Key clinical-trial evidence for posaconazole

Posaconazole (NOXAFIL®) is indicated for use in the treatment of the following invasive fungal infections in patients 18 years of age or older:

• Invasive aspergillosis in patients with disease that is refractory to, or are intolerant of, amphotericin B, itraconazole, or voriconazole
• Oesophageal candidiasis in patients with disease that is refractory to, or who are intolerant of, amphotericin B, fluconazole, or itraconazole
• Fusariosis, zygomycosis, cryptococcosis, chromoblastomycosis, and mycetoma in patients with disease refractory to other therapy, or patients who are intolerant of other therapy
• Coccidioidomycosis.

Posaconazole is also indicated for:

• The treatment of oropharyngeal candidiasis in immunocompromised adults, including patients with disease that is refractory to itraconazole and fluconazole.
• Prophylaxis of invasive fungal infections, including both yeasts and moulds, in patients 13 years of age and older who are at high risk of developing these infections, such as patients with prolonged neutropaenia or haematopoietic stem cell transplant recipients.

Clinical studies

Prophylaxis of aspergillus and candida infections with posaconazole oral suspension

• Two large, randomised, controlled studies were conducted using posaconazole as prophylaxis for the prevention of invasive fungal infections (IFIs) among patients at high risk.
• Study one was a randomised, double-blind trial that compared posaconazole oral suspension (200 mg three times a day) with fluconazole capsules (400 mg once daily) as prophylaxis against invasive fungal infections in allogeneic haematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) [1,2].
• The primary efficacy endpoint was the incidence of proven/probable IFIs at 16 weeks post-randomization as determined by an independent blinded external expert panel.
• A key secondary endpoint was the incidence of proven/probable IFIs during the on-treatment period (first dose to last dose of study medication + 7 days).
• The mean duration of therapy was comparable between the two treatment groups (80 days, posaconazole; 77 days, fluconazole).
• Study two was a randomised, evaluator-blinded study that compared posaconazole oral suspension (200 mg three times a day) with fluconazole suspension (400 mg once daily) or itraconazole oral solution (200 mg twice a day) as prophylaxis against IFIs in neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukaemia or myelodysplastic syndromes [3].
• The primary efficacy endpoint was the incidence of proven/probable IFIs as determined by an independent, blinded external expert panel during the on-treatment period.
• A key secondary endpoint was the incidence of proven/probable IFIs at 100 days post-randomization.
• The mean duration of therapy was comparable between the two treatment groups (29 days, posaconazole; 25 days, fluconazole/itraconazole).
• In both prophylaxis studies, aspergillosis was the most common breakthrough infection. There were significantly fewer breakthrough Aspergillus infections in patients receiving posaconazole prophylaxis when compared to control patients receiving fluconazole or itraconazole.
• In Study 2, a significant decrease in all cause mortality in favour of posaconazole was observed [posaconazole 49/304 (16 %) vs. fluconazole/itraconazole 67/298 (22%) p = 0.048]. Based on Kaplan-Meier estimates, the probability of survival up to day 100 after randomization was significantly higher for posaconazole recipients.
• In Study 1, overall mortality was similar (posaconazole, 25% vs. fluconazole, 28%); however, the proportion of IFI-related deaths was significantly lower in the posaconazole group (4/301) compared with the fluconazole group (12/299; p = 0.0413).
• Table 1 summarises the results of both studies.

* In study 2, this was the period from randomization to last dose of study medication plus 7 days; in study 1, it was the period from first dose to last dose of study medication plus 7 days.

**In study 2, this was the period from randomization to 100 days post-randomization; in study 1, it was the period from the Baseline day to 111 days post-baseline. a) fluconazole (study 1); fluconazole/itraconazole (study 2).

Treatment of azole-susceptible oropharyngeal candidiasis

• A randomised, double-blind, controlled study was completed in HIV-infected patients with azole-susceptible oropharyngeal candidiasis (OPC).
• The primary efficacy variable was the clinical success rate (defined as cure or improvement) after 14 days of treatment [4].
• Patients were treated with posaconazole or fluconazole oral suspension (both posaconazole and fluconazole were given as follows: 100 mg twice a day for 1 day followed by 100 mg once a day for 13 days).
• Posaconazole and fluconazole demonstrated equivalent clinical success rates at day 14 as well as 4 weeks after the end of treatment.
• However, posaconazole demonstrated a significantly better sustained mycological response rate than fluconazole.
• Results are summarised in Table 2.

