Post-hoc analysis of the safety and efficacy of isavuconazole in older patients with invasive fungal disease from the VITAL and SECURE studies

Isavuconazole is a triazole with broad-spectrum antifungal activity. In this post-hoc analysis of two prospective clinical trials (VITAL and SECURE), the safety and efficacy of isavuconazole in patients aged ≥ 65 years with invasive fungal diseases were evaluated. Patients were divided into two subgroups (≥ 65 and < 65 years). Adverse events (AEs); all-cause mortality; and overall, clinical, mycological, and radiological response were assessed. A total of 155 patients ≥ 65 years were enrolled in both trials. Most patients reported AEs. In the isavuconazole arm of both studies, serious AEs (SAEs) were greater in patients ≥ 65 versus < 65 years: 76.7% versus 56.9% (VITAL); 61.9% versus 49.0% (SECURE). In SECURE, SAE rates were similar in the ≥ 65 years subgroup of both treatment arms (61.9% vs 58.1%), while in the < 65 years subgroup the SAE rate was lower in the isavuconazole arm (49.0% vs 57.4%). In VITAL, all-cause mortality through day 42 (30.0% vs 13.8%) was higher, and overall response at end of treatment (27.6% vs 46.8%) was lower in patients ≥ 65 years versus < 65 years. In SECURE, all-cause mortality was similar between both subgroups, and isavuconazole (20.6% vs 17.9%) and voriconazole (22.6% vs 19.4%) treatment arms. The overall response was lower in the ≥ 65 years than the < 65 years subgroup in the isavuconazole (23.7% vs 39.0%) and voriconazole (32.0% vs 37.5%) arms. The safety and efficacy of isavuconazole were better in patients < 65 versus ≥ 65 years, and the safety profile was more favorable than that of voriconazole in both subgroups. Clinicaltrials.gov identifier NCT00634049 and NCT00412893.

age-related changes in organ function, and a higher risk of adverse drug reactions, could make older individuals more vulnerable to fungal infections and the clinical management of their IFDs more challenging 19,20 .
As the pace of population aging increases worldwide, the proportion of individuals aged over 60 years is estimated to double (from 12 to 22%) between 2015 and 2050 21,22 . A gap in understanding the safety and efficacy profile of antifungal drugs in older individuals exists since randomized controlled trials are mainly focused on the overall population 19 . Therefore, there is a growing need for safe and effective therapeutic options for IFDs in this population.
Isavuconazole, the active moiety of the water-soluble prodrug isavuconazonium sulfate, is a broad-spectrum triazole approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of IA and IM in adults 23,24 . For the optimal use of isavuconazole in older individuals, it is essential to understand its safety and efficacy profile in this age group. To this end, we conducted a post-hoc analysis of two prospective clinical trials to evaluate the safety and efficacy of isavuconazole in patients with IFDs aged ≥ 65 years.

Methods
Study design. Data from two prospective clinical trials, VITAL (NCT00634049, completed in 2016) and SECURE (NCT00412893, completed in 2013), were analyzed for patients aged ≥ 65 and < 65 years ( Fig. 1) 25,26 . Both studies were conducted in compliance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice Guidelines (ICH-GCP). The final protocols and amendments were reviewed and approved by the Institutional Review Boards and Independent Ethics Committees of the investigational centers at participating sites and details are provided in Supplementary Information. Patients provided written informed consent. The study designs of these two trials have been published previously 25,26 and are summarized below.
VITAL study. This was a single-arm, open-label study conducted to evaluate isavuconazole in the treatment of IA in patients with renal impairment (defined as calculated creatinine clearance [CLCr] < 50 mL/min at enrollment) requiring primary therapy or in patients with rare IFDs including patients with mucormycosis (primary therapy or refractory or intolerant to other therapies) or patients infected with rare yeasts or dimorphic fungi (i.e., fungal pathogens other than Aspergillus fumigatus or Candida species) with or without renal impairment. Patients were required to meet the criteria for proven, probable, or possible IFD described by the European Organization for the Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria 27,28 . A total of 146 adult patients from 34 centers worldwide were treated with isavuconazole.
