Summary Basis of Decision for Oritiniv

Clinical Pharmacology

Oritiniv contains oritavancin, a semisynthetic glycopeptide antibiotic that inhibits the growth of gram-positive bacteria. Oritavancin has three mechanisms of action that contribute to the concentration-dependent bactericidal activity of Oritiniv:

1. inhibition of the transglycosylation (polymerization) step of cell wall biosynthesis by binding to the stem peptide of peptidoglycan precursors;

2. inhibition of the transpeptidation (crosslinking) step of cell wall biosynthesis by binding to the peptide bridging segments of the cell wall; and

3. disruption of bacterial membrane integrity, leading to depolarization, permeabilization, and rapid cell death.

The clinical pharmacology data submitted included 106 clinical studies that evaluated the pharmacodynamics, pharmacokinetics, safety, and efficacy of oritavancin. Most of these studies were legacy studies conducted when the dosing regimen under consideration was 200 mg (or 300 mg if body weight exceeded 110 kg) oritavancin infused over 1 hour, once daily for 3 to 7 days. Ultimately, the proposed dosing regimen was a single 1,200 mg oritavancin dose infused over 3 hours. As such, these studies were only considered as supportive and their relevance is limited. Overall, the results of these studies supported the safety profile of Oritiniv.

Oritavancin has been shown to interfere with phospholipid-dependent assays due to an in vitro reaction with phospholipids. In studies, oritavancin was found to increase the magnitude and duration of five phospholipid-dependent coagulation assays tested, indicating that the blood took longer than usual to clot. The authors of the studies concluded that this phenomenon should not have any in vivo implications in animals or patients treated with oritavancin. An in vitro study also demonstrated that oritavancin is not removed from the blood by hemodialysis.

Initial studies conducted with lower doses (1.5 to 232 mg oritavancin) than the proposed dose (1,200 mg) indicated that the pharmacokinetic data was linear over the dose range, with an area under the plasma concentration-time curve (AUC) increasing proportionally with dose, and with low clearance (1 to 5% recovered in urine/feces after 1 to 2 weeks). The terminal half-life was estimated to be 195 to 251 hours depending on the dose in the initial studies. Based on population pharmacokinetic analyses from two subsequent Phase III studies, oritavancin demonstratated a terminal half-life of approximately 245 hours and a clearance of 0.445 L/h.

A thorough QT study conducted in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) 14 guidelines, showed no clinically relevant prolongation of the QT interval, and a mild, non-meaningful PR interval prolongation.

The pharmacokinetic data of patients with acute bacterial skin and skin structure infections (ABSSSI) was comparable following administration of either 1,200 mg oritavancin without hydroxypropyl-β-cyclodextrin in dextrose (HPβCD) administered over 3 hours or the proposed formulation (1,200 mg oritavancin with HPβCD administered over 1 hour). Both AUC from 0 to 72 hours (AUC_0-72h) and from 0 to 168 hours (AUC_0-168h) were bioequivalent between groups.

The results of a pharmacokinetic study examining the use of 800 mg oritavancin in hepatically-impaired patients (Child-Pugh category of moderate) indicated that their AUC was 10 to 15% lower than that of healthy individuals. A second statistical analysis using geometric means that took into account various confounding factors revealed bioequivalence between the groups. No dosage adjustment is required in patients with mild and moderate hepatic impairment.

Oritavancin is a weak inhibitor of cytochrome P450 (CYP) enzymes CYP2C9 (a warfarin substrate) and CYP2C19, and is a weak inducer of CYP3A4 and CYP2D6. There was no drug-drug interaction between oritavancin and warfarin; however a subsequent Monte Carlo simulation using data from the SOLO studies revealed that a small proportion of patients may be impacted by this interaction.

Overall, the clinical pharmacology data support the use of Oritiniv for the recommended indication. Pharmacokinetic-pharmacodynamic modelling and target attainment analysis of the pivotal SOLO I and SOLO II Phase III clinical studies (described in the Clinical Efficacy section below) supported the proposed single 1,200 mg oritavancin dosing regimen. For further details, please refer to the Product Monograph for Oritiniv, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Oritiniv (oritavancin) for the treatment of adult patients with acute bacterial and skin structure infections (ABSSSI) was primarily evaluated based on the results of two pivotal Phase III clinical studies (SOLO I [TMC-ORI-10-01] and SOLO II [TMC-ORI-10-02]). These studies were identically designed, international, multicentre, double-blind, randomized, parallel group, active-comparator, non-inferiority studies that compared the efficacy of a single intravenous (IV) 1,200 mg dose of Oritiniv, followed by placebo infusions every 12 hours to IV vancomycin (1 g or 15 mg/kg every 12 hours) for 7 to 10 days.

