Regulatory Decision Summary for Vabomere

This New Drug Submission (NDS) was submitted to obtain market authorization for Vabomere (meropenem and vaborbactam) for the treatment of bacterial infections in adults: with or without associated bacteremia, complicated urinary tract infections including pyelonephritis; complicated intra-abdominal infection; and hospital acquired pneumonia, including ventilator associated pneumonia; and infections due to gram-negative organisms in adults with limited treatment options.

On April 18, 2024, Health Canada communicated a Notice of Deficiency (NOD) to the Sponsor as the Sponsor had inadvertently submitted the interim report on Study 506 which included 39 patients and was released in 2016, rather than submitting the final report on all 77 patients, released in 2017. The Sponsor’s NOD response provided the final report on Study 506.

The Canadian regulatory decision on the review of Vabomere was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) were used as additional references.

Vabomere is a combination of meropenem, a carbapenem antibiotic, with vaborbactam, a β-lactamase inhibitor of carbapenemase inactivation of meropenem, by Klebsiella pneumonia carbapenemase (KPC) in particular. KPC often causes carbapenem resistance in Enterobacterales. Infections with carbapenem-resistant bacteria such as Carbapenem Resistant Enterobacterales (CRE) are rare but associated with high morbidity and mortality. Vabomere to treat carbapenem-resistant bacterial infections addresses an unmet medical need in Canada.

The Sponsor submitted data from two pivotal phase 3 clinical trials (Study 505 and 506) to support the efficacy and safety of Vabomere for two indications:

• complicated urinary tract infection (cUTI) and acute pyelonephritis (AP) (Study 505), and

• infections caused by KPC-Producing CRE, including cUTI/AP, complicated intra-abdominal infection (cIAI), hospital acquired pneumonia (HAP), including ventilator associated pneumonia (VAP), and bacteremia (Study 506).

However, following review, the primary evidence that supported the efficacy and safety of Vabomere for the recommended indication was from the phase 3 randomized controlled trial Study 506 in adults with known or suspected serious infections with CRE.

Study 505, a multicenter, randomized, double-blind, double-dummy, non-inferiority trial, compared the efficacy and safety of Vabomere (meropenem 2 g-vaborbactam 2 g) to piperacillin-tazobactam (piperacillin 4 g/tazobactam 0.5 g) every 8 hours in 545 adults with cUTI and AP. After ≥ 15 intravenous (IV) study drug doses, patients could be switched to oral levofloxacin. One co-primary efficacy endpoint was overall success (clinical cure or improvement and microbiologic eradication) at the end of IV treatment in microbiological modified intention-to-treat (m-MITT) patients (who had received study drug and had a baseline uropathogen). The other was microbial eradication at test of cure (TOC, 1 week after IV treatment), in m-MITT and microbially evaluable (ME) patients (the ME population included m-MITT patients without key violations of inclusion/exclusion criteria). 1.6% of Vabomere-treated infections were meropenem-resistant, and 0.5% had KPC-producing CRE. 59% of MITT patients had pyelonephritis and 40% cUTI; 66% were female. The mean age was 54 years.

Overall success after IV treatment was in 98.4% of Vabomere patients and 94.0% of piperacillin-tazobactam patients: a difference of 4.5% (95% confidence interval [CI]: 0.7%, 9.1%). Eradication trended higher with Vabomere than piperacillin-tazobactam in m-MITT (66.7% versus 57.7%) and ME (66.3% versus 60.4%) populations. The treatment differences in the m-MITT and ME populations were non-inferior, 9.0% (95% CI: -0.9%, 18.7%) and 5.9% (-4.2%, 16%) with a non-inferiority margin of -15%.

The most frequent adverse reactions were headache (8.8%), phlebitis/infusion-site reactions (4.4%), and diarrhea (3.3%). There were one severe and one life-threatening case of infusion-related adverse reactions which were labelled as Severe Warnings and Precautions. Other Severe Warnings and Precautions included such hypersensitivity reactions, seizures, and reduced serum valproic acid levels (potentially risking breakthrough seizures).

