Summary Basis of Decision for Baxdela

Clinical Pharmacology

The clinical pharmacology data submitted included Phase I and multiple dose-ranging studies (e.g., single dose, single ascending dose, multiple dose, multiple ascending dose) which used multiple formulations of delafloxacin. Following a 300 mg dose of delafloxacin administered intravenously, the following pharmacokinetic parameters were observed: a maximum concentration (C_max) of 8.94 ± 2.54 mcg/mL; a time to reach C_max (T_max) of 1.00 hour; a terminal elimination half-life (t_1/2) of 5.61 ± 1.70 hours; an area under the concentration-time curve (AUC) of 21.8 ± 4.54 mcg∙h/mL; and a systemic clearance of 14.1 ± 2.81 L/h. Additionally, the pharmacokinetic parameters of delafloxacin following steady state (multiple dose, every 12 hours) 300 mg intravenous administration included: a C_max of 9.29 ± 1.83 mcg/mL; a T_max of 1.00 hour; an AUC of 23.4 ± 6.90 mcg∙h/mL; and a systemic clearance of 13.8 ± 3.96 L/h. The accumulation ratio for the dosing regimen of 300 mg administered intravenously twice daily was 1.09, suggesting little accumulation of delafloxacin with repeated dosing. The maximum tolerated dose for a single intravenous dose of delafloxacin was considered to be 900 mg. Overall, under the conditions tested, the results suggested that delafloxacin was generally well tolerated by the healthy adult participants in the studies.

In a Phase I photosensitivity study in healthy adult participants (number of participants [n] = 52), neither delafloxacin at 200 mg/day and 400 mg/day (0.22- and 0.44-fold the recommended daily oral dosage, respectively) for 6 days nor placebo demonstrated clinically significant phototoxic potential at the wavelengths tested (295 nm to 430 nm). However, the active comparator (lomefloxacin) demonstrated a moderate degree of phototoxicity at ultraviolet A 335 nm and 365 nm wavelengths. The potential for phototoxic reactions should always be considered when caring for patients on delafloxacin or any other marketed fluoroquinolone. As such, consistent with other fluoroquinolones, a statement pertaining to the risk of phototoxicity as a class effect with the use of fluoroquinolones has been included the Warnings and Precautions section of the Product Monograph for Baxdela.

The absolute bioavailability for Baxdela 450 mg tablets administered as a single dose was 58.8%. Following a single 300 mg intravenous dose or a single 450 mg oral dose, the systemic exposures (AUC up to the last quantifiable time-point [AUC_0-t] and AUC to infinite time [AUC_0-inf]) were comparable, therefore supporting the proposed dosing regimen for Baxdela, including the switch from the intravenous formulation to the oral formulation. Delafloxacin steady state was achieved within approximately three days, with an accumulation of 36% and 10% following oral and intravenous administration, respectively. The plasma protein binding of delafloxacin was approximately 84%. The pharmacokinetics of delafloxacin was characterized by a complex disposition and was best described by a three-compartment model with mixed linear and non-linear elimination combined with linear renal clearance, and parallel fast and slow absorption following oral administration.

The metabolic and excretion profiles of delafloxacin were similar following oral and intravenous administration. Following the administration of a single 200 mg oral dose of ¹⁴C-labelled delafloxacin, radioactivity was rapidly absorbed with a T_max of approximately 0.79 hours and a mean plasma t_1/2 of 3.85 hours. Approximately 50% of the dose was eliminated in the urine and 48% was eliminated in the feces. Unchanged parent drug was the major component recovered from the plasma, urine, and feces. Similarly, following the administration of a single intravenous dose of 300 mg ¹⁴C-labelled delafloxacin, the mean (coefficient of variation [%CV]) C_max of 8.76 (24.5%) mcg/mL was reached at 1 hour after the start of the infusion. The mean (%CV) plasma elimination t_1/2 was 3.65 (18.6%) hours. Approximately 65% of the radioactivity was excreted in the urine and 29% was excreted in the feces. The parent compound was the dominant compound in the plasma, urine, and feces, and only one glucuronide metabolite representing more than 5% of the sample radioactivity was identified in the plasma and urine. Following multiple intravenous administrations of 300 mg delafloxacin, the mean AUCs from 0 to 12 hours (AUC_0-12) in alveolar macrophages and epithelial lining fluid were 83% and 65%, respectively, of the free-plasma AUC_0-12, confirming the presence of intrapulmonary delafloxacin at clinically relevant concentrations.

Delafloxacin was studied in patients with mild (estimated glomerular filtration rate [eGFR] >50 to 80 mL/min/1.73m²), moderate (eGFR >30 to 50 mL/min/1.73m²), and severe (eGFR ≤30 mL/min/1.73m²) renal impairment. Following the intravenous administration of a single 300 mg dose, delafloxacin exposure (AUC_0-t) was 1.3-, 1.7-, 2.1-, 3.5-, and 4.1-fold higher in patients with mild, moderate, and severe renal impairment and in patients with end-stage renal disease who received delafloxacin 1 hour before or within 1 hour after hemodialysis, respectively, when compared to subjects with normal renal function. Similarly, the exposure of sulfobutylether-β-cyclodextrin, an excipient in the intravenous formulation, was 1.2-, 2.2-, 5.3-, 8.5-, and 29.8-fold higher in patients with mild, moderate, and severe renal impairment and in patients with end-stage renal disease who received the intravenous infusion 1 hour before or within 1 hour after hemodialysis, respectively, when compared to subjects with normal renal function. No dose adjustment is required for patients with mild and moderate renal impairment; however, a dose adjustment from 300 mg intravenously every 12 hours to 200 mg intravenously every 12 hours is recommended for patients with severe renal impairment.

