Narrator: Mechanism of Action and Data for Jakafi^® (ruxolitinib) in patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea

Narrator: Jakafi (ruxolitinib) is indicated for treatment of polycythemia vera (PV) in adults who have had an inadequate response to or are intolerant of hydroxyurea.

Dr Erba: Hello, my name is Harry Erba. I'm a professor of internal medicine at the University of Alabama at Birmingham where I serve as the director of the hematologic malignancies program as well as the associate director of the cancer center for clinical research. For the last 20 years I have been a clinical investigator evaluating novel therapies for people with myeloid neoplasms including the myeloproliferative neoplasms.

Narrator: This promotional presentation is being sponsored by Incyte Corporation.

Dr Erba: The information that I will present is all consistent with the labeled indication and consistent with FDA regulations.

We will also discuss important safety information regarding Jakafi.

Dr Erba: JAK-STAT pathway is critically important for transducing signals of cytokines and growth factors binding to the plasma membrane of a hematopoietic cell and transducing that signal into the nucleus where the cell can be triggered to proliferate or to turn genes on that are necessary for normal differentiation.

Dr Erba: We also know that in these myeloproliferative neoplasms … that JAK1 and JAK2 are overactive. And this can be due to mutation or other pathways leading into JAK1 and JAK2.

Dr Erba: We know that Jakafi is both a JAK1 and JAK2 tyrosine kinase inhibitor.

Dr Erba: Once Jakafi binds to JAK1 and JAK2 it will downregulate, inhibit the activity of that enzyme. Now it's important to realize that JAK1 and JAK2 are critically important for normal life. We need to continue to make blood cells. We need to continue to fight infections and produce inflammatory reactions against pathogens.

Dr Erba: And so when we use Jakafi, based on this mechanism of action, it's important to remember that we are going to individualize the dose of Jakafi so that this pathway is modulated but not completely inhibited.

Dr Erba: And therefore knowledge of the mechanism of action of Jakafi is critical to the use of this in everyday clinical situations.

Narrator: The RESPONSE Trial. A Randomized study of Efficacy and Safety in POlycythemia vera with JAK iNhibitor ruxolitinib verSus bEst available care.

Dr Erba: Let's now review the RESPONSE trial design.

Dr Erba: The RESPONSE trial was a randomized Phase III study that compared Jakafi to best available therapy for patients with polycythemia vera who were either intolerant of or had an inadequate response to hydroxyurea as defined by the European Leukemia Network.

Dr Erba: Patients had to have a persistent phlebotomy requirement and as well they also had to have measurable splenomegaly by MRI.

Dr Erba: There was a pre-randomization phase where all of the patients were kind of brought to the same starting gate.

Dr Erba: The hematocrit had to be controlled to less than 45%. And then they were randomized between Jakafi 10 milligrams twice daily or best available therapy.

Dr Erba: Now what I find interesting about this clinical trial is that the patients who were randomized to best available therapy—and remember they were intolerant of or had an inadequate response to hydroxyurea—almost 60% stayed on or received hydroxyurea.

Dr Erba: The primary analysis was done at 32 weeks. The primary endpoint was a composite of hematocrit control with freedom from phlebotomy as well as a 35% or more reduction in splenic volume by MRI.

Narrator: More specifically, to achieve the Hematocrit Control endpoint, patients could not become eligible for phlebotomy between weeks 8 and 32. Phlebotomy eligibility was defined as hematocrit >45% that is ≥3 percentage points higher than baseline or hematocrit >48%, whichever was lower.

Dr Erba: The two groups were well matched for age, gender.

About half of the patients in both groups had resistance to and the other half intolerance of hydroxyurea.

Many of these patients had prior thromboembolic events.

Dr Erba: As you can see patients had a hematocrit less than 45% at the time of randomization. However, the median white blood cell count and platelet count were above normal.

Narrator: RESPONSE: Efficacy data

Dr Erba: Twenty-three percent of patients treated with Jakafi achieved the composite endpoint versus only less than 1% of patients on best available therapy.

And in fact, at 48 weeks, 22 of the 25 patients maintained the composite endpoint.

Dr Erba: Jakafi demonstrated superior results compared to best available therapy at 32 weeks in these patients.

