Amphotericin B Formulations Research Articles

Formulation of Amphotericin B in PEGylated Liposomes for Improved Treatment of Cutaneous Leishmaniasis by Parenteral and Oral Routes.

Liposomal amphotericin B (AmB) or AmBisome® is the most effective and safe therapeutic agent for visceral leishmaniasis (VL), but its clinical efficacy is limited in cutaneous leishmaniasis (CL) and HIV/VL co-infection. The aim of this work was to develop a formulation of AmB in PEGylated liposomes and compare its efficacy to AmBisome® in a murine model of CL. Formulations of AmB in conventional and PEGylated liposomes were characterized for particle size and morphology, drug encapsulation efficiency and aggregation state. Those were compared to AmBisome® in Leishmania amazonensis-infected BALB/c mice for their effects on the lesion size growth and parasite load. The conventional and PEGylated formulations showed vesicles with 100–130 nm diameter and low polydispersity, incorporating more than 95% of AmB under the non-aggregated form. Following parenteral administration in the murine model of CL, the PEGylated formulation of AmB significantly reduced the lesion size growth and parasite load, in comparison to control groups, in contrast to conventional liposomal AmB. The PEGylated formulation of AmB was also effective when given by oral route on a 2-day regimen. This work reports for the first time that PEGylated liposomal AmB can improve the treatment of experimental cutaneous leishmaniasis by both parenteral and oral routes.

Pharmacokinetic study of AmB-NP-GR: A new granule form with amphotericin B to treat leishmaniasis and fungal infections

Amphotericin B (AmB) has been the gold standard to treat systemic fungal infections. The use of AmB is restricted to hospitals because it poses several risks, mainly risks related to its high nephrotoxicity. Given the importance of this drug in medicine, new therapeutics and AmB formulations with nanotechnological improvements are required and could bring many benefits to patients. A new drug formulation with gastro-resistant coated granules has been proposed. The lipid-based system containing AmB was produced and used as raw material in the granulation/coated process. The new developed formulation (AmB-NP-GR) was characterized by optical microscopy, granulometry, and atomic force microscopy (AFM) after disintegration test. AmB-NP-GR showed granular shape, with most granules measured between 250 and 500 µm (37 ± 7% w/w). The AFM images indicated that the granule formulation should disintegrate in the intestine, to release the lipid-based carriers, making them available for absorption and allowing them to reach the blood circulation. The developed formulation was administered to rats in a single dose of 4.0 or 8.0 mg kg−1 and the pharmacokinetics was studied. The samples were analyzed by liquid chromatography coupled to mass spectrometry. Before the pharmacokinetic studies were conducted, the bioanalytical method was validated according to the EMA guideline and all evaluated parameters agreed with this guideline. The pharmacokinetic results showed that Cmax was similar for both doses and that tmax was reached at 4−12 h for dose of 4.0 mg kg−1 and 4 h for dose of 8.0 mg kg−1. The half-life related to the dose of 8.0 mg kg−1 increased significantly compared to the dose of 4.0 mg kg−1 (an increase of more than 3 times). In addition, the mean residence time related to the dose of 8.0 mg kg−1 was 4 times higher than for the lower dose. The clearance value showed to be higher for the lower dose. Together, these results provide important conclusions for experimental design of other in vivo safety and efficacy studies of AmB-NP-GR.

Self-assembling, supramolecular chemistry and pharmacology of amphotericin B: Poly-aggregates, oligomers and monomers

Antifungal drugs such as amphotericin B (AmB) interact with lipids and phospholipids located on fungal cell membranes to disrupt them and create pores, leading to cell apoptosis and therefore efficacy. At the same time, the interaction can also take place with cell components from mammalian cells, leading to toxicity. AmB was selected as a model antifungal drug due to the complexity of its supramolecular chemical structure which can self-assemble in three different aggregation states in aqueous media: monomer, oligomer (also known as dimer) and poly-aggregate. The interplay between AmB self-assembly and its efficacy or toxicity against fungal or mammalian cells is not yet fully understood. To the best of our knowledge, this is the first report that investigates the role of excipients in the supramolecular chemistry of AmB and the impact on its biological activity and toxicity. The monomeric state was obtained by complexation with cyclodextrins resulting in the most toxic state, which was attributed to the greater production of highly reactive oxygen species upon disruption of mammalian cell membranes, a less specific mechanism of action compared to the binding to the ergosterol located in fungal cell membranes. The interaction between AmB and sodium deoxycholate resulted in the oligomeric and poly-aggregated forms which bound more selectively to the ergosterol of fungal cell membranes. NMR combined with XRD studies elucidated the interaction between drug and excipient to achieve the AmB aggregation states, and ultimately, their diffusivity across membranes. A linear correlation between particle size and the efficacy/toxicity ratio was established allowing to modulate the biological effect of the drug and hence, to improve pharmacological regimens. However, particle size is not the only factor modulating the biological response but also the equilibrium of each state which dictates the fraction of free monomeric form available. Tuning the aggregation state of AmB formulations is a promising strategy to trigger a more selective response against fungal cells and to reduce the toxicity in mammalian cells.