Population modeling and simulations were performed to predict delafloxacin and sulfobutylether-β-cyclodextrin exposure in patients with severe renal impairment receiving 200 mg delafloxacin (3,200 mg of sulfobutylether-β-cyclodextrin) intravenously every 12 hours. Simulated steady-state delafloxacin AUC_0-24 and sulfobutylether-β-cyclodextrin AUC_0-12 values were 1.1- and 3.4-fold higher in patients with severe renal impairment, respectively, when compared to subjects with normal renal function. Although there are uncertainties about the safety margins of sulfobutylether-β-cyclodextrin, this excipient is already used in other approved parenteral drug products at similar or higher levels compared to Baxdela. Therefore, the proposed dose reduction to 200 mg intravenously every 12 hours for patients with severe renal impairment is acceptable. To mitigate the risk associated with increased exposure to sulfobutylether-β-cyclodextrin, the Product Monograph for Baxdela states that sulfobutylether-β-cyclodextrin accumulation occurs in patients with moderate and severe renal impairment and that serum creatinine levels should be closely monitored in these patients receiving intravenous Baxdela. It should be noted that Baxdela is not recommended for patients with end-stage renal disease who are on hemodialysis.

Following the oral administration of a single 400 mg dose, delafloxacin exposure (AUC_0-t) was 1.0-, 1.4-, and 1.5-fold higher in patients with mild, moderate, and severe renal impairment. However, in simulations using a population that resembled patients in Study ML-3341-306 (see Clinical Efficacy section) who had community-acquired bacterial pneumonia (CABP), the predicted steady-state delafloxacin AUC_0-24 following 450 mg administered orally every 12 hours in patients with severe renal impairment was 1.8-fold higher when compared with patients with normal renal function. Considering the relevant predicted delafloxacin exposure increases in this patient population, a statement was added to the Product Monograph for Baxdela to highlight that the efficacy and safety data for Baxdela tablets used in patients with severe renal impairment are limited and these patients should be closely monitored during treatment with oral Baxdela.

Delafloxacin exposure was only increased by 1.1- to 1.2- fold in patients with mild (Child-Pugh Class A), moderate (Child-Pugh Class B), or severe (Child-Pugh Class C) hepatic impairment, suggesting that no dose adjustment is required for these patients. Based on the population pharmacokinetic analyses, there was no evidence that gender, race, age, body weight, or disease states affected the steady-state pharmacokinetics of delafloxacin.

Delafloxacin was neither an inhibitor nor an inducer of any cytochrome P450 (CYP) isoforms in vitro, except for a mild induction of CYP2C9 at concentrations above clinically relevant exposures and an induction of CYP3A4 at clinically relevant concentrations. However, the co-administration to healthy participants of a single oral dose of 5 mg midazolam with a 450 mg oral dose of delafloxacin after 5 days of 450 mg oral delafloxacin every 12 hours did not affect the AUC and C_max values of midazolam, suggesting that delafloxacin is not a clinically relevant CYP3A inducer. Delafloxacin was not an inhibitor of the multidrug resistance protein 1 (MDR1), breast cancer resistance protein (BCRP), organic anion transporter (OAT)1, OAT3, organic anion transporting polypeptide (OATP)1B1, OATP1B3, bile salt export pump (BSEP), organic cation transporter (OCT)1, OCT2, multidrug and toxin extrusion protein (MATE)1, and MATE2K, or a substrate of OAT1, OAT3, OCT1, OCT2, OATP1B1, and OATP in vitro at clinically relevant concentrations. However, delafloxacin was shown to be a substrate of P-glycoprotein (P-gp) and BCRP in vitro, although no dedicated clinical trials were conducted to assess the clinical relevance of these results. As a risk mitigation strategy, the proposed Product Monograph for Baxdela states that the clinical relevance of the co-administration of delafloxacin and P-gp and/or BCRP inhibitors is unknown.

The clinical antibacterial activity of delafloxacin, like other fluoroquinolones, is best described by the ratio of the unbound drug AUC over 24 hours (fAUC₂₄) divided by the minimum inhibitory concentration (MIC), i.e., the fAUC₂₄/MIC ratio, based on animal models of infection. Using the predicted delafloxacin exposure in patients with ABSSSI derived from the population pharmacokinetic analyses and the fAUC₂₄/MIC ratios associated with net bacterial stasis, the results from the pharmacokinetic-pharmacodynamic target attainment analyses suggested that the delafloxacin fAUC₂₄/MIC ratio achieved in patients with ABSSSI should be adequate to treat the majority of infections caused by susceptible Staphylococcus aureus, Escherichia coli, and other Enterobacteriaceae, as well as Pseudomonas aeruginosa. Similarly, using the predicted delafloxacin exposure in patients with CABP and the fAUC₂₄/MIC ratios associated with 1-Log₁₀ colony-forming unit reduction, the results from the pharmacokinetic-pharmacodynamic target attainment analyses suggested that the delafloxacin fAUC₂₄/MIC ratio achieved in patients with CABP should be adequate to treat the majority of infections caused by susceptible Streptococcus pneumoniae, Haemophilus parainfluenzae, and Staphylococcus aureus. However, the percent probabilities of target attainment were lower for Klebsiella pneumoniae and Pseudomonas aeruginosa at relevant MICs, therefore, other supportive data should be used to determine the appropriateness of delafloxacin for the treatment of CABP caused by these bacteria.

Pharmacokinetic-pharmacodynamic relationships for efficacy were also evaluated using data from the Phase III trials and the predicted delafloxacin exposure derived from the population pharmacokinetic analyses. However, considering the high rate of success for the main efficacy endpoints, the identification of pharmacokinetic-pharmacodynamic relationships was limited. Nevertheless, the high percentage of patients achieving the efficacy endpoints and the inferences based on the pharmacokinetic-pharmacodynamic relationships, although limited, provided support for the proposed delafloxacin dosing in patients with ABSSSI and CABP.

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

Clinical Efficacy

The primary source of evidence to support the efficacy and safety of Baxdela for the treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP) was derived from three pivotal Phase III trials. Studies RX-3341-302 and RX-3341-303 were conducted in adult patients with ABSSSI and study ML-3341-306 was conducted in adult patients with CABP.

