Dysautonomia, Familial

Scientists have written a review to discuss emerging research and evidence of the roles of alternative splicing defects in major neurodegenerative diseases. They also summarize the latest advances in RNA-based therapeutic strategies to target these disorders. Alternative splicing, a clever way a cell generates many different variations of messenger RNAs -- single-stranded RNAs involved in protein synthesis -- and proteins from the same stretch of DNA, plays an important role in molecular biology. Progressing rapidly, the field of alternative splicing is a complex topic and the scientific literature on it is already extensive. David Nikom, a student in the UC Riverside Neuroscience Graduate Program, and his advisor, Sika Zheng, an associate professor of biomedical sciences in the UCR School of Medicine and director of the Center for RNA Biology and Medicine, have written a review in Nature Reviews Neuroscience to discuss emerging research and evidence of the roles of alternative splicing defects in major neurodegenerative diseases. They also summarize the latest advances in RNA-based therapeutic strategies to target these disorders. According to them, the topic of alternative splicing in neurodegenerative disease is particularly relevant in view of the increasing frequency of neurodegenerative disease worldwide and the urgent need for novel approaches for their treatment and management. They argue that since aberrant splicing dysregulation occurs commonly in neurodegenerative disease, the promise of using RNA therapies is important to understand and well-suited for a review. Titled "Alternative Splicing in Neurodegenerative Disease and the Promise of RNA Therapies," their review aims at providing comprehensive, all-inclusive knowledge for a scientific audience interested in the topic. It synthesizes knowledge and discoveries from decades of research made by many labs worldwide on Alzheimer's disease, Parkinson's disease, Huntington's disease, ALS, frontal temporal dementia, etc. The work is supported by grants to Zheng from the National Institutes of Health. In the following Q&A, Zheng and Nikom unpack key aspects of the review. Q: What is alternative splicing dysregulation? Once the DNA of a gene is transcribed into a pre-messenger RNA (RNA before it is spliced), only a small fraction of the pre-messenger RNA makes into the final messenger RNA, or mRNA, transcript that encodes protein. Alternative splicing is a process by which a cell can select which of those protein-coding parts to include in the resulting RNA or protein. Alternative splicing dysregulation is when this process goes wrong in some way. The cell chooses to include the wrong protein-coding parts or exclude some correct parts. This can cause all sorts of problems with the resulting protein: it could be shorter than it is supposed to be which would disrupt its normal function in the cell, or it could result in the protein not being produced at all. Q: What role does alternative splicing play in molecular biology? Alternative splicing greatly expands the diversity of the proteins that can be made from a single gene. This is important because multicellular organisms make so many different types of cells that compose the diverse tissue types of their body. But each cell only has the same genetic code. To produce the dazzling complexity of multicellular life, cells depend on alternative splicing to give them the flexibility to make large families of similar proteins with different tissue-specific and developmental stage-specific functions. For example, certain alternative splicing networks are only activated during embryonic development and get shut down when the organism matures. Q: Briefly, how does it contribute to the molecular pathology of a wide range of neurodegenerative diseases? Certain organs rely on alternative splicing to generate cellular diversity more than others. We don't know why for sure, but the brain has more alternative splicing going on than any other organ in the body. Scientists speculate this might be due to the brain's unique complexity, rapid evolution, or the extraordinary diversity of cell types it contains. What we do know is that there are a lot of brain-specific alternative splicing events that consistently go wrong in neurological diseases. These include neurodevelopmental disorders, like autism spectrum disorder, or neurodegenerative diseases, like Alzheimer's Disease or ALS. The best understood example we have so far has to do with dysregulated alternative splicing in ALS. Scientists found these erroneous splicing events lead to production of aberrant proteins or reduction of normal proteins, which ultimately affect neuronal health and function. Some other neurodegenerative diseases with dysregulated alternative splicing include frontotemporal dementia, Parkinson's disease, Familial dysautonomia, Huntington's disease, spinal muscular atrophy, and Duchenne muscular dystrophy. Q: Does alternative splicing play a role in other diseases? Alternative splicing has