The SOLO I study enrolled 954 patients who were randomized 1:1 to receive Oritiniv (total number [n] = 475) or vancomycin (n = 479). The SOLO II study enrolled 1,005 patients who were also randomized 1:1 to receive Oritiniv (n = 503) or vancomycin (n = 502).

The demographic and baseline characteristics were generally balanced between the two treatment groups for both of the SOLO studies as well as between the two SOLO studies, with few notable exceptions. There were a limited number of patients who were 65 years of age or greater, had moderate or severe renal function, or had hepatic impairment. Across the two studies, approximately 64% of patients were Caucasian and 65% were males. The mean age was 45 years and the mean body mass index was 27 kg/m². Approximately 60% of patients were enrolled from the United States and 27% of patients from Asia. Diabetes mellitus was present in 14% of patients. The types of ABSSSI across both trials included cellulitis/erysipelas (40%), wound infection (29%), and major cutaneous abscesses (31%). Median infection area at baseline across both trials was 266.6 cm².

The SOLO I and SOLO II studies 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). Therefore, three efficacy endpoints were considered relevant in the review of the pivotal Phase III ABSSSI SOLO studies: the primary endpoint of early clinical response (at the 48 to 72 hour early clinical evaluation [ECE] visit; based on the 2010 FDA Guidance), the key secondary endpoint of investigator-assessed clinical cure (at post-therapy evaluation [PTE] visit 7 to 14 days after the end of blinded therapy; based on the 2012 EMA guidance), and a second key secondary endpoint of lesion size reduction of 20% or greater (at the ECE visit; recommended primary endpoint per the 2013 FDA guideline).

The primary endpoint of early clinical response was a composite endpoint that included cessation of spread/reduction in size of the baseline lesion, absence of fever, and no use of rescue antibiotic medication. To be categorized as a success, a patient had to meet all of these components. For the key secondary endpoint of investigator-assessed clinical cure, a patient was categorized as a clinical success if the patient experienced a complete or nearly complete resolution of baseline signs and symptoms related to primary ABSSSI site (erythema, induration/edema, purulent drainage, fluctuance, pain, tenderness, local increase in heat/warmth) such that no further treatment with antibacterial drugs was needed. For the other key secondary endpoint of lesion size reduction of 20% or greater, lesion size reduction was calculated using lesion measurements taken at the ECE visit as compared to the baseline visit. The primary endpoint and two key secondary endpoints were prespecified for non-inferiority testing with a margin of 10% using the modified intention to treat (mITT) population.

For the primary endpoint of early clinical response at ECE visit, treatment success was reported in a similar percentage of patients in the Oritiniv and vancomycin treatment groups: for SOLO I (Oritiniv, 82.3%; vancomycin, 78.9%) with a treatment difference of 3.4% (95% CI: -1.6, 8.4) and for SOLO II (Oritiniv, 80.1%; vancomycin, 82.9%) with a treatment difference of -2.7% (95% CI: -7.5, 2.0).

For the key secondary endpoint of investigator-assessed clinical cure, a similar percentage of patients were considered clinically cured in the treatment groups in SOLO I (Oritiniv, 79.6%; vancomycin, 80.0%) with a treatment difference of -0.4% (95% CI: -5.5, 4.7) and SOLO II (Oritiniv, 82.7%; vancomycin, 80.5%) with a treatment difference of 2.2% (95% CI: -2.6, 7.0).

For the second key secondary endpoint, the percentage of patients with a lesion size reduction of 20% or greater from baseline at the ECE visit was similar in the treatment groups in SOLO I (Oritiniv, 86.9%; vancomycin, 82.9%) with a treatment difference of 4.1% (95% CI: -0.5, 8.6) and SOLO II (Oritiniv, 85.9%; vancomycin, 85.3%) with a treatment difference of 0.6% (95% CI: -3.7, 5.0).

For both studies, all three endpoints demonstrated statistically significant non-inferiority, with the lower limit of the 95% confidence interval falling within the prespecified non-inferiority margin of -10%. These results demonstrated that Oritiniv was non-inferior to vancomycin in the treatment of adult patients with ABSSSI. Sensitivity analyses were supportive of the primary analysis.