Patients received six doses of either oral or intravenous (IV) isavuconazole 200 mg (administered as isavuconazonium sulfate 372 mg) every 8 h, followed by a once-daily dose until resolution of IFD or for a maximum of 180 days. SECURE study. This randomized, double-blind, non-inferiority study that compared isavuconazole with voriconazole for the treatment of IA was conducted at 102 centers across 26 countries worldwide. Overall, 516 adult patients were randomized (1:1) and treated (258 per group). Patients who met the criteria for proven, probable, or possible IFD caused by Aspergillus species or other filamentous fungi based on EORTC/MSG guideline were eligible for enrollment 28 .
Patients were randomized to receive either isavuconazole or voriconazole. Isavuconazole 200 mg (i.e., isavuconazonium sulfate 372 mg) was administered IV every 8 h on days 1 and 2, followed by either IV or oral isavuconazole 200 mg once daily. Voriconazole 6 mg/kg was administered IV twice daily on day 1, followed by 4 mg/ Figure 1. Description of the studies used in this post-hoc analysis and study design. AEs = adverse events, bid = twice a day, IFD = Invasive fungal disease; IA = invasive aspergillosis, IV = Intravenous, q8h = every 8 h, qd = once a day, RCT = randomized controlled trial, RI = Renal impairment.
In SECURE, the number of patients aged ≥ 65 years and those < 65 years were nearly equal between both treatment arms. At baseline, most parameters were comparable between the ≥ 65 years and < 65 years subgroups in the isavuconazole and voriconazole treatment arms (Table 1). Among all high-risk factors, uncontrolled malignancy status was more prevalent in the ≥ 65 years subgroup (77.8%) than the < 65 years (63.9%) subgroup in the isavuconazole arm, although hematologic malignancy was more prevalent in the < 65 years subgroup (90.4%) than the ≥ 65 years subgroup (71.0%) in the voriconazole arm. At baseline, most patients had probable or possible IFD in both subgroups of both treatment arms ( Table 1). The most common underlying disease was acute myeloid leukemia in both subgroups of both treatment arms ( Table 2).
In SECURE, a similar proportion of AEs was reported in both subgroups of the isavuconazole arm (≥ 65 years: 98.4%, < 65 years: 95.4%), with gastrointestinal disorders (≥ 65 years: 73.0%, < 65 years: 66.0%) being the most common. However, a higher proportion of infections and infestations was reported in the ≥ 65 years subgroup (69.8%) than the < 65 years subgroup (55.7%) in the isavuconazole arm (Table 4); and a higher incidence of psychiatric disorders was reported in the ≥ 65 years subgroup (46.8%) than the < 65 years subgroup (28.9%) in the voriconazole arm.

Efficacy.
In VITAL, all-cause mortality through day 42 after treatment with isavuconazole was higher in the ≥ 65 years than the < 65 years subgroup (30.0% vs 13.8%, Table 5). The overall response at EOT was lower in the ≥ 65 years subgroup than the < 65 years subgroup (27.6% vs 46.8%, Table 6); similar results were noted for clinical response, mycological response, and radiological response at day 42 and EOT (Table 7).
