Q&A: Investigational therapy shows potential for treating patients with IPF

Saracatinib appeared to be “equal or superior” in stopping fibrotic responses compared with two FDA-approved antifibrotic drugs, according to a preclinical study published in American Journal of Respiratory and Critical Care Medicine.

These findings indicate that saracatinib (AZD0530, AstraZeneca) may work as a treatment for patients with idiopathic pulmonary fibrosis after additional studies are conducted, according to a press release from National Jewish Health.

With these promising results, researchers are now working on a phase 1/2 trial that involves a patient population of adults with IPF to see how saracatinib performs against placebo.

Healio spoke with Farida Ahangari, MD, one of the lead authors of this study and assistant professor in pulmonary, critical care and sleep medicine at Yale School of Medicine, to hear more about the preclinical findings, future research and its broader implications.

Healio: What are the current treatments for IPF?

Ahangari: Two antifibrotic drugs, pirfenidone (Esbriet, Genentech) and nintedanib (Ofev, Boehringer Ingelheim) were approved by the FDA in 2014 for the treatment of IPF. Clinical trials and real-world experience demonstrate that, while on average, both drugs slow the rate of decline in lung function, responses are variable, and these drugs neither cure IPF nor improve the symptoms.

Healio: What is the need for new treatments for IPF?

Ahangari: The median survival of IPF is 3 to 5 years after initial diagnosis, meaning half of patients diagnosed with the disease will die within 3 to 5 years. Although there are two FDA-approved drugs, lung transplantation remains the only curative treatment for pulmonary fibrosis. There is an urgent need for the development of more effective and safe therapies to restore the quality of life of patients with IPF.

Healio: What was the rationale for evaluating saracatinib for IPF?

Ahangari: In evaluating 32 separate therapies, already developed for other conditions, we identified saracatinib as the best candidate for IPF treatment. Saracatinib, a selective Src kinase inhibitor, was originally developed for oncological indications. We undertook a disease-agnostic complementary bioinformatics approach and identified a robust transcriptomic connection between saracatinib and IPF, which led us to explore the potential therapeutic benefit of this drug in IPF.

Healio: Can you briefly explain the design and findings of the study?

Ahangari: This study was a multicenter collaboration between National Jewish Health, Icahn School of Medicine at Mount Sinai, Yale School of Medicine and AstraZeneca. Using an in-silico data-driven approach, we identified a robust connection between the transcriptomic changes in IPF disease and those induced by saracatinib. Based on these observations, we investigated the antifibrotic effects of saracatinib relative to nintedanib and pirfenidone in three preclinical models:

• in vitro, in normal human lung fibroblasts (NHLFs);
• in vivo, in two established murine models of pulmonary fibrosis; and
• ex vivo, using precision cut lung slices from murine models as well as patients with IPF and healthy donors.

In each model, the effectiveness of saracatinib in blocking fibrogenic responses was equal or superior to nintedanib and pirfenidone which confirmed the potential therapeutic efficacy of saracatinib in human lung fibrosis.

Healio: The FDA has approved nintedanib and pirfenidone for treating pulmonary fibrosis. How do you expect saracatinib to perform compared with those two drugs?

Ahangari: Our observation from three comprehensive preclinical models identified that saracatinib worked as well or better than two approved drugs in blocking fibrogenic responses. This shows promise as a treatment for IPF. Our primary focus in the current clinical trial is to show that saracatinib is safe in humans, and if we show that it is safe and effective, we are very hopeful that we can improve the quality of life in patients.

Healio: What are your plans for future research, and how will it be different from this study?

Ahangari: My main research focus is to understand the pathogenesis of pulmonary fibrosis to find the best therapy for this disease. My goal is to translate mechanistic research findings into drug development to help patients with this fatal disease.

Healio: If future research is positive, how would the availability of saracatinib potentially change the treatment paradigm for IPF?

Ahangari: If we show this drug is safe and effective in IPF, it would be a big change for patients with this debilitating disease. It would improve the quality of life in patients with IPF.

For more information:

Farida Ahangari, MD, can be reached at farida.ahangari@yale.edu. The other lead investigators of this study include Gregory P. Downey, MD, of National Jewish Health; Naftali Kaminski, MD, of Yale School of Medicine; Joel T. Dudley, PhD, and Christine Becker, PhD, both of Icahn School of Medicine at Mount Sinai; and Leslie P. Cousens, PhD, of AstraZeneca.

References:

• Ahangari F, et al. Am J Respir Crit Care Med. 2022;doi:10.1164/rccm.202010-3832OC.
• ClinicalTrials.Gov. Saracatinib in the Treatment of Idiopathic Pulmonary Fibrosis (STOP-IPF). https://clinicaltrials.gov/ct2/show/NCT04598919. Accessed Nov. 23, 2022.
• Experimental cancer drug could be effective in treating idiopathic pulmonary fibrosis. https://www.nationaljewish.org/about/news/press-releases/2022-news/experimental-cancer-drug-could-be-effective-in-treating-ipf. Published Oct. 13, 2022. Accessed Oct. 19, 2022.