Comprehensive Report on BZ371A (DrugBank ID: DB18101)

I. Executive Summary

BZ371A (DrugBank ID: DB18101) is an investigational biotech therapeutic, specifically a synthetic peptide, developed by Biozeus Biopharmaceutical S.A. It is a lead candidate derived from the company's BZ371 peptide platform. The primary mechanism of action of BZ371A is the enhancement of nitric oxide synthase (NOS) activity, which leads to increased local production of endogenous nitric oxide (NO) and subsequent vasodilation.[1] This localized action is a key feature, aiming to minimize systemic exposure and associated side effects.[1]

The BZ371A clinical development program is currently focused on sexual dysfunction. It is being investigated for erectile dysfunction (ED), particularly in patients who have undergone radical prostatectomy, and for Female Sexual Arousal Disorder (FSAD), where it is also associated with the product name APHRA.[2] Phase 1 clinical trials for these sexual dysfunction indications have been completed, reportedly demonstrating good local tolerability and no systemic exposure with topical gel formulations.[4] Phase 2 trials are ongoing or planned for ED and FSAD.[6]

Beyond sexual health, the BZ371 platform, and BZ371A specifically, show preclinical promise for ophthalmic conditions. Notably, BZ371A has received Orphan Drug Designation (ODD) from the U.S. Food and Drug Administration (FDA) for the treatment of Anterior Ischemic Optic Neuropathy (AION).[8] Other eye diseases like glaucoma are also under preclinical investigation.[2] Furthermore, a related peptide from the platform, BZ371B, is in preclinical development for pulmonary diseases, administered via inhalation.[2] The consistent emphasis on local action across different formulations (topical gel, eye drops, inhalation) underscores a core strategic advantage of the BZ371 platform.

II. Introduction to BZ371A

BZ371A is an investigational drug product identified by the DrugBank accession number DB18101.[11] It is classified as a biotech product, more specifically a synthetic peptide or protein-based therapy.[11]

Nomenclature and Identification:

The primary identifier used is BZ371A. However, it is also referred to by several synonyms, including BZ-371A and, significantly, PnPP-19.12 The peptide PnPP-19 has an amino acid sequence of GERRQYFWIAWYKLANSKK.14 This sequence is also attributed to BZ-371A, indicating that PnPP-19 is the core active pharmaceutical ingredient or a very closely related molecular entity.8 The NCI Drug Dictionary also lists "NOS enhancer BZ371A".3

Origin and Developer:

BZ371A, through its identity as PnPP-19, originates from an engineered peptide derived from non-contiguous domains of PnTx2-6, a natural toxin found in the venom of the Brazilian armadeira spider, Phoneutria nigriventer.15 This synthetic 19-amino acid peptide was designed to retain therapeutic activity while minimizing toxicity associated with the native toxin.17 The developer of BZ371A and the BZ371 peptide platform is Biozeus Biopharmaceutical S.A., a clinical-stage biotechnology company based in Brazil.1

The established molecular identity between BZ371A and PnPP-19 is pivotal, as a considerable body of preclinical and mechanistic research has been published under the PnPP-19 designation. This allows for a more comprehensive understanding of BZ371A by integrating these findings.

Table 1: BZ371A - Key Drug Profile

Attribute	Value	Source Snippet(s)
DrugBank ID	DB18101	User Query, 11
Generic Name/Synonyms	BZ371A, BZ-371A, PnPP-19, NOS enhancer BZ371A	3
Developer	Biozeus Biopharmaceutical S.A.	1
Drug Type	Biotech, Synthetic Peptide	User Query, 11
Chemical Nature	19 amino acid peptide: GERRQYFWIAWYKLANSKK (derived from Phoneutria nigriventer toxin PnTx2-6 origin)	14
Primary Mechanism of Action	Nitric Oxide Synthase (NOS) Enhancer	1

III. BZ371 Peptide Platform and Mechanism of Action

BZ371A is the lead candidate from Biozeus Biopharmaceutical's patented BZ371 peptide platform.[2] This platform comprises a novel class of small synthetic therapeutic peptides designed for local action through topical administration, aiming to restore physiological nitric oxide (NO) production without inducing systemic exposure.[2]