Liposomal Amphotericin-B in Saline Shows Promising Efficacy against Candida auris compared to Azoles, Echinocandins and Other Amphotericin-B Formulations in Dextrose and Deoxycholate Suspension

Fungal infection caused by <em>Candida auris</em> is now a global crisis. Its multidrug-resistant nature and onerous identification have left limited therapeutic options resulting in 30-60% mortality. Amphotericin-B (AmB) being potent fungicidal, broad-spectrum and rare resistance, is considered gold-standard antifungal drug. Yet, its antifungal potential is not fully recognized and realized under the pretext of its potential nephrotoxicity.

Mucormycosis in Indian COVID-19 Patients: Insight into Its Patho-Genesis, Clinical Manifestation, and Management Strategies.

Mucormycosis in patients who have COVID-19 or who are otherwise immunocompromised has become a global problem, causing significant morbidity and mortality. Infection is debilitating and fatal, leading to loss of organs and emotional trauma. Radiographic manifestations are not specific, but diagnosis can be made through microscopic examination of materials collected from necrotic lesions. Treatment requires multidisciplinary expertise, as the fungus enters through the eyes and nose and may even reach the brain. Use of the many antifungal drugs available is limited by considerations of resistance and toxicity, but nanoparticles can overcome such limitations by reducing toxicity and increasing bioavailability. The lipid formulation of amphotericin-B (liposomal Am-B) is the first-line treatment for mucormycosis in COVID-19 patients, but its high cost and low availability have prompted a shift toward surgery, so that surgical debridement to remove all necrotic lesions remains the hallmark of effective treatment of mucormycosis in COVID-19. This review highlights the pathogenesis, clinical manifestation, and management of mucormycosis in patients who have COVID-19.

Amphotericin B nanohydrogel ocular formulation using alkyl glyceryl hyaluronic acid: Formulation, characterization, and in vitro evaluation

The present study focused on the development of an amphotericin B (AmB) nanoformulation for ophthalmic applications. Accordingly, AmB nanohydrogels (AHA/AmB) using alkyl glyceryl hyaluronic acid (Hyalorepair®, AHA), a hydrophobized hyaluronic acid, were prepared by employing the dialysis method, followed by assessments of physical properties, drug efficacy, and toxicity. In the AHA/AmB formulation, AmB existed in a self-aggregated and amorphous state in the hydrophobic environment of the AHA moiety. AHA/AmB was shown in vitro to interact with mucin, which is known to be expressed in the corneal epithelium and was expected to improve its corneal retention. Compared with the conventional AmB formulation, amphotericin B sodium deoxycholate, AHA/AmB had the same in vitro antifungal activity but significantly lower in vitro toxicity. These findings indicate that nanohydrogels prepared with AHA possess high fungal selectivity and serve as a promising system for ophthalmic AmB delivery.

Enabling Oral Amphotericin B Delivery by Merging the Benefits of Prodrug Approach and Nanocarrier-Mediated Drug Delivery.

