BSG-005: A Novel Polyene Macrolide Antifungal Agent – Development and Therapeutic Potential

1. Executive Summary

BSG-005 (DrugBank ID: DB18014) is an investigational small molecule antifungal agent, specifically identified as a novel, chemically modified nystatin-like polyene macrolide. This agent is under development by Biosergen, originating from foundational research conducted at the Norwegian University of Science and Technology (NTNU) and SINTEF.[1] BSG-005 exhibits broad-spectrum fungicidal activity, achieved by binding to ergosterol in the fungal cell membrane, which leads to pore formation, disruption of membrane integrity, and subsequent cell death. Preclinical investigations have highlighted its potent activity against a diverse range of fungal pathogens, including strains resistant to existing antifungal classes.[3]

A primary differentiating characteristic of BSG-005 is its potentially superior safety profile, particularly concerning nephrotoxicity, when compared to established polyenes such as Amphotericin B. This improved safety has been suggested by preclinical data and further supported by initial findings from Phase 1a clinical trials in healthy volunteers.[3]

Currently, BSG-005 has completed Phase 1a studies and is progressing through Phase 1b clinical development (NCT06678113) for the treatment of invasive fungal infections (IFI). Interim data from this Phase 1b study indicate clinical benefit and good tolerability in critically ill patients. Biosergen is also exploring innovative formulations, including BSG005 Nano Lung and BSG005 Nano Oral, to potentially broaden its therapeutic applications.[3] BSG-005 has received Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) for the treatment of invasive aspergillosis.[3] Collectively, these attributes position BSG-005 as a promising next-generation polyene antifungal with the potential to address significant unmet medical needs in the management of severe and life-threatening IFIs. The strategic development of BSG-005, from its bioengineered origins to the pursuit of novel formulations and orphan drug status, reflects a concerted effort to deliver a "best-in-class" polyene. This approach aims to retain the potent, broad-spectrum fungicidal action characteristic of polyenes while mitigating their well-documented systemic toxicities, particularly kidney damage.[2]

2. Introduction to BSG-005

2.1. Identification and Classification

BSG-005 is cataloged in the DrugBank database under the accession number DB18014 and is classified as a Small Molecule.[1] Chemically, BSG-005 belongs to the polyene macrolide class of antifungal agents. It is specifically described as a novel, chemically modified derivative of nystatin, often referred to as a "nystatin-like molecule".[2] Polyene macrolides are characterized by a large macrolide ring structure containing multiple conjugated double bonds and typically a D-mycosamine sugar moiety. Their antifungal activity is primarily mediated through interaction with ergosterol, a key sterol component of fungal cell membranes. The development of BSG-005 from a nystatin backbone, through genetic engineering and subsequent chemical modifications, is aimed at optimizing its therapeutic index by enhancing efficacy and/or reducing toxicity associated with older polyenes.

2.2. Origin and Development

The foundational research leading to the discovery of BSG-005 spans two decades and was conducted at the Norwegian University of Science and Technology (NTNU) in Trondheim, Norway, in collaboration with SINTEF Materials and Chemistry, a prominent Scandinavian research organization. This initial work received funding from the Research Council of Norway.[3] The clinical development of BSG-005 is currently being advanced by Biosergen AS, a clinical-stage biotechnology company focused on addressing life-threatening fungal infections.[3]

The initial discovery of BSG-005 involved the genetic engineering of Streptomyces noursei, the bacterium responsible for the natural production of nystatin A1. This bioengineering strategy was employed to generate a library of novel polyene antifungal compounds, from which BSG-005 was selected for its promising characteristics.[2] This hybrid approach, combining biosynthetic engineering to create a novel polyene scaffold with subsequent chemical modifications, was aimed at optimizing the molecule's properties.[2] The goal was to retain or enhance antifungal potency while mitigating the toxicities associated with the parent compound, nystatin.[2]

