Buloxibutid (C21/VP-01): A Comprehensive Monograph on a First-in-Class AT2R Agonist for Idiopathic Pulmonary Fibrosis

Executive Summary

Buloxibutid is an investigational, first-in-class, orally available small molecule that functions as a potent and highly selective agonist of the Angiotensin II Type 2 Receptor (AT2R).[1] Developed by Vicore Pharma, it is primarily being evaluated for the treatment of Idiopathic Pulmonary Fibrosis (IPF), a chronic, progressive, and ultimately fatal lung disease characterized by an irreversible decline in lung function.[3] The current standard of care for IPF, comprising the antifibrotic agents nintedanib and pirfenidone, offers only a modest benefit by slowing the rate of disease progression and is frequently associated with significant tolerability issues that lead to treatment discontinuation.[5]

Buloxibutid represents a paradigm shift in the therapeutic approach to IPF. Its novel, upstream mechanism of action targets the protective arm of the renin-angiotensin system, which is highly expressed on alveolar epithelial type 2 cells (AEC2s), the progenitor cells critical for lung repair.[7] By stimulating these cells, Buloxibutid promotes a multimodal cascade of effects, including the inhibition of pro-fibrotic signaling, the resolution of existing scar tissue, and the active repair of the alveolar structure.[7]

This unique mechanism provides a strong biological rationale for the unprecedented clinical results observed in the Phase IIa AIR trial. In this study, treatment with Buloxibutid over 36 weeks resulted not in a slowing of functional decline, but in a statistically significant mean improvement in Forced Vital Capacity (FVC), the primary measure of lung function in IPF.[11] This remarkable efficacy signal was coupled with an excellent safety and tolerability profile, notably a lack of the severe gastrointestinal side effects that plague current therapies.[11]

The ongoing, global Phase IIb ASPIRE trial is designed to confirm these findings in a larger, placebo-controlled setting.[3] If the results of the AIR trial are replicated, Buloxibutid’s differentiated profile—combining a potentially disease-modifying reparative mechanism, superior clinical efficacy, and a favorable safety profile—positions it to become a transformative, foundational therapy for IPF, addressing the profound unmet medical need of this devastating disease.

Section 1: Compound Profile and Physicochemical Properties

1.1. Identification and Nomenclature

Buloxibutid is a small molecule drug candidate that has been assigned multiple identifiers and developmental codes throughout its history. A comprehensive list is essential for accurate cross-referencing across scientific literature, clinical trial registries, and chemical databases.

• Generic Name: Buloxibutid [1]
• Synonyms and Developmental Codes: The compound is widely known by its developmental code C21. Other identifiers used include C 21, C-21, COMPOUND 21, AT2 Agonist C21, M24, and VP-01.[1]
• Database and Registry Identifiers:
• DrugBank ID: DB18038 [1]
• CAS Number: 477775-14-7 [1]
• UNII (Unique Ingredient Identifier): RC2V4W0EYC [1]
• PubChem CID: 9804984 [15]
• ChEMBL ID: ChEMBL189568 [15]
• IUPAC Name: The systematic chemical name for the compound is butyl N-[4-(imidazol-1-ylmethyl)phenyl]-5-(2-methylpropyl)thiophen-2-yl]sulfonylcarbamate.[15]

1.2. Chemical Structure and Properties

Buloxibutid is classified as a small molecule belonging to several chemical classes, including amides, sulfones, and sulfur compounds, reflecting its complex structure.[1] Its fundamental chemical and physical characteristics are critical determinants of its pharmacokinetic and pharmacodynamic behavior.

• Chemical Formula:  [1]
• Molecular Weight: The average molecular weight is reported as 475.62 g·mol⁻¹ to 475.63 g·mol⁻¹, with a precise monoisotopic mass of 475.159948774 Da.[1]
• Structural Representations:
• SMILES: CCCCOC(=O)NS(=O)(=O)C1=C(C=C(CC(C)C)S1)C1=CC=C(CN2C=CN=C2)C=C1 [1]
• InChI: InChI=1S/C23H29N3O4S2/c1-4-5-12-30-23(27)25-32(28,29)22-21(14-20(31-22)13-17(2)3)19-8-6-18(7-9-19)15-26-11-10-24-16-26/h6-11,14,16-17H,4-5,12-13,15H2,1-3H3,(H,25,27) [1]
• Physicochemical Parameters: The compound's physicochemical properties, summarized in Table 1, provide a quantitative basis for understanding its drug-like characteristics. The high logarithmic partition coefficient (logP) indicates significant lipophilicity, while the polar surface area and hydrogen bonding capacity are within ranges typical for orally administered drugs.