Primary Mechanism of Action: Nitric Oxide Synthase (NOS) Enhancement

The core mechanism of BZ371A (PnPP-19) is its function as a Nitric Oxide Synthase (NOS) enhancer or Nitric Oxide Stimulant.1 Upon topical application, BZ371A is believed to induce the local expression or enhance the activity of NOS enzymes within the target tissue.2 This action leads to an increased endogenous production of NO.2 The elevated local concentrations of NO, a potent vasodilator, subsequently mediate the therapeutic effects, such as increased blood flow in erectile tissue or modulation of intraocular pressure.1 Research on PnPP-19 specifically confirms its pro-erectile effects are mediated via nitric oxide regulation and the NO/cGMP pathway.17 This approach of enhancing endogenous NO production, rather than delivering NO exogenously, is proposed to offer a more physiological, controlled, and sustained NO supply, potentially avoiding the limitations and systemic effects associated with direct NO donor drugs.2

Pharmacological Profile and Key Advantages

A significant claimed advantage of the BZ371 platform is the localized action of its peptides, which is intended to prevent systemic exposure and thereby minimize systemic side effects.1 Phase 1 clinical data for APHRA, a BZ371A-based product for FSAD, reportedly confirmed the absence of systemic exposure after topical application.4 This localized activity is central to the safety proposition of BZ371A. Furthermore, for FSAD, APHRA is described as inducing local vasodilation and increased blood flow independently of external stimuli.4

The effectiveness of this local action heavily relies on formulation technology. Patent literature (US20240317806A1) pertaining to PnPP-19 describes topical formulations incorporating permeation-enhancing excipients. These formulations are designed to improve peptide absorption and penetration through the skin and mucosa (e.g., crossing the tunica albuginea in penile tissue) while maintaining localized effects and improving stability.[15] This highlights that the delivery system is as critical to the drug's therapeutic profile as the peptide itself.

Additional Mechanistic Aspects of PnPP-19 (BZ371A)

Beyond its primary role as an NOS enhancer, preclinical research on PnPP-19 has revealed other biological activities. Studies suggest PnPP-19 can induce antinociception by activating CB1, μ, and δ opioid receptors.16 Specifically, it has been shown to selectively activate μ-opioid receptors, leading to an indirect inhibition of calcium channels and a reduction in calcium influx in dorsal root ganglion (DRG) neurons, a mechanism that does not involve β-arrestin2 recruitment.16 The relevance of these additional mechanisms to the currently pursued indications of sexual dysfunction and AION, which are primarily based on vasodilation via NOS enhancement, is not yet fully elucidated and may depend on dosage and route of administration, or could represent distinct therapeutic avenues for PnPP-19.

IV. Therapeutic Indications and Clinical Development Program

The BZ371 peptide platform, with BZ371A as a key molecule, is being explored for a range of therapeutic applications. Current clinical development is primarily focused on sexual dysfunction, while ophthalmic and pulmonary indications are in earlier, preclinical stages. The versatility of the platform, targeting different conditions through a common NOS-enhancing mechanism, is a notable feature of Biozeus's strategy.

Table 2: Overview of BZ371 Platform - Therapeutic Programs

Therapeutic Area	Specific Indication(s)	Compound(s)	Route of Administration	Current Development Phase	Key Notes	Source Snippet(s)
Sexual Dysfunction	Erectile Dysfunction (General)	BZ371A (PnPP-19)	Topical Gel	Phase 2 ongoing	Targets PDE5i non-responders/intolerant	2
	Erectile Dysfunction (Post-Radical Prostatectomy)	BZ371A (PnPP-19)	Topical Gel	Phase 2 ongoing (NCT05558007)	Supportive therapy for penile integrity	2
	Female Sexual Arousal Disorder (FSAD)	BZ371A / APHRA	Topical Gel	Phase 1 completed; Phase 2 ongoing/planned (NCT06116045, NCT06651541)	APHRA is the product name for FSAD; Phase 2 funded by FINEP grant	1
Ophthalmic Diseases	Anterior Ischemic Optic Neuropathy (AION)	BZ371A (PnPP-19)	Topical Eye Drops	Preclinical	FDA Orphan Drug Designation granted (07/26/2021; #806120)	2
	Glaucoma	BZ371A (PnPP-19)	Topical Eye Drops	Preclinical	Demonstrated IOP reduction and neuroprotection in animal models	2
	Diabetic Retinopathy	BZ371A (PnPP-19)	Topical Eye Drops	Preclinical		2
	Dry Age-Related Macular Degeneration	BZ371A (PnPP-19)	Topical Eye Drops	Preclinical		2
Pulmonary Diseases	Pulmonary Arterial Hypertension (PAH, esp. Group 3)	BZ371B	Inhalation	Preclinical	Selective pulmonary action, potential for combination therapy	2
	Acute Respiratory Distress Syndrome (ARDS)	BZ371B	Inhalation	Preclinical	Potential to reduce ICU stay	2
	Chronic Obstructive Pulmonary Disease (COPD)	BZ371B	Inhalation	Preclinical	With or without PAH	2
Other Investigated Areas*	Binge Drinking, Tobacco Use Disorder, Hypertension, Hypercholesterolemia	BZ371A	Topical	Phase 2 (per Ozmosi)	Less emphasized in Biozeus communications; potentially exploratory	13

