FDA Public Workshop Summary—Coccidioidomycosis (Valley Fever): Considerations for Development of Antifungal Drugs

Abstract

Coccidioidomycosis is a fungal disease endemic to the southwestern United States, Mexico, and Central and South America. Prevalence rates are increasing steadily, and new endemic areas of Coccidioides are emerging. Standard treatment is often administered for months to decades, and intolerance to medications and treatment failures are common. No new treatments for coccidioidomycosis have been approved in the United States in nearly 40 years. On 5 August 2020, the US Food and Drug Administration convened experts in coccidioidomycosis from academia, industry, patient groups, and other government agencies to discuss the disease landscape and strategies to facilitate product development for treatment of coccidioidomycosis. This article summarizes the key topics concerning drug development for coccidioidomycosis presented by speakers and panelists during the workshop, such as unmet need, trial designs, endpoints, incentives, research and development support, and collaborations to facilitate antifungal drug development.

antifungal drugs, coccidioidomycosis, valley fever, rare diseases, drug development

Within the endemic region of the United States, coccidioidomycosis is a growing threat, with no new drugs approved for treatment in nearly 40 years. There are scientific and economic challenges in conducting lengthy clinical trials of vaccines or novel treatments for a largely geographically restricted fungal disease, which is perceived as relatively rare. On 5 August 2020, the US Food and Drug Administration (FDA) convened a public workshop that included experts from academia, industry, patient groups, and other government agencies to better understand the current state of coccidioidomycosis and potential strategies to facilitate the development of drugs for treatment of coccidioidomycosis. This workshop consisted of 2 sessions followed by a panel discussion, which provided a public forum for presentations and multiple stakeholder discussions. This article presents a high-level overview of the key topics in the order they were presented and discussed during the workshop. Additional details and all workshop materials can be found on the public workshop webpage (https://www.fda.gov/news-events/fda-meetings-conferences-and-workshops/coccidioidomycosis-valley-fever-considerations-development-antifungal-drugs-08052020–08052020).

SESSION 1: EPIDEMIOLOGY, CLINICAL MANIFESTATIONS, AND DEVELOPMENT RESOURCES

Epidemiology

Coccidioidomycosis, also known as valley fever, is a New World disease caused by 2 Coccidioides species found in the soils of northern Mexico, Central and South America, and the United States, largely in the southwest, but emerging in the Pacific northwest [1, 2]. Normal climatic events, in addition to dust storms and earthquakes, disturb the soil and release fungal spores into the air, where they may be inhaled and lead to infection [3]. According to the Centers for Disease Control and Prevention, 14364 cases were reported in 2017 [4]. However, an estimated 150000 people are infected annually in the United States, of which approximately one-third experience symptomatic disease [5]. Prevalence is increasing steadily and new areas of endemicity are emerging in the United States (Oregon and Washington), as well as in Colombia, Brazil, and Guatemala. The range of Coccidioides in the soil might be expected to increase with rising temperatures related to climate change.

Primary pulmonary coccidioidomycosis may present as a community-acquired pneumonia, resulting in delayed care-seeking by patients and frequent initial misdiagnosis by physicians. Pulmonary coccidioidomycosis may disseminate to other parts of the body including bones, joints, or central nervous system. Disseminated coccidioidomycosis can present as skin lesions, osteomyelitis, synovitis, or meningitis. Extrapulmonary dissemination occurs in approximately 5 of every 100 diagnosed cases [6, 7] and is more likely to occur in males, pregnant women, immunocompromised individuals, and those of Black or Filipino ancestry.

The standard of care treatments for coccidioidomycosis are off-label azole antifungal drugs (eg, fluconazole, itraconazole, voriconazole, posaconazole, isavuconazonium). Adverse effects are relatively common and can impact patient adherence and may therefore limit the utility of the drugs. The 2 FDA-approved treatments for coccidioidomycosis, ketoconazole and amphotericin B, are associated with serious adverse effects [8, 9]. Amphotericin B is used primarily to treat severe disease, as rescue treatment, or when azoles are contraindicated (eg, pregnancy). The effect of treatment on primary pulmonary infection and symptoms have not been well characterized. With or without treatment, most patients with primary pulmonary coccidioidomycosis improve, although there may be instances of relapse in some patients. Although approved, ketoconazole is rarely used at present for the coccidioidomycosis treatment, largely owing to a perceived greater rate of side effects compared to other azoles. Disseminated coccidioidomycosis requires more aggressive and lengthy treatment. Coccidioidal meningitis is universally fatal if untreated; relapse after treatment discontinuation is common; therefore, therapy for meningitis is lifelong [10].

