Summary Basis of Decision for Vabomere

Clinical Pharmacology

Vabomere is an antibacterial treatment containing the medicinal ingredients meropenem trihydrate and vaborbactam. Meropenem exerts bactericidal activity by inhibiting peptidoglycan cell wall synthesis as a result of binding to and inhibiting the activity of essential penicillin-binding proteins (PBPs). Vaborbactam is a non-beta-lactam inhibitor of class A and class C serine beta-lactamases, including Klebsiella pneumoniae carbapenemase (KPC). It acts by forming a covalent adduct with beta-lactamases and is stable to beta-lactamase-mediated hydrolysis. Vaborbactam has no antibacterial activity.

The pharmacokinetics of both meropenem and vaborbactam, evaluated separately, were characterized in healthy adults with normal renal function after single and multiple (every 8 hours for 7 days) 3-hour infusions of Vabomere. Each infusion contained 2 g meropenem and 2 g vaborbactam (in total, 4 g Vabomere). The pharmacokinetics of meropenem and vaborbactam were similar following the administration of single and multiple doses of Vabomere.

The maximum plasma concentration (C_max) and the area under the plasma drug concentration-time curve (AUC) of meropenem and vaborbactam proportionally increased with dose across the dose range studied (1 g to 2 g for meropenem and 0.25 g to 2 g for vaborbactam) when administered as a single 3-hour intravenous infusion. No accumulation of meropenem or vaborbactam was observed following multiple intravenous infusions administered every 8 hours for 7 days in subjects with normal renal function.

The major pharmacokinetic aspects of absorption, distribution, metabolism, and elimination of Vabomere have been well characterized in healthy subjects. Vabomere is administered intravenously, and therefore has 100% bioavailability. Radiolabelled vaborbactam was found to be widely distributed in tissues when administered by intravenous infusion to Sprague-Dawley rats. The highest mean drug-derived tissue concentration was found in the kidneys, prostate, urinary bladder, seminal vesicle, and liver. The lowest mean drug-derived tissue concentration was found in the spinal cord and brain. Meropenem is detectable at very low concentrations in animal breast milk. Meropenem-vaborbactam should not be used in breastfeeding women unless the potential benefit justifies the potential risk to nursing children. Approximately 28% of a meropenem dose is metabolized via hydrolysis. Vaborbactam does not undergo metabolism. Both meropenem and vaborbactam are primarily excreted as unchanged drug in the urine and are eliminated rapidly, with a terminal elimination half-life of approximately 1.0 h and 1.3 h, respectively.

The pharmacokinetics of meropenem was not found to be affected by liver disease in patients with hepatic impairment. Vaborbactam does not undergo hepatic metabolism. Therefore, the systemic clearance of meropenem and vaborbactam is not expected to be affected by hepatic impairment.

Pharmacokinetic studies with meropenem and vaborbactam in patients with renal impairment have shown that the plasma clearance of both meropenem and vaborbactam correlates with creatinine clearance.

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

Clinical Efficacy

Data from two Phase III studies were submitted to support the clinical efficacy of Vabomere: Study 505 and Study 506.

Study 505 was a double-blind, non-inferiority study designed to compare the efficacy and safety of Vabomere to piperacillin-tazobactam in adults with complicated urinary tract infection (cUTI) and acute pyelonephritis (AP). Of 550 randomized patients, 545 modified intention-to-treat (MITT) patients received at least one dose of study drug. The microbiological MITT (m-MITT) population included 374 MITT patients with baseline evidence of bacterial infection. Within the MITT population, 59% of patients had AP and 40% of patients had cUTI. Three infections treated with Vabomere were found to be meropenem-resistant: one infection caused by K. pneumoniae carbapenemase (KPC)-producing K. pneumoniae which was expected to be vaborbactam sensitive, and two infections caused by Pseudomonas aeruginosa which were not expected to be vaborbactam sensitive.

