Arrowhead Pharma Shows ARO-RAGE Achieves High Gene Knockdown in Asthma Patients

Arrowhead Pharmaceuticals, Inc. (NASDAQ: ARWR) has announced promising interim clinical data for their investigational RNAi-based treatment, ARO-RAGE, aimed at addressing inflammatory lung diseases such as asthma. The data was presented at the American Thoracic Society (ATS) 2024 International Conference and highlighted a significant reduction in soluble RAGE (sRAGE) levels in both bronchoalveolar lavage fluid (BALF) and serum in a dose-dependent manner among healthy volunteers and patients with mild to moderate asthma.

Dr. James Hamilton, Chief of Discovery and Translational Medicine at Arrowhead, expressed optimism regarding their proprietary TRiMTM platform. According to Dr. Hamilton, ARO-RAGE demonstrated a profound and sustained knockdown effect in the lungs of asthma patients, suggesting the potential for bi-monthly dosing while maintaining a favorable safety and tolerability profile. Encouraged by these findings, Arrowhead plans to initiate a Phase 2 study by late 2024.

Key results from the ongoing study as of April 5, 2024, include:
- Dose-dependent reductions in sRAGE in both BALF and serum following single and multiple ARO-RAGE doses in healthy volunteers.
- A reduction of serum sRAGE by up to 88%, with an average maximum reduction of 77% after two doses in asthma patients.
- Long-lasting pharmacodynamic effects that support dosing every two months.
- Limited plasma exposure following a single dose in healthy volunteers.
- Favorable safety and tolerability, with no serious adverse effects related to the study drug and no adverse events leading to trial withdrawal.

Safety evaluations showed no patterns of negative effects on systemic safety labs or lung function indicators such as FEV1, FVC, or DLCO. Arrowhead also presented preclinical data on two other pulmonary programs utilizing their TRiMTM platform: ARO-TSLP, targeting the cytokine thymic stromal lymphopoietin (TSLP) to mitigate asthmatic inflammation, and ARO-IAV, aimed at silencing conserved influenza A viruses including H5N1.

The pulmonary TRiMTM delivery platform is designed to selectively deliver therapeutic siRNAs to the lung epithelium, leveraging an integrin αvβ6 targeting moiety for effective gene silencing upon inhalation through a nebulizer.

ARO-RAGE targets the receptor for advanced glycation end-products (RAGE), which mediates inflammatory cascades involved in asthma and various inflammatory diseases. By silencing RAGE expression in pulmonary epithelial cells, ARO-RAGE aims to reduce RAGE-dependent inflammatory pathways, potentially decreasing exacerbation frequency and improving airflow in asthma patients.

The ARORAGE-1001 Phase 1/2 study (NCT05276570) is a randomized, double-blinded, placebo-controlled trial involving normal healthy volunteers and patients with mild to moderate asthma, as well as patients with high baseline fractional exhaled nitric oxide (FeNO). Participants receive ascending doses of ARO-RAGE or placebo via nebulizer, with study objectives including safety, tolerability, pharmacokinetics, and pharmacodynamics assessments.

Arrowhead Pharmaceuticals is focused on developing medicines for intractable diseases through RNA interference (RNAi), a natural gene-silencing mechanism. Their RNAi-based therapeutics aim to achieve rapid, deep, and durable knockdown of target genes, leveraging a broad portfolio of RNA chemistries and delivery methods.

The interim results for ARO-RAGE and other lung-targeted programs indicate promising advancements in the treatment of inflammatory lung diseases, positioning Arrowhead Pharmaceuticals at the forefront of RNAi-based therapeutic development.