Truxima® Clinical Evidence in RA

© Celltrion Healthcare Co., Ltd. 2018 HCTRU-17 PB-0418/02

1. European Medicines Agency. Assessment Report: Truxima. 2016. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/004112/WC500222695.pdf Accessed March 2018. 2. US Food and Drug Administration. Scientific considerations in demonstrating biosimilarity to a reference product. Guidance for industry. 2015 Available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm291128.pdf Accessed March 2018. 3. Henry D and Taylor C. Semin Oncol 2014;41:S13-S20. 4. British Society for Rheumatology. Position statement on biosimilar medicines (January 2017). Available at: https://www.nras.org.uk/data/files/revised_bsr_biosimilars_position_statement_jan_2017.pdf Accessed March 2018. 5. American College of Rheumatology. Position Statement (2018). Available at: https://www.rheumatology.org/Portals/0/Files/Biosimilars-Position-Statement.pdf. Accessed March 2018. 6. Boross P and Leusen J-HW. Am J Cancer Res. 2012;2:676-90. 7. European Medicines Agency. Truxima Summary of Product Characteristics. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004112/WC500222694.pdf. Accessed March 2018. 8. Yoo DH, Suh CH, Shim SC et al. Ann Rheum Dis. 2017 Mar;76(3):566-570. 9. Yoo DH, Suh CH, Shim SC et al. BioDrugs. 2017 Aug;31(4):357-367. 10. Park W, Suh CH, Shim SC et al. BioDrugs. 2017 Aug;31(4):369-377. 11. Suh CH, Berrocal Kasay A, Chalouhi El-Khouri E et al. Arthritis Rheumatol. 2016; 68 (suppl 10). 12. Yoo DH, Bozic Majstorovic L, Berrocal Kasay A et al. Arthritis Rheumatol. 2016; 68 (suppl 10).  13. Suh CH, E. Chalouhi El Khouri, Miranda P. et al. Ann Rheum Dis. 2017;76(Suppl 2):824. 14. Shim SC, Bozic Majstorovic L, Berrocal Kasay A et al. Arthritis Rheumatol. 2017; 69 (suppl 10). 

