This year’s ATS meeting was inspiring in terms of progress in research and treatment, and also in how much more is needed. Our biggest takeaway is that idiopathic pulmonary fibrosis (IPF) is a tough nut to crack, and patients need better treatment options. For better or worse, the IPF community across the board recognizes that the existing therapies are simply not good enough for patients from both a survival and quality of life perspective. In addition, nucleotide/AAV gene therapy for lung disease continues to lack significant traction.

The meeting reinforced the core belief on which Gordian’s lung program is founded:

1. Patient matching novel preclinical models are needed that closely resemble human disease features, both pathological and -omic. 
2. Testing the scores of potential targets that patient predictive models produce in such models will be required to maximize probability of translation.  

Gordian aims to bridge this gap by identifying human genetic targets that are active drivers of the disease in preclinical models. These targets can be coupled with existing delivery technology to produce novel therapies for prevalent, age-related disease.

Here are our highlights from #ATS2024:

Progress developing therapies for fibrotic lung diseases

• We were thrilled to see positive results presented from three promising phase 2 clinical trials (Pliant, Endeavor, Vicore). Notably, two of these trials were presented by Dr. Toby Maher, an advisor to the Gordian lung program. 
• Insightful discussions from clinical experts shed light on the data from phase 3 IPF trials and the valuable lessons learned from failures. We learned that phase 2 trials often lack representation from general patient populations (ZEPHYRUS-1 and ISABELA 1 and 2).  
• Academic and industry discussion around the need for better patient segmentation based on omics-based technology. Duke University’s efforts in identifying proteomic markers using samples from the Idiopathic Pulmonary Fibrosis–Prospective Outcomes (IPF-PRO) registry were particularly encouraging. 
• There was an emphasis on the need for composite endpoints to assess treatment efficacy in IPF clinical trials by focusing on how the patient “feels, functions and survives.” There was significant support for designing future IPF clinical trials to include endpoints mirroring the lived experiences of IPF patients by including various clinical outcomes (e.g., respiratory hospitalization and patient-reported outcomes) rather than relying solely on forced vital capacity (FVC)to determine the outcomes of IPF clinical trials.

What’s new in preclinical IPF research

Traditionally, the IPF field has relied on single-dose bleomycin models and simple 2D fibroblast cultures for drug discovery. However, at ATS2024, we saw a big push for more sophisticated models to improve the translation of preclinical results into clinical success. 

• Precision-cut lung slices (PCLS) from both diseased and healthy human patients are emerging as a key translational model for IPF. Many academic and industry experts are now focusing on using PCLS as a go-to model for testing drugs.

• Significant advances in fundamental methods related to the PCLS model were discussed, and we have already begun implementing these learnings by processing human and rat lung slices using current best practices. 
• Recognizing the shortcomings of the single-dose bleo model, our industry colleagues are developing variations of the chronic-dose bleo model and aged models and validating these models with standard-of-care drugs. 
• Single nucleus RNAseq of PCLS is increasingly used as an endpoint to study the mechanism of action (MOA) of therapies in human systems.