Table 1: Buloxibutid Identification and Physicochemical Properties

Parameter	Value	Source
Generic Name	Buloxibutid	1
DrugBank ID	DB18038	1
CAS Number	477775-14-7	1
Chemical Formula		1
Molecular Weight (Average)	475.62 g·mol⁻¹	1
logP	4.58	1
pKa (Strongest Acidic)	4.61	1
pKa (Strongest Basic)	6.47	1
Polar Surface Area	90.29 Ų	1
Hydrogen Bond Acceptors	4	1
Hydrogen Bond Donors	1	1
Rotatable Bonds	10	1

1.3. Formulation, Solubility, and Stability

The practical aspects of handling and administering Buloxibutid are directly influenced by its physicochemical properties. As a white to yellow solid powder, its solubility profile is a key consideration for formulation development.[18]

• Solubility: The high logP value of 4.58 is predictive of the compound's observed solubility characteristics: it is reported as insoluble in water but highly soluble in organic solvents such as dimethyl sulfoxide (DMSO), with reported concentrations reaching 50-95 mg/mL.[14] This inherent lipophilicity, while often beneficial for membrane permeability and absorption, presents a significant challenge for creating an aqueous formulation suitable for administration. The successful development of an oral dosage form for Buloxibutid is therefore critically dependent on advanced formulation science. Detailed protocols have been published for preparing in vivo solutions using various excipients and co-solvents, including combinations of DMSO, PEG300, Tween-80, SBE-β-CD, and corn oil, to create stable and bioavailable suspensions or solutions.[18] This demonstrates that the challenge of poor aqueous solubility has been overcome to enable effective oral delivery in clinical settings.
• Storage and Stability: For research and manufacturing purposes, specific storage conditions are required to maintain the compound's integrity. The powder form is stable for up to three years when stored at -20°C. Once dissolved in a solvent, stock solutions should be aliquoted and stored at -80°C for long-term stability (up to one year) to prevent degradation from repeated freeze-thaw cycles.[14]

Section 2: Pharmacology and Mechanism of Action

2.1. The Renin-Angiotensin System (RAS) in Lung Fibrosis

The therapeutic rationale for Buloxibutid is rooted in a modern understanding of the Renin-Angiotensin System (RAS). Classically, the RAS is known for its "pressor" arm, where angiotensin II binds to the Angiotensin II Type 1 Receptor (AT1R), leading to vasoconstriction, inflammation, sodium retention, and fibrosis—all processes implicated in the pathogenesis of IPF. However, the RAS also contains a counter-regulatory, protective "non-pressor" arm, mediated primarily by the Angiotensin II Type 2 Receptor (AT2R).[1] Activation of the AT2R generally opposes the effects of AT1R signaling, promoting vasodilation, anti-inflammatory effects, and tissue repair.[2] Buloxibutid is designed to selectively harness this protective pathway, representing a targeted therapeutic strategy to rebalance the RAS in favor of tissue regeneration and away from fibrosis.

2.2. Primary Target and Binding Affinity

Buloxibutid's pharmacological activity is defined by its precise and potent interaction with its molecular target.

• Target: The primary molecular target is the human Type-2 angiotensin II receptor (AGTR2), a 41 kDa G-protein coupled receptor.[1]
• Action: Buloxibutid functions as a direct agonist of the AT2R, meaning it binds to and activates the receptor to initiate downstream signaling.[1]
• Selectivity: The compound exhibits exceptional selectivity for the AT2R over the AT1R. The reported binding affinity (Ki) for AT2R is 0.4 nM, indicating very high potency. In contrast, its affinity for the AT1R is greater than 10,000 nM (>10 µM).[14] This translates to a selectivity ratio of over 25,000-fold, which is a critical feature. This high degree of selectivity ensures that the therapeutic effects are precisely mediated through the protective AT2R pathway, while avoiding the potentially detrimental pro-fibrotic and pro-inflammatory consequences of activating the AT1R.

2.3. Molecular Mechanism of Action: An Upstream, Multimodal Approach

Buloxibutid is described as a first-in-class therapeutic that engages an "upstream" mechanism with multimodal effects, distinguishing it from existing IPF treatments.[2] This mechanism is centered on the AT2R, which is highly expressed on alveolar epithelial type 2 cells (AEC2s).[7] AEC2s are the progenitor cells of the lung alveoli; they are responsible for producing surfactant and differentiating into alveolar epithelial type 1 cells (AEC1s) to repair lung tissue after injury. In IPF, AEC2s are dysfunctional, contributing directly to the fibrotic process.[7]

By agonizing the AT2R on these critical cells, Buloxibutid initiates a coordinated cascade of reparative and anti-fibrotic actions:

