Which Second-Generation JAK Inhibitors Take the Spotlight in 2025?

John Mascarenhas, MD, of the Icahn School of Medicine at Mount Sinai, discussed novel type 2 Janus kinase (JAK) inhibitors for the treatment of myelofibrosis, their unique mechanism of action, and how they differ from type 1 inhibitors such as ruxolitinib.

The first type 2 JAK inhibitor in the spotlight for 2025 is AJ1-11095, which inhibits both the on and off JAK2 protein.

“Preclinically, it is a very potent JAK inhibitor,” Dr. Mascarenhas said. “It’s able to overcome JAK2 inhibitor signaling resistance from prior type 1 JAK inhibitors. It holds the potential of having a more profound effect on the disease process, and we are soon to find out whether that is coming along.”

Data from a phase 1 dose-escalation study will be presented at the 67th Annual Society of Hematology Annual Meeting & Exposition in December.

Another JAK2V617F-selective inhibitor, INCB160058, binds with the pseudokinase domain of JAK2V617F. “[It] essentially changes the confirmation of the enzyme and reverts it back to a wild type of normal JAK protein,” Dr. Mascarenhas explained. “It holds the potential of reversing the mutated phenotype to a normal phenotype and changing the disease process, potentially even reducing the malignant clone over time.”