February 28, 2022

AbbVie Seeks New Indication for IMBRUVICA® (ibrutinib) in Pediatric Patients with Chronic Graft Versus Host Disease (cGVHD)

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- cGVHD is a life-threatening and rare condition that currently does not have an approved treatment for children under 12 and can occur in patients after receiving peripheral blood or bone marrow stem cell transplantation
- If approved, IMBRUVICA would offer pediatric and adolescent patients the first BTKi treatment option with an oral suspension formulation to help manage their cGVHD after failure of one or more lines of systemic therapy
- The sNDA and NDA submissions were primarily based on results of three years of data from the Phase 1/2 iMAGINE clinical trial
- IMBRUVICA was the first treatment approved in the U.S. in 2017 for adult patients with cGVHD after failure of one or more lines of systemic therapy

NORTH CHICAGO, Ill., Feb. 28, 2022 /PRNewswire/ -- AbbVie (NYSE: ABBV), today announced the submission of a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) for IMBRUVICA® (ibrutinib) for the treatment of pediatric and adolescent patients one year and older with chronic graft versus host disease (cGVHD) after failure of one or more lines of systemic therapy. A New Drug Application (NDA) was also submitted for an oral suspension formulation of IMBRUVICA to provide an alternative administration option for pediatric patients. If approved, this represents AbbVie's first pediatric indication for IMBRUVICA.

cGVHD is a life-threatening complication for about 14,000 patients each year after receiving a donor stem cell or bone marrow transplantation.1,2 Nearly half of these transplant patients develop cGVHD, and there are currently no FDA-approved treatment options for children under 12.3 The applications seek to update the IMBRUVICA U.S. Prescribing Information primarily based on the analysis of three years of data from the Phase 1/2 iMAGINE clinical trial, including use of a new oral suspension formulation of the treatment.

"We are committed to this work with IMBRUVICA in the hopes of providing the first FDA-approved BTKi treatment option for younger patients with cGVHD, including a new oral suspension formulation," said James Dean, M.D., Ph.D., IMBRUVICA Global Development Lead and Executive Medical Director at AbbVie. "For young children, the availability of a liquid oral suspension versus an oral capsule or tablet can be significant to enable them to take the recommended dose and address challenges swallowing capsules or tablets."

The iMAGINE clinical trial enrolled 59 patients 1-19 years of age with relapsed/refractory (R/R) or new-onset moderate/severe cGVHD. The primary endpoints of the study were pharmacokinetics (PK) and safety; secondary endpoints included overall response rate. Results showed an overall response rate of 78 percent with IMBRUVICA and that PK data was consistent with adult dosing of IMBRUVICA. After 20 weeks, sustained response rates were observed in 70 percent and 58 percent of treatment-naive and R/R responders, respectively. Safety was consistent with the established profile for IMBRUVICA, with observed adverse events (AEs) consistent with those observed in adult patients with moderate to severe cGVHD. The most common Grade ≥3 AEs (≥ 5% of subjects) overall were pyrexia (8.5%), neutropenia (6.8%), stomatitis (6.8%), hypoxia (6.8%), osteonecrosis (6.8%), alanine aminotransferase increased (5.1%), hypokalemia (5.1%), and pneumothorax (5.1%).

"It is important to empower patients and their families with evidence-based knowledge and I am encouraged by the results from the iMAGINE clinical trial of IMBRUVICA," said Dr. Paul A. Carpenter, attending physician at Seattle Children's Hospital and study principal investigator. "Results show that PK and safety were consistent with the known profile of IMBRUVICA and that of cGVHD. Efficacy results, including sustained response rates, were also encouraging."

In 2017, IMBRUVICA was first approved as a single-agent therapy for adult patients with cGVHD who have experienced failure of prior systemic therapy, becoming the first FDA-approved treatment for adults with cGVHD. IMBRUVICA could be the first FDA-approved BTKi treatment option for pediatric and adolescent patients with cGVHD.