1. Promotes Alveolar Repair and Integrity: Preclinical and ex vivo studies using human lung tissue have demonstrated that Buloxibutid directly enhances the health and function of AEC2s. It improves their viability, stimulates the secretion of essential surfactants like surfactant protein B and C (with increases of 70% and 120%, respectively), and promotes their differentiation to replenish the gas-exchanging AEC1 population. This process actively restores the fundamental structure and function of the alveoli, addressing the root cause of tissue damage in IPF.[7]
2. Inhibits Pro-Fibrotic Signaling: Buloxibutid directly counteracts the central driver of fibrosis, Transforming Growth Factor beta 1 (TGFβ1). In precision-cut human IPF lung slices, clinically relevant concentrations of Buloxibutid dose-dependently reduced TGFβ1 protein expression by up to 61% and mRNA expression by up to 56%.[8] This potent inhibition of TGFβ1 signaling leads to downstream reductions in the differentiation of fibroblasts into myofibroblasts (the primary collagen-producing cells) and a decrease in the production of extracellular matrix components like collagen type I alpha 1, which was reduced by 45%.[8]
3. Enhances Resolution of Existing Fibrosis: In addition to preventing new scar formation, Buloxibutid appears to promote the breakdown of existing fibrotic tissue. It achieves this by upregulating the expression of collagenase matrix metalloproteinases (MMPs), such as MMP-13.[7] These enzymes are responsible for degrading excess collagen, thereby facilitating the resolution of established fibrosis.

This mechanism is fundamentally different from that of current therapies, which act further downstream to broadly inhibit fibrotic processes. By targeting the progenitor AEC2s, Buloxibutid acts "upstream" to not only block fibrosis but to actively promote tissue repair and regeneration. This three-pronged approach—inhibiting pro-fibrotic signals, resolving existing scar tissue, and repairing the alveolar epithelium—constitutes a synergistic and potentially disease-modifying therapeutic strategy.

2.4. Preclinical and Ex Vivo Pharmacodynamics

The multimodal mechanism of action has been validated in a range of preclinical and ex vivo models that demonstrate its therapeutic potential across multiple pathological processes relevant to IPF and related conditions.

• Anti-fibrotic and Anti-inflammatory Effects: In experimental models of bleomycin-induced lung injury, Buloxibutid attenuates the progression of lung fibrosis and pulmonary hypertension.[16] In vitro studies using human umbilical vein endothelial cells (HUVECs) show that it prevents TNFα-induced endothelial inflammation, leukocyte adhesion, and reactive oxygen species (ROS) production, effects that were confirmed to be AT2R-mediated.[16]
• Vascular and Hemodynamic Effects: The AT2R is known to mediate vasodilation. In the Sugen-Hypoxia preclinical model of pulmonary hypertension, treatment with Buloxibutid significantly reduced vascular remodeling, improved hemodynamics, and decreased the deposition of collagen in the pulmonary vasculature.[14] These findings suggest a beneficial effect on the vascular dysfunction that often accompanies IPF.
• Renal and Natriuretic Effects: In vivo studies in rats have demonstrated that intravenous infusion of Buloxibutid causes a dose-dependent increase in urine flow and sodium excretion. This effect was completely blocked by an AT2R antagonist, confirming the receptor's involvement and suggesting a potential role for the drug in regulating fluid balance.[16]

Section 3: Clinical Development Program for Idiopathic Pulmonary Fibrosis (IPF)

3.1. Overview of Clinical Program and Regulatory Status

The clinical development of Buloxibutid for IPF is being conducted by Vicore Pharma AB.[3] Recognizing the significant unmet medical need in this rare and life-threatening disease, regulatory agencies worldwide have granted the program special designations to facilitate and expedite its development.

• Orphan Drug Designation: This status, which provides incentives for the development of drugs for rare diseases, has been granted to Buloxibutid for IPF by the European Commission (2016), the United States Food and Drug Administration (FDA) (2017), and Japan's Ministry of Health, Labour and Welfare (MHLW) (2025).[3]
• Fast Track Designation: In January 2025, the US FDA granted Buloxibutid Fast Track designation. This is intended to expedite the review of drugs that treat serious conditions and fill an unmet medical need, allowing for more frequent interactions with the FDA and eligibility for accelerated approval and priority review.[3]

3.2. Phase I Pharmacodynamic Evaluation (NCT05277922)

The first-in-human study of Buloxibutid was a Phase I, open-label, pharmacodynamic trial designed to confirm its predicted vascular effects in a clinical setting.[21] The study enrolled five healthy male volunteers and used venous occlusion plethysmography to measure forearm blood flow (FBF).

