Meropenem-vaborbactam: A New Hope June 1st, 2018 Pavithra Srinivas, PharmD, BCPS, AAHIVP Infectious Diseases Clinical Pharmacy Specialist

Objectives Recognize challenges associated with treatment of MDR Gram-negative infections Describe the spectrum of activity and characteristics of meropenem/vaborbactam Summarize the evidence for meropenem/vaborbactam’s place in therapy

Burden of Antimicrobial Resistance Antibiotic resistance associated with over $20 billion in direct health care related costs MDR Gram negative infections associated with significant clinical and economic burden Increased severity of illness Higher hospital and antibiotic costs Increased hospital and ICU length of stay CRE: Carbapenem Resistant Enterobacteriaceae Biggest challenge: Limited treatment options Kaye KS, Pogue JM. Pharmacotherapy 2015; 35(10): 949-962

β-lactam Resistance Porin loss/deletion β-lactamase Efflux pump Antibiotic Periplasmic space Enzyme Porin loss/deletion β-lactamase Efflux pump Cytoplasm Munoz-Price L, Weinstein RA. N Engl J Med. 2008; 358 : 1271-1281

Types of β-lactamases Ambler class Active site Type Examples β-lactam antimicrobial(s) affected A Serine Narrow spectrum Extended-spectrum (ESBL) Carbapenemases TEM-1, SHV-1 CTX-M KPC Penicillins Cephalosporins, BL-BLIC Carbapenems B Zinc Metallo-β-lactamases NDM, VIM, IMP All β-lactams C Cephalosporinases AmpC 1st – 3rd generation cephalosporins D OXA-type enzymes OXA-23, OXA-48 Ranges from penicillins to all β-lactams BL-BLIC: β-lactam/β-lactamase inhibitor combinations Toussaint KA, Gallagher JC. Ann Pharmacother 2015; 49(1): 86-98

CRE Treatment Optimal treatment largely unknown Monotherapy vs combination therapy Depends on in vitro susceptibility, source and severity of infection Limited available options: Polymyxins, aminoglycosides, tigecycline, fosfomycin, carbapenems Toxicity concerns and further resistance development 18-48% CRE-related mortality rate Ceftazidime/avibactam Morrill HJ, et al. Open Forum Infect Dis 2015; 2(2): ofv050 Rodriguez-Bano J, et al. Clin Microbiol Rev 2018; 31(2): e00079-17

Ceftazidime-avibactam FDA approved in February 2015 Complicated urinary tract infections (cUTI) and acute pyelonephritis (AP) Complicated intra-abdominal infections (cIAI), with metronidazole Ceftazidime + novel β-lactamase inhibitor Active against Ambler Class A (KPC), C and some Class D (OXA) enzymes Resistance concerns No activity against Ambler Class B (metallo-β-lactamase) enzymes Emergence of resistance during therapy, via mutations in the blaKPC-3 gene Reported in 10-30% of cases Rodriguez-Bano J, et al. Clin Microbiol Rev 2018; 31(2): e00079-17 Shields RK, et al. Open Forum Infect Dis 2017; 4: ofx101 Shields RK, et al. Clin Infect Dis 2016; 63(12): 1615-1618

Vaborbactam Cyclic boronic acid based β-lactamase inhibitor Potent activity against Ambler Class A & C β-lactamases KPC, CTX-M, AmpC, TEM, SHV Does NOT enhance susceptibility for: Pseudomonas aeruginosa Acinetobacter spp. Organisms exhibiting Ambler Class B or D β-lactamases Lomovskaya O, et al. Antimicrob Agents Chemother 2017; 61(11): e01443-17 Meropenem/vaborbactam (Vabomere™) [package insert]. Parsippany, NJ: The Medicines Company; August 2017

Vaborbactam vs Avibactam Partner β-lactam Meropenem Ceftazidime Structure Boronic acid Diazabicyclooctane Active site Serine β-lactamase inhibition (Ambler Class) TEM, SHV, CTX-M, KPC (A) +++ Metallo-β-lactamases (B) - AmpC (C) ++ OXA-type carbapenemases (D) + Lomovskaya O, et al. Antimicrob Agents Chemother 2017; 61(11): e01443-17 Wong D, et al. Drugs 2017; 77: 615-628

