• Arrowhead Pharmaceuticals Inc. is actively advancing the clinical exploration of ARO-RAGE, the company’s investigational RNA interference (RNAi) therapeutic designed to reduce the production of the receptor for advanced glycation end products (RAGE) as a potential treatment for asthma and other inflammatory pulmonary diseases.
• ARO-RAGE, a novel RNAi-based therapy, stands out as the only one in development aimed at RAGE for asthma, positioning it at the forefront of innovative therapeutic strategies.
• ARO-RAGE exhibits unparalleled safety and efficacy, slashing lung inflammation markers by up to 94% without compromising lung function, heralding a revolutionary breakthrough in severe asthma treatment.

RAGE is recognized as a key upstream mediator in both Type-2 and non-Type-2 inflammatory pathways, playing a critical role in the pathogenesis of asthma and various inflammatory diseases. The approach of silencing RAGE expression through RNAi aims to decrease the expression of RAGE protein on pulmonary epithelial cells. By reducing RAGE expression in the pulmonary epithelium, this strategy seeks to diminish RAGE-dependent inflammatory pathways, potentially leading to fewer exacerbations and enhanced airflow in asthma patients.

As of 2023, an estimated 55 million individuals across the 7MM (United States, Germany, France, Italy, Spain, the United Kingdom, and Japan), as reported by DelveInsight’s “Asthma – Market Insight, Epidemiology And Market Forecast – 2034”, are grappling with asthma, presenting a formidable respiratory challenge. Despite the availability of various asthma treatments, there remains a substantial unmet need among patients with severe asthma who continue to experience persistent symptoms and frequent exacerbations. If approved, ARO-RAGE has the potential to address this gap, offering a fundamentally new mechanism of action that could improve airflow and reduce exacerbation frequency for these patients. This innovative approach could significantly impact the asthma market, providing a much-needed alternative for those who do not respond adequately to existing therapies.

Arrowhead Pharmaceuticals Inc. is set to present findings for a first-in-human study of ARO-RAGE, a novel inhaled RNAi therapy for asthma, at the American Thoracic Society (ATS) 2024 International Conference. ARORAGE-1001 (NCT05276570) is an ongoing first-in-human Phase I/IIa trial designed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of ARO-RAGE in healthy volunteers and patients with asthma. 

The study enrolled 73 healthy volunteers and 25 asthma patients; participants were randomly assigned to receive either ARO-RAGE (n = 71) or placebo (n = 27). The study observed no deaths, treatment-related serious adverse events (TEAEs), or study discontinuations due to TEAEs. Lung function changes from baseline over time were comparable between the ARO-RAGE and placebo groups.

Pharmacokinetic analysis revealed that plasma exposure to ARO-RAGE was dose-dependent and remained low, indicating effective retention of the drug within the lungs and minimal systemic bioavailability. ARO-RAGE was predominantly cleared from systemic circulation within 48 h post-dose, with no signs of systemic accumulation at a monthly dosing interval.

Remarkably, treatment with ARO-RAGE resulted in a dose-responsive reduction of sRAGE protein levels in both serum and bronchoalveolar lavage fluid (BALF). In healthy volunteers, BALF sRAGE levels decreased by 94% ± 4% (mean ± SD), and serum sRAGE levels decreased by 88% ± 10% 4 weeks after two doses of 184 mg ARO-RAGE, while placebo-treated individuals showed minimal changes. Similar reductions in serum sRAGE were observed in both healthy volunteers and asthma patients.

In conclusion, ARO-RAGE has demonstrated a robust safety profile in both healthy volunteers and asthma patients. The inhalation of ARO-RAGE did not negatively impact lung function and resulted in minimal systemic exposure. The pronounced and sustained reductions in sRAGE levels in serum and BALF underscore effective target engagement within the lungs, bolstering the rationale for ongoing clinical development of ARO-RAGE. Arrowhead plans to initiate a Phase IIb study in an estimated 500 severe adult asthmatic patients stratified for blood eosinophil levels to measure exacerbation rate, FEV1, and QoL.

Based on DelveInsight’s “Asthma – Market Insight, Epidemiology, and Market Forecast – 2034”, the asthma market in 2023 was estimated to be approximately USD 19 billion in the 7MM, which is likely to surge at a considerable CAGR during the forecast period.