One co-primary efficacy endpoint was the proportion of patients with overall success. Overall success was defined as clinical cure or improvement and microbiological eradication from more than 10⁵ colony-forming units (CFU)/mL to less than 10⁴ CFU/mL at the end of intravenous treatment in the m-MITT population (who had received study drug and had a baseline uropathogen). Overall success was observed in 98.4% of patients treated with Vabomere and in 94.0% of patients treated with piperacillin-tazobactam; a difference of 4.5% between the treatment groups (95% confidence interval [CI]: 0.7%, 9.1%).

The other co-primary efficacy endpoint was the proportion of patients with microbial eradication to less than 10³ CFU/mL at test of cure, one week after the end of intravenous treatment, in the m-MITT and microbially evaluable populations. Eradication was observed in a greater proportion of patients treated with Vabomere than in patients treated with piperacillin-tazobactam in the m-MITT (66.7% versus 57.7%) and microbiologically evaluable (66.3% versus 60.4%) populations. The treatment differences in the m-MITT (9.0% [95% CI: -0.9%, 18.7%]) and microbiologically evaluable (5.9% [95% CI: -4.2%, 16%]) populations were both found to be non-inferior with Vabomere compared to piperacillin-tazobactam, with a non-inferiority margin of -15%.

Study 506 was an open study in adult patients known or suspected to have carbapenem-resistant Enterobacteriaceae (CRE) infections, specifically cUTI, AP, complicated intra-abdominal infection (cIAI), hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), or bacteremia. Randomization was stratified by infection type. Seventy-seven patients were screened and randomized 2:1 to compare the efficacy of 7 to 14 days of treatment with Vabomere (52 patients) to 7 to 14 days of treatment with the best available therapy (BAT; 25 patients). Patients were excluded from the study if they had a history of significant hypersensitivity or allergy to beta-lactam antibiotics, device- or line-associated infections, immediately life-threatening disease, endocarditis, meningitis, osteomyelitis, or infection with Class B or Class D beta-lactamases.

The planned primary endpoints of this study were evaluated in subsets of the microbiological carbapenem-resistant Enterobacteriaceae MITT (mCRE-MITT) population (patients with CRE infection, randomized to the study drug, and who received at least one dose of the study drug). However, the study was stopped early for benefit with Vabomere after enrolling 75 patients, where the initial planned sample size was 150 patients. Due to the loss of statistical power with the smaller sample size, patients were considered in aggregate in post hoc analyses.

In the entire mCRE-MITT population, 59% (19/32) of patients treated with Vabomere and 27% (4/15) of patients treated with the BAT had clinical cure (p = 0.02). The mortality rate at Day 28 was 16% (5/32) in patients treated with Vabomere and 33% (5/15) in patients treated with the BAT (p = 0.20). In the safety population, the rate of in-study mortality within 60 days was 20% (10/50) in patients treated with Vabomere and 24% (6/25) in patients treated with the BAT. In the mCRE-MITT population, eradication at test of cure (one week after study drug treatment) was observed in 9% (3/32) of patients treated with Vabomere and 27% (4/15) of patients treated with the BAT. Data interpretation is limited by the post hoc analysis of the small randomized study populations.

Indication

The proposed indication was accompanied by a list of examples of Gram-negative organisms against which Vabomere may be effective, which was revised in the approved indication to specify Enterobacterales, such as Enterobacter cloacae, Escherichia coli, and Klebsiella pneumoniae.

Additional guidelines were added to the Product Monograph for Vabomere to state that Vabomere should only be used to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. This is intended to reduce the development of drug-resistant bacteria and maintain the effectiveness of Vabomere and other antibacterial drugs. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

For more information, refer to the Product Monograph for Vabomere, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

In Study 505, similar rates were observed in patients treated with Vabomere versus patients treated with piperacillin-tazobactam with respect to adverse events (39.0% versus 35.5%), study drug-related adverse events (15.1% versus 12.8%), serious adverse events (4.0% versus 4.4%), severe adverse events (2.6% versus 4.8%), adverse events leading to study drug discontinuation (2.6% versus 5.1%), life-threatening adverse events (1.1% versus 1.0%), and mortality (0.7% versus 0.7%).