• Methodology: Ascending microdoses of Buloxibutid (ranging from 3 to 200 µg/min) were infused sequentially via an intra-arterial line into the forearm. This method allowed for the assessment of local vascular effects while minimizing systemic exposure.[21]
• Results: The study successfully demonstrated a dose-dependent vasodilatory response. Infusion of Buloxibutid led to increases in FBF ranging from 17.2% to a maximum of 60.5% at the highest dose, compared to baseline.[21] These findings provided the first clinical evidence in humans that Buloxibutid activates the AT2R pathway to produce a physiological effect consistent with its mechanism of action.
• Safety: The intra-arterial infusions were safe and well-tolerated. There were no drug-related adverse events reported and no clinically relevant changes in systemic blood pressure or heart rate, confirming the safety of the compound at these dose levels in an acute setting.[21]

3.3. Phase IIa AIR Trial (NCT04533022): A Paradigm-Shifting Proof-of-Concept in IPF

The AIR trial was a pivotal proof-of-concept study that generated highly encouraging and unexpected results, setting the stage for late-stage development.

3.3.1. Study Design and Patient Population

AIR was a 36-week, multicenter, open-label, single-arm trial that enrolled 52 participants with a centrally confirmed diagnosis of IPF who were not receiving approved anti-fibrotic therapy. All participants received oral Buloxibutid at a dose of 100 mg twice daily (BID).[4] The primary objective was to evaluate the safety and efficacy of the drug, with the primary efficacy endpoint being the change in FVC from baseline.

3.3.2. Efficacy Results - Forced Vital Capacity (FVC)

The efficacy results from the AIR trial were remarkable and represented a potential breakthrough in IPF treatment. The historical and expected trajectory for untreated IPF patients is a progressive and irreversible decline in FVC, estimated at approximately 180 mL over a 36-week period.[11] Buloxibutid not only halted this decline but appeared to reverse it.

Table 2: Summary of Phase IIa AIR Trial Efficacy and Biomarker Results

Endpoint	Result	Timepoint	N-value	Significance
Mean Change in FVC from Baseline (mL)	+216 mL	36 weeks	28	p<0.001 vs. expected decline
Responder Rate: FVCpp Increase >0%	40%	36 weeks	48	N/A
Responder Rate: FVCpp Increase >5%	25%	36 weeks	48	N/A
Responder Rate: FVCpp Increase >10%	19%	36 weeks	48	N/A
Change in Plasma TGFβ1	-57%	24 weeks	27	N/A
Change in Plasma MMP-13	+67%	24 weeks	27	p=0.01

• Primary Finding: The final analysis of patients who completed 36 weeks of treatment (n=28) showed a mean increase in observed FVC of 216 mL from baseline. This represents a positive difference of nearly 400 mL compared to the expected decline in untreated patients (p<0.001).[11] This result challenges the long-held belief that lung function loss in IPF is irreversible and suggests a potential for disease modification.
• Responder Analysis: A high proportion of patients experienced a clinically meaningful improvement in lung function, as detailed in Table 2. At 36 weeks, 40% of patients in the full analysis set (n=48) had an increase in FVC percent predicted (FVCpp) from baseline. Notably, 25% of patients had an improvement of >5%, and 19% had an improvement of >10%.[4] These responder rates compare very favorably with those from the pivotal trials of the current standard-of-care therapies, where only 6-11% of patients achieved a >5% increase in FVCpp over 52 weeks.[4]

3.3.3. Biomarker Analysis

The compelling clinical efficacy data were strongly supported by changes in plasma biomarkers that directly reflect Buloxibutid's proposed mechanism of action.

• TGFβ1: A trend towards a reduction in plasma levels of the key pro-fibrotic cytokine TGFβ1 was observed, with one analysis reporting a 57% decrease at 24 weeks.[11] This provides evidence that the drug is engaging its target and inhibiting a central pathway of fibrosis.
• MMP-13: Conversely, plasma levels of MMP-13, a collagenase enzyme involved in the breakdown of scar tissue, showed a statistically significant increase of 67% at 24 weeks (p=0.01).[13] This supports the hypothesis that Buloxibutid promotes the resolution of existing fibrosis.

3.3.4. Safety and Tolerability Profile

A key differentiator for Buloxibutid in the AIR trial was its excellent safety and tolerability profile, particularly in contrast to existing IPF therapies.