As the experience of many clinical mycology researchers has clearly shown, collaboration with researchers outside of the United States presents opportunities to expand networks of trial sites that could facilitate startup of clinical trials (as already noted with the endemicity of coccidioidomycosis in the Americas). The need for successful therapies and effective vaccines in coccidioidomycosis is evident to clinical scientists in the endemic regions, and international collaborations have been successful [11–13].

Resources Provided by The National Institute of Allergy and Infectious Diseases

The National Institute of Allergy and Infectious Diseases (NIAID) supports basic, translational, and clinical research focused on coccidioidomycosis using multiple mechanisms, including investigator-initiated grants, targeted grant and contract programs, preclinical services, and clinical trials. In 2019, NIAID organized a workshop to engage the research community in a discussion of the vaccine strategies for endemic fungal pathogens, including Coccidioides. NIAID Program Officers leveraged the positive outcomes of that workshop to develop a targeted initiative, and in 2022, NIAID intends to award cooperative agreements to establish multidisciplinary teams to conduct coccidioidomycosis-related translational and clinical research for the improved diagnosis, treatment, and prevention of coccidioidomycosis (RFA-AI-20-056). This initiative, known as Coccidioidomycosis Collaborative Research Centers, is expected to leverage unique research resources and patient populations from endemic regions to advance the field.

In addition to monetary funding, NIAID provides preclinical services (https://www.niaid.nih.gov/about/dmid-preclinical-clinical-services-contacts) through a suite of service contracts to support the development of anti-infective therapeutics, vaccines, and diagnostics. These free, gap-filling services lower the risk related to development and advance promising discoveries along the product development pathway. NIAID’s preclinical services include a suite of in vitro and in vivo services that have provided supportive data to antifungal drug development programs, including those targeting coccidioidomycosis. Product developers targeting coccidioidomycosis have also leveraged other preclinical services such as pharmacokinetic analysis, toxicology studies, formulation, and chemistry. NIAID has utilized clinical trial mechanisms to support efforts targeting coccidioidomycosis. Through the NIAID-supported Phase 1 Clinical Trial Units for Therapeutics, VT-1598 (Mycovia Pharmaceuticals) is under evaluation in a single, ascending-dose study in healthy adults [14]. In addition to the Phase 1 trials, NIAID’s Vaccine Treatment and Evaluation Units have also been used to support clinical studies in coccidioidomycosis [15].

Animal Models of Coccidioidomycosis

Mouse models of coccidioidomycosis were established 70 years ago and are the most used animal models. Numerous genetically susceptible mouse models are available to simulate host metabolic and immunologic system defects [16, 17]. However, coccidioidomycosis is a more rapidly progressive disease in mice (death occurs within days to a few weeks) than in humans, which somewhat limits the translation from mice to humans. Mice are typically exposed intranasally to imitate the typical route of exposure in humans [17]. Mice are considered well-developed models, optimal for preclinical testing due to their size and cost effectiveness. Fungal burden and survival rates are common endpoints in mouse studies, and reduction in colony-forming units is typically the primary measure of drug efficacy [17]. Rabbit models are useful for modeling meningitis, with the ability to repeatedly sample cerebrospinal fluid without sacrificing the animal [18]. Studies of naturally-infected pet dogs in endemic regions allow assessment of pulmonary disease over a longer period than in rodents using radiography and serology [19, 20]. Larger animals, such as nonhuman primates (both naturally and laboratory infected) could be studied; however, challenges include drug administration in comparatively noncompliant animals, high cost, and the likely need for anesthesia to monitor quantitative parameters [16].

SESSION 2: CLINICAL TRIAL CONSIDERATIONS FOR COCCIDIOIDOMYCOSIS TREATMENT

Regulatory Pathways for Antifungal Drug Development

There are 2 FDA-approved antifungal drugs for the treatment of coccidioidomycosis. Since the introduction of intravenous amphotericin B in 1957 and oral ketoconazole in 1981, no new drugs have been approved for this condition. Novel investigational antifungals include VT-1598, nikkomycin Z, olorofim, ibrexafungerp, and fosmanogepix [21]. The presentation from FDA outlined key considerations regarding drug development for coccidioidomycosis, including regulatory pathways and trial designs. Three regulatory pathways can be pursued for antifungal drug development for coccidioidomycosis. The first is traditional approval, in which the efficacy of an investigational drug is evaluated based on clinical endpoints (eg, clinical response, mortality). The second is accelerated approval, in which the efficacy of an antifungal drug is evaluated based on surrogate endpoints or intermediate clinical endpoints that are reasonably likely to predict clinical benefit. Accelerated approval has been used for treatments for certain infections in which a period of months to years may be required to measure clinical endpoints. The third pathway, Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD) [22], is an option when drugs are intended for well-defined limited patient populations with unmet medical need.

