HDAC2

Immunotherapy is one of the pillars in the fight against cancer and aims to enable the body's own immune system to fight a tumor. A recent study now shows that removing certain enzymes that regulate epigenetic processes from the so-called dentritic cells of the immune system influences their development and thus improves anti-tumor immunity. This finding could lead to new therapeutic strategies in immunotherapy. Immunotherapy is one of the pillars in the fight against cancer and aims to enable the body's own immune system to fight a tumor. A recent study now shows that removing certain enzymes that regulate epigenetic processes from the so-called dentritic cells of the immune system influences their development and thus improves anti-tumor immunity. This finding could lead to new therapeutic strategies in immunotherapy. The study by Cristiano De Sá Fernandes from Maria Sibilia's research group at the Center for Cancer Research and the Comprehensive Cancer Center of MedUni Vienna and Vienna General Hospital was recently published in Cell Reports. Cancer cells are the body's own cells that do not divide and develop as intended and abandon their place and function in the body. The difficult thing about fighting them is that, as the body's own cells, the immune system cannot recognize them well and therefore cannot fight them. This is where immunotherapy kicks-in: It enables the patient's own immune system to identify the cancer cells and activate the body's own defenses. Dendritic cells (DCs) are important cells of the immune system that develop from precursor cells and can form different subgroups by changing their gene activity. These subgroups fulfill different functions in the immune system. However, it is not yet known exactly how certain epigenetic changes in chromatin (the material that makes up chromosomes) influence the development of DCs. In the study, the researchers inhibited two enzymes that regulate such epigenetic processes to see how this affects the development and function of DCs. They focused on the specific enzymes HDAC1 and HDAC2. Improved immune response Through multi-omics analyses, i.e. the analysis of several biological data such as gene expression and chromatin accessibility, the researchers found that the development of certain subgroups of DCs was impaired by the absence of HDAC1. This shows that HDAC1 plays a crucial role in their development. In the absence of HDAC1, DCs change their immune response, which improves tumor surveillance. Removing the enzyme HDAC2, on the other hand, had no major effect on the development of DCs. In summary, the study shows that the removal of HDAC1 influences the development of certain DC subsets and improves anti-tumor immunity. These findings could lead to new therapeutic strategies in cancer immunotherapy. This study was conducted as part of the FWF-funded PhD program DocFunds "Tissue Home," first author Cristiano de Fernandes was a PhD student.

First orphan drug designation for Nana-val granted in EBV+ solid tumors Seventh orphan drug designation for Nana-val globally; fifth granted by the FDA SAN DIEGO, Dec. 12, 2023 (GLOBE NEWSWIRE) -- Viracta Therapeutics, Inc. (Nasdaq: VIRX), a clinical-stage precision oncology company focused on the treatment and prevention of virus-associated cancers that impact patients worldwide, today announced that the U.S. Food and Drug Administration (FDA) has granted an orphan drug designation (ODD) to Nana-val (nanatinostat in combination with valganciclovir), the company's all-oral investigational therapy targeting Epstein-Barr virus (EBV)-associated cancers, for the treatment of nasopharyngeal carcinoma (NPC). This represents the first ODD granted for Nana-val in Epstein-Barr virus-positive (EBV+) solid tumors and outside of EBV-associated lymphomas. The FDA previously granted Nana-val ODD for the treatment of T-cell lymphoma, post-transplant lymphoproliferative disorder, plasmablastic lymphoma, and EBV+ diffuse large B-cell lymphoma, not otherwise specified. "This orphan drug designation highlights the urgent need for new targeted treatment options for patients with rare diseases such as nasopharyngeal carcinoma, which is highly associated with EBV," said Mark Rothera, President and Chief Executive Officer of Viracta. "We are encouraged by the interim data from the Phase 1b/2 study of