• Serious Adverse Events (SAEs): Crucially, there were no drug-related SAEs, severe adverse events, or treatment-related deaths reported during the 36-week study.[11]
• Gastrointestinal (GI) Tolerability: The drug demonstrated excellent GI tolerability.[11] This is a major potential advantage, as severe diarrhea and nausea are the primary dose-limiting toxicities for nintedanib and pirfenidone, respectively, leading to high rates of treatment discontinuation in the real world.
• Most Common Adverse Event: The most frequently reported treatment-emergent adverse event considered potentially related to the drug was mild to moderate, reversible hair loss (alopecia), which occurred in 10 of the 52 participants (19.2%). Only one patient discontinued treatment due to this side effect, suggesting it was generally manageable.[13]

3.4. Phase IIb ASPIRE Trial (NCT06588686): Design and Objectives of the Pivotal Confirmatory Study

Building on the highly successful AIR trial, Vicore Pharma has initiated the ASPIRE trial, a global, pivotal study designed to confirm the efficacy and safety of Buloxibutid in a rigorous, controlled setting.

• Study Design: ASPIRE is a 52-week, randomized, double-blind, placebo-controlled, parallel-group trial.[3]
• Enrollment and Arms: The trial plans to enroll 270 participants with IPF, randomized 1:1:1 into three arms (90 patients per arm):

1. Buloxibutid 100 mg BID
2. Buloxibutid 50 mg BID
3. Placebo BID.[12]

• Patient Population: The study will enroll a broad IPF population, including patients who are treatment-naïve as well as those on a stable background therapy of nintedanib. This design will allow for evaluation of Buloxibutid as both a monotherapy and an add-on treatment.[5]
• Primary Endpoint: The primary efficacy endpoint is the absolute change from baseline in FVC (in mL) at week 52. This is the established registrational endpoint required by regulatory authorities for the approval of new IPF therapies.[3]
• Key Secondary Endpoints: Secondary objectives include comprehensive assessments of safety, tolerability, pharmacokinetics, and the proportion of patients with disease progression (defined as a composite of FVC decline, hospitalization, or death).[12]

Section 4: Pharmacokinetics and Drug-Drug Interaction Profile

4.1. ADME Profile

Comprehensive data on the absorption, distribution, metabolism, and excretion (ADME) of Buloxibutid in humans is being formally collected as part of the ongoing clinical trials.[7] However, preclinical data and the design of the clinical studies provide important initial information.

• Pharmacokinetics in Animals: Studies in rats indicate that Buloxibutid has an oral bioavailability of 20-30% and an estimated plasma half-life of approximately 4 hours.[18] This pharmacokinetic profile is consistent with and supports the twice-daily (BID) oral dosing regimen being used in the clinical trials.

4.2. Potential for Drug-Drug Interactions (DDIs)

The protocols for the Phase II trials offer significant clues regarding the metabolic pathways of Buloxibutid and its potential for clinically relevant drug-drug interactions (DDIs).

• CYP450 Metabolism: The protocol for the Phase IIa AIR trial included exclusion criteria for patients receiving concomitant treatment with strong inducers (e.g., rifampicin, St. John's Wort) or strong inhibitors (e.g., ketoconazole, clarithromycin) of the Cytochrome P450 3A4 (CYP3A4) enzyme.[31] This is a standard practice in clinical trials when a drug is known or suspected to be a substrate of a specific CYP enzyme. It strongly suggests that CYP3A4 is a major pathway for the metabolism of Buloxibutid.
• Interaction with Pirfenidone: A critical element of the Phase IIb ASPIRE trial design is the explicit prohibition of concomitant treatment with pirfenidone, one of the current standards of care for IPF. The protocol cites the potential risk of DDIs as the reason for this exclusion.[25] This indicates that a clinically significant interaction between Buloxibutid and pirfenidone is known or highly suspected, which will have direct implications for future clinical practice.
• Compatibility with Nintedanib: In contrast, the ASPIRE trial is specifically designed to evaluate Buloxibutid as an add-on therapy for patients on a stable dose of nintedanib.[3] This implies that no clinically prohibitive DDI is expected between Buloxibutid and nintedanib, allowing for their potential use in combination. The differing DDI profiles with the two standard-of-care agents create a bifurcated and strategically important pathway for the clinical positioning of Buloxibutid. It can be envisioned as a replacement for pirfenidone (in monotherapy) or as a complementary add-on to nintedanib.

Section 5: Competitive Landscape and Future Outlook

5.1. Current Standard of Care for IPF: Nintedanib and Pirfenidone

The therapeutic landscape for IPF is currently dominated by two approved antifibrotic drugs: nintedanib (Ofev®) and pirfenidone (Esbriet®). While they represented a major advance at the time of their approval, they have significant limitations.

