MOA of Jakafi–JAK1 and JAK2 inhibitor

Jakafi is a JAK inhibitor that targets dysregulated JAK-STAT signaling

Jakafi (ruxolitinib) is an oral Janus kinase 1 (JAK1) and JAK2 inhibitor that targets an underlying mechanism of myelofibrosis.^1,2 In the phase III clinical trials, responses were seen in spleen volume reduction and Total Symptom Score* with Jakafi in both JAK2V617F-positive and JAK2V617F-negative patients, relative to placebo.³

Watch the MOA video about Jakafi

Learn about the role of JAK1 and JAK2 inhibitors in the JAK pathway, the pathophysiology of myelofibrosis and how Jakafi works.

*The Total Symptom Score included the following symptoms: abdominal discomfort, early satiety, pain under left ribs, pruritus, night sweats and bone/muscle pain.

Open transcript

UNDERSTANDING THE JAK PATHWAY IN MYELOFIBROSIS

One important signal transduction pathway is the JAK-STAT pathway. Why is it important?
Janus kinases (JAKs) are cytoplasmic kinases that play significant roles in important physiological processes, including hematopoiesis, cell proliferation and proper immune function.

JAK signaling begins when a cytokine or growth factor binds to its transmembrane receptor. This activates specific JAK proteins which subsequently recruit the STATs (Signal Transducers and Activators of Transcription). Once activated, STATs dimerize and travel to the nucleus, where they modulate gene expression.

The unique combination of cytokine or growth factor, receptor, JAK protein and STAT determines a specific cellular response. For instance, JAK1 is believed to signal the cell to produce cytokines, and JAK2 is implicated in cell proliferation.

What happens when JAK signaling goes wrong?
JAK signaling is complex, and may become dysregulated for many reasons, including:

JAK2 mutations
Receptor mutations (eg, MPL mutations)
Increased JAK1 signaling
Excess cytokines
Damaged intracellular signaling mechanisms (eg, those involving SOCS)

JAK dysregulation may lead to excessive transcription, cell proliferation and increased levels of inflammatory cytokines. Inhibiting one component of aberrant JAK may reduce dysregulated JAK signaling in general.

Ruxolitinib, the first FDA-approved JAK inhibitor
Ruxolitinib, a kinase inhibitor, inhibits JAK1 and JAK2, which mediate the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function.

INDICATION
Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis.

IMPORTANT SAFETY INFORMATION

Treatment with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia. A complete blood count must be performed before initiating therapy with Jakafi. Complete blood counts should be monitored as clinically indicated and dosing adjusted as required
The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache
Patients with platelet counts <200 X 10⁹/L at the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If clinically indicated, platelet transfusions may be administered
Patients developing anemia may require blood transfusions. Dose modifications of Jakafi for patients developing anemia may also be considered
Neutropenia (ANC <0.5 X 10⁹/L) was generally reversible and was managed by temporarily withholding Jakafi
Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal and viral infections. Active serious infections should have resolved before starting Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection (including herpes zoster) and initiate appropriate treatment promptly
A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with renal or hepatic impairment [see Dosage and Administration]. Patients should be closely monitored and the dose titrated based on safety and efficacy
There are no adequate and well-controlled studies of Jakafi in pregnant women. Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus
Women taking Jakafi should not breast-feed. Discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother

Please see Full Prescribing Information.

References:

Jakafi Prescribing Information. Incyte Corporation. June 2012.
Anand S, Stedham F, Gudgin E, et al. Increased basal intracellular signaling patterns do not correlate with JAK2 genotype in human myeloproliferative neoplasms. Blood. 2011;118:1610-1621.
Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366:799-807.