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FDA Grants Accelerated Approval For The Medicines Company (MDCO)'s UTI Drug



8/30/2017 5:38:56 AM

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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–

PARSIPPANY, N.J.--(BUSINESS WIRE)--The Medicines Company (NASDAQ:MDCO) today announced that the U.S. Food and Drug Administration (FDA) has approved VABOMERE™ (meropenem and vaborbactam) for injection 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. VABOMERE is a drug containing meropenem, an antibacterial, and vaborbactam, which inhibits certain types of resistance mechanisms used by bacteria.

“Carbapenem antibiotics have been the preferred drugs for treating serious infections, such as cUTI, due to Enterobacteriaceae-producing, extended-spectrum beta-lactamases. With the dissemination of the KPC enzyme, new drugs that address this resistance mechanism to carbapenems are a welcome addition to our armamentarium.”

VABOMERE addresses gram-negative bacteria that produce beta-lactamase enzymes that have spread in the United States and Europe, particularly the Klebsiella pneumoniae carbapenemase (KPC) enzyme. KPC-producing bacteria are responsible for a large majority of all carbapenem-resistant Enterobacteriaceae in the United States and are classified by the U.S. Centers for Disease Control (CDC) to be an urgent antimicrobial resistance threat. VABOMERE was granted priority review and approval as a Qualified Infectious Disease Product (QIDP) in accordance with the Generating Antibiotics Incentives Now (GAIN) Act, which made VABOMERE eligible for the FDA’s fast-track program, and approval now secures a five-year regulatory extension of exclusivity under the Hatch-Waxman Act, which means that patent coverage and exclusivity in the United States are expected to extend into 2031. VABOMERE was developed by The Medicines Company’s Infectious Disease Business and is a key addition to its leading portfolio of infectious disease products that provide broad treatment coverage for many of the highest-priority, drug-resistant pathogens identified by the CDC and the World Health Organization (WHO).

“We are grateful to the FDA for working with us to advance the development and approval of VABOMERE for cUTI on an accelerated basis to make this important treatment available to physicians and patients, who carry significant risks of death and mortality, at the soonest possible time,” said Clive Meanwell, M.D., Ph.D., Chief Executive Officer of The Medicines Company. “VABOMERE represents a significant new advancement in addressing KPC-producing Enterobacteriaceae, for which there are currently limited treatment options. We look forward to a successful U.S. launch of VABOMERE, leveraging our established, fully dedicated commercial infrastructure, and to expanding VABOMERE into other global markets.”

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 commented, “Carbapenem antibiotics have been the preferred drugs for treating serious infections, such as cUTI, due to Enterobacteriaceae-producing, extended-spectrum beta-lactamases. With the dissemination of the KPC enzyme, new drugs that address this resistance mechanism to carbapenems are a welcome addition to our armamentarium.”

The FDA approval of VABOMERE was supported by TANGO-1, a Phase III, multi-center, randomized, double-blind, double-dummy study to evaluate the efficacy, safety and tolerability of VABOMERE compared to piperacillin-tazobactam in the treatment of cUTI, including acute pyelonephritis, in adults. The trial enrolled 550 adult patients who were randomized 1:1 to receive VABOMERE (meropenem 2g - vaborbactam 2g) as a three-hour IV infusion every eight hours, or piperacillin 4g - tazobactam 500mg as a 30-minute IV infusion every eight hours, each for up to 10 days.

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.

Michael Dudley, PharmD, FIDSA, Senior Vice President, Head of R&D and Co-Leader for The Medicines Company’s Infectious Disease Business, noted, “We are grateful for the support of patients, families, and investigators that contributed to the rapid development of VABOMERE as it progressed from discovery in our laboratories to availability for patients in under eight years. This unprecedented speed has, in no small way, been due to our outstanding collaboration with, and support received from, the Biomedical Advanced Research and Development Authority (BARDA).”

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 October 4-8, 2017 in San Diego. Last month, the Company announced cessation of enrollment in TANGO-2 following a recommendation by the independent Data and Safety Monitoring Board, which concluded that a risk-benefit analysis of available data no longer supported randomization of additional patients to the “best available therapy” comparator arm.

We expect that VABOMERE will be available in the fourth quarter of 2017. The FDA approval of VABOMERE triggered a $40 million milestone payment obligation to the former securityholders of Rempex Pharmaceuticals, Inc., which we acquired in December 2013.

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

Recommended Dosage

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

eGFRa

(mL/min/1.73m2)

Recommended Dosage Regimen for
VABOMERE (meropenem and
vaborbactam)b, c, d

Dosing Interval
30 to 49

VABOMERE 2 grams (meropenem 1 gram and
vaborbactam 1 gram)

Every 8 hours
15 to 29

VABOMERE 2 grams (meropenem 1 gram and
vaborbactam 1 gram)

Every 12 hours
Less than 15

VABOMERE 1 gram (meropenem 0.5 grams
and vaborbactam 0.5 grams)

Every 12 hours
a. As calculated using the Modification of Diet in Renal Disease (MDRD) formula as follows: eGFR (mL/min/1.73m2) = 175 x (serum creatinine)-1.154 x (age)-0.203x (0.742 if female) x (1.212 if African American).
b. All doses of VABOMERE are administered intravenously over 3 hours.
c. Doses adjusted for renal impairment should be administered after a hemodialysis session.
d. The total duration of treatment is for up to 14 days.

Microbiology

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.

Resistance

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.

Antimicrobial Activity

VABOMERE has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections.

Gram-negative bacteria:

  • Enterobacter cloacae species complex
  • Escherichia coli
  • Klebsiella pneumoniae

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.

Gram-negative bacteria:

  • Citrobacter freundii
  • Citrobacter koseri
  • Enterobacter aerogenes
  • Klebsiella oxytoca
  • Morganella morganii
  • Proteus mirabilis
  • Providencia spp.
  • Pseudomonas aeruginosa
  • Serratia marcescens

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.

Dilution Techniques

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).

Diffusion Techniques

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

Pathogen

Minimum Inhibitory
Concentrations (mcg/mL)

Disk Diffusion
(zone diameters in mm)

Enterobacteriaceae

S I R

S

I

R

=4/8 8/8 =16/8

=17

14-16

=13

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.

Quality Control

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.

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