In SECURE, all-cause mortality through day 42 was similar between both subgroups and both the isavuconazole (20.6% vs 17.9%) and voriconazole (22.6% vs 19.4%) treatment arms (Table 5). Overall response at EOT was lower in the ≥ 65 years compared to the < 65 years subgroup in the isavuconazole arm (23.7% vs 39.0%) and in the voriconazole arm (32.0% vs 37.5%) ( Table 6); similar results were noted for clinical response, mycological response, and radiological response (except in voriconazole arm at EOT) at day 42 and EOT (Table 7). Additionally, overall response at EOT was higher in the voriconazole arm (32.0%) than the isavuconazole arm (23.7%) in the ≥ 65 years subgroup. Moreover, although clinical response at EOT in the ≥ 65 years subgroup was similar in both treatment arms (isavuconazole: 55.3%; voriconazole: 52.0%), the mycological (isavuconazole: 23.7%; voriconazole: 32.0%) and radiological responses (isavuconazole: 21.1%; voriconazole: 33.3%) at EOT were lower in the isavuconazole arm compared to the voriconazole arm. Table 4. Treatment-emergent adverse events by system organ class (safety population). Treatment-emergent AE is an AE starting after the first study drug administration until 28 days after the last dose of the study drug. AE adverse events. a System organ classes with most frequent AEs or AEs of special interest are listed. b Overall: Total number of patients who had treatment-emergent AEs.

Discussion
Currently, available treatment options for IFDs have certain constraints in the older population such as significant DDIs or drug safety and tolerability issues, which may impact their clinical use 19,20 . Therefore, the exploration of the effectiveness of new antifungal agents in older individuals is imperative. Here, we report the findings from a post-hoc analysis of two phase 3 studies of isavuconazole. This analysis indicated, as expected, that the safety and efficacy outcomes were broadly more favorable in the < 65 years compared to the ≥ 65 years subgroup in both studies. However, it must be considered that the number of patients was relatively lower in the ≥ 65 years subgroup in both studies. In addition, the studies were not powered to detect statistical treatment differences between subgroups. In VITAL, all-cause mortality through day 42 was higher in the ≥ 65 years subgroup. In SECURE, all-cause mortality through day 42 was similar between both subgroups and treatment arms, and the safety profile favored isavuconazole over voriconazole in both subgroups.
Aging is an important factor in both drug and dose regimen selection, together with careful monitoring of benefit and risk. Age-associated changes in the biochemical composition of tissues and progressive decrease in physiological capacity may affect the response to a drug 30 , therefore, the safety profile of any therapeutic agent needs to be monitored closely in older individuals. In VITAL, the overall safety profile was more favorable in the < 65 years subgroup compared to the ≥ 65 years subgroup except for drug-related AEs and drug-related AEs leading to permanent discontinuation, which were higher in the < 65 years subgroup. This difference could be attributed to the small sample size (n = 30) in the ≥ 65 years subgroup.
The safety data from the current post-hoc analysis for the SECURE study demonstrated less frequent AEs with isavuconazole treatment compared to voriconazole in both subgroups. Similar to the results of the global analysis 25 , the ≥ 65 years and < 65 years subgroups receiving isavuconazole showed fewer drug-related AEs, as well as AEs and drug-related AEs leading to discontinuation compared with patients receiving voriconazole. Furthermore, drug-related AEs frequently associated with voriconazole such as psychiatric disorders and eye disorders were less common with isavuconazole in the ≥ 65 years subgroup. Similarly, for the < 65 years subgroup, drug-related laboratory abnormalities, hepatobiliary disorders, psychiatric disorders, and eye disorders were also less common in the isavuconazole arm.
Azole antifungals are known to cause hepatocellular injury, thus monitoring of hepatic enzymes is necessitated while receiving treatment 31,32 . Reduced hepatotoxicity with isavuconazole use was reported when compared to Table 5. Analysis of all-cause mortality through Day 42. Crude mortality rates are calculated within treatment group. The 95% CI for treatment group is based on a binomial distribution. CI confidence interval, ITT intent to treat, mITT modified ITT, n number of patients. a Patients with the last known survival status before day 42 assessment/missing; treated as death(s) while calculating all-cause mortality.  Table 6. DRC-assessed overall response at end of treatment (mITT population). Crude success rates and exact binomial CIs were calculated within treatment. Complete and partial response referred to the resolution of attributable clinical symptoms and physical findings. Failure (no resolution) was defined as no resolution and/ or worsening of any attributable clinical symptoms and physical findings. The 95% CI for treatment group is based on a binomial distribution. CI confidence interval, DRC data review committee, mITT modified intent to treat, n number of patients. a One patient with missing response had an outcome as Failure.  Other AEs known to be associated with voriconazole (including eye disorders) and discontinuations due to AEs were also less common in the isavuconazole arm compared to the voriconazole arm, consistent with the results of the global analysis 25 .
