IMI/REL Proves Effective Against Certain Drug-Resistant Bacterial Infections

A pivotal phase 3 study has found Merck’s investigational beta-lactamase inhibitor imipenem/relebactam (IMI/REL) to be an effective, well-tolerated therapy for certain imipenem-non-susceptible bacterial infections; the data from the RESTORE-IMI 1 study was presented at the 28th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) in Madrid, Spain.

“Infections caused by resistant organisms are difficult to treat due to limited available treatment options and to toxicity associated with some alternative treatments,” author Amanda Paschke, MD, the director of infectious disease clinical research at Merck Research Laboratories, told our sister publication MD Magazine.

She added that individuals with a serious infection caused by multidrug-resistant (MDR) Gram-negative bacteria tend to be at increased risk for adverse outcomes, longer hospital stays, and higher health care-associated costs. Thus, more treatments are needed for these individuals.

For the multicenter, double-blind, controlled phase 3 trial, investigators sought to compare the safety and efficacy of IMI/REL with colistin plus imipenem/cilastatin (COL+IMI) in patients with imipenem-non susceptible bacteria infections.

Thus, investigators randomized 47 patients with either hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP), complicated intra-abdominal infection (cIAI), or complicated urinary tract infection (cUTI), 2:1 to receive the novel ß-lactamase inhibitor IMI/REL (n = 31) or COL+IMI (n = 16).

In total, 31 patients (HABP/VABP, n = 11; cUTI, n = 16; cIAI, n = 4) met the microbiological intent-to-treat baseline criteria, of which 29% had APACHE-II scores >15, 23% had creatinine clearance <60 mL/min, and 35% were ≥65 years of age. The patients with cUTI/cIAI received the therapies for 5-21 days, while those with HABP/VABP received therapy for 7-21 days.

The primary outcome, Dr. Paschke noted, was a favorable overall response to treatment, which was comparable between the IMI/REL and the colistin plus IMI arms. In fact, a favorable overall response was achieved by 71.4% of patients in the IMI/REL arm (95% CI, 49.8 to 86.4) compared with 70.0% in the colistin plus IMI arm (95% CI, 39.2 to 89.7), for an unadjusted difference of 1.4% (adjusted diff., —7.3%; 90% CI, –27.5 to 21.4).

In the HABP/VABP group, 7 of 8 patients (87.5%; 95% CI, 50.8 to 99.9) displayed a favorable response in the IMI/REL arm compared with 2 of 3 (66.7%) in the colistin plus IMI arm. In the cUIT groups, 8 of 11 patients (72.7%; 95% CI, 42.9 to 90.8) in the IMI/REL arm showed an overall favorable response compared with 5 of 5 (100%; 95% CI, 51.1 to 100.0) in the colistin plus IMI arm. For the cIAI group, both arms had a response rate of 0% (n = 2 for both).

“A key secondary endpoint of the study was safety,” Dr. Paschke said. “IMI-REL was well tolerated; among all treated patients, drug-related adverse events [AEs] occurred in 16.1% of IMI/REL and 31.3% of colistin+IMI patients, with treatment-emergent nephrotoxicity observed in 10% [3 of 29 patients] and 56% [9 of 16 patients], respectively [P = .002].”

With regard to 28-day all-cause mortality, the IMI/REL arm had a rate of 9.5% (n = 2; 95% CI, 1.4 to 30.1) compared to 30% in the colistin plus IMI arm (n = 3; 95% CI, 10.3 to 60.8) for an adjusted difference of —17.3% (90% CI, –46.4 to 6.7).

“The trial design is unusual in its blinded design and use of a defined comparator, rather than comparing to ‘best-available therapy,’ This allowed for a scientifically robust comparison to an appropriate treatment regimen,” Dr. Paschke explained. “Another important feature of the study is that patients were identified for enrollment based on a broth microdilution testing panel, the gold standard, to confirm that pathogens were imipenem non-susceptible as well as colistin- and IMI/REL-susceptible. This testing, incorporated into first-line susceptibility testing conducted as part of routine clinical care, enabled patients with resistant pathogens to be enrolled and given appropriate treatment without further delays, which can lead to poor outcomes in these patients.”

She added that this trial will be the basis for Merck’s initial New Drug Application filing with US Food and Drug Administration (FDA). IMI/REL was previously granted a Fast Track designation by the FDA, due to its potential in an unmet medical need.

“Another larger, Phase 3 trial is ongoing in HABP/VABP,” Dr. Paschke shared. “We look forward to contributing to the knowledge of antibacterial therapy in this very challenging disease state.”

A previous version of this article can be found on MDMagazine.com.