Amphotericin B (AmB) is gold standard therapy for leishmaniasis and fungal infections. Considering the global disease burden, nearly 90% of cases occur in economically vulnerable countries, making the cost of AmB therapy a critical healthcare challenge in controlling disease burden. All currently marketed AmB products are administered through an intravenous (i.v.) route and involve high treatment costs. Designing an orally effective AmB formulation can substantially reduce the cost of therapy and improve patient compliance. However, it is a challenging task because of the distinctive physicochemical properties of AmB. Previously, we developed a lipid-based prodrug of AmB, AmB-oleyl conjugate (AmB-OA), which showcased remarkable stability in the gastrointestinal (GI) environment and improved intestinal permeation. Hereby, we have developed self-nanoemulsifiying drug delivery system (SNEDDS) of AmB-OA to further enhance the oral bioavailability of AmB and potentiate its therapeutic benefits. SNEDDS was developed by screening a wide range of oils, surfactants, and cosurfactants, and formulation composition was optimized using extreme vertices design. AmB-OA SNEDDS possessed the ability of quick self-nanoemulsification on dilution (droplet size ∼56 nm) along with remarkable stability in the GI environment. Accelerated stability (40 °C/75% relative humidity) studies and freeze-thaw cycling studies proved that the formulation was stable at tropical conditions as well as temperature cycling stress. Drug transport analysis in Caco-2 cells revealed a remarkable increase in drug transport for AmB-OA SNEDDS compared to AmB along with minimal cellular toxicities. AmB-OA SNEDDS showcased ∼8.9-fold higher AUCTot than AmB in in vivo pharmacokinetic study, proving the effectiveness of formulation to enhance oral bioavailability. In vivo toxicity analysis highlighted the ameliorated toxicity risk associated with SNEDDS formulation. Therefore, the AmB-OA SNEDDS formulation may provide a cost-friendly and effective strategy to resolve the oral AmB drug delivery challenge.

149. Efficacy of Cochleated Amphotericin B (CAMB) in Mouse and Human Mucocutaneous Candidiasis

Background Candida albicans causes debilitating mucosal infections in patients with inherited susceptibility to chronic mucocutaneous candidiasis (CMC), often requiring long-term azole-based treatment. Due to increasing azole resistance, alternative treatments are desirable. Acquired resistance to amphotericin B (AMB) is rare but AMB use is limited by parenteral administration and nephrotoxicity. Cochleated AMB (CAMB) is a new oral formulation of AMB and thus an attractive option for oropharyngeal candidiasis (OPC), esophageal candidiasis (EC) and vulvovaginal candidiasis (VVC). We assessed the efficacy of CAMB in mouse models of OPC and VVC and in 4 patients with azole resistant CMC manifesting as OPC, EC or VVC.Methods Act1 -/- mice were infected with C. albicans in models of OPC and VVC and were treated once daily via oral gavage with CAMB or vehicle or intraperitoneal AMB-deoxycholate (AMBd) from day 1 through 4 post-infection (pi). At day 5 pi, the tongue or vaginal tissue was harvested to quantify fungal burden. Patients with azole resistant CMC enrolled in a phase 2A CAMB dose escalation study. The primary endpoint was clinical improvement at 2 weeks based on an efficacy scale, followed by optional extension for long-term suppression of CMC to assess safety and efficacy.ResultsCAMB-treated mice had significantly reduced tongue and vaginal tissue fungal burden compared to vehicle-treated mice, while they exhibited comparable fungal control relative to AMBd-treated mice. Among 4 CAMB-treated patients, 3 reached clinical efficacy by 2 weeks at a dose of 400 mg twice daily and one reached clinical efficacy at 200 mg twice daily. Three of 4 patients continued on the extension phase past 48 months with sustained clinical improvement of OPC and EC; patient #3 had relapse of esophageal symptoms at week 24 and was withdrawn from further study. Clinical response was not seen for onychomycosis or VVC. CAMB was safe and well-tolerated without renal toxicity.ConclusionOral administration of CAMB in IL-17-signaling deficient mice resulted in reduced tongue and vaginal tissue fungal burden during mucosal C. albicans infections. A proof-of-concept clinical trial in humans with inherited CMC showed efficacy in OPC and EC with good tolerability and safety.DisclosuresBenjamin Colton, PharmD, Merck (Shareholder)Pfizer (Shareholder) Ruying Lu, n/a, Matinas BioPharma Inc. (Employee)Matinas BioPharma Inc. (Employee, Shareholder) Theresa Matkovits, PhD, Matinas BioPharma (Employee, Shareholder) Raphael J. Mannino, n/a, Matinas BioPharma Inc. (Employee, Shareholder) Michail Lionakis, MD, ScD, Matinas BioPharma (Research Grant or Support)

Amphotericin B induces epithelial voltage responses in people with cystic fibrosis

