Date: 2016-03-09
Type of
information: Publication of results in a medical journal
phase: 3
Announcement: publication of results in The Lancet Infectious Diseases
Company: Basilea Pharmaceutica (Switzerland) Astellas Pharma (Japan)
Product: Cresemba® (isavuconazole)
Action
mechanism:
- systemic antifungal agent. Isavuconazole is an investigational intravenous and oral broad-spectrum antifungal. It has a fungicidal effect by blocking the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of the enzyme lanosterol 14 alpha demethylase. In collaboration with Astellas Pharma, isavuconazole is being investigated in phase 3 clinical studies for the treatment of severe invasive fungal infections. The drug demonstrated in-vitro and in-vivo coverage of a broad range of yeasts (such as Candida species) and molds (such as Aspergillus species) as well as in-vitro activity against less prevalent but often fatal molds including those that cause mucormycosis. In clinical studies to date, isavuconazole achieved predictable drug levels supporting reliable dosing and a switch from intravenous administration to a once-daily oral dose. The intravenous formulation of isavuconazole, which is water-soluble, does not contain potentially kidney damaging solubilizers and has the potential to be given also to patients with pre-existing renal impairment.
Disease: invasive fungal disease caused by Aspergillus species or other filamentous fungi
Therapeutic
area: Infectious diseases
Country:
Trial
details:
- The SECURE study is a global double-blind randomized phase 3 study, designed to evaluate the safety and efficacy of once-daily isavuconazole versus twice-daily voriconazole for up to 84 days of therapy in the primary treatment of invasive fungal disease caused by Aspergillus species or other filamentous fungi. Five hundred and twenty-seven (527) patients were enrolled in the study. The primary endpoint of this non-inferiority study is all-cause mortality through day 42.
The VITAL study is an open-label phase 3 study in the treatment of aspergillosis patients with pre-existing renal impairment or with invasive fungal disease caused by emerging and often fatal fungi. The study is evaluating the safety and efficacy of intravenously (i.v.) and orally administered isavuconazole versus i.v. caspofungin followed by oral voriconazole in the treatment of invasive Candida infections. The study's primary efficacy endpoint of overall response will be moved to the end of intravenous treatment and assessed by a Data Review Committee. The previous assessment at two weeks after i.v. and oral treatment will remain a secondary efficacy endpoint. There are no changes in the overall operational study conduct. The protocol change will facilitate the comparison to data obtained from previous registration trials in invasive Candida infections. The study is expected to continue to recruit in 2014.
- Data on a sub-group of mucormycosis patients from the VITAL study supported the mucormycosis registrations for Cresemba® in the U.S. and Europe, in addition to the invasive aspergillosis indication.
Latest
news:
- • On March 9, 2016, Basilea Pharmaceutica announced that results from the open-label phase 3 VITAL study evaluating Cresemba® (isavuconazole) in adult patients with mucormycosis were published in The Lancet Infectious Diseases. The article is titled "Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis. VITAL study evaluated the efficacy and safety of isavuconazole 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 overall response at Day 42 as assessed by an independent data-review committee (DRC); secondary endpoints included assessments of all-cause mortality at Days 42 and 84.
- • On May 14, 2014, Basilea Pharmaceutica reported that detailed efficacy and safety data of the isavuconazole invasive aspergillosis study (SECURE) were presented at the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) in Barcelona, Spain. Treatment emergent adverse events for isavuconazole were statistically fewer relative to the study comparator voriconazole in the System Organ Classes of hepatobiliary (8.9% vs. 16.2%), skin (33.5% vs. 42.5%) and eye disorders (15.2% vs. 26.6%). In addition, isavuconazole (42.4%) showed statistically fewer study drug-related adverse events relative to voriconazole (59.8%). In both treatment groups, the most common treatment emergent adverse events for isavuconazole and voriconazole respectively were nausea (27.6% vs. 30.1%), vomiting (24.9% vs 28.2 %), pyrexia (fever) (22.2% vs 30.1%) and diarrhea (23.7% vs 23.2%). Previously announced topline data showed that the randomized, double-blind SECURE study met the primary objective of demonstrating non-inferiority of isavuconazole versus voriconazole for the primary treatment of invasive fungal disease caused by Aspergillus species or certain other filamentous fungi. Baseline characteristics of the severely ill patient population enrolled in this trial were balanced between treatment groups and were reflective of patients at risk for invasive fungal disease (mean age 51 years, 84% hematologic malignancies, 66% neutropenic and 20% allogeneic haematopoietic stem-cell transplantation).
- The primary endpoint of all-cause mortality through day 42 in the intent-to-treat population (ITT, N=516) was 18.6% in the isavuconazole (ISA) treatment group and 20.2% in the voriconazole (VRC) group. The upper limit of the 95% confidence interval of the adjusted treatment group difference was 5.7% which is below the pre-specified 10% non-inferiority margin. All-cause mortality through day 42 in patients with proven/probable invasive fungal disease (modified intent-to-treat population, mITT) was 19.6% (ISA) and 23.3% (VRC).
