Progressive pulmonary fibrosis (PPF) represents one of the most challenging phenotypes within the interstitial lung disease (ILD) space and is defined by worsening fibrosis observed by high-resolution computed tomography scans, declining lung function, and persistent symptoms. Although the approval of antifibrotics have expanded treatment options in recent years, they primarily slow functional decline rather than halt or completely reverse fibrosis. Patients frequently continue to experience breathlessness, reduced exercise tolerance, and diminished quality of life. As a result, the unmet needs in PPF remain substantial, says GlobalData, a leading intelligence and productivity platform.
The most pressing unmet need remains therapeutic efficacy beyond the slowing of lung function decline. The current approved antifibrotics, Boehringer Ingelheim’s Ofev (nintedanib) and Jascayd (nerandomilast), have demonstrated an ability to reduce the rate of forced vital capacity decline, but they do not restore lost lung capacity or prevent progression in all patients. Furthermore, the side-effect profile of these products, specifically the gastrointestinal issues, can limit the adherence of patients.
As a result, there is a clear need for therapies that target novel mechanisms of action, such as the lysophosphatidic acid receptor 1 (LPA1) antagonist admilparant by Bristol Myers Squibb, which is in Phase III trials, to increase treatment options available to patients. LPA mediates a multicellular response to wound healing and collagen deposition, and inhibition of LPA1 interrupts this fibrotic cascade, reducing epithelial injury, inflammation, and fibrosis in PPF patients.
Connor Daniels, Healthcare Analyst at GlobalData, comments: “Combination approaches that leverage multiple mechanisms of action may ultimately be required, but robust data supporting this is currently lacking. Until treatments can meaningfully alter the prognosis of patients, PPF will remain a disease that is managed rather than modified.”
A second major gap lies in diagnosis and disease monitoring. PPF is not a single disease but a clinical behavior that can arise from diverse underlying ILDs, including autoimmune-associated and hypersensitivity-related ILD. As a result, identifying which patients will transition to a progressive phenotype remains a challenge. Diagnostic delays can be common due to variability in imaging interpretation, which further complicates patient assessment. Identification of reliable biomarkers capable of predicting progression would be crucial to identify patients at risk of progression and guide therapeutic selection, but this has proved to be a challenge so far due to the heterogeneity of the condition.
The abundance of biomarkers, such as IGFBP2, PTX3, LGALS1, LGALS9, and MMP2, has been shown to change as the progression of the fibrosis is slowed after treatment with Ofev for one year, according to a 2025 study by Miceli and colleagues in Scientific Reports. This shows that fibrosis-related biomarkers do change in response to treatment and therefore may be crucial to monitor disease progression and therapeutic response, but a lot more research is required to validate this.
Daniels adds: “Advances in high-resolution computed tomography quantification and AI-assisted imaging analysis have shown promise, but these are yet to be fully integrated into patient care. Without earlier identification and risk management, opportunities for timely intervention may be missed.”
Finally, the broader supportive care landscape available to patients is a significant unmet need. Physicians can find it challenging to decide whether to prescribe a patient an immunomodulator, an antifibrotic, or a combination of the two. Therefore, further education is required to help fill this knowledge gap and help physicians make the best decisions for their patients.
Daniels concludes: “Addressing PPF comprehensively will also require more than novel drugs. It will require multidisciplinary care models that involve pulmonary rehabilitation, oxygen therapy, as well as pharmaceutical intervention, to create a comprehensive approach to improve patients’ quality of life.”