2.3. Chemical Structure and Properties

BSG-005 is consistently described as a "chemically modified nystatin-like molecule".[2] While detailed structural elucidation is not fully provided in the available documents, some key features differentiate it from nystatin and other analogues. One source, comparing BSG005 (referred to as compound 3 in that specific study) with another nystatin analogue, S44HP, indicates that BSG-005 possesses a methyl group at the C-16 position (S44HP has a carboxyl group at this position) and a hydroxyl group at the C-10 position. These specific structural modifications have been shown to influence antifungal activity, particularly when further N-substitutions are made on the mycosamine sugar.[8]

A unique CAS number for BSG-005 is not explicitly stated in the documents focused on this compound. The DrugBank entry DB18014 also does not list a CAS number at present.[1] Other CAS numbers identified in the broader search pertain to different compounds: 1400-61-9 is the CAS number for nystatin [15], and 1858206-58-2 corresponds to Edralbrutinib [17], confirming that BSG-005 is a distinct chemical entity. The absence of a widely disseminated CAS number for BSG-005 at this stage of development might indicate that its precise chemical structure remains proprietary or is pending comprehensive cataloging in public chemical databases.

3. Pharmacology of BSG-005

3.1. Mechanism of Action

BSG-005 is classified as a polyene macrolide antifungal agent.[3] Its primary mode of action is fungicidal, meaning it directly kills fungal cells, as opposed to fungistatic agents which merely inhibit their growth. This cidal activity is considered an advantage, particularly in terms of reducing the potential for the development of antifungal resistance.[3]

The molecular mechanism of BSG-005 is consistent with that of other polyenes, such as Amphotericin B and its parent molecule, nystatin. It selectively targets the fungal cell membrane by binding with high affinity to ergosterol, a sterol unique to fungal cell membranes and essential for their structural integrity and fluidity. Upon binding to ergosterol, BSG-005 molecules aggregate and insert into the membrane, forming transmembrane pores or ion channels.[5] This pore formation disrupts the osmotic integrity of the fungal cell membrane, leading to the leakage of essential intracellular components, particularly potassium ions, and ultimately results in cell death.[5] The selective toxicity of polyenes for fungal cells over mammalian cells is attributed to their preferential binding to ergosterol over cholesterol, the predominant sterol in mammalian cell membranes. The fungicidal mechanism, which involves direct physical disruption of the cell membrane, is inherently less susceptible to common resistance mechanisms that affect antifungals targeting specific enzymes or cell wall synthesis pathways. This characteristic likely contributes to BSG-005's reported efficacy against strains resistant to other antifungal classes like azoles and echinocandins.[5]

3.2. Pharmacodynamics

3.2.1. In Vitro Antifungal Activity

BSG-005 has demonstrated broad-spectrum in vitro antifungal activity against a wide range of clinically important fungal pathogens. Its efficacy extends to various species of Candida (including C. albicans, the multidrug-resistant C. auris, and C. glabrata), Aspergillus (including A. fumigatus), Fusarium, Mucor (a causative agent of mucormycosis), and Cryptococcus.[3] A key finding is its activity against fungal strains that have developed resistance to other commonly used antifungal agents, such as azoles and echinocandins.[5]

Minimum Inhibitory Concentration (MIC) studies have been conducted to quantify its potency. In one comprehensive study, BSG-005 exhibited a consistent MIC value of 1 mg/L against all tested strains of A. fumigatus, C. albicans, C. auris, and C. glabrata, underscoring its broad and uniform activity at this concentration.[2]

Table 1: In Vitro Antifungal Activity of BSG-005 (MIC values)

Fungal Species	Strain(s) Example(s) from	BSG-005 MIC (mg/L)	Comparator MICs (mg/L) (Fluconazole, Micafungin, Posaconazole if available for same strains)
Aspergillus fumigatus	293, 41, 11628	1	Posaconazole: 0.5, 0.25, 8 2
Candida albicans	K1, 2-76, 98-17, 580	1	Fluconazole: 0.5, 0.25, 16, 0.5; Micafungin: 0.016, 0.008, 0.03, 0.008 2
Candida glabrata	5376, 5592, 10956	1	Fluconazole: 2, 32, 2; Micafungin: 0.008, 0.016, 0.25 2
Candida auris	B11804, B11219, B11221, B11104	1	Fluconazole: 2, >256, 128, >256; Micafungin: 0.5, 4, 1, 0.25 2