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 methicillin-resistant Staphylococcus aureus (MRSA), consistent efficacy results were seen across all clinically relevant endpoints.

Overall, the evidence reviewed from the two pivotal Phase III ABSSSI SOLO studies demonstrated that Oritiniv was non-inferior to vancomycin for the treatment of ABSSSI in adult patients.

Indication

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

Oritiniv (oritavancin) for injection is indicated for 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, Streptococcus anginosus group (includes Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus), and Enterococcus faecalis (vancomycin susceptible isolates only).

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Oritiniv and other antibacterial drugs, Oritiniv should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

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

Clinical Safety

The clinical safety of Oritiniv was primarily evaluated based on data from the pivotal, Phase III SOLO studies (described in the Clinical Efficacy section). The safety population in the pooled SOLO studies included 1,959 patients who were treated with at least one dose of study drug (976 with Oritiniv and 983 with vancomycin). The median duration of treatment was 8 days for both groups.

In the pooled data from both studies (SOLO pool), the proportion of patients who reported at least one treatment emergent adverse event (TEAE) was similar in the Oritiniv and vancomycin groups (55.3% for Oritiniv versus [vs.] 56.9% for vancomycin). These values were also similar when considering the study-specific data (SOLO I [60.0% for Oritiniv vs. 63.8% for vancomycin] and SOLO II (50.9% for Oritiniv vs. 50.2% for vancomycin). In the SOLO pool, the incidence of TEAE by system organ class was similar in both treatment groups, with the exception of a lower incidence of skin and subcutaneous tissue disorders in the Oritiniv group (10.3% for Oritiniv vs. 15.9% for vancomycin). Otherwise, the incidence of patients with any adverse event (AE) leading to study drug discontinuation (3.7% for Oritiniv vs. 4.2% for vancomycin), serious adverse events (SAE; 5.8% for Oritiniv vs. 5.9% for vancomycin), or any AE leading to death (0.2% for Oritiniv vs. 0.3% for vancomycin) were comparable and slightly lower in the Oritiniv group.

The most common TEAEs (occurring with 4% or greater incidence) reported in the SOLO pool had similar incidences in patients treated with Oritiniv vs. vancomycin. These included nausea (9.9% for Oritiniv vs. 10.5% for vancomycin), headache (7.1% for Oritiniv vs. 6.7% for vancomycin) and vomiting (4.6% for Oritiniv vs. 4.7% for vancomycin). The most frequent SAEs in patients treated with Oritiniv were cellulitis (1.1%), osteomyelitis (0.4%), abscess on limb (0.3%), pneumonia (0.3%), skin infection (0.3%), and subcutaneous abscess (0.3%). In patients treated with vancomycin, the most frequent SAEs were cellulitis (1.2%) and skin infection (0.3%). There were five deaths in the SOLO pool study; two in patients treated with Oritiniv, and three in those treated with vancomycin. The causes of death in the patients treated with Oritiniv were sepsis and electromechanical dissociation. For those treated with vancomycin, the causes of death were septic shock, acute myocardial infarction, and dementia with Parkinsonism. None of the deaths were considered related to study drug.

A 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 SAEs were slightly higher in the Oritiniv (0.6%) group compared to the vancomycin (0.1%) group. An AE of increased alanine transaminase (ALT) was more common in the Oritiniv group (2.8% vs. 1.5% for vancomycin). Of the ten patients in the Oritiniv group with aspartate aminotransferase (AST) or ALT elevations greater than five times the upper limit of normal, eight had their values return to baseline levels, one had levels that were decreasing to baseline, and one was lost to follow up. No cases met Hy’s law. A higher incidence of tachycardia was reported in the Oritiniv group with no clear relationship to study drug. Relevant AESIs included hypersensitivity, infusion site reactions/phlebitis, osteomyelitis, transient transaminase elevations and inaccuracies of coagulation assays after the administration of Oritiniv. 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.

Appropriate warnings and precautions are in place in the approved Product Monograph for Oritiniv to address the identified safety concerns. Serious hypersensitivity reactions, including anaphylaxis, have been reported with the use of oritavancin products. A Serious Warnings and Precautions box describing serious hypersensitivity reactions, including anaphylaxis, has been included in the Product Monograph for Oritiniv.

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 for Oritiniv.