ABSSSI: Studies RX-3341-302 and RX-3341-303

The clinical efficacy of Baxdela was evaluated in studies RX-3341-302 and RX-3341-303, two Phase III, multicentre, randomized, double-blind, double-dummy, active-controlled non-inferiority studies. Both studies evaluated the efficacy of Baxdela compared to vancomycin ± aztreonam (V/A) in adult patients with ABSSSI. In study RX-3341-302, Baxdela was administered as a 300 mg intravenous dose every 12 hours. In study RX-3341-303, Baxdela was administered as a 300 mg intravenous dose every 12 hours for 6 doses with a mandatory switch to a 450 mg oral dose every 12 hours. The treatment duration for both studies was 5 to 14 days.

In studies RX-3341-302 (n = 660) and RX-3341-303 (n = 850), 1,510 patients were randomized (1:1) to receive Baxdela or V/A. The intention-to-treat (ITT) population included 754 patients in the Baxdela arm and 756 patients in the V/A arm. In the Baxdela arm of the pooled ABSSSI studies, the median age was 48.0 years old and the majority of patients were male (62.1%) and White (85.5%); this was comparable to the V/A arm. The demographic and baseline characteristics were generally balanced between the two treatment arms of each respective study and comparable between the two ABSSSI studies with a few notable exceptions. In the ITT analysis set, there was a higher proportion of elderly patients (i.e., more than 65 years of age and more than 75 years of age) and a higher proportion of patients classified as obese (i.e., a body mass index of 30 mg/kg² or greater) in study RX-3341-303 compared to study RX-3341-302. In addition, there were nearly twice as many patients from North America in study RX-3341-302 (82.1%) compared to study RX-3341-303 (46.8%). Both studies had a very limited number patients with severe renal impairment, which has been labelled accordingly in the Product Monograph for Baxdela. Taken together, the ABSSSI studies represented the target population for the proposed indication.

The two respective primary endpoints were met in each of the two respective ABSSSI pivotal Phase III studies. The first primary endpoint was defined as the objective clinical response at 48 to 72 hours (± 2 hours) after initiation of treatment. Clinical response was defined as a 20% or greater reduction in ABSSSI lesion size spread as determined by digital planimetry of the leading edge of erythema. In study RX-3341-302, the proportion of patients considered responders with an objective response at 48 to 72 hours was 78.2% in the Baxdela arm compared to 80.9% in the V/A arm, with a difference in objective response rate of -2.6% (95% confidence interval [CI]: -8.8, 3.6). In study RX-3341-303, the proportion of patients with an objective response at 48 to 72 hours was 83.7% in the Baxdela arm compared to 80.6% in the V/A arm, with a difference in objective response rate of 3.1% (95% CI, -2.0, 8.3). The lower limit of the 95% CI was greater than the prespecified non-inferiority margin of -10.0% in both studies, demonstrating that intravenous and intravenous to oral Baxdela was non-inferior to V/A in the treatment of adult patients with ABSSSI.

Multiple sensitivity analyses of the primary endpoint of objective clinical response were performed in the following analysis sets to investigate the robustness of the primary efficacy results: CE72O (clinically evaluable at 48 to 72 hours ± 2 hours for the objective response), MITT (microbiological intention-to-treat; all patients in the ITT analysis set in which a bacterial pathogen known to cause ABSSSI was identified at baseline), and ME72O (microbiologically evaluable at 48 to 72 hours ± 2 hours for the objective response). These sensitivity analyses were overall supportive and corroborated the non-inferiority finding of Baxdela to V/A in the primary analysis.

The subgroup analyses of objective response at 48 to 72 hours in the ITT and CE72O analysis sets were generally comparable between the two treatment arms as well as across the two studies, and they corroborated the primary endpoint findings. The sample size of the subgroup of patients with burn infections was too small to draw any meaningful conclusions.

The second primary endpoint was the investigator-assessed response of cure at the follow-up visit (i.e., Day 14 ± 1). The response of cure was defined as the complete resolution of all baseline signs and symptoms of ABSSSI. The response of success (i.e., cure or improved) was a sensitivity analysis to the primary endpoint, where improved was defined as some symptoms remained but the patient had improved to the extent that no additional antimicrobial treatment was necessary.

In study RX-3341-302, the proportion of patients with an investigator-assessed response of cure at the follow-up visit in the ITT analysis set was 52.0% in the Baxdela arm compared to 50.5% in the V/A arm, with a difference in response rate of 1.5% 95% CI: -6.1, 9.1). In study RX-3341-303, the proportion of patients with an investigator-assessed response of cure at the follow-up visit was 57.7% in the Baxdela arm compared to 59.7% in the V/A arm, with a difference in response rate of -2.0% (95% CI: -8.6, 4.6). Baxdela was non-inferior to V/A as the lower limit of the 95% CI was less than the prespecified non-inferiority margin of -10.0%. In the sensitivity analysis, the proportion of patients with a response of success was 81.6% in the Baxdela arm compared to 83.3% in the V/A arm (difference: -1.7% [95% CI: -7.6, 4.1]) in study RX-3341-302 and 87.2% in the Baxdela arm compared to 84.8% in the V/A arm (difference: 2.5% [95% CI: -2.2, 7.2]) in study RX-3341-303. This was also consistent with the findings of the primary endpoint, as the lower limit of the 95% CI was greater than the prespecified non-inferiority margin of -10.0%, establishing non-inferiority of Baxdela compared to V/A in the treatment of adult patients with ABSSSI.

The primary endpoint of investigator-assessed response of cure was considered more representative of the efficacy of Baxdela, while the response of success was considered to have clinical relevance. Accordingly, both the primary endpoint based on cure and the sensitivity analysis based on success were included in the Product Monograph for Baxdela.