Note: Indications listed under "Other Investigated Areas" are primarily sourced from third-party databases (Ozmosi) and are not as prominently featured in Biozeus's direct communications as sexual dysfunction, ophthalmic, or pulmonary indications.

A. Sexual Dysfunction

1. Erectile Dysfunction (ED) BZ371A is being developed as a topical treatment for ED. Its mechanism, involving local NOS enhancement and subsequent vasodilation in cavernosal tissue, offers a potential alternative or adjunct to existing therapies.2 A key focus is on patient populations with high unmet needs. This includes individuals who have undergone radical prostatectomy (RP), where nerve damage can impair NO-mediated erectile function.2 For these patients, BZ371A is positioned as a supportive therapy to aid in the recovery and maintenance of penile health and erectile capability.6 Another target group includes men who are non-responsive to or intolerant of oral phosphodiesterase type 5 (PDE5) inhibitors.2 The clinical development for ED includes a completed Phase 1 trial (NCT05332340) that assessed the safety and pharmacokinetics of topically applied BZ371A gel in healthy male and female volunteers.5 Currently, a Phase 2 trial (NCT05558007) is actively recruiting patients who have undergone RP to evaluate the safety and efficacy of BZ371A gel (5mg/mL) when used in conjunction with daily tadalafil (a PDE5 inhibitor) or an oral placebo.6 This trial underscores the strategy of potentially combining BZ371A with existing ED treatments, leveraging its synergistic effect with PDE5 inhibitors noted by Biozeus.2
2. Female Sexual Arousal Disorder (FSAD) Recognizing the significant unmet need in female sexual health, Biozeus is developing APHRA, a product based on the BZ371A peptide, for the treatment of FSAD.1 FSAD is often characterized by insufficient genital blood flow and arousal. APHRA, applied topically to the vaginal area, aims to enhance local NO production, thereby increasing blood flow to genital tissues and restoring physiological arousal responses, independent of external stimuli.4 FSAD affects a substantial portion of the female population, yet there are no FDA-approved drugs specifically for this condition, highlighting the potential impact of APHRA.4 A Phase 1 trial for APHRA has been completed, reportedly confirming its safety, local tolerability, and, importantly, a lack of systemic exposure after topical application in women.4 Biozeus is now advancing APHRA into Phase 2 clinical trials, with full funding for these studies in Brazil secured through a grant from FINEP, a Brazilian governmental institution.1 Two Phase 2 trials are listed: NCT06116045 is actively recruiting participants to evaluate different doses of BZ371A gel (2.5 mg and 7.5 mg) against placebo 7, and NCT06651541 is planned but not yet recruiting.12 The dual Phase 2 trial approach may indicate an intent to explore various dosing regimens or patient subgroups to optimize the therapeutic strategy for FSAD.

B. Ophthalmic Diseases

BZ371A, formulated as an eye drop, is in preclinical development for several ophthalmic conditions.2 The proposed mechanism involves local NO enhancement leading to a reduction in intraocular pressure (IOP) and neuroprotective effects around the optic nerve head.2

* Anterior Ischemic Optic Neuropathy (AION): Significantly, BZ371A has received Orphan Drug Designation (ODD) from the FDA for the treatment of AION.2 This designation, granted on July 26, 2021 (Designation Number: 806120) 9, provides incentives for the development of BZ371A for this rare and serious optic nerve condition. This regulatory milestone for a preclinical asset suggests a strong scientific rationale and potential for an accelerated development pathway.