Source:.[2]

3.2.2. In Vivo Efficacy (Preclinical Animal Models)

The in vivo efficacy of BSG-005 has been evaluated in neutropenic mouse models, which are standard for assessing antifungal activity against opportunistic pathogens. Studies have focused on invasive candidiasis (IC) and invasive pulmonary aspergillosis (IPA).[2]

Against Aspergillus fumigatus in the IPA model, BSG-005 demonstrated dose-dependent killing activity in the lungs. The pharmacokinetic/pharmacodynamic (PK/PD) index associated with net stasis (no net change in fungal burden over 96 hours) was a median 96-hour Area Under the Concentration-Time Curve (AUC)/MIC ratio of 102.4. The corresponding maximum plasma concentration (Cmax)/MIC target for stasis was 1.41.[2]

In the IC model, BSG-005 was effective against various Candida species, with efficacy measured by a reduction in kidney fungal burden (CFU counts). The PK/PD targets for stasis varied by species:

• For Candida albicans, the median 96-h AUC/MIC was 29.3, and the Cmax/MIC target was 0.60.[2]
• Candida glabrata required the lowest exposure for stasis, with a median 96-h AUC/MIC of 6.08 and a Cmax/MIC target of 0.22.[2]
• Candida auris, a typically multidrug-resistant species, required higher exposures, with a median 96-h AUC/MIC of 18.7 and a Cmax/MIC target of 0.48.[2]

Preclinical data also suggest that BSG-005 possesses a three-to-fourfold potency advantage over current standard-of-care polyenes, such as Amphotericin B or its lipid formulation AmBisome, when compared at equivalent doses in relevant animal models.[6] The observation that PK/PD targets for stasis differ among fungal species, despite a uniform in vitro MIC of 1 mg/L, indicates that in vivo conditions—such as drug distribution to infection sites, host immune interactions, and the intrinsic virulence or growth characteristics of the fungi—play a crucial role in modulating the efficacy of BSG-005. This highlights the necessity of in vivo studies for accurately predicting clinical effectiveness and informing dosing strategies.

4. Pharmacokinetics

4.1. Preclinical Pharmacokinetics (Murine Models)

Pharmacokinetic studies of BSG-005 in murine models have been conducted primarily using intraperitoneal (IP) administration.[2] These studies have shown that BSG-005 exposure, as measured by maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC), increases in a dose-dependent manner across the tested dose ranges.[2]

Key pharmacokinetic parameters derived from single-dose IP studies in a murine candidiasis model (with doses ranging from 0.5 mg/kg to 32 mg/kg) are summarized as follows [2]:

• Cmax: Ranged from approximately 0.19 mg/L at lower doses to 1.62 mg/L at higher doses.
• AUC0–inf: Ranged from 1.36 mg·h/L to 57.6 mg·h/L.
• Elimination Half-life (t1/2): Ranged from approximately 6.6 hours to 16 hours.

Table 2: Pharmacokinetic Parameters of BSG-005 in Murine Candidiasis Model (Single IP Dose)

Dose (mg/kg, IP)	Cmax (mg/L) (Approximate/Range)	AUC0–inf (mg·h/L) (Approximate/Range)	t1/2 (hours) (Approximate/Range)
0.5	0.19	1.36	6.6
(up to) 32.0	1.62	57.6	16

Source:.[2]

4.2. Human Pharmacokinetics (Phase 1a Healthy Volunteers)

The initial human pharmacokinetic evaluation of BSG-005 was conducted in a Phase 1a clinical trial. This study was a double-blind, placebo-controlled design, incorporating both Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD) cohorts, involving up to 72 healthy male volunteers (one source also mentions females).[3]

In the SAD part, four cohorts received doses up to 0.1 mg/kg. BSG-005 was reported to be safe and well-tolerated at these levels. Importantly, pharmacokinetic assessments indicated that drug exposure in these healthy volunteers reached levels comparable to or approaching the No Observed Adverse Effect Level (NOAEL) established in preclinical toxicology studies.[7]