been linked to about 15% of human genetic diseases and cancers. Mutations in the components that regulate alternative splicing are causative for many diseases, both common and rare. Myotonic dystrophy, myelodysplastic syndromes (bone marrow cancers), retinal degenerative disorders like retinitis pigmentosa, and progeria (rare premature aging syndrome) are prominent examples of diseases caused by splicing defects. Q: You conclude the review with the latest advances in RNA-based therapeutic strategies developed to target the underlying splicing mechanisms. What are some of these advances? A good example of targeting underlying splicing mechanisms to treat diseases is with a disease called spinal muscular atrophy, a major genetic disease of children and infants. Humans carry two near identical copies of the Survival Motor Neuron gene: SMN1 and SMN2 which are essential for the survival of all animal cells. Patients with Spinal Muscular Atrophy have loss of SMN1; SMN2 is the only source of the SMN protein in patients. The critical difference between SMN1 and SMN2 is splicing of exon 7, a small fragment of protein-coding sequence within the SMN gene. Unlike SMN1 exon 7, SMN2 exon 7 is usually not included in most tissues. The exon 7-skipped transcript generated by SMN2 produces a partially functional and unstable protein. The first therapeutic approval for SMA targets the SMN2 pre-mRNA and binds to a region that is accessed by the splicing machinery to remove exon 7. This ultimately leads to blocking of the removal of exon 7 and promotes the formation of functional SMN protein. By promoting splicing of exon 7, this drug (Spinraza) increased SMN expression in the cell from the SMN2 gene, compensating for the loss of SMN1, and preventing the loss of cells in the central nervous system. This story is a textbook example of a splicing mechanism that can be targeted to treat an otherwise fatal disease in children. The hope is to understand many more splicing mechanisms and find new ways to target them to treat other diseases. Some of the latest advances:

DUBLIN, June 15, 2023 /PRNewswire/ -- Endo International plc (OTC: ENDPQ) announced today that one of its operating companies, Par Pharmaceutical, Inc., has begun shipping dexlansoprazole 30 mg capsules, a generic version of Takeda's Dexilant®. This additional dosage strength rounds out the product family, now with both 30 mg and 60 mg delayed-release capsules. "We're proud to provide this high-quality, affordable generic medication to appropriate patients," said Scott Sims, Senior Vice President and General Manager, Injectable Solutions & Generics at Endo. "The dexlansoprazole product family strengthens our portfolio and our reputation as a reliable supplier." Dexlansoprazole is a proton pump inhibitor with a novel delivery system approved for the treatment of erosive esophagitis and heartburn associated with symptomatic non-erosive gastroesophageal reflux disease (GERD). According to IQVIA™, Dexilant® 30 mg sales were approximately $45 million for the 12 months ended April 30, 2023. Dexilant® is a registered trademark of Takeda Pharmaceuticals U.S.A., Inc. IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS Dexlansoprazole delayed-release capsules are contraindicated in patients with known hypersensitivity to any component of the formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis and urticaria. PPIs, including dexlansoprazole delayed-release capsules, are contraindicated with rilpivirine-containing products. WARNINGS AND PRECAUTIONS Dexlansoprazole Delayed-Release Capsules, 60 mg, contain FD&C Yellow #5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow #5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity. Presence of Gastric Malignancy: In adults, symptomatic response to therapy with dexlansoprazole does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing in adult patients who have a suboptimal response or an early symptomatic relapse after completing treatment with a PPI. In older patients, also consider an endoscopy. Acute Tubulointerstitial Nephritis (TIN): TIN has been observed in patients taking PPIs and may occur at any point during PPI therapy. Patients may present with varying signs and symptoms, from symptomatic hypersensitivity reactions to non-specific symptoms of decreased renal function (eg, malaise, nausea, anorexia). Discontinue dexlansoprazole and evaluate patients with suspected acute TIN. Clostridium difficile-Associated Diarrhea: Published observational studies suggest that PPI therapy like dexlansoprazole may be associated with an increased risk of Clostridium difficile-associated diarrhea, especially in hospitalized patients. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Bone Fracture: Several published observational studies suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the conditions being treated. Severe Cutaneous Adverse Reactions: Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with the use of PPIs. Discontinue dexlansoprazole delayed-release capsules at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. Cutaneous and Systemic Lupus Erythematosus (CLE and SLE): CLE and SLE have been reported in patients taking PPIs. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematosus cases were CLE. The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly. SLE is less commonly reported than CLE in patients receiving PPIs. Onset of SLE typically occurred within days to years after initiating treatment primarily in patients ranging from young adults to the elderly. The majority of patients presented with rash; however, arthralgia and cytopenia were also reported. Avoid administration of PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE are noted in patients receiving dexlansoprazole delayed-release capsules, discontinue the drug and refer the patient to the appropriate specialist for evaluation. Cyanocobalamin (Vitamin B12) Deficiency: Daily treatment with any acid-suppressing medications over a long period of time (eg, longer than three years) may lead to malabsorption of cyanocobalamin (Vitamin B12) caused by hypo- or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature. Hypomagnesemia and Mineral Metabolism: Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in at-risk patients. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI. For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (eg, diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically. Interactions with Investigations for Neuroendocrine Tumors: Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Healthcare providers should temporarily stop dexlansoprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. Interaction with Methotrexate: Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients. Fundic Gland Polyps: PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, especially beyond one year. Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy. Use the shortest duration of PPI therapy appropriate to the condition being treated. Risk of Heart Valve Thickening in Pediatric Patients Less Than Two Years of Age: Dexlansoprazole is not recommended in pediatric patients less than two years of age. ADVERSE REACTIONS Adults (≥2%): diarrhea, abdominal pain, nausea, upper respiratory tract infection, vomiting, and flatulence. Patients 12 to 17 years of age (≥5%): headache, abdominal pain, diarrhea, nasopharyngitis, and oropharyngeal pain. USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause adverse effects on fetal bone growth and development. Pediatrics: Based on data with lansoprazole, dexlansoprazole is not effective in patients with symptomatic GERD 1 month to less than 1 year of age and nonclinical studies have demonstrated adverse effects in juvenile rats. INDICATIONS AND USAGE Healing of Erosive Esophagitis (EE): Dexlansoprazole delayed-release capsules are indicated in patients 12 years of age and older for healing of all grades of EE for up to eight weeks. Maintenance of Healed Erosive Esophagitis and Relief of Heartburn: Dexlansoprazole delayed-release capsules are indicated in patients 12 years of age and older to maintain healing of EE and relief of heartburn for up to six months in adults and 16 weeks in patients 12 to 17 years of age. Treatment of Symptomatic Non-Erosive Gastroesophageal Reflux Disease: Dexlansoprazole delayed-release capsules are indicated in patients 12 years of age and older for the treatment of heartburn associated with symptomatic non-erosive gastroesophageal reflux disease (GERD) for four weeks. Please click for Full Prescribing Information. About Endo Endo (OTC: ENDPQ) is a specialty pharmaceutical company committed to helping everyone we serve live their best life through the delivery of quality, life-enhancing therapies. Our decades of proven success come from passionate team members around the globe collaborating to bring treatments forward. Together, we boldly transform insights into treatments benefiting those who need them, when they need them. Learn more at or connect with us on LinkedIn. Cautionary Note Regarding Forward-Looking Statements Certain information in this press release may be considered "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995 and any applicable Canadian securities legislation including, but not limited to, the statements by Mr. Sims, any statements relating to product launch, commercialization, sales, supply or distribution, and any statements that refer to expected, estimated or anticipated future results or that do not relate solely to historical facts. Statements including words or phrases such as "believe," "expect," "anticipate," "intend," "estimate," "plan," "will," "may," "look forward," "intend," "guidance," "future," "potential" or similar expressions are forward-looking statements. All forward-looking statements in this communication reflect the Company's current views as of the date of this communication about its plans, intentions, expectations, strategies and prospects, which are based on the information currently available to it and on assumptions it has made. Actual