FDA Advisory Committee Meeting

SILVER SPRING, MD. – A novel treatment for invasive aspergillosis and invasive mucormycosis gained the support of a Food and Drug Administration advisory panel, although members were more ambivalent about the mucormycosis indication, based on the small amount of data available in those patients.

At a meeting on Jan. 22, the FDA’s Anti-Infective Drugs Advisory Committee voted 11-0 that there was “substantial evidence” that isavuconazonium, an antifungal prodrug, was safe and effective for the treatment of invasive aspergillosis, a life-threatening condition most commonly seen in immunocompromised patients. The drug was studied in a phase III study comparing isavuconazonium to voriconazole, the standard of care, in more than 500 patients.

The panel voted 8-2, with one abstention, that there was substantial evidence it was safe and effective for treating patients with invasive mucormycosis, with panelists voting on both sides of the question citing the study of only 37 patients that used historical controls as an issue. Those supporting approval for mucormycosis said that, if approved, the manufacturer, Astellas, should be required to conduct a phase IV trial further evaluating this treatment for patients with this infection.

Isavuconazonium is a prodrug of isavuconazole, a triazole antifungal, and would be available in an oral capsule formulation and a powder formulation that is reconstituted for intravenous administration (and needs to be administered through an in-line filter in case of particulate formation).

For aspergillosis, “I do believe that this drug provides a reasonable alternative to the current therapies that are available without additional toxicities,” said panelist Dr. Paige Waterman of the Global Emerging Infections Surveillance and Response System at the Walter Reed Army Medical Center, Silver Spring, Md. Other panelists agreed with her recommendations that labeling should make clear that it should not be used in people under age 18 years or in pregnant women, that a filter should be used when administered intravenously, and that labeling should include a statement about the increased risk of hepatotoxicity that also appears in the labeling of other drugs in the same class.

Because it has been associated with a shortened QT interval, she said that screening ECGs should be recommended for patients and that there should be some extra caution when it is prescribed to people who are Asian or of Asian descent, since drug concentrations were slightly higher among Asian patients who received the drug. Other recommendations from panelists included the need to conduct studies of the drug to provide information on therapeutic drug monitoring and in people under 18 years.

For treatment of invasive mucormycosis, an even rarer fungal infection which, in hospitals, is associated with the use of contaminated materials or organ transplantation, the panelists were more hesitant, but those voting in favor of approval cited the significance of the condition and the reasonable efficacy results in the study, stressing that postmarketing studies were critical. Panelists also noted that more clinical data are clearly needed in patients with this infection and the lack of data directly comparing it to amphotericin B – the only FDA-approved drug for this indication – was problematic.

Elizabeth Mechcatie/Frontline Medical News

“This drug really does fill an unmet need; I have high hopes that it is at least as good as amphotericin. But I do think we need more data to confirm that,” said Dr. Michael Neely, chair of antimicrobial stewardship at Children’s Hospital, Los Angeles, who was among those voting in favor of this indication. It appears to have a better safety profile and it would be available in both oral and intravenous formulations, he added. Amphotericin B is available only in an intravenous (IV) formulation.

If approved, isavuconazonium would provide an alternative to voriconazole for treating aspergillosis, and the IV formulation does not contain cyclodextrin, unlike the IV formulation of voriconazole, which limits its use in patients with moderate to severe renal dysfunction, according to Astellas. Safety concerns specific to isavuconazonium include QT-segment shortening and particulate formation in the IV formulation, according to the FDA.

The randomized, double-blind, international, noninferiority study compared treatment with isavuconazonium to voriconazole in 516 adults with invasive aspergillosis. In the randomized study, the mean age of patients was 51 years, 60% were men, most were white, 11% were in the United States and Canada, 20% had had an allogeneic bone marrow transplant, and 70% had an uncontrolled malignancy at baseline (Infect. Drug Resist. 2013;6:16374). The primary effectiveness endpoint, all-cause mortality through day 42, was 19% in those on isavuconazonium, compared with 20% in those on voriconazole. The study met the prespecified noninferiority margin. The rates of deaths and serious adverse events were similar to voriconazole, and there were fewer adverse events in those on isavuconazonium requiring discontinuation of the drug (14% vs. 23%).