In the MAD part, two cohorts received doses up to 0.05 mg/kg daily for 7 days. BSG-005 also demonstrated good safety and tolerability in this multiple-dosing regimen. A key objective of the MAD study was to determine the dose level necessary to achieve steady, clinically relevant plasma concentrations.[7]

The overall conclusion from the Phase 1a program was that BSG-005 exhibited a favorable safety and pharmacokinetic profile in healthy volunteers, supporting its progression into Phase 2 clinical trials.[7] The ability to achieve plasma concentrations in humans that approach preclinical safety thresholds (NOAELs) without inducing significant safety concerns is a critical positive indicator at this stage of drug development. It suggests a potentially viable therapeutic window, implying that doses predicted to be efficacious from animal PK/PD studies might be achievable and safely administered to patients.

5. Clinical Development Program

5.1. Overview of Clinical Trials

Phase 1a (Healthy Volunteers):

• Status: Successfully completed.[3]
• Objectives: The primary objectives were to evaluate the safety, tolerability, and pharmacokinetics of BSG-005 in healthy adult subjects.[7]
• Design: The trial was a double-blind, placebo-controlled study, featuring Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD) cohorts.[20]
• Key Findings:
• Safety: BSG-005 was demonstrated to be safe and well-tolerated at doses up to 0.1 mg/kg in the SAD cohorts and up to 0.05 mg/kg in the MAD cohorts. No Serious Adverse Events (SAEs) were reported. Adverse events (AEs) that occurred were generally mild to moderate in severity and included headache, dizziness, fever, increased heart rate, and infusion-related reactions. Phlebitis at the infusion site was noted in four subjects during the MAD phase.[3]
• Laboratory Parameters: There were no clinically relevant alterations in laboratory values for kidney function (including NAG and creatinine), liver function, or serum potassium levels. ECG monitoring revealed no clinically relevant changes.[3]
• Pharmacokinetics: The pharmacokinetic profile was established, with drug exposures in healthy volunteers reaching levels at or near the preclinical No Observed Adverse Effect Level (NOAEL) at doses that were well-tolerated.[7]

Phase 1b (Patients with Invasive Fungal Infections - IFI; NCT06678113):

• Status: This trial is currently ongoing and actively recruiting participants.[9]
• Official Title: "Study to Assess the Safety and Efficacy of Intravenous BSG005 in Patients With Invasive Fungal Infection".[9]
• Sponsor: Biosergen AS.[9]
• Phase: Designated as Phase 1/2 or Phase 1b.[9]
• Study Design: This is an open-label, single-arm, dose-escalation and dose-finding study. It is planned to enroll approximately 15 patients distributed across three cohorts, with five patients per cohort. BSG-005 is administered via intravenous (IV) infusion.[9]
• Patient Population: The study enrolls adult patients (18 years and older) diagnosed with uncomplicated IFI. There is a preference for enrolling patients with infections caused by Aspergillus spp. and Candida spp.. The trial design also accommodates patients who have failed previous standard-of-care antifungal treatments or those with pre-existing mild to moderate kidney impairment, positioning BSG-005 as a potential "rescue therapy".[9]
• Objectives: The primary objectives are to assess the safety and efficacy of IV BSG-005 in patients with IFI and to determine appropriate dosing regimens for further investigation.[9]
• Dosage Regimen: The study employs an intra-patient dose-escalation strategy. Cohort 1 commences with a daily dose of 0.1 mg/kg for the initial three days. Dose escalation occurs by 0.1 mg/kg increments every three days (or earlier, at the investigator's discretion), up to a maximum of 1.0 mg/kg. The starting dose for Cohort 2 will be determined by a Data Safety Review Committee (DSRC) based on the findings from Cohort 1, with subsequent escalation up to a maximum of 2.0 mg/kg. A similar approach will be used for Cohort 3, with a maximum dose of 3.0 mg/kg. The maximum treatment duration is planned for up to 28 days.[9]
• Interim Results (Cohorts 1 & 2, as of February 2025): Preliminary data from the first two cohorts have provided compelling proof-of-concept. All eight patients (out of ten enrolled across both cohorts) who completed treatment experienced clinical benefits. This included two patients achieving complete recovery (one with critical Mucormycosis) and six showing significant improvements. BSG-005 demonstrated efficacy against various infections, including those caused by drug-resistant strains. Tolerability was good, with key laboratory parameters such as creatinine, potassium, and magnesium remaining stable. One patient withdrew due to non-severe dyspnea and hypotension during dosing. The favorable tolerability profile observed prompted investigators to request and receive approval for dose escalation and extended treatment durations.[5]
• Study Start Date, Estimated Primary Completion Date, Primary/Secondary Outcome Measures for NCT06678113: Specific details regarding the study start date, estimated primary completion date, and the formally defined primary and secondary outcome measures for NCT06678113, as per registry definitions [24], were not explicitly available in the provided documents. However, the general objectives focus on safety and efficacy, with observed outcomes including clinical improvement, recovery rates, and tolerability.[5]