In study RX-3341-302, the investigator-assessed response of cure and the sensitivity analysis of success were consistent and supportive of the primary endpoint (i.e., non-inferiority of Baxdela to V/A was demonstrated) in the following analysis sets: CEFUI (clinically evaluable at the follow-up visit for the investigator-assessed response), MEFUI (microbiologically evaluable at the follow-up visit for the investigator-assessed response), and MITT. In study RX-3341-303, non-inferiority was demonstrated in the investigator-assessed response of cure in the ITT and MITT analysis sets and in the investigator-assessed response of success in all four (i.e., ITT, MITT, CEFUI, MEFUI) analysis sets. However, non-inferiority of Baxdela to V/A was not demonstrated in the investigator-assessed response of cure in the CEFUI and MEFUI analysis set.

The subgroup analyses of investigator-assessed response at the follow-up visit, for both cure and success, in the ITT and CEFUI analysis sets were generally comparable between the two treatment arms as well as across the two studies, and corroborated the second primary endpoint findings. The sample size of the subgroup of patients with burn infection was too small to draw any meaningful conclusions. In both studies, the investigator-assessed responses of cure at the follow-up visit for wound infections were generally lower (including response rates of less than 40% in the Baxdela arm) than those observed for cellulitis/erysipelas and major cutaneous infections. In addition, all of the response rates in the Baxdela arm were lower than those in to the V/A arm in both the ITT and CEFUI analysis sets. This was significant (i.e., lower limit of 95% CI less than 0 for the difference in cure rate response) in the CEFUI analysis set of study RX-3341-303; however, the success rate was comparable between the two treatment arms.

Given the non-inferiority finding of Baxdela to V/A for the two primary endpoints, the secondary endpoints were tested in a prespecified sequential hierarchical order for superiority in both studies. The first secondary endpoints of both studies were not met. In study RX-3341-302, Baxdela was not superior to V/A in investigator-assessed response of cure at the follow-up visit. In study RX-3341-303, Baxdela was not superior to V/A in the investigator-assessed response in patients with a baseline body mass index of 30 kg/m² or greater at the late follow-up visit.

In the pooled ABSSSI analysis, the clinical outcomes (i.e., objective response at 48 to 72 hours and investigator-assessed response at the follow-up visit) by baseline pathogen were generally comparable between the Baxdela and the V/A arms in the MITT population. The objective response at 48 to 72 hours for Staphylococcus aureus, one of the most common causative pathogens in ABSSSI, was 85.0% in the Baxdela arm compared to 83.0% in the V/A arm. The objective response at 48 to 72 hours for methicillin-resistant Staphylococcus aureus (MRSA), which is of particular interest in the context of antimicrobial resistance, was 86.8% in the Baxdela arm compared to 85.8% in the V/A arm. As expected, the sensitivity analysis of investigator-assessed response of success (Staphylococcus aureus: Baxdela 86.2%, V/A 83.0%; MRSA: Baxdela 84.7%, V/A 82.3%) were higher than the primary endpoint of the investigator-assessed response of cure (Staphylococcus aureus: Baxdela 51.1%, V/A 49.7%; MRSA: Baxdela 46.5%, V/A 44.0%). Both the response of cure and the response of success rates were included in the Product Monograph for Baxdela.

CABP: Study ML-3341-306

Study ML-3341-306 was a Phase III, multicentre, randomized, double-blind, active-controlled non-inferiority study that evaluated the efficacy of intravenous-to-oral Baxdela compared to moxifloxacin in adult patients with CABP. Patients received Baxdela 300 mg intravenously every 12 hours for at least 6 doses with an option to switch to Baxdela 450 mg orally every 12 hours thereafter. The treatment duration was from 5 to 10 days.

The first primary analysis was conducted in the ITT population and included a total of 859 randomized (1:1) patients (Baxdela n = 431; moxifloxacin n = 428). The second primary analysis was conducted in the modified ITT (ModITT) population, which was defined as all patients who were randomized, received at least one dose of study drug, and were in the Pneumonia Patient Outcomes Research Team (PORT) Risk Class III and above. The ModITT analysis set included 746 patients (Baxdela n = 376, moxifloxacin n = 370).

Taken as a whole, the patient demographics and baseline characteristics were generally balanced between the two treatment arms, comparable between the ITT and ModITT analysis sets, and represented the target population for the intended indication. In the ITT population, the median age was 62.0 years old with 44.5% of patients 65 years of age or older and 21.2% of patients 75 years of age or older. This was comparable to patients in the ModITT population, where the median age was 64.0 years old with 48.3% of patients 65 years of age or older and 23.9% of patients 75 years of age or older. Patients in both the ITT and ModITT analysis sets of study ML-3341-3036 were predominantly male (58.7% in ITT, 60.5% in ModITT) and White (ITT 91.5%, ModITT 91.6%).

The first primary endpoint was the early clinical response (ECR), defined as improvement at 96 hours (± 24 hours) after the first dose of the study drug in at least two of the following symptoms: pleuritic chest pain, frequency or severity of cough, amount and quality of productive sputum and dyspnea, and no worsening of any of the other symptoms. In the ITT population, the ECR rate was 88.9% in the Baxdela arm and 89.0% in the moxifloxacin arm, with a difference in responder rate of -0.2% (95% CI: -4.4, 4.1). The lower limit of the 95% CI was greater than the pre-specified non-inferiority margin of -12.5%, demonstrating that Baxdela was non-inferior to moxifloxacin in the treatment of adults with CABP.

The sensitivity analysis of ECR stratified by PORT Risk Class, history of chronic obstructive pulmonary disease or asthma, and prior systemic antimicrobial use in the ITT population was consistent and corroborated the primary endpoint finding of non-inferiority. Similar observations were made in the sensitivity analyses of ECR without stratification in all the population sets analyzed, including MITT-1 (patients in the MITT population who had a bacterial pathogen at baseline detected by all methods), MITT-2 (patients in the MITT population who had a bacterial pathogen at baseline detected by culture only), CE-ECR (clinically evaluable at 96 [± 24] hours for ECR), ME-1ECR (patients in the MITT-1 population who were microbiologically evaluable at 96 [± 24] hours for ECR), and ME-2ECR (patients in the MITT-2 population who were microbiologically evaluable at 96 [± 24] hours for ECR). The subgroup analyses of ECR were generally consistent and supportive of the primary endpoint with similar responder rates between the Baxdela and moxifloxacin arms.