In patients treated with Vabomere, the most frequently reported adverse drug reactions were headache (8.8%) and phlebitis/infusion site reactions (4.4%). One severe and one life-threatening infusion-related adverse event accounted for both severe and life-threatening study drug-related adverse events (labelled under Serious Warnings and Precautions in the Product Monograph for Vabomere). Increased aspartate transferase (1.8%), hypoglycemia (0.4%), bile duct stone (0.4%), and azotemia (0.4%) were severe adverse events labelled as adverse drug reactions.

In Study 506, 75 of the 77 randomized patients in the MITT population received at least one dose of study drug, and were considered the primary safety population. In the m-MITT population, 54 patients met the MITT criteria and had an infection caused by a Gram-negative pathogen at baseline. In the mCRE-MITT population, 47 patients met the m-MITT criteria and had a CRE infection. In the MITT population, 45% of patients had a cUTI or AP, 36% of patients had bacteremia, 9% of patients had HABP or VABP, and 9% of patients had cIAI. The mean age of patients was 63 years, 43% of patients were female, and 73% of patients had a Charlson comorbidity score of 5 or higher. Systemic inflammatory response syndrome was observed in 43% of patients, and 32% of patients were immunocompromised. In the m-MITT population, 81% of patients had a K. pneumoniae infection, 13% of patients had an E. coli infection, and 6% of patients had infections caused by the E. cloacae species complex. The carbapenemases detected in patients with CRE infections were predominantly KPC, with the exception of one patient treated with the BAT and five patients treated with Vabomere, in whom Ambler class B and D carbapenemases were detected.

In patients with HABP, VABP, and/or bacteremia, the mortality rate at Day 28 was 22% (4/18) in patients treated with Vabomere and 44% (4/9) in patients treated with the BAT. For cases of cUTI or AP, the overall success rate was 33% (4/12) in patients treated with Vabomere and 50% (2/4) in patients treated with the BAT. For cases of cIAI, both patients treated with Vabomere (2/2) and neither of the patients treated with the BAT (0/2) had clinical cure.

In the groups treated with Vabomere versus BAT in Study 506 (50 and 25 MITT patients, respectively), there were fewer treatment-emergent adverse events (TEAEs) (84% versus 92%), drug-related TEAEs (24% versus 44%), drug-related serious adverse events (0% versus 8%), deaths (20% versus 24%), and study discontinuations due to TEAEs (16% versus 20%). The most frequently reported adverse drug reactions (reported in at least 10% of patients) were fungal opportunistic infections (16% versus 4%), gastrointestinal hemorrhage (14% versus 0%), musculoskeletal and connective tissue disorders (12% versus 0%), diarrhea (12% versus 16%), and hypokalemia (10% versus 8%). A fatal gastrointestinal hemorrhage occurred with concomitant heparin use, which was not found to be related to Vabomere but was included in the labelling due to the increased frequency of gastrointestinal hemorrhage with Vabomere. Severe adverse events of increased blood alkaline phosphatase and hypokalemia were not found to have individually been caused by Vabomere, but are listed as adverse drug reactions in the labelling. Based on the current labelling for meropenem, fatal hypersensitivity reactions, seizures, and the co-administration with valproic acid or divalproex sodium are listed as Serious Warnings and Precautions in the Product Monograph for Vabomere.

Based on the collective evidence, the recommended indication for Vabomere was restricted to the treatment of bacteria known or suspected to be carbapenem-resistant, Vabomere-sensitive, and responsible for cUTI/AP, cIAI, HABP, VABP, associated bacteremia, or Gram-negative infections with limited treatment options.