Reference

Truxima®▼ (rituximab) •100mg concentrate for solution for infusion •500mg concentrate for solution for infusion • Prescribing Information Please read the Summary of Product Characteristics (SPC) before prescribing. • Presentation Clear Type I glass vials with butyl rubber stopper containing 100 mg of rituximab in 10mL. Clear Type I glass vials with butyl rubber stopper containing 500 mg of rituximab in 50mL. • Indications Non-Hodgkin’s Lymphoma (NHL): Truxima is indicated for the treatment of previously untreated patients with stage III-IV follicular lymphoma in combination with chemotherapy. Truxima maintenance therapy is indicated for the treatment of follicular lymphoma patients responding to induction therapy. Truxima monotherapy is indicated for treatment of patients with stage III-IV follicular lymphoma who are chemo-resistant or are in their second or subsequent relapse after chemotherapy. Truxima is indicated for the treatment of patients with CD20 positive diffuse large B cell non-Hodgkin’s lymphoma in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy. Chronic Lymphocytic Leukaemia (CLL): Truxima in combination with chemotherapy is indicated for the treatment of patients with previously untreated and relapsed/refractory CLL. Rheumatoid Arthritis (RA): Truxima in combination with methotrexate is indicated for the treatment of adult patients with severe active RA who have had an inadequate response or intolerance to other disease-modifying anti-rheumatic drugs (DMARD) including one or more tumour necrosis factor (TNF) inhibitor therapies. Granulomatosis with Polyangiitis (GPA) and Microscopic Polyangiitis (MPA): Truxima, in combination with glucocorticoids, is indicated for the induction of remission in adult patients with severe, active GPA (Wegener’s) and MPA. • Dosage and administration Truxima should be administered under the close supervision of an experienced healthcare professional, and in an environment where full resuscitation facilities are immediately available. Premedication consisting of an anti-pyretic and an antihistaminic should always be given before each administration of Truxima. In patients with NHL and CLL, premedication with glucocorticoids should be considered if Truxima is not given in combination with glucocorticoid-containing chemotherapy. In patients with RA, premedication with 100 mg intravenous (IV) methylprednisolone should be completed 30 minutes prior to Truxima infusions to decrease the incidence and severity of infusion related reactions (IRRs). In patients with GPA or MPA, methylprednisolone given intravenously for 1 to 3 days at a dose of 1000 mg per day is recommended prior to the first infusion of Truxima. This should be followed by oral prednisone 1 mg/kg/day during and after Truxima treatment. Follicular NHL: Combination therapy - The recommended dose of Truxima in combination with chemotherapy for induction treatment of previously untreated or relapsed/ refractory patients with follicular lymphoma is: 375 mg/m2 body surface area per cycle, for up to 8 cycles. Maintenance therapy - The recommended dose of Truxima used as a maintenance treatment for patients with previously untreated follicular lymphoma who have responded to induction treatment is: 375 mg/m2 body surface area once every 2 months (starting 2 months after the last dose of induction therapy) until disease progression or for a maximum period of two years. Relapsed/refractory follicular lymphoma - The recommended dose of Truxima used as a maintenance treatment for patients with relapsed/refractory follicular lymphoma who have responded to induction treatment is: 375 mg/m2 body surface area once every 3 months (starting 3 months after the last dose of induction therapy) until disease progression or for a maximum period of two years. Monotherapy - The recommended dose of Truxima monotherapy used as induction treatment for adult patients with stage III-IV follicular lymphoma who are chemoresistant or are in their second or subsequent relapse after chemotherapy and for patients who have responded to previous treatment with Truxima monotherapy for relapsed/refractory follicular lymphoma is: 375 mg/m2 body surface area, administered as an IV infusion once weekly for four weeks. Diffuse Large B cell NHL: Truxima should be used in combination with CHOP chemotherapy. The recommended dosage is 375 mg/m2 body surface area, administered on day 1 of each chemotherapy cycle for 8 cycles after IV infusion of the glucocorticoid component of CHOP. Dose adjustments during treatment: No dose reductions of Truxima are recommended. When Truxima is given in combination with chemotherapy, standard dose reductions for the chemotherapeutic medicinal products should be applied. CLL: Prophylaxis with adequate hydration and administration of uricostatics starting 48 hours prior to start of therapy is recommended for CLL patients to reduce the risk of tumour lysis syndrome. For CLL patients whose lymphocyte counts are > 25 x 109/L it is recommended to administer prednisone/prednisolone 100 mg IV shortly before infusion with Truxima to decrease the rate and severity of acute infusion reactions and/or cytokine release syndrome. The recommended dosage of Truxima in combination with chemotherapy for previously untreated and relapsed/refractory patients is 375 mg/m2 body surface area administered on day 0 of the first treatment cycle followed by 500 mg/m2 body surface area administered on day 1 of each subsequent cycle for 6 cycles in total. The chemotherapy should be given after Truxima infusion. RA: Patients treated with Truxima must be given the patient alert card with each infusion. A course of Truxima consists of two 1000 mg IV infusions. The recommended dosage of Truxima is 1000 mg by IV infusion followed by a second 1000 mg IV infusion two weeks later. The need for further courses should be evaluated 24 weeks following the previous course. Retreatment should be given at that time if residual disease activity remains, otherwise retreatment should be delayed until disease activity returns. GPA and MPA: Patients treated with Truxima must be given the patient alert card with each infusion. The recommended dosage of Truxima for induction of remission therapy of GPA and MPA is 375 mg/m2 body surface area, administered as an IV infusion once weekly for 4 weeks (four infusions in total). Pneumocystis jiroveci pneumonia (PCP) prophylaxis is recommended for patients with GPA or MPA during and following Truxima treatment, as appropriate. Special populations Paediatric population The safety and efficacy of Truxima in children below 18 years has not been established. No data are available. Elderly No dose adjustment is required