Buloxibutid (C21, AT2R Agonist) for IPF: AIR & ASPIRE Trials
Vicore's Buloxibutid (C21): first-in-class oral AT2R agonist. AIR Ph2a FVC +216 mL at 36 weeks. FDA Fast Track. ASPIRE Ph2b (NCT06588686) ongoing.
Introduction: A Different Molecular Strategy to Pirfenidone / Nintedanib
Pirfenidone and nintedanib have taught the field that IPF progression can be slowed, but no approved drug has meaningfully improved lung function. Against that backdrop, Vicore Pharma (Sweden) is developing Buloxibutid (C21 / VP01), a first-in-class oral selective AT2 receptor agonist. In the AIR Phase 2a trial, mean FVC increased by +216 mL over 36 weeks, a qualitatively distinct signal from existing SOC[1].
In January 2025, FDA granted Buloxibutid Fast Track designation for IPF[2]. The global ASPIRE Phase 2b trial (NCT06588686) completed enrollment on 22 April 2026 (>360 patients across 100+ sites in 14 countries, including 29 US sites), with a topline readout expected mid-2027[3][6]. This article reviews the mechanism, trial data, preclinical evidence, and competitive landscape using public sources only.
1. Compound Profile
| Item | Detail |
|---|---|
| Generic name (INN) | Buloxibutid |
| Development codes | C21 (Compound 21), VP01 (Vicore internal code) |
| Sponsor | Vicore Pharma Holding AB (Gothenburg, Sweden) |
| Modality | Oral small-molecule, first-in-class non-peptide selective AT2 receptor agonist (ATRAG) |
| Dose | 100 mg PO BID |
| Indication | Idiopathic pulmonary fibrosis (IPF) |
| Status | Phase 2b ASPIRE (NCT06588686) enrollment completed (22 April 2026), 52-week placebo-controlled, n=360, topline mid-2027 expected |
| Regulatory designations | FDA Orphan Drug; FDA Fast Track (January 2025) |
C21 is distinct from peptide AT2R ligands (CGP42112, β-Pro7 Ang III) as an orally active small molecule with a PK profile suitable for chronic dosing.
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2. Disease Context: Why No Drug Has Improved IPF
IPF is driven by recurrent injury to alveolar epithelial type 2 (AEC2) cells and aberrant repair that accumulates myofibroblasts. Approved SOC slows progression but does not restore AEC2 function or resolve established fibrosis, leaving a long-standing demand for a class that can reverse or repair existing fibrosis.
Vicore's hypothesis places Buloxibutid in a space SOC does not address: AT2R-driven AEC2 functional recovery and tissue repair. The AIR trial produced a directional signal consistent with that hypothesis.
3. Mechanism of Action: Driving the "Protective Arm" of RAS via AT2R
The Two Pillars of the RAS: AT1R vs AT2R
The renin-angiotensin system (RAS) contains two receptor classes for angiotensin II: AT1R drives the classical pro-inflammatory, pro-proliferative, pro-fibrotic pathway (antagonized by ARBs such as losartan), while AT2R mediates the counter-regulatory "protective arm"[4]:
- Activation of the NO–cGMP axis
- Antagonism of AT1R signaling via phosphatases such as SHP-1
- Anti-inflammatory, anti-fibrotic, and tissue-repair effects
AT2R Agonism vs ARB: a Fundamental Difference
ARBs remove the AT1R harm, but AT2R agonists push the AT2R benefit, potentially engaging active tissue-protective and reparative actions that ARBs cannot reach. This is the core of Buloxibutid's differentiation within the IPF pipeline.
Action in IPF Pathology
Vicore's proposed mechanism has three pillars: AEC2 functional recovery, attenuation of vascular remodeling, and fibrosis resolution. Preclinically, C21 reduced fibrosis progression, pulmonary hypertension, macrophage infiltration, and collagen accumulation, and improved cardiac function in the bleomycin rat model[4].
4. Clinical Evidence: AIR Phase 2a (36-Week Single-Arm)
| Item | Detail |
|---|---|
| Design | Open-label, single-arm, multicenter, 36 weeks |
| Population | Centrally confirmed IPF; treatment-naïve or SOC-discontinued |
| N | 52 enrolled / 28 in primary efficacy analysis at Week 36 |
| Trial ID | ClinicalTrials.gov: NCT04533022 |
| Dose | Buloxibutid 100 mg PO BID |
| Primary endpoint | Change in FVC from baseline (normalized to 24-week decline rate) |
Key Results[1]
- Mean FVC change from baseline at Week 36: +216 mL (n=28, p<0.001)
- 65% of patients showed FVC improvement
- Plasma MMP-13 increased and TGF-β1 trended lower, consistent with a matrix-remodeling and anti-fibrotic biomarker profile
- Safety: no treatment-related serious AEs. The most characteristic AE was mild-to-moderate, reversible hair thinning (n=10)
- Presented: ATS 2024 (Abstract A1055), ERS 2024 (OA2859)
A placebo-controlled comparison awaits ASPIRE, but an absolute FVC increase in IPF is historically rare, which is why this readout attracted attention.