Expedited Pathways for Antifungal Drug Development

Expedited pathways available to drug developers pursuing treatments for coccidioidomycosis include Fast Track, Accelerated Approval and Breakthrough Therapy designations, if their product meets the criteria established for each of these designations [23]. For example, products that are being developed for treatment of coccidioidomycosis may be eligible for Qualified Infectious Disease Product (QIDP) designation [24]; a drug that is designated as a QIDP and is approved for the use for which the QIDP designation was granted will receive a 5-year extension to any exclusivity for which the application qualifies upon approval. Priority review designation is granted to the first application or efficacy supplement submitted for a specific drug product and indication for which QIDP designation was granted. Products with QIDP designation are also eligible for Fast Track designation. Fast Track designation allows frequent interaction with FDA as well as submission and review of portions of a new drug application known as a rolling review process. Breakthrough Therapy designation, available for drugs demonstrating substantial improvement over available therapies, confers all the benefits of Fast Track designation, with the addition of intensive FDA guidance and eligibility for priority review [23].

Efficacy Evaluation

To support a labeled indication for coccidioidomycosis, substantial evidence of effectiveness from human trials should be provided. In vitro and animal studies demonstrating a drug’s antifungal activity against Coccidioides provide supportive information. When using animal models, the route of administration, latency to initiate treatment (trigger-to-treat), and study endpoints (eg, mortality, reduction of fungal burden) should be considered. Pharmacokinetic-pharmacodynamic (PK-PD) assessments in animal models may be used to inform dose selection in humans and other aspects of clinical trial design.

When designing a clinical trial to seek an indication for coccidioidomycosis, developers may consider non-inferiority (NI) or superiority trial designs. A drug or regimen recognized as a current standard of care is acceptable as an active comparator. An NI trial design would require evidence of efficacy of the control arm to justify an NI margin. A superiority design could include a placebo where feasible and ethical, or an active control. In limited circumstances, a single-arm study may be considered, in which case an external control would be needed to interpret the results.

Clinical endpoints for coccidioidomycosis should be selected taking into consideration how the disease manifests in the population (eg, localized pulmonary vs disseminated). Additionally, patient reported outcome (PRO) measures may be appropriate as trial endpoints. FDA’s PRO guidance describes measurement principles that apply generally to all types of clinical outcome assessments [25]. Finally, diagnostic tests do not have to be FDA-cleared or FDA-approved for use in a clinical trial if they are being used for enrichment purposes; however, the performance characteristics of the test should be submitted for review.

Updates to the Mycosis Study Group (MSG) Scoring System

The original MSG scoring system was aimed at all fungal infections and was not specific to coccidioidomycosis [26]. Subsequently, MSG-derived coccidioidomycosis-specific scoring systems were developed and used to determine efficacy of several antifungal therapies for coccidioidomycosis. To improve the MSG scoring system’s ability to support trials of therapies for coccidioidomycosis and relevant clinical manifestations, researchers at the Valley Fever Institute at Kern Medical (Bakersfield, California, USA) have proposed a revised version, MSG 2.0, a draft of which has been submitted to the Coccidioidomycosis Study Group for consensus. The MSG 2.0 is expected to provide a more complete and non-subjective system of evaluation, using parameters that are clinically available and reproducible. This scoring system is currently being reviewed by experts but is not yet in use.

The changes proposed include:

• Removal of temperature and headache severity as parameters, which are no longer considered scientifically reproducible;

• Division of nonmeningeal disease (NMD) and meningeal disease (MD) into separate classifications;

• Separation of chronic pulmonary disease as a distinct category;

• Reduction in the weight of fixation titers and diagnostic criteria, as these tests are not available to all patients.

