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Torque Presents New Preclinical Data for Three Deep-Primed Cellular Immunotherapy Programs, Including Newly Unveiled Deep TLR, at SITC 2019 Meeting

On November 8, 2019 Torque, a clinical-stage immuno-oncology company developing Deep Primed T cell immunotherapy to direct immune power deep within the tumor microenvironment, reported new preclinical data for its lead Deep IL-15 Primed T cell, Deep Il-12 Primed T cell, and Deep TLR Primed T cell therapeutics programs as well as for the company’s proprietary Slipstream process for manufacturing these first-in-class, multi-targeted cellular immunotherapies (Press release, Torque Therapeutics, NOV 8, 2019, View Source [SID1234550775]). The data are being presented today at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 34th Annual Meeting being held November 6–10, 2019 in National Harbor, Maryland.

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"These studies build on previous findings demonstrating the potential for the Deep-Primed technology platform to create a new class of multi-targeted T cell therapy that targets tumor antigens with specificity in the tumor microenvironment, with integrated and coordinated cytokine activation that drives a full response against tumors with heterogenous antigens," said Thomas Andresen, PhD, Chief Scientific Officer of Torque. "These preclinical studies provide the foundation for Torque’s first clinical trial for Deep IL-15 Primed multi-targeted T cells that is now under way, and for the Deep IL-12 and Deep TLR programs that we are preparing to move into clinical trials in the latter part of this year and in 2020, including a combination study of Deep IL-12 and Deep IL-15 Primed T cells."

Highlights of the four preclinical presentations follow, and copies of the posters are available on the Torque website: https://bit.ly/34yZnTU

Poster #P671: "Delivery of TLR7 agonists by Deep-Primed T cells induces immune activation and improves anti-tumor activity in mice while circumventing systemic toxicity"
Presenter: Austin Boesch, PhD, Torque
Key findings from the study:

In preclinical models, Deep TLR-Primed T cells display superior efficacy, pharmacodynamics, and safety compared to T cells alone or to T cells co-administered with systemic TLR agonists.
Torque’s Deep-Primed technology allows the delivery of small molecules to the tumor microenvironment, with controlled doses.
Compared to intratumoral delivery, agonist delivery via Deep-Primed tumor antigen-specific autologous T cells can target a wider variety of tumors, including distant metastases.
Deep TLR-Primed T cells have the potential to improve agonist pharmacokinetic profile through sustained delivery over time in the tumor microenvironment and draining lymph nodes, with limited systemic exposure.
Poster #P211: "Combining Deep IL-12 Primed and Deep IL-15 Primed T cells leverages complementary mechanisms to enhance anti-tumor activity"
Presenter: Katharine Sackton, PhD, Torque
Key findings from the study:

In preclinical models, modular tethering of Deep IL-12 and Deep IL-15 to T cells uniquely leverages their complementary functions as immunomodulators to maximize anti-tumor activity, without notable toxicity.
Poster #P473: "Adoptive Transfer of Deep IL-12 Primed T-cells Increases Sensitivity to PD-L1 Blockade for Superior Efficacy in Checkpoint Refractory Tumors"
Presenter: Gulzar Ahmad, PhD, Torque
Key findings from the study:

In a preclinical checkpoint-refractory cancer model, adoptive cell transfer with tumor-specific T cells carrying surface-tethered Deep IL-12, which focuses immune activity in the tumor microenvironment, repolarizes immunosuppressive cells in the tumor, enhances anti-tumor efficacy, and synergizes with checkpoint inhibition.
Poster #P157: "Optimized process for manufacturing Deep-Primed T cells creates product with improved functional characteristics and reactivity against multiple tumor-associated antigens"
Presenter: Shawn P. Carey, PhD, Torque
Key findings from the study:

