Meeting the Therapeutic Challenges of Emergent and Rare Invasive Fungal Diseases Through Novel Clinical Trial Designs

Meeting the Therapeutic Challenges of Emergent and Rare Invasive Fungal Diseases Through Novel Clinical Trial Designs

  • Post category:Drug Updates
  • Reading time:11 mins read

Introduction

(Article introduction authored by ICU Editorial Team)

Treatments for rare and emerging invasive fungal diseases (IFDs) are urgently needed.

Diseases such as mucormycosis, hyalohyphomycosis, and phaeohyphomycosis occur less frequently than invasive aspergillosis, making randomized controlled clinical trials impractical.

Single-arm trials with high-quality external controls and nonclinical studies, including pharmacokinetic/pharmacodynamic data from animal models, may demonstrate the effectiveness of new drugs.

Control populations may include historical data, patient registries, or contemporaneous external groups. Collaboration among clinicians, sponsors, and regulatory agencies is crucial for developing innovative trial designs. For rare IFDs, traditional trials are impractical due to low incidence rates.

A review of pathways used for rare cancers and metabolic diseases is necessary to find feasible development pathways for antifungal drugs. Repurposing drugs and innovative strategies like target trial emulation may also be effective.

Rare fungal pathogens include various yeasts, molds, and dimorphic molds, affecting immunocompromised patients, including those with neutropenia, T-cell dysfunction, diabetes, or severe COVID-19. The prevalence of these diseases varies by region and patient population, posing significant threats to immunocompromised individuals.

Drug approvals for rare IFDS

The limited treatment options for rare invasive fungal diseases (IFDs) are a critical unmet medical need. Global guidelines highlight these limitations, knowledge gaps, and management constraints.

Over the past 60 years, only four drugs—amphotericin B deoxycholate, amphotericin B lipid complex, voriconazole, and isavuconazonium sulfate—have been approved by the FDA for treating mucormycosis and other rare IFDs. Approvals for these treatments have been based on noncomparative, open-label studies or case series, except for isavuconazonium sulfate.

Approved in 2015 for invasive aspergillosis and mucormycosis, its approval for mucormycosis was supported by both a randomized controlled trial and an open-label, noncomparative trial.

The new drug application included a comparative analysis with matched, contemporaneously treated controls from a fungal registry to support efficacy and safety. The all-cause mortality rate by day 42 was 38%, and the overall clinical response at the end of treatment was 31%, showing isavuconazonium’s effectiveness for mucormycosis.

Additional supportive data came from murine models of pulmonary mucormycosis. Isavuconazonium was as effective as high-dose liposomal amphotericin B in protecting neutropenic mice in a pulmonary infection model but not in diabetic ketoacidotic mice. Safety data were primarily obtained from a controlled clinical trial in invasive aspergillosis.

Drug-approvals-for-rare-IFDS

Recently developed antifungal agents show promise against rare molds and yeasts, including mucormycetes, l. prolificans, scedosporium spp., fusarium spp., triazole-resistant aspergillus spp., scopulariopsis spp., c. auris, c. haemulonii, t. asahii, magnusiomyces spp., saprochaete spp., and endemic fungi like coccidioides spp. and emergomyces spp.

These agents, under clinical investigation, include encochleated amphotericin b, f901318, fosmanogepix, ibrexafungerp, olorofim, opelconazole, oteseconazole, pc945, rezafungin, scy-247, and vt-1598. Lessons from drug approvals for rare cancers and metabolic disorders may aid in developing novel antifungals for life-threatening but less common fungal pathogens.

Drug approvals for rare cancers and inborn errors of metabolism

Understanding regulatory approaches for drugs for rare cancers and metabolic diseases can help address challenges in developing drugs for rare ifds. Unlike the limited drugs approved for rare ifds, many drugs have been approved for rare cancers and metabolic diseases. Between 1987 and 2011, the fda approved 45 drugs for 68 rare cancers, with one-third of the 99 supporting trials being randomized and 63% based on a single trial with a median sample size of 54 patients. Most approvals were based on the overall objective response rate, with time-to-event endpoints being less common.

Recently, nonrandomized studies have supported approvals for some oncologic drugs for rare cancers. Between 2019 and 2021, 11 oncologic drugs were approved, with three receiving traditional approval and eight receiving accelerated approval based on intermediate clinical endpoints and duration of response.

These studies were often single-arm, open-label, and multicenter, with enrollments ranging from 28 to 314 participants. The primary endpoint was typically the objective response rate, assessed by an independent review committee.

Accelerated approval requires a surrogate or intermediate clinical endpoint likely to predict clinical benefit, with a postapproval requirement for a confirmatory study.

Approvals for drugs for rare metabolic diseases, such as uridine triacetate, cerliponase alfa, lonafarnib, and cyclic pyranopterin monophosphate, were based on single-arm trials compared to matched historical controls, with additional confirmatory evidence from animal models, mechanistic data, and historical disease data.

Approaches to the assessment of efficacy of antifungal agents for rare IFDS

Drug approval must be based on substantial evidence of effectiveness and safety for the intended use. The FDA has approved drugs for rare cancers and metabolic diseases using single controlled trials with confirmatory preclinical evidence. These strategies could be applied to rare IFDs. Efficacy assessment for antifungal drugs might involve controlled trials with nonclinical evidence, including predictive animal models.

FDA guidelines provide resources for efficient drug development and potential clinical study designs for antifungal drugs treating rare IFDs. The Limited Population Pathway for Antibacterial and Antifungal Drugs aids in approving treatments for serious infections in limited patient populations with unmet needs, like those with rare IFDs. Success requires robust control datasets.