Meropenem-vaborbactam (Vabomere™) FDA approval: October 2017 Treatment of cUTI and pyelonephritis caused by susceptible pathogens Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae complex Organism MIC (meropenem/vaborbactam) S I R Enterobacteriaceae ≤ 4/8 8/8 ≥ 16/8 MIC: Minimum inhibitory concentration (mcg/mL) Meropenem/vaborbactam (Vabomere™) [package insert]. Parsippany, NJ: The Medicines Company; August 2017

Pharmacokinetics Meropenem Vaborbactam Half-life 1.22 ± 0.3 hours Volume of distribution 20.2 L 18.6 L Intrapulmonary penetration rate 63% 53% Excretion 40-60% in urine 75-95% in urine Pharmacodynamic parameter %T > MIC AUC24/MIC Meropenem and vaborbactam achieve a similar time course of concentration in plasma and ELF Meropenem/vaborbactam (Vabomere™) [package insert]. Parsippany, NJ: The Medicines Company; August 2017

Dosing Considerations Dosing: 4 grams IV every 8 hours Meropenem 2 grams + vaborbactam 2 grams (1:1 ratio) 3-hour IV infusion eGFR* (ml/min/1.73m2) Recommended dose (as total of meropenem and vaborbactam) ≥ 50 4 grams every 8 hours 30-49 2 grams every 8 hours 15-29 2 grams every 12 hours < 15 1 gram every 12 hours For reference, regarding BL/BLI combination ratio previously: PIP/TAZO (8:1 ratio), CAZ/AVI (4:1 ratio) *Calculated using MDRD formula Meropenem/vaborbactam (Vabomere™) [package insert]. Parsippany, NJ: The Medicines Company; August 2017

Precautions Seizure potential CNS effects Thrombocytopenia Risk factors: CNS disorders, bacterial meningitis, renal dysfunction Risk of breakthrough seizures due to drug-interaction with valproic acid CNS effects Neuro-motor impairments including headaches, paresthesia, delirium Thrombocytopenia Increased risk in patients with renal dysfunction Clostridium difficile-associated diarrhea Meropenem/vaborbactam (Vabomere™) [package insert]. Parsippany, NJ: The Medicines Company; August 2017

Clinical Trials TANGO: Targeting Antibiotic Non-susceptible Gram-negative Organisms TANGO I TANGO II Features Site/Indication focused Pathogen-focused Patients cUTI and acute pyelonephritis cUTI, cIAI, HABP/VABP and/or bacteremia due to CRE Design Randomized 1:1 Double-blind Randomized 2:1 Open-label Comparator Piperacillin-tazobactam “Best Available Therapy” Status Completed Loutit J, et al. Oral Abstract. ID Week, New Orleans, October 2016

TANGO I - Study Design Meropenem-vaborbactam (M-V) vs Piperacillin/tazobactam (P-T) for cUTI and acute pyelonephritis Design Randomized, double blind, double dummy, active controlled, non-inferiority Intervention M-V 2-2 g IV q8h over 3 hours Optional switch to PO levofloxacin Total duration 10 days P-T 4.5 g IV q8h over 30 minutes Population Inclusion: Adults with cUTI or acute pyelonephritis and ≥ 2 signs/symptoms Require at least 5 days of IV antibiotics Exclusion: CrCl <30 mL/min or receipt of antibiotic within 48 hours Endpoints Clinical cure or improvement and microbiological eradication composite at end of therapy Non-inferiority margin set at -15% Demographics N = 272 N = 273 Mean age: 53 years Mean age: 52.6 years 59.2% acute pyelonephritis 59% acute pyelonephritis 40.8% cUTI 41% cUTI 28.3% met SIRS 33% met SIRS 46% with E.coli at baseline 43% with E.coli at baseline FDA endpoint: clinical cure or improvement and microbiological eradication at EOT EMA endpoing: Microbiological eradication at TOC visit (7d post therapy) Loutit J, et al. Oral Abstract. ID Week, New Orleans, October 2016

TANGO I - Results 4.5, 95% CI [0.7, 9.1] 9.0, 95% CI [-0.9, 18.7] Among patients with cUTI, including AP, and growth of a baseline pathogen, M-V vs P-T resulted in a composite outcome of complete resolution or improvement of symptoms along with microbial eradication that met the noninferiority criterion. Kaye KS, et al. JAMA 2018; 319(8): 788-799 Loutit J, et al. Oral Abstract. ID Week, New Orleans, October 2016