Nana-val in patients with recurrent or metastatic EBV-positive nasopharyngeal carcinoma, supporting the continued advancement of the study with a new split daily dosing regimen at higher doses. With sites open and enrolling the sixth dose cohort of the study, we are on track to expand into the Phase 2 portion in 2024. The growing clinical data in both the lymphoma and solid tumor settings, further validates the therapeutic potential of Nana-val to treat EBV-positive cancers, an underserved area of high unmet medical need.” The FDA’s Office of Orphan Products Development grants orphan status to drugs and biologics being developed to treat, diagnose, or prevent a rare disease or condition affecting fewer than 200,000 people in the U.S. ODD is designed to provide drug developers with various benefits to support the development of novel drugs, including the potential for seven years of market exclusivity upon FDA approval for the disease or condition for which the drug has ODD, eligibility for tax credits toward qualified clinical trial costs, exemptions from certain FDA application fees, reduced annual product user fees, clinical trial protocol design and drug development assistance, and potential qualification for expedited drug development programs. About the Phase 1b/2 Study of Nana-val in R/M EBV+ NPC and Other EBV+ Solid Tumors This Phase 1b/2 trial (NCT05166577) is an open-label, multinational clinical trial evaluating Nana-val alone and in combination with pembrolizumab. The Phase 1b dose escalation part is designed to evaluate safety and to select the recommended Phase 2 dose (RP2D) of Nana-val in patients with recurrent or metastatic (R/M) Epstein-Barr virus-positive (EBV+) nasopharyngeal carcinoma (NPC). Along with the U.S. Food and Drug Administration’s Project Optimus initiative, at the start of Phase 2, up to 40 patients with R/M EBV+ NPC will be randomized to receive either the RP2D or a dose level below the RP2D in a dose-optimization cohort. Once the RP2D has been confirmed, up to 60 patients with R/M EBV+ NPC will be randomized to receive Nana-val at the RP2D with or without pembrolizumab to further evaluate antitumor activity, safety and tolerability, pharmacokinetics, and potential pharmacodynamic biomarkers. Additionally, patients with other advanced EBV+ solid tumors will be enrolled to receive Nana-val at the RP2D in a Phase 1b dose expansion cohort. About Nana-val (Nanatinostat and Valganciclovir) Nanatinostat is an orally available histone deacetylase (HDAC) inhibitor being developed by Viracta. Nanatinostat is selective for specific isoforms of Class I HDACs, which are key to inducing viral genes that are epigenetically silenced in Epstein-Barr virus (EBV)-associated malignancies. Nanatinostat is currently being investigated in combination with the antiviral agent valganciclovir as an all-oral combination therapy, Nana-val, in various subtypes of EBV-associated malignancies. Ongoing trials include a pivotal, global, multicenter, open-label Phase 2 basket trial in multiple subtypes of relapsed or refractory (R/R) EBV+ lymphoma (NAVAL-1) as well as a multinational Phase 1b/2 clinical trial in patients with recurrent or metastatic (R/M) EBV+ NPC and other EBV+ solid tumors. About EBV-Associated Cancers Approximately 90% of the world’s adult population is infected with EBV. Infections are commonly asymptomatic or associated with mononucleosis. Following infection, the virus remains latent in a small subset of cells for the duration of the patient’s life. Cells containing latent virus are increasingly susceptible to malignant transformation. Patients who are immunocompromised are at an increased risk of developing EBV-positive (EBV+) lymphomas. EBV is estimated to be associated with approximately 2% of the global cancer burden including lymphoma, nasopharyngeal carcinoma (NPC), and gastric cancer. About Viracta Therapeutics, Inc. Viracta is a clinical-stage precision oncology company focused on the treatment and prevention of virus-associated cancers that impact patients worldwide. Viracta’s lead product candidate is an all-oral combination therapy of its proprietary investigational drug, nanatinostat, and the antiviral agent valganciclovir (collectively referred to as Nana-val). Nana-val is currently being evaluated in multiple ongoing clinical trials, including a