* Other Retinal Diseases: Preclinical investigations also cover glaucoma, diabetic retinopathy, and dry age-related macular degeneration.2 Preclinical studies using PnPP-19 (BZ371A) have shown promising results in animal models of glaucoma, demonstrating IOP reduction and safety for ocular application.10

C. Pulmonary Diseases (BZ371B)

A distinct peptide from the platform, BZ371B, is being developed for lung diseases, with administration via inhalation.2 BZ371B is designed to act as a local vasodilator and a selective bronchodilator with anti-inflammatory activity, aiming to reduce pulmonary arterial pressure.2

* Pulmonary Arterial Hypertension (PAH): A key target is PAH, particularly WHO Group 3 PAH (PAH secondary to pulmonary diseases), which represents an unmet medical need. BZ371B is proposed to offer advantages over existing PAH drugs by not causing systemic hypotension and by selectively acting on the pulmonary vasculature, thereby improving the ventilation/perfusion ratio.2

* Other Pulmonary Conditions: Preclinical exploration also includes Acute Respiratory Distress Syndrome (ARDS), with potential applications in scenarios like COVID-19-associated ARDS, and Chronic Obstructive Pulmonary Disease (COPD).2

All pulmonary indications for BZ371B are currently in the preclinical stage of development.2

D. Other Investigated Areas

Third-party drug development databases, such as Ozmosi, list BZ371A in Phase 2 trials for indications including binge drinking, tobacco use disorder, hypertension, and hypercholesterolemia.13 However, these indications are not prominently featured in Biozeus's direct communications, suggesting they may be more exploratory or based on broader hypotheses related to NO pathway modulation.

V. Clinical Trial Data

The clinical development of BZ371A and its related compound APHRA is actively progressing, primarily focusing on sexual dysfunction. Phase 1 studies have been completed, and Phase 2 trials are underway or planned.

Table 3: Summary of Key Clinical Trials for BZ371A and Related Compounds (APHRA)

NCT Number	Trial Title/Objective	Phase	Condition(s)	Compound	Intervention(s) & Dosage	Comparator(s)	Status (Recruitment, Overall)	Sponsor	Key Reported Outcomes/Endpoints (if available)	Source Snippet(s)
NCT05332340	Phase 1 Clinical Trial to evaluate safety and pharmacokinetic of BZ371A in a gel form applied in the genitalia of healthy men and women	1	Healthy Volunteers (PK/Safety for ED/Prostate Cancer context)	BZ371A	Topical gel	N/A	Completed	Biozeus Biopharmaceutical S.A.	Safety, tolerability, pharmacokinetics (systemic bioavailability)	5
APHRA Phase 1 (NCT not specified)	Safety and tolerability of APHRA topical application in women	1	Healthy Female Volunteers (for FSAD)	APHRA (BZ371A peptide)	Topical application	N/A	Completed	Biozeus Biopharmaceutical S.A.	Confirmed safety, tolerability; no systemic exposure; no local/severe side effects	4
NCT05558007	Safety and Efficacy Evaluation of BZ371A Topically Applied on Prostatectomized Patients	2	ED post-Radical Prostatectomy, Prostate Cancer	BZ371A	BZ371A topical gel (1.5 mL of 5mg/mL) + daily oral Tadalafil 5mg OR BZ371A topical gel + daily oral Placebo	Daily oral Tadalafil 5mg + Topical Placebo	Recruiting (Primary Completion: Dec 2024; Study End: Jan 2025)	Biozeus Biopharmaceutical S.A.	Efficacy, safety, tolerability	6
NCT06116045	Evaluation of the Efficacy, Safety and Tolerability of BZ371A in Women with Sexual Arousal Disorder	2	Female Sexual Arousal Disorder (FSAD)	BZ371A	BZ371A topical gel (2.5 mg/0.5 ml or 7.5 mg/1.5 ml)	Placebo topical gel (1.0 ml)	Recruiting (Primary Completion: Mar 2025)	Biozeus Biopharmaceutical S.A.	Efficacy in increasing sexual arousal; safety, tolerability	7
NCT06651541	Phase 2 Parallel Clinical Study to Evaluate the Efficacy in Increasing Sexual Arousal, Safety and Tolerability of BZ371A in Gel Form Applied to Women with Sexual Arousal Disorder	2	Female Sexual Arousal Disorder (FSAD)	BZ371A	BZ371A topical gel	Not specified (likely placebo)	Not Yet Recruiting	Biozeus Biopharmaceutical S.A.	Efficacy in increasing sexual arousal; safety, tolerability	12

