Dr Gerds on the Distinct Mechanisms of Action of Approved JAK Inhibitors for Myelofibrosis

“[All the approved JAK inhibitors] inhibit wild-type JAK2, but the other [targets] they inhibit separates them and helps us begin to understand which population of patients they may be most effective for.”

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 mechanisms of action and differentiated clinical applications of the 4 FDA-approved JAK inhibitors available for the treatment of patients with myelofibrosis.

Although all 4 agents share a fundamental mechanism of action, their specific non-overlapping targets dictate their unique clinical utility, Gerds began. Regarding fundamental similarity, all 4 JAK inhibitors inhibit wild-type JAK2. However, it is the inhibition of other specific molecules that distinguishes them from each other and allows hematologists to determine the patient population for which each may be most effective, Gerds summarized.

Ruxolitinib (Jakafi) inhibits JAK1 and JAK2 and remains the standard of care for treating patients who require spleen reduction and symptom improvement and who have relatively preserved blood counts, or who may be progressing toward transplant, Gerds said. In contrast, other JAK inhibitors exhibit specific actions that tailor their use to different clinical challenges, he noted. For instance, pacritinib (Vonjo) is a JAK2 inhibitor that also mildly inhibits JAK1 and notably hits FLT3, he explained. The inhibition of FLT3, shared with fedratinib (Inrebic), accounts for some common adverse effects, such as gastrointestinal toxicity, but may also provide an antiproliferative effect, according to Gerds. Crucially, pacritinib also inhibits ACVR1, which is important in the hepcidin pathway and in inflammatory anemia, he reported. Furthermore, it inhibits IRAK1, which is known to be important in the pathobiology of myelodysplastic syndromes, he contextualized. Based on these specific targets, pacritinib is highly suitable for patients with cytopenic myelofibrosis, particularly those exhibiting low platelet counts, he emphasized.

Momelotinib (Ojjaara) is another JAK1/JAK2 inhibitor, similar to ruxolitinib, but unique in that it also inhibits ACVR1. Targeting the ACVR1 pathway is significant because if hepcidin levels can be lowered, the associated anemia can be alleviated, Gerds stated. Thus, momelotinib is a rational choice for patients requiring a JAK inhibitor who are also anemic, he continued.

Fedratinib inhibits JAK1, JAK2, and FLT3. The efficacy of this agent is supported by strong second-line data stemming from the phase 2 JAKARTA-2 trial (NCT01523171). The clinical results confirmed that fedratinib can successfully be positioned after ruxolitinib in the treatment sequence and still successfully regain symptom and spleen responses that had previously been lost, Gerds concluded.