Key evidence from clinical trials for posaconazole

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

• Invasive aspergillosis in patients with amphotericin B, itraconazole, or voriconazole intolerant or refractory disease.
• Esophageal Candidiasis in patients with disease refractory or intolerant to amphotericin B, fluconazole or itraconazole.

• Fusariosis, zygomycosis, cryptococcosis, chromoblastomycosis, and mycetoma in patients with disease refractory to another therapy, or intolerant to another therapy.

• Coccidioidomycosis

Posaconazole is also indicated for:

• Treatment of oropharyngeal candidiasis in immunocompromised adults, including patients with disease that is refractory to itraconazole and fluconazole.
• Prophylaxis of invasive fungal infections, including yeast and mold, in patients 13 years of age and older who are at high risk of developing these infections, such as patients with prolonged neutropenia or hematopoietic stem cells transplant recipients

Clinical studies

Prophylaxis of Aspergillus and Candida infections with posaconazole oral suspension

• Two large, randomized, controlled studies using posaconazole were performed as prophylaxis for the prevention of invasive fungal infections (IFIs) among high-risk patients.
• Study one was randomized, double-blind trial comparing posaconazole oral suspension (200 mg three times a day) with fluconazole capsules (400 mg once a day) as prophylaxis against invasive fungal infections in allogeneic hematopoietic stem cell transplant (HSCT) recipients versushost disease (GVHD).
• the primary effectiveness end point 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 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 randomized, evaluator-blind study comparing posaconazole oral suspension (200 mg three times daily) with fluconazole suspension (400 mg once daily) or oral itraconazole solution (200 mg twice daily) as prophylaxis against IFI in neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes.
• The primary efficacy endpoint was the incidence of proven / probable IFIs as determined by an independent and blinded external panel of experts during the treatment period.
• A key secondary endpoint was the incidence of proven / probable IFIs 100 days after 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 advance infection. There were significantly fewer advanced Aspergillus infections in patients receiving posaconazole prophylaxis compared to control patients receiving fluconazole or itraconazole.
• In Study 2, a significant decrease in all-cause mortality was observed in favor of posaconazole. [posaconazole 49/304 (16 %) vs. fluconazole / itraconazole 67/298 (22%) p = 0.048]. According to 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 to the fluconazole group (12/299; p = 0.0413).
• Table 1 summarizes the results of both studies.

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

** In Study 2, this was the period from randomization to 100 days after randomization; in study 1 it was the period from Base day to 111 days after the baseline. a ); fluconazole (study1); Fluconazole / itraconazole (Study 2)

Treatment of Azole Susceptible Oropharyngeal Candidiasis

• A randomized, double-blind, controlled study was completed in HIVpatients infected 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.
• Patients were treated with posaconazole or fluconazole oral suspension (both posaconazole and fluconazole were administered as follows: 100 mg twice daily for 1 day followed by 100 mg once daily for 13 days).
• Posaconazole and fluconazole demonstrated equivalent clinical success rates on day 14 and 4 weeks after the end of treatment.
• However, posaconazole demonstrated a significantly better sustained mycological response rate than fluconazole.
• The results are summarized in Table 2.

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

b The 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 to be refractory if OPC did not improve or worsen after standard treatment 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 Fluconazole or itraconazole treatment was not discontinued for more than 14 days prior to posaconazole treatment.
• In a open study 89 HIV-infected subjects met these strict criteria for refractory OPC infection
• Forty-five subjects with refractory OPC were treated with 400 mg of posaconazole oral suspension twice daily for 3 days, followed by 400 mg once daily for 25 days with an additional treatment option during a 3-month maintenance period .
• After a dosage amendment, 44 other subjects were treated with 400 mg of posaconazole twice daily for 28 days.
• The efficacy of posaconazole was assessed by the clinical success rate (cure or improvement) after 4 weeks of treatment.
• The overall clinical success rate was 74.2%.
• The clinical success rates for the original and modified dosing regimens were similar (73.3% and 75.0%, respectively).

Invasive aspergillosis treatment

• The efficacy and survival benefit of oral posaconazole for the treatment of invasive aspergillosis in patients with amphotericin B-resistant disease (including liposomal formulations), itraconazole or voriconazole, or in patients intolerant to these drugs, was demonstrated in 107 enrolled patients. in a salvage therapy trial.
• Patients received 800 mg posaconazole / day in divided doses for up to 585 days.
• Most of the patients were severely immunocompromised with underlying conditions, such as hematologic malignancies, including the bone marrow. transplant; solid organ transplant; solid tumors and / or AIDS.
• Success was defined as complete resolution (complete response) or clinically significant improvement (partial response) of all signs, symptoms, and radiographic findings attributable to fungal infection. Stable, noprogressive Illness and failure were considered not a success.
• A panel of independent experts reviewed all patient data, including the diagnosis of invasive aspergillosis, refractoriness, and intolerance to previous therapy, and the clinical outcome in parallel and blind fashion with an external control group of 86 patients treated with standard therapy. , mainly at the same time and at the same time. same sites as patients enrolled in the posaconazole trial.
• Most aspergillosis cases were considered refractory in both the posaconazole group (88%) and 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, randomized, controlled study, so all comparisons with the external control group should be considered in this context.
• The results are summarized in Table 3.

Coccidioidomycosis Treatment

• The efficacy of posaconazole in the primary treatment of non-meningeal coccidioidomycosis was demonstrated in 15 clinically evaluable patients, included in an open, non-comparative trial, who received 400 mg posaconazole daily for 6 months.
• A satisfactory response (defined as an improvement of at least 50% from the Cocci score as defined by the Coccidioidomycosis test group) was observed in 12 of 15 patients (80%) after an average of 4 months of posaconazole treatment .
• In another open, non-comparative trial, the safety and efficacy of posaconazole 400 mg twice daily were evaluated 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 or years before treatment with posaconazole.
• At the end of posaconazole treatment, a satisfactory response was achieved (complete or partial resolution of the signs and symptoms present at the start of the study) as determined by an independent panel for 11/16 (69%) of patients.
• A patient with CNS The disease that failed fluconazole therapy had a successful outcome after 12 months of posaconazole therapy.

Posaconazole site in fungal infections.

• • Posaconazole is available as an injection (18 mg / ml for patients over 18 years of age; approved by the US FDA in 2014), delayed release tablets (100 mg for patients over 13 years of age; approved by the US FDA. In 2013), oral suspension (40 mg / ml for patients 13 years and older; approved by the US FDA in 2006) for the treatment of oropharyngeal candidiasis and the treatment and prophylaxis of invasive fungal infections .
  • In Europe and the United Kingdom, posaconazole oral suspension is approved for the same indications.
  • Posaconazole 40 mg / ml oral suspension is a fully subsidized drug available in New Zealand for use in the treatment and prophylaxis of invasive fungal infections and oropharyngeal candidiasis in immunocompromised patients.
  • The wealth of modeled cost-effectiveness analyzes from a healthcare provider's perspective on the use of prophylactic posaconazole suggests that it is a dominant or cost-effective option in relation to prophylaxis with standard azole therapy (i.e. fluconazole or itraconazole) in neutropenic patients with acute myelogenous leukemia / myelodysplastic syndromes and fluconazole in patients with graft-versus-host disease.