A. Phase 1 Clinical Studies

1. NCT05332340 (BZ371A in Healthy Volunteers): This Phase 1 study was designed to evaluate the safety and pharmacokinetics of BZ371A administered as a topical gel to the genitalia of healthy male and female volunteers.5 It is also linked in some databases to supportive care for erectile dysfunction post-radical prostatectomy and prostate cancer, suggesting its initial safety assessment was broad.11 The trial, sponsored by Biozeus Biopharmaceutical S.A., has been reported as completed.11 The primary objectives were to assess safety, tolerability, and systemic bioavailability.5 While detailed peer-reviewed publications of the results are not available in the provided information, the progression to Phase 2 studies implies an acceptable safety and pharmacokinetic profile.
2. APHRA (BZ371A for FSAD) Phase 1: A separate Phase 1 trial for APHRA, the BZ371A-based product for FSAD, has also been completed.1 According to Biozeus, this trial confirmed the safety and tolerability of APHRA when applied topically to women. Importantly, it was reported that there was no systemic exposure of the peptide after local application, and no local or severe side effects were observed.4 These findings are crucial as they support the core value proposition of local action and enhanced safety.

B. Phase 2 Clinical Studies (Ongoing and Planned)

1. NCT05558007 (BZ371A for ED post-Radical Prostatectomy): This ongoing Phase 2 trial is evaluating the safety and efficacy of topically applied BZ371A gel (1.5 mL of a 5mg/mL concentration) in men who have undergone radical prostatectomy and are experiencing erectile dysfunction.6 The study employs a design where BZ371A is assessed in combination with daily oral tadalafil (5mg) or daily oral placebo, with a control arm receiving tadalafil plus topical placebo.25 The trial is actively recruiting, with an estimated primary completion date of December 31, 2024, and an estimated study completion date of January 31, 2025.26 This study design allows for the assessment of BZ371A both as a potential monotherapy (when compared against tadalafil + topical placebo, assuming the oral placebo arm with topical BZ371A shows effect) and as an adjunctive therapy to PDE5 inhibitors.
2. NCT06116045 (BZ371A/APHRA for FSAD): This Phase 2 trial is actively recruiting women with FSAD to evaluate the efficacy, safety, and tolerability of BZ371A gel.7 Participants will receive either BZ371A gel at doses of 2.5 mg (0.5 mL) or 7.5 mg (1.5 mL), or a placebo gel.7 The primary objective is to assess the efficacy in increasing sexual arousal, with secondary objectives focusing on safety and tolerability.7 The estimated primary completion date for this study is March 31, 2025.7
3. NCT06651541 (BZ371A/APHRA for FSAD): A second Phase 2 trial for BZ371A in FSAD is planned but not yet recruiting.12 This "Phase 2 Parallel Clinical Study" also aims to evaluate the efficacy in increasing sexual arousal, safety, and tolerability of BZ371A in gel form applied to women with sexual arousal disorder.12 The initiation of multiple Phase 2 trials for FSAD suggests a strong focus by Biozeus on this indication and may involve exploring different patient populations, dosing regimens, or more specific endpoints based on learnings from the initial Phase 2 study and FDA guidance.4

The progression of BZ371A into multiple Phase 2 trials, particularly with the financial backing from institutions like FINEP for FSAD research [1], indicates a commitment to developing this peptide platform for sexual dysfunction. However, the absence of detailed, peer-reviewed publications for the completed Phase 1 studies remains an information gap for a full external assessment of the foundational safety and PK data.

VI. Preclinical Evidence

The therapeutic potential of BZ371A, largely through studies on its identical or near-identical peptide PnPP-19, is supported by a body of preclinical research, particularly in the areas of erectile dysfunction and ophthalmic conditions.

