FDA Panel Backs New Antifungal Isavuconazonium (Cresemba)

Troy Brown, RN

January 22, 2015

An advisory committee to the US Food and Drug Administration (FDA) voted unanimously to recommend isavuconazonium (ISA) (Cresemba, Astellas Pharma, Inc) for the treatment of adults with invasive aspergillosis (IA) and voted (8 yes, 2 no, 1 abstain) to recommend the drug for the treatment of adults with invasive mucormycosis (IM).

Potentially Fatal Infections

IA is a potentially fatal angioinvasive infection that is mostly seen in severely immunocompromised patients. Voriconazole is the recommended first-line treatment and there is little agreement regarding treatment of patients who fail to respond to or are intolerant of voriconazole. Amphotericin formulations, itraconazole, and caspofungin are also currently approved by the FDA for treatment of IA.

IM is a catastrophic fungal infection caused by the filamentous fungi of the order Mucorales of the subphylum Mucoromycotina. In addition to conditions predisposing patients to IA, patients with poorly controlled diabetes mellitus with or without ketoacidosis, patients undergoing dialysis with iron overload, and patients with trauma or burns are also at risk.

IM treatment includes treating the underlying condition, surgical debridement, and antifungal therapy. Because it is rare, there are no published well-controlled, comparative antifungal treatment studies. Amphotericin B is approved by the FDA for the treatment of IM.

ISA is a triazole antifungal drug. It is available as oral and intravenous (IV) preparations. The IV formulation may precipitate in the tubing or container so it was given through an inline filter to remove particulates for the study. ISA is given in an oral or IV loading dose of 200 mg every eight hours for the first 48 hours and the maintenance dose is 200 mg per day orally or IV.

The Anti-Infective Drugs Advisory Committee's votes follow a discussion of data from 9766-CL-0104 (SECURE), a phase 3 global, multicenter, randomized, double-blind, controlled noninferiority study that compared ISA to voriconazole in patients with IA, and 9766-CL-0103 (VITAL), an open-label, multicenter, single-arm study in patients with IA and renal impairment (GFR < 50 mL/min) or patients with invasive fungal disease caused by rare molds, yeasts, or dimorphic fungi. The FDA has granted orphan drug status to ISA for IA and IM. Hematologic malignancy was the underlying condition for most patients in both studies.

Noninferior for Treatment of IA

Patients enrolled in SECURE were randomly assigned in a 1:1 ratio to receive treatment with either ISA (n = 258) or voriconazole (n = 258). The study's primary endpoint was the all-cause mortality rate through day 42. Secondary endpoints were Independent Data Review Committee (DRC)-assessed overall response at end of treatment (EOT) (key secondary endpoint), all-cause mortality through day 84, DRC-assessed overall response at days 42 and 84, and clinical, mycological, and radiological response at EOT and days 42 and 84.

ISA demonstrated noninferiority compared with voriconazole for the primary endpoint. The all-cause mortality rate through day 42 was 18.6% for ISA and 20.2% for voriconazole in the intent-to-treat (ITT) population (95% confidence interval, -8.0 to 5.9).

The DRC-assessed overall response rates at EOT were similar between the groups (35% for ISA and 36.4% for voriconazole) in the modified ITT (mITT) population.

"Overall, I think the quality of the data is…quite good," voting committee member Yu Shyr, PhD, from Vanderbilt University School of Medicine, Nashville, Tennessee, said.

Demonstrated Efficacy for Treatment of IM

The VITAL study consisted of 146 patients, including a subgroup of 37 patients with IM.

The study's primary endpoint was DRC-assessed overall response at day 42. Secondary endpoints were DRC-assessed overall response at EOT and day 84, DRC-assessed clinical, mycological, and radiological success at EOT and days 42 and 84, and survival rate by days 42, 84, 120, and 180.

Because the applicant and the FDA agree that mortality through day 42 is the most relevant primary endpoint, DRC-assessed overall response at day 42 was assessed as a secondary efficacy outcome.

The DRC also evaluated disease location, therapy status (ie, primary, refractory, or intolerant) and attributable mortality.

Overall mortality at day 42 (38%) and day 84 (43%) were similar to those in the primary treatment group (33% at day 42 and 42% at day 84).

The DRC-assessed overall response rate at EOT was 31.4% in the mITT-Mucorales population (14.3% complete success and 17.1% partial success). The DRC assessed 28.6% of patients to be stable. For patients in the primary therapy group, the DRC judged 31.6% to be a success (15.8% complete success and 15.8% partial success).

The DRC assessments of success rates at EOT were higher for clinical response (45.2%) than mycological (34.3%) and radiological (18.2%) for the patients in the mITT-mucorales group and 55.6%, 31.6%, and 16.7%, respectively, for patients in the primary therapy group.

"Given the availability of the comparator, I believe we met a reasonable measure of efficacy with the data that [were] presented. Post-marketing surveillance becomes critical for this indication," said voting temporary committee member Paige E. Waterman, MD, from Armed Forces Health Surveillance Center, US Army, Walter Reed National Military Medical Center, and Walter Reed Army Institute of Research, Silver Spring, Maryland.

"There could certainly be some more work linking what they've seen in animals to what actually occurs in humans. There's a relative lack of pharmacokinetic, pharmacodynamic, pharmacotoxic data that we've seen today," voting committee member Marc H. Scheetz, PharmD, from Midwestern University Chicago College of Pharmacy, Downers Grove, Illinois, said of his abstention from the vote on whether to recommend ISA for IM.

"Favorable Safety Profile"

The safety population included all patients who were given at least one dose of the study drug, although the safety analysis concentrates on trial 9766-CL-104.

Rates of mortality and nonfatal adverse events were similar between treatment groups (ISA: 31.5%, 81/257; VRC: 33.6%, 87/259). Overall, the incidence of treatment-emergent serious adverse reactions was slightly lower in the ISA group (134/257: 52.1%) than in the voriconazole group (149/259: 57.5%). Fewer patients in the ISA group experienced adverse reactions that led to discontinuation of therapy.

Rates of treatment-emergent adverse events leading to death were similar between treatment groups. Treatment-emergent adverse events leading to death that were reported in at least 2% of patients in the treatment groups were septic shock (ISA: 3.1% vs VRC: 1.5%), sepsis (2.7% vs 1.9%), respiratory failure (2.3% vs 2.3%), acute myeloid leukemia (1.2% vs 2.7%), and multiorgan failure (0.4% vs 2.3%).

One (0.4%) short QT adverse event occurred in the integrated safety population, and it was in an ISA-treated patient.

The committee members have disclosed no relevant financial relationships.

US Food and Drug Administration (FDA)-Anti-Infective Drugs Advisory Committee Meeting, January 22, 2015.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.