Differences in adverse events included lower rates of hepatobiliary disorders, including hyperbilirubinemia, abnormal hepatic function, and jaundice (9% vs. 16%); skin and subcutaneous tissue disorders, including rash, erythema, and drug eruption (34% vs 43%) associated with isavuconazonium, compared with voriconazole. Common adverse events included nausea (28%), vomiting (25%), and diarrhea (24%). Decreases in the QT segment occurred in 7.5% of those on isavuconazonium, compared with 4.5% of those on voriconazole, but were not associated with clinical events.

The prospective, open-label, single-arm study evaluated isavuconazonium in 37 patients with proven or probable mucormycosis infections, whose mean age was 49 years; 59% had a hematologic malignancy, and about 40% were neutropenic at baseline. All-cause mortality at day 42 was almost 38%, which was similar to the mortality rate for amphotericin in the literature, according to Astellas.

There are about 12,000 cases of aspergillosis and about 500 cases of mucormycosis in the United States every year, the company said. In addition to voriconazole, other drugs approved for invasive aspergillosis include amphotericin formulations, itraconazole, and caspofungin. The FDA usually follows the recommendations of its advisory panels. The FDA is expected to make a decision by March 8, according to Astellas, which plans to market the drug as Cresemba if approved. It is also under review in Europe for the same indications.

Panelists were cleared of potential conflicts of interest related to the topic of the meeting. In some cases, a panelist may be given a waiver but not at this meeting.

[email protected]

SILVER SPRING, MD. – A novel treatment for invasive aspergillosis and invasive mucormycosis gained the support of a Food and Drug Administration advisory panel, although members were more ambivalent about the mucormycosis indication, based on the small amount of data available in those patients.

At a meeting on Jan. 22, the FDA’s Anti-Infective Drugs Advisory Committee voted 11-0 that there was “substantial evidence” that isavuconazonium, an antifungal prodrug, was safe and effective for the treatment of invasive aspergillosis, a life-threatening condition most commonly seen in immunocompromised patients. The drug was studied in a phase III study comparing isavuconazonium to voriconazole, the standard of care, in more than 500 patients.

The panel voted 8-2, with one abstention, that there was substantial evidence it was safe and effective for treating patients with invasive mucormycosis, with panelists voting on both sides of the question citing the study of only 37 patients that used historical controls as an issue. Those supporting approval for mucormycosis said that, if approved, the manufacturer, Astellas, should be required to conduct a phase IV trial further evaluating this treatment for patients with this infection.

Isavuconazonium is a prodrug of isavuconazole, a triazole antifungal, and would be available in an oral capsule formulation and a powder formulation that is reconstituted for intravenous administration (and needs to be administered through an in-line filter in case of particulate formation).

For aspergillosis, “I do believe that this drug provides a reasonable alternative to the current therapies that are available without additional toxicities,” said panelist Dr. Paige Waterman of the Global Emerging Infections Surveillance and Response System at the Walter Reed Army Medical Center, Silver Spring, Md. Other panelists agreed with her recommendations that labeling should make clear that it should not be used in people under age 18 years or in pregnant women, that a filter should be used when administered intravenously, and that labeling should include a statement about the increased risk of hepatotoxicity that also appears in the labeling of other drugs in the same class.

Because it has been associated with a shortened QT interval, she said that screening ECGs should be recommended for patients and that there should be some extra caution when it is prescribed to people who are Asian or of Asian descent, since drug concentrations were slightly higher among Asian patients who received the drug. Other recommendations from panelists included the need to conduct studies of the drug to provide information on therapeutic drug monitoring and in people under 18 years.

For treatment of invasive mucormycosis, an even rarer fungal infection which, in hospitals, is associated with the use of contaminated materials or organ transplantation, the panelists were more hesitant, but those voting in favor of approval cited the significance of the condition and the reasonable efficacy results in the study, stressing that postmarketing studies were critical. Panelists also noted that more clinical data are clearly needed in patients with this infection and the lack of data directly comparing it to amphotericin B – the only FDA-approved drug for this indication – was problematic.

