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South Korean Company, Yuhan Pharmaceuticals Partners with Cyclica to Advance R&D Across Two Separate Programs for Oncology

On November 7, 2019 Renowned South Korean healthcare company, Yuhan Pharmaceuticals (Yuhan) and Cyclica Inc. (Cyclica), a leading neo biotechnology company reported a collaboration to apply Cyclica’s proprietary AI-integrated drug discovery platform in two separate R&D programs (Press release, YuHan, NOV 7, 2019, View Source [SID1234550669]). Yuhan is keen on implementing innovative technologies to enhance drug development efforts and will utilize Cyclica’s unique end-to-end AI-integrated drug discovery platform across diverse therapeutic areas to develop novel advanced lead-like molecules with desired chemical properties against the targets of interest determined by Yuhan’s R&D priorities.

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Yuhan will leverage Cyclica’s integrated drug discovery platform, Ligand DesignTM and Ligand Express to generate novel chemical entities with desired polypharmacological, physicochemical, and ADMET properties while providing insights into systems biology and structural pharmacogenomics.

Cyclica will receive an upfront payment as well as receive milestone payments upon the completion of specific objectives. Through this collaboration, Yuhan and Cyclica envision a long-term relationship to enhance future R&D and drug discovery efforts to identify novel solutions for unaddressed therapeutic needs.

Yuhan CEO and President Jung Hee Lee said, "We are very pleased to be collaborating with Cyclica to apply its proprietary AI-integrated drug discovery platform in our R&D programs, and hope to expand our partnership upon the success of the collaboration. Yuhan is dedicated to offering first-in-class to the patients within a short time by applying new computational methods, including AI and Big Data that can shorten the time and the cost required for drug development."

"It’s an honour to collaborate with Yuhan, a visionary company that is thinking deeply about the future of the discovery of better medicines, and the application of new computational methods, including machine and deep learning. I am confident that this collaboration, and the future relationship with Yuhan and Cyclica will benefit patients waiting for new and better medicines." said Naheed Kurji, President and CEO of Cyclica.

Phase 3 Trial of NINLAROTM (ixazomib) as First Line Maintenance Therapy Met Primary Endpoint in Multiple Myeloma Patients not treated with Stem Cell Transplantation

On November 7, 2019 Takeda Pharmaceutical Company Limited (TSE: 4502/NYSE: TAK) ("Takeda") reported the randomized, Phase 3 TOURMALINE-MM4 study met its primary endpoint of progression free survival (PFS) (Press release, Takeda, NOV 7, 2019, View Source [SID1234550668]). The trial evaluated the effect of single-agent oral NINLARO (ixazomib) as a first line maintenance therapy versus placebo in adult patients diagnosed with multiple myeloma not treated with stem cell transplantation. TOURMALINE-MM4 is the first industry sponsored Phase 3 trial to explore the concept of "switch" maintenance, the use of medicines not included in initial induction therapy, in this setting. NINLARO is currently not approved for this specific use.

"We are very encouraged by the results of the TOURMALINE-MM4 trial and continue our forward momentum in developing maintenance options for multiple myeloma patients. Importantly, this is the third positive Phase 3 readout from the TOURMALINE clinical trial program," said Phil Rowlands, Ph.D., Head, Oncology Therapeutic Area Unit, Takeda. "We remain committed to bringing this convenient and well-tolerated treatment option to patients."

The safety profile of NINLARO in the maintenance setting was consistent with previously reported results of single-agent NINLARO use, and there were no new safety signals identified in TOURMALINE-MM4.

Full data results will be submitted for presentation at an upcoming medical meeting.

