Use of Expanded Access Fosmanogepix in Two Pediatric Patients With Rhino‐Orbital‐Cerebral Mucormycosis

ABSTRACT

Mucormycosis is a severe fungal infection with high morbidity and mortality. Pharmacotherapeutic options are limited, often used in combination, and associated with significant adverse effects. Fosmanogepix is an investigational antifungal with a novel mechanism of action and has shown broad in vitro activity. Early clinical trials suggest a manageable adverse effect profile, making it an attractive treatment option. Two pediatric patients presented in diabetic ketoacidosis and were found to have extensive rhino‐orbital‐cerebral mucormycosis. Treatment with standard of care, including liposomal amphotericin B, micafungin, and azole antifungals along with nonpharmacologic measures, was unable to eradicate the infection. Expanded access fosmanogepix was added to the multimodal treatment regimens. Each patient improved and more poorly tolerated antifungals were able to be discontinued. Both patients completed several months of fosmanogepix, tolerated therapy well, and survived their deadly infections.

1. Introduction

Mucormycosis is a rare, highly aggressive fungal infection associated with limited treatment success with currently approved antifungal agents. Further, recommended treatments, including amphotericin and azole antifungals, have significant adverse effect profiles requiring frequent monitoring [1]. Despite appropriate antifungal therapy and aggressive surgical debridement, mortality rates remain alarmingly high, ranging from 30% to 70% and up to 90% in cases of disseminated disease [2].

Type 1 diabetes mellitus (T1DM), especially in severe diabetic ketoacidosis (DKA), is a predisposing risk factor for mucormycosis, although infections typically occur more frequently in adults than in children [3, 4]. Reported cases of mucormycosis in children associated with diabetes are relatively rare, with one report finding that children tend to be older and have established diabetes, though mucormycosis at diabetic diagnosis does occur [4]. Interestingly, some countries have seen an association with COVID‐19, termed COVID‐19‐associated mucormycosis [5], in pediatric patients with T1DM.

Fosmanogepix (FMGX) is an intravenously and orally available first‐in‐class investigational agent of the “gepix” class currently in Phase III development in adults with invasive fungal infections. FMGX inhibits the fungal enzyme glycosylphosphatidlyinositol (GPI)—anchored wall transfer protein 1 (Gwt1), causing a loss of cell wall viability [6]. Gwt1 is found in many fungal species, allowing FMGX to display broad‐spectrum activity [6]. However, it is highly selective for fungal Gwt1 and demonstrates no activity toward the human variation of this protein, resulting in a low potential of target‐based adverse drug reactions [6].

Phase I pharmacokinetic (PK) and pharmacodynamic (PD) studies performed in healthy adults indicate FMGX is a water‐soluble prodrug rapidly metabolized to manogepix (MGX) by alkaline phosphatases [6, 7]. It is over 90% orally bioavailable and widely distributed to tissues, including the central nervous system (CNS) [6, 7] FMGX has an elimination half‐life of 2 to 2.5 days and demonstrates linear pharmacokinetics [7]. Loading doses can lead to achievement of steady‐state concentration within 24 h while initiating treatment at maintenance doses achieves such concentrations after 7 to 14 days [7]. It appears to be renally and hepatically cleared with fecal and biliary elimination [7].

FMGX demonstrates in vitro activity against most clinically relevant Candida spp., Aspergillus spp., Fusarium spp., Scedosporium spp., and Lomentospora spp [8]. Efficacy is predicted by the ratio of the area under the concentration‐time curve to minimum inhibitory concentration (AUC/MIC) in yeasts and AUC to minimum effective concentration (AUC/MEC) in mold infections [9]. A pre‐clinical study investigated FMGX activity against two varieties of Rhizopus (i.e., arrhizus var. arrhizus and arrhizus var. delemar) in the lungs of immunosuppressed mice, finding increased survival time and prolonged overall survival compared to placebo [10]. Combining FMGX with liposomal amphotericin B (L‐AMB), again in murine pulmonary R. arrhizus var. delemar infection, was found to prolong survival from 6.5 days to over 21 days and overall survival increased from 5% to 70% when compared to placebo (p‐value < 0.0001) [11]. Currently, there is no published data on FMGX activity against Rhizopus in children. Here, we describe two pediatric patients successfully treated for rhinocerebral Rhizopus infection with regimens containing FMGX.