PnPP-19 (BZ371A) in Erectile Dysfunction:

Preclinical studies have demonstrated that PnPP-19, the synthetic peptide derived from the Phoneutria nigriventer spider toxin PnTx2-6, effectively potentiates erectile function.17 This pro-erectile effect is mediated through the nitric oxide/cyclic guanosine monophosphate (NO/cGMP) signaling pathway.17 Animal models have shown efficacy with PnPP-19 administered subcutaneously, intravenously, and, importantly for current clinical development, via topical application.17 A key finding from these studies is that PnPP-19, unlike its parent toxin PnTx2-6, does not modulate Na+ channels, thereby exhibiting non-toxic properties even at high doses in animals and demonstrating low immunogenicity in mice.17 Some reviews also suggest that PnPP-19's mechanism in ED involves central nervous system activation in addition to nitric oxide regulation.12

PnPP-19 (BZ371A) in Glaucoma and Ocular Hypertension:

In the context of ophthalmic applications, PnPP-19 (as BZ371A eye drops) has shown promise in preclinical models of glaucoma and ocular hypertension.10 Studies in rats demonstrated that a single topical instillation of PnPP-19 solution could reduce intraocular pressure (IOP) in both normotensive and ocular hypertensive eyes for up to 24 hours, without apparent toxicity.10 The proposed mechanism involves the induction of nitric oxide, which may improve the conventional outflow of aqueous humor and potentially prevent the progression of optic nerve degeneration.10 Ocular safety has been supported by the Hen's Egg Test-Chorioallantoic Membrane (HET-CAM) assay, where PnPP-19 was classified as non-irritant, and electroretinography (ERG) studies in rats showed no adverse effects on retinal function after PnPP-19 administration.23 These findings provide a strong rationale for its development in AION, for which it has FDA ODD, and other ischemic retinopathies.2

General Preclinical Profile of BZ371A:

Biozeus reports that animal studies with BZ371A have demonstrated a promising safety profile, consistent with its local action as an NOS enhancer.1 Patent information (US20240317806A1) for PnPP-19 formulations highlights features designed for enhanced topical absorption and penetration, with preclinical data indicating detection of the peptide in target tissues like the foreskin and smooth muscle layer within 15 minutes of application in relevant models.15 This rapid local tissue availability is crucial for the intended therapeutic effects.

The development of BZ371A/PnPP-19 from a natural toxin by engineering out toxicity while retaining desired bioactivity represents a sound drug discovery approach, potentially de-risking its development pathway compared to entirely de novo compounds. The robust preclinical data for ED and ocular conditions provide a solid foundation for the ongoing and planned clinical trials.

VII. Safety and Tolerability Profile

The safety and tolerability profile of BZ371A is a central aspect of its development, with a strong emphasis on its localized action and lack of systemic exposure when administered topically.

Phase 1 Human Data (BZ371A and APHRA):

The completed Phase 1 clinical trial NCT05332340 was designed to evaluate the safety and pharmacokinetics of BZ371A gel applied to the genitalia of healthy male and female volunteers.5 While detailed published results are pending, the progression to Phase 2 studies suggests that an acceptable safety profile was observed.

For APHRA, the BZ371A-based product for Female Sexual Arousal Disorder (FSAD), Biozeus has reported that the Phase 1 clinical trial confirmed its safety and tolerability following topical application in women.4 Critically, these studies reported no evidence of systemic exposure of the peptide after local application. Furthermore, no local or severe side effects were reported in this Phase 1 FSAD study.4 This lack of systemic absorption is a key differentiating factor and supports the premise of a favorable safety profile, particularly when compared to systemically acting drugs for sexual dysfunction.

Preclinical Safety Data (PnPP-19/BZ371A):

Preclinical investigations with PnPP-19 (the peptide core of BZ371A) further reinforce the safety expectations. Animal studies have indicated that PnPP-19 does not induce signs of toxicity in various tissues, including the brain, heart, lung, liver, and kidney.18 Unlike its parent spider toxin, PnPP-19 does not modulate Na+ channels, which is a significant de-risking factor.17 It has also been shown to not cause death or hypersensitivity reactions and to possess low immunogenicity in murine models.18

In the context of ophthalmic applications, PnPP-19 demonstrated safety in the HET-CAM assay, being classified as non-irritant, and electroretinography studies in rats revealed no adverse effects on retinal function.23

Expected Safety Profile:

Based on the mechanism of local NOS enhancement and the consistent findings of no systemic exposure with topical formulations, BZ371A is anticipated to have a favorable safety profile characterized by minimal systemic side effects.1 This is a significant potential advantage, particularly for indications like ED and FSAD, where existing systemic therapies can be associated with undesirable adverse events. The ongoing Phase 2 trials will provide more extensive data on the safety and tolerability of BZ371A in patient populations.