For the first secondary endpoint of ECR with the addition of improvement of vitals signs in the ITT population, Baxdela was superior to moxifloxacin as the lower limit of the 95% CI for the difference in ECR rate exceeded zero (Baxdela 52.7%, moxifloxacin 43.0%; difference: 9.7% [95% CI: 3.0, 16.3]).

The second primary endpoint was the investigator-assessed clinical outcome at the test of cure (TOC; i.e., 5 to 10 days after the last dose of the study drug). The clinical outcome of success was defined as the resolution or near resolution of the symptoms of CABP present at study entry, no use of additional antimicrobial therapy for the current infection, and no new symptoms associated with the current CABP infection.

In the ModITT population, the success rate of clinical outcome at TOC, stratified by PORT Risk Class, and history of chronic obstructive pulmonary disease or asthma, was 91.0% in the Baxdela arm compared to 89.2% in the moxifloxacin arm, with a difference of 1.1% (95% CI: -3.2%, 5.5%). Baxdela was non-inferior to moxifloxacin as the lower limit of the 95% CI was greater than the prespecified non-inferiority margin of -10.0%.

The sensitivity analyses of clinical outcome at TOC without stratification were generally supportive and corroborated the non-inferiority finding of the primary endpoint irrespective of the population set analyzed. The populations in which sensitivity analyses were conducted were the ModITT-TOC (the ModITT population that was assessed at the TOC for clinical outcome), ModCE-TOC (modified clinically evaluable at TOC for clinical outcome), and ModME-TOC (modified microbiologically evaluable at TOC for clinical outcome). The sensitivity analyses of clinical outcome at the TOC, stratified by age categories, were generally consistent with the primary endpoint results, except for patients 75 years of age and older in the ModCE-TOC population, where the lower limit of the 95% CI was less than the non-inferiority margin of -10.0% (Baxdela 97.3%, moxifloxacin 96.6%; difference -2.0% [95% CI: -11.1, 7.1]). The subgroup analyses were also generally consistent and supportive of the primary endpoint with comparable success rates between the Baxdela and moxifloxacin arms.

For the secondary endpoint of ECR, Baxdela was non-inferior but not superior to moxifloxacin with comparable ECR responder rates in the ModITT (Baxdela 88.6%, moxifloxacin 88.4%; difference 0.2% [95% CI: -4.4, 4.8]) and ModCE-ECR (the ModCE population at 96 Hours [± 24 hours] who were assessed for ECR) populations (Baxdela 90.2%, moxifloxacin 90.8%; difference -0.6% [95% CI: -5.0, 3.7]). For the secondary endpoint of ECR with the addition of improvement in vital signs, Baxdela was superior to moxifloxacin as the lower limit of the 95% CI exceeded zero in the ModITT population (Baxdela 50.5%, moxifloxacin 40.5%; difference of 10.0% [95% CI: 2.8, 17.0]) and in the ModCE-ECR population (Baxdela 54.1%, moxifloxacin 44.2%, difference of 9.9% [95% CI: 3.1, 16.6]).

The MITT population consisted of all randomized patients who had a baseline pathogen identified that was known to cause CABP. The clinical outcome (i.e., ECR and clinical outcome of success at TOC) by baseline pathogen were generally comparable between the Baxdela and the moxifloxacin arms in the MITT population. The ECR for Streptococcus pneumoniae, the most common causative pathogen in CABP, was 90.8% in the Baxdela arm compared to 86.8% in the moxifloxacin arm. The investigator-assessed clinical response of success at TOC for Streptococcus pneumoniae was 90.0% in the Baxdela arm compared to 89.6% in the moxifloxacin arm. The ECR for Pseudomonas aeruginosa, which is of particular interest in the context of antimicrobial resistance in the treatment of CABP, was 92.3% in the Baxdela arm compared to 90.9% in the moxifloxacin arm. The investigator-assessed clinical response of success at TOC for Pseudomonas aeruginosa was 84.6% in the Baxdela arm compared to 100.0% in the moxifloxacin arm.

Indication

The New Drug Submission for Baxdela was filed by the sponsor with the following proposed indication, which Health Canada subsequently approved:

Acute Bacterial Skin and Skin Structure Infections

Baxdela is indicated in adults for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by the following susceptible microorganisms: Staphylococcus aureus (including methicillin-resistant [MRSA] and methicillin-susceptible [MSSA] isolates), Staphylococcus haemolyticus, Staphylococcus lugdunensis, Streptococcus agalactiae, Streptococcus anginosus Group (including Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus), Streptococcus pyogenes, Enterococcus faecalis, Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, and Pseudomonas aeruginosa.

Community-Acquired Bacterial Pneumonia

Baxdela is indicated in adults for the treatment of community-acquired bacterial pneumonia (CABP) caused by the following susceptible microorganisms: Streptococcus pneumoniae, Staphylococcus aureus (methicillin-susceptible [MSSA] isolates only), Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Haemophilus influenzae, Haemophilus parainfluenzae, Chlamydia pneumoniae, Legionella pneumophila, and Mycoplasma pneumoniae.

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

Clinical Safety

The clinical safety of Baxdela was evaluated in studies RX-3341-302, RX-3341-303, and ML-3341-306 described in the Clinical Efficacy section above.

ABSSSI: Studies RX-3341-302 and RX-3341-303

The pooled safety population from the pivotal Phase III ABSSSI studies (RX-3341-302 and RX-3341-303) included 1,492 patients (i.e., 741 patients in the Baxdela arm and 751 patients in the V/A arm). The median duration of study drug exposure in the pooled Phase III ABSSSI studies was 6 days in each of the respective Baxdela and V/A arms. Overall, the safety population was considered adequate for the safety assessment of Baxdela.

