FDA Approves Expanded Use of CRESEMBA® (isavuconazonium sulfate) in Children with Invasive Aspergillosis and Invasive Mucormycosis

CRESEMBA is the only azole antifungal therapy approved for pediatric patients as young as one affected by these serious, potentially life-threatening infections 

Approval based on results of two pediatric studies in children aged 1 to 17

NORTHBROOK, Ill., Dec. 8, 2023 /PRNewswire/ -- Astellas Pharma US, Inc. (President: Mark Reisenauer, "Astellas") today announced that the U.S. Food and Drug Administration (FDA) has approved CRESEMBA^® (isavuconazonium sulfate), an azole antifungal drug, for the treatment of invasive aspergillosis (IA) and invasive mucormycosis (IM) in pediatric patients. CRESEMBA for injection is approved for adults and now for pediatric patients 1 year of age and older. CRESEMBA capsules are approved for adults and now for pediatric patients 6 years of age and older who weigh 16 kilograms (kg) and greater. With this approval, CRESEMBA is now the only azole antifungal therapy approved for the treatment of IA and IM in patients as young as one.

"Invasive fungal infections are a significant concern to healthcare professionals who care for pediatric, adolescents and young adults with hematologic malignancies, transplant recipients and primary immune deficiencies," said Antonio C. Arrieta, M.D., medical director, Pediatric Infectious Disease, Children's Health of Orange County. "IA, currently the most common invasive mold infection in these patients, and IM are associated with significant morbidity and high fatality rates. The FDA approval of CRESEMBA for pediatric patients adds a much-needed treatment option."

"The recent COVID-19 pandemic drove an uptick in these serious and life-threatening fungal infections, presenting an even greater urgency to address this growing unmet medical need," said Lynn Fenicchia, senior vice president and Head of US Medical Specialties Business Unit, Astellas. "Patients are waiting, and we know that young IA and IM patients are most at risk. Today's approval will bring hope to this highly vulnerable patient population with limited treatment options."

The approval is based on results from two pediatric clinical studies, including a Phase 2 open-label, non-comparative, multicenter study (NCT03816176) evaluating the safety, efficacy and pharmacokinetics of CRESEMBA for the treatment of IA or IM in pediatric patients aged 1 to 17 years old. In the study, 31 patients aged 1 to 17 with possible, probable or proven IA or IM were treated with CRESEMBA (10 mg/kg) every 8 hours on days 1 and 2, and once-daily thereafter for ≤84 days for IA or ≤180 days for IM. Median treatment duration was 55 days. All-cause case fatality through Day 42 was 6.5% and through day 84 was 9.7% which occurred during the follow-up period and none were considered treatment-related. Successful response rates were 54.8% at the end of treatment. Treatment emergent adverse events (TEAEs) occurred in 93.5% of patients and 29.0% patients experienced drug-related TEAEs. Treatment was withdrawn in two patients due to TEAEs. Serious TEAEs occurred in 58.1% of patients and were assessed as drug-related by the investigator in one patient. These data were presented as an oral abstract presentation during IDWeek 2023 on October 13^th and a session during Trends in Medical Mycology (TIMM) 2023 on October 22^nd.  

In addition, the FDA granted pediatric exclusivity for CRESEMBA, which extends the period of market exclusivity for CRESEMBA in the United States by an additional six months.

About Invasive Aspergillosis and Invasive Mucormycosis 
Invasive aspergillosis can be a life-threatening fungal infection that is seen predominantly in immunocompromised patients, such as patients with leukemia.¹ Invasive mucormycosis is a rare and often life-threatening fungal infection.² IA and IM are a major cause of morbidity and death among immunocompromised and hospitalized pediatric patients.³

About CRESEMBA^® (isavuconazonium sulfate)  
CRESEMBA^® (isavuconazonium sulfate) is an azole antifungal indicated for the treatment of invasive aspergillosis and invasive mucormycosis as follows:⁴

• CRESEMBA for injection: adults and pediatric patients 1 year of age and older
• CRESEMBA capsules: adults and pediatric patients 6 years of age and older who weigh 16 kg and greater

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 for CRESEMBA (isavuconazonium sulfate)

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.

