Regulatory Decision Summary for Recarbrio

The purpose of this New Drug Submission (NDS)-New Active Substance (NAS) was to obtain market authorization, pursuant to section C.08.0004 of the Food and Drugs Regulations, for Recarbrio filed by Merck Canada Inc.

Recarbrio (500 mg imipenem, 500 mg cilastatin, and 250 mg relebactam; sterile powder for solution; intravenous (IV) infusion) is indicated for the treatment of hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), complicated urinary tract infections (cUTI), and complicated intra-abdominal infections (cIAI) in patients 18 years of age and older who have limited or no alternative treatment options. Upon review of the submitted data package, Health Canada authorized Recarbrio as filed. This submission was filed and reviewed under the Priority Review Policy.

Recarbrio (imipenem/cilastatin/relebactam) is a new beta-lactam/beta-lactamase inhibitor combination indicated for the treatment of hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), complicated urinary tract infections (cUTI), and complicated intra-abdominal infections (cIAI) in patients 18 years of age and older who have limited or no alternative treatment options.

The combination imipenem/cilastatin has been approved for almost forty years in Canada for the intravenous treatment of various bacterial infections, such as lower respiratory tract, urinary tract, and intra-abdominal infections. The therapeutic innovation in Recarbrio is the addition of relebactam (a beta-lactamase inhibitor from the diazobicyclooctane (DABCO) family) to imipenem/cilastatin in a fixed-dose combination for protection and potentiation of imipenem. In line with relevant European Medicines Agency (EMA; 2014) and United States Food and Drug Administration (FDA; 2017) guidelines, Recarbrio was developed via a streamlined drug development program that allows seeking initial approval of a drug based on limited clinical data when the proposed drug product is addressing an unmet medical need in treatment of infections caused by multidrug-resistant pathogens in patients with limited or no alternative treatments available.

In order to demonstrate the clinical efficacy and safety of Recarbrio relative to the active control colistin, the sponsor conducted the pivotal Phase 3 study PN013 in patients with bacterial infections including HABP/VABP, cUTI and cIAI caused by imipenem-nonsusceptible pathogens. This was the main source of clinical evidence supporting the three indications. The trial was designed as an estimation trial (only for descriptive comparison of efficacy) and, with a small sample size of 47 randomized patients (2:1), was not sufficiently powered for a formal statistical testing of efficacy endpoints. This flexible study design was acceptable in the context of the streamlined drug development approach. The trial met its primary efficacy endpoint of favorable overall response in the primary and supportive analysis datasets for HABP/VABP and cUTI, and thus Recarbrio showed adequate efficacy in these two indications. For the cIAI indication, none of the patients with intra-abdominal infection achieved a favorable clinical response in the primary analysis dataset in either treatment group. The cIAI patients achieved a favorable efficacy outcome only in the supportive dataset and the response rates were very low. The low efficacy result for cIAI was due to (i) the sample size of patients with cIAI in the primary efficacy population being smaller than in the supportive efficacy population, (ii) the baseline medical complexity in these patients (greater disease severity, confounding medical conditions), and (iii) the fact that missing or indeterminate data were considered treatment failures. Overall, the efficacy results (favorable overall response rates) for the three proposed indications were comparable between Recarbrio (71.4%) and colistin (70.0%).

Because of the small sample size in Study PN013, the clinical data to support the use of Recarbrio in cUTI and cIAI is considered limited. The approval of Recarbrio in these two indications is based on Health Canada’s prior approval and clinical experience with imipenem/cilastatin, PK/PD analyses for efficacy of imipenem and relebactam (PK modeling and simulations), clinical efficacy data from the two Phase 2 studies in patients with imipenem-susceptible pathogens, and limited clinical efficacy data from the Phase 3 study PN013 in patients with imipenem-nonsusceptible pathogens.

To further support the HABP/VABP indication, the sponsor conducted the Phase 3 study PN014 that was adequately powered for a non-inferiority statistical testing with 537 randomized patients (1:1). The trial met its primary efficacy endpoint of all-cause mortality at Day 28 post-randomization. The mortality rate was lower with Recarbrio (15.9%) than with the active control piperacillin/tazobactam (21.3%). Recarbrio was established to be non-inferior to piperacillin/tazobactam in the treatment of HABP/VABP in adults.

Across the clinical program, similar safety profiles were observed between Recarbrio and the controls (colistin or piperacillin/tazobactam). However, from a nephrotoxicity perspective, the renal safety profile of Recarbrio was more favorable than colistin. None of the observed deaths were related to Recarbrio. The most common adverse events (AEs) related to Recarbrio were pyrexia, diarrhea, nausea, infusion site reactions, increased alanine aminotransferase (ALT), and increased aspartate aminotransferase (AST). All these AEs were expected and consistent with the use of imipenem/cilastatin, and have been mitigated by appropriate labeling. Three patients experienced the serious adverse events (SAEs) increased ALT, increased AST, and thrombocytopenia with Recarbrio. These SAEs were of severe intensity, led to treatment discontinuation, and resolved. Most of the patients completed study treatment. The rate of treatment discontinuation due to AEs was low in all treatment groups and not considered a major concern for Recarbrio. The sponsor adequately addressed the potential safety risks in the approved Product Monograph. Overall, the safety profile of Recarbrio at the proposed dosing regimens appeared to be acceptable and manageable. Therefore, there are no major safety concerns that would preclude the clinical use of Recarbrio in humans as indicated.

Phase 1 clinical trials showed that Recarbrio penetrates the pulmonary tissues at sufficient concentrations and is safe and well-tolerated in patients. Relebactam alone or its combination with imipenem-cilastatin does not prolong the QTc interval to a clinically relevant extent. The recommended adjustment in dosing in patients with renal impairment is expected to achieve efficacy targets. Based on population pharmacokinetics analyses, age, gender, and ethnicity are not expected to significantly impact the pharmacokinetics of Recarbrio.

Given the regulatory and marketing history of imipenem/cilastatin, the majority of the non-clinical program focused on relebactam. Safety pharmacology testing in animals and in vitro did not find a risk of cardiovascular, respiratory, or neuro-behavioural disruption. Microbiological investigations found that relebactam increased pathogen susceptibility to imipenem in vitro and in global surveillance isolates and In vitro studies found the rate of resistance development to imipenem/relebactam to be low. Pharmacokinetic evaluations in animals showed relebactam was distributed from maternal plasma to fetal plasma in rats and rabbits and was secreted in the milk of rats. This information is captured in the proposed Product Monograph. Relebactam was generally well tolerated in repeat-dose toxicity and developmental and reproductive studies. The only target organ of toxicity identified in monkeys was the kidney. Relebactam was found to be non-mutagenic and non-genotoxic. In the reproductive and developmental toxicity studies, relebactam had no effects on fertility, reproductive performance, or early embryonic development. However, embryo-fetal development studies with imipenem/Cilastatin found an increase in embryonic loss. This is adequately captured in the Product Monograph.

An updated Risk Management Plan (RMP) for Recarbrio was reviewed by Health Canada and considered acceptable. Risks have been communicated in the approved Product Monograph and will continue to be monitored post market as outlined in the Risk Management Plan, with routine pharmacovigilance activities.

The chemistry and manufacturing information submitted for Recarbrio has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications.

Following the review of the data submitted by the sponsor, Health Canada has determined that the overall benefit-harm-uncertainty profile of Recarbrio is favorable when used under the conditions of use recommended in the approved Product Monograph. Therefore, A Notice of Compliance is recommended.

For further details about Recarbrio, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.