pivotal, global, multicenter, open-label Phase 2 basket trial for the treatment of multiple subtypes of relapsed or refractory (R/R) Epstein-Barr virus-positive (EBV+) lymphoma (NAVAL-1), as well as a multinational, open-label Phase 1b/2 clinical trial for the treatment of patients with recurrent or metastatic (R/M) EBV+ nasopharyngeal carcinoma (NPC) and other advanced EBV+ solid tumors. Viracta is also pursuing the application of its “Kick and Kill” approach in other virus-related cancers. For additional information, please visit Forward-Looking Statements This communication contains "forward-looking" statements within the meaning of the Private Securities Litigation Reform Act of 1995, including, without limitation, statements regarding: the details, timeline and expected progress for Viracta's ongoing and anticipated clinical trials and updates regarding the same, the Company’s expectations of the significance and implications of the preliminary interim data from its clinical trials and preclinical studies disclosed herein, the Company’s expectations related to the FDA submission process and timelines and expectations regarding our target patient populations. Risks and uncertainties related to Viracta that may cause actual results to differ materially from those expressed or implied in any forward-looking statement include, but are not limited to: Viracta's ability to successfully enroll patients in and complete its ongoing and planned clinical trials; Viracta's plans to develop and commercialize its product candidates, including all oral combinations of nanatinostat and valganciclovir; the timing of initiation of Viracta's planned clinical trials; the timing of the availability of data from Viracta's clinical trials; previous preclinical and clinical results may not be predictive of future clinical results; the timing of any planned investigational new drug application or new drug application; Viracta's plans to research, develop, and commercialize its current and future product candidates; the clinical utility, potential benefits, and market acceptance of Viracta's product candidates and Viracta's ability to manufacture or supply nanatinostat, valganciclovir, and pembrolizumab for clinical testing. If any of these risks materialize or underlying assumptions prove incorrect, actual results could differ materially from the results implied by these forward-looking statements. Additional risks and uncertainties that could cause actual outcomes and results to differ materially from those contemplated by the forward-looking statements are included under the caption "Risk Factors" and elsewhere in Viracta's reports and other documents that Viracta has or will file, with the SEC from time to time and available at The forward-looking statements included in this communication are made only as of the date hereof. Viracta assumes no obligation and does not intend to update these forward-looking statements, except as required by law or applicable regulation. Investor Relations Contact: Ashleigh Barreto Head of Investor Relations & Corporate Communications Viracta Therapeutics, Inc. abarreto@viracta.com SOURCE Viracta Therapeutics, Inc.

Niraparib and abiraterone acetate plus prednisone combination therapy also showed clinically relevant improvement versus standard of care in time to symptomatic progression and time to cytotoxic chemotherapy MADRID, Oct. 22, 2023 /PRNewswire/ -- The Janssen Pharmaceutical Companies of Johnson & Johnson today announced results from the final analysis (FA) of the Phase 3 MAGNITUDE study, in which a pre-planned multivariate analysis [MVA] showed niraparib, a highly selective poly (ADP-ribose) polymerase (PARP) inhibitor, combined with abiraterone acetate and given with prednisone, improved overall survival (OS) and time to symptomatic progression (TSP) and showed a favorable trend in time to cytotoxic chemotherapy (TCC) in patients with metastatic castration-resistant prostate cancer (mCRPC) with BRCA alterations. These data were featured today in a Late-Breaking Mini Oral Presentation Session (Abstract #LBA85) at the European Society for Medical Oncology (ESMO) 2023 Congress taking place October 20-24 in Madrid, Spain.1 The FA of the MAGNITUDE study included 225 patients with BRCA-positive mCRPC (the largest population studied to date), where 113 patients were randomized