The Medicines Company announces TANGO-2 trial of meropenem-vaborbactam (formerly, Carbavance) stopped early for superior benefit-risk compared to best available therapy for CRE
The Medicines Company (NASDAQ:MDCO) today announced positive results from an interim analysis of the TANGO-2 trial of its fixed-dose, investigational antibiotic combination, meropenem-vaborbactam. Randomization in the trial was stopped early, following a recommendation by the TANGO-2 independent Data and 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 concluded that a risk-benefit analysis of available data no longer supported randomization of additional patients to the best available therapy comparator arm. The Company will continue to enroll patients into an amended, single-arm study protocol for treatment with meropenem-vaborbactam at selected sites.
The Company expects that data from the TANGO-2 trial will be presented at a future medical conference and published in a peer-reviewed journal.
The Company today also announced that it has selected, and both U.S. and European regulatory authorities have accepted, VabomereTM as the U.S. and European trade name for meropenem-vaborbactam, assuming marketing applications are approved. Previously, meropenem-vaborbactam was commonly referred to as “Carbavance.”
The DSMB’s recommendation to discontinue randomization into the TANGO-2 trial was based on the results of an interim analysis of data from TANGO-2, which showed that, for efficacy, statistically-significant differences favor meropenem-vaborbactam over best available therapy for clinical cure at the test of cure visit in the protocol-specified primary population (all patients with microbiologically-evaluable CRE). Mortality rates were also lower among patients treated with meropenem-vaborbactam. The DSMB also noted a clear difference in renal toxicity, with lower rates of renal adverse events and serum creatinine increases among patients treated with meropenem-vaborbactam than best available therapy – particularly among patients receiving colistin and aminoglycosides.
Keith S. Kaye, MD, MPH, Professor of Medicine at the University of Michigan, and the principal investigator for TANGO-2, stated, “We are grateful for the oversight of the DSMB and for their recommendations. This real-world study involving critically-ill, complex patients met its aims at this interim analysis. Results of TANGO-2 are thoroughly impressive and demonstrate notable efficacy and safety advantages of meropenem-vaborbactam compared to ‘best available therapy’ in the treatment of patients with selected serious infections, suspected or known to be due to CRE. We expect to present details of the TANGO-2 data in a peer-reviewed publication and at a medical conference in the future.”
Michael Dudley, PharmD, Senior Vice President, Head of R&D and Co-Leader for The Medicines Company’s Infectious Disease Business, added, “We are grateful to the patients and families that participated in this trial. We have followed the DSMB’s advice and ended randomization into the trial. We are amending the study protocol to now enroll patients only into the meropenem-vaborbactam treatment group. We expect this extension of TANGO-2 will build on our body of knowledge of CRE patients – which includes information from a case series of 256 patients managed at many of the TANGO-2 study sites prior to the start of the trial, which was recently published in the journal, Open Forum Infectious Diseases. The need for data on the efficacy and safety of new therapies for treating CRE is well recognized and has been highlighted by both the U.S. Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO), each of which has prioritized CRE infections at the top of its list of antimicrobial drug resistance threats worldwide. We are very pleased with the data on Vabomere from TANGO-2.”
TANGO-2 is a multi-center, randomized, open-label Phase III clinical trial of meropenem-vaborbactam versus “best available therapy” in patients with serious infections (complicated urinary tract infections (cUTI), bacteremia, hospital-acquired or ventilator-associated bacterial pneumonia, and complicated intraabdominal infections) suspected or documented to be caused by CRE. Patients with CRE were randomized to receive either meropenem-vaborbactam 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 selected for each patient by the investigator based on laboratory and other patient data, and thus represents the current standard of care used for the treatment of CRE infections.
About Vabomere™ (formerly also known as Carbavance)
Vabomere™ (meropenem-vaborbactam) is a fixed-dose combination of the carbapenem, meropenem, and the novel beta-lactamase inhibitor, vaborbactam. Vabomere is an investigational agent not approved for commercial use in any market. The combination is being developed to treat serious gram-negative infections, such as cUTI, including those infections caused by bacteria resistant to currently available carbapenems. Vabomere’s development has been supported by a cost-share contract with the Biomedical Advanced Research and Development Authority (BARDA).
Vabomere was designed to address gram-negative bacteria that produce new beta-lactamase enzymes that have spread in the United States and Europe, particularly the Klebsiella pneumoniae carbapenemase (KPC) enzyme. KPC-producing bacteria are the predominant form of CRE in the United States and are classified by the CDC to be an urgent antimicrobial resistance threat. A Phase III clinical trial of Vabomere in cUTI and acute pyelonephritis (TANGO-1) was successfully completed in 2016.
Vabomere has been designated by the U.S. Food and Drug Administration (FDA) as a Qualified Infectious Disease Product (QIDP), as authorized under the GAIN Act. It was also granted Fast Track status by the FDA for the treatment of cUTI and pyelonephritis. QIDP designation also provides for additional market exclusivity, if approved.
The NDA for Vabomere was accepted for filing by the FDA with a priority review classification in February 2017 and a PDUFA date in the third quarter of 2017. In July 2017, the European Medicines Agency (EMA) accepted for review a marketing authorization application (MAA) for Vabomere.
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 has shown increasing resistance to widely-used beta-lactam class antibiotics due to the production of enzymes known as beta-lactamases, which degrade these antibiotics. The worldwide dissemination of newer beta-lactamases, known as carbapenemases, has been responsible for resistance to carbapenem and other classes of antibiotics. In the United States, the Klebsiella pneumoniae carbapenemase enzyme is responsible for over 90% of carbapenemase-mediated resistance in CRE. Patients at particular risk for CRE infections include the elderly, immune compromised and those with underlying comorbidities, including malignancies. Infections due to CRE are associated with high antibiotic failure rates, high mortality (20% to 50%), and high cost of care for hospitals, third party payers and society ($10,000 to $84,000 per episode). Due to the paucity of antibiotics with activity against CRE pathogens, physicians often treat CRE infections with combinations of older antibiotics, many of which have significant toxicities, most notably renal toxicity.
In light of the high morbidity and mortality associated with CRE infections and the critical role of carbapenem antibiotics in the treatment of resistant gram negative infections, the spread of CRE has been designated as an urgent antimicrobial resistance threat by the CDC and a critical priority for new drugs by the WHO.
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 is currently developing Vabomere to treat serious gram-negative infections, such as complicated urinary tract infections, including those infections caused by bacteria resistant to currently available carbapenems. MDCO IDC has a leading pipeline of novel agents directed towards existing and emerging multidrug-resistant bacteria.
Since 2014, we have successfully developed and launched two antibiotics against serious infections: Orbactiv® (oritavancin) for the treatment of acute bacterial skin and skin-structure infections in adults, including those due to 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 prescribing information, please see www.orbactiv.com and www.minociniv.com.
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 up to $132 million to support the development of new antibiotics to fight drug-resistant, gram-negative infections. 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. The initial $32 million award supports a Phase IIIb trial of Vabomere for the treatment of gram-negative infections in hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP). The initial award, as well as funding provided under any subsequent options exercised by BARDA, will also support the advancement of additional 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 three critical therapeutic areas: serious infectious disease care, cardiovascular care and surgery and perioperative care. The Company is headquartered in Parsippany, New Jersey, with global innovation centers in California and Switzerland.
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 for Vabomere 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 for Vabomere 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 May 5, 2017, which are incorporated herein by reference. The Company specifically disclaims any obligation to update these forward-looking statements.