Oral therapy GRI-0621 boosts lung function, repairs tissue in IPF: Data
Experimental treatment also reduced scarring, was well tolerated
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Treatment with GRI-0621, an experimental oral therapy from GRI Bio, boosts lung function in adults with idiopathic pulmonary fibrosis (IPF), according to top-line data from a Phase 2a clinical trial.
The study (NCT06331624) met its primary goal, demonstrating no safety or tolerability concerns after 12 weeks of daily treatment, as well as no signs of digestive issues when used in combination with other approved IPF medicines. Secondary measures were also met, including improvements in biomarkers indicating reduced lung fibrosis, or scarring, and the repair of lung tissue.
“The positive Phase 2a results represent an important milestone for our IPF program and a compelling early signal of GRI-0621’s disease-modifying potential,” Marc Hertz, PhD, CEO of GRI Bio, said in a company press release. “These results reinforce our belief in GRI-0621’s differentiated mechanism and support its potential to go beyond slowing disease progression by directly impacting core drivers of IPF.”
GRI-0621 designed to inhibit key immune cell
A type of pulmonary fibrosis, IPF is marked by progressive scarring in the lungs that drives symptoms like shortness of breath and a dry, hacking cough.
A hallmark of IPF is the destruction of the alveolar basement membrane, an ultrathin layer of tissue separating the alveoli, tiny air-filled sacs, from the blood-filled capillaries in the lungs. This membrane provides structural support, anchors cells, and acts as a selective barrier while remaining sufficiently thin to permit rapid gas exchange.
Two anti-fibrotic medications approved for IPF, pirfenidone (sold as Esbriet and generics) and Ofev (nintedanib), have been shown to slow the decline in lung function. However, they can’t stop or reverse the disease.
“IPF remains one of the most devastating respiratory diseases, with limited treatment options and a significant need for therapies that can do more than slow decline and address the underlying biology of the disease,” Hertz said.
GRI-0621 is designed to inhibit type 1 invariant natural killer T-cells, a kind of immune cell that’s thought to drive injury, inflammatory response, and fibrosis in IPF.
Therapy showed no safety, tolerability concerns
The Phase 2a study enrolled 35 adults, ages 40 to 85, with IPF who were randomly assigned to receive 4.5 mg of GRI-0621 or an equal amount of a placebo once daily for 12 weeks. Most participants (80%) were also treated with pirfenidone or Ofev as standard of care. Lung function was assessed using forced vital capacity (FVC), which measures the volume of air a person can forcibly exhale.
At 12 weeks, GRI-0621 showed no safety or tolerability concerns, with the most common adverse events being dry skin, dry lips, and muscle or joint pain. Cough and gastrointestinal disorders occurred at lower rates with GRI-0621 than with the placebo.
Lung function improved in patients treated with GRI-0621, as indicated by a 99 mL increase in FVC relative to the placebo. Among patients receiving both GRI-0621 and standard of care, FVC increased by 139 mL compared with those receiving placebo plus standard of care.
Because FVC assessments can vary from visit to visit, the researchers excluded extreme FVC data points. In that case, GRI-0621-treated patients experienced a 54 mL increase in FVC compared with the placebo, and those taking both GRI-0621 and standard of care saw an 81 mL increase.
Overall, 39% of patients treated with GRI-0621 showed an increase in FVC at 12 weeks, compared with 80% in the placebo arm who showed a decline.
“Treatment of patients with IPF in the GRI-0621 Phase 2a trial was observed to be safe and well tolerated through the completion of the 12-week study,” said Toby Maher, MD, PhD, professor of clinical medicine at the Keck School of Medicine of USC in Los Angeles. “FVC improved in patients treated with GRI-0621, with more patients experiencing an increase at 12 weeks than with standard of care.”
Several biomarkers improved with GRI-0621
GRI-0621 also improved blood biomarkers of collagen turnover, indicating a resolution of fibrosis and the stimulation of alveolar basement membrane repair.
Treatment reduced PRO-C6, a biomarker of type VI collagen production and fibrosis, by 3%, whereas placebo/standard of care saw it increase by 12%. Consistently, C6M, a biomarker of type VI collagen degradation, rose with GRI-0621 by 6% but fell by 3% with placebo/standard of care.
In addition to a favorable safety and tolerability profile, GRI-0621 demonstrated meaningful improvement in biomarkers suggesting fibrosis resolution and repair of the alveolar basement membrane.
GRI-0621 increased PRO-C4, a biomarker of type IV collagen production and basement membrane repair, by 9%, whereas placebo/standard care showed a 2% decrease. C4Ma3, a biomarker for type IV collagen degradation, was also lower with GRI-0621 compared to placebo/standard of care (10% vs 24%). These results demonstrated a shift from ongoing basement membrane destruction with placebo to stability with GRI-0621.
“Secondary endpoints related to the effect of GRI-0621 on biomarkers associated with disease progression provided evidence that GRI-0621 maintains a net anti-fibrotic effect compared to standard of care,” Maher said. “We look forward to watching the clinical advancement of GRI-0621 as a potential treatment for patients with IPF.”
GRI-0621 treatment also led to reductions in the activity of neutrophils and macrophages, immune cells that are upregulated in IPF and associated with disease progression. At the same time, the activity of genes related to fibrosis, disease progression, and death decreased in GRI-0621-treated patients compared with those taking the placebo.
“In addition to a favorable safety and tolerability profile, GRI-0621 demonstrated meaningful improvement in biomarkers suggesting fibrosis resolution and repair of the alveolar basement membrane,” Hertz said. “With this mechanistic proof-of-biology in hand, we are well-positioned to advance toward the next stage of development.”
