Astellas Announces Publication of CRESEMBA® (Isavuconazonium Sulfate) Pivotal Phase 3 Study Results in The Lancet

Dec 09, 2015, 18:45 ET from Astellas

NORTHBROOK, Ill., Dec. 9, 2015 /PRNewswire/ -- Astellas today announced that results from the pivotal Phase 3 SECURE trial evaluating CRESEMBA® (isavuconazonium sulfate) in adult patients with invasive aspergillosis were published in The Lancet. The article, titled "Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial," appears in the December 9th online issue and will appear in a future print issue of The Lancet.  

"It is important for physicians to have alternative treatment options. SECURE is the first randomized, global trial to support the use of CRESEMBA for the primary treatment of adult patients with invasive aspergillosis," said Andrew J. Ullmann, professor of infectious diseases at Julius-Maximilians-University, Wurzburg, Germany.

SECURE is the pivotal study on which the registration for the invasive aspergillosis indication for CRESEMBA was based.

"Invasive aspergillosis is a life-threatening fungal infection predominantly occurring in immunocompromised patients, including those with cancer, particularly leukemias," said Bernie Zeiher, M.D., president, development at Astellas. "CRESEMBA helps to fulfill an important medical need, which underscores Astellas' long-standing commitment to improving patient care."

CRESEMBA is co-developed with Basilea Pharmaceutica International Ltd. CRESEMBA is approved in the United States to treat invasive aspergillosis and invasive mucormycosis in adults, and was launched by Astellas in 2015. Outside the United States, Basilea has full rights for CRESEMBA, which is approved in Europe by the European Commission for the treatment of adult patients with invasive aspergillosis and also for the treatment of mucormycosis for whom amphotericin B is inappropriate.

About SECURE
SECURE is a Phase 3, randomized, double-blind, active-control study of 527 adult patients with invasive aspergillosis or other filamentous fungi at multiple sites globally. The primary endpoint of the trial was non-inferiority of all-cause mortality through Day 42 in patients who received at least one dose of the study drug. The trial evaluated CRESEMBA at a loading dose of 372 mg of isavuconazonium sulfate (equivalent to 200 mg of isavuconazole) intravenously (IV) every 8 hours for the first 48 hours. Beginning on day 3, patients received intravenous or oral therapy of 372 mg of isavuconazonium sulfate (equivalent to 200 mg of isavuconazole) compared to voriconazole at a loading dose of 6 mg/kg IV every 12 hours for the first 24 hours and 4 mg/kg IV every 12 hours for the following 24 hours followed by 200 mg oral therapy every 12 hours.

CRESEMBA demonstrated non-inferiority to voriconazole on the primary endpoint of all-cause mortality through Day 42 in patients with proven, probable or possible invasive fungal disease. All-cause mortality through Day 42 in the intent-to-treat population was 18.6 percent in the CRESEMBA treatment group and 20.2 percent in the voriconazole treatment group [95% CI: –8.0, 5.9]. Topline data were previously presented at the 25th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), held from April 25 – 28, 2015.

About Invasive Aspergillosis
Invasive aspergillosis is a life-threatening fungal infection that is seen predominantly in immunocompromised patients, such as patients with leukemia. Invasive aspergillosis is known for high morbidity and mortality.

About CRESEMBA®

Indications and Usage
CRESEMBA is an azole antifungal indicated for patients 18 years of age and older for the treatment of invasive aspergillosis and invasive mucormycosis.

Specimens for fungal culture and other relevant laboratory studies (including histopathology) to isolate and identify causative organism(s) should be obtained prior to initiating antifungal therapy. Therapy may be instituted before the results of the cultures and other laboratory studies are known. However, once these results become available, antifungal therapy should be adjusted accordingly.

