Clinical Trials

Date: 2018-04-23

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) 2018 meeting

Company: Melinta Therapeutics (USA - CT)

Product: Vabomere™ (formerly known as Carbavance) meropenem-vaborbactam

Action mechanism:

• antibiotic. Vabomere™ (formerly also known as Carbavance) is a fixed-dose combination of the carbapenem, meropenem, and the novel beta-lactamase inhibitor, vaborbactam. 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). Ir has been designated by the 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.
• In January  2018, The Medicines Company announced the closing of the sale of its infectious disease business unit to Melinta Therapeutics .

 

Disease: complicated urinary tract infections (cUTI)

Therapeutic area: Infectious diseases

Country:

Trial details:

• TANGO 1 is a multi-center, randomized, double-blind, double-dummy Phase 3 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 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.
• 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 carbapenem-resistant Enterobacteriaceae. 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.

Latest news:

• • On April 23, 2018, Melinta Therapeutics has presented detailed results from the Vabomere™ (meropenem and vaborbactam) Phase 3 TANGO II trial at the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) 2018 meeting. The majority of patients enrolled in TANGO II presented at baseline with severe co-morbidities including compromised immune systems or renal insufficiency, each of which can complicate treatment and have a negative impact on clinical outcomes.
• Summaries of the key findings from poster and oral presentations made at ECCMID 2018 are as follows:
• P0285:Meropenem-vaborbactam versus best-available therapy for carbapenem-resistant Enterobacteriaceae infections in TANGO II: outcomes in patients with cancer. Patients with underlying malignancies and immunocompromised patients are particularly susceptible to CRE infections, which can have a significant impact on mortality. In TANGO II, 43 patients were enrolled who had a confirmed CRE at baseline (mCRE-MITT population). Among these patients, 15 had a prior or ongoing malignancy, the majority of whom were immunocompromised. The eight patients treated with Vabomere™ experienced higher clinical cure rates at end of treatment (EOT) and test-of cure (TOC) visits and an improved day-28 mortality (87.5%, 75.0% and 12.5%) compared to the seven who received BAT (14.3%, 0% and 57.1%). In the broader MITT population, the 12 cancer patients treated with Vabomere™ reported fewer drug-related adverse events (16.7% vs. 33.3%), serious adverse events (25.0% vs. 77.8%), and renal adverse events (8.3% vs. 22.2%) than did the nine patients treated with BAT.
• O0608:Meropenem-vaborbactam versus best available therapy for infections due to carbapenem-resistant Enterobacteriaceae in TANGO II: impact of prior antibiotic failure on clinical outcomes. Nine patients in the mCRE-MITT population had been deemed by the investigator to have failed prior antimicrobials, all of whom were randomized to the Vabomere™ arm. To examine clinical cure and day-28 mortality rates in Vabomere™ - and BAT-treated patients in comparable populations, these nine prior-failures were excluded from the analysis, which resulted in clinical cure rates for the 19 patients treated with Vabomere™ at EOT and TOC of 84.2% and 68.4%, respectively, and 28-day mortality of 5.3%. This compares favorably to the clinical cure rates and 28-day mortality of the 28 patients who received BAT (33.3%, 26.7% and 33.3%, respectively).
• P2205:Ex vivo characterization of effects of renal replacement therapy modalities and settings on pharmacokinetics of meropenem-vaborbactam. Individuals with end-stage renal disease (ESRD) receiving renal replacement therapy (RRT) are also at increased risk of infection by carbapenem-resistant organisms. An ex vivo analysis found that there was negligible adsorption of Vabomere™ by the dialysis filter.
• Overall, Vabomere™ was well tolerated in Phase 3 trials. The most common adverse events (?3% of patients) were diarrhea, anemia, and hypokalemia.• On October 5, 2017, new data from TANGO II study of Vabomere® (meropenem and vaborbactam)have been 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.
• 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 forVabomere® (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.
• • On July 25, 2017, The Medicines Company announced positive results from an interim analysis of the TANGO-2 trial of its 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 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.
• • On June 27, 2016, The Medicines Company announced that 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.
• TANGO 1  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.  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 visit in the mMITT and microbiologic evaluable 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.
• • On May 26, 2016, The Medicines Company has announced the completion of patient enrollment in the Phase 3 TANGO 1 study of Carbavance® (meropenem-vaborbactam) developed for the treatment of complicated urinary tract infections. TANGO 1 was initiated in the fourth quarter of 2014 under a cost-share agreement with the Biomedical Advanced Research and Development Authority (BARDA) to support the development of Carbavance®. Top-line data are expected in the second half of 2016.

   

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