in elderly patients (aged >65 years). Method of administration: The prepared Truxima solution should be administered as an IV infusion through a dedicated line. It should not be administered as an IV push or bolus. Patients should be closely monitored for the onset of cytokine release syndrome. Patients who develop evidence of severe reactions, especially severe dyspnoea, bronchospasm or hypoxia should have the infusion interrupted immediately. Patients with NHL should then be evaluated for evidence of tumour lysis syndrome including appropriate laboratory tests and, for pulmonary infiltration, with a chest X-ray. In all patients, the infusion should not be restarted until complete resolution of all symptoms, and normalisation of laboratory values and chest X-ray findings. At this time, the infusion can be initially resumed at not more than one-half the previous rate. Mild or moderate IRRs usually respond to a reduction in the rate of infusion. The infusion rate may be increased upon improvement of symptoms. First infusion: The recommended initial rate for infusion is 50 mg/h; after the first 30 minutes, it can be escalated in 50 mg/h increments every 30 minutes, to a maximum of 400 mg/h. Subsequent infusions: All indications Subsequent doses of Truxima can be infused at an initial rate of 100 mg/h, and increased by 100 mg/h increments at 30 minute intervals, to a maximum of 400 mg/h. RA only Alternative subsequent, faster, infusion schedule: If patients did not experience a serious infusion related reaction with their first or subsequent infusions of a dose of 1000mg. Truxima administered over the standard infusion schedule, a more rapid infusion can be administered for second and subsequent infusions using the same concentration as in previous infusions (4 mg/mL in a 250 mL volume). Initiate at a rate of 250 mg/hour for the first 30 minutes and then 600 mg/hour for the next 90 minutes. If the more rapid infusion is tolerated, this infusion schedule can be used when administering subsequent infusions. Patients who have clinically significant cardiovascular disease, including arrhythmias, or previous serious infusion reactions to any prior biologic therapy or to rituximab, should not be administered the more rapid infusion. • Contraindications Hypersensitivity to the active substance or to murine proteins, or to any of the other excipients; active, severe infections; patients in a severely immunocompromised state, severe heart failure (NYHA Class IV) or severe, uncontrolled cardiac disease (in patients with RA, MPA and GPA). • Precautions and warnings Progressive multifocal leukoencephalopathy (PML): Patients must be monitored at regular intervals for any new or worsening neurological symptoms or signs that may be suggestive of PML. If PML is suspected, further dosing must be suspended until PML has been excluded. The clinician should evaluate the patient to determine if the symptoms are indicative of neurological dysfunction, and if so, whether these symptoms are possibly suggestive of PML. If any doubt exists, further evaluation, including MRI scan preferably with contrast, cerebrospinal fluid (CSF) testing for JC Viral DNA and repeat neurological assessments, should be considered. If a patient develops PML the dosing of Truxima must be permanently discontinued. Non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia: Infusion related reactions: Truxima is associated with infusion related reactions (IRRs), which may be related to release of cytokines and/or other chemical mediators. This set of reactions which includes syndrome of cytokine release, tumour lysis syndrome and anaphylactic and hypersensitivity reactions; rapid tumour lysis and features of tumour lysis syndrome in addition to fever, chills, rigors, hypotension, urticaria, angioedema and other symptoms. Severe cytokine release syndrome is characterised by severe dyspnea, often accompanied by bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. This syndrome may be associated with some features of tumour lysis syndrome such as hyperuricaemia, hyperkalaemia, hypocalcaemia, hyperphosphaetemia, acute renal failure, elevated lactate dehydrogenase (LDH) and may be associated with acute respiratory failure and death. Patients with a high tumour burden or with a high number (≥25 x 109/L) of circulating malignant cells such as patients with CLL, who may be at higher risk of especially severe cytokine release syndrome, should be treated with extreme caution. Consideration should be given to the use of a reduced infusion rate for the first infusion in these patients or a split dosing over two days during the first cycle and any subsequent cycles if the lymphocyte count is still >25 x 109/L. Anaphylactic and other hypersensitivity reactions have been reported following the IV administration of proteins to patients. In contrast to cytokine release syndrome, true hypersensitivity reactions typically occur within minutes after starting infusion. Medicinal products for the treatment of hypersensitivity reactions, e.g., epinephrine (adrenaline), antihistamines and glucocorticoids, should be available for immediate use in the event of an allergic reaction during administration of Truxima. Cardiac disorders: Angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure and/or myocardial infarction have occurred in patients treated with rituximab. Therefore patients with a history of cardiac disease and/or cardiotoxic chemotherapy should be monitored closely. Haematological toxicities: Although Truxima is not myelosuppressive in monotherapy, caution should be exercised when considering treatment of patients with neutrophils < 1.5 x 109/L and/or platelet counts < 75 x 109/L. Regular full blood counts, including neutrophil and platelet counts, should be performed during Truxima therapy. Infections: Truxima should not be administered to patients with an active, severe infection (e.g. tuberculosis, sepsis and opportunistic infections).Physicians should exercise caution when considering the use of Truxima in patients with a history of recurring or chronic infections or with underlying conditions which may further predispose patients to serious infection. Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatment with Truxima. Patients with active hepatitis B disease should not be treated with Truxima. Patients with positive hepatitis B serology (either HBsAg or HBcAb) should consult liver disease experts before start of treatment and should be monitored and managed following local medical standards to prevent hepatitis B reactivation. Immunisation: The safety of immunisation with live viral vaccines, following Truxima therapy has not been studied for NHL and CLL