2. Case One

The first patient was a 15‐year‐old, 71‐kg, black male diagnosed with rhinocerebral mucormycosis during admission for DKA. Upon admission, blood glucose was 415 mg/dL and glycated hemoglobin (A1C) was 15.6%; the patient had a known history of poorly controlled T1DM that was initially diagnosed at 9 years of age. Past medical history was significant for well‐controlled asthma and a recent dental visit for tooth pain. The patient's chest X‐ray was normal while computed tomography scan (CT) and magnetic resonance imaging (MRI) indicated invasive sinusitis on the right side of his face. He was initiated on empiric L‐AMB, vancomycin, ceftazidime, and metronidazole. Rhizopus sp. grew in the right sinus abscess and cheek tissue culture. Susceptibility testing indicated MICs as follows: amphotericin B 0.125 mcg/mL, itraconazole 0.25 mcg/mL, micafungin > 8 mcg/mL, posaconazole 0.125 mcg/mL, and voriconazole 4 mcg/mL. Due to the difficulty treating this organism, the patient's immunocompromised state, and severity of sinusitis, empiric treatment was expanded to include posaconazole and micafungin. Bacterial cultures were positive for methicillin‐sensitive Staphylococcus aureus and S. epidermidis ; the patient was de‐escalated to appropriate antibiotics and completed 4 weeks of antibiotic therapy.

Hyperbaric oxygen was initiated to increase oxygenation and reduce fungal growth but discontinued after eight sessions due to patient intolerance. Additional symptoms of neurodegeneration during admission included lateral rectus palsy and hypoesthesia, but the patient remained alert and oriented and retained movement of all extremities.

Granulocyte macrophage‐colony stimulating factor (GM‐CSF) was added thrice weekly to increase the absolute neutrophil count. Multiple electrolyte disturbances were noted during treatment, including hyperphosphatemia, hypomagnesemia, and hypokalemia. Additionally, the patient's oral intake decreased; this was attributed to increased depression during his prolonged admission and contributed to difficulties in managing glycemic control and appropriate posaconazole concentrations throughout the hospital stay.

Due to lack of significant improvement, expanded access to FMGX was requested from Pfizer via WEP Clinical, the contract research organization that operationally manages the Expanded Access Program, and FMGX was obtained after 3 months secondary to logistical constraints. During this time, the patient remained stable on various antifungal regimens (Figure 1). Fungal susceptibility testing for FMGX indicated an MIC of 2 mcg/mL. Risks and benefits were discussed with the patient's family and FMGX 800 mg (11.6 mg/kg) daily was started orally. The recommended dosing strategy determined by WEP Clinical and Pfizer, who owned FMGX at that time, mirrored adult dosing considering the weight of the patient. Although loading doses are available for the intravenous formulation of FMGX, only oral medication was ordered and the patient started on the maintenance dose. Based on sponsor recommendations, clinical and electrocardiogram (EKG) monitoring was performed at baseline and days 3, 7, 14, 42, and end of therapy; the patient had no cardiac abnormalities for the duration of treatment. Throughout antifungal therapy and prior to FMGX initiation, renal function declined, likely due to L‐AMB, with an increase in serum creatinine (SCr) from 0.6 mg/dL at baseline to a peak of 4.04 mg/dL; urinary output remained stable. L‐AMB was tapered from 10 mg/kg daily in an effort to maintain the antifungal activity while reducing the nephrotoxic effects but ultimately was discontinued within a week of FMGX initiation. Subsequently, micafungin was discontinued to streamline therapy. Posaconazole was replaced by oral isavuconazole due to inability to consistently attain therapeutic posaconazole concentrations (range < 0.1 to 1 mcg/mL). FMGX was well‐tolerated by the patient.

FIGURE 1.

Treatment regimens for patient one.

The patient underwent six sinus debridements and a hemicraniectomy for intracranial abscess drainage. Cultures drawn on day 1 (right maxillary sinus) and day 11 (right cheek) grew Rhizopus species; no follow‐up cultures or histopathology detected organisms. After 5 months, the patient was discharged home to continue FMGX and isavuconazole. EKG, complete metabolic panels (CMP), and complete blood counts (CBC) were followed and remained normal for the duration of treatment, with the exception of SCr, for which he continues to be monitored. Although the FMGX duration was originally planned for 9 months, adherence waned during the 5th month and discontinued after 6 months. The patient was unable to provide rationale for discontinuing FMGX and denied difficulty tolerating it. He historically had trouble maintaining adherence to chronic medications. Isavuconazole was continued to complete 12 months of antifungal therapy. Over 2 years after antifungal discontinuation, the patient continues to do well with no signs or symptoms of relapsed infection. This marks the first known use of FMGX in an adolescent patient for rhinocerebral mucormycosis.

3. Case Two

Four days after being diagnosed with Streptococcal pharyngitis and COVID‐19 infections, an otherwise healthy 10‐year‐old, 55‐kg, white male presented to the emergency department with left‐sided facial swelling and Kussmaul respirations. Initial glucose was 345 mg/dL, A1C was 13.2%, and he was diagnosed with T1DM complicated by DKA. CT and MRI revealed left preseptal and orbital cellulitis, along with acute sinusitis extending toward the left inferior rectus and inferior oblique muscles. Bony erosion raised concern for a fungal infection, prompting initiation of empiric L‐AMB and micafungin. Posaconazole was initiated but switched to isavuconazole due to persistent prolonged QT interval (Figure 2). Shortly after their initiation, micafungin and posaconazole were briefly held due to acute liver failure attributed to acute infection versus medications. After resolution, the antifungals were restarted without adverse hepatic effects.

