Regulatory Decision Summary for Oritiniv

This New Drug Submission was filed to obtain market authorization for Oritiniv (oritavancin phosphate) in the treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of the following Gram-positive microorganisms: Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcusanginosus group (includes S. anginosus, S. intermedius, and S. constellatus), and Enterococcus faecalis (vancomycin susceptible isolates only).

Oritiniv is administered as a single 1,200 mg intravenous dose.

The submission was filed and accepted for review under the Priority Review Policy.

The Canadian regulatory decision of the review of Oritiniv 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.

Oritiniv (oritavancin) is a semi-synthetic glycopeptide antibiotic medication. Oritiniv inhibits the transglycosylation step of bacterial cell wall synthesis, similar to other glycopeptides, by binding to the stem peptide of peptidoglycan precursors; however, it additionally inhibits transpeptidation and disrupts the bacterial membrane integrity. Oritiniv has demonstrated potent in vitro activity against Gram-positive pathogens including Methicillin-resistant Staphylococcus aureus (MRSA).

The primary evidence for the efficacy and safety of Oritiniv for the treatment of adult patients with ABSSSI relied on two pivotal Phase 3 clinical trials, SOLO I (TMC-ORI-10-01) and SOLO II (TMC-ORI-10-02).

The pivotal trials were identically designed, Phase 3, international, multi-centre, randomized, double-blind, active-comparator, non-inferiority clinical trials in patients with acute bacterial skin and skin structure infections (ABSSSI). Patients were randomized (1:1) to either a single 1,200 mg dose of Oritiniv or vancomycin (1 gram (g) or 15 milligram (mg)/kilogram (kg) given twice daily for 7 to 10 days). The SOLO I trial enrolled 954 patients (Oritiniv, n = 475; vancomycin, n = 479) and the SOLO II trial enrolled 1,005 patients (Oritiniv, n = 503; vancomycin, n = 502). The safety population consisted of 1,959 patients (Oritiniv, n = 976; vancomycin, n = 983) from the pooled SOLO trial data who were treated with at least one dose of study drug. The median duration of treatment was 8 days in both the oritavancin and vancomycin groups.

The demographic and baseline characteristics were generally balanced between the two treatment groups of each SOLO trial as well as between the two SOLO trials with few notable exceptions. There were a limited number of patients that were 65 years of age or greater, had moderate or severe renal function, or hepatic impairment.

SOLO 1 and SOLO II were initially designed to meet the regulatory requirements of the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) at the time the studies were conducted; however, subsequently published EMA and FDA ABSSSI guidelines recommended the use of alternate primary efficacy endpoints (lesion size reduction and clinical cure at end of treatment). Three efficacy endpoints were considered relevant in the review of the pivotal Phase 3 SOLO trials:

• the primary endpoint of early clinical response (at the 48-72 hour early clinical evaluation (ECE) visit: based on the 2010 FDA Guidance),

• the key secondary endpoint of clinical cure (at post therapy evaluation (PTE) visit 7-14 days after the end of blinded therapy: based on the 2012 EMA guideline) and

• another key secondary endpoint of lesion size reduction ≥ 20% (at the ECE visit: recommended primary endpoint per the 2013 FDA guideline).

In SOLO I, an early clinical response at ECE was seen in a similar percentage of patients in the treatment groups (Oritiniv, 82.3%; vancomycin, 78.9%) with a treatment difference of 3.4% (95% confidence interval [CI]: -1.6, 8.4). In SOLO II, early clinical response at ECE was also seen in a similar percentage of patients in the treatment groups (Oritiniv, 80.1%; vancomycin, 82.9%) with a treatment difference of -2.7% (95% CI: -7.5, 2.0).

The key secondary efficacy endpoint was met for investigator-assessed clinical cure at PTE in both SOLO I and SOLO II. In SOLO I, there were similar percentages of patients cured in the treatment groups (Oritiniv, 79.6%; vancomycin, 80.0%) with a treatment difference of -0.4% (95% CI: -5.5, 4.7). Similarly, in SOLO II (Oritiniv, 82.7%; vancomycin, 80.5%), the treatment difference was 2.2% (95% CI: -2.6, 7.0).

The other key secondary endpoint was met (lesion size reduction > 20% from baseline at ECE) in both SOLO I and SOLO II. In SOLO I, there were similar percentages of patient successes in the treatment groups (Oritiniv, 86.9%; vancomycin, 82.9%) with a treatment difference of 4.1% (95% CI: -0.5, 8.6). Similarly, in SOLO II (Oritiniv, 85.9%; vancomycin, 85.3%) the treatment difference was 0.6% (95% CI: -3.7, 5.0).