BackgroundApproximately 10% of people with cystic fibrosis (CF) have mutations that result in little to no CFTR production and thus cannot benefit from CFTR modulators. We previously found that Amphotericin B (AmB), a small molecule that forms anion channels, restored HCO3− secretion and increased host defenses in primary cultures of CF airway epithelia. Further, AmB increased ASL pH in CFTR-null pigs, suggesting an alternative CFTR-independent approach to achieve gain-of-function. However, it remains unclear whether this approach can be effective in people. MethodsTo determine whether AmB can impact physiology in people with CF, we first tested whether Fungizone, a clinically approved AmB formulation, could cause electrophysiological effects consistent with anion secretion in primary cultures of CF airway epithelia. We then evaluated the capacity of AmB to change nasal potential difference (NPD), a key clinical biomarker, in people with CF not on CFTR modulators. ResultsAmB increased transepithelial Cl− current and hyperpolarized calculated transepithelial voltage in primary cultures of CF airway epithelia from people with two nonsense mutations. In eight people with CF not on CFTR modulators, intranasal Fungizone treatment caused a statistically significant change in NPD. This change was similar in direction and magnitude to the effect of ivacaftor in people with a G551D mutation. ConclusionsOur results provide the first evidence that AmB can impact a clinical biomarker in people with CF. These results encourage additional clinical studies in people with CF to determine whether small molecule anion channels can provide benefit.

Development of an amphotericin B micellar formulation using cholesterol-conjugated styrene-maleic acid copolymer for enhancement of blood circulation and antifungal selectivity.

Amphotericin B (AmB) is an effective antifungal agent for life-threatening systemic fungal infections. However, its poor solubility in water and organic solvents makes it difficult to formulate. We previously reported AmB-encapsulated micellar formations using styrene-maleic acid copolymer (SMA) and butylated SMA. These micelles make AmB water-soluble; however, the blood circulation of AmB by these intravenous administrations was as low as that of Fungizone®, a conventional micellar formulation of AmB. The destabilization of SMA micelles by salt in the blood has been suggested to be a cause of low blood circulation. Therefore, in this study, to reduce salt-induced instability and increase blood circulation of the micelles, we covalently attached cholesterol molecules to the SMA backbone because AmB interacts with sterols. This AmB nanoparticle micellar formulation (Cho-SMA/AmB micelles) was water-soluble, stable in the presence of salts, and formed a complex with albumin. Compared with Fungizone®, this formulation had equal antifungal activity and markedly improved blood circulation and lower toxicity. Its toxicity was further reduced in the presence of albumin. Taken together, our results indicate that Cho-SMA/AmB micelles could be an intravenous formulation with high antifungal selectivity, and drug interactants-conjugated SMA system could be applied to a variety of drug-loaded nanomicellar systems.

Safety, Tolerability, and Pharmacokinetics of a Novel Oral Amphotericin B Formulation (iCo-019) following Single-Dose Administration to Healthy Human Subjects: an Alternative Approach to Parenteral Amphotericin B Administration.

This study evaluated the safety, tolerability, and pharmacokinetics of a novel oral amphotericin B (AmB) formulation (iCo-019) following single doses to healthy humans. The data from this study suggest that iCo-019 has a long circulation time and systemic exposure without the associated gastrointestinal, liver, and kidney toxicity associated with AmB. This novel oral AmB formulation can serve as a new treatment strategy to overcome the limitations of the use of parenterally administered AmB products.

Encochleated Amphotericin B: Is the Oral Availability of Amphotericin B Finally Reached?

As the oldest and for many decades the only available agent for the treatment of life-threatening invasive fungal diseases, amphotericin B (AmB) is known for its broad-spectrum fungicidal activity against a wide range of yeasts and molds. However, the main drawback of the present formulations remains its toxicity, the limited use to intravenous administration, and the higher costs associated with the better tolerated lipid formulations. The novel nanoparticle-based encochleated AmB (CAmB) formulation encapsulates, protects, and delivers its cargo molecule AmB in the interior of a calcium-phospholipid anhydrous crystal. Protecting AmB from harsh environmental conditions and gastrointestinal degradation, CAmB offers oral availability in conjunction with reduced toxicity. Matinas BioPharma, Bedminster, NJ is on the way to develop CAmB named MAT2203, currently undergoing Phase II clinical trials.