Table 3: Overview of BSG-005 Clinical Development Program

Trial Phase	Identifier	Status	Patient Population	Key Objectives	Key Reported Findings/Endpoints
Phase 1a	N/A	Completed	Healthy Volunteers	Safety, Tolerability, PK	Safe and well-tolerated up to 0.1 mg/kg (SAD) and 0.05 mg/kg (MAD). Mild-moderate AEs (headache, dizziness, fever, infusion reactions, phlebitis). No SAEs. No significant lab/ECG changes. PK established. 3
Phase 1b/2	NCT06678113	Recruiting	Patients with IFI (rescue therapy, including those with renal impairment or failed prior therapy)	Safety, Efficacy, Dose-finding	Interim (Cohorts 1&2): All 8/10 completing patients showed clinical benefit (2 complete recoveries, 6 significant improvements). Good tolerability; stable renal/hepatic markers. Effective vs. resistant strains. Dose escalation approved. 5

Source:.[3]

5.2. Future Development Plans

Biosergen has outlined an ambitious strategy for the continued development of BSG-005:

• Phase 2 Trials: A comprehensive multi-trial Phase 2 program is planned, with the goal of achieving broad labeling for BSG-005 across various invasive fungal infections. The company is currently in consultation with the Central Drugs Standard Control Organisation (CDSCO) of India to define the pathway for initiating a Phase 2 trial in India.[3]
• Regulatory Submissions:
• Biosergen intends to advance towards an Investigational New Drug (IND) application with the U.S. FDA by the end of 2025, following a pre-IND consultation to align on clinical trial design and data requirements.[10]
• A New Drug Application (NDA) filing in the U.S. is anticipated by the end of 2025.[11]
• The company aims to file for marketing approval for the treatment of Aspergillosis in both the EU and the U.S. by 2029, with launches for other indications projected for 2030.[3]
• Innovative Formulations: To expand the therapeutic utility of BSG-005, novel formulations are under development:
• BSG005 Nano Lung: This formulation is specifically engineered for targeted delivery to the lungs, a common site for severe fungal infections like aspergillosis.[3]
• BSG005 Nano Oral: An oral formulation is being developed to enable effective systemic delivery via the oral route. This could significantly enhance patient convenience, facilitate prophylactic use in high-risk populations, and allow for home-based treatment or step-down therapy following initial IV administration.[3] The development of both intravenous and advanced nano-formulations (Nano Lung, Nano Oral) suggests a comprehensive strategy by Biosergen to establish BSG-005 as a versatile antifungal agent. While the IV formulation addresses the critical need for treating acute, severe IFIs in hospitalized patients, the nano-formulations could significantly broaden its applicability. A targeted lung delivery system could enhance local drug concentrations for pulmonary infections while potentially minimizing systemic exposure. An effective oral formulation would represent a major breakthrough for polyene antifungals, which are typically limited by poor oral bioavailability, thereby enabling outpatient treatment, long-term prophylaxis, and easier management of chronic or less severe infections. This multi-formulation approach indicates an intent to cover a wide spectrum of clinical needs in IFI management.