Torque’s Slipstream cell manufacturing process is optimized to produce Deep-Primed multi-targeted T cells with substantive increases in characteristics associated with clinical efficacy: Antigen reactivity, memory phenotype, and polyfunctionality.
Modularity of the Slipstream process has been demonstrated by simultaneously training T cell clones reactive to cancer and virus-associated antigens.
Deep-Primed multi-targeted T cells with cell-associated Deep IL-15 or Deep IL-12 drives enhanced T cell function in vitro.
About Deep-Primed T Cell Therapeutics
Torque is developing a new class of Deep-Primed cellular immunotherapy designed to overcome the key challenges limiting broad use of cellular therapy in oncology, including the ability to target tumors that express multiple heterogeneous antigens, the ability to overcome the immunosuppressive tumor microenvironment that shuts down T cell function, and the need for cost-effective outpatient treatment with a high margin of safety. Deep-Priming is a unique technology platform that harnesses natural T cell biology and the power of cytokine activation to prime and boost a full immune response in the tumor microenvironment. Deep-Primed T cells are designed to:

Activate a Deep Immune Response Against Solid Tumors & Hematologic Cancers: Natural T cell receptors are primed to target multiple tumor antigens and retain their natural ability to integrate with the full immune system to direct a deep and comprehensive immune response against cancer.
Prime and Boost Broad Immune Cell Engagement to Overcome Immunosuppression in the Tumor Microenvironment: Deep-Primed T cells carry surface-anchored cytokines and immunomodulators to jump-start the engagement and coordination of the full network of immune cells to direct immune power in the tumor microenvironment, without significant systemic exposure.
Torque’s first clinical program, TRQ-1501 (Deep IL-15 Primed T cells), has received FDA Fast Track designation for the treatment of relapsed or refractory solid tumors and lymphomas and is currently in a Phase 1/2 clinical trial for this indication.

BERG Presents Data Demonstrating That BPM31510 Promotes Cytotoxic T-cell Function And Influences Checkpoint Receptor Expression Patterns To Potentially Synergize Anti-Cancer Effect In Combination With I/O Therapies

On November 8, 2019 BERG, a clinical stage biopharmaceutical company that uses artificial intelligence (AI) to discover the underlying biology of disease, reported results from a study of its investigational drug BPM31510 (ubidecarenone) characterizing its immunomodulatory properties ex vivo and in tumor bearing mice. The study, presented as a poster at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting in National Harbor, Md., demonstrates a novel immuno-supportive activity of BPM31510 associated with enhanced T-cell function and diminished T-cell exhaustion which may contribute to its anti-tumor activity and synergize with Immuno-Oncology therapies (Press release, Berg, NOV 8, 2019, View Source [SID1234550774]).

"Compromised T-cell function has a major impact on the effective anti-cancer response and outcomes observed in I/O therapies," said Dr. Niven R. Narain, BERG Co-founder, President and Chief Executive Officer. "The ability of BPM31510 to influence specific phenotypic attributes in T-cells to improve its effectiveness in the cancer microenvironment by targeting mitochondrial function represents a novel approach to impact immune system to improve cancer outcomes."

Combination of immunotherapies is under active investigation to improve anti-cancer outcomes. Immunometabolism is recognized as an important component of the immune function repertoire, an area with high untapped potential. BPM31510 impact on mitochondrial function and metabolism represents a novel and unique mechanism through its ability to synergize anti-cancer activities of I/O therapies in preclinical models and is under active investigation at BERG.

"These data set the stage to further explore BPM31510 impact on anti-tumor immunity and how to best deploy BPM31510 as part of an immunotherapy cocktail," said Vikas P. Sukhatme MD ScD, Professor of Medicine at Emory University School of Medicine and a Scientific Advisory Board member of BERG.

Details of the presentations include:
Date: Friday, November 8, 2019
BPM31510, a Metabolic Modulating Anti-Cancer Agent, Demonstrates Immune Potentiating Properties by Promoting Cytotoxic T Cells and Reversing Indices of Exhaustion and Immunosuppression
Abstract ID: P633 (Immune-stimulants and immune modulators)
Location: Poster Hall, Prince George AB of the Gaylord National Hotel & Convention Center, National Harbor MD, USA
Time: 7:00 AM – 8:00 PM

BERG collaborates with leading institutions like MD Anderson Cancer Institute (solid tumor and pancreatic trials), Harvard/BIDMC (Project Survival) and Stanford University (GBM trial), among others, in its commitment to serve patients afflicted with cancer.

