Saracatinib as Effective, or Superior to Ofev, Esbriet in IPF Models: Study
Phase 1/2 trial now enrolling, testing oral therapy in humans
AstraZeneca’s experimental oral therapy saracatinib — originally developed to treat certain cancers — was found to be at least as effective, and even superior to the approved therapies Ofev (nintedanib) and Esbriet (pirfenidone) in treating idiopathic pulmonary fibrosis (IPF) in several preclinical models of the respiratory disease.
The oral therapy was identified as an IPF treatment candidate based on a computational approach that analyzed the potential anti-fibrotic effects of several medications developed for other indications.
“There is an urgent need for better drugs, and more effective therapies, that safely modify the course of IPF and restore quality of life to patients,” Farida Ahangari, MD, the study’s first author and an assistant professor of medicine at Yale School of Medicine, said in a university press release.
“To our knowledge, this is the first study that has used a computational approach to link a drug developed for [other] indications to IPF, and then validate the efficacy of the drug in multiple systems using [cellular and animal] models, resulting in a human clinical trial in IPF patients,” Ahangari said.
The study, “Saracatinib, a Selective Src Kinase Inhibitor, Blocks Fibrotic Responses in Preclinical Models of Pulmonary Fibrosis,” was published in the American Journal of Respiratory and Critical Care Medicine.
Saracatinib now testing in humans
These now-published findings supported the launch of a Phase 1/2 trial, called STOP-IPF (NCT04598919), that is testing saracatinib against a placebo in up to 100 adults with IPF.
Enrollment is still ongoing at the four U.S. study sites. Participants must be age 40 or older, and can have IPF of any duration. All must be of nonchildbearing potential or agree to the use of an acceptable method of contraception.
“Patient recruitment for the study has previously been slow because of the pandemic,” said Danielle Antin-Ozerkis, MD, the principal investigator of the trial’s Yale site and an associate professor of medicine and medical director of the Yale Interstitial Lung Disease Center of Excellence.
“We are optimistic that now recruitment will increase even more. We know that IPF patients really want to participate in trials and to help move the field forward,” Antin-Ozerkis added.
IPF is the most common form of pulmonary fibrosis, though its specific cause is unknown. It affects about 50,000 people in the U.S. each year, and is marked by excessive inflammation and lung scarring that makes it difficult for patients to breathe.
This is due to fibroblast maturation into myofibroblasts — the main cellular drivers of lung fibrosis that produce excessive amounts of extracellular matrix (ECM) molecules. ECM molecules surround and support cells, but can cause tissue scarring when produced in excess.
To date, Boehringer Ingelheim’s Ofev and Genentech’s Esbriet (also available in generic forms) are the only anti-fibrotic therapies approved for IPF. Taken in the form of oral capsules, both have been shown to lessen lung fibrosis and slow IPF progression.
However, “responses are variable and side effects are common” with both medications, according to the researchers.
To identify potentially safer, but as-effective IPF therapies, the Yale scientists teamed up with researchers from the National Jewish Yale School of Medicine, the Mount Sinai Icahn School of Medicine, and National Jewish Health. The team then conducted a screening of 32 therapies already in development for other indications.
The screening was based on a computational approach that helped compare gene activity profiles between lab-grown human cells exposed to each of these medications and 700 different diseases.
This type of analysis is expected to help identify therapies with the potential to reverse a disease’s signature. In the case of IPF, AstraZeneca’s saracatinib was identified as the best candidate.
Saracatinib, formerly known as AZD0530, is a potent and selective suppressor of the Src family of protein tyrosine kinases (SFKs). This group of enzymes is implicated in the regulation of important cellular functions, such as cell growth, maturation, and survival.
The therapy was originally developed for different types of solid tumors — so its safety and pharmacokinetics, meaning the medication’s movement into, through, and out of the body, already have been evaluated in multiple clinical trials.
Previous preclinical studies also showed that SFKs are activated by TGF-beta, one of the major pro-fibrotic molecules, subsequently promoting myofibroblast maturation.
Using multiple preclinical models for testing
In the new testing, the team compared the anti-fibrotic effects of saracatinib with those of Ofev and Esbriet. They used lab-grown human lung fibroblasts, IPF-induced mouse models, and lab-grown lung tissue slices from these mouse models, IPF patients, and healthy people.
Results showed that, in each model, saracatinib was as effective or even superior to either IPF therapy at reducing fibrotic responses.
Analysis of lab-grown human lung fibroblasts exposed to TGF-beta revealed that saracatinib’s benefits were associated with the suppression of specific pathways associated with fibrosis. These include TGF-beta, Wnt signaling, and epithelial mesenchymal transition (EMT). EMT is a cellular process whose dysregulation is key for cancer cell growth and for the development and progression of fibrosis.
Also, saracatinib reverted many fibrosis-related pathways, such as EMT, immune responses, and ECM organization, in both mouse models, while lessening inflammation and fibrosis in lab-grown lung slices from IPF patients who underwent lung transplant.
“This finding that fibrosis is changed in tissue obtained from a human with the disease is very promising,” Ahangari said.
These results, first submitted for publication in 2020, but published only now, identified “novel Src-dependent fibrogenic pathways and support the study of the therapeutic effectiveness of saracatinib in IPF treatment,” the researchers wrote.
Based on these promising findings, the National Jewish Health launched the STOP-IPF trial, in collaboration with Yale, the Icahn School of Medicine, Baylor Scott & White Research Institute, and AstraZeneca. The study also is being funded by the National Center for Advancing Translational Science.
Initiated in late 2020, the trial got off to a slow start, due to the COVID-19 pandemic. It’s now actively recruiting participants, who are being randomly assigned to receive either 125 mg of oral saracatinib, or a placebo, once daily for 24 weeks, or nearly six months.
The trial’s main goals include assessing the therapy’s safety, tolerability, pharmacokinetics, and pharmacodynamics, or its effects on the body. The other endpoint, or key goal, is to determine the treatment’s effectiveness, as measured through changes in a lung function test.
Secondary goals include changes in other lung function measures, as well as quality of life.
The trial is expected to be completed in June 2023.
Also previously developed as a potential therapy for alcoholism and Parkinson’s disease psychosis, Saracatinib had been granted orphan drug status in the U.S. in 2019 for the treatment of IPF. That designation is expected to accelerate its clinical development and regulatory review.