Study 506 was a multicenter, randomized, open study in adults with CRE infections: cUTI, AP, cIAI, bacterial HAP, bacterial VAP, or bacteremia. 77 patients were randomized 2:1 to compare 7 to 14 days of Vabomere (n = 52) and “best available therapy” (BAT, n = 25). The study was stopped early for benefit after enrolling 75 patients, half the planned sample. 75 MITT patients received ≥ 1 study drug dose and were the primary safety population. 45% of the MITT patients had cUTI or AP, 36% bacteremia, 9% HABP/VABP, and 9% cIAI. Patients were 43% female with a mean age 63 years. 73% had a Charlson comorbidity score ≥ 5, 43% systemic inflammatory response syndrome, 37% diabetes, and 32% immunocompromise. The most common pathogens were Klebsiella pneumonia (81%) and Escherichia coli (13%). With the exception of 1 BAT and 5 Vabomere patients with Ambler class B/D carbapenemases (not expected to be vaborbactam-sensitive), the identified carbapenemases in CRE were KPC.

In the post hoc analysis of the aggregated mCRE-MITT population, clinical cure was in 59% of Vabomere patients (19/32) versus 27% of BAT patients (4/15); all-cause mortality at day 28 was 16% with Vabomere (5/32) and 33% with BAT (5/15). In the safety population, in-study mortality within 60 days was 20% with Vabomere (10/50) and 24% with BAT (6/25). In mCRE-MITT patients, eradication at TOC was in 9% with Vabomere (3/32) and 27% with BAT (4/15).

The most frequent adverse drug reactions (ADRs) (≥ 10%) were fungal opportunistic infections (16% vs 4%), gastrointestinal (GI) hemorrhage (14% vs 0%), musculoskeletal and connective-tissue disorders (12% vs 0%), diarrhea (12% vs 16%), and hypokalemia (10% vs 8%). The investigator did not consider a fatal GI hemorrhage with concomitant heparin use to be drug-related; however, given the increased frequency of GI hemorrhage it was included in the labelling as a potential risk. Additionally, labelling in the Product Monograph due to the meropenem component of the combination were added to the Serious Warnings and Precautions section and included fatal hypersensitivity reactions, seizures, and cautious use with co-administration with valproic acid/divalproex sodium.

A limitation of the data from Study 505 was that overall success and microbial eradication were non-inferior nor superior with Vabomere versus piperacillin-tazobactam in unselected cUTI/AP. Only 1.6% of patients were meropenem-resistant and 0.5% had KPC-producing CRE; thus, the vaborbactam contribution to the observed efficacy via its primary mechanism of action of KPC inhibition was uncertain. Meropenem alone is approved in Canada for the treatment of cUTI. The addition of vaborbactam to meropenem adds safety risks of adverse drug reactions and potential for antimicrobial resistance. In the absence of anticipated carbapenem resistance and vaborbactam susceptibility, the net benefit of adding vaborbactam to meropenem was not established. Similarly, meropenem alone has been approved for cIAI, HAP, VAP, and bacteremia and there was no direct or indirect supporting evidence of a net benefit with the addition of vaborbactam to meropenem in the absence of carbapenem resistance.

The clinical pharmacology and non-clinical data package supported the recommended indication.

Vaborbactam is a non-β-lactam inhibitor of class A and class C serine β-lactamases, including KPC. It acts by forming a covalent adduct with β-lactamases and is stable to β-lactamase-mediated hydrolysis. Vaborbactam had no observable antibacterial activity. Vaborbactam does not inhibit class D carbapenemases such as OXA-48 or class B metallo-β-lactamases such as New Delhi metallo-beta-lactamase (NDM) and Verona integron-encoded metallo-β-lactamase (VIM). With respect to resistance, there was evidence that resistance mechanisms that affect meropenem-vaborbactam antibacterial activity include metallo-β lactamases and oxacillinases with carbapenemase activity, porin mutations affecting outer membrane permeability, overexpression of efflux pumps, and increases in KPC-producing gene (blaKPC) copy numbers.

Based on the totality of evidence including experience with meropenem alone, pharmacokinetic-pharmacodynamic and microbiological analyses of meropenem/vaborbactam, and Vabomere treatment of cUTI/AP in Study 505 and of CRE in Study 506, and in the context of the unmet need to treat carbapenem-resistant bacterial infections, the indication was restricted to the treatment of cUTI/AP, HAP/VAP, cIAIA, associated bacteremia, and other infections with limited treatment options, known or suspected to be caused by carbapenem-resistant, Vabomere-susceptible Gram-negatives.

A Risk Management Plan (RMP) for Vabomere (meropenem and vaborbactam) was submitted by Xediton Pharmaceuticals Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimise risks associated with the product.

In sum, based on the evidence reviewed and in the context of the defined, rare, and unmet need, Vabomere presented an acceptable and manageable safety profile in its intended population. The overall benefit-harm-uncertainty profile of Vabomere was favourable; therefore, Vabomere was recommended for market authorization.

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