About the TOURMALINE-MM4 Trial

TOURMALINE-MM4 is a randomized, placebo-controlled, double-blind Phase 3 study of 706 patients, designed to determine the effect of single-agent oral NINLAROTM (ixazomib) maintenance therapy on progression-free survival (PFS), compared to placebo, in adult patients newly diagnosed with multiple myeloma not treated with stem cell transplantation, who have completed 6-12 months of initial therapy and achieved a partial response or better. For additional information, please visit View Source

About Multiple Myeloma

Multiple myeloma is a life-threatening rare blood cancer that arises from the plasma cells, a type of white blood cell that is made in the bone marrow. These plasma cells become abnormal, multiply and release a type of antibody known as a paraprotein, which causes symptoms of the disease, including bone pain, frequent or recurring infections and fatigue, a symptom of anemia. These malignant plasma cells have the potential to affect many bones in the body and can cause a number of serious health problems affecting the bones, immune system, kidneys and red blood cell count. The typical multiple myeloma disease course includes periods of symptomatic myeloma followed by periods of remission. Nearly 230,000 people around the world live with multiple myeloma, with approximately 114,000 new cases diagnosed globally each year.

About NINLAROTM (ixazomib) capsules

NINLARO (ixazomib) is an oral proteasome inhibitor which is being studied across the continuum of multiple myeloma treatment settings. NINLARO was first approved by the U.S. Food and Drug Administration (FDA) in November 2015 and is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. NINLARO is currently approved in more than 60 countries, including the United States, Japan and in the European Union, with more than 10 regulatory filings currently under review. It was the first oral proteasome inhibitor to enter Phase 3 clinical trials and to receive approval.

The comprehensive ixazomib clinical development program, TOURMALINE, includes several ongoing pivotal trials, which together are investigating major multiple myeloma patient populations:

TOURMALINE-MM1, investigating ixazomib vs. placebo in combination with lenalidomide and dexamethasone in relapsed and/or refractory multiple myeloma
TOURMALINE-MM2, investigating ixazomib vs. placebo in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma
TOURMALINE-MM3, investigating ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed multiple myeloma following induction therapy and autologous stem cell transplant (ASCT)
TOURMALINE-MM4, investigating ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed multiple myeloma who have not undergone ASCT
In addition to the TOURMALINE program, ixazomib is being evaluated in multiple therapeutic combinations for various patient populations in investigator initiated studies globally.

NINLAROTM (ixazomib) capsules: Global Important Safety Information

SPECIAL WARNINGS AND PRECAUTIONS
Thrombocytopenia has been reported with NINLARO (28% vs. 14% in the NINLARO and placebo regimens, respectively) with platelet nadirs typically occurring between Days 14-21 of each 28-day cycle and recovery to baseline by the start of the next cycle. It did not result in an increase in hemorrhagic events or platelet transfusions. Monitor platelet counts at least monthly during treatment with NINLARO and consider more frequent monitoring during the first three cycles. Manage with dose modifications and platelet transfusions as per standard medical guidelines.

Gastrointestinal toxicities have been reported in the NINLARO and placebo regimens respectively, such as diarrhea (42% vs. 36%), constipation (34% vs. 25%), nausea (26% vs. 21%), and vomiting (22% vs. 11%), occasionally requiring use of antiemetic and anti-diarrheal medications, and supportive care.

Peripheral neuropathy was reported with NINLARO (28% vs. 21% in the NINLARO and placebo regimens, respectively). The most commonly reported reaction was peripheral sensory neuropathy (19% and 14% in the NINLARO and placebo regimens, respectively). Peripheral motor neuropathy was not commonly reported in either regimen (< 1%). Monitor patients for symptoms of peripheral neuropathy and adjust dosing as needed.

Peripheral edema was reported with NINLARO (25% vs. 18% in the NINLARO and placebo regimens, respectively). Evaluate patients for underlying causes and provide supportive care, as necessary. Adjust the dose of dexamethasone per its prescribing information or the dose of NINLARO for severe symptoms.

Cutaneous reactions occurred in 19% of patients in the NINLARO regimen compared to 11% of patients in the placebo regimen. The most common type of rash reported in both regimens was maculo-papular and macular rash. Manage rash with supportive care, dose modification or discontinuation.

Hepatotoxicity, drug-induced liver injury, hepatocellular injury, hepatic steatosis, and hepatitis cholestatic have been uncommonly reported with NINLARO. Monitor hepatic enzymes regularly and adjust dose for Grade 3 or 4 symptoms.