patients and vaccination with live virus vaccines is not recommended. Patients treated with Truxima may receive non-live vaccinations. Skin reactions: Severe skin reactions such as Toxic Epidermal Necrolysis (Lyell’s Syndrome) and Stevens – Johnson syndrome, some with fatal outcome, have been reported. In case of such an event, with suspected relationship to Truxima, treatment should be permanently discontinued. Rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis: Methotrexate (MTX) naïve populations with RA: The use of Truxima is not recommended in MTX-naïve patients since a favourable benefit risk relationship has not been established. Infusion related reactions: Truxima is associated with IRRs, which may be related to release of cytokines and/or other chemical mediators. Premedication consisting of an analgesic/anti-pyretic drug and an anti-histaminic drug, should always be administered before each infusion of Truxima. In RA, premedication with glucocorticoids should also be administered before each infusion of Truxima in order to reduce the frequency and severity of IRRs. Severe IRRs with fatal outcome have been reported in RA patients in the post-marketing setting. In RA most infusion-related events reported in clinical trials were mild to moderate in severity. The most common symptoms were allergic reactions like headache, pruritus, throat irritation, flushing, rash, urticaria, hypertension, and pyrexia. In general, the proportion of patients experiencing any infusion reaction was higher following the first infusion than following the second infusion of any treatment course. The incidence of IRR decreased with subsequent courses. The reactions reported were usually reversible with a reduction in rate, or interruption, of rituximab infusion and administration of an anti-pyretic, an antihistamine, and, occasionally, oxygen, intravenous saline or bronchodilators, and glucocorticoids if required. Closely monitor patients with pre-existing cardiac conditions and those who experienced prior cardiopulmonary adverse reactions. Medicinal products for the treatment of hypersensitivity reactions, e.g., epinephrine (adrenaline), antihistamines and glucocorticoids, should be available for immediate use in the event of an allergic reaction during administration of Truxima. IRRs for patients with GPA and MPA were similar to those seen for RA patients in clinical trials. Cardiac disorders: Angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure and/or myocardial infarction have treated with rituximab. Therefore patients with a history of cardiac disease and/or cardiotoxic chemotherapy should be monitored closely. Infections: Based on the mechanism of action of Truxima and the knowledge that B cells play an important role in maintaining normal immune response, patients have an increased risk of infection following Truxima therapy. Serious infections, including fatalities, can occur during therapy with Truxima. Truxima should not be administered to patients with an active, severe infection (e.g. tuberculosis, sepsis and opportunistic infections). Physicians should exercise caution when considering the use of Truxima in patients with a history of recurring or chronic infections or with underlying conditions which may further predispose patients to serious infection. It is recommended that immunoglobulin levels are determined prior to initiating treatment with Truxima. Very rare cases of fatal progressive multifocal leukoencephalopathy (PML) have been reported following use of rituximab for the treatment of RA and autoimmune diseases including Systemic Lupus Erythematosus (SLE) and vasculitis. Hepatitis B Infections: Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatment with Truxima. Patients with active hepatitis B disease should not be treated with Truxima. Patients with positive hepatitis B serology (either HBsAg or HBcAb) should consult liver disease experts before start of treatment and should be monitored and managed following local medical standards to prevent hepatitis B reactivation. Late neutropenia: Measure blood neutrophils prior to each course of Truxima, and regularly up to 6-months after cessation of treatment, and upon signs or symptoms of infection. Skin reactions: Severe skin reactions such as Toxic Epidermal Necrolysis (Lyell’s Syndrome) and Stevens – Johnson syndrome, some with fatal outcome, have been reported. In case of such an event, with suspected relationship to Truxima, treatment should be permanently discontinued. Immunisation: Physicians should review the patient’s vaccination status and follow current immunisation guidelines prior to Truxima therapy. Vaccination should be completed at least 4 weeks prior to first administration of Truxima. The safety of immunisation with live viral vaccines, following Truxima therapy has not been studied and vaccination with live virus vaccines is not recommended whilst on Truxima or whilst peripherally B cell depleted. Patients treated with Truxima may receive non-live vaccinations. Concomitant/sequential use of other DMARDs in RA: The concomitant use of Truxima and anti-rheumatic therapies other than those specified under the RA indication and posology is not recommended. Malignancy: Immunomodulatory drugs may increase the risk of malignancy. On the basis of limited experience with rituximab in RA patients the present data do not