RNA interference silences RAGE with no detrimental effect on lungs in patients with asthma

Key takeaways:

• The receptor for advanced glycation end-products (RAGE) regulates pathways that contribute to inflammation.
• Soluble RAGE protein decreased in a dose-dependent manner with treatment.

SAN DIEGO — Study participants tolerated an inhaled therapeutic that silences the expression of a receptor for advanced glycation end-products in the lungs, according to a poster at the American Thoracic Society International Conference.

Healthy volunteers and patients with asthma both tolerated the novel treatment, which is based on an RNA interference mechanism, John C. Huetsch, MD, senior medical director of clinical development, Arrowhead Pharmaceuticals, and colleagues wrote.

John C. Huetsch

The target mRNA in this case is a transcript for a receptor for advanced glycation end-products (RAGE), Huetsch told Healio.

“It’s a pattern recognition receptor expressed in pulmonary epithelium. It binds to a broad array of ligands in the airway,” he said. “It has been implicated as being necessary for turning on pathways, canonical pathways for type 2 inflammation, in the airways.”

This receptor also has been implicated in activating downstream inflammasome and mediators, Huetsch continued.

“The idea here is that our drug would silence RAGE production in pulmonary epithelium and, by doing that, would bring anti-inflammatory effects into the airway,” he said.

ARORAGE-1001 is a first-in-human, ongoing, randomized, double-blind, placebo-controlled phase 1/2a study. Huetsch was at the conference to present an interim analysis of its safety, tolerability, target engagement and pharmacokinetics.

The study included 73 healthy volunteers (mean age, 34.7 years; 28.8% male) and 25 patients with asthma (mean age, 36 years; 32% male), with 71 randomly assigned to ARO-RAGE treatment and 27 to placebo.

Healthy volunteers received a single dose and the treatment group receiving multiple doses, with two doses at 4-week intervals in ascending doses from 10 mg to 184 mg.

“With this drug modality, target engagement effects are usually quite prolonged over time,” Huetsch said.

None of the participants experienced any treatment-related serious treatment-emergent adverse events or dropped out of the study due to treatment-emergent adverse events, nor were there any deaths.

“Externally, events were reflective of things that happened to otherwise healthy people —colds, COVID, headaches — nothing that has really stood out,” Huetsch said.

The participants in the treatment group and among the healthy controls experienced similar changes from baseline lung function over time.

“This is inhaled therapy into the lung. We are very interested in lung safety. So, we’ve been measuring spirometry, using capacity as a safety measure,” Huetsch said. “No concerning trends.”

Also, plasma exposure to ARO-RAGE depended on the dose. The researchers called it low and consistent with drug retention in the lung and with low systemic bioavailability.

Within 48 hours of dosing, ARO-RAGE was largely cleared from systemic circulation, the researchers continued. Monthly dosing intervals did not indicate any evidence of systemic accumulation.

“Very little of the drug gets into the systemic vasculature,” Huetsch said. “Safety labs have looked fine.”

After treatment with ARO-RAGE, soluble RAGE protein decreased in a dose-responsive manner in serum and in bronchoalveolar lavage fluid (BALF).

“This is a membrane-bound receptor. It’s hard to get pulmonary epithelial cells. It’s easy to measure things in the airway and blood,” Huetsch said.

“The membrane by the receptor gets cleaved to points called soluble RAGE that get secreted into the bloodstream, secreted into the airway,” he continued. “That’s what we’re measuring as a biomarker of target engagement.”

At 4 weeks, the healthy controls experienced mean decreases of 94% ± 4% in their BALF soluble RAGE and 88% ± 10% in their serum soluble RAGE after two 184 mg doses of ARO-RAGE. The placebo groups experienced minimal changes, the researchers said.

“Small doses lead to moderate silencing. Higher doses, almost complete silencing in the airway,” Huetsch said.

This deep depletion after a single higher dose reached its maximum at approximately 4 to 6 weeks, Huetsch said, followed by a slow return to baseline.

The treatment’s effects on the soluble RAGE in both healthy controls and patients with asthma alike were similar, the researchers continued.

The small amounts of ARO-RAGE that entered systemic circulation in the healthy controls then disappeared “pretty quickly,” Huetsch said, which was in line with the researchers’ previous animal data.

Huetsch further pointed out that bronchoscopies of healthy controls at 1 month after the highest dose showed a 95% loss of RAGE in the airway that was maintained at deep levels at 2 months after 2 doses.

“It goes to the lung. It stays in the lung. It is leading to target silencing that is quite profound and long lasting,” Huetsch said.

The healthy controls had deeper depletion of RAGE in their blood after two doses, compared with one dose, and the patients with asthma experienced similar effects, Huetsch continued.

Overall, the researchers categorized treatment with ARO-RAGE as well tolerated with no associations with detrimental effects on lung function including FEV₁, forced vital capacity or diffusing capacity of the lungs for carbon dioxide in addition to minimal extra-pulmonary exposure.

Also, they said, the prolonged and dose-responsive decreases in serum and BALF soluble RAGE suggest effective target engagement in the lung and that clinical development of ARO-RAGE should continue.

Huetsch further noted that RAGE essentially is upstream of the cytokines that monoclonal antibodies typically used to treat asthma directly target.

“By turning this off, we could have a very broad anti-inflammatory effect that could be relevant to really any severe asthma patients, no matter whether they are eosinophil-high or eosinophil-low,” he said. “That’s what made it attractive as a target.”

Data indicate that RAGE is relevant for inflammatory signaling in COPD and cystic fibrosis as well, Huetsch said.

“Beyond asthma, I think that there is rationale to consider this as central therapy for other lung diseases,” he said.

Huetsch said that another arm of this trial has enrolled patients with high FeNO levels to see if ARO-RAGE has an anti-inflammatory effect as a biomarker.

“That should read out later this year,” he said.

Also, a phase 2 study will enroll patients with both type 2 high and type 2 low severe asthma.

“The primary endpoint will be asthma worsening, so asthma exacerbations and milder markers,” Huetsch said, “to see if the drug actually controls asthma.”