Pregnancy- NINLARO can cause fetal harm. Advise male and female patients of reproductive potential to use contraceptive measures during treatment and for an additional 90 days after the final dose of NINLARO. Women of childbearing potential should avoid becoming pregnant while taking NINLARO due to potential hazard to the fetus. Women using hormonal contraceptives should use an additional barrier method of contraception.

Lactation- It is not known whether NINLARO or its metabolites are excreted in human milk. There could be potential adverse events in nursing infants and therefore breastfeeding should be discontinued.

SPECIAL PATIENT POPULATIONS
Hepatic Impairment: Reduce the NINLARO starting dose to 3 mg in patients with moderate or severe hepatic impairment.

Renal Impairment: Reduce the NINLARO starting dose to 3 mg in patients with severe renal impairment or end-stage renal disease (ESRD) requiring dialysis. NINLARO is not dialyzable and, therefore, can be administered without regard to the timing of dialysis.

DRUG INTERACTIONS
Co-administration of strong CYP3A inducers with NINLARO is not recommended.

ADVERSE REACTIONS
The most frequently reported adverse reactions (≥ 20%) in the NINLARO regimen, and greater than in the placebo regimen, were diarrhea (42% vs. 36%), constipation (34% vs. 25%), thrombocytopenia (28% vs. 14%), peripheral neuropathy (28% vs. 21%), nausea (26% vs. 21%), peripheral edema (25% vs. 18%), vomiting (22% vs. 11%), and back pain (21% vs. 16%). Serious adverse reactions reported in ≥ 2% of patients included thrombocytopenia (2%) and diarrhea (2%). For each adverse reaction, one or more of the three drugs was discontinued in ≤ 1% of patients in the NINLARO regimen.

Data From Intensity Therapeutics’ Phase 1/2 Study of INT230-6 Highlight Prolonged Disease Control, Abscopal Effects and Immune Response Activity in Patients With Advanced Solid Tumors

On November 7, 2019 Intensity Therapeutics, Inc., a clinical-stage biotechnology company developing proprietary intratumoral immunotherapy products to kill tumors and increase immune system recognition of solid cancers, reported new preliminary data from the ongoing Phase 1/2 clinical study of INT230-6, the Company’s lead product candidate (Press release, Intensity Therapeutics, NOV 7, 2019, View Source [SID1234550667]). These data will be presented on Saturday, November 9, in an oral podium presentation at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 34th Annual Meeting, being held in National Harbor, MD.

"The data being presented at SITC (Free SITC Whitepaper) advance our understanding of this new treatment, and identify a patient population that seems to derive the most benefit," said presenter and study investigator Jacob Thomas, MD, Assistant Professor of Clinical Medicine, Keck School of Medicine of the University of Southern California. "Our study included a highly refractory patient population, nonetheless several patients have had long term benefit. We observed a disease control rate of 39 percent in evaluable patients, with several patients showing disease control for over one year. In patients that had over 50 percent of total tumor burden injected, seven out of eight patients have shown disease control including all four patients enrolled with metastatic breast cancer. The treatment is well tolerated, and no patients had to discontinue therapy due to treatment-related toxicity. Additional benefits included tumor shrinkage and no further tumor growth or new tumors."

"We are excited that the data thus far reproduce the animal findings that intratumoral injection of INT230-6 stays in the tumor and the patients tolerate the procedure and drugs well. It also demonstrates cancer cell death in treated and in uninjected tumors with systemic immune activation," said Ian B. Walters, MD, Chief Medical Officer of Intensity Therapeutics. "Having the ability to safely reduce tumor cell burden and prime an immune response is an important advance in our ability to manage refractory cancers, we look forward to evaluating the combination with Keytruda and other immune agents."

The oral podium presentation includes data on 45 heavily pretreated patients with 17 different types of advanced or metastatic solid tumors who have failed a median of three prior therapies and are not candidates for approved, available therapies.