FIGURE 2.

Treatment regimens for patient two.

Tissue pathology was concerning for zygomycetes with angioinvasive features although sinus cultures never yielded growth. Rhizopus oryzae was ultimately identified via microbial cell‐free DNA testing and fungal polymerase chain reaction (PCR) from numerous tissues on his left side, including inferior and middle turbinates, frontal and maxillary sinus, left orbit, hard palate, cheek, and several others in his nasal, oral, and gingival mucosa. The infection progressed with MRI indicating worsening sinusitis, premaxillary abscesses, progressive hard palate necrosis, and a new abscess at the cerebellopontine angle cistern with deficits in cranial nerves V and VI, all contributing to the diagnosis of rhino‐orbital‐cerebral mucormycosis.

The patient underwent 11 procedures, including debridements, removal of the left cheek soft tissue, maxillary bone, hard palate, orbital floor, and two left upper incisors. He completed 20 sessions of hyperbaric oxygen therapy and received GM‐CSF every other day, although it was discontinued due to local injection reactions.

After 2 months, expanded‐access FMGX was obtained and added to L‐AMB, micafungin, and isavuconazole. The patient received a loading dose of 1000 mg (18.9 mg/kg) intravenously every 12 h for two doses, then transitioned to 800 mg (15.2 mg/kg) orally administered once daily as recommended by Basilea Pharmaceutica. CMP, CBC, and EKGs were closely monitored. He experienced intermittent nausea but did not require dosage or interval adjustment. Three weeks after FMGX was initiated, MRI indicated abscesses were decreasing in size. L‐AMB dose was tapered due to nephrotoxicity and discontinued after 4 months. Repeat MRIs continued to demonstrate decreases in size of the initial abscess, and micafungin was discontinued.

Two months after FMGX was initiated, histopathology from sinus debridement showed clear margins without fungal elements. The patient then underwent multiple reconstructive procedures, including maxillary reconstruction, revision of a left cheek free mucocutaneous flap, and full‐thickness skin grafting.

After a 5‐month admission and 3 months of FMGX therapy, the patient was discharged home on oral isavuconazole and FMGX. He continued both agents on an outpatient basis with frequent monitoring until he completed 11 months of antifungal therapy. One year later, he remains infection‐free.

4. Discussion

Mucormycosis is associated with high morbidity and mortality, particularly when involving the brain [1, 2]. This rare infection is caused by filamentous fungi, including Rhizopus species. It invades and rapidly destroys tissue due to its angioinvasive nature and often affects the nasal mucosa, sinuses, and brain [12]. Exposure occurs through inhalation of fungal spores in organic matter [12]. The infection predominantly impacts those with immunocompromise, although approximately 9% of patients have no identifiable underlying condition [12, 13]. T1DM can result in poor immune system function via impairment of innate and adaptive immunity [14]. Persistently elevated blood glucose can reduce the number of circulating dendritic cells, leading to an increase in neutrophil dysfunction and apoptosis of natural killer cells, and destruction of vascular tissues due to oxidative stress [14]. In nasal epithelial cells, glucose‐regulated protein 78 (GRP78) is the primary receptor utilized by Rhizopus for initial infection [15]. In patients with increased glucose levels, GRP78 is upregulated, increasing infection risk [15]. Therefore, multiple factors provide an ideal growth environment for these opportunistic organisms.

The treatment approach for mucormycosis typically involves a combination of antifungal therapy and aggressive surgical intervention [1, 16]. A combination therapeutic approach provides enhanced effects of the drugs and broader pathogen coverage compared to monotherapy. L‐AMB is often paired with other antifungals, such as echinocandins and/or triazoles [1, 17, 18]. Alongside antifungal therapy, aggressive surgical debridement is a critical aspect of mucormycosis management. Necrosis in affected tissues can limit the delivery of antifungal drugs, making the surgical removal of infected tissue essential for effective eradication. In patients with rhino‐orbital‐cerebral mucormycosis, surgical intervention has been shown to yield better outcomes and facilitate local control of the infection [19]. Hyperbaric oxygen therapy has also been linked with improved outcomes by enhancing the oxygenation of hypoxic tissues, improving the efficacy of both the immune response and antifungal therapy, reducing edema, and promoting wound healing [20]. However, mucormycosis morbidity and mortality rates remain high despite these multimodal treatment strategies and additional therapeutic options are needed.