Comments From Pharmaceutical Industry

Given the economic and scientific challenges with drug development for coccidioidomycosis, including refractory disease, 5 industry presentations highlighted lessons learned from their respective development programs for olorofim, VT-1161, VT-1598, ibrexafungerp, and nikkomycin Z. The presenters noted that product development for coccidioidomycosis can be lengthy and is a risky financial commitment because the market opportunity is limited. External funding and support beyond industry may be required to help with development costs and commercial sustainability once the drug is on the market. Scientific challenges include complexities around use and development of PRO measures given the heterogeneity of the disease. Furthermore, clinical trials for coccidioidomycosis have been challenging given that it is relatively rare (enrollment issues), and there are uncertainties regarding case definitions, clinical outcome assessments, endpoint definitions, and the duration of treatment. Regarding endpoints, although 6-week mortality may be suitable for evaluating invasive pulmonary aspergillosis [27], it is not appropriate for diseases like coccidioidomycosis that progress over a longer period. The industry participants discussed possible solutions to the scientific and economic issues for drug development, such as clinical trial networks, streamlined regulatory pathways for development programs and further discussions with regulatory authorities regarding data needed for approval of a coccidioidomycosis indication if the product is already approved for another indication.

Treatment Studies: Past, Present, and Future

The Mycosis Study Group (MSG) was originally founded after an NIAID contract was awarded in 1978 to the University of Alabama, with the goal to perform multicenter collaborative clinical trials for the prevention and treatment of invasive fungal infections. The coccidioidomycosis subgroup within the MSG was instrumental in evaluating therapies, including fluconazole, itraconazole, and posaconazole. After these early advances, drug development has been mostly inactive; no controlled trials for coccidioidomycosis have been conducted since 2007. In response to the lack of progress, and the need for support beyond industry, members of the Coccidioidomycosis Study Group (CSG), a voluntary collaboration of clinicians and researchers, have organized a clinical consortium comprised of experts from UC Davis, Kern Medical, the Mayo Clinic in Arizona, and the University of Arizona (Tucson) aimed to increase the number of treatment trials for coccidioidomycosis. Future endeavors of the CSG could also include designing coccidioidomycosis studies; however, collaborative efforts with MSG and others will be needed for additional design and administrative support.

Panel Discussion: Next Steps

Several key messages and opportunities for collaboration presented in the workshop are highlighted below.

Addressing Lack of Investment

Business models for development of treatments and vaccines for coccidioidomycosis compete poorly against other investment opportunities. Established mechanisms of preclinical and clinical support services offered by NIAID could facilitate drug development of promising candidates but may not address the lack of financial investment. Increasing FDA incentives for industry might also be helpful. Finally, as coccidioidomycosis is a biohazard within the endemic regions of the United States, BARDA could have a role in development of vaccines and treatments.

Developing Patient-Reported Outcome Measures

Recognizing that coccidioidomycosis is a heterogeneous disease, endpoints should represent the outcomes that are most relevant to patients. The patient-focused discussions emphasized the importance of patient-centered endpoints and use of existing database(s) to further study endpoint development. Patients with severe and disseminated coccidioidomycosis have reported wide-ranging and severe symptoms from both the disease and the therapies. Disease-specific PROs are necessary to capture the patient experience. The true burden of disease, including the financial and psychological impact, has yet to be calculated but is thought to be substantial. It is possible, using electronic tools such as the CURE ID smartphone app (developed in collaboration with FDA and National Institutes of Health [NIH]), for patients to complete health questionnaires regularly during treatment. Such data may allow clinicians to identify the patients’ find most problematic symptoms, and then factor those into developing study endpoints. Researchers at the Valley Fever Institute have employed several different scoring systems related to physical functioning, psychological well-being, and the impact of adverse reactions with coccidioidomycosis therapeutics on quality of life. Scoring systems include EuroQol EQ-5D-5L [28], PROMIS SF12v2 [15], and PROMIS Short Form v2.0—Ability to Participate in Social Roles and Activities 4a [15]. Ensuring the feasibility of PROs as endpoints will depend on minimizing missing data in patient reports, providing accurate language translations of surveys, and reaching low-literacy populations.

