptomycin, or linezolid.
Activity against Meropenem Non-susceptible Bacteria in Animal Infection Models
Vaborbactam restored activity of meropenem in animal models of infection (e.g., mouse thigh infection, urinary tract infection and pulmonary infection) caused by some meropenem non-susceptible KPC-producing Enterobacteriaceae.
VABOMERE has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections.
The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro MIC less than or equal to the susceptible breakpoint for VABOMERE against isolates of a similar genus or organism group. However, the efficacy of VABOMERE in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.
Susceptibility Test Methods
When available, the clinical microbiology laboratory should provide cumulative reports of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid in selecting the most appropriate antibacterial drug for treatment.
Quantitative methods are used to determine antimicrobial MICs. These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method (broth and/or agar). The MIC values should be determined using serial dilutions of meropenem combined with a fixed concentration of 8 mcg/mL of vaborbactam. The MIC values should be interpreted according to the criteria in Table 6 (below).
Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized method. This procedure uses paper disks impregnated with 20 mcg of meropenem and 10 mcg vaborbactam to test the susceptibility of bacteria to meropenem and vaborbactam. The disk breakpoints are provided in Table 6 (below).
Table 6: Susceptibility Interpretive Criteria for Meropenem/Vaborbactam
S = Susceptible; I = Intermediate; R = Resistant
A report of Susceptible (S) indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of Intermediate (I) indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of the drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant (R) indicates that the antimicrobial drug is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentrations usually achievable at the infection site; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy of supplies and reagents used in the assay, and the techniques of the individuals performing the test. Standard meropenem and vaborbactam powder should provide the following range of MIC values noted in Table 7 (below). For the diffusion technique using the 20 mcg meropenem/10 mcg vaborbactam disk, the criteria in Table 6 (above) should be achieved.
Table 7: Acceptable Quality Control Ranges for Meropenem/Vaborbactam
IMPORTANT SAFETY INFORMATION
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
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 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
In addition to the development and approval of VABOMERE, MDCO IDC has,
since 2014, successfully developed 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
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 the timing and success of a commercial launch of VABOMERE in