• Mechanism of Action: Both drugs act as broad, downstream inhibitors of fibrotic processes. Nintedanib is a multi-tyrosine kinase inhibitor that targets receptors involved in fibroblast proliferation and differentiation, such as VEGFR, FGFR, and PDGFR.[32] Pirfenidone has a less well-defined mechanism but is known to inhibit TGFβ-induced collagen synthesis and reduce the production of other pro-fibrotic and pro-inflammatory mediators.[32]
• Efficacy: The established clinical benefit of both nintedanib and pirfenidone is a slowing of the rate of FVC decline by approximately 50% compared to placebo over one year.[33] They do not halt the progression of the disease, nor do they reverse existing fibrosis or improve lung function. Head-to-head and real-world studies suggest their efficacy is broadly comparable.[36]
• Tolerability and Safety: The use of both drugs is severely limited by their adverse event profiles.
• Nintedanib: The most common and problematic side effect is diarrhea, which occurs in over 60% of patients and can be severe, often leading to dose reduction or discontinuation. Nausea, vomiting, and elevated liver enzymes are also common.[32]
• Pirfenidone: The most common side effects are gastrointestinal (nausea, dyspepsia, anorexia) and dermatological, specifically a photosensitivity rash that requires patients to practice strict sun avoidance and use high-SPF sunscreen year-round.[33]
• Unmet Need: Due to this significant side effect burden, a large proportion of IPF patients either cannot tolerate the medications, must take reduced and potentially less effective doses, or choose not to initiate therapy at all.[5] This leaves a substantial unmet need for more effective and better-tolerated treatments.

5.2. Buloxibutid's Differentiated Profile: A Comparative Analysis

Buloxibutid is not positioned as an incremental improvement over the current standard of care but as a potentially disruptive therapy with a fundamentally different profile, as summarized in Table 3. The combination of a novel, reparative mechanism, a signal of efficacy that surpasses the established benchmark of slowing decline, and a markedly improved safety and tolerability profile suggests that Buloxibutid could redefine the treatment goals for IPF.

Table 3: Comparative Profile: Buloxibutid vs. Standard of Care (Nintedanib & Pirfenidone)

Feature	Buloxibutid (Based on Phase IIa data)	Nintedanib	Pirfenidone
Mechanism of Action	Upstream AT2R Agonist; Promotes alveolar repair, inhibits TGFβ1, resolves fibrosis	Downstream Multi-Tyrosine Kinase Inhibitor	Downstream Broad Antifibrotic and Anti-inflammatory
Primary Efficacy Outcome	Mean FVC Improvement (+216 mL at 36 wks)	Slowing of FVC Decline (~50% vs. placebo)	Slowing of FVC Decline (~50% vs. placebo)
Key Adverse Events	Reversible mild/moderate hair loss (19%); Excellent GI tolerability	Diarrhea (>60%), Nausea, Vomiting, Elevated LFTs	Nausea, Dyspepsia, Anorexia, Photosensitivity Rash
Dosing Frequency	Twice Daily (BID)	Twice Daily (BID)	Thrice Daily (TID)

5.3. Future Directions and Unanswered Questions

The future of Buloxibutid hinges on the successful outcome of the ongoing Phase IIb ASPIRE trial.

• Primary Question: The most critical question is whether the large, randomized, placebo-controlled ASPIRE trial will confirm the magnitude and statistical significance of the FVC benefit observed in the open-label AIR trial. Replication of an FVC improvement, or even stabilization, would be a transformative result.
• Long-Term Outcomes: ASPIRE will also provide crucial data on key secondary endpoints, including the drug's impact on disease progression, respiratory-related hospitalizations, and all-cause mortality, which are essential for defining its full clinical value.
• Potential in Other Indications: The mechanism of Buloxibutid, which involves promoting vasodilation and reducing vascular remodeling, suggests therapeutic potential beyond IPF. Indeed, development programs have been reported for other conditions associated with vascular dysfunction and fibrosis, including pulmonary arterial hypertension and Raynaud's disease.[17]

Conclusion

Buloxibutid (C21) has emerged as a highly promising, first-in-class investigational therapy for Idiopathic Pulmonary Fibrosis. Its unique, upstream mechanism of action, centered on the selective agonism of the protective AT2R on alveolar progenitor cells, offers a fundamentally different therapeutic strategy from the current standard of care. Rather than merely slowing the downstream consequences of fibrosis, Buloxibutid appears to promote a multimodal response of tissue repair, fibrosis inhibition, and scar resolution.

The results from the Phase IIa AIR trial provide compelling, albeit early, evidence of this mechanism's potential, demonstrating an unprecedented average improvement in lung function and a favorable safety profile that stands in stark contrast to the tolerability issues of existing agents. This combination of superior efficacy and safety positions Buloxibutid not as an incremental advance, but as a potentially disruptive technology capable of shifting the treatment paradigm from managing decline to promoting recovery.