In Vitro and In Vivo Study of Amphotericin B Formulation with Quaternized Bioreducible Lipidoids

Invasive fungal infections are well-known causes of morbidity and mortality in immunocompromised patients. Amphotericin B (AmB) is a polyene fungicidal agent with excellent properties of the broad antifungal spectrum, high activity, and relatively rare drug resistance. However, significant toxicities limit the clinical application of AmB and its conventional formulation AmB deoxycholate (Fungizone). Here we investigated nanoparticle formulations of AmB using synthetic biodegradable lipidoids and evaluated their stability, in vitro antifungal efficacy, and in vivo toxicity and pharmacokinetics. We found that the AmB formulated using a mixture of quaternized lipidoid (Q78-O14B) and DSPE-PEG2000 has the size around 70-100 nm and is stable during storage. The formulation showed no hemotoxicity to red blood cells (RBCs) in vitro. It also possesses the highest antifungal activity (in vitro) and lowest toxicity (both in vitro and in vivo). These metrics are significantly superior to the commercial antifungal product Fungizone. Meanwhile, AmB/Q78-O14B-P exhibited prolonged blood circulation in comparison to Fungizone in vivo. In AmB/Q78-O14B-P formulation, AmB was still detectable in the liver, spleen, and lung tissues with a concentration above the minimum inhibitory concentrations 72 h after low-dose intravenous injection. Based on these results, AmB in lipidoid nanoparticle formulation may produce sustained antifungal activity against blood-borne and systemic organ infections. Moreover, the new AmB formulation showed low nephrotoxicity and hepatotoxicity in rats even at high doses, allowing a dramatically wider and safer therapeutic window than Fungizone. This method provides a means to develop much needed antifungal agents that will be more therapeutically efficacious, more affordable (than AmBisome), and less toxic (than Fungizone) for the treatment of systemic fungal infections.

Synthesis and evaluation of styrene-maleic acid copolymer conjugated amphotericin B.

Amphotericin B (AmB), which plays a central role in the treatment of systemic fungal infections, is difficult to formulate because it's sparingly soluble in water and organic solvents. We previously prepared AmB-loaded micelles using styrene-maleic acid copolymer (SMA). Although solubilization was achieved by this formulation, stability in the blood circulation was as insufficient as that of Fungizone®, which is a conventional formulation of AmB. Meanwhile, it is well known that polymer-drug conjugates are more stable in circulation than drug-loaded micelles. Therefore, in this study, we developed covalently conjugated SMA-AmB (SMA-AmB conjugate). The SMA-AmB conjugate was found to be soluble and present as micelles in aqueous solution. Furthermore, it was revealed that this micelle behaves as a larger molecule by forming a complex with albumin. The circulation in the blood increased significantly compared to that of Fungizone®, which was suggested to be due to this complex-forming ability. Although in vitro and in vivo antifungal activity of the SMA-AmB conjugate against Saccharomyces cerevisiae was reduced by 1/3 compared to that of Fungizone®, hemolysis decreased to 1/40 or less, and the LD50 decreased to 1/10. In conclusion, it is expected that the SMA-AmB conjugate can be a polymer-therapeutic agent with high antifungal selectivity.

Synergistic antifungal interactions of amphotericin B with 4-(5-methyl-1,3,4-thiadiazole-2-yl) benzene-1,3-diol

Amphotericin B (AmB) is a very potent antifungal drug with very rare resistance among clinical isolates. Treatment with the AmB formulations available currently is associated with severe side effects. A promising strategy to minimize the toxicity of AmB is reducing its dose by combination therapy with other antifungals, showing synergistic interactions. Therefore, substances that display synergistic interactions with AmB are still being searched for. Screening tests carried out on several dozen of synthetic 1,3,4-thiadiazole derivatives allowed selection of a compound called 4-(5-methyl-1,3,4-thiadiazole-2-yl) benzene-1,3-diol (abbreviated as C1), which shows strong synergistic interaction with AmB and low toxicity towards human cells. The aim of the present study was to investigate the type of in vitro antifungal interactions of the C1 compound with AmB against fungal clinical isolates differing in susceptibility. The results presented in the present paper indicate that the C1 derivative shows strong synergistic interaction with AmB, which allows the use of a dozen to several dozen times lower AmB concentration necessary for 100% inhibition of the growth of pathogenic fungi in vitro. Synergistic interactions were noted for all tested strains, including strains with reduced sensitivity to AmB and azole-resistant isolates. These observations give hope for the possibility of application of the AmB - C1 combinatory therapy in the treatment of fungal infections.

