Management of encephalopathy, including WE

Randomized 1:1:1

Baseline characteristics overview

ET, essential thrombocythemia; IPSS, International Prognostic Scoring System; JAK, Janus-associated kinase; PV, polycythemia vera; qd, once daily.

The recommended daily dose is 400 mg; therefore, only the 400‑mg arm will be shown relative to placebo

Baseline Characteristics

Baseline demographics and disease characteristics²

^aSpleen size measured by palpation.

^bAs measured by MRI or CT.

Additional Trial Information

Select inclusion criteria¹

A diagnosis of intermediate-2 or high-risk myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis with splenomegaly.

Study endpoints¹

Primary endpoint

The proportion of patients achieving greater than or equal to a 35% reduction from baseline in spleen volume at the end of cycle 6 as measured by magnetic resonance imaging (MRI) or computed tomography (CT) with a scan 4 weeks later.

Secondary endpoint

Secondary endpoints included the proportion of patients with a 50% or greater reduction in Total Symptom Score (TSS) from baseline to the end of cycle 6 as measured by the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 diary.

Treatment period²

Patients continued to receive INREBIC^® as long as they were benefiting (defined as having had a complete or partial remission, clinical improvement, or stable disease) and had not experienced progressive disease/relapse (as defined by the modified IWG-MRT criteria) or unacceptable toxicity requiring discontinuation of INREBIC^®.

IWG-MRT, International Working Group–Myeloproliferative Neoplasms Research and Treatment.

Proportion of patients with SVR ≥35% from baseline at the end of cycle 6 as measured by MRI or CT with a follow-up scan 4 weeks later^a

P<0.0001

Based on Kaplan-Meier estimates, the median duration of spleen response was 18.2 months for the INREBIC^® 400-mg group

^aIntent-to-treat (ITT) population.

Percent change in spleen volume from baseline at the end of cycle 6 as measured by MRI or CT for each patient^a

^aPatients with available percent change in spleen volume at the end of cycle 6.

INREBIC^® demonstrated a statistically significant reduction in TSS vs placebo¹

Proportion of patients with ≥50% reduction in TSS from baseline at the end of cycle 6 as measured by the MFSAF^a

P<0.0001

^aIn symptom-evaluable population.

Percent change in TSS from baseline at the end of cycle 6 as measured by the MFSAF for each patient^a

^aPatients with available percent change in TSS at the end of cycle 6 as measured by the modified MFSAF v2.0 diary.

The modified MFSAF v2.0 is a patient diary capturing the 6 core symptoms of MF: night sweats, itching, abdominal discomfort, early satiety, pain under the ribs on the left side, and bone or muscle pain.

Reduction in TSS by Cycle

Proportion of patients achieving ≥50% reduction in TSS by cycle up to 6 cycles^2,a,b

A key secondary endpoint evaluated TSS from baseline to the end of cycle 6 as measured by the modified MFSAF v2.0 diary

^aIn ITT population with nonmissing baseline TSS.

^bData for placebo patients in study who crossed over to INREBIC^® treatment are not counted after the date of crossover.

Reduction in Individual Symptoms

Proportion of patients achieving ≥50% reduction in individual symptom scores at the end of cycle 6 with nonzero baseline scores^1,a

^aAs measured by the modified MFSAF v2.0 diary.

The NCCN Guidelines^® include fedratinib³

^*NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

INREBIC^® in patients previously treated with ruxolitinib (JAKARTA2)²

Limitations

JAKARTA2 study design and select patient characteristics

• Single-arm, open-label, phase-2 study in 97 primary or secondary myelofibrosis patients resistant or intolerant to ruxolitinib per investigator assessment

• The primary endpoint was the proportion of patients achieving ≥35% spleen volume reduction at the end of cycle 6 as measured by MRI or CT

• Median exposure to ruxolitinib prior to enrollment in study was 10.7 months

• Median exposure to INREBIC^® during enrollment in study was 24 weeks (range 0.7-79.4 weeks)

Methodology for spleen and symptom assessment

• Post hoc analyses of spleen volume in the ITT population and Total Symptom Score

• Only patients who were confirmed responders at the end of cycle 6 were included; patients missing spleen volume assessments at the end of cycle 6 were considered nonresponders

^†Includes patients with an evaluable baseline and ≥1 post-baseline assessment of Total Symptom Score.

Adverse reactions with INREBIC^® in patients previously treated with ruxolitinib

Hematologic adverse reactions (ITT)

^aPresented values are worst-grade values regardless of baseline.

Nonhematologic adverse reactions reported (ITT)

ALT, alanine aminotransferase; AST, aspartate aminotransferase.

^aIncludes cystitis.

^bPresented values are worst-grade values regardless of baseline.

^cOf 96 evaluable patients.

Additional NCCN Guidelines^® recommendations for fedratinib³

Limitations: JAKARTA2, a phase-2, single-arm, open-label study, was prematurely terminated, which impacts the interpretability of the data. No conclusions regarding the benefits or risks of fedratinib in patients who are resistant or intolerant to ruxolitinib can be established based on this study. These data are not included in the Prescribing Information.