Elizabeth Mechcatie/Frontline Medical News

“This drug really does fill an unmet need; I have high hopes that it is at least as good as amphotericin. But I do think we need more data to confirm that,” said Dr. Michael Neely, chair of antimicrobial stewardship at Children’s Hospital, Los Angeles, who was among those voting in favor of this indication. It appears to have a better safety profile and it would be available in both oral and intravenous formulations, he added. Amphotericin B is available only in an intravenous (IV) formulation.

If approved, isavuconazonium would provide an alternative to voriconazole for treating aspergillosis, and the IV formulation does not contain cyclodextrin, unlike the IV formulation of voriconazole, which limits its use in patients with moderate to severe renal dysfunction, according to Astellas. Safety concerns specific to isavuconazonium include QT-segment shortening and particulate formation in the IV formulation, according to the FDA.

The randomized, double-blind, international, noninferiority study compared treatment with isavuconazonium to voriconazole in 516 adults with invasive aspergillosis. In the randomized study, the mean age of patients was 51 years, 60% were men, most were white, 11% were in the United States and Canada, 20% had had an allogeneic bone marrow transplant, and 70% had an uncontrolled malignancy at baseline (Infect. Drug Resist. 2013;6:16374). The primary effectiveness endpoint, all-cause mortality through day 42, was 19% in those on isavuconazonium, compared with 20% in those on voriconazole. The study met the prespecified noninferiority margin. The rates of deaths and serious adverse events were similar to voriconazole, and there were fewer adverse events in those on isavuconazonium requiring discontinuation of the drug (14% vs. 23%).

Differences in adverse events included lower rates of hepatobiliary disorders, including hyperbilirubinemia, abnormal hepatic function, and jaundice (9% vs. 16%); skin and subcutaneous tissue disorders, including rash, erythema, and drug eruption (34% vs 43%) associated with isavuconazonium, compared with voriconazole. Common adverse events included nausea (28%), vomiting (25%), and diarrhea (24%). Decreases in the QT segment occurred in 7.5% of those on isavuconazonium, compared with 4.5% of those on voriconazole, but were not associated with clinical events.

The prospective, open-label, single-arm study evaluated isavuconazonium in 37 patients with proven or probable mucormycosis infections, whose mean age was 49 years; 59% had a hematologic malignancy, and about 40% were neutropenic at baseline. All-cause mortality at day 42 was almost 38%, which was similar to the mortality rate for amphotericin in the literature, according to Astellas.

There are about 12,000 cases of aspergillosis and about 500 cases of mucormycosis in the United States every year, the company said. In addition to voriconazole, other drugs approved for invasive aspergillosis include amphotericin formulations, itraconazole, and caspofungin. The FDA usually follows the recommendations of its advisory panels. The FDA is expected to make a decision by March 8, according to Astellas, which plans to market the drug as Cresemba if approved. It is also under review in Europe for the same indications.

Panelists were cleared of potential conflicts of interest related to the topic of the meeting. In some cases, a panelist may be given a waiver but not at this meeting.

[email protected]

SILVER SPRING, MD. – A novel treatment for invasive aspergillosis and invasive mucormycosis gained the support of a Food and Drug Administration advisory panel, although members were more ambivalent about the mucormycosis indication, based on the small amount of data available in those patients.

At a meeting on Jan. 22, the FDA’s Anti-Infective Drugs Advisory Committee voted 11-0 that there was “substantial evidence” that isavuconazonium, an antifungal prodrug, was safe and effective for the treatment of invasive aspergillosis, a life-threatening condition most commonly seen in immunocompromised patients. The drug was studied in a phase III study comparing isavuconazonium to voriconazole, the standard of care, in more than 500 patients.

The panel voted 8-2, with one abstention, that there was substantial evidence it was safe and effective for treating patients with invasive mucormycosis, with panelists voting on both sides of the question citing the study of only 37 patients that used historical controls as an issue. Those supporting approval for mucormycosis said that, if approved, the manufacturer, Astellas, should be required to conduct a phase IV trial further evaluating this treatment for patients with this infection.

Isavuconazonium is a prodrug of isavuconazole, a triazole antifungal, and would be available in an oral capsule formulation and a powder formulation that is reconstituted for intravenous administration (and needs to be administered through an in-line filter in case of particulate formation).