Hypersensitivity Reactions: Anaphylactic reactions, with fatal outcome, have been reported during treatment with CRESEMBA. Serious skin reactions, such as Stevens Johnson syndrome, have been reported during treatment with other azole antifungal agents. Discontinue CRESEMBA if anaphylactic or serious skin reactions occur, and initiate supportive treatment as needed.

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

In adult patients, the most frequently reported adverse reactions among CRESEMBA-treated patients were nausea (26%), vomiting (25%), diarrhea (22%), headache (17%), elevated liver chemistry tests (16%), hypokalemia (14%), constipation (13%), dyspnea (12%), cough (12%), peripheral edema (11%), and back pain (10%).

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

In pediatric patients, the most frequently reported adverse reactions were diarrhea (26%), abdominal pain (23%), vomiting (21%), elevated liver chemistry tests (18%), rash (14%), nausea (13%), pruritus (13%), and headache (12%).

In general, adverse reactions in pediatric patients (including serious adverse reactions and adverse reactions leading to permanent discontinuation of CRESEMBA) were similar to those reported in adults.

For Full Prescribing Information, please visit here.

About Astellas Pharma US
Astellas Pharma US, Inc. is a U.S. affiliate of Tokyo-based Astellas Pharma Inc., a pharmaceutical company conducting business in more than 70 countries around the world. Astellas stands on the forefront of healthcare change to turn innovative science into value for patients. Keeping our focus on addressing unmet medical needs and conducting our business with ethics and integrity enables us to improve the health of people throughout the U.S. and around the world. CRESEMBA was licensed from and co-developed with Basilea Pharmaceutica International Ltd, Allschwil. For more information on Astellas, please visit: https://www.astellas.com/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-us. 

About Astellas
Astellas Pharma Inc. is a pharmaceutical company conducting business in more than 70 countries around the world. We are promoting the Focus Area Approach that is designed to identify opportunities for the continuous creation of new drugs to address diseases with high unmet medical needs by focusing on Biology and Modality. Furthermore, we are also looking beyond our foundational Rx focus to create Rx+^® healthcare solutions that combine our expertise and knowledge with cutting-edge technology in different fields of external partners. Through these efforts, Astellas stands on the forefront of healthcare change to turn innovative science into VALUE for patients. For more information, please visit our website at https://www.astellas.com/en.

Cautionary Notes
In this press release, statements made with respect to current plans, estimates, strategies and beliefs and other statements that are not historical facts are forward-looking statements about the future performance of Astellas. These statements are based on management's current assumptions and beliefs in light of the information currently available to it and involve known and unknown risks and uncertainties. A number of factors could cause actual results to differ materially from those discussed in the forward-looking statements. Such factors include, but are not limited to: (i) changes in general economic conditions and in laws and regulations, relating to pharmaceutical markets, (ii) currency exchange rate fluctuations, (iii) delays in new product launches, (iv) the inability of Astellas to market existing and new products effectively, (v) the inability of Astellas to continue to effectively research and develop products accepted by customers in highly competitive markets, and (vi) infringements of Astellas' intellectual property rights by third parties.

¹ Thornton CR. Detection of invasive aspergillosis. Adv Appl Microbiol. 2010;70:187-216. doi: 10.1016/S0065-2164(10)70006-X. Epub 2010 Mar 6. PMID: 20359458.
² Zhang Y, Sung AH, Rubinstein E, Benigno M, Chambers R, Patino N, Aram JA. Characterizing patients with rare mucormycosis infections using real-world data. BMC Infect Dis. 2022;22(1):154. doi: 10.1186/s12879-022-07115-w. PMID: 35164701; PMCID: PMC8845356.
³ Pana ZD, Roilides E, Warris A, Groll AH, Zaoutis T. Epidemiology of Invasive Fungal Disease in Children. J Pediatric Infect Dis Soc. 2017;6(suppl_1):S3-S11. doi:10.1093/jpids/pix046
⁴ CRESEMBA [package insert]. Northbrook, IL: Astellas Pharma US, Inc.

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SOURCE Astellas Pharma US, Inc.