Nanoemulsions Loaded with Amphotericin B: Development, Characterization and Leishmanicidal Activity.

Leishmaniasis is one of the most neglected diseases in the world. Its most severe clinical form, called visceral, if left untreated, can be fatal. Conventional therapy is based on the use of pentavalent antimonials and includes amphotericin B (AmB) as a second-choice drug. The micellar formulation of AmB, although effective, is associated with acute and chronic toxicity. Commercially-available lipid formulations emerged to overcome such drawbacks, but their high cost limits their widespread use. Drug delivery systems such as nanoemulsions (NE) have proven ability to solubilize hydrophobic compounds, improve absorption and bioavailability, increase efficacy and reduce toxicity of encapsulated drugs. NE become even more attractive because they are inexpensive and easy to prepare. The aim of this work was to incorporate AmB in NE prepared by sonicating a mixture of surfactants, Kolliphor® HS15 (KHS15) and Brij® 52, and an oil, isopropyl myristate. NE exhibited neutral pH, conductivity values consistent with oil in water systems, spherical structures with negative Zeta potential value, monomodal size distribution and average diameter of drug-containing droplets ranging from 33 to 132 nm. AmB did not modify the thermal behavior of the system, likely due to its dispersion in the internal phase. Statistically similar antileishmanial activity of AmB-loaded NE to that of AmB micellar formulation suggests further exploring them in terms of toxicity and effectiveness against amastigotes, with the aim of offering an alternative to treat visceral leishmaniasis.

O desafio de novas vias de administração para Anfotericina B

Leishmaniasis represents a group of diseases with a great clinical and epidemiological diversity, it is classified in two main forms: cutaneous and visceral. A prevalence of 12 million cases is estimated worldwide and this number continues to increase, with 1.5 to 2 million new cases per year, especially in tropical and subtropical areas. Amphotericin B (AmB) is a poorly water-soluble drug and poorly absorbed in the gastrointestinal tract. It is used in first-line treatment for invasive fungal infections and is the most potent commercially available leishmaniasis drug. All drug formulations available are administered parenterally, which hampers their viability at remote sites. In addition, the conventional formulation of AmB shows high nephrotoxicity. The lipid formulation have less side effect, but have the same efficacy. Because of this, there is a growing search for new formulations of AmB, with emphasis on intravenous cationic liposomal formulations and lipid nanoformulations, such as oral self-emulsifying delivery systems. Some of these oral formulations are already in clinical trials, being a hope in the treatment of fungal diseases and leshimaniasis.

Leishmanicidal effects of amphotericin B in combination with selenium loaded on niosome against Leishmania tropica.

The strategy for improving the treatment of leishmaniasis by the World Health Organization, is the development of new drugs and combination therapy. The aim of this survey was to investigate the effect of amphotericin B (AmB) in combination with selenium, in a simple or niosomal form, on Leishmania tropica (L. tropica) by in vitro advanced assays. In this study, a niosomal formulation of AmB with selenium was prepared and characterized based on size and morphology. Using MTT assay, macrophage model, flow cytometry, and qPCR, the cytotoxicity and efficiency of the niosomal formulation and simple form of combination were evaluated. No toxicity was reported for both the niosomal and simple form of the combination. The niosomal formulation significantly showed higher inhibitory effect on the promastigote and amastigote forms of L. tropica than simple combination form. Interleukin (IL)-10 significantly decreased while the level of IL-12 and metacasoase as Th-1 activator significantly increased (P < 0.001). The findings of this study indicated that niosomes are the stable carriers for this combination, easy to produce and provide promising results as an effective formulation in the inhibition of extracellular and intracellular forms of L. tropica in compared with simple combination form.

