Arrowhead Pharmaceuticals’ Proprietary Pulmonary TRiM Platform Achieves High Levels of Target Gene Knockdown & Long Duration of Effect

Arrowhead Pharmaceuticals Inc. recently announced interim results from an ongoing Phase 1/2 clinical study of ARO-RAGE, the company’s investigational RNA interference (RNAi) therapeutic designed to reduce production of the receptor for advanced glycation end products (RAGE) as a potential treatment for inflammatory pulmonary diseases, such as asthma. These data represent the first clinical demonstration of the potential utility of Arrowhead’s proprietary Targeted RNAi Molecule (TRiM) platform optimized for delivery to the lungs.

Matthias Salathe, MD, Professor, Pulmonary, Critical Care and Sleep Medicine, and Vice Chancellor for Research at the University of Kansas Medical Center, said “These interim ARO-RAGE Phase 1/2 data are highly encouraging. Unmet need continues to exist for many patients with severe asthma who suffer from persistent symptoms and exacerbations, despite current therapies. Reducing expression of the RAGE protein in pulmonary epithelial cells to the degree that ARO-RAGE has demonstrated to date in this study has the potential to treat patients with asthma and other inflammatory lung diseases in a fundamentally new way. RAGE represents a promising target for intervention as its activation has been implicated as a proximal regulator of the inflammatory cascade in the asthmatic airway, and thus RAGE silencing may result in potent anti-inflammatory effects. I look forward to the availability of additional results from this important trial.”

Interim results from ARO-RAGE administration in Part 1 of the ongoing Phase 1/2 study in normal healthy volunteers include:

• Reductions in soluble RAGE (sRAGE) as measured in serum after two doses on Day 1 and Day 29
  -Mean maximum reduction at 92 mg dose was 80% with a maximum reduction of 90%
  -Mean maximum reductions at 10 to 44 mg dose levels showed a dose response ranging from 31% to 59%
• Duration of pharmacologic effect persisted for at least 6 weeks after the second administration of the 92 mg dose with further follow up ongoing
  -Interim results for this cohort are only available through Day 71
• Reductions in sRAGE as measured in bronchoalveolar lavage fluid (BALF) at Day 31 after a single dose
  -Mean reduction at 92 mg dose was 75% with a maximum reduction of 92%
  -Mean reductions at 10 to 44 mg doses ranged from 44% to 52%
• Reductions in serum sRAGE were also observed after a single dose
  -Mean maximum reduction at 92 mg dose was 56% with a maximum reduction of 68%
  -Mean maximum reductions at 10 to 44 mg dose levels showed a dose response and ranged from 23% to 53%
• The pooled placebo groups experienced a mean sRAGE increase of 8% in BALF and a mean decrease of 1% in serum
• Safety and tolerability
  -Overall, no patterns of adverse changes in any clinical safety parameters
  -No reported serious or severe adverse events
  -No dropouts related to drug or related to adverse events
• These results include 4 of 5 escalating dose levels. Data are not yet available for single or multiple dose cohorts at 184 mg, the highest dose being tested

Christopher Anzalone, PhD, President and CEO at Arrowhead, said “We think these interim data with ARO-RAGE represent clinical validation of Arrowhead’s inhaled pulmonary TRiM platform and, specifically, of ARO-RAGE as a potential new therapy to treat patients with inflammatory lung diseases. The high level of target gene knockdown, the long duration of effect, and the promising safety and tolerability results are all very encouraging signs for our growing pipeline of RNAi therapeutic candidates that leverage this same platform. We look forward to providing additional data at our upcoming R&D Day on June 1, 2023, and at future medical meetings.”

ARORAGE-1001 (NCT05276570) is a Phase 1/2a, randomized, double-blinded, placebo-controlled study in normal healthy volunteers (NHV), Part 1, and patients with mild-to-moderate asthma, Part 2. The single ascending dose portion of the study includes 5 sequentially enrolled NHV cohorts with escalating single-dose levels. The multiple ascending dose portion of the study includes 5 NHV cohorts and 3 asthma patient cohorts. The objectives of the study include the assessment of safety and tolerability, pharmacokinetics, and pharmacodynamics of ARO-RAGE in NHVs and patients with asthma.

RAGE is implicated in the pathogenesis of numerous inflammatory diseases, including asthma. Reduction of RAGE expression via RNAi is designed to reduce the amount of RAGE protein expressed on pulmonary epithelial cells. Reduced RAGE expression in the pulmonary epithelium may result in reduction of RAGE-dependent inflammatory pathways, leading to decreased exacerbation frequency and improved airflow in patients with asthma.

Arrowhead Pharmaceuticals develops medicines that treat intractable diseases by silencing the genes that cause them. Using a broad portfolio of RNA chemistries and efficient modes of delivery, Arrowhead therapies trigger the RNA interference mechanism to induce rapid, deep, and durable knockdown of target genes. RNA interference, or RNAi, is a mechanism present in living cells that inhibits the expression of a specific gene, thereby affecting the production of a specific protein. Arrowhead’s RNAi-based therapeutics leverage this natural pathway of gene silencing. For more information, visit www.arrowheadpharma.com.