Biosimilars-ZARXIO

The role of biosimilars

What are biosimilars?

Biosimilars are biologic medicines that are highly similar to their reference biologic, as they have demonstrated no clinically meaningful differences in safety, purity, and potency compared to that of the reference biologic.¹

Because biologics are larger, more complex, and of higher molecular weight than small-molecule medicines, biosimilars are subject to a step-wise, multifaceted regulatory approval pathway.¹

Biosimilars are not generics²

In order to prove biosimilarity and gain FDA approval, biosimilar data must include analytical studies, pre-clinical testing, and clinical trials, which typically include a comparative design study or studies which are sufficient to demonstrate safety, purity, and potency.¹

Molecules increase in size from small chemical molecules to biosimilars

Biosimilarity based on a Totality of Evidence¹

The FDA established an approval pathway for sponsors of a biologic product seeking approval as a biosimilar to a reference product based on a totality of evidence.

To gain approval, a biosimilar must be comparable to the reference biologic in terms of structure, function, animal toxicity, human pharmacokinetics (PK) and pharmacodynamics (PD), immunogenicity, clinical safety, and efficacy¹

Biosimilar development goal: Demonstrate biosimilarity to reference biologic^1,8

Totality of evidence chart

*The nature and scope of the clinical study or studies will depend on the nature and extent of residual uncertainty about biosimilarity after conducting structural and functional characterization and, where relevant, animal studies.

Please visit Sandoz-biosimilars.com to learn more about Sandoz leadership in the newly emerging market of biosimilars

Sandoz: the biosimilar pathway pioneer

The efforts of Sandoz led to the development of the first biosimilar to receive FDA approval. Sandoz selected comprehensive methods to fully characterize and evaluate ZARXIO in order to meet all FDA requirements.⁹

Biosimilar requirements

*The use of EU-approved NEUPOGEN^® as comparator for the non-clinical development of ZARXIO is considered justified by the high level of similarity between EU-approved and US-licensed NEUPOGEN^®.¹⁴

References: 1. US Department of Health and Human Services. Scientific considerations in demonstrating biosimilarity to a reference product. Washington, DC: US Dept of Health and Human Services; April 2015. 2. US Food and Drug Administration. Information for consumers (biosimilars). http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDeveloped andApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm241718.htm. Accessed May 3, 2017. 3. Revers L, Furczon E. An introduction to biologics and biosimilars. Part I: Biologics: what are they and where do they come from? Canadian Pharmacists Journal/Revue des Pharmaciens du Canada. 2010;143(3):134-139. 4. Declerck PJ. Biologicals and biosimilars: a review of the science and its implications. GaBI Journal. 2012;1(1):13-16. 5. US Food and Drug Administration. Frequently asked questions about therapeutic biological products. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDeveloped andApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm113522.htm. Accessed May 3, 2017. 6. Cortés J, Curigliano G, Diéras V. Expert perspectives on biosimilar monoclonal antibodies in breast cancer. Breast Cancer Res Treat. 2014;144(2):233-239. 7. Brinks V. Immunogenicity of biosimilar monoclonal antibodies. GaBl Journal. 2013;2(4):188-193. 8. McCamish M, Woollett G. The state of the art in the development of biosimilars. Clin Pharmacol Ther. 2012;91:405-417. 9. FDA approves first biosimilar product Zarxio [press release]. US Food and Drug Administration; March 6, 2015. http://www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/ucm436648.htm. Accessed May 3, 2017. 10. Data on file. Sandoz Inc. Princeton, NJ. 11. Blackwell K, Semiglazov V, Krasnozhon D, et al. Comparison of EP2006, a filgrastim biosimilar, to the reference: a phase III, randomized, double-blind clinical study in the prevention of severe neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy. Ann Oncol. 2015;26(9):1948-1953. http://annonc.oxfordjournals.org/content/26/9/1948.full.pdf. Accessed May 3, 2017. 12. ZARXIO Prescribing Information. Sandoz Inc. August 2019. 13. NEUPOGEN^® Prescribing Information. Amgen Inc. June 2018. 14. US Food and Drug Administration. Slides for the January 7, 2015 Meeting of the Oncologic Drugs Advisory Committee. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM431118.pdf. Published January 7, 2015. Accessed May 3, 2017.

ZARXIO is a registered trademark of Novartis AG.
NEUPOGEN is a registered trademark of Amgen Inc.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

ZARXIO is contraindicated in patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors such as filgrastim or pegfilgrastim products.

WARNINGS AND PRECAUTIONS

Splenic rupture, including fatal cases, has been reported following the administration of filgrastim products. Patients who report left upper abdominal or shoulder pain should be evaluated.

Acute respiratory distress syndrome (ARDS) has been reported in patients receiving filgrastim products. Patients who develop fever and lung infiltrates or respiratory distress should be evaluated. Discontinue ZARXIO in patients with ARDS.

Serious allergic reactions, including anaphylaxis, have been reported in patients receiving filgrastim products. The majority of reported events occurred upon initial exposure. Provide symptomatic treatment for allergic reactions. Allergic reactions, including anaphylaxis, in patients receiving filgrastim products can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue ZARXIO in patients with serious allergic reactions.

Sickle cell crisis, in some cases fatal, has been reported with the use of filgrastim products in patients with sickle cell trait or sickle cell disease.