A pharmacokinetic (PK) analysis revealed limited exposure in the blood of INT230-6’s active anticancer agents, cisplatin (CIS) and vinblastine (VIN), supporting that the majority of INT230-6 is retained in the tumor, with few systemic toxicities. The findings are consistent with the low incidence of systemic adverse events despite intratumoral doses of INT230-6 escalating up to 160 mL, which is twice the amount of VIN that would typically be contained in a standard intravenous (IV) dose.

Furthermore, the immune activation data observed were consistent with nonclinical data, as local delivery of INT230-6 into tumors induced an immune response with increases of CD4+ and CD8+ T-cells in the blood and in the tumor microenvironment without any immune-related adverse events. An abscopal response was demonstrated in seven patients who overall showed tumor shrinkage in 10 non-injected tumors.

Oral Podium Presentation Information

Title: Intratumoral INT230-6 injection into solid tumors kills tumors and induces immune cell infiltration leading to abscopal responses and prolonged disease control in multiple refractory cancer types
Abstract Number: O31
Date/Time: Saturday, November 9, 2019, 3:45-4:00 p.m. ET
Session: Concurrent Session 309: Single Agent Phase 1 Clinical Trials
Location: Prince George’s Exhibition Hall C
Presenter: Jacob Thomas, MD, Assistant Professor of Clinical Medicine, University of Southern California

About INT230-6

INT230-6, Intensity’s lead proprietary product candidate, is designed for direct intratumoral injection. INT230-6 was discovered using Intensity’s proprietary DfuseRx℠ technology platform. The drug is comprised of two proven, potent anti-cancer agents, cisplatin and vinblastine, and a penetration enhancer molecule that helps disperse the drugs throughout tumors for diffusion into cancer cells. In preclinical studies, INT230-6 eradicated tumors by a combination of direct tumor killing, releasing tumor antigens and recruitment of immune cells to the tumor. Results generated by the National Cancer Institute (NCI) showed treatment with INT230-6 in in vivo models of severe cancer resulted in substantial improvement in overall survival compared to standard therapies. Further, INT230-6 provided complete responder animals with long-term, durable protection from multiple re-challenges of the initial cancer and resistance to other cancers. The NCI and Intensity collaborative research, published in July 2019, showed that there was also strong synergy when INT230-6 was combined with anti-PD-1 and anti-CTLA-4 antibodies. INT230-6 is being evaluated in a Phase 1/2 clinical study (NCT03058289) in patients with various advanced solid tumors. There have been no dose limiting adverse events observed in patients to date, even when dosing into deep tumors in the lung and liver. Several patients demonstrated tumor shrinkage, symptomatic improvement, and evidence of cancer cell death and immune cell activation on tumor biopsy.

Navidea Biopharmaceuticals Announces Preclinical Therapeutic Research Collaboration with IMV Inc. to Explore the Potential Combinatory Effect with Their Platform-Based Immunotherapies

On November 7, 2019 Navidea Biopharmaceuticals, Inc. (NYSE American: NAVB), a company focused on the development of precision immunodiagnostics and immunotherapeutics, and IMV Inc. (Nasdaq: IMV; TSX: IMV), a clinical stage biopharmaceutical company pioneering a novel class of immunotherapies, reported that they have entered a preclinical research collaboration to explore the potential combinatory effect of their platform-based immunotherapies (Press release, Navidea Biopharmaceuticals, NOV 7, 2019, View Source [SID1234550666]).

The purpose of this collaboration is to conduct preclinical studies to evaluate the combinatory effect of Navidea’s proprietary activated macrophage targeting therapeutics along with IMV’s DPX-based immunotherapies. Navidea and IMV will jointly conduct the research throughout the duration of the study.

"We are thrilled to begin this collaboration with IMV to investigate the use of their DPX platform technology in conjunction with Navidea’s in a relevant preclinical tumor model," said Michael Rosol, PhD, Chief Medical Officer at Navidea Biopharmaceuticals. "The combination of IMV’s DPX-based immunotherapies with Navidea’s CD206-targeted therapeutic could lead to a powerful new approach to treating a variety of cancers."