Dr Erba: In terms of hematocrit control and freedom from phlebotomy that was achieved in 60% of patients receiving Jakafi versus only 19% of patients on best available therapy. Likewise, for control of splenomegaly with a decrease in splenic volume by 35% or more as measured by MRI, that was achieved in 40% of patients that were receiving Jakafi versus less than 1% of patients on best available therapy…

Narrator: Important Safety Information

• Treatment with Jakafi^® (ruxolitinib) 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
• 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
• Severe neutropenia (ANC <0.5 × 10⁹/L) was generally reversible by withholding Jakafi until recovery
• Serious bacterial, mycobacterial, fungal and viral infections have occurred. Delay starting Jakafi until active serious infections have resolved. Observe patients receiving Jakafi for signs and symptoms of infection and manage promptly. Use active surveillance and prophylactic antibiotics according to clinical guidelines
• Tuberculosis (TB) infection has been reported. Observe patients taking Jakafi for signs and symptoms of active TB and manage promptly. Prior to initiating Jakafi, evaluate patients for TB risk factors and test those at higher risk for latent infection. Consult a physician with expertise in the treatment of TB before starting Jakafi in patients with evidence of active or latent TB. Continuation of Jakafi during treatment of active TB should be based on the overall risk-benefit determination
• Progressive multifocal leukoencephalopathy (PML) has occurred with Jakafi treatment. If PML is suspected, stop Jakafi and evaluate
• Herpes zoster infection has been reported in patients receiving Jakafi. Advise patients about early signs and symptoms of herpes zoster and to seek early treatment. Herpes simplex virus reactivation and/or dissemination has been reported in patients receiving Jakafi. Monitor patients for the development of herpes simplex infections. If a patient develops evidence of dissemination of herpes simplex, consider interrupting treatment with Jakafi; patients should be promptly treated and monitored according to clinical guidelines
• Increases in hepatitis B viral load with or without associated elevations in alanine aminotransferase and aspartate aminotransferase have been reported in patients with chronic hepatitis B virus (HBV) infections. Monitor and treat patients with chronic HBV infection according to clinical guidelines
• When discontinuing Jakafi, myeloproliferative neoplasm-related symptoms may return within one week. After discontinuation, some patients with myelofibrosis have experienced fever, respiratory distress, hypotension, DIC, or multi-organ failure. If any of these occur after discontinuation or while tapering Jakafi, evaluate and treat any intercurrent illness and consider restarting or increasing the dose of Jakafi. Instruct patients not to interrupt or discontinue Jakafi without consulting their physician. When discontinuing or interrupting Jakafi for reasons other than thrombocytopenia or neutropenia, consider gradual tapering rather than abrupt discontinuation
• Non-melanoma skin cancers (NMSC) including basal cell, squamous cell, and Merkel cell carcinoma have occurred. Perform periodic skin examinations
• Treatment with Jakafi has been associated with increases in total cholesterol, low-density lipoprotein cholesterol, and triglycerides. Assess lipid parameters 8-12 weeks after initiating Jakafi. Monitor and treat according to clinical guidelines for the management of hyperlipidemia
• Another JAK-inhibitor has increased the risk of major adverse cardiovascular events (MACE), including cardiovascular death, myocardial infarction, and stroke (compared to those treated with tumor TNF blockers) in patients with rheumatoid arthritis, a condition for which Jakafi is not indicated. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with Jakafi particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur
• Another JAK-inhibitor has increased the risk of thrombosis, including deep venous thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which Jakafi is not indicated. In patients with myelofibrosis (MF) and polycythemia vera (PV) treated with Jakafi in clinical trials, the rates of thromboembolic events were similar in Jakafi and control treated patients. Patients with symptoms of thrombosis should be promptly evaluated and treated appropriately
• Another JAK-inhibitor has increased the risk of lymphoma and other malignancies excluding NMSC (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which Jakafi is not indicated. Patients who are current or past smokers are at additional increased risk. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with Jakafi, particularly in patients with a known secondary malignancy (other than a successfully treated NMSC), patients who develop a malignancy, and patients who are current or past smokers
• In myelofibrosis and polycythemia vera, the most common nonhematologic adverse reactions (incidence ≥15%) were bruising, dizziness, headache, and diarrhea. In acute graft-versus-host disease, the most common nonhematologic adverse reactions (incidence >50%) were infections (pathogen not specified) and edema. In chronic graft-versus-host disease, the most common nonhematologic adverse reactions (incidence >20%) were infections (pathogen not specified) and viral infections
• Avoid concomitant use with fluconazole doses greater than 200 mg. Dose modifications may be required when administering Jakafi with fluconazole doses of 200 mg or less, or with strong CYP3A4 inhibitors, 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 breastfeed during treatment and for 2 weeks after the final dose

Please see accompanying Full Prescribing Information for Jakafi.

Dr Erba: Thank you for joining me here today.