1413. A Phase IIa Efficacy, Safety, Tolerability and Pharmacokinetic (PK) Study of Encochleated Amphotericin B in Patients with Mucocutaneous (Esophogeal, Oropharyngeal, Vulvovaginal) Candidiasis Who are Refractory or Intolerant to Standard Non-Intravenous Therapies

BackgroundCurrent oral therapeutic options for chronic mucocutaneous candidiasis (CMC) are often associated with resistance and toxicity. Amphotericin B (AMB) has broad fungicidal activity and markedly resists emergence of resistance but requires parenteral administration and monitoring for significant nephrotoxicity, which worsens with chronic treatment. Encochleated amphotericin B (CAMB) is a novel oral formulation of AMB. In animal models, CAMB demonstrates antifungal activity with similar efficacy as intraperitoneal AMB deoxycholate, but without the associated toxicity. This on-going patient volunteer study assesses the efficacy, safety, tolerability and PK of CAMB in patients with CMC who are refractory or intolerant to standard oral azole antifungals.MethodsFour patients have completed the clinical protocol treatment period: 3 patients with STAT3 deficient Hyper IgE syndrome and CMC, and one patient with chronic esophageal candidiasis. Eligible patients were dose escalated (Figure 1), with option of enrolling in an extension phase. Serial plasma PK samples were collected over 24 hours over the study period, with data available from two patients (Figure 2). ResultsCAMB was well tolerated by all four patients, and all are currently on the extension phase (Figure 3). There was significant improvement in clinical severity symptom scores of esophageal and oropharyngeal symptoms; CAMB01 achieved reduction in clinical symptoms by 57% (800 mg/day), CAMB02 by 85% (400 mg/day), CAMB03 50% (800 mg/day) and CAMB04 50% (800 mg/day). CAMB02 maintained higher plasma PK exposure throughout the study compared with CAMB01, a possible explanation for clinical response at a lower 400 mg/day dose. Reported adverse events were grade 1, mostly nausea and dizziness. There were no signs of liver, kidney or hematologic toxicity in any of the patients, with CAMB01 and CAMB02 receiving study drug for ~1 year.ConclusionCAMB was well tolerated in patient volunteers with long-standing symptomatic azole-resistant CMC. All four patients have met the primary endpoint of achieving 3 50% clinical response. CAMB is a promising oral therapy for patients with history of CMC, with potential use in treatment and prophylaxis of invasive fungal infections.Disclosures M. Lionakis, Matinas BioPharma Inc: Research Support, Research support. R. Lu, Matinas BioPharma Inc: Employee and Shareholder, Salary. R. Mannino, Matinas BioPharma Inc: Employee and Shareholder, Salary.

Systematic review and network meta-analysis of clinical outcomes associated with isavuconazole versus relevant comparators for patients with invasive aspergillosis

Objectives: Voriconazole, amphotericin B (AmB) formulations, and isavuconazole are all included in guideline recommendations for treatment of patients with invasive aspergillosis (IA) but the relative efficacy of isavuconazole versus AmB formulations has not been directly compared. We aimed to estimate the relative efficacy of isavuconazole compared with AmB deoxycholate (AmB-D), liposomal AmB (L-AmB), and voriconazole for the treatment of patients with proven/probable IA.Methods: Nine literature databases were screened for randomized controlled trials comparing treatments with any of voriconazole, AmB-D, L-AmB and isavuconazole for treatment of proven/probable IA. Articles meeting the criteria were included in a meta-analysis to determine the efficacy of AmB-D, L-AmB and voriconazole relative to isavuconazole based on all-cause mortality (ACM) and overall response using a fixed-effects model.Results: Four articles were identified that compared L-AmB with AmB-D (Study 1), standard-dose L-AmB (3–5 mg/kg/day) with high-dose L-AmB (10 mg/kg/day; Study 2), voriconazole with AmB-D (Study 3), and isavuconazole with voriconazole (Study 4). In the network meta-analysis, isavuconazole was statistically superior to AmB-D on both ACM (odds ratio [95% credible intervals] shown as natural log, 1.00 [0.26, 1.74]) and overall response (−1.39 [−2.21, −0.63]). Differences between isavuconazole, and standard-dose L-AmB, high-dose L-AmB and voriconazole were not statistically significant for either ACM (0.18 [−1.17, 1.53], 0.50 [−1.11, 2.13] and 0.32 [−0.19, 0.84], respectively) or overall response (−0.99 [−2.21, 0.29], −0.89 [−2.41, 0.65] and 0.06 [−0.43, 0.57], respectively).Conclusions: This data suggests that the efficacy of isavuconazole for treatment of IA is superior to AmB-D and comparable with both L-AmB and voriconazole.