Marianne Stanford, PhD, Vice President Research & Development at IMV Inc., said, "At IMV, we continue to explore new combinations for our DPX-based compounds and seek all possible ways to tackle hard-to-treat cancers. We are pleased to collaborate with Navidea Biopharmaceuticals and hope to identify novel targets for further clinical studies."

Teva and Celltrion Announce the Availability of TRUXIMA® (rituximab-abbs) Injection, the First Biosimilar to Rituxan® (rituximab) in the United States

On November 7, 2019 Teva Pharmaceuticals USA, Inc., a U.S. affiliate of Teva Pharmaceutical Industries Ltd. (NYSE and TASE: TEVA), Celltrion, Inc., (KRX KRX:068270) and Celltrion Healthcare, Co., Ltd. (KRX KOSDAQ:091990), reported that TRUXIMA (rituximab-abbs) injection is the first biosimilar to the reference product Rituxan1 (rituximab) now available in the United States with a full oncology label (Press release, Teva, NOV 7, 2019, View Source [SID1234550665]). TRUXIMA is currently indicated for the treatment of adult patients with non-Hodgkin’s Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL):

Non-Hodgkin’s Lymphoma (NHL)
Relapsed or refractory, low grade or follicular, CD20-positive B-cell NHLas a single agent
Previously untreated follicular, CD20-positive, B-cell NHL in combination with first line chemotherapy and, in patients achieving a complete or partial response to a rituximab product in combination with chemotherapy, as single-agent maintenance therapy
Non-progressing (including stable disease), low-grade, CD20positive, B-cell NHL as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy
Previously untreated diffuse large B-cell, CD20-positive NHL in combination with (cyclophosphamide, doxorubicin, vincristine, and prednisone) (CHOP) or other anthracycline-based chemotherapy regimens
Chronic Lymphocytic Leukemia (CLL)
In combination with fludarabine and cyclophosphamide (FC), for the treatment of adult patients with previously untreated and previously treated CD20-positive CLL
"We are excited about the first FDA-approved biosimilar to rituximab in the U.S.," stated Brendan O’Grady, Executive Vice President and Head of North America Commercial at Teva. "Teva’s commitment to biosimilars is focused on the potential to create lower healthcare costs and increased price competition. This focus is consistent with Teva’s mission of making accessible medications to help improve the lives of patients."

TRUXIMA was approved by the U.S. Food and Drug Administration (FDA) as the first rituximab biosimilar. The approval was based on a review of a comprehensive data package inclusive of foundational and extensive analytical characterization, nonclinical data, clinical pharmacology, immunogenicity, clinical efficacy, and safety data. In May 2019, the FDA approved TRUXIMA to match all of the reference product’s oncology indications for NHL and CLL. In light of a patent settlement with Genentech, Celltrion and Teva have a pending FDA submission for rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA), and microscopic polyangiitis (MPA), and a license from Genentech to expand the TRUXIMA label to include these indications in Q2 2020.

"We are pleased to announce the launch of the first rituximab biosimilar, TRUXIMA, with our marketing partner Teva in the U.S." said Mr. Hyoung-Ki Kim, Vice Chairman at Celltrion Healthcare. "We believe that the introduction of TRUXIMA into the U.S. market will contribute to addressing unmet needs of U.S. patients as well."

The Wholesale Acquisition Cost (WAC or "list price") for TRUXIMA will be 10 percent lower than the reference product. TRUXIMA is being made available through primary wholesalers at a WAC of $845.55 for 100mg vial and $4227.75 for 500mg vial. Actual costs to individual patients and providers for TRUXIMA are anticipated to be lower than WAC because WAC does not account for additional rebates and discounts that may apply. Savings on out-of-pocket costs may vary depending on the patient’s insurance payer and eligibility for participation in the assistance program.

