Results of Open-Label Trial for CRESEMBA® (isavuconazonium sulfate) Treatment of Invasive Mucormycosis Published in The Lancet Infectious Diseases
NORTHBROOK, Ill., March 9, 2016 /PRNewswire/ -- Astellas today announced that results from the Phase 3 VITAL trial evaluating CRESEMBA® (isavuconazonium sulfate) in adult patients with invasive mucormycosis were published in The Lancet Infectious Diseases. The article, titled "Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis," appears in the March 8, 2016 online issue and will appear in a future print issue of The Lancet Infectious Diseases.
VITAL is the study from which a sub-group of patients supported the registration for the invasive mucormycosis indication for CRESEMBA.
"Mucormycosis is a rare fungal infection that occurs predominantly in immunocompromised patients, particularly those undergoing treatment for hematological malignancies. Without prompt diagnosis and treatment, mucormycosis has a mortality rate exceeding 90 percent," said Bernie Zeiher, M.D., president of development at Astellas. "CRESEMBA fulfills an important medical need for immunocompromised patients and their healthcare providers, and highlights Astellas' efforts to pursue treatments for life-threatening infectious diseases."
CRESEMBA is co-developed with Basilea Pharmaceutica International Ltd. CRESEMBA is approved in the United States to treat invasive mucormycosis and invasive aspergillosis 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 mucormycosis for whom amphotericin B is inappropriate and for adult patients with invasive aspergillosis.
VITAL is a global, open-label non-comparative study that evaluated the efficacy and safety of CRESEMBA for the treatment of invasive aspergillosis in patients with renal impairment, and for invasive fungal disease caused by mucormycetes and other emerging fungal pathogens. The primary study endpoint was an independent data-review committee (DRC)-assessed overall response at Day 42; secondary endpoints included assessments of overall response at EOT and all-cause mortality at Days 42 and 84. The trial evaluated CRESEMBA at an oral or intravenous (IV) loading regimen of 372 mg of isavuconazonium sulfate (equivalent to 200 mg of isavuconazole) every eight hours for six doses, followed by CRESEMBA 200 mg daily until resolution of the infection, failure, or more than 180 days.
Thirty-seven mucormycosis patients received CRESEMBA: 21 patients for primary therapy, 11 for refractory disease, and five after intolerance to other antifungals. Day 42 all-cause mortality, was 38 percent whilst all all-cause mortality was 43 percent by Day 84. These results provide evidence that CRESEMBA is effective for the treatment for mucormycosis, in light of the natural history of untreated mucormycosis. The efficacy of CRESEMBA for the treatment for invasive mucormycosis, however, has not been evaluated in concurrent, controlled clinical trials.
Thirty-five of 37 (95%) of patients experienced at least one adverse event (AE) during treatment and 28 patients had serious AEs. The most common AEs reported (>10% of patients) were vomiting (32%), diarrhea (27%), nausea (27%), pyrexia (37%), constipation (22%), decreased appetite (16%), headache (16%), peripheral oedema (16%), abdominal pain (14%), dyspnea (14%), pneumonia (14%), back pain (11%), cough (11%), hypoglycemia (11%), insomnia (11%) and restlessness (11%).
About Invasive Mucormycosis
Invasive mucormycosis is a rapidly progressing and devastating invasive fungal infection. Invasive mucormycosis is also known for high morbidity and mortality.
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
- 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.
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.
You are encouraged to report negative side effects of prescription drugs to the FDA.
Visit www.fda.gov/medwatch or call 1‐800‐FDA‐1088.
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.
Astellas is a pharmaceutical company dedicated to improving the health of people around the world through the provision of innovative and reliable pharmaceutical products. For more information on Astellas, please visit our website at www.astellas.us. You can also follow us on Twitter at @AstellasUS, Facebook at www.facebook.com/AstellasUS or LinkedIn at www.linkedin.com/company/astellas-pharma.
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