Regulatory Decision Summary for Baxdela

This New Drug Submission (NDS) - New Active Substance (NAS) was filed by Xediton Pharmaceuticals Inc., to obtain market authorization, pursuant to section C.08.004 of the Food and Drugs Regulations, of Baxdela (delafloxacin) for the following indications:

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.

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.

The recommended dosing regimen for Baxdela is 300 mg intravenously (IV) every 12 hours administered over 60 minutes by infusion or 450 mg orally (PO) every 12 hours. The total duration of treatment is 5 to 14 days for ABSSSI and 5 to 10 days for CABP, at the discretion of the treating healthcare professional.

The NDS for Baxdela was filed and accepted for review under Health Canada’s Priority Review Policy in the context of increasing antimicrobial resistance.

The Canadian regulatory decision of the review of Baxdela 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 added reference.

Acute skin and skin structure infections (ABSSSI) are bacterial infections of the skin and underlying tissues and can include cellulitis/erysipelas, wound infection, major cutaneous abscess and burn infection. Most ABSSSI are caused by Gram-positive bacteria (e.g., Staphylococcus aureus including methicillin-resistant S. aureus [MRSA]). Community-acquired bacterial pneumonia (CABP) are acute bacterial infections of the lung that are acquired outside the hospital setting. The most common causative bacteria for CABP is Streptococcus pneumoniae. The treatment of ABSSSI and CABP depend on multiple factors (e.g., type and severity of infection, local microbial and antimicrobial resistance patterns, presence of patient comorbidities etc.) and will typically require antimicrobial therapy.

Baxdela (delafloxacin) is an anionic fluoroquinolone antibacterial drug. Delafloxacin, like other fluoroquinolones, targets DNA synthesis. It inhibits both bacterial DNA gyrase (topoisomerase II) and topoisomerase IV and does not inhibit human topoisomerase II in vitro. Delafloxacin has broad spectrum antibiotic activity, with potent activity against Gram-positive and Gram-negative bacterial species in vitro.

The primary source of evidence to support the efficacy and safety of Baxdela for the treatment of adult patients with ABSSSI and CABP was derived from 3 pivotal Phase 3 trials. Studies RX-3341-302 and RX-3341-303 were conducted in patients with ABSSSI and study ML-3341-306 was conducted in patients with CABP. All 3 pivotal Phase 3 studies were designed to meet the different regulatory requirements of the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA).

The patient demographics and baseline characteristics were generally balanced between the two treatment arms of each respective study and overall, collectively represented the target populations for the proposed indications.

Acute bacterial skin and skin structure infections (ABSSSI)

Studies RX-3341-302 and RX-3341-303 were Phase 3, multi-centered, randomized, double-blind, double-dummy, active-controlled non-inferiority (NI) trials. Study RX-3341-302 evaluated the efficacy and safety of Baxdela 300 mg intravenously (IV) every 12 hours compared with vancomycin ± aztreonam (V/A) and study RX-3341-303 evaluated the efficacy and safety of Baxdela 300 mg IV every 12 hours for 6 doses with a mandatory switch to Baxdela 450 mg (PO) orally every 12 hours compared to V/A in adult patients with ABSSSI. The treatment duration for both studies was 5 to 14 days. A total of 1510 patients (Study 302 n = 660, Study 303 n = 850) were randomized (1:1) and included in the intention-to-treat (ITT) population (Baxdela n = 754, V/A n = 756).

The two primary endpoints, objective response after initiation of treatment and investigator-assessed response of cure, were met in each of the two pivotal ABSSSI Phase 3 studies. The objective response involved an assessment at 48 to 72 hours (±2 hours) after initiation of treatment. Clinical response was defined as ≥20% reduction in lesion size as determined by digital planimetry of the leading-edge erythema. In study RX-3341-302, the proportion of patients considered clinical responders at 48 to 72 hours was 78.2% in the Baxdela arm compared to 80.9% in the V/A arm. The difference in objective response rate was -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. The difference in response rate was 3.1% (95% CI, -2.0, 8.3). The lower limit (LL) of the 95% CI was greater than the prespecified non-inferiority margin (NIM) of -10.0% in both RX-3341-302 and RX-3341-303, demonstrating that IV and IV to PO Baxdela was non-inferior (NI) to V/A in the treatment of adult patients with ABSSSI.

The second primary endpoint was investigator-assessed response of cure at the follow-up (FU) visit (i.e., 14 ± 1 days). 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 RX-3341-302, the proportion of patients with investigator-assessed response of cure at FU in the ITT population was 52.0% in the Baxdela arm compared to 50.5% in the V/A arm. The difference in response rate was 1.5% (95% CI: -6.1, 9.1). In RX-3341-303, the proportion of patients with investigator-assessed response of cure at FU 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 LL of the 95% CI was greater than the prespecified NIM of -10.0%. The sensitivity analyses based on the response of success (RX-3341-302: Baxdela arm 81.6%, V/A arm 83.3%, difference: -1.7% [95% CI: -7.6, 4.1]; RX-3341-303: Baxdela arm 87.2%, V/A arm 84.8%, difference: 2.5% [95% CI: -2.2, 7.2]) were also consistent with the NI findings of Baxdela compared to V/A in the treatment of adult patients with ABSSSI.