VIII. Regulatory Status

A significant regulatory milestone has been achieved for BZ371A in the context of its ophthalmic development program.

Table 4: Regulatory Designations for BZ371 Platform Compounds

Compound	Designation	Regulatory Body	Indication	Date Granted	Designation Number	Source Snippet(s)
BZ371A (PnPP-19 / 19 amino acid synthetic peptide NOS-enhancer)	Orphan Drug Designation	U.S. Food and Drug Administration (FDA)	Treatment of Anterior Ischemic Optic Neuropathy (AION)	July 26, 2021	806120	2

Details of Orphan Drug Designation:

BZ371A, identified in FDA records under names such as "19 amino acid synthetic peptide NOS-enhancer" or its synonym PnPP-19, was granted Orphan Drug Designation (ODD) by the U.S. Food and Drug Administration (FDA) for the "Treatment of anterior ischemic optic neuropathy".8 This designation was granted on July 26, 2021, with the designation number 806120.8 The sponsor listed for this designation is Biozeus Biopharmaceutical SA.9

The status of this ODD is "Designated," indicating that while the criteria for orphan designation have been met, BZ371A is not yet FDA-approved for this orphan indication.9

The FDA ODD for AION is a noteworthy achievement, particularly as the ophthalmic program for BZ371A is currently in the preclinical stage.[2] Orphan drug status is granted to drugs intended to treat rare diseases or conditions (affecting fewer than 200,000 people in the U.S.) and provides various development incentives, such as market exclusivity for a period upon approval, tax credits for qualified clinical testing, and waiver of FDA application fees.[30] This designation can facilitate and potentially accelerate the development of BZ371A for AION, a serious condition with limited treatment options. This regulatory recognition underscores the potential of BZ371A to address an unmet medical need in this rare ophthalmic disease.

No other specific regulatory designations (e.g., Fast Track, Breakthrough Therapy) for BZ371A or APHRA for other indications were found in the provided materials.

IX. Formulation and Administration

The BZ371 peptide platform leverages different formulations and routes of administration tailored to specific therapeutic areas, with a consistent emphasis on localized drug delivery.

Topical Gel Formulation for Sexual Dysfunction:

For the treatment of erectile dysfunction (BZ371A) and female sexual arousal disorder (APHRA, based on BZ371A peptide), the primary formulation is a topical gel.1 Patent US20240317806A1 provides detailed insights into these topical pharmaceutical formulations of PnPP-19 (BZ371A). These formulations are designed to comprise the synthetic peptide at concentrations typically between 0.1% and 0.7% (w/v), along with specific excipients such as a surfactant (e.g., Poloxamer 188, Poloxamer 407, or a combination, at 2.5% to 18.0% w/v), propylene glycol (7.5% to 30.0% w/v), and a buffer to maintain a pH between 4.0 and 6.5 (e.g., sodium acetate or potassium phosphate).15

These formulations are engineered for several improved properties, including enhanced peptide absorption and penetration through the skin and mucosa (e.g., foreskin of the penis, vaginal mucosa, and the smooth muscle layer of the penis and vagina), improved stability (shelf-life), rapid onset of action (reportedly within 5 to 30 minutes), a pleasant sensation upon application, and reduced skin or mucosal irritation.15 The ability of the formulation to facilitate peptide transit across the fibrous tunica albuginea of the penis without causing systemic effects is a key design feature for ED applications.15 The clinical trials for ED (NCT05558007) and FSAD (NCT06116045, NCT06651541) utilize BZ371A in a gel form for topical application to the genital area.5

Ophthalmic Formulation:

For eye diseases, including AION, glaucoma, diabetic retinopathy, and dry age-related macular degeneration, BZ371A is being developed as a peptide eye drop.2 Preclinical studies have demonstrated the efficacy of PnPP-19 (BZ371A) in reducing intraocular pressure when administered as an eye drop in animal models.10

Inhaled Formulation (BZ371B):

For pulmonary diseases such as PAH, ARDS, and COPD, the BZ371 platform includes a distinct peptide, BZ371B, which is designed for administration via inhalation.2 This route allows for direct delivery to the lungs, aiming for local vasodilation and bronchodilation.