5. ASPIRE Phase 2b Design (NCT06588686)
| Item | Detail |
|---|---|
| Design | Global, randomized, double-blind, placebo-controlled, parallel-group |
| Duration | 52 weeks |
| Arms | Buloxibutid 100 mg BID / 50 mg BID / placebo |
| N | 360 (expanded from 270) |
| Background | Nintedanib add-on permitted (sub-analysis planned) |
| Primary endpoint | Change in FVC at Week 52 |
| Trial initiation announced | 10 September 2024 (FPI: 9 December 2024) |
| Enrollment completed | 22 April 2026 (>360 patients, 14 countries, 100+ sites)[6] |
| Topline expected | Mid-2027 |
| Cash runway | Into H2 2028 (as of April 2026)[6] |
Two design points are strategically important: ASPIRE permits nintedanib co-administration, enabling evaluation of additive effect on existing SOC, and it performs dose finding (100 vs 50 mg BID) concurrently[3].
6. Competitive Landscape
- Approved SOC: pirfenidone (Esbriet), nintedanib (Ofev) — both slow decline but do not improve function. Nintedanib is a multi-target TKI; pirfenidone is a broad weak-inhibitor.
- Nerandomilast (BI 1015550, brand Jascayd): PDE4B selective inhibitor; FDA approved IPF 2025-10-07 and PPF 2025-12-19 (China NMPA also approved PPF on 2025-12-10). SOC add-on capable.
- Rentosertib (ISM001-055): TNIK inhibitor; GENESIS-IPF Phase 2a showed +98.4 mL FVC change at 12 weeks.
- ENV-101 (taladegib): Hedgehog / SMO inhibitor; Phase 2a TLC between-group difference +257 mL (p=0.004, 12 weeks, Lancet Respir Med 2025).
- Admilparant (BMS-986278): LPA1 antagonist; ALOFT Phase 3 ongoing.
No other AT2R agonist is in IPF clinical development, so Buloxibutid retains the first-in-class position within the AT2R class[4]. Historical studies of ACE inhibitors / ARBs as IPF adjuncts failed to show benefit, reinforcing that AT2R activation, rather than AT1R blockade, is the differentiating strategy here.
7. Preclinical Evaluation
Publicly available C21 preclinical data[4]:
- Bleomycin rat lung fibrosis (Sprague-Dawley, 2.5 mg/kg intratracheal): attenuated progression, reduced pulmonary hypertension, macrophage infiltration, collagen accumulation, and improved cardiac function (Rathinasabapathy 2018, Front Physiol).
- Bleomycin mouse lung fibrosis: comparator study vs β-Pro7 Ang III and pirfenidone (Clin Sci 2025).
- Sugen-hypoxia rat PH model: oral C21 improved pulmonary hypertension.
- In vitro AEC2 bleomycin injury: attenuated alveolar epithelial cell death.
For practical preclinical implementation, see Bleomycin Lung Fibrosis Model Pitfalls, Hydroxyproline Assay, and Ashcroft Score Guide. To capture the AEC2-recovery component of Buloxibutid's MOA, endpoints should extend beyond tissue collagen quantification to include alveolar epithelial markers (SP-C, HOPX, LAMP3).
8. Points to Watch
- ASPIRE Phase 2b readout: whether FVC improvement reproduces under placebo control will define the fate of the entire class.
- Nintedanib combination effect: whether additive benefit on top of SOC is demonstrated. Could establish a standard combination design.
- Dose response: the 100 vs 50 mg BID comparison will set the late-stage dose strategy.
- Follow-on AT2R agonists: whether any class follower advances to Phase 2a, which would indicate generalizability of the MOA.
- Biomarkers capturing AEC2 recovery: integration of SP-D, KL-6, SP-A, or image-based quantitative metrics in Phase 2b.
References
1. Vicore Pharma. Positive final results from the Phase 2a AIR trial: buloxibutid improves lung function over 36 weeks in IPF. Press release, 2024. Vicore Pharma / ATS 2024 Abstract A1055: ATSjournals
2. Vicore Pharma. FDA grants Vicore's buloxibutid Fast Track designation for IPF. Press release, January 2025. Vicore Pharma
3. Vicore Pharma. Vicore initiates the global randomized Phase 2b ASPIRE trial. Press release, September 2024. Vicore Pharma / ClinicalTrials.gov: NCT06588686
4. Rathinasabapathy A, et al. The Selective Angiotensin II Type 2 Receptor Agonist, Compound 21, Attenuates the Progression of Lung Fibrosis and Pulmonary Hypertension in an Experimental Model of Bleomycin-Induced Lung Injury. Front Physiol. 2018;9:180. PubMed 29636695 / Frontiers
5. Vicore Pharma program page – C21 in IPF. Vicore Pharma
6. Vicore Pharma. Vicore completes enrollment in the Phase 2b ASPIRE trial of buloxibutid in IPF. Press release, 2026-04-22. BioSpace