Orexo to Present at Jefferies 2019 Healthcare Conference

On November 8, 2019 Orexo AB (publ), the fully integrated specialty pharmaceutical company addressing opioid addiction and pain, reported that the company will present at the Jefferies Healthcare Conference on Wednesday, November 20, 2019, at 10.40 am GMT at the Waldorf Hilton Hotel in London, UK (Press release, Orexo, NOV 8, 2019, View Source [SID1234550773]). President and CEO, Nikolaj Sørensen, will provide an update on Orexo’s market, sales development, pipeline progression and the growth strategy, focusing on broadening the product portfolio and building a presence in the increasingly important and complementary digital therapeutics market.

The presentation will be made available at Orexo’s website, www.orexo.com, under the Investor section.

For further information, please contact
Orexo AB (publ.)
Lena Wange, IR and Communications Manager
Tel: +46 (0)18-780-88-00
E-mail: [email protected]

BerGenBio Presents Updated Phase 2 NSCLC Clinical and Translational Data for Bemcentinib in Combination With KEYTRUDA®

On November 8, 2019 BerGenBio ASA (OSE:BGBIO), a clinical-stage biopharmaceutical company developing novel, selective AXL kinase inhibitors for multiple cancer indications, reported comprehensive clinical and translational data from Cohort A of its Phase II clinical trial (BGBC008) evaluating bemcentinib, its first in class selective AXL inhibitor, in combination with MSD’s, (a tradename of Merck & Co., Inc., Kenilworth, NJ., USA) anti-PD-1 therapy KEYTRUDA (pembrolizumab), as a potential new treatment regimen for previously treated advanced non-small cell lung cancer (NSCLC) at an oral presentation at the prestigious High Impact Clinical Trial session at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) (6-10 November 2019) conference in Washington DC (Press release, BerGenBio, NOV 8, 2019, View Source [SID1234550772]).

In cohort A, 44 patients were evaluable for response; of IHC evaluable patients: 50% were composite AXL positive, 52% were PD-L1 negative (<1%TPS), and 38% patients were PD-L1 low positive (1-49% TPS). The primary endpoint of Overall Response Rate (ORR) was met, with 33% ORR in AXL positive patients; five times the response rate of AXL negative patients (7%).

A secondary endpoint of median Progression Free Survival (mPFS) reported significant 3-fold improvement in AXL positive vs negative patients – 8.4 months in composite AXL positive patients significantly surpassing what has been shown historically in second line treatment with PD-1 inhibitor monotherapy.

Dr. Matthew Krebs, MD, PhD, the lead investigator who will give the presentation at SITC (Free SITC Whitepaper) said: "The clinical benefit seen with the drug combination in AXL positive patients is impressive and provides a potential new treatment approach for patients with low or negative PD-L1 status. The mPFS observed for the AXL positive patients is far higher than that seen with pembrolizumab monotherapy results from earlier clinical trials for patients with PD-L1<50%. Furthermore, the combination is well tolerated by patients."

RNA sequence analysis of pretreatment patient biopsies revealed that clinical benefit from the combination therapy correlates with total tumor AXL expression. A proprietary predictive signature for response to bemcentinib and pembrolizumab combination derived from the transcriptional analysis is enriched for genes associated with epithelial-to-mesenchymal transition (EMT) and myeloid cell activation. "This is exactly where we know AXL is important." added Professor James Lorens PhD, Chief Scientific Officer of BerGenBio.

The gene expression measured in responding patients correlates with gene signatures known to be associated with poor prognosis and lack of response to immunotherapy. This indicates that previously treated patients are particularly benefiting despite exhibiting these adverse traits. Professor Hani Gabra MD PhD, Chief Medical Officer of BerGenBio said: "This indicates that bemcentinib is conditioning the tumor microenvironment in AXL positive patients and optimizing pembrolizumab response in these previously treated patients."