Study controls

A key element in assessing drug efficacy is having an appropriate control population and understanding the natural history of the disease. Controls can include historical data, patient registries, and contemporaneous external groups. The lack of high-quality external controls limits clinical trials for rare IFDs. Data can be collected prospectively during trials or retrospectively. Examples of prospectively collected registries for rare diseases include those for cancers, cystic fibrosis, genetic diseases, metabolic disorders, and immunodeficiencies.

For study protocol development, sources of external control should be evaluated for accessible clinical data and feasibility for establishing a well-matched control group before trial enrollment. Patient-level data should be available, and criteria must define control group enrollment.

Matching for prior antifungal treatment, extent of IFD, and prognostic factors is crucial. Multiple control sources, as used in the pretomanid trial for tuberculosis, can address limitations like heterogeneity and publication bias.

Creating databases for rare IFDs would benefit from specified guidance for regulatory approval of investigational agents.

Animal models

Carefully designed studies of investigational antifungal agents in predictive laboratory animal models of rare IFDs can provide critical data on drug activity compared to standard treatments. The nonclinical studies of isavuconazonium for pulmonary and disseminated mucormycosis illustrate this approach.

Luo et al. demonstrated that isavuconazonium significantly prolonged survival and reduced fungal burden in immunocompromised mice with pulmonary mucormycosis, comparable to liposomal amphotericin B.

These findings support clinical trial results from Marty et al., where the 42-day mortality rate was similar between isavuconazonium and amphotericin B-treated patients.

Animal models can be used for studying various IFDs, including mucormycosis, scedosporiosis, fusariosis, trichosporonosis, and candidiasis caused by C. auris, to understand the activity of new antifungal agents against rare IFDs.

Efficacy end points

Clinical trials for rare IFDs can use mortality and global clinical response criteria as endpoints. Mortality rates can be analyzed as all-cause mortality or fungal-free survival. Mortality endpoints are advantageous due to their objective measurement, standardized reporting, and clinical importance.

However, large sample sizes and comorbid conditions can be confounding factors. Despite this, a significant difference in treatment effect may still be observed in small trials.

Global clinical response, used in candidemia trials, may also be valid for rare IFDs. Efficacy can be demonstrated by showing superiority or noninferiority to existing therapies. Noninferiority could be valuable if the new agent has advantages like reduced toxicity or better pharmacokinetics. A desirability of outcome ranking analysis could incorporate toxicity into noninferiority outcomes.

Reliable efficacy assessment requires combining multiple diagnostic strategies due to the limited sensitivity and specificity of current tests. Innovative biomarkers and imaging techniques can monitor treatment response.

Consistent time points for outcome assessment between study and historical controls are important. Patient-reported outcomes could be useful for chronic mycoses, but specific instruments for rare IFDs are not widely available.

Assessment of safety

Patient-level safety data for the investigational drug at its intended dose and duration should be evaluated. Supportive safety data can come from human pharmacokinetic/safety studies, published clinical studies, patient registry databases, case series, and case reports.

Early discussions with regulatory agencies are crucial to agree on the clinical and nonclinical studies needed and the required size of the safety database. For drugs already approved for more common IFDs, the existing safety database might suffice. For new molecular entities, the adequacy of the safety database must be determined. Isavuconazole’s approval for mucormycosis was based on efficacy data from the VITAL study and safety data from the SECURE study.

A balance is needed between limited efficacy data for rare IFDs and a larger safety database. Unlike rare cancers and metabolic diseases, antifungal agents will likely be used for a broader patient range with IFDs beyond the approved indications.

Alternative approaches to meeting challenges of rare IFDs

Repurposing drugs originally developed for other purposes can be a pragmatic solution for treating rare IFDs. Many licensed drugs, including antibacterial agents, immunomodulatory drugs, statins, and NSAIDs, have shown antifungal activity in vitro and in vivo.

For example, miltefosine, used for leishmaniasis, has been advocated for use against rare IFDs like C. auris, Mucorales, Scedosporium spp, and Lomentospora spp. The FDA has approved compassionate use of miltefosine for refractory Scedosporium infections. More studies are needed to characterize the potential of such repurposed agents against rare fungal pathogens.

When randomized trials are infeasible, observational data can be used to emulate target trials, applying randomized trial design concepts to estimate the causal effect of an intervention.

For instance, the COHERE study used target trial emulation to demonstrate the safety of withdrawing primary prophylaxis against Pneumocystis pneumonia in HIV patients on antiretroviral therapy.

Similarly, marginal structural models used in clinical cohort databases found no significant difference in mortality rates when comparing early versus late antiretroviral therapy initiation in HIV patients with cryptococcal meningitis.

Future directions

To advance pathways for antifungal drug development for rare IFDs, and to build on the 2020 FDA workshop on antifungal drugs, continued engagement with stakeholders is essential to further develop a consensus among clinical investigators, industry, the FDA, and other regulatory agencies, such as the European Medicines Agency. Given that there are emerging novel antifungal agents with activity against rare fungal pathogens, a timely workshop to discuss innovative trial designs would help to advance the field. In addition to panelists with infectious diseases expertise, participation of members of the Division of Rare Diseases and Medical Genetics and the Office of Oncologic Diseases and Rare Disease Drug Development Council at the FDA may provide valuable perspective and experience.

Sources: Thomas J Walsh, Meeting the Therapeutic Challenges of Emergent and Rare Invasive Fungal Diseases Through Novel Clinical Trial Designs, Open Forum Infectious Diseases, Volume 11, Issue 6, June 2024, ofae257, https://doi.org/10.1093/ofid/ofae257