seem to suggest any increased risk of malignancy. However, the possible risk for the development of solid tumours cannot be excluded at this time. • Interactions Currently, there are limited data on possible drug interactions with Truxima. In CLL patients, co-administration with rituximab did not appear to have an effect on the pharmacokinetics of fludarabine or cyclophosphamide. In addition, there was no apparent effect of fludarabine and cyclophosphamide on the pharmacokinetics of rituximab In RA patients, co-administration with methotrexate had no effect on the pharmacokinetics of rituximab in rheumatoid arthritis patients. Patients with human anti-mouse antibody or human anti-chimeric antibody (HAMA/HACA) titres may have allergic or hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal antibodies. • Fertility, pregnancy and lactation Contraception in males and females: Due to the long retention time of Truxima in B cell depleted patients, women of childbearing potential should use effective contraceptive methods during and for 12 months following treatment with Truxima. Pregnancy: IgG immunoglobulins are known to cross the placental barrier. B-cell levels in human neonates following maternal exposure to Truxima have not been studied in clinical trials. There are no adequate and well-controlled data from studies in pregnant women, however transient B-cell depletion and lymphocytopenia have been reported in some infants born to mothers exposed to rituximab during pregnancy. Similar effects have been observed in animal studies. For these reasons Truxima should not be administered to pregnant women unless the possible benefit outweighs the potential risk. Breast-feeding: Whether Truxima is excreted in human milk is not known. However, because maternal IgG is excreted in human milk, and rituximab was detectable in milk from lactating monkeys, women should not breastfeed while treated with Truxima and for 12 months following Truxima treatment. Fertility: Animal studies did not reveal deleterious effects of rituximab on reproductive organs. • Side-effects In NHL and CLL patients Very common (≥1/10) and common (≥1/100 to <1/10) side-effects: bacterial infections, viral infections, bronchitis, neutropenia, leucopenia, febrile neutropenia, thrombocytopenia, infusion related reactions, angioedema, nausea, pruritus, rash, alopecia, fever, chills, asthenia, headache, decreased IgG levels; sepsis, pneumonia, febrile infection, herpes zoster, respiratory tract infection, fungal infections, infections of unknown aetiology, acute bronchitis, sinusitis, hepatitis B, anaemia, pancytopenia, granulocytopenia, hypersensitivity, hyperglycaemia, weight decrease, peripheral oedema, face oedema, increased LDH, hypocalcaemia, paraesthesia, hypoaesthesia, agitation, insomnia, vasodilatation, dizziness, anxiety, lacrimation disorder, conjunctivitis, tinnitus, ear pain, myocardial infarction, arrhythmia, atrial fibrillation, tachycardia, cardiac disorder, hypertension, orthostatic hypotension, hypotension, bronchospasm, respiratory disease, chest pain, dyspnoea, increased cough, rhinitis, vomiting, diarrhoea, abdominal pain, dysphagia, stomatitis, constipation, dyspepsia, anorexia, throat irritation, urticaria, sweating, night sweats, skin disorder, hypertonia, myalgia, arthralgia, back pain, neck pain, pain, tumour pain, flushing, malaise, cold syndrome, fatigue, shivering, and multi-organ failure. Uncommon (< 1/100) but potentially serious side-effects: coagulation disorders, aplastic anaemia, haemolytic anaemia, lymphadenopathy, depression, nervousness, dysgeusia, left ventricular failure, supraventricular tachycardia, ventricular tachycardia, angina, myocardial ischaemia, bradycardia, asthma, bronchiolitis obliterans, lung disorder, hypoxia, abdominal enlargement, and infusion site pain. In RA patients Very common (≥1/10) and common (≥1/100 to <1/10) side-effects: upper respiratory tract infection, urinary tract infections, Infusion related reactions (hypertension, nausea, rash, pyrexia, pruritus, urticaria, throat irritation, hot flush, hypotension, rhinitis, rigors, tachycardia, fatigue, oropharyngeal pain, peripheral oedema, erythma), headache, decreased IgM levels, bronchitis, sinusitis, gastroenteritis, tinea pedis, neutropenia, hypercholesterolemia, paraesthesia, migraine, dizziness, sciatica, alopecia, depression, anxiety, dyspepsia, diarrhoea, gastro-oesophageal reflux, mouth ulceration, upper abdominal pain, arthralgia /musculoskeletal pain, osteoarthritis, bursitis, decreased IgG levels Uncommon (< 1/100) but potentially serious side-effects: Infusion related reactions (generalized oedema, bronchospasm, wheezing, laryngeal oedema, angioneurotic oedema, generalized pruritis, anaphylaxis, anaphylactoid reaction). In GPA and MPA patients Adverse drug reactions occurring at 6-months in ≥ 5% of patients receiving rituximab, and at a higher frequency than the comparator group, in the pivotal clinical study: thrombocytopenia, diarrhoea, dyspepsia, constipation, peripheral oedema, cytokine release syndrome, urinary tract infection, bronchitis, herpes zoster, nasopharyngitis, decreased haemoglobin, hyperkalaemia, muscle spasms, arthralgia, back pain, muscle weakness, musculoskeletal pain, pain in extremities, dizziness, tremor, insomnia, cough, dyspnoea, epistaxis, nasal congestion, acne, hypertension, flushing