The ongoing Phase IIb ASPIRE trial is the pivotal next step. Its design is well-suited to definitively answer whether the remarkable promise shown in early studies can be translated into a robust, statistically validated clinical benefit. If successful, Buloxibutid has the potential to become the new cornerstone of IPF therapy, offering a more effective and better-tolerated treatment that could meaningfully alter the course of this devastating disease.

Works cited

1. Buloxibutid: Uses, Interactions, Mechanism of Action | DrugBank ..., accessed October 7, 2025, https://go.drugbank.com/drugs/DB18038
2. vicorepharma.com, accessed October 7, 2025, https://vicorepharma.com/our-programs/rare-lung-diseases/c21-ipf-fibrosis/#:~:text=Buloxibutid%20(C21)%20is%20a%20first,of%20the%20renin%2Dangiotensin%20system.
3. Buloxibutid Receives Orphan Drug Designation in Japan for the Treatment of Idiopathic Pulmonary Fibrosis - BioSpace, accessed October 7, 2025, https://www.biospace.com/press-releases/buloxibutid-receives-orphan-drug-designation-in-japan-for-the-treatment-of-idiopathic-pulmonary-fibrosis
4. The AIR Phase 2 Trial of the Angiotensin II Type 2 Receptor Agonist ..., accessed October 7, 2025, https://www.atsjournals.org/doi/10.1164/ajrccm.2025.211.Abstracts.A7747
5. The FDA Grants Vicore's Buloxibutid Fast Track Designation for Idiopathic Pulmonary Fibrosis, accessed October 7, 2025, https://vicorepharma.com/mfn_news/the-fda-grants-vicores-buloxibutid-fast-track-designation-for-idiopathic-pulmonary-fibrosis/
6. Pirfenidone and Nintedanib in Pulmonary Fibrosis: Lights and Shadows - MDPI, accessed October 7, 2025, https://www.mdpi.com/1424-8247/17/6/709
7. Buloxibutid - Pulmonary Fibrosis Foundation, accessed October 7, 2025, https://www.pulmonaryfibrosis.org/patients-caregivers/medical-and-support-resources/clinical-trials-education-center/pipeline/drug/idiopathic-pulmonary-fibrosis/vp01-(c21)
8. Effects of the angiotensin II type 2 receptor agonist buloxibutid on ..., accessed October 7, 2025, https://publications.ersnet.org/content/erj/64/suppl68/PA3380
9. Study Details | NCT06588686 | A Trial to Evaluate Efficacy and ..., accessed October 7, 2025, https://clinicaltrials.gov/study/NCT06588686
10. VICORE PHARMA - Final Phase 2a AIR Data for Buloxibutid in IPF, accessed October 7, 2025, https://vicorepharma.com/wp-content/uploads/2024/05/buloxibutid-ats-ph2a-air-data-webcast_22may2024.pdf
11. Vicore Announces Positive Final Results from the Phase 2a AIR ..., accessed October 7, 2025, https://vicorepharma.com/mfn_news/vicore-announces-positive-final-results-from-the-phase-2a-air-trial-demonstrating-buloxibutid-improves-lung-function-over-36-weeks-in-patients-with-idiopathic-pulmonary-fibrosis/
12. Vicore Initiates the Global, Randomized Phase 2b ASPIRE Trial Evaluating the Disease-Modifying Potential of Buloxibutid in Idiopathic Pulmonary Fibrosis - PSI CRO, accessed October 7, 2025, https://psi-cro.com/vicore-initiates-the-global-randomized-phase-2b-aspire-trial-evaluating-the-disease-modifying-potential-of-buloxibutid-in-idiopathic-pulmonary-fibrosis/
13. Buloxibutid, A Novel Angiotensin II Type 2 Receptor Agonist, Stabilized and Improved Lung Function in Individuals - ATS Journals, accessed October 7, 2025, https://www.atsjournals.org/doi/pdf/10.1164/ajrccm-conference.2024.209.1_MeetingAbstracts.A1055?download=true
14. Buloxibutid | Angiotensin Receptor agonist | Mechanism ..., accessed October 7, 2025, https://www.selleckchem.com/products/buloxibutid.html
15. Buloxibutid - Wikipedia, accessed October 7, 2025, https://en.wikipedia.org/wiki/Buloxibutid
16. AT2 Agonist C21 | Buloxibutid | CAS#477775-14-7 - MedKoo Biosciences, accessed October 7, 2025, https://www.medkoo.com/products/16861
17. Vicore Pharma - Buloxibutid - AdisInsight - Springer, accessed October 7, 2025, https://adisinsight.springer.com/drugs/800052428
18. Buloxibutid (Synonyms: AT2 receptor agonist C21) - MedchemExpress.com, accessed October 7, 2025, https://www.medchemexpress.com/buloxibutid.html