results may differ materially and adversely from current expectations based on a number of factors, including, among other things, the outcome of the Company's contingency planning and restructuring activities; the timing, impact or results of any pending or future litigation, investigations, proceedings or claims, including opioid, tax and antitrust related matters; any actual or contingent liabilities; settlement discussions or negotiations; the Company's liquidity, financial performance, cash position and operations; the risks and uncertainties associated with chapter 11 proceedings; the time, terms and ability to confirm a sale of the Company's businesses under Section 363 of the U.S. Bankruptcy Code; the risk that the Company's chapter 11 cases may be converted to cases under chapter 7 of the Bankruptcy Code; the adequacy of the capital resources of the Company's businesses and the difficulty in forecasting the liquidity requirements of the operations of the Company's businesses; the unpredictability of the Company's financial results; the Company's ability to discharge claims in chapter 11 proceedings; negotiations with the holders of the Company's indebtedness and its trade creditors and other significant creditors; the risks and uncertainties with performing under the terms of the restructuring support agreement and any other arrangement with lenders or creditors while in chapter 11 proceedings; the performance, including the approval, introduction, and consumer and physician acceptance of new products and the continuing acceptance of currently marketed products; and the Company's ability to obtain and successfully manufacture, maintain and distribute a sufficient supply of products to meet market demand in a timely manner. The Company expressly disclaims any intent or obligation to update these forward-looking statements, except as required to do so by law. Additional information concerning risk factors, including those referenced above, can be found in press releases issued by the Company, as well as the Company's public periodic filings with the U.S. Securities and Exchange Commission and with securities regulators in Canada, including the discussion under the heading "Risk Factors" in the Company's most recent Annual Report on Form 10-K and any subsequent Quarterly Reports on Form 10-Q or other filings with the U.S. Securities and Exchange Commission. SOURCE Endo International plc

The all-oral, once-daily combination regimen also demonstrates the potential of immune restoration in this patient population VIENNA, June 10, 2022 /PRNewswire/ -- The Janssen Pharmaceutical Companies of Johnson & Johnson today announced new and updated results from the Phase 2 CAPTIVATE study evaluating IMBRUVICA® (ibrutinib) in combination with venetoclax (I+V) as a potential fixed-duration (FD) treatment in adult patients with previously untreated chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Updated data from the FD cohort with three years of follow-up shows that I+V continues to demonstrate deep and durable responses and clinically meaningful progression-free survival (PFS) and overall survival (OS) in the first-line treatment setting. New data will be presented from the minimal residual disease (MRD) cohort, which suggests immune restoration with this combination. These data will be presented during the 2022 European Hematology Association (EHA) Annual Congress taking place in Vienna, Austria June 9-12 (Abstracts #S144 and #P669). "These promising data highlight the complementary mechanism of action between ibrutinib and venetoclax in a fixed-duration combination regimen," said Carol Moreno, M.D., Ph.D., Consultant Hematologist, Hospital de la Santa Creu Sant Pau, Autonomous University of Barcelona, Barcelona, Spain, and study investigator.† "The CAPTIVATE study suggests that this combination may have the potential to provide treatment-free remissions for patients and effectively eradicate CLL cells and help to restore normal B cells to healthy donor levels in patients with previously untreated CLL/SLL." The Phase 2 CAPTIVATE (PCYC-1142) study (NCT02910583) – sponsored by Pharmacyclics LLC, an AbbVie Company, and Janssen Biotech, Inc. – enrolled 323 patients with previously untreated CLL/SLL who were younger than 70 years, including patients with high-risk disease, in two cohorts: an FD cohort where all patients stopped therapy after 12 cycles of the combination, regardless of MRD status; and an MRD-guided cohort where treatment duration was guided by the patients' MRD status after 12 cycles of I+V combination (patients who met criteria for confirmed undetectable minimal residual disease [uMRD] were randomized 1:1 to placebo or IMBRUVICA®; patients who did not meet uMRD criteria were randomized to IMBRUVICA® or I+V).1,2 Three-Year Follow-Up Data from the FD Cohort of the Phase 2 CAPTIVATE (PCYC-1142) Study of IMBRUVICA®-Based Combination Regimen in Previously Untreated Patients with CLL/SLL ( Abstract #P669 ) 1 After an additional year of follow-up data from the FD