The overall proportion of patients with at least one treatment-emergent adverse event (TEAE) was lower in the Baxdela arm compared to the V/A arm in study RX-3341-302 (47.5% versus [vs] 59.2%); higher in the Baxdela arm compared to the V/A arm in study RX-3341-303 (43.6% vs 39.3%); and comparable between the Baxdela and V/A arms (45.1% vs 47.7%) in the pooled Phase III ABSSSI analysis. The TEAEs by system organ class of gastrointestinal disorders (i.e., nausea, diarrhea, vomiting) were reported more frequently in the Baxdela arm (14.4% vs 9.1%) in the pooled Phase III ABSSSI studies. Otherwise, the incidence of patients with any serious TEAE (3.6% vs 3.5%), treatment-related TEAE (22.1% vs 26.1%), TEAE leading to premature study drug discontinuation (1.8% vs 3.5%), TEAE leading to death (0.1% vs 0.4%), and TEAE of special interest (10.0% vs 13.6%) were either comparable or lower in the Baxdela arm than in the V/A arm.

In the pooled ABSSSI studies, the most common TEAEs by preferred term in the Baxdela arm, with corresponding proportion in the V/A arm, were diarrhea (7.8% vs 3.2%), nausea (7.6% vs 6.3%), infection (5.9% vs 5.1%), and infusion site extravasation (5.5% vs 7.2%). The majority of TEAEs were mild or moderate in intensity in both studies. In the pooled Phase III ABSSSI analysis, severe TEAEs were reported in 3.5% of patients in the Baxdela arm and 2.8% of patients in the V/A arm.

The proportion of patients with a serious adverse event (SAE) was similar between the two treatment arms and in each of studies RX-3341-302 and RX-3341-303. In the pooled Phase III ABSSSI analysis, the incidence of SAEs was 3.6% in the Baxdela arm and 3.5% in the V/A arm. Treatment-related SAEs were reported in 0.3% of patients in the Baxdela arm and 0.5% of patients in the V/A arm. The SAEs related to treatment in the Baxdela arm included one patient with increased alanine aminotransferase and aspartate transaminase and one patient with urticaria.

Death was reported in 1 patient (0.1%) in the Baxdela arm and in 3 patients (0.4%) in the V/A arm across the pooled Phase III ABSSSI studies. The death in the Baxdela arm was due to septic shock and the deaths in the V/A arm were due to myocardial infarction, intestinal ischemia, and pulmonary embolism. None of the deaths were considered treatment related.

In the pooled Phase III ABSSSI analysis, the most commonly reported adverse events of special interest (AESIs) in the Baxdela arm, with corresponding incidence in the V/A arm, were potential allergic reaction (3.6% vs 5.2%), hepatic-related events (3.1% vs 4.0%), and potential myopathy (2.0% vs 4.5%). All other AESIs were reported at a frequency of 1% or less.

Generally, there were minimal mean changes from baseline in hematology and chemistry parameters in both ABSSSI pivotal studies, and the changes were similar between each respective treatment arm. There were no notable differences or findings in the vital signs and physical examination measurements between the treatment arms across the two Phase III pivotal ABSSSI studies.

CABP: Study ML-3341-306

The safety population from study ML-3341-306 consisted of 856 patients who received at least one dose of study drug: 429 patients in the Baxdela arm and 427 patients in the moxifloxacin arm. The median duration of study drug exposure was 9 days, with 6 days of intravenous exposure and 2 days of oral exposure in each of the respective Baxdela and moxifloxacin arms.

In general, the overall incidences of TEAEs (30.5% vs 26.2%), treatment-related TEAEs (15.2% vs 12.6%), SAEs (5.4% vs 4.7%), TEAEs leading to drug discontinuation (3.5% vs 1.6%), TEAEs leading to death (2.1% vs 1.6) and TEAEs of special interest (7.9% vs 7.5%) were more common in the Baxdela arm than in the moxifloxacin arm, respectively.

The most commonly reported TEAEs by patient in the Baxdela arm, with corresponding incidence in the moxifloxacin arm, were diarrhea (4.7% vs 3.3%), increased transaminases (3.0% vs 1.4%), headache (1.9% vs 2.6%), hypokalemia (1.9% vs 0.5%), and nausea (1.2% vs 1.2%). The majority of TEAEs in study ML-3341-306 were assessed as mild to moderate in severity. Severe TEAEs were reported in 4.4% of patients in the Baxdela arm and 3.3% of patients in the moxifloxacin arm. The proportion of patients with an SAE was similar between the two treatment arms (Baxdela 5.4%, moxifloxacin 4.7%). Treatment-related SAEs were reported in 0.7% of patients in the Baxdela arm and were due to hypersensitivity and Clostridioides difficile colitis; both resulted in the discontinuation of study drug.

The incidence of deaths were comparable between the Baxdela arm (2.1% [9 patients]) and the moxifloxacin arm (1.6% [7 patients]) and all the deaths were considered unrelated to study drug. Treatment-emergent adverse events leading to study drug discontinuation were higher in the Baxdela arm (3.5%) than in the moxifloxacin arm (1.6%). The TEAEs leading to study drug discontinuation (hypersensitivity and increased hepatic enzyme) were considered definitely treatment-related in the Baxdela arm.

The most commonly reported AESIs in the Baxdela arm, with corresponding incidence in the moxifloxacin arm, were hepatic-related events (5.1% vs 2.8%) and potential allergic reaction (1.9% vs 0.9%). The majority of these hepatic-related events were due to increased transaminases (3.0% vs 1.4%), most were considered related to study drug but did not result in study drug discontinuation, and most were mild to moderate in severity. None of the hepatic-related events were considered SAEs. All other AESIs were reported with an incidence of less than 0.5% in the Baxdela arm.