Please consult the SPC for details of other side-effects.

• Legal Category POM

• Marketing Authorisation (MA) numbers EU/1/16/1167/002 (100mg) EU/1/16/1167/001 (500mg)

• MA holder Celltrion Healthcare Hungary Kft

Further information from: Celltrion Healthcare Hungary Kft., 1062 BudapestVáci út 1-3. WestEnd Office Building B torony. Hungary

For medical information enquiries, please contact medicalinfo@celltrion.com ® Truxima is a registered trade mark of Celltrion, Inc. and is used under license.

© Celltrion Healthcare Co., Ltd. 2018.Date of Preparation April 2018

Prescribing Information

Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Celltrion Healthcare and its authorised commercialisation partners.

DLBCL, Diffuse Large B-Cell Lymphoma; DMARD, Disease-Modifying AntiRheumatic Drug; FL, Follicular Lymphoma; TNF-α, Tumour Necrosis Factor Alpha

Truxima® proved to have the same mechanism of action as reference rituximab.6

A biosimilar is a biological medicinal product that is not identical, but highly similar, to an already approved biological medicinal product (reference product).2

Truxima® is the 1st biosimilar rituximab in oncology, approved by the European Medicines Agency (EMA) on Feb 2017.1

• The inclusion of biosimilars as a therapeutic choice for patients initiating a new biologic therapy is recommended.

• Switching to biosimilars should be on a case-by-case basis, and all patients starting or switching to biosimilars should be registered with the BSR Biologic Registers.

• Treatment decisions must be discussed in partnership with the patient and the physician.

British Society for Rheumatology January 2017

• The approval process for biosimilars needs to place safety and efficacy, supported by scientifically sound evidence, as the highest priorities.

• With the need for more cost-effective biologic therapeutics, biosimilars offer hope of cost reduction if physicians and patients can be sufficiently reassured of their efficacy and safety through rigorous scientific study of these products.

American Collegeof Rheumatology

March 2018

Emerge as a cost-effective alternative to biologics, reducing pressure on healthcare costs

Drive innovation in the biological market through competition

Able to provide a wider range of benefits for all stakeholders in the medical community

Increase patient access to important biological therapy globally

Truxima® is indicated for the treatment of:7

* Or in patients with Stage III-IV FL who are in their second or subsequent relapse after chemotherapy For more information, please refer to the prescribing information on page 8 of this booklet.

•�Previously untreated stage III-IV FL

• FL responding to induction therapy

• Chemo-resistant stage III-IV FL*

• CD20-positive DLBCL

•�Previously untreated

•�Relapsed or refractory

•�Severe, active granulomatosis with polyangiitis (Wegener’s) (GPA) and microscopic polyangiitis (MPA)

•�Severe active RA with inadequate response or intolerance to other DMARDs, including ≥1 TNF-α inhibitor

NHL CLL GPA & MPA RA

In combination with: Chemotherapy

Or as: Monotherapy Maintenance therapy (of FL responding to induction therapy)

Recommended dose: 375 mg/m2

In combination with: Chemotherapy

Recommended dose:

• 375 mg/m2 for 1st treatment cycle

• 500 mg/m2 in subsequent cycles

In combination with: Glucocorticoids

Recommended dosage: 375 mg/m2

In combination with: Methotrexate

Recommended dose: 1000 mg

Rheumatologists’ Perception of Biosimilars4,5

ADCC, Antibody-Dependent Cell-mediated Cytotoxicity; CDC, Complement-Dependent Cytotoxicity; Fc, Fragment crystallizable; MAC, Membrane Attack Complex

Rituximab

CD20

ADCC

CDC

Apoptosis

Fc Receptor

Effector Cell

C1q

MAC

Mechanism of actionBiosimilars are expected to:3

Truxima® C

linical Evid

ence in RA

0203

Study design8-10

Main Study: To demonstrate the pharmacokinetic (PK) equivalence of Truxima® and reference rituximab in patients with RA.8,9

OLE Study: To compare the efficacy and safety of Truxima® in patients with RA who received and maintained Truxima® treatment throughout the main study & OLE (maintenance group) with those who received reference rituximab during the main study and switched to Truxima® during the OLE (switch group).10

Truxima® Demonstrated Equivalent Pharmacokinetics to Reference Rituximab8

Objective8-10

Truxima® in Patients with RA: PK, Efficacy, Safety, and Switchability

Administration Period

OLE, Open Label Extension

Phase I Study

Main Study Open Label Extension

Infusions at Week 0

& Week 2

Follow-up Monitoring

Up to 2 courses of Truxima®2 infusions2 weeks

apart

Truxima®(n=103)

1st course 2nd course

Mainte-nance(n=58)

Week 24

Week 104

Week 72

Week 0

Week 80

Week 48

Infusions at Week 0

& Week 2

Follow-up Monitoring

Up to 2 courses of Truxima®2 infusions2 weeks

apart

ReferenceRituximab

(n=51)