About cGVHD

cGVHD occurs when donated peripheral blood or bone marrow stem cells view the recipient's body as foreign and the donated cells launch an immune attack on the body.4 cGVHD impacts major organs, with the skin, eyes, mouth and liver being most common.5 About 35 percent of the estimated 8,000 patients who undergo life-saving allogeneic Hematopoietic Stem Cell Transplant (HSCT) per year develop cGVHD that requires systemic treatment.4 Additionally, cGVHD is the most common cause of morbidity after allogeneic transplant.6 Steroids are the current standard treatment for pediatric cGVHD.7

About the iMAGINE Study

iMAGINE (PCYC-1146-IM) is an interventional single group treatment Phase 1/2 study, which enrolled 59 pediatric patients with chronic graft versus host disease (cGVHD). In the two-part study, Part A patients ages one to <12 years with moderate or severe cGVHD after failure of one or more lines of systemic therapy received IMBRUVICA oral suspension or capsule starting at 120mg/m2 once daily. To determine the Recommended Pediatric Equivalent Dose (RPED), dosage was escalated to 240mg/m2 after 14 days if no Grade 3 or higher related toxicity was observed. In Part B, patients 12 to <22 years of age with moderate or severe cGVHD who were newly diagnosed or had failed one or more lines of systemic therapy were given 420mg IMBRUVICA orally once daily. Once the RPED was determined in Part A, patients 1 to <12 years of age with new-onset or relapsed/refractory cGVHD could be enrolled in Part B.  Primary endpoints included pharmacokinetics (PK) and safety, and secondary endpoints included overall response rate (ORR; CR/PR) per 2014 NIH criteria, overall survival, duration of response (DOR), and patient reported outcomes.

About IMBRUVICA

IMBRUVICA® (ibrutinib) is a once-daily oral medication that is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie Company and Janssen Biotech, Inc. IMBRUVICA® blocks the Bruton's tyrosine kinase (BTK) protein, which is needed by normal and abnormal B cells, to multiply and spread. By blocking BTK, IMBRUVICA may help move abnormal B cells out of their nourishing environments in the lymph nodes, bone marrow, and other organs.8,9,10

IMBRUVICA® is approved in more than 100 countries and has been used to treat more than 250,000 patients worldwide. There are more than 50 company-sponsored clinical trials, including 18 ongoing or completed Phase 3 studies, over 11 years evaluating the efficacy and safety of IMBRUVICA®.

IMBRUVICA® was first approved by the U.S. Food and Drug Administration (FDA) in November 2013, and today is indicated for adult patients in six disease areas, including five hematologic cancers. These include adults with CLL/small lymphocytic lymphoma (SLL) with or without 17p deletion (del17p) and adults with Waldenström's macroglobulinemia (WM), as well as adult patients with previously treated mantle cell lymphoma (MCL)*, adult patients with previously treated marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy*, as well as adult patients with previously treated chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic therapy.11

*Accelerated approval was granted for MCL and MZL based on overall response rate. Continued approval for MCL and MZL may be contingent upon verification and description of clinical benefit in confirmatory trials.

Since 2019, the National Comprehensive Cancer Network® (NCCN®), recommends ibrutinib (IMBRUVICA®) as a preferred regimen for first-line treatment of CLL/SLL, with Category 1 status for previously untreated patients without del17p. Additionally, IMBRUVICA® is a preferred treatment regimen for previously untreated patients with del17p. Since January 2020, the NCCN Guidelines recommend IMBRUVICA® as a category 2A preferred regimen for the treatment of relapsed/refractory MCL. Since September 2020, the NCCN Guidelines recommend IMBRUVICA® with or without rituximab as a Category 1 preferred regimen for both untreated and previously treated WM patients.12

For more information, visit www.IMBRUVICA.com.

Important Side Effect Information

Before taking IMBRUVICA®, tell your healthcare provider about all of your medical conditions, including if you:

  • have had recent surgery or plan to have surgery. Your healthcare provider may stop IMBRUVICA® for any planned medical, surgical, or dental procedure.
  • have bleeding problems
  • have or had heart rhythm problems, smoke, or have a medical condition that increases your risk of heart disease, such as high blood pressure, high cholesterol, or diabetes
  • have an infection
  • have liver problems
  • are pregnant or plan to become pregnant. IMBRUVICA® can harm your unborn baby. If you are able to become pregnant, your healthcare provider will do a pregnancy test before starting treatment with IMBRUVICA®. Tell your healthcare provider if you are pregnant or think you may be pregnant during treatment with IMBRUVICA®.
    • Females who are able to become pregnant should use effective birth control (contraception) during treatment with IMBRUVICA® and for 1 month after the last dose.
    • Males with female partners who are able to become pregnant should use effective birth control, such as condoms, during treatment with IMBRUVICA® and for 1 month after the last dose.
  • are breastfeeding or plan to breastfeed.  Do not breastfeed during treatment with IMBRUVICA® and for 1 week after the last dose.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking IMBRUVICA® with certain other medicines may affect how IMBRUVICA® works and can cause side effects.