to niraparib plus abiraterone acetate and prednisone (AAP) and 112 patients were assigned to placebo plus AAP. At 35.9 months median follow-up (9.1 additional months follow-up from the second interim analysis, presented at ASCO GU 2023), a prespecified MVA, adjusting for baseline imbalances, showed an OS benefit favoring patients who received niraparib plus AAP compared to the placebo plus AAP arm (Hazard Ratio [HR]=0.66; 95 percent Confidence Interval [CI], 0.46-0.95]). Continued trend in improvement in TSP was also observed in patients who received niraparib and AAP compared to patients randomized to placebo plus AAP (HR 0.56; 95 percent CI, 0.37-0.85). Additionally, an evaluation of TCC indicated a favorable trend among patients with BRCA mutations treated with niraparib and AAP (HR 0.60; 95 percent CI, 0.39-0.92). Finally, 70 percent of the patients in the niraparib and AAP arm received subsequent life-prolonging therapy compared to 86 percent of the patients assigned to placebo plus AA. Patient-reported outcomes were also assessed in the FA. Results indicate that patients with BRCA mutations treated with niraparib and AAP experienced a trend towards delayed time to worst pain progression (HR 0.81; 95 percent CI, 0.52-1.25) and pain interference progression (HR 0.77; 95 percent CI, 0.48-1.23) compared with the placebo arm. "The overall survival seen in the MAGNITUDE pre-planned multivariate analysis is promising for patients with BRCA-mutated mCRPC, a population more likely to experience poor outcomes," said Kim Chi*, M.D., Medical Oncologist at BC Cancer - Vancouver and principal investigator of the MAGNITUDE study. "These data, with key signals of improvements in overall survival, disease progression, and quality of life measures, underscore the significance of this new treatment option for patients." The FA observed no new safety signals and no cases of myelodysplastic syndrome or acute myeloid leukemia were observed among patients in the niraparib and AAP arm. Niraparib plus AAP had higher rates of adverse events (AEs) of special interest than the placebo arm, with the most common of any grade including anaemia (52.4 percent versus 22.7 percent) and thrombocytopenia (24.1 percent versus 9.5 percent), respectively. The differences in safety between treatment arms were driven by known hematologic toxicities with niraparib. "We are dedicated to advancing the science of prostate cancer and developing new targeted treatment options to extend patients' lives," said Angela Lopez-Gitlitz, M.D., Vice President, Late Development Oncology, Prostate Cancer, Janssen Research & Development, LLC. "These data highlight the importance of identifying patients with genetically defined cancer to better inform treatment protocols and ensure they receive available therapies tailored to their unique needs." About Niraparib Niraparib is an orally administered, highly selective poly (ADP-ribose) polymerase (PARP) inhibitor that is currently being studied by Janssen for the treatment of patients with prostate cancer. Additional ongoing studies include the Phase 3 AMPLITUDE study (NCT04497844), evaluating the combination of niraparib and AAP in a biomarker-selected patient population with metastatic castration-sensitive prostate cancer (mCSPC). In April 2016, Janssen Biotech, Inc. entered a worldwide (except Japan) collaboration and license agreement with TESARO, Inc. (acquired by GlaxoSmithKline [GSK] in 2019) for exclusive rights to niraparib in prostate cancer. In the United States, niraparib is indicated for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy; and for the maintenance treatment of adult patients with deleterious or suspected deleterious germline BRCA-positive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. Niraparib is currently marketed by GSK as ZEJULA®. In April 2023, Janssen received approval from the European Commission for AKEEGA™ (niraparib and abiraterone acetate) in the form of a dual action tablet (DAT), plus prednisone or prednisolone, in patients with mCRPC and BRCA mutations based on data from the MAGNITUDE study. Health Canada (June 2023) and the U.S. Food and Drug Administration (August 2023) also have authorized/approved AKEEGA™. Reviews are ongoing in other regions. About abiraterone acetate Abiraterone acetate is an orally administered androgen biosynthesis