The Medicines Company Announces Positive Top- Line Results for Phase 3 TANGO 1 Clinical Trial of CARBAVANCE®

27 Jun 2016
  • CARBAVANCE (meropenem-vaborbactam) met both FDA and EMA pre-specified primary endpoints in patients with complicated urinary tract infections (cUTI)
  • CARBAVANCE demonstrated statistical superiority over piperacillin-tazobactam, with overall success in 98.4% of treated patients, using FDA primary endpoint
  • CARBAVANCE safety comparable to piperacillin-tazobactam
  • TANGO 1 clinical data will support global regulatory submissions
  • The Company expects to submit a New Drug Application (NDA) to the FDA in early 2017
  • FDA has designated CARBAVANCE as a Qualified Infectious Disease Product (QIDP), as authorized under the GAIN Act, and granted Fast Track status
  • CARBAVANCE development program targets urgent and growing global threat of deadly gram-negative superbugs referred to as carbapenem-resistant Enterobacteriaceae (CRE)
  • The Company will host a conference call and audio webcast at 8:30 a.m., EDT, today

PARSIPPANY, N.J.--(BUSINESS WIRE)--Jun. 27, 2016-- The Medicines Company (NASDAQ:MDCO) today announced that its investigational antibiotic, CARBAVANCE® (meropenem-vaborbactam), met both FDA and EMA pre-specified primary endpoints in the Phase 3 TANGO 1 clinical trial in patients with cUTI. CARBAVANCE also demonstrated statistical superiority over piperacillin-tazobactam, with overall success in 98.4% of patients treated with CARBAVANCE, using the FDA primary endpoint. CARBAVANCE was well tolerated in the trial. The Company will present the complete results of TANGO 1 at an upcoming infectious disease conference.

“The results of TANGO 1 are compelling,” said Jeff Loutit, MBChB, Vice President and Chief Medical Officer of the Infectious Disease Group of The Medicines Company, who led the study. “Clinical and microbiological responses with CARBAVANCE in TANGO 1 were among the highest of clinical trials recently conducted with new antimicrobial agents. The demonstration of superiority with CARBAVANCE treatment over piperacillin-tazobactam in the FDA primary endpoint and the robust effects in other endpoints demonstrates the potential gains we can make clinically in the treatment of gram-negative infections. We believe that TANGO 1 provides the pivotal clinical data necessary for the submission of an NDA with the U.S. Food and Drug Administration (FDA) and a marketing authorization application (MAA) with the European Medicines Agency (EMA).”

Keith Kaye M.D., MPH, Corporate Vice President of Quality, Infection Prevention and Antimicrobial Stewardship at Detroit Medical Center said, “The threat of antibiotic resistance, particularly resistance to carbapenems, is growing rapidly here in the U.S. and around the world. CRE infections are one of the deadliest, with mortality reaching 40%. The U.S. Centers for Disease Control and Prevention (CDC) considers CRE as one of the top three most urgent drug-resistant infectious disease threats and the only one of the top three that causes systemic infections. The need for antimicrobials capable of effectively treating CRE and other resistant organisms is exceedingly high. The data from the CARBAVANCE development program overall may provide physicians with encouragement that new and effective treatment options are on the way.”

Michael N. Dudley, PharmD, Senior Vice President, Head of R&D and Co-Leader of the Infectious Disease Group of The Medicines Company, said, “We are grateful to all of the patients and physicians who participated in TANGO 1. We congratulate them and our CARBAVANCE team, which discovered and advanced a new chemical entity from the chemist’s bench in our laboratories through the successful completion of a pivotal Phase 3 trial with exceptional speed. The rapid development of CARBAVANCE and the success of TANGO 1 were significantly aided by our collaboration with the Biomedical Advanced Research and Development Authority (BARDA). We are grateful to BARDA for its ongoing support as we continue to advance meropenem-vaborbactam. We expect to file an NDA with the FDA in early 2017.”

Clive Meanwell, M.D., Ph.D., Chief Executive Officer of The Medicines Company, added, “We are delighted with the results from TANGO 1, which further evidence the strength of our product discovery and development capabilities and reflect our continuing commitment to and execution against our strategy to focus on the four potential blockbuster products in our development pipeline, including CARBAVANCE. Today’s announcement also demonstrates the compelling attributes of our Infectious Disease Group and the attractive value proposition it provides. We continue to aggressively drive the development of our other three investigational agents—our PCSK9 synthesis inhibitor for lowering LDL-c; our lipid modulating agent, MDCO-216, which contains ApoA1-Milano and is targeted at arterial plaque regression; and our IV anesthetic and sedation agent, ABP-700—and we look forward to important news flow regarding these potential blockbusters over the second half of 2016.”

TANGO 1 Top-Line Results
TANGO 1 is a multi-center, randomized, double-blind, double-dummy Phase 3 study to evaluate the efficacy, safety and tolerability of CARBAVANCE 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 CARBAVANCE (meropenem 2g-vaborbactam 2g) as a 3-hour IV infusion every 8 hours or piperacillin 4g-tazobactam 500mg as a 30 minute IV infusion every 8 hours, each for up to 10 days. After a minimum of 5 days of IV therapy, patients who met protocol-defined criteria of improvement were transitioned to oral levofloxacin.