How should I take IMBRUVICA®?

  • Take IMBRUVICA® exactly as your healthcare provider tells you to take it.
  • Take IMBRUVICA® 1 time a day.
  • Swallow IMBRUVICA® capsules or tablets whole with a glass of water.
  • Do not open, break or chew IMBRUVICA® capsules.
  • Do not cut, crush or chew IMBRUVICA® tablets.
  • Take IMBRUVICA® at about the same time each day.
  • If you miss a dose of IMBRUVICA® take it as soon as you remember on the same day. Take your next dose of IMBRUVICA® at your regular time on the next day. Do not take extra doses of IMBRUVICA® to make up for a missed dose.
  • If you take too much IMBRUVICA® call your healthcare provider or go to the nearest hospital emergency room right away.

What should I avoid while taking IMBRUVICA®?

  • You should not drink grapefruit juice, eat grapefruit, or eat Seville oranges (often used in marmalades) during treatment with IMBRUVICA®. These products may increase the amount of IMBRUVICA® in your blood.

What are the possible side effects of IMBRUVICA®?

IMBRUVICA® may cause serious side effects, including:

  • Bleeding problems (hemorrhage) are common during treatment with IMBRUVICA®, and can also be serious and may lead to death. Your risk of bleeding may increase if you are also taking a blood thinner medicine. Tell your healthcare provider if you have any signs of bleeding, including: blood in your stools or black stools (looks like tar), pink or brown urine, unexpected bleeding, or bleeding that is severe or that you cannot control, vomit blood or vomit looks like coffee grounds, cough up blood or blood clots, increased bruising, dizziness, weakness, confusion, change in your speech, or a headache that lasts a long time or severe headache. 
  • Infections can happen during treatment with IMBRUVICA®. These infections can be serious and may lead to death. Tell your healthcare provider right away if you have fever, chills, weakness, confusion, or other signs or symptoms of an infection during treatment with IMBRUVICA®.
  • Decrease in blood cell counts. Decreased blood counts (white blood cells, platelets, and red blood cells) are common with IMBRUVICA®, but can also be severe.  Your healthcare provider should do monthly blood tests to check your blood counts.
  • Heart problems. Serious heart rhythm problems (ventricular arrhythmias, atrial fibrillation, and atrial flutter), heart failure, and death have happened in people treated with IMBRUVICA®, especially in people who have an increased risk for heart disease, have an infection, or who have had heart rhythm problems in the past. Tell your healthcare provider if you get any symptoms of heart problems, such as feeling as if your heart is beating fast and irregular, lightheadedness, dizziness, shortness of breath, swelling of the feet, ankles, or legs, chest discomfort, or you faint.  If you develop any of these symptoms, your healthcare provider may do a test to check your heart (ECG) and may change your IMBRUVICA® dose.
  • High blood pressure (hypertension). New or worsening high blood pressure has happened in people treated with IMBRUVICA®. Your healthcare provider may start you on blood pressure medicine or change current medicines to treat your blood pressure.
  • Second primary cancers. New cancers have happened during treatment with IMBRUVICA®, including cancers of the skin or other organs.
  • Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure and the need for dialysis treatment, abnormal heart rhythm, seizure, and sometimes death. Your healthcare provider may do blood tests to check you for TLS.

The most common side effects of IMBRUVICA® in adults with B-cell malignancies (MCL, CLL/SLL, WM and MZL) include:

  • diarrhea
  • tiredness
  • muscle and bone pain
  • rash
  • bruising

The most common side effects of IMBRUVICA® in adults with cGVHD include:

  • tiredness
  • bruising
  • diarrhea
  • mouth sores (stomatitis)
  • muscle spasms
  • nausea
  • pneumonia

Diarrhea is a common side effect in people who take IMBRUVICA®. Drink plenty of fluids during treatment with IMBRUVICA® to help reduce your risk of losing too much fluid (dehydration) due to diarrhea. Tell your healthcare provider if you have diarrhea that does not go away.

These are not all the possible side effects of IMBRUVICA®. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use of IMBRUVICA® 

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use IMBRUVICA® for a condition for which it was not prescribed. Do not give IMBRUVICA® to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about IMBRUVICA® that is written for health professionals.

Uses

What is IMBRUVICA® (ibrutinib)?

