Ruxolitinib MOA - aaaa PDF

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Summary

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Description

Understanding how Jakafi (ruxolitinib) inhibits* overactive JAK pathway signaling ®

* 1

Indications and Usage Jakafi is indicated for treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea. 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.

Polycythemia vera Polycythemia vera (PV) is a chronic, progressive myeloproliferative neoplasm (MPN) characterized by increased myeloid, erythroid, and megakaryocytic cell proliferation without significant bone marrow fibrosis.2,3

PV and MF: Mecha Cytokines and growth factors

Erythrocytosis (elevated total red blood cell mass) is the most prominent clinical expression of PV, and it distinguishes PV from all other MPNs, including essential thrombocythemia and primary myelofibrosis.4 PV may progress to myelofibrosis as bone marrow becomes more fibrotic.5

JAK2 JAK2

Myelofibrosis

JAK1 Activated STAT

Myelofibrosis (MF) is a serious, progressive hematologic malignancy characterized by bone marrow fibrosis, abnormal cytokine expression, extramedullary hematopoiesis, constitutional symptoms, anemia, and shortened survival.5 All of the signs or symptoms are not necessarily present in all patients.6 Extramedullary hematopoiesis often results in splenomegaly.7 Newly detected or recent growth of a palpable spleen is a sign of disease progression.8

Nucleus

Median overall survival in high-risk or intermediate-2–risk MF is less than 5 years.9

PV25,26 Hyperproliferation of hematopoietic cells Splenomegaly Abnormally elevated hematocrit Proinflammatory cytokine expression

PV27 Long-term complications

Prog mar

Pres lead and

JAK, Janus-associated kinase; MPL, myeloproliferative leukemia virus oncogene; SO

2

The importance of the JAK pathway 1

Signaling of the JAK pathway plays a key role in normal cell functioning24,28-30

2

JAK-STAT signaling activates transcription in the nucleus28,31-33

3

The complex JAK pathway ma

Well-regulated JAK signaling is ess and immune function. Intracellular JAK signaling.24,28

Cytokines bind to receptors and ac and activators of transcription (STA Inside the nucleus the STATs bind lated to cell survival, differentiation

CALR, calreticulin.

4

Jakafi (ruxolitinib) is an oral JAK1 and JAK2 inhibitor1 ®

-37

Jakafi: Mechanism of action1

In patients with polycyth had an inadequate respo of hydroxyurea

Approval in PV was based on evidence fro open-label, active-controlled phase 3 trial therapy in 222 patients with PV who had intolerant of hydroxyurea, required phleb

Primary end point*

A significantly larger proportion of pat the primary end point—a composite of in spleen volume at week 32—compar P < 0.0001)1

— 60% of patients receiving Jakafi and therapy achieved Hct control

— 38% of patients receiving Jakafi and therapy achieved ≥35% reduction in

Overall, 77% of patients in the group re of the primary end point, compared wit

* The primary end point of the RESPONSE trial was the proportion of subjects achieving a res eligibility beginning at the week 8 visit and continuing through week 32) and spleen volume hematocrit >45% that is at least 3 percentage points higher than the hematocrit obtained a of all randomized subjects who achieved the primary end point and maintained their respo week 32, with complete hematologic remission defined as achieving hematocrit control, pla †

Best available therapy included hydroxyurea (60%), interferon/pegylated interferon (12%), an

Risk for thrombocytopenia, anemia, and neutropenia1 Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia, which are each dose-related effects. Perform a pre-treatment complete blood count (CBC), and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated

In patients with intermed In COMFORT-I,‡ 42% of patients taking a ≥35% reduction in spleen volume at receiving placebo (P < 0.0001)1,35

Manage thrombocytopenia by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi

In COMFORT-II,§ 29% of patients receiv spleen volume at week 48, compared w therapy|| (P < 0.0001)1,36

Severe neutropenia (ANC 10%) were bruising, dizziness and headache A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or fluconazole or in patients with renal or hepatic impairment. Patients should be closely monitored and the dose titrated based on safety and efficacy 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

Severe neutropenia (ANC...