For the FDA, 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 188/192 patients (98.4%) in the meropenem-vaborbactam group and in 171/182 patients (94.0%) in the piperacillin-tazobactam group—a difference of 4.5% (95% CI: 0.7 % to 9.1%).

For the EMA, the primary assessment was defined as microbiologic outcome of eradication (baseline bacterial pathogen reduced to < 103 CFU/ml) at the test-of-cure (TOC) visit in the mMITT and microbiologic evaluable (ME) patient populations. For the mMITT patient population, the microbiological eradication was 128/192 patients (66.7%) in the meropenem-vaborbactam group and 105/182 patients (57.7%) in the piperacillin-tazobactam group—a difference of 9.0% (95% CI: -0.9% to 18.7%). For the ME patient population, the microbiological eradication was 118/178 patients (66.3%) in the meropenem-vaborbactam group and 102/169 patients (60.4%) in the piperacillin-tazobactam group—a difference of 5.9% (95% CI: -4.2% to 16%).

In the safety population (272 in the meropenem-vaborbactam group; 273 in the piperacillin-tazobactam group), there were 106 patients (39.0%) that reported treatment emergent adverse events (TEAEs) in the meropenem-vaborbactam group and 97 patients (35.5%) that reported TEAEs in the piperacillin-tazobactam group. Drug-related TEAEs were reported with similar frequency in the meropenem-vaborbactam group (15.1% of patients) and the piperacillin-tazobactam group (12.8% of patients). Study drug discontinuation due to adverse events occurred in 7 patients (2.6%) that received meropenem-vaborbactam and 14 patients (5.1 %) that received piperacillin-tazobactam. Serious adverse events (SAEs) occurred in 11 patients (4%) that received meropenem-vaborbactam and 12 patients (4.4%) that received piperacillin-tazobactam. There were 2 deaths in each treatment group.

Conference Call/Audio Webcast Information
The Medicines Company will host a conference call and audio webcast today at 8:30 a.m., EDT. The call can be accessed by dialing (877) 359-9508 (U.S. and Canada) or (224) 357-2393 (international) and entering passcode 36664352. To access the live audio webcast, or the subsequent archived recording, visit the "Investors Relations—Events" section of The Medicines Company website at www.themedicinescompany.com. The audio webcast will be recorded and available for replay on The Medicines Company website for 30 days following the call.

About CARBAVANCE® (meropenem-vaborbactam)
CARBAVANCE, an investigational agent not approved for commercial use in any market, is a combination of the carbapenem, meropenem, and the novel beta-lactamase inhibitor vaborbactam (formerly known as RPX7009) administered as a fixed combination by IV infusion and is being developed to treat serious gram-negative infections, such as cUTIs, including those infections caused by bacteria resistant to currently available carbapenems.

CARBAVANCE was designed to address gram-negative bacteria that produce new beta-lactamase enzymes that have spread in the U.S. and Europe, including strains producing the Klebsiella pneumoniae carbapenemase (KPC) enzyme. KPC-producing bacteria are the predominant form of CRE in the U.S. and are classified by the U.S. Centers for Disease Control and Prevention to be an urgent antimicrobial resistance threat.

About TANGO 2
TANGO 2 is a Phase 3, multi-center, randomized, open-label study of CARBAVANCE (meropenem-vaborbactam) versus “best available therapy” in subjects with selected serious infections due to CRE. Approximately 150 study subjects with cUTI, nosocomial pneumonia and/or bacteremia will be randomly assigned (2:1) to CARBAVANCE or “best available therapy” for up to 14 days. This study is ongoing and an interim analysis will provide supportive data for the NDA.

About BARDA
In February 2014, the CARBAVANCE program was awarded a contract by BARDA (contract HHSO100201400002C) that included an initial commitment of $19.8 million and subsequent option periods over 5 years that, if completed, would bring the total value of the award to approximately $91.8 million to support the development of CARBAVANCE. BARDA awarded the second option on October 31, 2014 and the third option on October 1, 2015, bringing the total BARDA commitment to $53.8 million. In December 2015, BARDA increased the amount authorized under the third option by $2.0 million, thus increasing BARDA’s total commitment to $55.8 million. The BARDA contract is a cost-sharing arrangement that includes non-clinical development activities, clinical studies, manufacturing, and associated regulatory activities.

About The Medicines Company
The Medicines Company's purpose is to save lives, alleviate suffering and contribute to the economics of healthcare by focusing on leading acute/intensive care hospitals worldwide. Its vision is to be a leading provider of solutions in three areas: serious infectious disease care, acute cardiovascular care and surgery and perioperative care. The Company operates in the Americas, Europe and the Middle East and Asia Pacific regions with global centers today in Parsippany, N.J. and Zurich.

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," "hopes," and "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 our product candidates, including CARBAVANCE, will advance in the clinical trials process on a timely basis or at all, whether physicians, patients and other key decision makers will accept clinical trial results, whether the Company will make regulatory submissions for its product candidates on a timely basis or at all, whether its 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 SEC on May 9, 2016 , which are incorporated herein by reference. The Company specifically disclaims any obligation to update these forward-looking statements.

Source: The Medicines Company

The Medicines Company
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Christopher Visioli, +1 973-290-6162
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Christopher.Visioli@themedco.com
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Krishna Gorti, M.D., +1 973-290-6122
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