In this post-hoc analysis, the proportion of AEs with severe intensity was higher in the ≥ 65 years subgroup than the < 65 years subgroup in both studies for the isavuconazole arm. However, the intensity of AEs was similar in the voriconazole arm for both subgroups. Additionally, the proportion of patients with SAEs was noticeably higher in ≥ 65 years subgroup than in the < 65 years subgroup in both studies, probably due to increased comorbidities in the ≥ 65 years subgroup. Furthermore, impaired renal clearance is likely to contribute to an increase in AE incidence in patients with IFDs 35 . Patients with renal impairment were included in VITAL and the proportion of such patients was higher in the ≥ 65 years subgroup compared to the < 65 years subgroup. This may also have contributed to the observed higher proportion of SAEs in the ≥ 65 years subgroup.
Previously, studies assessing mortality in older individuals with IFDs reported a greater prevalence of highrisk factors and worse survival outcomes 14,16,18,22 . In line with these previous studies, data from VITAL revealed that all-cause mortality through day 42 was higher in the ≥ 65 years subgroup than the < 65 years subgroup. In SECURE, all-cause mortality was comparable in the isavuconazole and voriconazole arms, with slightly worse outcomes in the ≥ 65 years subgroup than the < 65 years subgroup.
In VITAL, all efficacy outcomes assessed through EOT were lower in the ≥ 65 years subgroup than the < 65 years subgroup. Clinical response (an individual component of the overall response) was better than the overall response in both subgroups. This may be explained by the observed lower radiological response rates. The rates of mycological and radiological responses, components of overall response, were impacted by missing assessments. Patients with no post-baseline mycological and radiological assessments were conservatively considered failures, and consequently, overall response was assessed as failure in these patients. In SECURE, overall, clinical, and mycological response rates at EOT were lower in the ≥ 65 years than the < 65 years subgroup in both treatment arms. Similar to VITAL, lower overall response compared to clinical response was observed in both subgroups of both treatment arms. The probability of IFDs may be higher in patients whose immune capabilities are more profoundly compromised 36,37 , and underlying disease presentation and subsequent management is more complex. Therefore, it might be reasonable to assume that this would be reflected in poorer treatment outcomes in older individuals.
Since older individuals are usually prescribed several medications and the risk of serious DDIs is more likely 19,38 , it is important to carefully assess the existing drug regimen before adding an azole, to avoid potentially serious and life-threatening DDIs. It is estimated that > 40% of individuals aged ≥ 65 use ≥ 5 medications, and 12% use ≥ 10 different medications 39 . Optimization of antifungal therapy is an urgent need, particularly in the older population experiencing worse disease outcomes and high mortality rates. Although more studies are required, the fact that a lesser degree of interaction observed between isavuconazole and immunosuppressive agents in healthy adults than those reported for other triazole antifungal agents is encouraging 40,41 . Isavuconazole is a valuable addition to antifungal treatment regimens and may be a particularly useful treatment option in older patients with IFDs.
One limitation other than those inherent to any post-hoc analysis was a relatively small sample size for individual age-stratified subgroups, most notably for the ≥ 65 years subgroup in both studies. In addition, the VITAL and SECURE studies were not powered to detect statistical treatment differences between subgroups, and patients enrolled in these controlled trials may not be fully representative of all IFDs affecting older populations. Given the lack of direct clinical evidence for antifungal treatment outcomes in older individuals, real-world studies in older populations may substantiate findings from this study and provide insights into treating IFDs in older patients. Currently, clinicians involved in treating such patients depend solely on pharmacological data for treatment decisions including dose and drug selection.

Data availability
The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.