In Study 505, overall success and microbial eradication were non-inferior or superior with Vabomere compared to piperacillin-tazobactam in the treatment of cUTI/AP. However, with 0.5% of Vabomere-treated patients harbouring KPC-producing CRE, the contribution of vaborbactam to the efficacy of Vabomere via its primary mechanism of action (KPC inhibition) was unclear. Meropenem alone is approved for the treatment of cUTI. The addition of vaborbactam to meropenem adds risks of adverse drug reactions and selection for antimicrobial resistance. Therefore, without carbapenem resistance and vaborbactam susceptibility, the net benefit of adding vaborbactam to meropenem was not established.

Meropenem alone is also approved for the treatment of cIAI, HABP, VABP, and bacteremia. In these indications proposed for Vabomere, the submission did not provide direct supporting evidence or suggest a benefit to adding vaborbactam to meropenem for cases of infection without carbapenem resistance.

Based on the data reviewed by Health Canada, and in the context of a defined, rare, and unmet medical need, Vabomere presented an acceptable and manageable safety profile in its intended patient population. As the overall benefit-harm-uncertainty profile of Vabomere was favourable, it was recommended for market authorization.

For more information, refer to the Product Monograph for Vabomere, approved by Health Canada and available through the Drug Product Database.

The non-clinical testing strategy for Vabomere included numerous in vitro and in vivo studies evaluating both medicinal ingredients, alone or in combination. Most studies submitted as part of the non-clinical package for Vabomere evaluated the use of vaborbactam alone, as it is a new active substance in Canada.

Data from the non-clinical microbiology studies indicated that vaborbactam is a non-beta-lactam inhibitor of class A and class C serine beta-lactamases, including Klebsiella pneumoniae carbapenemase (KPC). It acts by forming a covalent adduct with beta-lactamases and is stable to beta-lactamase-mediated hydrolysis. Vaborbactam has no antibacterial activity. Vaborbactam was not found to inhibit class D carbapenemases such as OXA-48 or class B metallo-beta-lactamases.

In in vitro studies, K. pneumoniae, Escherichia coli, and the Enterobacter cloacae species complex (all of which are Gram-negative micro-organisms) were susceptible to meropenem-vaborbactam. In the clinical studies that followed, the efficacy of meropenem-vaborbactam was demonstrated in these pathogens, which were involved in complicated urinary tract infections, including pyelonephritis.

In vitro studies also indicated that other micro-organisms (including Gram-negative, Gram-positive, and anaerobic micro-organisms which are relevant to the approved indications) would be susceptible to meropenem and/or meropenem-vaborbactam in the absence of acquired resistance mechanisms. However, clinical efficacy has not been established against these pathogens.

Therefore, the Gram-negative micro-organisms against which efficacy was observed in clinical studies are specified in the Product Monograph for Vabomere. Additionally, guidelines were added to state that Vabomere should only be used to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. This is intended to reduce the development of drug-resistant bacteria and maintain the effectiveness of Vabomere and other antibacterial drugs.

Pharmacodynamic studies included enzyme inhibition and animal models of infection and in vitro receptor binding. An in vitro hollow fiber pharmacodynamic model of infection was evaluated, which included clinical isolates of K. pneumoniae, E. coli, E. cloacae, and Pseudomonas aeruginosa. Results indicated that a dosage regimen of meropenem 2 g and vaborbactam 2 g administered every 8 hours via a 3-hour infusion was required to produce antibacterial activity and suppress the development of resistance.

In animal models of infection, vaborbactam was found to potentiate the bacterial killing activity of meropenem in infections caused by KPC-producing strains of K. pneumoniae, E. coli, and E. cloacae. In a mouse neutropenic thigh model, the combination of vaborbactam and meropenem was found to generally be effective against P. aeruginosa and Acinetobacter baumanii strains that are non-susceptible to meropenem alone. In in vitro receptor binding and enzyme inhibition studies, vaborbactam did not display any inhibitory activity.