inhibitor. In the United States, abiraterone acetate is indicated with prednisone for the treatment of mCRPC and high-risk mCSPC. About Metastatic Castration-Resistant Prostate Cancer Metastatic castration-resistant prostate cancer characterizes cancer that no longer responds to androgen deprivation therapy and has spread to other parts of the body. The most common metastatic sites are bones, followed by lungs and liver. Prostate cancer is the second most common cancer in men worldwide, behind lung cancer. More than one million patients around the world are diagnosed with prostate cancer each year. Patients with mCRPC and homologous recombination repair (HRR) gene alterations, of which BRCA mutations are the most common, are more likely to have aggressive disease, poor outcomes and a shorter survival time.2,3,4,5 About MAGNITUDE MAGNITUDE (NCT03748641) is a Phase 3, randomized, double-blind, placebo-controlled, multi-center clinical study evaluating the safety and efficacy of the combination of niraparib and AAP for patients with mCRPC, with or without certain HRR gene alterations, and who have not received prior therapy for mCRPC except for up to four months of AAP. The study included patients with (HRR biomarker [BM] positive; ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, PALB2) and without specified gene alterations (HRR BM negative), who were randomized 1:1 to receive niraparib 200 mg once daily plus AAP or placebo plus AAP.2 A total of 423 patients with HRR gene alterations were enrolled, 225 (53.2 percent) of whom had BRCA mutations.3,4 The primary endpoint of the MAGNITUDE trial was radiographic progression free survival (rPFS) assessed by blinded independent central review.5 Secondary endpoints included TCC, TSP and OS. Analysis of the group of patients with BRCA alterations was alpha controlled for rPFS and prespecified for other endpoints. IMPORTANT SAFETY INFORMATION FOR AKEEGA™ 4 WARNINGS AND PRECAUTIONS The safety population described in the WARNINGS and PRECAUTIONS reflect exposure to AKEEGA™ in combination with prednisone in BRCAm patients in Cohort 1 (N=113) of MAGNITUDE. Myelodysplastic Syndrome/Acute Myeloid Leukemia AKEEGA™ may cause myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). MDS/AML, including cases with fatal outcome, has been observed in patients treated with niraparib, a component of AKEEGA™. All patients treated with niraparib who developed secondary MDS/cancer-therapy-related AML had received previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy. For suspected MDS/AML or prolonged hematological toxicities, refer the patient to a hematologist for further evaluation. Discontinue AKEEGA™ if MDS/AML is confirmed. Myelosuppression AKEEGA™ may cause myelosuppression (anemia, thrombocytopenia, or neutropenia). In MAGNITUDE Cohort 1, Grade 3-4 anemia, thrombocytopenia, and neutropenia were reported, respectively in 28%, 8%, and 7% of patients receiving AKEEGA™. Overall, 27% of patients required a red blood cell transfusion, including 11% who required multiple transfusions. Discontinuation due to anemia occurred in 3% of patients. Monitor complete blood counts weekly during the first month of AKEEGA™ treatment, every two weeks for the next two months, monthly for the remainder of the first year and then every other month, and as clinically indicated. Do not start AKEEGA™ until patients have adequately recovered from hematologic toxicity caused by previous therapy. If hematologic toxicities do not resolve within 28 days following interruption, discontinue AKEEGA™ and refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions AKEEGA™ may cause hypokalemia and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1)]. In post-marketing experience, QT prolongation and Torsades de Pointes have been observed in patients who develop hypokalemia while taking abiraterone acetate, a component of AKEEGA™. Hypertension and hypertensive crisis have also been reported in patients treated with niraparib, a component of AKEEGA™. In MAGNITUDE Cohort 1, which used prednisone 10 mg daily in combination with AKEEGA™, Grades 3-4 hypokalemia was detected in 2.7% of patients on the AKEEGA™ arm and Grades 3-4 hypertension were observed in 14% of patients on the AKEEGA™ arm. The safety of AKEEGA™ in patients with New York Heart Association (NYHA) Class II to IV heart