Important Safety Information

CONTRAINDICATIONS

  • CRESEMBA is contraindicated in persons with known hypersensitivity to isavuconazole
  • Coadministration of strong CYP3A4 inhibitors, such as ketoconazole or high-dose ritonavir (400 mg every 12 hours), with CRESEMBA is contraindicated because strong CYP3A4 inhibitors can significantly increase the plasma concentration of isavuconazole
  • Coadministration of strong CYP3A4 inducers, such as rifampin, carbamazepine, St. John's wort, or long acting barbiturates with CRESEMBA is contraindicated because strong CYP3A4 inducers can significantly decrease the plasma concentration of isavuconazole
  • CRESEMBA shortened the QTc interval in a concentration-related manner. CRESEMBA is contraindicated in patients with familial short QT syndrome

WARNINGS AND PRECAUTIONS
Hepatic Adverse Drug Reactions (e.g., elevations in ALT, AST, alkaline phosphatase, total bilirubin) have been reported in clinical trials and were generally reversible and did not require discontinuation of CRESEMBA. Cases of severe hepatic adverse drug reactions including hepatitis, cholestasis or hepatic failure including death have been reported in patients with serious underlying medical conditions (e.g., hematologic malignancy) during treatment with azole antifungal agents, including CRESEMBA. Evaluate liver tests at the start and during therapy. Monitor patients who develop liver abnormalities during CRESEMBA therapy for severe hepatic injury. Discontinue if clinical signs and symptoms consistent with liver disease develop that may be attributable to CRESEMBA.

Infusion-Related Reactions including hypotension, dyspnea, chills, dizziness, paresthesia, and hypoesthesia were reported during intravenous administration of CRESEMBA. Discontinue the infusion if these reactions occur.

Serious Hypersensitivity and Severe Skin Reactions, such as anaphylaxis or Stevens Johnson syndrome, have been reported during treatment with other azole antifungal agents. Discontinue CRESEMBA if a patient develops a severe cutaneous adverse reaction. Caution should be used when prescribing CRESEMBA to patients with hypersensitivity to other azoles.

Embryo-Fetal Toxicity: During pregnancy, CRESEMBA may cause fetal harm when administered, and CRESEMBA should only be used if the potential benefit to the patient outweighs the risk to the fetus. Women who become pregnant while receiving CRESEMBA are encouraged to contact their physician.

Drug Interactions: Coadministration of CRESEMBA with strong CYP3A4 inhibitors such as ketoconazole or high-dose ritonavir and strong CYP3A4 inducers such as rifampin, carbamazepine, St. John's wort, or long acting barbiturates is contraindicated.

Drug Particulates: Following dilution, CRESEMBA intravenous formulation may form precipitate from the insoluble isavuconazole. Administer CRESEMBA through an in-line filter.

ADVERSE REACTIONS
The most frequent adverse events among CRESEMBA-treated patients were: nausea (26 percent), vomiting (25 percent), diarrhea (22 percent), headache (17 percent), elevated liver chemistry tests (16 percent), hypokalemia (14 percent), constipation (13 percent), dyspnea (12 percent), cough (12 percent), peripheral edema (11 percent), and back pain (10 percent).

The adverse reactions which most often led to permanent discontinuation of CRESEMBA therapy during the clinical trials were: confusional state (0.7 percent), acute renal failure (0.7 percent), increased blood bilirubin (0.5 percent), convulsion (0.5 percent), dyspnea (0.5 percent), epilepsy (0.5 percent), respiratory failure (0.5 percent), and vomiting (0.5 percent).

For Full Prescribing Information in the U.S., please visit www.astellas.us/docs/cresemba.pdf.

About Astellas Infectious Disease
Astellas is committed to the field of infectious diseases. Astellas is expanding the knowledge base of this therapeutic area and empowering physicians to make evidence-based clinical decisions.

Astellas' proud history of collaborating with investigators around the world provides ideal environments to study compounds that have the potential for significant breakthroughs for patients. In fact, Astellas has performed some of the world's largest clinical trials in fungal infections.

About Astellas
Astellas is a pharmaceutical company dedicated to improving the health of people around the world through provision of innovative and reliable pharmaceuticals. For more information on Astellas, please visit our website at www.astellas.us. Follow us on Twitter at www.twitter.com/AstellasUS. Visit our Facebook page at www.facebook.com/AstellasUS.

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