Janus kinase (JAK) inhibitors such as Incyte and Novartis’ Jakavi, Pfizer’s Xeljanz, and most recently Incyte and Eli Lilly’s Olumiant have been approved in inflammatory diseases such as rheumatoid arthritis, and more are in development. Genentech scientists believe JAK1 inhibition might work in another inflammatory condition: asthma. And they have early evidence they may have found a safe way to apply the mechanism to the lungs.
Scientists know that many patients’ asthma is driven by multiple type 2 cytokines in the interleukin (IL) family, which regulates immune response. For example, Sanofi and Regeneron’s Dupixent, which was just approved to treat asthma, targets the IL-4 receptor. Because several IL pathways, including IL-4, depend on the JAK1 enzyme for signal transduction, the hypothesis is that JAK1 inhibition that's restricted to the lungs could be used to control asthma.
Using that logic, Genentech scientists designed iJak-381, an inhalation form of a JAK1 inhibitor. Preclinical results in mice and guinea pig asthma models have been positive, the team reported in the journal Science Translational Medicine.
In the animal studies, iJak-381 successfully inhibited cytokine signaling, suppressed lung inflammation, and improved allergen-induced airway hypersensitivity, according to the team. What’s more important, in mouse models of asthma that's driven by three common human allergens—Aspergillus, Alternaria and house dust mite—the drug candidate exhibited a more potent effect on neutrophil-driven asthma compared with a standard-of-care corticosteroid.
Previous oral JAK-inhibiting compounds have been associated with side effects that would be considered unacceptable for an asthma therapy. A higher dose of Lilly’s Olumiant, for one, was given the thumbs-down by an independent FDA expert panel due to concerns about blood clots. Other risks including infection, anemia and neutropenia have also been observed in this drug class.
The Genentech team optimized iJak-381 so that it would stay in the lungs, minimizing the risk of systemic absorption. Results from the study provided direct evidence of a lung-restricted effect, the team reported. After administration, the drug didn’t affect splenic natural killer cell count—one of the most sensitive markers of systemic JAK inhibition—in mice and guinea pigs. The test in guinea pigs holds more importance because the animal can cough and its lungs are similar to human lungs, the researchers explained.
The study’s authors cautioned that clinical trials will be required to assess the drug’s potential therapeutic benefit and safety profile in humans. Based on the positive preclinical data, “clinical evaluation of this concept is therefore warranted,” they said in the study.