The choice of formulation and administration route is clearly tailored to maximize local drug concentration at the target tissue while minimizing systemic absorption, which is a central tenet of the BZ371 platform's therapeutic strategy and safety profile. The significant research and patent activity around topical formulations for PnPP-19 (BZ371A) highlight the critical role of drug delivery technology in realizing the therapeutic potential of these peptides.

X. Expert Opinion and Future Outlook

BZ371A, and the broader BZ371 peptide platform from which it originates, represents an innovative therapeutic approach with potential across multiple medical domains. The core mechanism of local nitric oxide synthase (NOS) enhancement, leading to endogenous nitric oxide (NO) production and vasodilation, is a scientifically sound strategy for conditions characterized by impaired vascular function or NO deficiency.[1]

Strengths and Potential:

The most significant potential advantage of BZ371A lies in its localized action and consequent lack of systemic exposure when administered topically.1 This characteristic, if robustly confirmed in later-stage clinical trials, could offer a superior safety and tolerability profile compared to existing systemic therapies, particularly in the realm of sexual dysfunction. For erectile dysfunction (ED), especially in challenging populations such as post-radical prostatectomy patients or PDE5 inhibitor non-responders, BZ371A could fill a substantial unmet medical need.2 Similarly, for Female Sexual Arousal Disorder (FSAD), where no FDA-approved pharmacological treatments currently exist, APHRA (the BZ371A-based product) could be a first-in-class therapy.4

The FDA Orphan Drug Designation for BZ371A in Anterior Ischemic Optic Neuropathy (AION) is a notable regulatory achievement that underscores its potential in a rare, serious ophthalmic condition.[8] This could provide a more streamlined development path for this indication. The preclinical data supporting efficacy in glaucoma models further broadens its potential in ophthalmology.[10] The platform's extension to inhaled BZ371B for pulmonary diseases like PAH also demonstrates versatility.[2]

The origin of PnPP-19 (BZ371A) as an engineered peptide from a spider toxin, refined to enhance therapeutic effects while minimizing toxicity, is a well-established drug discovery paradigm that may confer some advantages in terms of biological activity and de-risking.[17]

Challenges and Future Directions:

The primary challenge will be to translate promising preclinical and early-phase clinical findings into robust efficacy and safety data in larger, well-controlled Phase 2 and Phase 3 trials. While Phase 1 studies have reported good local tolerability and no systemic exposure for topical formulations 4, comprehensive, peer-reviewed publications of these Phase 1 results, including detailed pharmacokinetic and safety data, are essential for a thorough external assessment.

For the sexual dysfunction programs (ED and FSAD), demonstrating clinically meaningful efficacy that is superior to or complementary to existing options (or placebo, in the case of FSAD) will be critical. The design of FSAD trials is notoriously complex, and Biozeus's approach, incorporating FDA guidance with subjective and objective endpoints, will be keenly watched.[4]

The multi-modal preclinical activity of PnPP-19, including its effects on opioid and cannabinoid receptors for antinociception [16], presents both an opportunity and a complexity. Further research is needed to determine if these mechanisms contribute to its effects in the current lead indications or if they represent distinct therapeutic possibilities that could be pursued separately.

Commercialization and Partnerships:

Biozeus's stated strategy of out-licensing its products after achieving certain development milestones indicates a reliance on partnerships for late-stage development and commercialization.1 The company is actively seeking partners for ED and FSAD programs in key markets like the EU and US, and is also open to co-investors.4 The success of ongoing Phase 2 trials will be pivotal in attracting such partnerships. The prior licensing of an ED product from the BZ371 platform suggests a precedent for this model.4

Conclusion:

BZ371A, as a lead compound from the BZ371 NOS-enhancing peptide platform, holds considerable promise, particularly for topical treatment of sexual dysfunctions where local action and an improved safety profile are highly desirable. The FDA ODD for AION provides a strategic avenue in a rare disease. Successful completion and positive outcomes from the ongoing Phase 2 trials are crucial next steps to validate the therapeutic potential and attract the partnerships necessary for broader development and market entry. The long-term success will depend on robust demonstration of efficacy, confirmation of the favorable safety profile in larger patient populations, and successful navigation of the regulatory and commercial landscapes.

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