19. 3D structure for Buloxibutid (DB18038) | DrugBank Online, accessed October 7, 2025, https://go.drugbank.com/structures/small_molecule_drugs/DB18038
20. Buloxibutid (C21) – IPF - Vicore Pharma, accessed October 7, 2025, https://vicorepharma.com/our-programs/rare-lung-diseases/c21-ipf-fibrosis/
21. Utilizing venous occlusion plethysmography to assess vascular ..., accessed October 7, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10859786/
22. Utilizing venous occlusion plethysmography to assess vascular effects: A study with buloxibutid, an angiotensin II type 2 receptor agonist - PubMed, accessed October 7, 2025, https://pubmed.ncbi.nlm.nih.gov/38344891/
23. Conclusions Results Background and rationale Methods, accessed October 7, 2025, https://vicorepharma.com/wp-content/uploads/2024/10/air-iclaf-2024.pdf
24. AIR – an open-label, 36-week, clinical trial of buloxibutid – investigating the disease modifying potential of a novel angiotensin II type 2 receptor agonist in IPF - ERS Publications, accessed October 7, 2025, https://publications.ersnet.org/content/erj/64/suppl68/oa2859
25. A Trial to Evaluate Efficacy and Safety of Buloxibutid in People With Idiopathic Pulmonary Fibrosis. | Clinical Research Trial Listing - CenterWatch, accessed October 7, 2025, https://www.centerwatch.com/clinical-trials/listings/NCT06588686/a-trial-to-evaluate-efficacy-and-safety-of-buloxibutid-in-people-with-idiopathic-pulmonary-fibrosis
26. Buloxibutid in People With Idiopathic Pulmonary Fibrosis. - UCSD Clinical Trials, accessed October 7, 2025, https://clinicaltrials.ucsd.edu/trial/NCT06588686
27. A Trial to Evaluate Efficacy and Safety of Buloxibutid in People With Idiopathic Pulmonary Fibrosis., accessed October 7, 2025, https://www.trialstoday.org/trial/NCT06588686
28. Buloxibutid for Idiopathic Pulmonary Fibrosis - Clinrol, accessed October 7, 2025, https://www.clinrol.com/study/NCT06588686
29. ASPIRE IPF Ph2b trial - Vicore Pharma, accessed October 7, 2025, https://vicorepharma.com/our-programs/pipeline/aspire-ph2b-trial/
30. A Trial to Evaluate Efficacy and Safety of Buloxibutid in People With Idiopathic Pulmonary Fibrosis. | MedPath, accessed October 7, 2025, https://trial.medpath.com/clinical-trial/c020aa8b9926af77/nct06588686-efficacy-safety-buloxibutid-pulmonary-fibrosis
31. Study Details | NCT04533022 | Safety, Efficacy and Pharmacokinetics of C21 in Subjects With IPF | ClinicalTrials.gov, accessed October 7, 2025, https://clinicaltrials.gov/study/NCT04533022
32. Efficacy and safety of combination therapy with pirfenidone and nintedanib in patients with idiopathic pulmonary fibrosis - Frontiers, accessed October 7, 2025, https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1301923/full
33. A Comparison of the Effectiveness of Nintedanib and Pirfenidone in ..., accessed October 7, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10945152/
34. Pirfenidone and Nintedanib in idiopathic pulmonary fibrosis: Real ..., accessed October 7, 2025, https://www.journalpulmonology.org/en-pirfenidone-nintedanib-in-idiopathic-pulmonary-articulo-S2531043718300990
35. Use of Nintedanib and Pirfenidone in Non–Idiopathic Pulmonary Fibrosis Lung Disease | American Journal of Respiratory and Critical Care Medicine, accessed October 7, 2025, https://www.atsjournals.org/doi/full/10.1164/rccm.202012-4356RR
36. Comparison of the Effects of Nintedanib and Pirfenidone on Pulmonary Function Test Parameters and Radiological Findings in Patients with Idiopathic Pulmonary Fibrosis: A Real-Life Study - MDPI, accessed October 7, 2025, https://www.mdpi.com/1648-9144/61/2/283
37. Pirfenidone vs. nintedanib in patients with idiopathic pulmonary fibrosis: a retrospective cohort study - PubMed, accessed October 7, 2025, https://pubmed.ncbi.nlm.nih.gov/34666765/
38. Idiopathic pulmonary fibrosis - Treatment - NHS, accessed October 7, 2025, https://www.nhs.uk/conditions/idiopathic-pulmonary-fibrosis/treatment/
39. Nintedanib and Pirfenidone - antifibrotics for pulmonary fibrosis ..., accessed October 7, 2025, https://www.actionpf.org/information-support/anti-fibrotic-treatments-for-ipf