- Overall response (a composite of clinical, mycological and radiological responses) at end-of-therapy in the mITT population assessed by the independent data review committee was 35.0% for isavuconazole versus 36.4% for the comparator voriconazole.
- Isavuconazole posters and presentations at ECCMID 2014: A phase 3 randomised, double-blind trial evaluating isavuconazole vs. voriconazole for the primary treatment of invasive fungal disease caused by Aspergillus spp. or other filamentous fungi (SECURE) - J. Maertens, T. Patterson, G. Rahav, D. Kontoyiannis, K. Marr, R. Maher, M. Lee, B. Zeiher, A. Ullmann; Oral presentation O230a Pharmacodynamics of the new azole isavuconazole (ISA) in an Aspergillus fumigatus mouse infection model - S. Seyedmousavi, J. F. Meis, R. J. M. Bruggemann, W. J. G. Melchers, P. E. Verweij, J. W. Mouton; Poster P1698 In vivo efficacy of isavuconazole and amphotericin B in a non-neutropenic murine model of disseminated Absidia corymbifera - P. Warn, A. Sharp; Poster P0106
- Results from the SECURE and VITAL phase 3 studies will support regulatory submissions in Europe and in the U.S., which are planned for mid-2014.
- • On September 30, 2013, Basilea Pharmaceutica has announced positive topline data from the isavuconazole phase 3 invasive aspergillosis study (SECURE). The antifungal agent isavuconazole is being co-developed with Astellas Pharma Inc.
- The randomized, double-blind isavuconazole study (SECURE) achieved its primary objective in demonstrating non-inferiority versus voriconazole for the primary treatment of invasive fungal disease caused by Aspergillus species or certain other filamentous fungi. Isavuconazole was effective as determined by the primary endpoint of all-cause mortality through day 42 in the intent-to-treat population (N=516). The all-cause-mortality was 18.6% in the isavuconazole treatment group and 20.2% in the voriconazole group. The 95% confidence interval of the treatment difference between isavuconazole and voriconazole was within the pre-specified non-inferiority margin of 10%.
- The key secondary endpoint of overall success rate (composite of clinical, mycological, radiological responses) at the end-of-therapy in patients with proven/probable disease was similar between isavuconazole and voriconazole (35.0% and 36.4%, respectively). This outcome was based on a blinded assessment by the Independent Data Review Committee.
- Overall drug- and non-drug-related adverse events were reported in 96.1% and 98.5% of patients in the isavuconazole and voriconazole treatment groups, respectively. The most frequent adverse events reported were nausea, vomiting, pyrexia (fever), diarrhoea, and hypokalaemia (deficiency of potassium in the blood) which were reported at similar rates in both treatment groups. Study drug-related adverse events were reported in 42.4% and 59.8% of patients in the isavuconazole and voriconazole treatment groups, respectively.
- Update on other ongoing phase 3 isavuconazole studies (VITAL and ACTIVE): Enrollment in the open-label phase 3 isavuconazole study (VITAL) including patients with invasive fungal disease caused by mucormycetes and other emerging fungal pathogens and patients with aspergillosis and pre-existing renal impairment has been completed (N=150). Based on the investigator reported data, approximately 45 patients were enrolled with mucormycosis and a similar number of patients were enrolled with pre-existing renal impairment. Review of diagnosis and outcomes by an Independent Data Review Committee is ongoing.
- Enrollment in the randomized, double-blind phase 3 isavuconazole study (ACTIVE), evaluating the use of isavuconazole i.v. and oral versus caspofungin i.v. followed by oral voriconazole for the treatment of invasive Candida infections, is continuing.
- The data from the SECURE and VITAL studies could form the basis of an initial filing in the first part of 2014.
- • On July 17, 2013, Basilea Pharmaceutica has provided an update on the phase 3 program withisavuconazole that is being developed in collaboration with Astellas Pharma Inc. Topline data from the SECURE and VITAL phase 3 studies are on track to be available in the second half of 2013. With 150 patients enrolled, the VITAL study has now completed recruitment, which was extended beyond its initial target to further expand the database on the use of isavuconazole in the primary treatment of emerging fungal infections for which currently only limited treatment options exist. The data from the SECURE and VITAL studies could form the basis of an initial filing in the first part of 2014.
In addition, the European Medicines Agency has agreed to the Pediatric Investigation Plans (PIP) of isavuconazole for the treatment of invasive aspergillosis, mucormycosis and Candida infections in children.
• On December 14, 2012, Basilea Pharmaceutica and its partner Astellas Pharma have announced that patient recruitment for the isavuconazole phase 3 registration study SECURE has been completed. Isavuconazole is an investigational intravenous (i. v.) and oral broad-spectrum antifungal being jointly developed by Basilea and Astellas. Basilea and Astellas expect that results of this study will be available in the second half of 2013. In addition, enrollment into the VITAL study, an open-label phase 3 study of isavuconazole in the treatment of aspergillosis patients with pre-existing renal impairment or patients with invasive fungal disease caused by rare but often fatal molds, yeasts or dimorphic fungi has achieved the targeted recruitment of 100 patients and will continue to recruit to further expand the data base on the use of isavuconazole in the treatment of the diverse rare mold infections.
Is
general: Yes