The results of the non-clinical toxicology studies and the long history of use of meropenem in Canada and other jurisdictions were sufficient to demonstrate the safety of Vabomere in the non-clinical component of this submission. Few uncertainties were identified in the in vitro studies, and were mostly due to minor interactions between vaborbactam or meropenem with cytochrome P450 (CYP) enzymes and other transporters. The in vivo studies also showed few uncertainties. Most of the in vivo studies exposed the animals to vaborbactam, meropenem, or a combination of the two at levels several times higher than the recommended human dose for up to 3 months, without observing signs of toxicity.

Carcinogenicity or local tolerance studies were not submitted due to the short-term use of Vabomere (14 days and less) and the evaluation of local tolerance in the context of general toxicity studies. This is considered acceptable.

Genotoxicity studies were conducted with meropenem and vaborbactam individually, and no evidence of mutagenic potential was identified for either.

Reproductive and developmental toxicity studies were conducted with meropenem in male and female rats and in cynomolgus monkeys. No evidence of impaired fertility was observed in rats at doses up to 1,000 mg/kg/day (approximately 1.6 times the maximum recommended human dose [MRHD] based on body surface area comparison). No signs of reproductive toxicity were observed in monkeys at doses up to 360 mg/kg/day (approximately 1.2 times the MRHD based on body surface area comparison).

Vaborbactam was not found to have adverse effects on fertility in male and female rats at doses up to 1,000 mg/kg/day (approximately 1.6 times the MRHD based on body surface area comparison).

An early embryonic development study was conducted in female Sprague-Dawley rats, in which vaborbactam was administered by intravenous infusion for 15 minutes daily, starting 14 days prior to mating, during mating, and up to and including gestation day (GD) 7. No adverse maternal effects were observed with respect to clinical signs, body weights, food consumption, and gross pathology, and no adverse effects were observed on female reproduction at doses up to 1,000 mg/kg/day. Based on observations in this study, the no-observed-adverse-effect level (NOAEL) for female reproductive toxicity and early embryonic development is at least 1,000 mg/kg/day.

An embryo-fetal developmental toxicity study was conducted in pregnant Sprague-Dawley rats, in which vaborbactam was administered by intravenous infusion for 15 minutes daily starting from GD 6 up to and including GD 17. No adverse maternal effects were observed with respect to clinical signs, body weights, and food consumption. Additionally, no evidence was found of embryolethality, fetotoxicity, or teratogenicity at doses up to 1,000 mg/kg/day.

The effects of vaborbactam on the reproductive performance of female Sprague-Dawley rats (parental [F0] generation) and the developmental performance of male and female rats (first filial [F1] generation) were also evaluated. Vaborbactam was administered intravenously to pregnant rats (F0 generation) from GD 6 through post partum day 20 for 15 minutes daily. No adverse effects were observed with respect to pre- and postnatal reproductive and developmental toxicity parameters at doses up to 1,000 mg/kg/day.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Product Monograph for Vabomere. Considering the intended use of Vabomere, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Product Monograph for Vabomere, approved by Health Canada and available through the Drug Product Database.

The quality (chemistry and manufacturing) information submitted for Vabomere has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper pharmaceutical development and supporting studies were conducted and an adequate control strategy is in place for the commercial processes. Changes to the manufacturing process and formulation (if any) made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 48 months is acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC). After reconstitution, the solution should be further diluted immediately. Chemical and physical in-use stability (after dilution) has been demonstrated for up to 4 hours at room temperature (15 °C to 30 °C) or within 22 hours at 2 °C to 8 °C. From a microbiological perspective, the medicinal product should be used immediately upon reconstitution and dilution.

The proposed drug-related impurity limits are considered adequately qualified (e.g., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [ICH] limits and/or qualified from toxicological studies, as needed).

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy.)

All sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations.

The biologic raw materials used during manufacturing originate from sources with no or minimal risk of transmissible spongiform encephalopathy (TSE) or other human pathogens.