IMBRUVICA® (ibrutinib) is a prescription medicine used to treat adults with:

  • Mantle cell lymphoma (MCL) who have received at least one prior treatment
  • Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL)
  • Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) with 17p deletion
  • Waldenström's macroglobulinemia (WM)
  • Marginal zone lymphoma (MZL) who require a medicine by mouth or injection (systemic therapy) and have received a certain type of prior treatment
  • Chronic graft versus host disease (cGVHD) after failure of 1 or more lines of systemic therapy

It is not known if IMBRUVICA® is safe and effective in children.

Please see the full Important Product Information.

About AbbVie in Oncology
At AbbVie, we are committed to transforming standards of care for multiple blood cancers while advancing a dynamic pipeline of investigational therapies across a range of cancer types. Our dedicated and experienced team joins forces with innovative partners to accelerate the delivery of potentially breakthrough medicines. We are evaluating more than 20 investigational medicines in over 300 clinical trials across some of the world's most widespread and debilitating cancers. As we work to have a remarkable impact on people's lives, we are committed to exploring solutions to help patients obtain access to our cancer medicines. For more information, please visit http://www.abbvie.com/oncology.

About AbbVie
AbbVie's mission is to discover and deliver innovative medicines that solve serious health issues today and address the medical challenges of tomorrow. We strive to have a remarkable impact on people's lives across several key therapeutic areas: immunology, oncology, neuroscience, eye care, virology, women's health and gastroenterology, in addition to products and services across its Allergan Aesthetics portfolio. For more information about AbbVie, please visit us at www.abbvie.com. Follow @abbvie on Twitter, Facebook, Instagram, YouTube and LinkedIn.

Forward-Looking Statements
Some statements in this news release are, or may be considered, forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "anticipate," "project" and similar expressions, among others, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Such risks and uncertainties include, but are not limited to, failure to realize the expected benefits from AbbVie's acquisition of Allergan plc ("Allergan"), failure to promptly and effectively integrate Allergan's businesses, competition from other products, challenges to intellectual property, difficulties inherent in the research and development process, adverse litigation or government action, changes to laws and regulations applicable to our industry and the impact of public health outbreaks, epidemics or pandemics, such as COVID-19. Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," of AbbVie's 2021 Annual Report on Form 10-K, which has been filed with the Securities and Exchange Commission, as updated by its subsequent Quarterly Reports on Form 10-Q. AbbVie undertakes no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.

IMBRUVICA is a registered trademark of Pharmacyclics LLC.

1 Leukemia and Lymphoma Society. Graft Versus Host Disease. Available from: https://www.lls.org/treatment/types-of-treatment/stem-cell-transplantation/graft-versus-host-disease. Accessed February 2021.
2 Bachier CR, Aggarwal SK, et al. Epidemiology and Real-World Treatment of Chronic Graft-Versus-Host Disease Post Allogeneic Hematopoietic Cell Transplantation: A US Claims Analysis. Blood 2019; doi: https://doi.org/10.1182/blood-2019-13056
3 Robert Zeiser, Stephanie J Lee; Three FDA-approved therapies for chronic GVHD. Blood 2022; blood.2021014448. doi: https://doi.org/10.1182/blood.2021014448
4 Martin PJ, Lee SJ, Przepiorka D, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: VI. The 2014 Clinical Trial Design Working Group Report. Biol Blood Marrow Transplant. 2015;21(8):1343-1359. doi:10.1016/j.bbmt.2015.05.004
5 Lee SJ. Classification systems for chronic graft-versus-host disease. Blood. 2017;129(1):30-37. doi:10.1182/blood-2016-07-686642
6 Cooke KR, Luznik L, Sarantopoulos S, et al. The Biology of Chronic Graft-versus-Host Disease: A Task Force Report from the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease. Biol Blood Marrow Transplant. 2017;23(2):211-234. doi:10.1016/j.bbmt.2016.09.023
7 Baird K, Cooke K, Schultz KR. Chronic graft-versus-host disease (GVHD) in children. Pediatr Clin North Am. 2010;57(1):297-322. doi:10.1016/j.pcl.2009.11.003
8 Genetics Home Reference. Isolated growth hormone deficiency. http://ghr.nlm.nih.gov/condition/isolated-growth-hormone-deficiency. Accessed November 2021.
9 Turetsky A, et al. Single cell imaging of Bruton's tyrosine kinase using an irreversible inhibitor. Scientific Reports. 2014;6:4782.
10 de Rooij MF, Kuil A, Geest CR, et al. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood. 2012;119(11):2590-2594.
11 IMBRUVICA U.S. Prescribing Information, December 2020.
12 NCCN® Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma V4.2021. National Comprehensive Cancer Network. Accessed November 2021.

SOURCE AbbVie

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