Arrowhead Pharmaceuticals Inc. has announced interim results from an ongoing phase 1/2 clinical study of ARO-RAGE, an 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. \n\n\n\nThese data represent the first clinical demonstration of the potential utility of Arrowhead Pharmaceuticals’ proprietary targeted RNAi molecule (TRiM) platform optimized for delivery to the lungs.\n\n\n\nMatthias Salathe, 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. \n\n\n\n“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.”\n\n\n\nArrowhead Pharmaceuticals' study results\n\n\n\nInterim 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%, and mean maximum reductions at 10 to 44 mg dose levels showed a dose response ranging from 31% to 59%.\n\n\n\nThe results also showed the duration of pharmacologic effect persisted for at least 6 weeks after the second administration of the 92 mg dose. The mean reduction at the 92 mg dose was 75% with a maximum reduction of 92%, while mean reductions at 10 to 44 mg doses ranged from 44% to 52%. Reductions in serum sRAGE were also observed after a single dose.\n\n\n\nThe mean maximum reduction at the 92 mg dose was 56% with a maximum reduction of 68%, and the mean maximum reductions at 10 to 44 mg dose levels showed a dose response and ranged from 23% to 53%. There were no reported serious or severe adverse events. Data are not yet available for single or multiple dose cohorts at 184 mg, the highest dose being tested.\n\n\n\nChristopher Anzalone, president and CEO at Arrowhead Pharmaceuticals, 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.”\n\n\n\nEarlier this year, AstraZeneca’s Airsupra received U.S. approval as a new rescue treatment for asthma. Another company tackling asthma is a startup, Upstream Bio, which last year announced a trial to develop a new long-term asthma treatment.\n\n\n\nAbout RAGE\n\n\n\nRAGE 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.