The Fibrotic Frontier
Inside ARO-MMP7 and the Next Phase of Pulmonary RNAi
In the lungs, fibrosis begins as healing that will not stop. Cells meant to repair damage keep working long after the wound has closed, laying down thick scar tissue that stiffens the airways and steals breath a little at a time.
For decades, researchers have sought to interrupt this process—not by suppressing inflammation alone, but by reaching the root of epithelial dysfunction.
Arrowhead Pharmaceuticals believes RNA interference can do exactly that. Its investigational therapy, ARO-MMP7, takes aim at one of the most persistent drivers of fibrotic lung disease: matrix metalloproteinase 7 (MMP7).
1. The Program at a Glance
ARO-MMP7 is an RNA interference (RNAi) therapeutic designed to silence the MMP7 gene in the lung epithelium. MMP7 encodes a secreted enzyme that becomes pathologically overactive in Idiopathic Pulmonary Fibrosis (IPF), contributing to inflammation, abnormal repair, and scar formation.
The drug uses Arrowhead’s inhaled TRiM™ platform, which delivers RNAi triggers directly to epithelial cells through an αvβ6 integrin–targeted ligand. It is administered as a nebulized inhalation solution—marking the first inhaled RNAi therapeutic specifically targeting the biology of pulmonary fibrosis.
2. Why MMP7 Matters
MMP7 is a kind of molecular multitasker. In healthy tissue, it remodels the extracellular matrix and supports repair. In fibrotic disease, however, the same activity turns destructive. Overexpression of MMP7 drives chronic inflammation and epithelial injury, setting off a self-sustaining cycle of fibrosis.
Current IPF drugs modestly slow disease progression but do not address this epithelial origin. By silencing MMP7 itself, Arrowhead aims to interrupt the upstream signal that fuels fibrosis—an approach distinct from small-molecule antifibrotics that act primarily on fibroblasts or extracellular pathways.
3. From Animal Models to Human Trials
Preclinical work established the foundation for clinical development. In bleomycin-induced rat models of pulmonary fibrosis, RNAi-based MMP7 silencing significantly reduced fibrotic lesions, lowered inflammatory cell infiltration, and improved lung compliance. According to study data, treatment completely prevented the 28 percent mortality seen in untreated controls.
In non-human primates, a single inhaled dose achieved greater than 80 percent reduction of MMP7 protein in bronchoalveolar lavage (BAL) samples two weeks post-dose, with sustained knockdown over several months. Experiments in human precision-cut lung slices confirmed potent silencing of MMP7 mRNA (up to 86 percent), bridging animal data to human biology.
While the bleomycin model effectively demonstrates ARO-MMP7’s anti-fibrotic potential, it is an inflammation-heavy system that does not fully replicate the chronic, epithelial-driven pathology of human IPF—so translation to the clinic should be viewed with cautious optimism.
4. The Clinical Path (Updated October 2025)
The first-in-human Phase 1/2a study (NCT05537025) has completed as of September 5 2025, enrolling 105 participants across sites in Denmark, Italy, New Zealand, South Korea, Spain, and the United Kingdom. The interventional design evaluated inhaled, nebulized ARO-MMP7 versus placebo in both healthy volunteers and patients with IPF, progressing through single- and multiple-dose cohorts (15 mg → 224 mg).
The primary endpoint is safety and tolerability (TEAEs), with study end defined as up to 85 days or until sputum MMP7 returns to ≥ 70 percent of baseline, whichever occurs later. Secondary measures include spirometry (FEV₁, FVC) and pharmacokinetics, while exploratory endpoints quantify MMP7 protein in serum, BALF, and bronchosorption samples.
As of the October 15 2025 posting, no results have yet been released, but the data will serve as the first formal test of epithelial-directed RNAi for fibrotic disease.
5. Strategic Positioning
Within Arrowhead’s pulmonary portfolio, ARO-MMP7 represents the anti-fibrosis program (with ARO-RAGE as the anti-inflammation counterpart).
ARO-MUC5AC, originally conceived to reduce mucus hypersecretion, was discontinued at the end of FY 2024 after Arrowhead determined that target engagement could not be reliably assessed with available biomarkers, making further development impractical.
The company credits ARO-RAGE’s robust performance in human trials with de-risking the entire pulmonary platform, proving that inhaled RNAi can safely and effectively reach the lung epithelium. That validation set the stage for MMP7’s entry into the clinic.
Within the broader IPF landscape, ARO-MMP7’s epithelial-targeted RNAi approach distinguishes it from other late-stage programs such as Boehringer Ingelheim’s BI 1015550, a Phase 3 PDE4B inhibitor that modulates inflammation and fibroblast activity, and LYT-100, a deuterated pirfenidone analog in Phase 2 development.
These agents act downstream of the epithelial dysfunction that ARO-MMP7 seeks to correct, underscoring its differentiation while highlighting the intensity of competition in this therapeutic space.
In early 2025, Arrowhead granted Sarepta Therapeutics an exclusive worldwide license to the program, now designated SRP-1002.
Arrowhead completed the Phase 1/2a study and continues to supply clinical material, while Sarepta assumes responsibility for future development and commercialization—potentially exceeding $1 billion in cumulative milestones plus tiered royalties.
6. The Outlook
With dosing complete and data analysis underway, ARO-MMP7 (SRP-1002) stands at a defining threshold. The forthcoming readout will determine whether inhaled RNAi can safely and durably silence a fibrotic pathway in human lungs—something no therapy has yet achieved.
If successful, the implications extend beyond a single disease. A validated pulmonary RNAi platform could reach other interstitial and epithelial lung disorders, offering a modular approach to diseases long considered beyond the reach of genetic medicine.
Now advancing under Sarepta’s banner as SRP-1002, ARO-MMP7 may soon test whether the precision of RNA interference can finally breathe new life into the treatment of pulmonary fibrosis.
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