TANGO I - Adverse Effects Meropenem-vaborbactam (N = 272) Piperacillin-tazobactam (N = 273) Treatment emergent adverse events 39% 35.5% Drug-related adverse events 15.1% 12.8% Adverse effects occurring in > 1% of patients Headache 8.8% 4.4% Infusion-site reactions 0.7% Diarrhea 3.3% Hypersensitivity 1.8% Nausea 1.5% Other ADRs: hypersensitivity, nausea, AST/ALT increase, pyrexia, hypokalemia Meropenem/vaborbactam (Vabomere™) [package insert]. Parsippany, NJ: The Medicines Company; August 2017 Loutit J, et al. Oral Abstract. ID Week, New Orleans, October 2016

TANGO I - Summary Meropenem-vaborbactam Non-inferior and statistically superior to piperacillin-tazobactam for overall success at end of therapy for cUTI/AP Adverse effect profile similar to piperacillin-tazobactam

72 patients enrolled, 43 (59.7%) with baseline CRE TANGO II - Study Design Meropenem-vaborbactam (M-V) vs Best Available Therapy (BAT) for CRE Infections Design Randomized (2:1), open-label Intervention M-V 2-2 g IV q8h over 3 hours Total duration 7-14 days BAT Population Inclusion: Adults with confirmed cUTI/AP, HABP/VABP, bacteremia, or cIAI due to a known or suspected CRE pathogen, requiring at least 7 days of IV therapy Exclusion: Infections due to MBL or OXA-β-lactamase producing organisms, or receipt of >24 h of potentially effective antimicrobial therapy Endpoints Clinical cure and microbiological eradication (cUTI/AP, cIAI) 28-day all cause mortality (HABP/VABP, bacteremia) Baseline Characteristics 72 patients enrolled, 43 (59.7%) with baseline CRE N = 28 with baseline CRE N = 15 with baseline CRE Mean age: 64 years Mean age: 60 years 89% K. pnuemoniae 80% K. pneumoniae Kaye KS, et al. Poster #1862. ID Week, San Diego, October 2017 Wunderink R, et al. Poster #1867. ID Week, San Diego, October 2017

TANGO II - Best Available Therapy Monotherapy: 4/15 (26.7%) Aminoglycoside (1), carbapenem (1), ceftazidime-avibactam (1), polymyxin (1) Dual Therapy: 7/15 (46.7%) Carbapenem + aminoglycoside (1) Carbapenem + polymyxin (1) Carbapenem + tigecycline (2) Polymyxin + aminoglycoside (3) Triple Therapy: 1/15 (6.7%) Carbapenem + polymyxin + tigecycline (1) ≥ 4 Agents: 2/15 (13.3%) Carbapenem + polymyxin + tigecycline + aminoglycoside (2) Kaye KS, et al. Poster #1862. ID Week, San Diego, October 2017

TANGO II - Results 31, 95% CI [1.2, 60.7] p = 0.04 Kaye KS, et al. Poster #1862. ID Week, San Diego, October 2017

TANGO II - Results 41.8, 95% CI [11.1, 72.4] p = 0.008 Kaye KS, et al. Poster #1862. ID Week, San Diego, October 2017

TANGO II - Resistance Analysis M-V treatment associated with lower incidence of MIC increase than C-A (4% vs 25%) 4-fold increase in M-V MIC still maintained overall susceptibility (i.e. MIC ≤ 4) Increased expression of efflux pump C-A MIC increase conferred full resistance Mutations in blaKPC2 gene, porin channel deletion, efflux pump overexpression C-A resistant isolate maintained susceptibility to M-V M-V MIC increase in 1/25 patients (4%), C-A MIC increase in 1/4 patients (25%) M-V: meropenem-vaborbactam C-A: ceftazidime-avibactam Lomovskaya O, et al. Poster #1874. ID Week, San Diego, October 2017

On the horizon Pediatrics Pneumonia – HAP/VAP (TANGO III) Phase I, dose finding, PK, safety and tolerability study Recruiting, estimated completion in Sept 2019 Pneumonia – HAP/VAP (TANGO III) Phase III, double-blind, randomized study Piperacillin/tazobactam comparator arm Not yet recruiting

Summary Carbapenem-resistant Enterobacteriaceae (CRE) present a therapeutic challenge due to the limited availability of active antimicrobial agents Meropenem/vaborbactam is a new agent comprising a carbapenem and a novel β-lactamase inhibitor Meropenem-vaborbactam has demonstrated potent activity against KPC-producing CREs Concerns for developing resistance underscore the importance of judicious use of these new antimicrobials