Clinical laboratory TEAEs were generally more common in the Baxdela arm than in moxifloxacin arm. The most frequently reported drug-related clinical laboratory TEAE was increased transaminases (Baxdela 3.0% vs moxifloxacin 1.4%). Overall, there were few changes from baseline in hematology and chemistry parameters. In general, vital signs improved and mean values of vital sign measurements were comparable between the two treatment arms at all time points. There were no notable electrocardiogram or physical examination findings.

The NDS for Baxdela included a dedicated QTc study (RX-3341-111), which did not provide any evidence of QTc prolongation. The Product Monograph for Baxdela was labelled accordingly.

The overall review of the three pivotal Phase III studies demonstrated Baxdela to be non-inferior to comparator for the treatment of adult patients with ABSSSI and CABP. On the basis of the information reviewed from the pivotal Phase III studies, Baxdela presented an acceptable and manageable safety profile in consideration of the intended populations.

Appropriate warnings and precautions are in place in the approved Product Monograph for Baxdela to address the identified safety concerns.

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

Secondary Pharmacodynamics

Delafloxacin was screened for off-target effects in 75 radioligand receptor binding assays. Tested targets included gamma-aminobutyric acid, benzodiazepine, N-methyl-D-aspartate, adenosine, and muscarinic receptors, targets implicated in the neurological symptoms and tendinopathies of marketed fluoroquinolones. No clinically relevant target inhibition was observed; any substantial inhibition of these targets was observed at concentrations higher than what is in clinical use.

Pharmacology

The totality of evidence from safety pharmacology studies did not find any major safety concerns with respect to cardiovascular system, central nervous system, respiratory system, and gastrointestinal system function. In mice, doses of delafloxacin up to 300 mg/kg (associated with mean maximum concentration [C_max] values at least approximately 5-fold greater than that observed in humans) had no consistent effects on general behaviour, motor coordination, body temperature, nociception, and barbital- or ethanol-induced sleep, although transient sedation was observed.

Delafloxacin had no significant effects on the electroshock threshold and latency to pentylenetetrazole-induced convulsions in mice up to 300 mg/kg, and did not cause seizures up to 100 mg/kg when co-administered with fenbufen. Delafloxacin did not significantly inhibit the human ether-à-go-go-related gene potassium (K⁺) channel or prolong action potential duration in dog Purkinje fibres in vitro, at concentrations approximately 50-fold and approximately 33-fold higher than the unbound human plasma C_max level, respectively.

In anaesthetized dogs, delafloxacin did not result in prolongation of the corrected QT interval at a concentration producing plasma levels approximately 13-fold higher than the human plasma C_max level. At this concentration, there were transient decreases in mean arterial pressure, diastolic pressure, and systolic pressure (less than 20%), with related decreases in indices of cardiac contractility, as well as marked increases in pulmonary arterial pressure (44%) immediately following infusion and transient increases in left ventricular end diastolic pressure (45%). Lower concentrations associated with plasma levels approximately 4-fold higher than the human plasma C_max level did not produce any physiologically significant changes in hemodynamic or electrophysiologic parameters. Although QT interval prolongation is a known effect of other fluoroquinolones, this was not evident in the non-clinical cardiovascular safety pharmacology studies with delafloxacin.

Oral delafloxacin had no significant effects on respiratory rate, tidal volume, minute volume, or airway resistance in rats when administered up to 600 mg/kg, which was associated with plasma concentrations of approximately 2-fold the mean human plasma C_max. Oral delafloxacin had no effect on gastrointestinal transit times in rats up to 100 mg/kg. However, oral delafloxacin tested up to 30 mg/kg produced emetic and diarrheal effects in ferrets.

No specific studies on pharmacodynamic drug interactions were conducted, but safety pharmacology studies showed no meaningful interactions between delafloxacin and fenbufen, barbital, or ethanol in mice.

Pharmacokinetics

Validated liquid chromatography and mass spectrometry methods were used for the determination of delafloxacin in the plasma of rats, mice, rabbits and dogs. All five studies met the criteria established in International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guidelines.

Food interferes negatively with bioavailability of delafloxacin, reducing it approximately by half. Following intravenous administration, the exposure as measured by the concentration-time curve (AUC) of delafloxacin is at least twice the oral AUC in animals for the same dose. Oral bioavailability for the 5 mg/kg dose is 54% to 56% in animal species (except for rats) and generally decreases with higher doses. The mean delafloxacin plasma protein binding for humans is 84%, and 75% to 97% for other species.

Delafloxacin distributes to the liver, kidney, gastrointestinal tract, bladder, bone, and skin. In pregnant rats, delafloxacin mainly distributes in kidneys, bladder, and liver, and in much lower concentrations in the uterus, placenta, amniotic fluid, and total fetus. In lactating rats, delafloxacin distributes into breast milk.

Approximately 90% of radiolabeled delafloxacin was eliminated within 96 hours in rats and within 120 hours in dogs after oral and intravenous dosing, with 70% to 80% (rats) and 85% to 88% (dog) eliminated via feces, partly through biliary and/or intestinal secretion, and the remaining in urine. Unchanged delafloxacin is the major radioactive component in feces from rats (70% to 80%) and dogs (61% to 63%). Ester glucuronides, the major metabolites of delafloxacin, were mostly present in bile within 48 hours.

Delafloxacin induces minimal to no inhibition of cytochrome P450 (CYP)1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, and CYP3A. Delafloxacin has no potential for clinically relevant in vitro induction of CYP1A2, CYP2B6, CYP2C19, CYP2C8 or CYP2E1, but is a mild inducer of CYP2C9 and CYP3A4. Delafloxacin is not an inhibitor of the following hepatic and renal transporters in vitro at clinically relevant concentrations: multidrug resistance mutation 1 (MDR1)/P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporter (OAT)1, OAT3, organic anion-transporting polypeptide (OATP)1B1, OATP1B3, bile salt export pump (BSEP), organic cation transporter (OCT)1, and OCT2. Delafloxacin was not a substrate of OAT1, OAT3, OCT1, OCT2, OATP1B1 or OATP, but is a substrate of MDR1/P-gp and BCRP in vitro. Glucuronidation of delafloxacin is mediated mainly by uridine diphosphate glucuronosyltransferase-glucuronosyltransferase (UGT)1A1, UGT1A3, and UGT2B15.

