Summary Basis of Decision for Sivextro

Clinical Pharmacology

Sivextro (tedizolid phosphate) is a prodrug that is rapidly converted in vivo by phosphatases to the microbiologically active moiety tedizolid. Tedizolid binds to the peptidyl transferase of the 50S ribosomal subunit and inhibits protein synthesis. Results in in vitro time-kill studies show that tedizolid is bacteriostatic against staphylococci and streptococci.

A number of clinical studies were conducted to evaluate the clinical pharmacology and pharmacokinetics of various formulations of tedizolid phosphate in healthy volunteers and in patients with acute bacterial skin and skin structure infections. The clinical pharmacological data support the use of Sivextro for the specified indication.

A thorough QT Phase I study was conducted with respect to QT/QTc interval prolongation and proarrhythmic potential for non-arrhythymic drugs. The QT study did not demonstrate QT prolongation in healthy volunteers receiving single therapeutic or supratherapeutic dose.

Bioavailability studies were provided with an earlier form of the prodrug, a capsule, however the sponsor did not provide a comparative bioavailability study to bridge the capsule used in the initial studies with the proposed tablet formulation. The impact of the differences in the dosage form on the pharmacokinetics of tedizolid could not be determined. This issue is included in the Sivextro Product Monograph. The two Phase III clinical studies (described below in Clinical Efficacy) administered the proposed tedizolid phosphate tablets without regard to the timing of meals. The Phase III studies therefore support the dosing recommendations that Sivextrotablets may be taken with or without food.

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

Clinical Efficacy

The clinical efficacy of Sivextro was evaluated primarily in two Phase III multicentre, double-blind, non-inferiority studies. A total of 1,333 adults with acute bacterial skin and skin structure infections (ABSSSI) were randomized to receive Sivextro (tedizolid phosphate) 200 mg once daily for 6 days or the active comparator, linezolid, 600 mg every 12 hours for 10 days. Linezolid belongs to the same oxazolidinone class of antibiotics as tedizolid, and is approved by Health Canada for the treatment of complicated skin and skin structure infections (cSSSI) caused by methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA).

In Study 1 patients were treated with oral therapy, while in Study 2, patients could receive oral therapy after a minimum of 1 day of intravenous (IV) therapy at the investigator's discretion if two of the following four criteria were met:

• no increase in primary lesion size from baseline;
• oral temperature <37.7°C;
• no worsening of local signs/symptoms since previous visit;
• improvement in at least 1 local sign/symptom since previous visit.

Patients with cellulitis/erysipelas, major cutaneous abscess, or wound infection were enrolled in the studies. Patients with wound infections were allowed aztreonam and/or metronidazole as adjunctive therapy for gram-negative and/or anaerobic bacterial coverage, if needed. The intent-to-treat (ITT) patient population included all randomized patients.

The primary efficacy endpoint in Study 1 was early clinical response, defined as no increase from baseline lesion area at 48-72 hours after the first dose and oral temperature of ≤37.6°C, confirmed by a second temperature measurement within 24 hours in the ITT population. The primary endpoint in Study 2 was early clinical response, defined as at least a 20% decrease from baseline lesion area at 48-72 hours after the first dose in the ITT population.

Secondary efficacy endpoints included clinical response at the end of therapy (EOT) and investigator-assessed clinical response at the post-therapy (PT) evaluation (7-14 days after the end of therapy) in the ITT patient population. At the EOT and PT visits, clinical response was defined as resolution or near resolution of most disease-specific signs and symptoms, absence or near resolution of systemic signs of infection if present at baseline (lymphadenopathy, fever, >10% immature neutrophils, abnormal white blood cell count), and no new signs, symptoms, or complications attributable to the ABSSSI requiring further treatment of the primary lesion.