(a) Clinical success rate was defined as the number of cases assessed as having a clinical response (cure or improvement) divided by the total number of cases eligible for analysis.

(b) Mycological response rate was defined as mycological success (≤ 20 CFU/ml) divided by the total number of cases eligible for analysis.

** p = 0.04

Treatment of azole-refractory oropharyngeal candidiasis

• An episode of OPC was considered refractory if there was failure to improve or worsening of OPC after a standard course of therapy with fluconazole greater than or equal to 100 mg/day for at least 10 consecutive days or itraconazole 200 mg/day for at least 10 consecutive days and treatment with either fluconazole or itraconazole had not been discontinued for more than 14 days prior to treatment with posaconazole.
• In an open-label study 89 HIV-infected subjects met these strict criteria for refractory OPC Infection [5].
• Forty-five subjects with refractory OPC were treated with posaconazole oral suspension 400 mg twice daily for 3 days, followed by 400 mg once daily for 25 days with an option for further treatment during a 3-month maintenance period.
• Following a dosing amendment, a further 44 subjects were treated with posaconazole 400 mg twice daily for 28 days.
• The efficacy of posaconazole was assessed by the clinical success (cure or improvement) rate after 4 weeks of treatment.
• The overall clinical success rate was 74.2%.
• The clinical success rates for both the original and the amended dosing regimens were similar (73.3% and 75.0%, respectively).

Treatment of invasive aspergillosis

• The efficacy and survival benefit of oral posaconazole for the treatment of invasive aspergillosis in patients with disease refractory to amphotericin B (including liposomal formulations), itraconazole or voriconazole or in patients who were intolerant of these medicinal products, was demonstrated in 107 patients enrolled in a salvage therapy trial [6].
• Patients were administered posaconazole 800 mg/day in divided doses for up to 585 days.
• The majority of patients were severely immunocompromised with underlying conditions such as haematologic malignancies (including bone marrow transplantation), solid organ transplantation, solid tumours, and/or AIDS.
• A success was defined as either complete resolution (complete response) or a clinically meaningful improvement (partial response) of all signs, symptoms, and radiographic findings attributable to the fungal infection. Stable, non-progressive disease and failure were considered to be a non-success.
• An independent expert panel reviewed all patient data, including diagnosis of invasive aspergillosis, refractoriness, and intolerance to previous therapy, and clinical outcome in a parallel and blinded fashion with an external control group of 86 patients treated with standard therapy mostly at the same time and at the same sites as the patients enrolled in the posaconazole trial.
• Most of the cases of aspergillosis were considered to be refractory in both the posaconazole group (88%) and in the external control group (79%).
• At one year, the survival rate for posaconazole was 38% compared to 22% for the external control group.
• However, this was not a prospective, randomised controlled study and so all comparisons with the external control group must be viewed in this context.
• Results are summarised in table 3.

Treatment of coccidioidomycosis

• The efficacy of posaconazole in the primary treatment of non-meningeal coccidioidomycosis was demonstrated in 15 clinically evaluable patients, enrolled in an open-label, non-comparative trial, who received posaconazole 400 mg daily for 6 months [7].
• A satisfactory response (defined as an improvement of at least 50% of the Cocci score as defined by the Coccidioidomycosis trial group) was seen in 12 of 15 patients (80%) after an average of 4 months of posaconazole treatment.
• In a separate open-label, non-comparative trial, the safety and efficacy of posaconazole 400 mg twice a day was assessed in 16 patients with coccidioidomycosis infection refractory to standard treatment.
• Most had been treated with amphotericin B (including lipid formulations) and/or itraconazole or fluconazole for months to years prior to posaconazole treatment.
• At the end of treatment with posaconazole, a satisfactory response (complete or partial resolution of signs and symptoms present at baseline) as determined by an independent panel was achieved for 11/16 (69%) of patients.
• One patient with CNS disease who failed fluconazole therapy had a successful outcome following 12 months of posaconazole therapy.