cohort of CAPTIVATE, I+V continues to demonstrate deep, durable responses and clinically meaningful PFS, including in patients with del(17p)/TP53 mutated or unmutated immunoglobulin heavy chain gene (IGHV).1 The clinical data underscore the distinct and complementary modes of action of IMBRUVICA® and venetoclax (a BCL-2 inhibitor).1 IMBRUVICA® has been shown to mobilize CLL cells out of lymph nodes and other lymphoid niches and into peripheral blood where they are more susceptible to venetoclax-induced apoptosis, eliminating dividing and resting CLL cells.1 Key findings from the Phase 2 CAPTIVATE FD cohort study include: At a median follow-up of 38.7 months, the 36-month PFS rate was 88 percent for all treated patients, 80 percent for patients with del(17p)/TP53 mutated and 86 percent for unmutated IGHV patients (95 percent Confidence Interval [CI]).1 With an additional year of follow-up, no additional OS events occurred. The 36-month OS rate was 98 percent, overall (95 percent CI).1 The 36-month OS rates were similar in patients with del(17p)/TP53 mutated (96 percent) or unmutated IGHV (97 percent).1 The complete response (CR) rate was 57 percent (n=159; 95 percent CI, 50-65) and consistent across high-risk subgroups.1 Median duration of CR was not reached (n=91); the 24-month landmark estimate for duration of CR was 94 percent. Median duration of response was not reached for responding patients (n=153).1 Seventy-nine percent of patients (n=125) achieved undetectable uMRD at any time in the peripheral blood (PB) and/or bone marrow.1 Of patients with uMRD in PB at three months posttreatment, 78 percent (66/85) of evaluable patients maintained uMRD through 12 months posttreatment.1 All patients are currently off treatment.1 Frequently occurring treatment-emergent adverse events (TEAEs) (period from first dose until 30 days after the last dose of study treatment) were primarily Grade 1/2 in severity with the exception of neutropenia.1 Median time to onset of frequently occurring TEAEs generally occurred within four months (87-100 percent).1 The median time to resolution or improvement ranged from 16.5 days (diarrhea) to 42.5 days (arthralgia).1 No new serious adverse events or secondary malignancies have been reported since the primary analysis.1 Twelve patients who progressed after FD treatment with I+V have been retreated with single-agent IMBRUVICA®; 11 of the 12 patients were evaluable for response, with 10 responding.1 New Data from the MRD-Guided Cohort of the Phase 2 CAPTIVATE (PCYC-1142) Study of IMBRUVICA®-Based Combination Regimen Evaluating Immune Restoration in Previously Untreated Patients with CLL/SLL ( Abstract #S144 ) 2 Data on the changes over time in the cellular immune profile in patients with CLL/SLL treated with the I+V combination and age-matched healthy donors were featured in an oral presentation at EHA. The FD regimen of I+V in the confirmed uMRD placebo arm effectively eradicated CLL cells to healthy donor levels and enabled sustained regeneration of normal B cell counts.2 Immune restoration was evaluated in 79 previously untreated patients with CLL/SLL enrolled in the MRD cohort by monitoring changes over time in the cellular immune profile of patients treated with I+V combination regimen and compared to 20 age-matched healthy donors.2 Key findings from this analysis include: Patients with confirmed uMRD (n=40) had a significantly more pronounced decrease in circulating CLL cell count than patients with uMRD not confirmed (n=39).2 At Cycles seven and 16 the p-value was <0.0001 with I+V combination therapy.2 From Cycle 16 – 29, patients with Confirmed uMRD (n=40) had cell counts similar to those of healthy donors (≤0.8 cell/μL).2 Normalization of critical immune cells, including T-cell subsets, classical monocytes, and dendritic cell counts was observed in this population.2 "These new clinical and immune results from the CAPTIVATE study add further evidence of the promise of IMBRUVICA in a fixed-duration regimen for previously untreated CLL patients," said Craig Tendler, M.D., Vice President, Late Development and Global Medical Affairs, Janssen Research & Development, LLC. "IMBRUVICA has become a standard of care in CLL treatment, and we continue to explore novel combinations such as I+V which may offer the option of off-treatment, disease-free intervals for patients with B-cell malignancies." The CAPTIVATE study is part of a comprehensive development program exploring the potential of IMBRUVICA®-based FD therapy. Janssen continues to evaluate the I+V combination regimen and its potential to provide a FD treatment option for patients living with CLL/SLL. Recently, The New England Journal of Medicine Evidence published the primary analysis from the Phase 3 GLOW study, which evaluated the safety and efficacy of the I+V combination in older or unfit patients with CLL/SLL, and showed that the combination demonstrated superior PFS and deeper sustained responses compared to chemoimmunotherapy in first-line CLL.3 About IMBRUVICA® IMB­RUVICA® (ibrutinib) is