failure has not been established because these patients were excluded from MAGNITUDE. Monitor patients for hypertension, hypokalemia, and fluid retention at least weekly for the first two months, then once a month. Closely monitor patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia, or fluid retention, such as those with heart failure, recent myocardial infarction, cardiovascular disease, or ventricular arrhythmia. Control hypertension and correct hypokalemia before and during treatment with AKEEGA™. Discontinue AKEEGA™ in patients who develop hypertensive crisis or other severe cardiovascular adverse reactions. Hepatotoxicity AKEEGA™ may cause hepatotoxicity. Hepatotoxicity in patients receiving abiraterone acetate, a component of AKEEGA™, has been reported in clinical trials. In post-marketing experience, there have been abiraterone acetate-associated severe hepatic toxicity, including fulminant hepatitis, acute liver failure, and deaths. In MAGNITUDE Cohort 1, Grade 3-4 ALT or AST increases (at least 5 x ULN) were reported in 1.8% of patients. The safety of AKEEGA™ in patients with moderate or severe hepatic impairment has not been established as these patients were excluded from MAGNITUDE. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with AKEEGA™, every two weeks for the first three months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient's baseline should prompt more frequent monitoring and may require dosage modifications. Permanently discontinue AKEEGA™ for patients who develop a concurrent elevation of ALT greater than 3 x ULN and total bilirubin greater than 2 x ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation, or in patients who develop ALT or AST ≥20 x ULN at any time after receiving AKEEGA™. Adrenocortical Insufficiency AKEEGA™ may cause adrenal insufficiency. Adrenocortical insufficiency has been reported in clinical trials in patients receiving abiraterone acetate, a component of AKEEGA™, in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Monitor patients for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with abiraterone acetate. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased doses of corticosteroids may be indicated before, during, and after stressful situations. Hypoglycemia AKEEGA™ may cause hypoglycemia in patients being treated with other medications for diabetes. Severe hypoglycemia has been reported when abiraterone acetate, a component of AKEEGA™, was administered to patients receiving medications containing thiazolidinediones (including pioglitazone) or repaglinide. Monitor blood glucose in patients with diabetes during and after discontinuation of treatment with AKEEGA™. Assess if antidiabetic drug dosage needs to be adjusted to minimize the risk of hypoglycemia. Increased Fractures and Mortality in Combination with Radium 223 Dichloride AKEEGA™ with prednisone is not recommended for use in combination with Ra-223 dichloride outside of clinical trials. The clinical efficacy and safety of concurrent initiation of abiraterone acetate plus prednisone/prednisolone and radium Ra 223 dichloride was assessed in a randomized, placebo-controlled multicenter study (ERA-223 trial) in 806 patients with asymptomatic or mildly symptomatic castration-resistant prostate cancer with bone metastases. The study was unblinded early based on an Independent Data Monitoring Committee recommendation. At the primary analysis, increased incidences of fractures (29% vs 11%) and deaths (39% vs 36%) have been observed in patients who received abiraterone acetate plus prednisone/prednisolone in combination with radium Ra 223 dichloride compared to patients who received placebo in combination with abiraterone acetate plus prednisone. It is recommended that subsequent treatment with Ra-223 not be initiated for at least five days after the last administration of AKEEGA™, in combination with prednisone. Posterior Reversible Encephalopathy Syndrome AKEEGA™ may cause Posterior Reversible Encephalopathy Syndrome (PRES). PRES has been observed in patients treated with niraparib as a single agent at higher than the recommended dose of niraparib included in AKEEGA™. Monitor all patients treated with AKEEGA™ for signs and symptoms of PRES. If PRES is suspected, promptly discontinue AKEEGA™ and administer appropriate treatment. The safety of reinitiating