Community-acquired bacterial pneumonia (CABP)

Study ML-3341-306 was a Phase 3, multi-centered, randomized, double-blind, active-controlled non-inferiority trial evaluating the safety and efficacy of IV to PO Baxdela compared to moxifloxacin in adult patients with CABP. Patients received Baxdela 300 mg IV every 12 hours for at least 6 doses with an option to switch to Baxdela 450 mg PO 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. It was defined as all patients who were randomized, received at least one dose of study medication and were in the Pneumonia Patient Outcomes Research Team (PORT) Risk Class III and above. The ModITT population included 746 patients (Baxdela n = 376, moxifloxacin n = 370). Both primary endpoints were met in study ML-3341-306.

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 2 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 compared to 89.0% in the moxifloxacin arm. The difference in responder rate was -0.2% (95% CI: -4.4, 4.1). The LL of the 95% CI was greater than the pre-specified NIM of -12.5%, demonstrating that Baxdela was NI to moxifloxacin in the treatment of adult patients with CABP.

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 response 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 the TOC 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 NI to moxifloxacin in the treatment of adult patients with CABP, as the LL of the 95% CI was greater than the EMA prespecified NIM of -10.0%.

In the 3 pivotal Phase 3 studies, the microbiological ITT (MITT) population comprised all randomized patients who had a baseline pathogen identified that was known to cause ABSSSI or CABP, respectively.

The clinical outcome (i.e., objective response at 48 to 72 hours and investigator-assessed response of cure and success at FU in ABSSSI, and ECR at 96 hours and investigator-assessed clinical outcome at TOC in CABP) by baseline pathogen were generally comparable between the Baxdela arm and the comparator arm including for the most common causative pathogen of ABSSSI (S. aureus, including MRSA) and CABP (S. pneumoniae).

The most commonly reported related treatment-emergent adverse events (TEAEs) in the Baxdela arm were diarrhea (7.8%) and nausea (7.6%) in the pooled ABSSSI studies and diarrhea (4.7%) and transaminase elevations (3.0%) in the CABP study. Other TEAEs reported in the Baxdela arm of either study with a frequency of ≥2% included infection, infusion site extravasation, headache, vomiting and pyrexia. The majority of TEAEs were mild or moderate in severity. Related serious adverse events were reported in <1% of patients in the Baxdela arms of the pooled ABSSSI and CABP studies, respectively. The number of deaths were comparable between the treatment arms of each respective study and no deaths in the Baxdela arm were considered related to study drug. No new safety signals emerged from the review of the adverse events of special interest which were chosen based on medical issues of interest for the fluoroquinolone class of antibiotics. A dedicated QTc study (RX-3341-111) did not provide any evidence of QTc prolongation and the Baxdela Product Monograph (PM) was labelled accordingly.

The evidence derived from the 3 Phase 3 pivotal studies demonstrated the non-inferiority of Baxdela to comparator in the treatment of adult patients with ABSSSI and CABP. On the basis of the information reviewed from the pivotal Phase 3 studies, Baxdela presented an acceptable and manageable safety profile in consideration of the intended population.

Exposure to the excipient sulfobutylether--cyclodextrin (SBECD) found in Baxdela for injection increases significantly in patients with moderate and severe renal impairment. Considering that the margins of safety for SBECD are uncertain, close monitoring of the serum creatinine levels is recommended in these patients. Moreover, 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. Finally, Baxdela is not recommended for patients with end stage renal disease due to the lack of data and the expected increased exposure for delafloxacin and SBECD excipient (IV formulation only). No dose adjustment for Baxdela for injection or tablets is required for patients with mild, moderate, or severe hepatic impairment. Based on the population PK analyses, there was no evidence that gender, race, age, body weight, or disease states affected the steady-state delafloxacin pharmacokinetics, therefore, no dose adjustment based on these factors is required. This information is presented in the Baxdela Product Monograph.

The results of the comparative bioavailability study support the proposed administration of Baxdela tablets to be taken with or without food and without any dietary restrictions.

No significant Quality issues were noted during this review.

The final labelling and Product Monograph were considered acceptable.

A Risk Management Plan (RMP) for Baxdela 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 minimize risks associated with the product.

Overall, the benefit-harm-uncertainty profile was favourable for Baxdela for the recommended indications when used under the conditions of use as stated in the Product Monograph. Therefore, a Notice of Compliance (NOC) was recommended.

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