Multispectral immunofluorescence analysis detected tumor infiltrating AXL-expressing macrophages closely adjacent to T cells in the tumors of patients who responded to the combination therapy. "Seeing the AXL expressing macrophages interacting with T regulatory cells in the tumor of a patient who responded to the treatment really underscores the potential." added Dr. Krebs.

Prof. Lorens added: "Previously we only considered AXL expression in the tumor cells, ignoring the immune cell compartment of the tumor. Our deeper biomarker analysis clearly shows that our earlier tumor cell-only score did not fully capture the population of patients who benefit from the combination." A proprietary composite AXL tumor-immune score has now been developed, derived from gene expression and immunohistochemistry analysis that selects patients likely to benefit from bemcentinib.

Richard Godfrey, Chief Executive Officer of BerGenBio, said: "Our improved ability to select and predict patients with durable clinical benefit with a refined AXL composite biomarker is an important development for our AXL targeting clinical programs. Importantly for patients is the prolonged duration of benefit or mPFS and improved Overall Survival (mOS), which is still maturing, these are also critical regulatory end points. I look forward to reporting mOS and data from additional cohorts in the coming months."

Presentation details

A phase II study of bemcentinib (BGB324), a first-in-class selective AXL inhibitor, in combination with pembrolizumab in patients with advanced NSCLC: Updated analysis

Matthew G. Krebs, MD, PhD –The University of Manchester
Concurrent Session 206: High Impact Clinical Trials
Oral Session
08 November 2019: Prince George’s Exhibition Hall C
5:10 – 5:25 p.m. EST (Session runs from 4:50 – 6:15 p.m.)
Presentation will be available at www.bergenbio.com in the section: Investors/Presentations when the presentation starts.

About AXL

AXL kinase is a cell membrane receptor and an essential mediator of the biological mechanisms underlying life-threatening diseases. In cancer, AXL suppresses the body’s immune response to tumours and drives cancer treatment failure across many indications. Tumour AXL expression is associated with poor prognosis in NSCLC and most other cancer types. AXL inhibitors, therefore, have potential high value at the centre of cancer combination therapy, addressing significant unmet medical needs and multiple high-value market opportunities. Research has also shown that AXL mediates other aggressive diseases.

About Bemcentinib

Bemcentinib (formerly known as BGB324), is a potentially first-in-class selective AXL inhibitor in a broad phase II clinical development programme. Ongoing clinical trials are investigating bemcentinib in multiple solid and haematological tumours, in combination with current and emerging therapies (including immunotherapies, targeted therapies and chemotherapy), and as a single agent. Bemcentinib targets and binds to the intracellular catalytic kinase domain of AXL receptor tyrosine kinase and inhibits its activity. Increase in AXL function has been linked to key mechanisms of drug resistance and immune escape by tumour cells, leading to aggressive metastatic cancers.

Janssen Announces Submission of Supplemental New Drug Application to U.S. FDA Seeking Approval of IMBRUVICA® (ibrutinib) in Combination with Rituximab for Previously Untreated Patients with Chronic Lymphocytic Leukemia

On November 8, 2019 The Janssen Pharmaceutical Companies of Johnson & Johnson reported the submission of a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) seeking approval to expand the IMBRUVICA (ibrutinib) label to include the combination with rituximab for the first-line treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) (Press release, Johnson & Johnson, NOV 8, 2019, View Source [SID1234550771]). The submission is based on positive results from the investigational Phase 3 E1912 study designed and conducted by the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) and sponsored by the National Cancer Institute (NCI), which is part of the National Institutes of Health. The study met the primary endpoints of progression-free survival (PFS) and overall survival (OS) in patients aged 70 years or younger treated with IMBRUVICA plus rituximab, compared to the chemoimmunotherapy regimen of fludarabine, cyclophosphamide and rituximab (FCR). Results from the study were presented at the 2018 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and were recently published in The New England Journal of Medicine August 2019 issue.

