A first for IPF biomarkers: PROLIFIC risk score nears FDA qualification

The PROLIFIC Risk Score, a multi-biomarker blood test for idiopathic pulmonary fibrosis (IPF), has taken a significant step forward in regulatory recognition. In December 2025, the FDA’s Center for Drug Evaluation and Research accepted PROLIFIC’s Letter of Intent into its Biomarker Qualification Program; the first time an IPF biomarker has reached this milestone. This step underscores the potential of the Risk Score to improve how patients are stratified in clinical trials and how disease progression is predicted, addressing a key challenge in IPF drug development and patient care.

In this interview, Peter Schafer, Chair of PROLIFIC, discusses how the PROLIFIC Risk Score assesses IPF disease activity, the unmet needs it addresses in IPF, how it differs from current clinical measures, and the path toward full FDA qualification and impact on future clinical trials.

“While some medicines are already approved for the treatment of IPF, it is not generally understood which patients benefit the most from which drug, and where the greatest unmet medical need exists.”

The PROLIFIC Risk Score is a biomarker test that is prognostic for clinical outcomes in patients with IPF. The score is based on the concentrations of specific proteins in the blood that essentially predict the likelihood of disease progression, defined as death, lung transplant, or a ≥10% decline in Forced Vital Capacity (FVC) within one year. The proteins represent the main disease processes associated with IPF, namely:

• Lung cell injury (epithelial damage): Surfactant Protein D (SP-D) and Cancer Antigen 125 (CA-125);
• Scarring (fibrosis): Tenascin C (TNC); and
• Inflammation: B Lymphocyte Chemoattractant (BLC)-(CXCL13) and soluble Intercellular Adhesion Molecule 1 (sICAM-1).

The first step in the IPF disease process is lung cell injury caused by genetic mutations or environmental triggers, resulting in the loss of alveolar epithelial cells which are needed for proper oxygen and carbon dioxide exchange. When the epithelial cells die, they release proteins such as SP-D and CA-125. After those epithelial cells are gone, the lung tries to repair itself by making scar tissue in a process known as fibrosis. Fibrosis markers include collagens and other extracellular matrix proteins, such as TNC. Inflammation also occurs during the repair process as immune cells are recruited to fight lung infection, producing proteins such as BLC and sICAM-1. Since there is a lot of blood circulation through the lung, all these proteins can be easily measured in the blood. The higher the level of these proteins, the worse the prognosis, which is a greater likelihood of disease progression.

The PROLIFIC Risk Score can distinguish IPF patients who may remain stable from those at risk for rapid lung function declines, exacerbations and/or death. This has significant clinical utility because it could help optimize the timing and intensity of therapeutic treatments and help prioritize recipients for lung transplants, a scarce resource. The score would better inform patients and clinicians about the expected course of the disease and would lead to better shared decision-making and patient-centred care. From a patient perspective, these biomarkers may alleviate some of the uncertainty and the anxiety associated with the projected disease course and help them decide whether to explore novel therapies or accelerate referral for lung transplantation.

Breathing tests are an important tool for clinical evaluation, however there are some challenges associated with spirometry measurements such as Forced Vital Capacity. Accurate FVC measurement requires proper technique by the patient and coaching by the respiratory therapist. Improper positioning, inadequate inflation, airway obstruction, general fatigue, or anything that causes submaximal expiratory force will result in an inaccurate reading. Multiple readings are required (typically three) and they must be consistent to be considered valid. This is a scientific challenge, and some patients find the experience unpleasant. The Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) test is even more technically challenging. Furthermore, breathing tests alone are not considered adequate for determining prognosis, and factors such as gender and age are usually factored in, for example using the GAP (Gender, Age, and Pulmonary function) score. However, the gender and age-associated risk factors are based on rough averages measured across large populations, so they are not very personalized, and are not sensitive to change. Unlike the GAP score, the PROLIFIC Risk Score is based solely on the measurement of five specific proteins in the blood, irrespective of sex, age, etc., and is not subject to the biases of spirometry. Therefore, the PROLIFIC Risk Score is a much more objective and personalized snapshot of the disease processes at that point in time. Also, unlike high-resolution computed tomography (HRCT), a simple blood test has no risk associated with the cumulative effects of radiation from multiple scans over the lifetime of the patient.

The FDA’s acceptance of our initial letter of intent is an important milestone in the overall process of completing the Biomarker Qualification Program. Now we will submit the Qualification Plan, which will include more details about the IPF patient populations, statistical methods, and analytical performance studies for validation of the biomarker assays. If we are successful, the PROLIFIC Risk Score will be recognized as a Drug Development Tool to be used as a stratification factor or as eligibility criteria in clinical trials to identify patients who are more likely to have clinical events or disease progression (an enrichment tool). From there, additional applications may be considered. For example, we are currently exploring whether the same biomarkers can be used to measure prognosis in patients with other forms of progressive pulmonary fibrosis, such as rheumatoid arthritis associated interstitial lung disease. However, we are just in the early stages of conducting those studies.

During the development of new therapeutics, it is important to identify those patients who are in most need of the new treatment. While some medicines are already approved for the treatment of IPF, it is not generally understood which patients benefit the most from which drug, and where the greatest unmet medical need exists. Some therapies may work better in the early stages of diseases when the prognosis is better, while others may be more appropriate for use in the later stages when prognosis is worse. In order to accurately identify those patient subgroups, a well-qualified and validated biomarker test would be extremely useful because it could reduce the number of patients needed to see a significant improvement. That would be advantageous to reduce the size, duration, and costs of clinical trials, and most importantly optimize outcomes for the patients who so desperately need better treatments and a cure for IPF.

PROLIFIC, a collaborative biomarker consortium facilitated in part by the Pulmonary Fibrosis Foundation (PFF), uses data from the PFF Patient Registry and other sources to advance biomarker research in pulmonary fibrosis. Together, they aim to improve disease assessment, support personalized treatment strategies, and accelerate progress toward more effective therapies.