Dedicated patient support services are also available from Teva through the Comprehensive Oncology Reimbursement Expertise (CORE) program. CORE is available to help eligible patients, caregivers and healthcare professionals navigate the reimbursement process. CORE offers a range of services, including benefits verification and coverage determination, support for precertification and prior authorization, assistance with coverage guidelines and claims investigation, and support through the claims and appeals process. A savings program is also available for eligible commercially insured patients. To learn more, please visit TevaCORE.com. For healthcare professionals seeking additional information, there is also a dedicated site at TRUXIMAhcp.com.

Celltrion and Teva Pharmaceutical Industries Ltd. entered into an exclusive partnership in October 2016 to commercialize TRUXIMA in the U.S. and Canada.

Please see the Important Safety Information below including the Boxed Warning regarding fatal infusion-related reactions, severe mucocutaneous reactions, hepatitis B virus reactivation and progressive multifocal leukoencephalopathy. For more information, please visit the full prescribing information.

Important Safety Information

WARNING: FATAL INFUSION-RELATED REACTIONS, SEVERE MUCOCUTANEOUS REACTIONS, HEPATITIS B VIRUS REACTIVATION and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

Infusion-Related Reactions – Administration of rituximab products, including TRUXIMA, can result in serious, including fatal, infusion-related reactions. Deaths within 24 hours of rituximab infusion have occurred. Approximately 80% of fatal infusion-related reactions occurred in association with the first infusion. Monitor patients closely. Discontinue TRUXIMA infusion for severe reactions and provide medical treatment for Grade 3 or 4 infusion-related reactions

Severe Mucocutaneous Reactions – Severe, including fatal, mucocutaneous reactions can occur in patients receiving rituximab products

Hepatitis B Virus (HBV) Reactivation – HBV reactivation can occur in patients treated with rituximab products, in some cases resulting in fulminant hepatitis, hepatic failure, and death. Screen all patients for HBV infection before treatment initiation, and monitor patients during and after treatment with TRUXIMA. Discontinue TRUXIMA and concomitant medications in the event of HBV reactivation

Progressive Multifocal Leukoencephalopathy (PML), including fatal PML, can occur in patients receiving rituximab products

Warnings and Precautions

Infusion-Related Reactions – Rituximab products can cause severe, including fatal, infusion-related reactions. Severe reactions typically occurred during the first infusion with time to onset of 30-120 minutes. Rituximab product-induced infusion-related reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death.

Premedicate patients with an antihistamine and acetaminophen prior to dosing. Institute medical management (e.g. glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion-related reactions as needed. Depending on the severity of the infusion-related reaction and the required interventions, temporarily or permanently discontinue TRUXIMA. Resume infusion at a minimum 50% reduction in rate after symptoms have resolved. Closely monitor the following patients: those with pre-existing cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells (>25,000/mm3)

Severe Mucocutaneous Reactions – Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with rituximab products. These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these reactions has been variable and includes reports with onset on the first day of rituximab exposure. Discontinue TRUXIMA in patients who experience a severe mucocutaneous reaction. The safety of re-administration of rituximab products to patients with severe mucocutaneous reactions has not been determined.

Hepatitis B Virus Reactivation – Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with drugs classified as CD20-directed cytolytic antibodies, including rituximab products. Cases have been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation also has occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive and hepatitis B surface antibody [anti-HBs] positive).

HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA levels or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels. In severe cases increase in bilirubin levels, liver failure, and death can occur.

Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with TRUXIMA. For patients who show evidence of prior hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult with physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy before and/or during TRUXIMA treatment.

Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following TRUXIMA therapy. HBV reactivation has been reported up to 24 months following completion of rituximab therapy.

In patients who develop reactivation of HBV while on TRUXIMA, immediately discontinue TRUXIMA and any concomitant chemotherapy, and institute appropriate treatment. Insufficient data exist regarding the safety of resuming TRUXIMA treatment in patients who develop HBV reactivation. Resumption of TRUXIMA treatment in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing HBV.