In Study 1, 332 patients were treated with Sivextro oral therapy, while in Study 2, 332 patients received oral Sivextro after a minimum of 1 day of Sivextro IV therapy at the investigator's discretion. The early clinical response with Sivextro was comparable to the active comparator in both studies. In Study 1, the percentage of responders were 79.5% (264/332) versus (vs.) 79.4% (266/335) with 2-sided 95% Confidence Interval (CI: 0.1 (-6.1, 6.2) and in Study 2, 85.2% (283/332) vs. 82.6% (276/335) with 2-sided 95% CI: 2.6 (-3.0, 8.2) in the Sivextro and the active comparator arms, respectively. Secondary endpoints, that is (i.e.), clinical response at the EOT at (Day 11 or within 2 days of last dose) were also comparable in the Sivextro vs. the active comparator arms; 87.0% (578/664) vs. 87.9% (588/669) with 2-sided 95% CI: 0.8 (-4.4, 2.7) in Studies 1 and 2 combined. The investigator-assessed clinical response at the PT evaluation (7-14 days after the EOT) in the ITT patient population with both Studies 1 and 2 combined also supported Sivextro efficacy; i.e., 86.7% (576/664) vs. 86.8% (581/669) with 2-sided 95% CI: -0.1 (-3.8, 3.6) in the Sivextro vs. the active comparator arms.

In subgroup analyses, the rate of early clinical response at the 48 to 72 hour visit across demographic and other relevant subgroups [for example (e.g.) age, sex, race, body mass index group, geographic region, clinical syndrome, in IV drug users] supported the primary efficacy. The safety and efficacy of Sivextro in children less than 18 years of age have not been established. Slight efficacy differences in Sivextro vs. comparator were noted in patients with diabetes. In the neutropenic mouse thigh infection model, tedizolid could not demonstrate bacterial stasis with a human-equivalent dose. Patients with severe renal impairment (Creatinine clearance <30 mL/min) and severe hepatic impairment (Child Pugh score ≥9) were not enrolled in the controlled studies. All these issues have been adequately addressed by appropriate labelling in the Sivextro Product Monograph.

The rate of early clinical response at the 48 to 72 hour visit by baseline lesion area (i.e., <75 cm²;   ≥75 to 150 cm²; >150 to 300 cm²; 300 to 600 cm², >600 to 1,000 cm² and >1,000 cm²) was similar in patients treated with Sivextro or linezolid in the Phase III studies in the ITT analysis set.

The investigator assessed the clinical response at the PT evaluation by key target pathogen from the primary infection site or blood cultures for the Phase III controlled studies combined. In the microbiologically evaluable population (i.e., qualified number of patients ≥10) clinical success (>80% eradication) was demonstrated for the following key pathogens:

• Staphylococcus aureus (including MRSA);
• Staphylococcus pyogenes;
• Staphylococcus anginosus group;
• Staphylococcus agalactiae.

The pathogens Staphylococcus haemolyticus and Staphylococcus lugdunensis are generally considered commensals for ABSSI and were reported in lower than qualifying numbers (in <10 patients). Enterococcus faecalis (in 10 patients) demonstrated lower efficacy with Sivextro; i.e., 70% (7/10) with Sivextro vs. 100% (4/4) with linezolid. The majority of Enterococcus faecalis isolates were reported from polymicrobial infection. Insufficient data was available to support the use of Sivextro for Staphylococcus haemolyticus, Staphylococcus lugdunensis, and Enterococcus faecalis.

In the Phase III controlled studies, 10 patients with bacteremia at baseline were reported in the Sivextro group. The data included Staphylococcus aureus [number of patients (N) =6, (MRSA = 2, MSSA = 4)], Staphylococcus pyogenes (N = 2), Staphylococcus agalactiae (N = 1), and Staphylococcus constellatus (N = 10). Results showed that 100% (10/10) of patients who received Sivextro responded based on clinical response at the 48 to 72 hour visit and had negative cultures or were presumed to have negative cultures. At the PT evaluation, 8/10 patients were considered as a clinical success.