Considering Drug Development in Specific Populations

Immunocompromised patients such as transplant recipients and persons living with human immunodeficiency virus (HIV) are especially vulnerable to coccidioidomycosis [29]. Although a pool of immunocompromised patients may be too small to support a robust clinical trial for coccidioidomycosis, consideration could be given to prophylactic studies that may benefit immunocompromised populations. It is therefore important to characterize a drug’s pharmacokinetics across immunocompromised populations and to address potential drug-drug interactions and dosing in patients with renal and hepatic impairment. Pediatric patients also require special consideration. Enrollment of children in clinical trials is based on a risk-benefit assessment and on the product being studied. Variables that determine whether safety studies will be required in children may include the class of antifungal, type of toxicity, and whether the toxicity can be monitored and mitigated. The FDA may sometimes require studies in juvenile animals before proceeding with trials in pediatric patients [30]. Ultimately, decisions regarding enrollment of pediatric patients will be made based on an overall benefit-risk assessment based on data from animal and adults.

CONCLUSION

Coccidioidomycosis poses a major threat to public health in endemic regions, yet no vaccine has been developed, novel effective therapies are lacking, and drug development had stalled until recently. Several key messages from this workshop emerged regarding identifying challenges and opportunities for collaboration in this area. To facilitate drug development, public funding mechanisms, and expedited regulatory approaches are currently available. Much work lies ahead as a community to advance drug development efforts around endpoints, specifically PRO development, building a network of trial sites within and outside the United States and options for use of streamlined regulatory pathways.

New research collaborations have been proposed, including the Coccidioidomycosis Study Group clinical consortium and NIAID’s Coccidioidomycosis Collaborative Research Centers. Opportunities to streamline clinical development programs regarding trial size, clinical endpoints, and duration of follow-up warrant further exploration and discussion among multiple stakeholders.

Notes

Acknowledgements. The authors thank all panelists and speakers who participated in this workshop. All workshop panelists and speakers can be found on the meeting agenda here: https://www.fda.gov/media/141094/download. The authors also acknowledge all of the following individuals for their contributions to this article: Drs Erin Zeituni, Dennis Dixon, Lanling Zou, Baoying Liu, Barbara Mulach, and Dona Love from the National Institute of Allergy and Infectious Diseases (NIAID).

Disclaimer. S. N.’s contribution occurred entirely while she worked at the Food and Drug Administration (FDA), Silver Spring, Maryland, USA. She is currently affiliated with Johnson & Johnson. The views expressed in this article are those of the authors and do not necessarily reflect the opinions of their institutions or the official policy of the FDA. No official support or endorsement by the FDA is intended or should be inferred. Other author disclosures can be found at: https://www.fda.gov/news-events/fda-meetings-conferences-and-workshops/coccidioidomycosis-valley-fever-considerations-development-antifungal-drugs-08052020–08052020.

Financial support. This workshop was supported by the Center for Drug Evaluation and Research, US FDA.

Potential conflicts of interest. D. A. is a shareholder in/employee of SCYNEXIS, Inc., a biotechnology company developing antifungal medications for several fungal infections including coccidioidomycosis. A. C. has provided expert testimony in court cases. J. N. G. has served on the board of directors for Valley Fever Solutions, Inc., until 1 December 2020; reports that Valley Fever Solutions has licensed nikkomycin Z from the University of Arizona as a possible antifungal therapy. All stock sold to the company for $1062, January 2021. D. J. L. is a shareholder and CEO of Valley Fever Solutions, Inc. J. H. R. is a shareholder in/employee of F2G Ltd. D. A. S. has received research funding from Valley Fever Solutions, Inc. R. P. has received research grants from US Department of Labor (grant number SH-99067-SH0 Harwood Training Grant) and Centers for Disease Control and Prevention (CDC) (grant number CoAg NU50CK2020003659 Valley Fever Education), and travel support from NIAID (5–6 March 2019 Sponsored Participant). R. H. J. has received research grants from US Department of Labor (grant number SH-99067-SH0—Harwood Training Grant, NIAID, UCOP (University of California Office of the President), and CDC, honoraria from Horizon Therapeutics and F2G Ltd., and has served as a board member for the Cocci Study Group and CMERF (Community Medical Educational and Research Foundation). E. G. has received research grants from National Institutes of Health (NIH) and NIAID DMID (Conducted Phase 1 study of VT-1598. No payments made to E. G. or Mycovia Pharmaceuticals), and consulting fees from Mycovia Pharmaceuticals, Inc. (for attendance to FDA Workshop). L. F. S. has received research grants from NIH (various NIH grants over many years have supported mouse model studies), and travel support from FDA (provided travel support to attend the Antifungal Drug Workshop that resulted in this article). G. L. is a shareholder in/employee of Mayne Pharma. S. N. is an employee of Johnson & Johnson (future travel support, stock options; has been provided equipment for home office). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.