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

Pharmacodynamics

Data from non-clinical studies demonstrated that oritavancin is an effective inhibitor of gram-positive bacteria including resistant strains. These studies determined the dose-related pharmacodynamic (PD) antibiotic effects of oritavancin in vivo. In addition, secondary PD actions were explored, such as physiological processes and organ functions unrelated to antibiotic activities, including binding to receptors that regulate autonomic pharmacology and several major neurotransmitters.

The spectrum of oritavancin activity includes the gram-positive pathogens that cause acute bacterial skin and skin structure infections (ABSSSI), including staphylococci (methicillin-susceptible Staphylococcus [S.] aureus [MSSA], methicillin-resistant S. aureus [MRSA], heterogeneous vancomycin-intermediate S. aureus [hVISA], vancomycin-intermediate S. aureus [VISA], vancomycin-resistant S. aureus [VRSA] and linezolid- and daptomycin-non-susceptible strains), streptococci (including penicillin- and macrolide-resistant strains), and enterococci (vancomycin-sensitive enterococcus [VSE] and vancomycin-resistant enterococcus [VRE] with VanA and VanB phenotypes).

Secondary pharmacodynamics studies showed no interference with muscarinic or adrenergic receptors, indicating a low likelihood of effects on the autonomic nervous system. In addition, oritavancin did not exert non-selective effects on guinea pig ileum or atrial tissue. Oritavancin bound to D1 and D2 dopaminergic receptors in vitro with affinity constants (K_i) of 2.25 and 3.46 µM respectively, but in behavioral and central nervous system studies conducted in mice, and in toxicity studies conducted in rats and dogs, oritavancin administration was not associated with clinical signs characteristic of dopamine agonist or antagonist activity. In mice, an intravenous (IV) bolus of 50 mg/kg oritavancin caused mild hypothermia and increased hexobarbital sleep time, the latter possibly related to decreased metabolism of hexobarbital due to reduced cytochrome P450 activity.

In vitro, oritavancin blocked the sodium current (I_Na), transient outward potassium current (I_to), and human ether-a-go-go-related gene (hERG) cardiac ion channels with a half-maximal inhibitory concentration (IC₅₀) of 0.51, 4.2, 22 μM respectively. However, in vivo studies in dogs showed no widening of the QRS interval, QT prolongation, or proarrhythmic activity at plasma levels 56-fold above the IC₅₀ for I_Na.

Pharmacokinetics

The pharmacokinetics (PK) of oritavancin was studied in vivo in mice, rats, rabbits, and dogs, and in vitro in plasma samples from humans, mice, rats, and dogs, as well as in rhesus monkey liver microsomes.

Oritavancin showed linear, dose-proportional plasma kinetics, with peak concentrations at the first sampling time point following the end of infusion. No gender differences in PK were observed the across species studied.

A study in rats administered repeated single, daily IV injections of oritavancin at various doses for one month showed that there was no apparent increase in either AUC or C_max from Day 0 to Day 13 suggesting that oritavancin did not accumulate in the plasma after multiple dosing. Similar phenomena was observed in a multiple dose study performed in beagle dogs.

A Good Laboratory Practice-compliant study comparing formulations administered with and without hydroxypropyl-β-cyclodextrin in dextrose (HPβCD) showed no substantial differences in exposure, accumulation, tissue distribution, or elimination.

Quantitative whole body autoradiography studies in rats showed wide tissue distribution, peaking 1 to 6 hours post IV administration. Whole body autoradiography in pregnant rats showed no placental transfer; however, the study was limited due to a small sample size and the lack of clarity on whether the analysis was timed accurately to best determine the timing of transplacental transfer.

The serum protein binding of oritavancin was assessed in mice, rats, dogs, and humans, with protein binding averaging approximately 85% across species. The binding extent was fairly consistent across species. Human plasma showed the lowest binding at 81.9% and dog plasma was the highest at 87.1%.

An in vitro study conducted with hepatic microsomes from rhesus monkeys showed no indication of oritavancin metabolism. Studies in mice, rats, and dogs suggest that the primary route of elimination for oritavancin is via bile into the feces. In contrast to animals, where feces is the main route of excretion, the majority of the recovered dose in humans is found in urine (approximately 5%), with the remaining amount in feces (less than 1%).

A study in lactating rats showed that oritavancin is excreted in milk and absorbed orally by nursing pups, with radiolabelled drug detected in the plasma and tissue of most pups.