a once-daily oral medication that is jointly developed and commercialized by Janssen Biotech, Inc. and Pharmacyclics LLC, an AbbVie company. IMBRUVICA® blocks the Bruton's tyrosine kinase (BTK) protein, which is needed by normal and abnormal B cells, including specific cancer cells, to multiply and spread. By blocking BTK, IMBRUVICA® may help move abnormal B cells out of their nourishing environments and inhibits their proliferation.4,5,6 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 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 indications to treat adults with CLL/SLL with or without 17p deletion (del17p), and adults with Waldenström's macroglobulinemia (WM), and adult patients with previously treated mantle cell lymphoma (MCL)*, as well as to treat adult patients with previously treated marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy*, and adult patients with previously treated chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic therapy.7 *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 the initial treatment of CLL/SLL and has Category 1 treatment status for treatment-naïve patients without deletion 17p/TP53 mutation and as a preferred treatment for treatment-naïve patients with deletion 17p/TP53 mutation. The NCCN Guidelines® also recommend IMBRUVICA®, with or without rituximab, as a preferred regimen for the treatment of relapsed/refractory MCL, as a Category 1 preferred regimen for both untreated and previously treated WM patients, and as a preferred regimen for relapsed/refractory MZL.8 For more information, visit . IMBRUVICA® IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Hemorrhage: Fatal bleeding events have occurred in patients who received 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) occurred in 4.2% of patients, with fatalities occurring in 0.4% of 2,838 patients who received IMBRUVICA® in 27 clinical trials. Bleeding events of any grade including bruising and petechiae occurred in 39%, and excluding bruising and petechiae occurred in 23% of patients who received IMBRUVICA®, respectively. 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. Across clinical trials, 3.1% of 2,838 patients who received 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 21% of 1,476 patients who received 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. Cardiac Arrhythmias, Cardiac Failure and Sudden Death: Fatal and serious cardiac arrhythmias and cardiac failure have occurred with IMBRUVICA®. Deaths due to cardiac causes or sudden deaths occurred in 1% of 4,896 patients who received IMBRUVICA® in clinical trials, including in patients who received IMBRUVICA® in unapproved monotherapy or combination regimens. These adverse reactions occurred in patients with and without preexisting hypertension or cardiac comorbidities. Patients with cardiac comorbidities may be at greater risk of these events. Grade 3 or greater ventricular tachyarrhythmias were reported in 0.2%, Grade 3 or greater atrial fibrillation and atrial flutter were reported in 3.7%, and Grade 3 or greater cardiac failure was reported in 1.3% of 4,896 patients who received IMBRUVICA® in clinical trials, including in patients who received IMBRUVICA® in unapproved monotherapy or combination regimens. These events have occurred particularly in patients with cardiac risk factors including hypertension and diabetes mellitus, a previous history of cardiac arrhythmias, and in patients with acute infections. Evaluate cardiac history and function at baseline, and monitor patients for cardiac arrhythmias and cardiac function. Obtain further evaluation (e.g., ECG, echocardiogram) as indicated for patients who develop symptoms of arrhythmia (e.g., palpitations, lightheadedness, syncope, chest pain), new onset dyspnea, or other cardiovascular concerns. Manage cardiac arrhythmias and cardiac failure appropriately, follow dose modification guidelines, and consider the risks and benefits of continued IMBRUVICA® treatment. Hypertension: Hypertension occurred in 19% of 1,476 patients who received IMBRUVICA® in clinical trials. Grade 3 or greater hypertension occurred in 8% of patients. Based on data from 1,124 of these patients, the median time to onset was 5.9 months (range, 0.03 to 24 months). Monitor blood pressure in patients treated with IMBRUVICA®, initiate or adjust anti-hypertensive medication throughout treatment with IMBRUVICA® as appropriate, and follow dosage modification guidelines for Grade 3 or higher hypertension. Cytopenias: In 645 patients with B-cell malignancies who received IMBRUVICA® as a single agent, grade 3 or 4 neutropenia occurred in 23% of patients, grade 3 or 4 thrombocytopenia in 8% and grade 3 or 4 anemia in 2.8%, based on laboratory measurements. Monitor complete blood counts monthly. Second Primary Malignancies: Other malignancies (10%), including non-skin carcinomas (3.9%), occurred among the 1,476 patients who received 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®. 