1st course 2nd course

Switch(n=29)

The 90% CIs for the ratio of geometric means of Truxima® and reference rituximab for both both AUC0–last and Cmax were within the pre-defined bioequivalence range of 80% and 125%.8

80% 125%Equivalence Margin

AUC0-last

Cmax

89.2% 107.0%97.7%

92.0% 103.5%97.6%

Week

Reference rituximab

Truxima®

600

0

100

200

300

400

500

0 2 2422201816141210864

Seru

m c

once

ntra

tion

of

dru

g (

μg/m

l)

Drug infusion

Truxima® C

linical Evid

ence in RA

0405

*1 patient did not receive 2nd infusion **3 patients were discontinued due to consent withdrawal (1 Truxima®/ Truxima®, 2 US-RTX/ Truxima®)

Phase III Study

n=121**

Switching to Truxima® Demonstrated Comparable Efficacy and Safety to Maintaining Rituximab Treatment10

2nd Infusion Completion1st Infusion 3rd Infusion

Maintenance groupa Switch groupb

Number (%) of Patients

Any AEs 9 (23.7) 4 (20.0)

Any Serious AE 1 (2.6) 1 (5.0)

Infusion-related reaction 1 (2.6) 1 (5.0)

Infection 3 (7.9) 2 (10.0)

Malignancy or Lymphoma 0 0

Discontinuation due to AE 0 0

a. Patients treated with Truxima® during the preceding Main Study and also during the OLEb. Patients treated with reference rituximab during the preceding Main Study and with Truxima® during the OLE

Patient disposition & Study design11-14

• Part 1: To evaluate equivalence of Truxima® in patients with RA to EU and US-sourced reference rituximab (RTX) in terms of pharmacokinetics over the first 24 weeks.

• Part 2: To demonstrate comparability in efficacy and safety profiles of Truxima® to RTX (EU and US–sourced) in RA patients up to 24 weeks.

A total of 372 patients with active RA were randomised to receive Truxima® or RTX (EU and US-sourced).

Objective11-14

Comparability of Truxima® to:EU- or US- sourced Reference Rituximab

Maintenance Switch

EULAR-ESR EULAR-CRP

Prop

ortio

n of

pat

ient

s (%

) 100

0

20

40

60

8078.9

84.278.9

84.278.9

84.2

Week 8 Week 16 Week 24

100

0

20

40

60

8081.6 78.9 81.6 78.9

73.7

84.2

Week 8 Week 16 Week 24

Safety

Overall safety was similar between the maintenance and switch groups, and cumulative exposure to Truxima® did not increase the proportion of patients experiencing adverse events.10

Main Study Extension

n=47

Week 72

Week 24

Week 48

Week 0

EU RTXn=121**n=121**n=60 n=4756 completed

2nd infusion

n=121**140 completed

2nd infusion*n=121**n=121**n=161 n=121**n=122

n=64

n=60**

US RTXn=121**n=121**n=151

n=121**n=62

n=121**n=64

134 completed 2nd infusion

Efficacy: EULAR Response

The proportion of patients who achieved moderate or good EULAR responses in the maintained and switch groups was comparable.10

Truxima® C

linical Evid

ence in RA

0607

EULAR Response Rates

Efficacy and Pharmacokinetic Results were Comparable between Truxima® and RTX11,12

AUC0-last, Area Under the serum concentration-time Curve from time 0 to the last measurable concentration; AUC0-∞,Area Under the serum concen-tration-time Curve from time 0 extrapolated to infinity; Cmax, maximum concentration after the second infusion; CRP, C-Reactive Protein; DAS28, Disease Activity Score in 28 joints; ESR, Erythrocyte Sedimentation Rate

Switching to Truxima® was as Efficacious as Maintained Truxima® or RTX Treatment14

†Test/reference (Test vs. reference)

% Ratio of Geometric Means† (90% CI)

Truxima® vs. US-RTX Truxima® vs. EU-RTX EU-RTX vs. US-RTX

AUC0-last(h*㎍/mL) 97.07 (88.08, 106.99) 94.18 (85.40, 103.86) 103.07 (93.32, 113.85)

AUC0-∞(h*㎍/mL) 95.81 (87.39, 105.04) 89.89 (81.85, 98.72) 106.58 (97.03, 117.08)

Cmax(㎍/mL) 94.92 (89.61, 100.55) 89.00 (84.01, 94.28) 106.66 (100.56, 113.13)

Pharmacokinetics: Bioequivalence Test

The 90% CIs for the ratio of geometric means between the 3 treatment groups for all PK primary endpoints were entirely within the equivalence margin of 80-125%.11