Glomerulonephritis has occurred in patients receiving filgrastim products. The diagnoses were based upon azotemia, hematuria (microscopic and macroscopic), proteinuria, and renal biopsy. Generally, events of glomerulonephritis resolved after dose reduction or discontinuation of filgrastim products. If glomerulonephritis is suspected, evaluate for cause. If causality is likely, consider dose-reduction or interruption of ZARXIO.

Alveolar hemorrhage manifesting as pulmonary infiltrates and hemoptysis requiring hospitalization have been reported in healthy donors treated with filgrastim products undergoing peripheral blood progenitor cell (PBPC) collection mobilization. Hemoptysis resolved with discontinuation of filgrastim. The use of ZARXIO for PBPC mobilization in healthy donors is not an approved indication.

Capillary leak syndrome (CLS) has been reported after G-CSF administration, including filgrastim products, and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive appropriate treatment.

Confirm the diagnosis of severe chronic neutropenia (SCN) before initiating ZARXIO therapy. Myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) have been reported to occur in the natural history of congenital neutropenia without cytokine therapy. Cytogenetic abnormalities, transformation to MDS, and AML have also been observed in patients treated with filgrastim products for SCN. Abnormal cytogenetics and MDS have been associated with the eventual development of myeloid leukemia. The effect of filgrastim products on the development of abnormal cytogenetics and the effect of continued filgrastim administration in patients with abnormal cytogenetics or MDS are unknown. If a patient with SCN develops abnormal cytogenetics or myelodysplasia‚ the risks and benefits of continuing ZARXIO should be carefully considered.

Thrombocytopenia has been reported in patients receiving filgrastim products. Monitor platelet counts.

Leukocytosis:

Patients with Cancer Receiving Myelosuppressive Chemotherapy: White blood cell counts of 100‚000/mm³ or greater were observed in approximately 2% of patients receiving filgrastim at dosages above 5 mcg/kg/day. In patients with cancer receiving ZARXIO as an adjunct to myelosuppressive chemotherapy‚ to avoid the potential risks of excessive leukocytosis‚ it is recommended that ZARXIO therapy be discontinued if the ANC surpasses 10‚000/mm³ after the chemotherapy-induced ANC nadir has occurred. Monitor CBCs at least twice weekly during therapy.
Peripheral Blood Progenitor Cell (PBPC) Collection and Therapy: During the period of administration of ZARXIO for PBPC mobilization in patients with cancer, discontinue ZARXIO if the leukocyte count rises to >100,000/mm³.

Cutaneous vasculitis has been reported in patients treated with filgrastim products. In most cases‚ the severity of cutaneous vasculitis was moderate or severe. Most of the reports involved patients with SCN receiving long-term filgrastim therapy. Hold ZARXIO therapy in patients with cutaneous vasculitis. ZARXIO may be started at a reduced dose when the symptoms resolve and the ANC has decreased.

The possibility that ZARXIO acts as a growth factor for any tumor type cannot be excluded. The safety of filgrastim products in chronic myeloid leukemia (CML) and myelodysplasia has not been established. When ZARXIO is used to mobilize PBPC‚ tumor cells may be released from the marrow and subsequently collected in the leukapheresis product. Available data is limited and inconclusive.

The safety and efficacy of ZARXIO given simultaneously with cytotoxic chemotherapy have not been established. Do not use ZARXIO in the period 24 hours before through 24 hours after the administration of cytotoxic chemotherapy. The safety and efficacy of ZARXIO have not been evaluated in patients receiving concurrent radiation therapy. Avoid the simultaneous use of ZARXIO with chemotherapy and radiation therapy.

Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone-imaging changes on nuclear imaging.

Aortitis has been reported in patients receiving filgrastim products. It may occur as early as the first week after start of therapy. Manifestations may include generalized signs and symptoms such as fever, abdominal pain, malaise, back pain, and increased inflammatory markers (e.g., c-reactive protein and white blood cell count). Consider aortitis in patients who develop these signs and symptoms without known etiology. Discontinue ZARXIO if aortitis is suspected.

ADVERSE REACTIONS

Most common adverse reactions in patients:

With nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs (≥ 5% difference in incidence compared to placebo) are thrombocytopenia, nausea, pyrexia, chest pain, pain, fatigue, back pain, arthralgia, bone pain, pain in extremity, dizziness, cough, dyspnea, rash, blood lactate dehydrogenase increased and blood alkaline phosphatase increased

With AML (≥ 2% difference in incidence) are epistaxis, back pain, pain in extremity, erythema, and rash maculo-papular

With nonmyeloid malignancies undergoing myeloablative chemotherapy followed by BMT (≥ 5% difference in incidence) are rash and hypersensitivity

Undergoing peripheral blood progenitor cell mobilization and collection (≥ 5% incidence) are bone pain, pyrexia, blood alkaline phosphatase increased and headache

With severe chronic neutropenia (SCN) (≥ 5% difference in incidence) are arthralgia, bone pain, back pain, muscle spasms, musculoskeletal pain, pain in extremity, splenomegaly, anemia, upper respiratory tract infection, urinary tract infection, epistaxis, chest pain, diarrhea, hypoesthesia, and alopecia

To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

BIOSIMILARS

The role of biosimilars

What are biosimilars?

Biosimilars are not generics2

Biosimilarity based on a Totality of Evidence1

Biosimilar development goal: Demonstrate biosimilarity to reference biologic1,8