6. Safety and Tolerability

6.1. Preclinical Safety

Preclinical evaluation of BSG-005 has consistently indicated a safety profile superior to that of existing polyene antifungals, particularly Amphotericin B. No severe adverse effects were reported in these studies.[5] A critical aspect of its preclinical safety is the marked reduction in kidney toxicity. BSG-005 was described as "completely free of the kidney toxicity hampering other drugs in its class" and demonstrated very limited release of N-acetyl-β-D-glucosaminidase (NAG), a sensitive biomarker of renal tubular damage.[3] Furthermore, no genotoxicity was observed in preclinical safety assessments.[7]

6.2. Clinical Safety (Phase 1a - Healthy Volunteers)

In the Phase 1a clinical trial involving healthy volunteers, BSG-005 was found to be safe and well-tolerated at single ascending doses up to 0.1 mg/kg and multiple ascending doses up to 0.05 mg/kg.[3] No Serious Adverse Events (SAEs) were reported during this phase.[3] The adverse events (AEs) that did occur were predominantly mild to moderate in severity. Commonly reported AEs included headache, dizziness, fever, increased heart rate, and infusion-related reactions.[3] Laboratory monitoring revealed no clinically relevant changes in parameters of kidney function (including NAG and creatinine), liver function, or serum potassium levels. Electrocardiogram (ECG) assessments also showed no clinically relevant alterations.[3] Phlebitis at the infusion site was noted in four subjects during the multiple ascending dose part of the study, indicating a potential local tolerability consideration for IV administration.[7]

6.3. Clinical Safety (Phase 1b - Patients with IFI, Interim Data)

Interim data from the ongoing Phase 1b trial (NCT06678113) in patients with severe IFIs, many of whom were critically ill or had failed prior therapies, further support the tolerability of BSG-005. No severe side effects directly attributed to BSG-005 were observed in patients who completed treatment in the initial cohorts.[10] Key laboratory markers for safety, including creatinine (renal function), potassium, and magnesium levels, remained stable during treatment. This contrasts favorably with the known toxicities of Amphotericin B.[22] One patient voluntarily withdrew from the trial due to experiencing non-severe dyspnea and hypotension during dosing.[10] The observed good tolerability in this vulnerable patient population led investigators to request and receive approval for dose escalation and longer treatment durations, reflecting confidence in the drug's safety profile.[5]

Table 4: Key Safety Findings for BSG-005 (Clinical and Preclinical)

Study Type	Key Safety Observations	Renal Safety Notes
Preclinical (Animal Models)	Generally better safety than Amphotericin B; No severe AEs reported.5 No genotoxicity observed.7	Described as "completely free of kidney toxicity".11 Very limited release of NAG (kidney damage biomarker).3
Phase 1a (Healthy Volunteers)	No SAEs; Mild-moderate AEs (headache, dizziness, fever, infusion reactions, phlebitis). No significant lab/ECG changes.3	No clinically relevant changes in kidney parameters (NAG, creatinine).3
Phase 1b (IFI Patients, Interim)	No severe side effects in completed cohorts. One withdrawal (non-severe dyspnea/hypotension). Good tolerability allowing dose escalation.5	Stable creatinine, potassium, and magnesium levels observed.22

Source:.[3]

The consistent reporting of a favorable renal safety profile for BSG-005 throughout its preclinical and early clinical development is a particularly noteworthy finding. Nephrotoxicity is a major dose-limiting toxicity for conventional polyene antifungals like Amphotericin B, often restricting their use or requiring intensive monitoring.[5] The apparent renal-sparing characteristic of BSG-005, if maintained in later-phase, larger clinical trials, would represent a substantial clinical advantage. This could permit more aggressive or prolonged dosing regimens to achieve better fungicidal efficacy and potentially allow for its use in patients with pre-existing renal impairment, a population often excluded from or at high risk with standard polyene therapy. This improved safety profile is likely a direct result of the specific chemical modifications differentiating BSG-005 from nystatin, potentially altering its interaction with mammalian cell membranes (which contain cholesterol) relative to fungal membranes (which contain ergosterol), thereby reducing host cell toxicity.