At Week 24 Adjusted Mean (SE)

Estimate of Treatment Difference

95% CI of Treatment Difference

DAS28-CRP

Truxima® -2.14 (0.177)-0.05 (-0.29, 0.20)

RTX -2.09 (0.176)

DAS28-ESR

Truxima® -2.41 (0.182)-0.06 (-0.31, 0.19)

RTX -2.35 (0.182)

Efficacy: DAS28 Improvements at Week 24

DAS28 improvements were similar between the Truxima® and RTX groups. The 95% CI for the estimate of treatment difference in DAS28-CRP/ESR improvement at week 24 was entirely within the equivalence margin of ±0.6.12

Efficacy Results at Week 72

Efficacy, measured by DAS28 improvements and EULAR response rates, was comparable between patients who switched to Truxima® from RTX and those who maintained RTX or Truxima® treatment.14

DAS28-CRP Improvement

Infusion

Week 0 4 8 12 16 20 24 32 40 48 56 64 72

Mea

n o

f D

AS2

8

0

4

1

5

2

6

3

7

Week 24 Week 48 Week 72

Truxima® US-RTX EU-RTX Truxima® US-RTX EU-RTXUS-

RTX/US-RTX

Truxima®US-

RTX/Truxima®

EU-RTX/

Truxima®

Res

pons

e (%

)

100

0

20

40

60

80

42.6%

44.4%

33.9%40.3% 40.0% 34.5%

30.8% 28.1% 28.3%34.0%

40.0% 42.4% 42.4%

49.6% 48.1% 50.0%

60.0% 62.5% 63.3% 61.7%

Moderate Response Good Response

Truxima® C

linical Evid

ence in RA

0809

Truxima®/Truxima®

US-RTX/US-RTX

US-RTX/Truxima®

EU-RTX

EU-RTX/Truxima®

Pharmacodynamics

The B-cell depletion after the 1st infusion was comparable and maintained until the Week 72 in the all groups.14

Events, n (%)Truxima®/ Truxima®(N=122)

US-RTX/US-RTX(N=64)

US-RTX/Truxima®(N=62)

EU-RTX/ Truxima®(N=47)

AEs 48 (39.3) 21 (32.8) 26 (41.9) 10 (21.3)

Infections 21 (17.2) 14 (21.9) 14 (22.6) 3 (6.4)

URI 10 (8.2) 10 (15.6) 8 (12.9) 0

UTI 8 (6.6) 2 (3.1) 2 (3.2) 1 (2.1)

LRI 1 (0.8) 3 (4.7) 2 (3.2) 2 (4.3)

Gastroenteritis 0 0 2 (3.2) 0

Vaginitis 0 2 (3.1) 0 0

IRR 5 (4.1) 3 (4.7) 2 (3.2) 2 (4.3)

Grade 1 2 (1.6) 1 (1.6) 1 (1.6) 2 (4.3)

Grade 2 3 (2.5) 2 (3.1) 1 (1.6) 0

Hematology (Grade ≥3)

5 (4.1) 2 (3.1) 3 (4.8) 1 (2.1)

Anemia 0 1 (1.6) 1 (1.6) 0

Neutropenia 4 (3.3) 1 (1.6) 1 (1.6) 1 (2.1)

URI (upper respiratory infection), UTI (urinary track infection), LRI (lower respiratory infection)*Infections reported for more than 3% of patients are specified.**Hematology result based on clinical laboratory result by central lab.

Pharmacodynamic Profiles were Comparable between All Treatment Groups14

Truxima® was Well-Tolerated When Administered for up to 72 Weeks or after Switching from RTX14

Immunogenicity

No remarkable changes in immunogenicity profile were observed following the drug switch. Two patients (1 patient each in the US-RTX maintenance group and US-RTX/Truxima® switch group) had anti-drug antibody newly developed during the extension period.14

Truxima®/ Truxima®

US-RTX/US-RTX

US-RTX/Truxima®

EU-RTX

EU-RTX/Truxima®

1) pre-dose, 2) End of infusion (EOI), 3) 1hr EOI, 4) 24 hr after Start of infusion

Infusion

Week 0 7264565048403226241612842

Lower Limit of Normal(110 cells/μL)

1)2)3)4) 1)2)3) 1)2)3)

Med

ian β-

cell

coun

ts (

Cel

ls/μ

L)

180

0

80

20

100

40

120

60

140

160

Safety

The majority of adverse events (AEs), including infusion related reactions (IRR) were grade 1 or 2 in intensity. There were no cases of hypersensitivity leading to study drug discontinuation in the switch groups. No progressive multifocal leukoencephalopathy or malignancy was reported during the extension period.14

Truxima® C

linical Evid

ence in RA

1011