"ECOG-ACRIN’s E1912 is a landmark head-to-head clinical trial of an IMBRUVICA-based regimen versus FCR, the most common chemoimmunotherapy regimen established to date for the frontline treatment of younger adult patients with CLL," said Craig Tendler, M.D., Vice President, Clinical Development and Global Medical Affairs, Janssen Research & Development, LLC. "We look forward to working closely with the FDA to bring this new IMBRUVICA-based chemotherapy-free option to younger adult CLL patients based on the significant delay in disease progression and survival benefit as demonstrated in the E1912 study."

The sNDA is being reviewed by the U.S. FDA under the Real-Time Oncology Review (RTOR) pilot program. The program is designed to explore a more efficient review process, ensuring safe and effective treatments become available to patients earlier, while maintaining quality of review.

IMBRUVICA is a once-daily, first-in-class Bruton’s tyrosine kinase (BTK) inhibitor that is administered orally, and is jointly developed and commercialized by Janssen Biotech, Inc. and Pharmacyclics LLC, an AbbVie company.

About IMBRUVICA
IMBRUVICA (ibrutinib) is a once-daily oral medicine that works differently than chemotherapy as it blocks the Bruton’s tyrosine kinase (BTK) protein. The BTK protein sends important signals that tell B cells to mature and produce antibodies. BTK signaling is needed by specific cancer cells to multiply and spread.1,2 By blocking BTK, IMBRUVICA may help move abnormal B cells out of their nourishing environments in the lymph nodes, bone marrow, and other organs.3

IMBRUVICA is approved in more than 95 countries for at least one indication, and, to date, has been used to treat more than 170,000 patients worldwide across approved indications. It was first approved by the U.S. Food and Drug Administration (FDA) in November 2013, and today is indicated in six disease areas, including five hematologic cancers – chronic lymphocytic leukemia (CLL) with or without 17p deletion (del17p); small lymphocytic lymphoma (SLL) with or without del17p; Waldenström’s macroglobulinemia (WM); previously-treated patients with mantle cell lymphoma (MCL)*; previously-treated patients with marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy*; and previously-treated patients with chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic therapy.4

* 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.

As of early 2019, the National Comprehensive Cancer Network (NCCN), a not-for-profit alliance of 28 leading cancer centers devoted to patient care, research, and education, recommends ibrutinib (IMBRUVICA) as a preferred regimen for the initial treatment of CLL/SLL, and it is the only Category 1 single-agent regimen for treatment-naïve patients without deletion 17p. IMBRUVICA is the only FDA-approved medicine in WM and cGVHD. IMBRUVICA has been granted four Breakthrough Therapy Designations by the FDA, and it was one of the first medicines to receive U.S. approval with the Breakthrough Therapy Designation.

IMBRUVICA is a comprehensively studied molecule, with more than 150 active clinical trials studying IMBRUVICA alone and in combination with other medicines in several blood cancers and other serious diseases. For more information, visit www.IMBRUVICA.com.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA. Major hemorrhage (≥ Grade 3, serious, or any central nervous system events; e.g., intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post procedural hemorrhage) have occurred in 4% of patients, with fatalities occurring in 0.4% of 2,838 patients exposed to IMBRUVICA in 27 clinical trials. Bleeding events of any grade, including bruising and petechiae, occurred in 39% of patients treated with IMBRUVICA.

The mechanism for the bleeding events is not well understood.

Use of either anticoagulant or antiplatelet agents concomitantly with IMBRUVICA increases the risk of major hemorrhage. In IMBRUVICA clinical trials, 3.1% of patients taking IMBRUVICA without antiplatelet or anticoagulant therapy experienced major hemorrhage. The addition of antiplatelet therapy with or without anticoagulant therapy increased this percentage to 4.4%, and the addition of anticoagulant therapy with or without antiplatelet therapy increased this percentage to 6.1%. Consider the risks and benefits of anticoagulant or antiplatelet therapy when co-administered with IMBRUVICA. Monitor for signs and symptoms of bleeding.

Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections: Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 24% of 1,124 patients exposed to IMBRUVICA in clinical trials. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections.

Monitor and evaluate patients for fever and infections and treat appropriately.

Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (23%), thrombocytopenia (8%), and anemia (3%) based on laboratory measurements occurred in patients with B-cell malignancies treated with single agent IMBRUVICA.

Monitor complete blood counts monthly.

Cardiac Arrhythmias: Fatal and serious cardiac arrhythmias have occurred with IMBRUVICA therapy. Grade 3 or greater ventricular tachyarrhythmias occurred in 0.2% of patients, and Grade 3 or greater atrial fibrillation and atrial flutter occurred in 4% of 1,124 patients exposed to IMBRUVICA in clinical trials. These events have occurred particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmias.

Periodically monitor patients clinically for cardiac arrhythmias. Obtain an ECG for patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. Manage cardiac arrhythmias appropriately, and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.

Hypertension: Hypertension of any grade occurred in 12% of 1,124 patients treated with IMBRUVICA in clinical trials. Grade 3 or greater hypertension occurred in 5% of patients with a median time to onset of 5.9 months (range, 0.03 to 24 months).

Monitor blood pressure in patients treated with IMBRUVICA and initiate or adjust anti-hypertensive medication throughout treatment with IMBRUVICA as appropriate.

Second Primary Malignancies: Other malignancies (10%) including non-skin carcinomas (4%) have occurred in 1,124 patients treated with IMBRUVICA in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer (6%).

Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions.

Monitor patients closely and treat as appropriate.

Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA and for 1 month after cessation of therapy. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Advise men to avoid fathering a child during the same time period.

ADVERSE REACTIONS

B-cell malignancies: The most common adverse reactions (≥20%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were thrombocytopenia (58%)*, diarrhea (41%), anemia (38%)*, neutropenia (35%)*, musculoskeletal pain (32%), rash (32%), bruising (31%), nausea (26%), fatigue (26%), hemorrhage (24%), and pyrexia (20%).

The most common Grade 3 or 4 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (18%)*, thrombocytopenia (16%)*, and pneumonia (14%).

Approximately 7% (CLL/SLL), 14% (MCL), 14% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4-10% (CLL/SLL), 9% (MCL), and 7% (WM [5%] and MZL [13%]) of patients discontinued due to adverse reactions.

cGVHD: The most common adverse reactions (≥20%) in patients with cGVHD were fatigue (57%), bruising (40%), diarrhea (36%), thrombocytopenia (33%)*, muscle spasms (29%), stomatitis (29%), nausea (26%), hemorrhage (26%), anemia (24%)*, and pneumonia (21%).

The most common Grade 3 or higher adverse reactions (≥5%) reported in patients with cGVHD were pneumonia (14%), fatigue (12%), diarrhea (10%), neutropenia (10%)*, sepsis (10%), hypokalemia (7%), headache (5%), musculoskeletal pain (5%), and pyrexia (5%).

Twenty-four percent of patients receiving IMBRUVICA in the cGVHD trial discontinued treatment due to adverse reactions. Adverse reactions leading to dose reduction occurred in 26% of patients.

*Treatment-emergent decreases (all grades) were based on laboratory measurements.

DRUG INTERACTIONS

CYP3A Inhibitors: Co-administration of IMBRUVICA with strong or moderate CYP3A inhibitors may increase ibrutinib plasma concentrations. Dose modifications of IMBRUVICA may be recommended when used concomitantly with posaconazole, voriconazole, and moderate CYP3A inhibitors. Avoid concomitant use of other strong CYP3A inhibitors. Interrupt IMBRUVICA if strong inhibitors are used short-term (e.g., for ≤ 7 days). See dose modification guidelines in USPI sections 2.4 and 7.1.

CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA in patients with severe baseline hepatic impairment. In patients with mild or moderate impairment, reduce IMBRUVICA dose.