For aspergillosis, “I do believe that this drug provides a reasonable alternative to the current therapies that are available without additional toxicities,” said panelist Dr. Paige Waterman of the Global Emerging Infections Surveillance and Response System at the Walter Reed Army Medical Center, Silver Spring, Md. Other panelists agreed with her recommendations that labeling should make clear that it should not be used in people under age 18 years or in pregnant women, that a filter should be used when administered intravenously, and that labeling should include a statement about the increased risk of hepatotoxicity that also appears in the labeling of other drugs in the same class.

Because it has been associated with a shortened QT interval, she said that screening ECGs should be recommended for patients and that there should be some extra caution when it is prescribed to people who are Asian or of Asian descent, since drug concentrations were slightly higher among Asian patients who received the drug. Other recommendations from panelists included the need to conduct studies of the drug to provide information on therapeutic drug monitoring and in people under 18 years.

For treatment of invasive mucormycosis, an even rarer fungal infection which, in hospitals, is associated with the use of contaminated materials or organ transplantation, the panelists were more hesitant, but those voting in favor of approval cited the significance of the condition and the reasonable efficacy results in the study, stressing that postmarketing studies were critical. Panelists also noted that more clinical data are clearly needed in patients with this infection and the lack of data directly comparing it to amphotericin B – the only FDA-approved drug for this indication – was problematic.

Elizabeth Mechcatie/Frontline Medical News

“This drug really does fill an unmet need; I have high hopes that it is at least as good as amphotericin. But I do think we need more data to confirm that,” said Dr. Michael Neely, chair of antimicrobial stewardship at Children’s Hospital, Los Angeles, who was among those voting in favor of this indication. It appears to have a better safety profile and it would be available in both oral and intravenous formulations, he added. Amphotericin B is available only in an intravenous (IV) formulation.

If approved, isavuconazonium would provide an alternative to voriconazole for treating aspergillosis, and the IV formulation does not contain cyclodextrin, unlike the IV formulation of voriconazole, which limits its use in patients with moderate to severe renal dysfunction, according to Astellas. Safety concerns specific to isavuconazonium include QT-segment shortening and particulate formation in the IV formulation, according to the FDA.

The randomized, double-blind, international, noninferiority study compared treatment with isavuconazonium to voriconazole in 516 adults with invasive aspergillosis. In the randomized study, the mean age of patients was 51 years, 60% were men, most were white, 11% were in the United States and Canada, 20% had had an allogeneic bone marrow transplant, and 70% had an uncontrolled malignancy at baseline (Infect. Drug Resist. 2013;6:16374). The primary effectiveness endpoint, all-cause mortality through day 42, was 19% in those on isavuconazonium, compared with 20% in those on voriconazole. The study met the prespecified noninferiority margin. The rates of deaths and serious adverse events were similar to voriconazole, and there were fewer adverse events in those on isavuconazonium requiring discontinuation of the drug (14% vs. 23%).

Differences in adverse events included lower rates of hepatobiliary disorders, including hyperbilirubinemia, abnormal hepatic function, and jaundice (9% vs. 16%); skin and subcutaneous tissue disorders, including rash, erythema, and drug eruption (34% vs 43%) associated with isavuconazonium, compared with voriconazole. Common adverse events included nausea (28%), vomiting (25%), and diarrhea (24%). Decreases in the QT segment occurred in 7.5% of those on isavuconazonium, compared with 4.5% of those on voriconazole, but were not associated with clinical events.

The prospective, open-label, single-arm study evaluated isavuconazonium in 37 patients with proven or probable mucormycosis infections, whose mean age was 49 years; 59% had a hematologic malignancy, and about 40% were neutropenic at baseline. All-cause mortality at day 42 was almost 38%, which was similar to the mortality rate for amphotericin in the literature, according to Astellas.

There are about 12,000 cases of aspergillosis and about 500 cases of mucormycosis in the United States every year, the company said. In addition to voriconazole, other drugs approved for invasive aspergillosis include amphotericin formulations, itraconazole, and caspofungin. The FDA usually follows the recommendations of its advisory panels. The FDA is expected to make a decision by March 8, according to Astellas, which plans to market the drug as Cresemba if approved. It is also under review in Europe for the same indications.

Panelists were cleared of potential conflicts of interest related to the topic of the meeting. In some cases, a panelist may be given a waiver but not at this meeting.

[email protected]