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 pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IMBRUVICA® and for 1 month after the last dose. Advise males with female partners of reproductive potential to use effective contraception during the same time period. ADVERSE REACTIONS B-cell malignancies: The most common adverse reactions (≥30%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were thrombocytopenia (54.5%)*, diarrhea (43.8%), fatigue (39.1%), musculoskeletal pain (38.8%), neutropenia (38.6%)*, rash (35.8%), anemia (35.0%)*, and bruising (32.0%). The most common Grade ≥ 3 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (20.7%)*, thrombocytopenia (13.6%)*, pneumonia (8.2%), and hypertension (8.0%). Approximately 9% (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. Increased ibrutinib concentrations may increase the risk of drug-related toxicity. Dose modifications of IMBRUVICA® are 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). Avoid grapefruit and Seville oranges during IMBRUVICA® treatment, as these contain strong or moderate inhibitors of CYP3A. See dose modification guidelines in USPI sections 2.3 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 hepatic impairment. In patients with mild or moderate impairment, reduce recommended IMBRUVICA® dose and monitor more frequently for adverse reactions of IMBRUVICA®. Please click here to see the full Prescribing Information. About the Janssen Pharmaceutical Companies of Johnson & Johnson At Janssen, we're creating a future where disease is a thing of the past. We're the Pharmaceutical Companies of Johnson & Johnson, working tirelessly to make that future a reality for patients everywhere by fighting sickness with science, improving access with ingenuity, and healing hopelessness with heart. We focus on areas of medicine where we can make the biggest difference: Cardiovascular, Metabolism, & Retina; Immunology; Infectious Diseases & Vaccines; Neuroscience; Oncology; and Pulmonary Hypertension. Learn more at . Follow us at @JanssenGlobal and @JanssenUS. Janssen Research & Development, LLC and Janssen Biotech, Inc. are part of the Janssen Pharmaceutical Companies of Johnson & Johnson. †Dr. Moreno has served as a paid consultant to Janssen; she has not been paid for any media work. Cautions Concerning Forward-Looking Statements This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding product development and the potential benefits and treatment impact of IMBRUVICA® (ibrutinib). The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Janssen Research & Development, LLC or any of the other Janssen Pharmaceutical Companies and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product research and development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; manufacturing difficulties and delays; competition, including technological advances, new products and patents attained by competitors; challenges to patents; product efficacy or safety concerns resulting in product recalls or regulatory action; changes in behavior and spending patterns of purchasers of health care products and services; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and descriptions of these risks, uncertainties and other factors can be found in Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended January 2, 2022, including in the sections captioned "Cautionary Note Regarding Forward-Looking Statements" and "Item 1A. Risk Factors," and in Johnson & Johnson's subsequent Quarterly Reports on Form 10-Q and other filings with the Securities and Exchange Commission. Copies of these filings are available online at , or on request from Johnson & Johnson. None of the Janssen Pharmaceutical Companies nor Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments. 1 Moreno C., et al. Fixed-Duration Ibrutinib + Venetoclax for First-Line Treatment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: 3-Year Follow-Up From the FD Cohort of the Phase 2 CAPTIVATE Study. 2022 European Hematology Association Annual Congress. June 9-12, 2022. 2 Soloman I., et al. Immune Restoration and Synergistic Activity With First-Line Ibrutinib Plus Venetoclax: Translational Analyses of CAPTIVATE Patients with CLL. 2022 European Hematology Association Annual Congress. June 9-12, 2022. 3 Kater, A., et al. Fixed-Duration Ibrutinib-Venetoclax in Patients with Chronic Lymphocytic Leukemia and Comorbidities. NEJM Evidence. 2022. Accessed June 2022 4 Genetics Home Reference. Isolated growth hormone deficiency. . Accessed June 2022. 5 Turetsky A, et al. Single cell imaging of Bruton's tyrosine kinase using an irreversible inhibitor. Scientific Reports. 2014;6:4782. 6 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. 7 IMBRUVICA® U.S. Prescribing Information, May 2022. 8 NCCN® Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma V2.2022. National Comprehensive Cancer Network. Accessed June 2022. Media Inquiries: Christie Corbett +1 857-636-0211 Jessica Castles Smith +1 732-501-8181 Investor Relations: Raychel Kruper +1 732-524-6164 U.S. Medical Inquiries: +1 800-526-7736 SOURCE Janssen Oncology