^‡NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

Starting patients on INREBIC^®

• Assess thiamine levels. Do not start INREBIC^® in patients with thiamine deficiency; replete thiamine prior to treatment initiation and during treatment if thiamine levels are low

• Obtain the following blood tests prior to starting treatment with INREBIC^®, periodically during treatment, and as clinically indicated: thiamine (vitamin B1) level, complete blood count with platelets, creatinine and BUN, hepatic panel, and amylase and lipase

• Patients who are on treatment with ruxolitinib before the initiation of INREBIC^® must taper and discontinue according to the ruxolitinib prescribing information

• Avoid use of INREBIC^® with strong and moderate CYP3A4 inducers, with dual CYP3A4 and CYP2C19 inhibitors, and in patients with severe hepatic impairment

• The recommended dosage of INREBIC^® is 400 mg taken orally once daily for patients with a baseline platelet count of ≥50 x 10⁹/L

• Reduce the INREBIC^® dose to 200 mg once daily for patients using concomitant strong CYP3A4 inhibitors

• Reduce the INREBIC^® dose to 200 mg once daily for patients with severe renal impairment (creatinine clearance [CLcr] 15 mL/min to 29 mL/min)

• Interrupt dose until grade 4 neutropenia is resolved to ≤grade 2 or baseline. Restart dose at 100 mg daily below the last given dose

• Interrupt dose until ≥grade 3 ALT, AST, or bilirubin are ≤grade 1 or baseline. Restart dose at 100 mg daily below the last given dose. Monitor ALT, AST, and bilirubin (total and direct) more frequently following dose reduction. If reoccurrence of a ≥grade 3 elevation, discontinue treatment with INREBIC^®

• Interrupt dose until ≥grade 3 nonhematologic toxicities are resolved to ≤grade 1 or baseline. Restart dose at 100 mg daily below the last given dose

• If encephalopathy is suspected, immediately discontinue treatment with INREBIC^® and initiate parenteral thiamine treatment. Monitor until symptoms resolve or improve and thiamine levels normalize

• The median time to onset of any grade nausea, vomiting, and diarrhea was 1 day, with 75% of cases occurring within 2 weeks of treatment

• Treat diarrhea with antidiarrheal medications promptly at the first onset of symptoms

• Consider providing appropriate prophylactic antiemetic therapy (eg, 5-HT3 receptor antagonists) during INREBIC^® treatment

• INREBIC^® may be taken with or without food. Administration with a high-fat meal may reduce the incidence of nausea and vomiting

BUN, blood urea nitrogen.

Dose Modifications

Avoid use¹

• Avoid use of INREBIC^® with strong and moderate CYP3A4 inducers
• Avoid use of INREBIC^® with dual CYP3A4 and CYP2C19 inhibitors
• Avoid use of INREBIC^® in patients with severe hepatic impairment

Recommended dose modifications with INREBIC^®1

Discontinue INREBIC^® in patients unable to tolerate a dose of 200 mg daily

Consider dose reductions for patients who become transfusion dependent during treatment with INREBIC^®.

Thiamine levels and WE

Assess thiamine levels and nutritional status prior to starting INREBIC^®, periodically during treatment, and as clinically indicated. Do not start INREBIC^® in patients with thiamine deficiency; replete thiamine prior to treatment initiation and during treatment if thiamine levels are low. If WE is suspected, immediately discontinue treatment with INREBIC^® and initiate parenteral thiamine treatment. Monitor until symptoms resolve or improve and thiamine levels normalize.

Concomitant use of strong CYP3A4 inhibitors

Reduce INREBIC^® dose when administering with strong CYP3A4 inhibitors to 200 mg once daily. In cases where coadministration with a strong CYP3A4 inhibitor is discontinued, INREBIC^® dosage should be increased to 300 mg once daily during the first 2 weeks after discontinuation of the CYP3A4 inhibitor, and then to 400 mg once daily thereafter as tolerated.

Severe renal impairment

Reduce INREBIC^® dose to 200 mg once daily for patients with severe renal impairment (CLcr 15 mL/min to 29 mL/min).

Modifications in Trial

Dose modifications and treatment discontinuations with INREBIC^® during the randomized period¹

Dosage interruptions due to an adverse reaction occurred in 21% of patients

Adverse reactions requiring dosage interruption in >3% of patients who received INREBIC^® included diarrhea and nausea.

Permanent discontinuation due to an adverse reaction occurred in 14% of patients

Most frequent reasons for permanent discontinuation in ≥2% of patients included cardiac failure (3%), thrombocytopenia, myocardial ischemia, diarrhea, and increased blood creatinine (2% each).

Dosage reductions due to an adverse reaction occurred in 19% of patients

Adverse reactions requiring dosage reduction in >2% of patients who received INREBIC^® included anemia (6%), diarrhea (3%), vomiting (3%), and thrombocytopenia (2%).