Two case reports have been published describing the use of FMGX, one in an adolescent and one in an adult. The first case described FMGX use in a 14‐year‐old patient for long‐term cutaneous Fusarium infection [21]. The patient was immunocompromised secondary to STAT3 hyper‐immunoglobulin E syndrome. After several years of antifungal treatment, significant resistance had developed. Following 6 months of expanded access FMGX, the patient was able to achieve negative fungal cultures and histopathology. Although our patients were also immunocompromised young males with a difficult‐to‐treat mold, they differed in that they experienced an invasive infection with higher risks of morbidity and mortality. Another notable difference is the nausea and vomiting experienced by their patient, which necessitated a change in oral dosing from 800 mg once daily to 400 mg twice daily. Authors attributed this adverse effect to a lower weight (i.e., 50 kg) than one would expect in an adult patient. Conversely, our patients were able to tolerate the 800‐mg daily dose for the entire duration of therapy. At the time of FMGX initiation in our patients, the only oral dosing strategies were 800 mg daily or 400 mg twice daily regardless of age or weight. Administering FMGX with food does not affect efficacy but can reduce the risk for gastrointestinal effects most often noted with higher doses [7]. As FMGX administration is explored in additional ages and weights, it would be prudent to monitor whether lower‐weight patients experience more adverse effects and adjust dosing accordingly.

Another successful case with FMGX was described in a 40‐year‐old male status post hematopoietic stem cell transplant complicated by graft‐versus‐host disease [22]. He was noted to have disseminated Aspergillus calidoustus infection not responsive to traditional antifungal options; ultimately, his antifungal regimen included FMGX, L‐AMB, micafungin, terbinafine, and either voriconazole or isavuconazole. FMGX was obtained via emergency investigational new drug application with slightly different dosing than our patients, starting with an intravenous dose of 1 g every 12 h for two doses, then 600 mg infused over 3 h once daily. With clinical improvement, FMGX was changed to 400 mg orally twice daily. His other antifungal agents were de‐escalated by providers and self‐discontinued by the patient; at the time of publication, he continued tolerating FMGX monotherapy nearly a year later.

Adding FMGX was a turning point in treating our patients as well, although it is challenging to fully attribute treatment success to FMGX alone or to the synergistic effects of combined therapy. No data is currently available regarding the potential effects of using FMGX along with an azole or echinocandin. Each patient underwent extensive debridement, which provided a significant reduction in disease burden and allowed antifungal therapy to be better positioned to exert its activity. Of note, however, FMGX does distribute well to the CNS and could have provided significant antifungal effects where other agents could not. Additionally, adding FMGX allowed the care team to remove L‐AMB, which had caused significant nephrotoxicity in both patients.

Considering the use of FMGX in pediatric patients can be daunting in light of little available PK or PD information in this population. In considering FMGX, notable differences in adult and pediatric PK/PD factors must be recognized. A higher volume of distribution is likely in neonates, who have much higher total body water content, and may require a higher dosage [23]. Data regarding the extent of protein binding with FMGX has not yet been published; protein binding is decreased in younger populations and this impact must be considered [23]. Although the adverse effect profile of FMGX appears relatively benign, the gastrointestinal effects could be more significant. Renal and hepatic elimination may be immature in younger populations, which could alter clearance and perhaps necessitate an even longer dosing interval than once daily [23].

This report describes the first uses of FMGX in pediatric patients experiencing an invasive Rhizopus infection. Although FMGX is currently in Phase III development in adult patients, the use of expanded access FMGX with its novel mechanism of action and relative tolerability makes it an attractive consideration for patients with invasive fungal infections who have no other remaining treatment options. Dosing regimens for the pediatric population are currently provided by Basilea Pharmaceutica, the sponsor of FMGX, and are primarily based on body‐surface area which may provide an individualized option to ensure tolerability while maintaining efficacy.

Author Contributions

Misty M. Oldham: conceptualization, writing – original draft, writing – review and editing, supervision, formal analysis. Gwendolyn Buckendorf: writing – review and editing, writing – original draft. Islam Elmitwalli: writing – review and editing, writing – original draft. David P. Sparling: writing – original draft, writing – review and editing. Donna L. Tyungu: writing – original draft, writing – review and editing, conceptualization, supervision, formal analysis.

Funding

The authors have nothing to report.

Disclosure

AI use: No AI tools were used in the drafting of this manuscript, tables, or figures.

Conflicts of Interest

The authors declare no conflicts of interest.

Oldham M. M., Buckendorf G., Elmitwalli I., Sparling D. P., and Tyungu D. L., “Use of Expanded Access Fosmanogepix in Two Pediatric Patients With Rhino‐Orbital‐Cerebral Mucormycosis,” Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 46, no. 9 (2026): e70195, 10.1002/phar.70195.

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.