Antifungal Proves Mettle in Invasive Mold Disease
Published: Oct 15, 2014 | Updated: Oct 15, 2014
PHILADELPHIA -- The investigational antifungal agentisavuconazole proved equal to voriconazole (Vfend) in patients with neutropenia, researchers reported here.
In the SECURE trial, there was a 21% mortality during the 42-day study period and a 21% mortality among patients treated with voriconazole, according toThomas Patterson, MD, of the University of Texas at San Antonio, and colleagues.
Additionally, the agent -- designated as a Qualified Infectious Disease Product by the FDA -- appeared to have fewer treatment-related adverse effects, they reported at the annual IDWeek conference.
Patterson also noted that 43% of patients in the safety arm of the study who experienced neutropenia also were observed to have treatment-emergent adverse events compared with 58% of voriconazole patients, a difference that achieved statistical significance (P<0.05).
The adverse events' profile persisted for those patients with invasive fungal disease who did not experience neutropenia. Patterson said 42% of isavuconazole patients in this group experience treatment-emergent adverse events compared with 64% of voriconazole-treated patients, which was also statistically significant (P<0.05).
About 43% of non-neutropenic isavuconazole patients experienced serious treatment-related adverse effect compared with about 62% of voriconazole patients (P<0.05). About 13% of isavuconazole non-neutropenic patients discontinued treatment due to side effects versus 26% of patients on the voriconazole treatment regimen (P>0.05).
"We thought it was important in the SECURE trial to look at outcomes in neutropenia because it is one of the major risk factors for mortality in patients with invasive aspergillosis and mold disease, especially among those patients who have unresolved neutropenia in the course of the study," Patterson toldMedPage Today.
"By looking at this subgroup analysis we were able to show that isavuconazole and voriconazole had similar activity in this setting, establishing, I think, that isavuconazole could be used as an alternative agent in those patients with neutropenia and even those with unresolved neutropenia with invasive mold disease," he said.
The phase III, multicenter, randomized SECURE trial enrolled 527 adult patients who were diagnosed with proven, probable, or possible invasive fungal disease or other filamentous fungi. The primary endpoint was mortality at 42 days, but the patients were also followed for an additional 28 days for assessments of end of treatment overall success.
Patients were treated three times a day with isavuconazole for 2 days as a loading dose and then once a day after that. The drug can be given for 8 weeks, but it was administered for 6 weeks in SECURE. The drug can be given intravenously or orally.
"These patients had hematologic malignancies or were undergoing bone marrow transplant," he said, adding that other patients with immunosuppressive conditions were included.
In the patients who had neutropenia at baseline as their primary risk factor, the outcomes between the two drugs were similar for the primary endpoint of all-cause mortality at day 42, he said.
"This phase III study has been concluded," Patterson said. "It has been filed with the FDA for an indication for treating invasive mold disease. The drug will be reviewed by the FDA in March 2015."
"I think we know that we need more options. Patients need additional agents to combat invasive fungal infections," Patterson said. "This drug has the advantage of covering aspergillus or other molds and has pharmacokinetic characteristics that allow it to be used by intravenous route or orally in that setting."
In the neutropenic substudy, patients were about 50-years-old and more than half were men. Almost all the patients were being treated for a baseline hematological malignancy or bone marrow transplants.
For the primary endpoint of all-cause mortality at 42 days, there was no difference in outcome, Patterson reported. He illustrated that in the intention-to-treat neutropenic population, 21% of the patients on isavuconazole died and 21% of the voriconazole patients died. In the modified intention-to-treat analysis, 25% of 88 patients assigned to isavuconazole died compared with 23% of the 73 voriconazole patients die during the study period.
In the non-neutropenic intention-to-treat analysis, 11% of patients on isavuconazole died compared with 23% of the voriconazole patients, but that numerical advantage was not statistically significant.
In the secondary endpoint for end of treatment response, there were no statistically significant differences among patients who were neutropenic, who had unresolved neutropenia, who had resolved neutropenia, or who had non-neutropenic invasive disease.
In commenting on the study, Luis Ostrosky-Zeichner, MD, professor of medicine at the University of Texas Health Science Center in Houston, told MedPage Today that "there is a right drug for each patient so there is a need for additional options. These studies indicate that isavuconazole is at least as good as treatment with voriconazole and there are apparently fewer adverse events.
"The cost of new drugs can be an issue in their use, but clinicians are first going to consider the drug's efficacy. Then they will look at the safety of it and then comes the consideration of costs. But pricing of the drug will be important," he said.
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