Safety of long term posaconazole

• Safety data from the clinical development program (phase II/III trials) of the triazole antifungal agent, posaconazole, were analyzed [8].
• Incidences of treatment-emergent, treatment-related, and serious adverse events and abnormal laboratory parameters were recorded during these studies.
• A total of 428 patients with refractory invasive fungal infections (n = 362) or febrile neutropenia (n = 66) received posaconazole.
• 109 of these patients received posaconazole therapy for 6 months or less.
• The most common treatment-related adverse events were nausea (8%) and vomiting (6%).
• Treatment-related serious adverse events occurred in 8% of patients, and included low rates of treatment-related corrected QT interval and/or QT interval prolongation (1%) and elevation of hepatic enzymes (2%).
• Treatment-emergent, treatment-related adverse events occurred at similar rates in patients who received posaconazole therapy for more than 6 months and posaconazole therapy for 6 months or less.

Use in paediatric patients

• Itraconazole, voriconazole, and posaconazole showed comparable efficacy as antifungal prophylaxis in paediatric patients after allogeneic haematopoietic stem cell transplantation (HSCT) [9].
• Each of the 50 paediatric patients and adolescents (younger than 18 years) received itraconazole at a dosage of 2 × 5 mg per kg of body weight daily and voriconazole 2 × 100 mg daily (body weight less than 40 kg) or 2 × 200 mg (body weight more than 40 kg). The dosage of posaconazole was 3 × 4 mg per kg of body weight daily.
• None of the children included in this analysis had an invasive fungal infection prior to the planned allogeneic HSCT.
• The observation period was defined as the period from the day before the start of antifungal monoprophylaxis with itraconazole, voriconazole, or posaconazole through the date two weeks after the completion of oral antimycotic prophylaxis, up to a maximum of 220 days after HSCT.
• In all three groups, no case of proven or probable invasive fungal infection occurred during the observation period based on the EORTC National Institute of Allergy and Infectious Diseases Mycoses Study Group guidelines.
• Possible invasive fungal infections were observed in 2 (4%) out of 50 pediatric patients in the itraconazole group, as well as in 3 (6%) out of 50 cases in the voriconazole group. There were no possible invasive fungal infections observed in the posaconazole group.
• To make further statements regarding efficacy, the analysis of a larger number of patients is required.

Posaconazole tablet vs suspension in paediatric HSCT patients

• 63 paediatric patients with haemato-oncological malignancies who received posaconazole for antifungal prophylaxis after HSCT were analysed for efficacy, feasibility and the safety of posaconazole [10].
• 31 patients received posaconazole oral suspension and 32 received posaconazole tablets up to 200 days after transplantation.
• No possible, probable or proven invasive fungal infection was observed in either group.
• Posaconazole trough levels were significantly higher in the tablet group than in the suspension group at all analysed time points.
• Drug-related adverse events were similarly low in both groups.
• As early as day 3 after starting posaconazole tablets, over 50% of the posaconazole trough levels were >500 ng/mL, while this was observed on day 14 after start with posaconazole suspension.
• The administration of posaconazole tablets was safe, effective and feasible as antifungal prophylaxis in paediatric patients after HSCT.

Place of posaconazole in fungal infections

• Posaconazole is available as an injection (18 mg/ml for patients 18 years and older; US FDA approved in 2014), delayed-release tablets (100 mg for patients 13 years and older; US FDA approved in 2013) , oral suspension (40 mg/ml for patients 13 years and older; US FDA approved in 2006) for the treatment of oropharyngeal candidiasis and treatment and prophylaxis of invasive fungal infections.
• In Europe and UK, posaconazole oral suspension and tablets are approved for the same indications.
• Posaconazole oral suspension 40 mg/ml is a fully subsidised medication available in New Zealand for use in the treatment and prophylaxis of invasive fungal infections and oropharyngeal candidiasis in immunocompromised patients.
• The tablet formulation of posaconazole was fully funded in NZ in September 2016. The two formulations i.e. oral suspension and tablets are not interchangeable due to a difference in dosing of each formulation.
• Posaconazole is also available in NZ as an injection (18mg/ml) for the treatment and prophylaxis of invasive fungal infections in adults refractory to alternative therapy.
• The large body of modelled cost-effectiveness analyses from a healthcare payer perspective on the use of prophylactic posaconazole suggest that it is a dominant or cost-effective option relative to prophylaxis with standard azole therapy (ie, fluconazole or itraconazole) in neutropenic patients with acute myelogenous leukaemia/myelodysplastic syndromes and fluconazole in patients with graft-vs-host disease.