For all three clinically relevant endpoints in SOLO I and SOLO II, the lower limit of the 95% CI was greater than the prespecified non-inferiority margin of -10% demonstrating that Oritiniv was non-inferior to vancomycin in the treatment of adult patients with ABSSSI. Sensitivity analyses supported the conclusions from the primary analysis for all endpoints.

Subgroup analyses demonstrated consistent results for all clinically relevant endpoints regardless of gender, weight, body mass index, type and severity of ABSSSI, and/or whether the patient was pre-treated with antibiotics. Lower efficacy of Oritiniv was seen in subgroups of patients with major cutaneous abscesses and patients with comorbid diabetes mellitus. In the subgroup of patients with confirmed MRSA, consistent efficacy results were seen across all clinically relevant endpoints.

The most commonly (≥ 4%) reported treatment-emergent adverse events (TEAE) in the Oritiniv group were nausea (9.9%), headache (7.1%), and vomiting (4.6%). The most commonly reported serious adverse events (SAE) in the Oritiniv group were cellulitis (1.1%), osteomyelitis (0.4%), abscess limb (0.3%), pneumonia (0.3%), skin infection (0.3%) and subcutaneous abscess (0.3%). In the Oritiniv group, related SAE were reported in less than 1% of patients and overall lower compared to the vancomycin group. Deaths were comparable between the two treatment groups, with 2 (0.2%) in the Oritiniv group and 3 (0.3%) in the vancomycin group, none of which were related to study drug.

Review of adverse events of special interest (AESI) identified potential safety concerns for osteomyelitis, hepatic transaminase elevations, tachycardia, and interference with some coagulation assays. Osteomyelitis SAE were slightly higher in the Oritiniv (0.6%) group compared to the vancomycin (0.1%) group. An adverse event (AE) of increased alanine transaminase (ALT) was more common in the Oritiniv group (Oritiniv, 2.8%; vancomycin, 1.5%). Of the 10 patients in the Oritiniv group with ALT/aspartate transaminase (AST) elevations greater than 5x the upper limit of normal, levels returned to baseline (8) or were decreasing to baseline (1) or lost to follow up (1). There were no cases that met Hy’s law. A higher incidence of tachycardia was reported in the Oritiniv group with no clear relationship to study drug. There were a total of 5 deaths (2 in patients treated with oritavancin, and 3 in those treated with vancomycin). The causes of death were sepsis and electromechanical dissociation in the oritavancin group and septic shock, acute myocardial infarction, and dementia with Parkinsonism in the vancomycin group. None of these deaths were considered related to study drug. Relevant AESI included hypersensitivity, infusion site reactions/phlebitis, osteomyelitis, transient transaminase elevations, and inaccuracies of coagulation assays after oritavancin administration. Drug interactions, specifically with warfarin, and interference with coagulation assays (i.e. activated partial thromboplastin time, prothrombin time, International Normalized Ratio) were identified during review and labelled to mitigate risk.

The overall review of the two pivotal Phase 3 studies (SOLO I and SOLO II) demonstrated that Oritiniv was non-inferior to vancomycin for the treatment of adult patients with ABSSSI and presented an acceptable and manageable safety profile in consideration of the intended population.

The pharmacokinetic data of ABSSSI patients, administered either the 1,200 mg oritavancin formulation without the solubilizer HPβCD (three 400 mg vials administered over 3 hours) or the 1,200 mg oritavancin with the solubilizer HPβCD (one 1,200 mg vial administered over 1 hour) are comparable, and the formulations are considered bioequivalent.

The multiple mechanisms of action of Oritiniv may limit its propensity to select for high-level resistance. However, the mechanisms of resistance specific to Oritiniv were not studied. In serial passage studies, resistance to oritavancin was observed in isolates of Staphylococcus aureus and Enterococcus faecalis. Resistance to oritavancin was not observed in clinical studies.

Quality-related concerns with nitrosamine impurities initially led to an overall unfavourable benefit-harm-uncertainty risk profile for Oritiniv, and a Notice of Non-compliance (NON) recommendation issued on 24 February 2025. The Sponsor provided a response to the NON, and the quality review stream determined that the NON major objection was adequately addressed, as were all other concerns regarding the drug substance and drug product.

The final labelling and Product Monograph were considered acceptable.

A Risk Management Plan for Oritiniv submitted by Xediton Pharmaceuticals Inc. to Health Canada was considered acceptable, without further revision. The Sponsor was requested to submit a Periodic Safety Update Report/Periodic Benefit-Risk Evaluation Report after the first two years of marketing in Canada and to include an interval and a cumulative analysis of drug resistance.

Overall, the benefit-harm-uncertainty profile was favourable for Oritiniv 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 Oritiniv, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.