Pliant Therapeutics Reports Progress in Integrin-Based RNAi Delivery Platform, Advances Oncology Trial

Pliant Therapeutics is advancing its integrin-mediated drug delivery technology following encouraging preclinical findings demonstrating selective delivery of RNA interference (RNAi) therapies to tissues outside the liver. The South San Francisco-based biotechnology company also reported continued progress in its oncology clinical program and announced two additions to its executive leadership team.

In its third-quarter 2026 business update, Pliant highlighted non-human primate data showing that its proprietary delivery platform achieved greater than 75% target gene knockdown in skeletal and cardiac muscle eight weeks after administration, without significant activity in the liver or other unintended tissues.

The platform is designed to use integrin receptors as entry points for directing therapeutic payloads to specific cells and tissues. Drawing on a library of more than 15,000 characterized integrin-binding molecules and its understanding of tissue-specific receptor expression, Pliant is developing targeted delivery compounds intended to expand the reach of RNAi-based medicines beyond the liver.

The company’s approach separates the delivery component from the RNAi payload, allowing the same integrin-directed compound to potentially carry different RNAi sequences targeting individual genes. Pliant believes this modular design could support development across multiple therapeutic areas and may eventually accommodate drug payloads beyond RNAi.

Initial development efforts are concentrating on skeletal and cardiac muscle, with plans to pursue indications involving significant unmet medical need. Neuromuscular disorders and rare cardiomyopathies are among the areas being considered, particularly where gene-suppression approaches could offer therapeutic potential.

Pliant expects to provide additional information on its muscle-targeting programs, including preclinical findings, proposed indications and specific gene targets, in the coming months.

Alongside its delivery platform work, Pliant reported continued enrollment progress in FORTIFY, its Phase 1a/1b clinical study of PLN-101095, an oral small-molecule inhibitor targeting the αvβ8 and αvβ1 integrins.

The investigational drug is designed to interfere with activation of transforming growth factor beta (TGF-β), a signaling pathway associated with immune suppression in the tumor microenvironment. By inhibiting this pathway, Pliant aims to improve the effectiveness of immune checkpoint inhibitors in patients whose cancers have progressed despite prior treatment.

FORTIFY (NCT06270706) is evaluating PLN-101095 in combination with pembrolizumab in patients with advanced or metastatic solid tumors that have not responded to immune checkpoint inhibitor therapy.

The Phase 1b expansion portion will include as many as 102 patients across three groups: non-small cell lung cancer, clear cell renal cell carcinoma and tumors characterized by high tumor mutational burden.

Patients initially receive PLN-101095 at 1,000 mg twice daily as monotherapy for 14 days, followed by the addition of pembrolizumab. Enrollment continued ahead of schedule during the third quarter, with participating sites operating in the United States and Spain. The company plans to bring additional countries into the study over the next several months and anticipates interim clinical data in 2027.

Additional findings from the PLN-101095 Phase 1 program were presented at the annual meeting of the Society for Immunotherapy of Cancer (SITC). Pliant researchers reported that early increases in immune activation biomarkers during the initial monotherapy period were associated with subsequent clinical responses after pembrolizumab was introduced.

The findings offer preliminary support for the company’s hypothesis that inhibiting TGF-β signaling can help promote immune activation, encourage T-cell recruitment into tumors and strengthen the activity of cancer-killing immune cells.

Separately, researchers from the National Cancer Institute presented preclinical findings examining the combined inhibition of αvβ8 and αvβ1 integrins with anti-PD-1 treatment. The research showed reduced TGF-β signaling, changes in fibroblast populations within the tumor microenvironment and increased infiltration and activation of cytotoxic CD8+ T cells. These effects were associated with improved antitumor activity and survival in the study.

Learn more at www.PliantRx.com.