Dr Gerds on the Differences Between Available JAK Inhibitors for Myelofibrosis

“There are distinct differences between these JAK inhibitors that best position each of these agents in different populations of [patients with] myelofibrosis.”

Aaron T. Gerds, MD, MS, an assistant professor in the Department of Medicine at the Case Western Reserve University School of Medicine; the deputy associate director for Clinical Research and a member of the Developmental Therapeutics Program at Case Comprehensive Cancer Center; and a physician in the Department of Hematology and Medical Oncology at Cleveland Clinic, discussed the current paradigm and future trajectory of JAK inhibitors for the treatment of patients with myelofibrosis.

There are presently 4 JAK inhibitors approved by the FDA to manage myelofibrosis. Gerds addressed the common query regarding the necessity of developing further agents when the field already appears saturated. The core argument is that although these inhibitors may superficially seem similar, there are distinct differences between the available JAK inhibitors that position each agent optimally within different subpopulations of patients with myelofibrosis, he explained.

Each FDA-approved JAK inhibitor offers tailored mechanisms for patient care, Gerds stated. These differences allow hematologists to determine treatment strategies based on patient characteristics, he noted. For instance, pacritinib (Vonjo) inhibits JAK2, spares JAK1, and additionally inhibits ACVR1 and IRAK1. Due to these characteristics, pacritinib works within the myelodysplastic vein of myelofibrosis and is useful in managing cytopenic myelofibrosis, as well as anemia, Gerds contextualized. Similarly, momelotinib (Ojjaara) inhibits JAK1, JAK2, and ACVR1, and therefore may work best for anemic patients with myelofibrosis, according to Gerds. Another approved agent, fedratinib (Inrebic), is characterized by data supporting its use in the second-line setting, meaning it can be used after treatment with the JAK inhibitor ruxolitinib (Jakafi), he said. All 4 of these approved drugs are useful in the everyday treatment of myelofibrosis, Gerds summarized.

Gerds also highlighted the importance of continued drug development for patients with myelofibrosis, emphasizing the need for agents that operate via novel mechanisms. More JAK inhibitors are on the horizon that are structurally and mechanistically different from the currently available options, he added. Gerds pointed out that all currently FDA-approved JAK inhibitors are type 1 inhibitors; these inhibit the activated form of JAK2. In contrast, type 2 JAK inhibitors inhibit the inactive form of JAK2, which could result in a different potency, he reported.

Furthermore, there is a renewed interest in developing JAK2 V617F–specific JAK inhibitors. These specific inhibitors are directed toward the mutant form of JAK2 and spare wild-type JAK2, which may achieve a differential effect compared with the currently available drugs, he spotlighted. Other therapies, such as JAK2 degraders, fall under the umbrella of JAK inhibition and are intended to build on existing treatments, he concluded.