APT-101 Lowers Fibrosis, Inflammation in Mouse Model
Apie Therapeutics is set to apply with the FDA to begin clinical testing
The investigational oral therapy APT-101 was well tolerated and reduced fibrosis, or scarring, in a mouse model of systemic sclerosis (SSc), according to a recent presentation from the therapy’s developer, Apie Therapeutics.
Apie is developing APT-101 to treat interstitial lung disease (ILD), a term that encompasses a group of disorders marked by significant fibrosis and inflammation of the lungs. Patients with SSc often develop ILD as their disease progresses.
According to Apie, the company is on track to file an application with the U.S. Food and Drug Administration (FDA) to begin a clinical testing program for SSc patients, including those with ILD.
The company discussed the preclinical data at the International Workshop of Scleroderma Research, in a presentation titled, “Development of a Novel Small Molecule Anti-fibrotic and Anti-inflammatory Apelin Agonist, APT101, for the Treatment of Systemic Sclerosis Interstitial Lung Disease.”
“ILD is a common complication of systemic sclerosis that is associated with poor patient outcomes; yet no treatments exist that provide disease modification by addressing the underlying disease biology,” Esther M. Alegría, PhD, founder and CEO of Apie, said in a press release.
“As we described at the scleroderma workshop, we have promising evidence that APT-101 works upstream to reduce the severe fibrosis that drives ILD in patients with SSc and [idiopathic pulmonary fibrosis]. We look forward to working with the FDA to advance this novel experimental treatment into clinical trials,” Alegría said.
APT-101 is a small molecule that selectively and potently activates the apelin receptor, commonly known as APJ. This receptor is present in the endothelial cell layer that lines the blood vessels in several organs, including the lungs.
APJ signaling is normally involved in mediating reparative processes after an injury. Under disease conditions like ILD, however, these reparative processes can be overwhelmed, leading to the disruption of other pathways that instead promote inflammation, fibrosis, and tissue damage.
Apie hopes that by activating APJ upstream of these damaging pathways, APT-101 will enhance tissue repair and limit fibrosis and inflammation.
According to the presentation, APT-101 blocked the production of inflammatory and fibrotic markers in cultured human endothelial cells.
Apie also reported findings from a bleomycin model of lung injury and fibrosis. In the model, a chemical called bleomycin, which is normally used to treat cancer, is injected into the animal, where it causes scarring and inflammation such as that seen in SSc or idiopathic pulmonary fibrosis.
In a first set of experiments, oral APT-101 (7.5 or 30 mg/kg) was administered prophylactically, beginning at the time bleomycin was initiated — before symptom onset — and continuing twice daily for three weeks.
APT-101 led to statistically significant and dose-related reductions in fibrosis development and cell death compared to both a placebo and pirfenidone (marketed as Esbriet), an approved treatment for pulmonary fibrosis.
In the presentation, it was noted that APT-101 also led to a reduction in myofibroblasts — the cells responsible for the synthesis and buildup of scar tissue.
In another set of experiments, APT-101 administration was delayed, with treatment starting a week after bleomycin was administered and continuing twice daily for two weeks.
Data showed APT-101 was still beneficial, leading to significant reductions in fibrosis at the two highest tested doses. Inflammation was also reduced in a dose-dependent manner. This anti-inflammatory effect appeared to be additive to that of pirfenidone, meaning the magnitude of the benefit was larger than with either treatment alone.
The treatment was also well tolerated, Apie noted.
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