Toxicology

Repeat-dose toxicity in rats showed reduced hematologic parameters (red blood cell counts, hemoglobin, and hematocrit) and increased white blood cells, and elevated clinical chemistry parameters (blood urea nitrogen, alanine aminotransferase [ALT], aspartate aminotransferase [AST], and alkaline phosphatase [ALP]) consistent with hepatic toxicity. Histopathologic changes characterized by dose-dependent increases in eosinophilic-containing histiocytes in the liver, spleen, lymph nodes, sternum, femur, thymus, lungs, catheterized sites, and ovaries were also reported. Following repeat doses in dogs, histamine-mediated reactions, hematology changes (decreased erythrocytes, hemoglobin, hematocrit, platelets, lymphocytes, basophils, and reticulocytes), and elevated ALT, AST, ALP were associated with renal and liver toxicity. Histopathologic changes similar to those seen in rats were also reported in dogs.

Immunotoxicity studies in rats showed increased serum, histiocytes, and elevated primary antibody responses. Dose-related eosinophilic granule deposition in macrophages following administration of oritavancin for 2 weeks suppressed immune response to Candida albicans. The suppression of immune response appeared reversible after 30 days.

Local tolerance studies showed mild ocular and moderate dermal irritation.

Microbiology

The spectrum of oritavancin’s in vitro activity includes the key gram-positive ABSSSI pathogens Staphylococcus (S.) aureus (including MRSA), streptococci, and enterococci. The extended gram-positive spectrum of oritavancin activity results from its multiple mechanisms of action. It retains activity in vitro against vancomycin-non-susceptible pathogens and has a longer post-antibiotic effect than vancomycin.

Oritavancin minimum inhibitory concentrations (MICs) are lower than those of vancomycin and comparators against key gram-positive ABSSSI pathogens including MRSA. The in vitro activity of oritavancin is unaffected by resistance to oxacillin, linezolid, daptomycin, erythromycin and penicillin. Oritavancin’s in vitro activity is consistent across regions and by Panton-Valentine leukocidin virulence gene status.

In vitro stepwise selection showed a 4- to 8-fold increase in oritavancin MIC for S. aureus isolates of different drug resistance phenotypes. For Enterococcus faecalis and Enterococcus faecium isolates with reduced susceptibility to oritavancin, a 4- to 64-fold increase in oritavancin MIC was reported. In all instances tested, the MIC against the isolates did not exceed 1 mcg/mL. Results suggested a potential for emergence of oritavancin resistance during therapy. Resistance was observed in vitro but not clinically. In vitro studies evaluating the inhibitory effects of oritavancin in combination with an array of antimicrobial agents showed that oritavancin exhibits synergistic bactericidal activity in combination with gentamicin, moxifloxacin or rifampicin against isolates of MSSA, with gentamicin or linezolid against isolates of MRSA-hVISA, VISA, and VRSA, and with rifampin against isolates of VRSA. No antagonism between oritavancin and gentamicin, moxifloxacin, linezolid or rifampin was demonstrated. In a variety of animal models of bacterial infection, oritavancin is effective against a variety of gram-positive pathogens with diverse antibacterial resistance phenotypes. Front-loaded dosing, when the bacterial burden at the site of infection is predicted to be the highest, maximized efficacy.

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

The quality (chemistry and manufacturing) information submitted for Oritiniv 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). For Oritiniv 400 mg, the combined storage time (reconstituted solution in the vial and diluted solution in the bag) and 3 hours infusion time should not exceed 6 hours at room temperature (15 ºC to 30 ºC) or 12 hours if refrigerated (2 ºC to 8 ºC). For Oritiniv 1,200 mg, the combined storage time (reconstituted solution in the vial and diluted solution in the bag) and 1 hour infusion time should not exceed 4 hours at room temperature (15 ºC to 30 ºC) or 12 hours if refrigerated (2 ºC to 8 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. During the review of the initially submitted quality (chemistry and manufacturing) data package for Oritiniv, Health Canada identified deficiencies in the sponsor’s risk assessment of the potential for formation or introduction of nitrosamine impurities in the drug product. Consequently, a Notice of Non-Compliance (NON) was issued on February 24, 2025. The review of the sponsor’s response to the NON concluded that all issues of concern were addressed satisfactorily.

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. Additionally, none of the excipients used in the formulation of Oritiniv are of human or animal origin.