Progressive Multifocal Leukoencephalopathy (PML) – JC virus infection resulting in PML and death can occur in rituximab product-treated patients with hematologic malignancies. The majority of patients with hematologic malignancies diagnosed with PML received rituximab in combination with chemotherapy or as part of a hematopoietic stem cell transplant. Most cases of PML were diagnosed within 12 months of their last infusion of rituximab.

Consider the diagnosis of PML in any patient presenting with new-onset neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture.

Discontinue TRUXIMA and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML.

Tumor Lysis Syndrome (TLS) – Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, sometimes fatal, can occur within 12-24 hours after the first infusion of rituximab products in patients with NHL. A high number of circulating malignant cells (>25,000/mm3) or high tumor burden, confers a greater risk of TLS.

Administer aggressive intravenous hydration and anti-hyperuricemic therapy in patients at high risk for TLS. Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated.

Infections – Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of rituximab product-based therapy. Infections have been reported in some patients with prolonged hypogammaglobulinemia (defined as hypogammaglobulinemia >11 months after rituximab exposure). New or reactivated viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis B and C. Discontinue TRUXIMA for serious infections and institute appropriate anti-infective therapy. TRUXIMA is not recommended for use in patients with severe, active infections.

Cardiovascular Adverse Reactions – Cardiac adverse reactions, including ventricular fibrillation, myocardial infarction, and cardiogenic shock may occur in patients receiving rituximab products. Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of TRUXIMA for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina.

Renal Toxicity – Severe, including fatal, renal toxicity can occur after rituximab product administration in patients with NHL. Renal toxicity has occurred in patients who experience tumor lysis syndrome and in patients with NHL administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and TRUXIMA is not an approved treatment regimen. Monitor closely for signs of renal failure and discontinue TRUXIMA in patients with a rising serum creatinine or oliguria.

Bowel Obstruction and Perforation – Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving rituximab in combination with chemotherapy. In postmarketing reports, the mean time to documented gastrointestinal perforation was 6 (range 1-77) days in patients with NHL. Evaluate if symptoms of obstruction such as abdominal pain or repeated vomiting occur.

Immunization – The safety of immunization with live viral vaccines following rituximab product therapy has not been studied and vaccination with live virus vaccines is not recommended before or during treatment.

Embryo-Fetal Toxicity – Based on human data, rituximab products can cause fetal harm due to B-cell lymphocytopenia in infants exposed to rituximab in-utero. Advise pregnant women of the risk to a fetus. Females of childbearing potential should use effective contraception while receiving TRUXIMA and for 12 months following the last dose of TRUXIMA.

Most common adverse reactions in clinical trials of NHL (>25%) were: infusion-related reactions, fever, lymphopenia, chills, infection, and asthenia

Most common adverse reactions in clinical trials of CLL (>25%) were: infusion-related reactions and neutropenia

Nursing Mothers – There are no data on the presence of rituximab in human milk, the effect on the breastfed child, or the effect on milk production. Since many drugs including antibodies are present in human milk, advise a lactating woman not to breastfeed during treatment and for at least 6 months after the last dose of TRUXIMA due to the potential for serious adverse reactions in breastfed infants.

About TRUXIMA

TRUXIMA (rituximab-abbs) is a U.S. Food and Drug Administration (FDA)-approved biosimilar to RITUXAN (rituximab) for the treatment of adult patients with CD20-positive, B-cell NHL to be used as a single agent or in combination with chemotherapy or CLL in combination with fludarabine and cyclophosphamide (FC).

TRUXIMA has the same mechanism of action as Rituxan and has demonstrated biosimilarity to Rituxan through a totality of evidence.

About Celltrion Healthcare, Co. Ltd.

Celltrion Healthcare conducts the worldwide marketing, sales and distribution of biological medicines developed by Celltrion, Inc. through an extensive global network that spans more than 120 different countries. Celltrion Healthcare’s products are manufactured at state-of-the-art mammalian cell culture facilities, designed and built to comply with the US Food and Drug Administration (FDA) cGMP guidelines and the EU GMP guidelines.