Select hematologic events

Selected laboratory abnormalities that have worsened from baseline (≥20%) in patients receiving INREBIC^®a

^aWith a difference between arms of >10% when compared to placebo in JAKARTA during randomized treatment.

Dose reductions and discontinuations due to hematologic adverse reactions

• Thrombocytopenia-related dose reductions and discontinuations occurred in 2.1% of patients

• Anemia-related dose reductions (6%) and discontinuations (1%) occurred with INREBIC^®

Median time to onset of lab abnormalities

• The median time to the first onset of grade 3 anemia was approximately 2 months, with 75% of cases occurring within 3 months

• The median time to the first onset of grade 3 thrombocytopenia was approximately 1 month, with 75% of cases occurring within 4 months

Transfusions

• 51% of patients treated with INREBIC^® received red blood cell transfusions

• 3.1% of patients treated with INREBIC^® received platelet transfusions

Serious adverse reactions occurred in 21% of patients

• Serious adverse reactions that occurred in ≥2% of patients included cardiac failure (5%) and anemia (2%). Fatal adverse reactions of cardiogenic shock occurred in 1% of patients receiving INREBIC^®

Permanent discontinuation

• Permanent discontinuation due to an adverse reaction occurred in 14% of patients receiving INREBIC^®

Gastrointestinal (GI) and nonhematologic adverse reactions with INREBIC^®1

Management of GI adverse reactions

• Consider providing appropriate prophylactic antiemetic therapy (eg, 5-HT3 receptor antagonists) during INREBIC^® treatment

• Treat diarrhea with antidiarrheal medications promptly at the first onset of symptoms

• INREBIC^® may be taken with or without food. Administration with a high-fat meal may reduce the incidence of nausea and vomiting

Selected adverse reactions reported in patients on INREBIC^®

^aCommon Terminology Criteria for Adverse Events (CTCAE) version 4.03.

^bOnly 1 grade 4 event (anemia).

^cIncludes cystitis.

^dSelected laboratory abnormalities that have worsened from baseline (≥20%) in patients receiving INREBIC^® with a difference between arms of >10% when compared to placebo in JAKARTA during randomized treatment.

Timing of GI Toxicity

GI adverse reactions by cycle in the INREBIC^® 400-mg arm (n=96)^1,2

Treatment-emergent adverse reactions of diarrhea, nausea, or vomiting by cycle up to 6 cycles–All grades (all-treated population)

^aAdverse reactions were coded using MedDRA version 20.1.

Median time to onset

• The median time to onset of any grade nausea, vomiting, and diarrhea was 1 day, with 75% of cases occurring within 2 weeks of treatment

• The median time to onset of any grade transaminase elevation was approximately 1 month, with 75% of cases occurring within 3 months

Please see WARNINGS AND PRECAUTIONS: Gastrointestinal Toxicity.

INREBIC^® is available through the contracted specialty pharmacies or through authorized distributors for in-office dispensing by community physicians, hospitals, institutions, Veterans Affairs, and Department of Defense.

Please download the brochure below to find the listing of contracted specialty pharmacies and authorized distributors.

How to access INREBIC^® brochure

INREBIC^® product information

How supplied

• INREBIC^® 100-mg capsules are supplied in bottles of 120 count each

Storage

• Store below 86°F (30°C)

Commonly used ICD-10 codes*

• D47.4 (Osteomyelofibrosis)
• D75.81 (Myelofibrosis)

^*When selecting diagnosis codes, providers should consult a current ICD-10-CM manual and always select the most appropriate diagnosis code(s) with the highest level of detail to describe a patient’s actual condition.

Celgene Patient Support^®

A single source for access support

Celgene Patient Support^® provides

• A single Specialist assigned to help patients in your geographic area

• Assistance with understanding patient insurance coverage for INREBIC^®

• Information about financial assistance for INREBIC^®

Financial assistance

There are programs and organizations that may help pay for INREBIC^®, depending on a patient’s insurance situation.

Celgene Commercial Co-pay Program
Co-pay responsibility for INREBIC^® is reduced to $25 (subject to annual benefit limits) for eligible patients with commercial or private insurance (including healthcare exchanges).^†

Celgene Patient Assistance Program (PAP)
INREBIC^® may be available at no cost for qualified patients who are uninsured or underinsured.^‡

Independent third-party organizations
Patients who are unable to afford their medication (including patients with Medicare, Medicaid, or other government-sponsored insurance) may be able to receive help from independent third-party organizations.^§

Insurance-related assistance

Our Specialists are available to assist with each of the following steps in the insurance approval process for INREBIC^®‖:

• Benefits investigation

• Prior authorization assistance^¶

• Appeals assistance^¶

Enrolling in Celgene Patient Support^®

Visit us online at
www.celgenepatientsupport.com

E-mail us at patientsupport@celgene.com or fax to 1-800-822-2496

Need additional information?

Call us at 1-800-931-8691,
Monday–Friday, 8 AM–8 PM ET
(translation services available)

Celgene Patient Support^® is a registered trademark of Celgene Corporation. Other trademarks are the property of their respective owners.