RESTORE-IMI 2: Imipenem/Cilastatin Relebactam Non-inferior to Piperacillin/Tazobactam for HABP/VABP

Imipenem/cilastatin plus relebactam (Recarbrio) was approved by the US Food and Drug Administration (FDA) last July for the treatment of complicated urinary tract infections (cUTIs) and complicated intra-abdominal infections (cIAIs) in adult patients with limited or no available treatment options. Since then, the combination from Merck has been under investigation for the treatment of hospital-acquired or ventilator-associated bacterial pneumonia (HABP/VABP).

Now, new results from the phase 3 RESTORE-IMI 2 trial demonstrate that imipenem/cilastatin plus relebactam (IMI/REL) is non-inferior to piperacillin/tazobactam (PIP/TAZ) in patients with HABP/VABP. The data were released as part of the now-cancelled European Congress of Clinical Microbiology and Infectious Diseases (ECCMID).

In RESTORE-IMI 2, a randomized, controlled, double-blind phase 3 trial evaluating efficacy and safety of IMI/REL for HABP/VABP, 537 patients were randomized 1:1 to either 500 mg/250 mg IMI/REL or 4 g/500 mg PIP/TAZ every 6 hours intravenously for 7 to 14 days. Investigators obtained lower respiratory tract specimens <48 hours prior to screening, and also delivered empiric linezolid to patients until baseline cultures confirmed presence of methicillin-resistant Staphylococcus aureus (MRSA).

The modified intent-to-treat (MITT) population comprised 531 randomized patients with ≥1 dose of study drug, excluding patients with only gram-positive cocci present on baseline Gram stain.

Day 28 all-cause mortality and clinical response at early follow-up (7 to 14 days after completing therapy) made up the primary and secondary end points in the MITT population, respectively. Non-inferiority margins for those outcomes were 10% and -12.5%, respectively.

In the MITT population (264 IMI/REL, 267 PIP/TAZ), 48.6% had ventilated HABP or VABP, 42.9% were ≥ 65 years old, 66.1% were in the intensive care unit, 47.5% had APACHE-II scores ≥15, and 24.7% had moderate/severe renal impairment. Klebsiella pneumoniae (25.6%), Pseudomonas aeruginosa (18.9%), Acinetobacter calcoaceticus-baumannii complex (15.7%), and Escherichia coli (15.5%) were the most common causative pathogens in the microbiologic MITT population.

For both the primary and secondary efficacy end points, IMI/REL was non-inferior (p <0.001) to PIP/TAZ. The rates of adverse events (AEs) in the safety population (IMI/REL 226/266 [85.0%] vs PIP/TAZ 233/269 [86.6%]), as well as therapy discontinuations due to both overall AEs and specifically due to drug-related AEs, were similar across both treatment arms. Diarrhea, increase alanine aminotransferase, and increased aspartate aminotransferase were the most common AEs (6/266 [2.3%] each).

“IMI/REL is an efficacious and well-tolerated treatment option for HABP/VABP,” investigators concluded.

“The major take-home message…is this is a very welcome, interesting new option for the treatment of pneumonia...It doesn't have the indication yet, but it's exciting because [IMI/REL] performed very well compared to a standard agent that we use for the treatment of pneumonia,” Keith S. Kaye, MD, MPH, director of research in the Division of Infectious Disease at University of Michigan, told Contagion^® at ID Week 2019, when topline results of RESTORE-IMI 2 were first unveiled.

The FDA accepted a supplemental new drug application for IMI/REL in February 2020, and has set a Prescription Drug User Fee Act (PDUFA) goal date of June 4, 2020.

The abstract, “RESTORE-IMI 2: randomised, double-blind, phase III trial comparing efficacy and safety of imipenem/cilastatin (IMI)/relebactam (REL) versus piperacillin/tazobactam (PIP/TAZ) in adult patients with hospital-acquired or ventilator-associated bacterial pneumonia (HABP/VABP),” was released May 5, 2020, as part of the ECCMID Abstract Book 2020.