7. Therapeutic Potential and Regulatory Landscape

7.1. Target Indications

BSG-005 is being developed for the treatment of life-threatening invasive fungal infections (IFIs). These infections predominantly affect immunocompromised patients, such as individuals with AIDS, cancer patients undergoing chemotherapy or radiotherapy, and organ transplant recipients.3

The drug targets a broad range of clinically relevant fungal pathogens, including:

• Aspergillus species, the causative agents of aspergillosis.[3]
• Candida species, including C. albicans and the often multidrug-resistant C. auris.[3]
• Fusarium species.[3]
• Mucor species, responsible for mucormycosis.[3]
• Cryptococcus species.[3]

7.2. Key Advantages and Therapeutic Promise

BSG-005 exhibits several potential advantages that underscore its therapeutic promise:

• Broad-Spectrum Antifungal Coverage: Its efficacy against a wide array of fungal genera makes it a versatile agent capable of treating diverse IFIs.[3]
• Fungicidal Mechanism of Action: Unlike fungistatic drugs that only inhibit fungal growth, BSG-005 actively kills fungal cells. This cidal activity is crucial for eradicating infections, especially in immunocompromised hosts, and may reduce the likelihood of resistance development.[3]
• Efficacy Against Resistant Strains: BSG-005 has demonstrated activity against fungal strains that are resistant to other established antifungal classes, such as azoles and echinocandins, addressing a critical unmet need in the face of rising antifungal resistance.[5]
• Superior Safety Profile: Perhaps its most significant advantage is its improved safety profile, particularly the markedly reduced nephrotoxicity compared to conventional polyenes like Amphotericin B. This enhanced tolerability could permit higher or more sustained dosing, potentially leading to improved clinical outcomes and allowing its use in a broader patient population, including those with some degree of renal impairment.[3]

7.3. Regulatory Status

• FDA Orphan Drug Designation: The U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation to BSG-005 for the treatment of invasive aspergillosis. This designation is based on the condition affecting fewer than 200,000 patients per year in the United States and provides several incentives, including an expedited regulatory pathway, potential for prolonged market exclusivity upon approval (7 years), protocol assistance from the FDA, and tax credits for clinical trial costs.[3] The strategic focus on aspergillosis for orphan designation, despite BSG-005's broad-spectrum activity, allows Biosergen to leverage these developmental incentives for a key indication, while the drug's potential against other IFIs can be explored concurrently or subsequently.
• EMA Orphan Drug Application: Biosergen has also applied for Orphan Drug status for BSG-005 in Europe through the European Medicines Agency (EMA).[3] While the FDA designation is confirmed, the status of the EMA application was noted as pending or hoped for in the provided documents.

8. Conclusion

BSG-005 (DrugBank ID: DB18014) emerges from the available research as a highly promising, novel polyene macrolide antifungal agent with a distinct profile. Developed by Biosergen from foundational work at NTNU and SINTEF, this nystatin derivative has been engineered to retain potent, broad-spectrum fungicidal activity while significantly mitigating the severe toxicities, particularly nephrotoxicity, associated with older polyenes like Amphotericin B. Its mechanism of action, involving the disruption of fungal cell membrane integrity via ergosterol binding, is effective against a wide range of pathogens, including those resistant to other antifungal classes.

Preclinical studies have consistently demonstrated superior safety and comparable or enhanced efficacy relative to standard polyenes. Early clinical data from Phase 1a trials in healthy volunteers have corroborated this favorable safety profile and established initial human pharmacokinetics. The ongoing Phase 1b trial (NCT06678113) in patients with invasive fungal infections has yielded encouraging interim results, showing clinical benefits and good tolerability even in critically ill and treatment-refractory patients, leading to investigator-initiated dose escalations.

The FDA's granting of Orphan Drug Designation for invasive aspergillosis underscores the recognition of its potential to address unmet medical needs. Coupled with plans for further Phase 2 trials and the development of innovative nano-formulations for targeted lung delivery and oral administration, BSG-005 is strategically positioned to potentially transform the treatment paradigm for severe IFIs. If the promising safety and efficacy trends continue through later-stage clinical development, BSG-005 could offer a much-needed therapeutic advancement, providing a safer and effective option for vulnerable patient populations battling life-threatening fungal diseases.

9. References

[1]

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