AKEEGA™ in patients previously experiencing PRES is not known. Embryo-Fetal Toxicity The safety and efficacy of AKEEGA™ have not been established in females. Based on animal reproductive studies and mechanism of action, AKEEGA™ can cause fetal harm and loss of pregnancy when administered to a pregnant female. Niraparib has the potential to cause teratogenicity and/or embryo-fetal death since niraparib is genotoxic and targets actively dividing cells in animals and patients (e.g., bone marrow). In animal reproduction studies, oral administration of abiraterone acetate to pregnant rats during organogenesis caused adverse developmental effects at maternal exposures approximately ≥0.03 times the human exposure (AUC) at the recommended dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of AKEEGA™. Females who are or may become pregnant should handle AKEEGA™ with protection, e.g., gloves. Based on animal studies, AKEEGA™ may impair fertility in males of reproductive potential. ADVERSE REACTIONS The safety of AKEEGA™ in patients with BRCAm mCRPC was evaluated in Cohort 1 of MAGNITUDE. The most common adverse reactions (≥10%), including laboratory abnormalities, are decreased hemoglobin, decreased lymphocytes, decreased white blood cells, musculoskeletal pain, fatigue, decreased platelets, increased alkaline phosphatase, constipation, hypertension, nausea, decreased neutrophils, increased creatinine, increased potassium, decreased potassium, increased AST, increased ALT, edema, dyspnea, decreased appetite, vomiting, dizziness, COVID-19, headache, abdominal pain, hemorrhage, urinary tract infection, cough, insomnia, increased bilirubin, weight decreased, arrhythmia, fall, and pyrexia. Serious adverse reactions reported in >2% of patients included COVID-19 (7%), anemia (4.4%), pneumonia (3.5%), and hemorrhage (3.5%). Fatal adverse reactions occurred in 9% of patients who received AKEEGA™, including COVID-19 (5%), cardiopulmonary arrest (1%), dyspnea (1%), pneumonia (1%), and septic shock (1%). DRUG INTERACTIONS Effect of Other Drugs on AKEEGA™ Avoid coadministration with strong CYP3A4 inducers. Abiraterone is a substrate of CYP3A4. Strong CYP3A4 inducers may decrease abiraterone concentrations, which may reduce the effectiveness of abiraterone. Effects of AKEEGA™ on Other Drugs Avoid coadministration unless otherwise recommended in the Prescribing Information for CYP2D6 substrates for which minimal changes in concentration may lead to serious toxicities. If alternative treatments cannot be used, consider a dose reduction of the concomitant CYP2D6 substrate drug. Abiraterone is a CYP2D6 moderate inhibitor. AKEEGA™ increases the concentration of CYP2D6 substrates, which may increase the risk of adverse reactions related to these substrates. Monitor patients for signs of toxicity related to a CYP2C8 substrate for which a minimal change in plasma concentration may lead to serious or life-threatening adverse reactions. Abiraterone is a CYP2C8 inhibitor. AKEEGA™ increases the concentration of CYP2C8 substrates, which may increase the risk of adverse reactions related to these substrates. Please see the full Prescribing Information for AKEEGA™. 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: Oncology, Immunology, Neuroscience, Cardiovascular, Pulmonary Hypertension, and Retina. Learn more at . Follow us at @JNJInnovMed and @JanssenUS. Janssen Biotech, Inc. and Janssen Research & Development, LLC Johnson & Johnson companies. 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 niraparib. 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; Janssen Biotech, Inc., 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; competition, including technological advances, new products and patents attained by competitors; challenges to patents; 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 1, 2023, 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 Janssen Research & Development, LLC, Janssen Biotech, Inc., nor Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments. *Dr. Chi has been a paid consultant to Janssen; Dr. Chi has not been paid for any media work. ### Media Contacts: Suzanne Frost +1 416-317-0304 Brian Kenney +1 215-620-0111 Investor Relations: Raychel Kruper [email protected] U.S. Medical Inquiries: +1 800-526-7736 SOURCE Janssen Pharmaceutical Companies of Johnson & Johnson