During the original filing of this New Drug Submission (NDS), the proposed indication by the sponsor was the following:

• Sivextro (tedizolid phosphate) tablets and Sivextro for injection are indicated for the treatment of acute bacterial skin and skin structure infections (defined by the following infection types: cellulitis/erysipelas, major cutaneous abscess, or wound infection) caused by susceptible strains of the following gram-positive microorganisms in patients 12 years of age and older: Staphylococcus aureus (MRSA and MSSA strains, and cases with concurrent bacteremia); Staphylococcus haemolyticus; Staphylococcus lugdunensis; Streptococcus pyogenes; Streptococcus agalactiae; Streptococcus anginosus Group (including Streptococcus anginosus; Streptococcus intermedius and Streptococcus constellatus); and Enterococcus faecalis.

Due to lack of efficacy and safety data for children 12 years and older; and the lack of supporting data for the use of Sivextro for Staphylococcus haemolyticus, Staphylococcus lugdunensis, and Enterococcus faecalis, the indication approved by Health Canada is as follows:

• Sivextro (tedizolid phosphate) tablets and Sivextro for injection are indicated for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible strains of the following gram-positive microorganisms in adults 18 years of age and older; Staphylococcus aureus (including MRSA), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus Group (including Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus).

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

Clinical Safety

The clinical safety of Sivextro was evaluated in a number of controlled and uncontrolled studies in which 1,050 patients with acute bacterial skin and skin structure infections (ABSSSI) and 438 healthy subjects were exposed to Sivextro. In Phase I and Phase II studies, including doses other than the 200 mg therapeutic dose, the most common adverse drug reactions (ADRs) in subjects who received Sivextro were headache, diarrhea, and nausea. Treatment discontinuations due to ADRs occurred in 13/438 (3.0%) of subjects who received Sivextro and there were no serious adverse events that were considered by the investigator to be related to Sivextro. Increased adverse reactions were reported in a Phase II dose-ranging study in patients who received 400 mg once daily oral tedizolid phosphate di-sodium.

In the two controlled Phase III studies (Study 1 and Study 2, described in the Clinical Efficacy section), 662 patients were randomized to receive oral/IV Sivextro at 200 mg once daily for 6 days and 662 patients were treated with the active comparator, linezolid (600 mg administered every 12 hours), for 10 days. The median number of administrations was 6 for Sivextro. The overall incidence of ADRs (defined as treatment-emergent adverse events considered by the investigator as probably, possibly, or definitely related to the study drug) was 22.4% (148/662 patients) in the Sivextro group and 27.9% (185/662 patients) in the active comparator group. In Study 2, the study drug was to be administered intravenously for at least the first two administrations, with an optional switch to oral administration after specific predefined criteria were met. A total of 21.5% (71) of patients in the Sivextro group remained on IV therapy throughout the study. A total of 63.4% (210) of patients receiving Sivextro were switched to oral therapy after one to two infusions of the active study drug.

The most common ADRs in patients who received Sivextro were nausea, headache, diarrhea, and vomiting. Treatment discontinuations due to ADRs occurred in 3/662 (0.5%) of patients who received Sivextro and 6/662 (0.9%) of patients who received the comparator (linezolid). The most common reactions that led to discontinuations for both treatments were gastrointestinal disorders including vomiting and diarrhea. There were no serious adverse events that were considered by the investigator to be related to Sivextro. The safety profile was similar when comparing patients who received intravenous Sivextro alone to patients who received oral administration alone, except for a higher reported rate of gastrointestinal disorders associated with oral administration. Common adverse reactions (≥1% of incidence) were similar in the Sivextro and comparator groups. Based on standardized medical queries for oxazolidinone antibiotic class-related adverse reactions, peripheral neuropathy (hypoesthesia, paresthesia, facial VII^th cranial nerve paralysis), and optic neuropathy (visual acuity reduced and visual impairment) were reported in ≥1 patients who were treated with Sivextro. In the post-market data, a patient receiving Sivextro was reported with severe vomiting and hospitalization.

No significant effects on optic neuropathy or peripheral neuropathy were reported in healthy volunteers who received oral doses of Sivextro once daily for 10 days. Peripheral and optic neuropathy has been reported with linezolid, a drug in the oxazolidinone antibacterial class.

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

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