New prototype that regenerates stem cells may repair IPF scarring
Study provides proof of concept for upcoming Phase 1 trial of CMR316
Researchers have developed an inhalable prototype medicine that may be able to repair lung scarring caused by idiopathic pulmonary fibrosis (IPF) by stimulating the growth of stem cells directly in the lungs, a study reports.
The study provides pharmacological proof of concept for an upcoming Phase 1 clinical trial that’s evaluating CMR316, an investigational inhalable therapy similar to the designed prototype.
“Most drugs act by slowing the progression of disease; our approach is to make drugs that control cell fate to stop or reverse the disease process,” Peter G. Schultz, PhD, president and CEO of Scripps Research and co-senior author of the study, said in a press release.
The study, “Pharmacological expansion of type 2 alveolar epithelial cells promotes regenerative lower airway repair,” was published in PNAS.
IPF is a disease of unknown cause that’s marked by scarring, or fibrosis, of the lungs, which can lead to shortness of breath and a dry, hacking cough. Standard treatments focus on managing symptoms, slowing disease progression, and improving patients’ quality of life.
Scar tissue deposits affect the alveolar epithelial cells, which line the tiny air sacs in the lungs where gas exchange occurs. Type 1 alveolar epithelial cells aid gas exchange, while type 2 cells produce and release a fatty liquid that coats and supports the alveoli.
In an injury, type 2 alveolar cells, like stem cells, give rise to new type 1 cells to regenerate the alveoli. In progressive lung diseases like IPF, however, healthy type 2 cells are in short supply, compromising alveoli repair. So therapies that promote the growth of type 2 alveolar epithelial cells may stimulate the repair of the damaged alveoli.
“My approach toward regenerative medicine has been figuring out how to promote regenerative, proliferative repair of organs using drug-like molecules that act on endogenous stem cell populations,” said study co-senior author Michael J. Bollong, PhD, an associate professor at Scripps Research. “We chose the lung because the stem cell population of the lower airway doesn’t regenerate as effectively as one ages.”
Regenerating population of stem cells in IPF
The researchers used ReFRAME, a drug repurposing library built by CMR316’s developer Calibr-Skaggs, which funded the study, to identify mechanisms of approved drugs that could increase lung stem cell growth.
“ReFRAME allowed us to understand what the target was immediately, to start understanding how that biology made sense in the context of the lung, and to test the concept directly in vivo,” Bollong said.
ReFRAME detected a class of type 2 diabetes medications, known as DPP4 inhibitors, that could potentially activate the growth of type 2 alveolar epithelial cells.
Using mouse models of lung damage, experiments confirmed that DPP4 inhibitors selectively expanded type 2 alveolar cells and showed promise in treating fibrosis.
The effective dose in the mouse experiments was high and likely unsafe for clinical use in humans, so the researchers developed NZ-97, a locally delivered DPP4 inhibitor modified to persist in the lungs. It promoted lung damage repair in mouse models with minimal exposure outside the lungs and good tolerability.
“To effectively repair the lungs, the dosing would be roughly 50 to 100 times as much, so we needed to make a drug that inhibited DPP4 in the lung only,” Bollong said. “That’s why we went after a lung-targeted and lung-retained approach.”
NZ-97 is a prototype drug that’s chemically similar to CMR316, which will soon enter a Phase 1 clinical trial for testing in healthy volunteers and IPF patients. CMR316 will be administered once weekly via a nebulizer, a device that generates an inhalable mist to deliver the therapy directly into the lungs.
“What that ultimately allowed us to do is have a drug that could be administered at very low doses,” Bollong said. “People have been making DPP4 inhibitors for more than 20 years, so we could leverage that known chemical matter to make a very good version of the drug that’s efficacious, lung retained, and safe.”
CMR316 is also being considered for lung damage caused by other conditions, including influenza, COVID-19, and chronic obstructive pulmonary disease (COPD).
“This work reveals DPP4 as a central regulator of [type 2 alveolar epithelial cell] expansion and affords a promising therapeutic approach to broadly stimulate regenerative repair in pulmonary disease,” the researchers wrote.
“IPF makes the most sense as the first disease to investigate because it’s driven by a deficiency in this stem cell population,” Bollong said.
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