Based on an oral bioavailability study, delafloxacin meglumine was chosen over other sources of delafloxacin due to its higher bioavailability.

The most common adverse effects of delafloxacin in repeat-dose studies were gastrointestinal related (diarrhea, emesis, and dilated caeca). The highest oral doses of delafloxacin (no-observed-adverse-effect level [NOAEL]: 1,200 to 1,600 mg/kg/day) administered for 2 weeks to 3 months in rats were well tolerated and correspond to 4.6- to 5.6-fold the exposure observed in humans at the maximum recommended dose, based on AUC. The highest intravenous doses of delafloxacin (NOAEL: 75 mg/kg/day) administered for 14 to 28 days in dogs were also well tolerated and correspond to 1.2- to 2.2-fold the exposure observed in humans at the maximum recommended dose, based on AUC.

Delafloxacin was considered non-mutagenic in a bacterial reverse mutation assay. Delafloxacin was also not considered genotoxic in a mouse micronucleus test and a chromosomal aberration assay.

No carcinogenicity studies were required or submitted. Based on ICH guidelines, they are only required when the clinical use is continuous for at least 6 months.

The NOAEL varied greatly between studies, species, and stages of reproduction or development. In intravenous studies, the NOAEL varied between 10 to 120 mg/kg day for systemic toxicity, and 120 mg/kg/day for reproductive/embryonic toxicity, reproductive toxicity in the first filial (F1) generation, or neonatal toxicity in the second filial (F2) generation. In oral embryo-fetal development studies, the NOAEL was 200 mg/kg/day or less in rats and 0.1 to 0.4 mg/kg/day in rabbits. The proposed Product Monograph for Baxdela indicates that Baxdela is not recommended for pregnant or breastfeeding women.

A dose of 320 mg/kg/day delafloxacin was considered the NOAEL in juvenile dogs. The proposed Product Monograph for Baxdela indicates that Baxdela is not recommended in patients under 18 years of age.

All four studies performed with human blood showed no effect of delafloxacin on hemolysis. Three studies examining the sublocal, venous, and peri-venous irritation potential of delafloxacin versus control showed that both products induced some irritation at the injection site.

Iron anti-diarrhea treatment, aiming to counteract gastrointestinal effects of delafloxacin and given for 7 days in mini-pigs, lowered the bioavailability of delafloxacin. The oral administration of delafloxacin produced cecal dilation. The overall toxicity of delafloxacin is similar to other fluoroquinolones. Liver gene expression induced by treatment with delafloxacin is similar to levofloxacin.

Microbiology

Delafloxacin, like other fluoroquinolones, targets deoxyribonucleic acid (DNA) synthesis. It inhibits both bacterial DNA gyrase (topoisomerase II) and topoisomerase IV, and does not inhibit human topoisomerase II in vitro. The activity of delafloxacin appears to be largely bactericidal based on time-kill kinetic studies, and there is a trend toward concentration-dependent killing.

The spontaneous mutation frequency of delafloxacin in vitro appears to be very low (less than 10^-9). Delafloxacin resistance in vitro arose due to mutations in quinolone resistance-determining regions, including gyrase-encoding (gyrA, gyrB) and topoisomerase IV-encoding (parC, parE) genes. Overexpression of efflux pumps also led to increased minimum inhibitory concentrations (MICs).

In clinical study isolates, plasmid-mediated resistance elements that were associated with increased delafloxacin MICs included variants of quinolone resistance proteins, Oqx efflux pumps, and aminoglycoside acetyltransferase AAC-6’-IB-CR.

Delafloxacin has broad spectrum antibiotic activity, with potent activity against Gram-positive and Gram-negative bacterial species in vitro. There is evidence of cross-resistance between delafloxacin and other fluoroquinolones in vitro, as delafloxacin MICs were elevated against isolates resistant to other fluoroquinolones. However, there was evidence of efficacy against some fluoroquinolone-resistant isolates.

In the preclinical profiling and surveillance studies, delafloxacin had higher MICs against methicillin-resistant Staphylococcus aureus; vancomycin-resistant Enterococcus faecalis; extended-spectrum beta-lactamase-positive Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis; carbapenem-resistant Klebsiella pneumoniae; and ceftazidime-resistant Pseudomonas aeruginosa.

Delafloxacin did not show any substantial synergy or antagonism against a panel of antibiotics from diverse classes in various Gram-positive and Gram-negative strains. Pre-clinical profiling and/or surveillance study data supported the labelling of the bacterial species listed in the indications and their susceptibility testing interpretive criteria.

Delafloxacin activity was assessed in in vivo infection models (systemic lethal infections, thigh infections, pulmonary infections, pyelonephritis infections, pouch abscess models) in mice and/or rats against Gram-positive and Gram-negative pathogens. In most studies, the efficacy of delafloxacin was found to be similar to or more active than the comparator antibiotics.

The antibacterial activity of delafloxacin correlated best with the ratio of AUC of free plasma delafloxacin to MIC (fAUC/MIC) for Gram-positive and Gram-negative strains based on mouse thigh and lung infection models. Human pharmacokinetic and pharmacodynamic target attainment analyses were performed based on the fAUC/MIC values determined in the animal studies.

Quality control ranges for broth microdilution and disk diffusion testing have already been established with the Clinical Laboratory Standards Institute and are supported by the reviewed data. The susceptibility testing interpretive criteria (breakpoints) included in the Product Monograph for Baxdela appear appropriate and supported by the reviewed data.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Product Monograph for Baxdela. In view of the intended use of Baxdela, 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 Baxdela, approved by Health Canada and available through the Drug Product Database.

The quality (chemistry and manufacturing) information submitted for Baxdela 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).

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.

None of the excipients used in the formulation of Baxdela is of human or animal origin.