Update on Biosimilars

Transcription

1 Update on Biosimilars From Fiction to Formulary Natalie Nguyen, Pharm.D. PGY1 Pharmacy Administration Resident Virginia Commonwealth University Health System

2 Disclosures I have no disclosures or conflicts of interest.

3 Objectives 1. Compare and contrast key characteristics of biological agents with traditional smallmoleculechemicalagents. 2. Summarize the development of the current federal regulatory landscape of approving biosimilars. 3. Examine the efficacy and safety data of biosimilars approved in other countries. 4. Recognize key developments on biosimilars and their impact on pharmacy. 5. Determine formulary selection considerations when adding biosimilars into a hospital formulary system.

4 Characteristics Small molecules Biologics Size Structure Well defined, small molecules ~100s Daltons Simple structures Chemically identical to the reference product Immunogenicity Generally inert Manufacturing Organic medicinal chemical synthesis Can easily replicate the manufacture of the reference product can Stability Stable and predictable Route of Administration A Comparison of Small Molecules and Biologics Large, complex, protein/glycoprotein molecules >10,000 Daltons Primary, secondary, tertiary, quaternary Posttranslational modifications Potentially immunogenic Immunogenicity may not be exactly replicated Complex Produced in living systems Manufacturing process of the reference biologic product is typically proprietary and cannot be exactly replicated May be sensitive to physical conditions (E.g., storage conditions, ph, temperature, agitation) Can be administered orally Mostly injected or inhaled Hosp Pharm. 2014;49(Suppl 1):S1 S5. P & T. 2013;38(May):

5 Projected Year of U.S. Patient Expiration for Major Biologicals Product Brand Name(s) Year Filgrastim Neupogen 2013 Epoetin alfa Epogen, Procrit 2014 Pegfilgrastim Neulasta 2015 Palivizumab Synagis 2015 Rituximab Rituxan 2016 Cetuximab Erbitux 2016 Adalimumab Humira 2016 Infliximab Remicade 2018 Trastuzumab Herceptin 2019 Bevacizumab Avastin 2019 Darbepoetin Aranesp 2024 Etanercept Enbrel 2028 Biologics market projected to grow >80% : $138 billion in 2010 to $253 billion by 2020 Biosimilars are projected to be 20 to 30% cheaper than biologics Am J Health Syst Pharm. 2013;70: Worldwide market for biosimilars at its tipping point. Medcity news. Sept 2014.

6 Definitions Term Governing Body Definition Similar biotherapeutic product Biosimilar medicine = biosimilar Biosimilar World Health Administration European Medicines Agency US Food and Drug Administration A biotherapeutic product similar to an already licensed reference biotherapeutic product in terms of quality, safety, and efficacy. A product similar to an existing biological medicine, and the variability and any differences with its reference biological medicine will have been shown not to affect safety or effectiveness. A product highly similar to the reference product without clinically meaningful differences in safety, purity and potency. Pharmaceuiticals. 2012;5: What you Need to Know about Biosimilar Medicinal Products. European Commission

7 European Pathway to Biosimilars Similar biological medicinal products category established No. of biosimilar applications with EMA at all time high (8) Infliximab biosimilar (Inflectra) approved in EU Insulin glargine biosimilar from Eli Lilly and Boehringer Ingelheim under review by EMA Biosimilar G CSF (Zarzio ) prescribed more than originator Follitropin alfa biosimilar approved in EU g fig 1/ eng GB/GW 1856G Fig 1_reference.jpg

8 European Medicines Agency (EMA) 2001 Ad hoc working group for comparing medicinal products containing biotechnologyderived proteins as active substances 2003 Established new category of applications for similar biological medicinal products General guideline for biosimilars introduced: Guideline on Similar Biological Medicinal Products Guideline revised: aim of biosimilarity to establish similarity to the reference product, not clinical benefit Pharmaceuticals. 2012;5:

9 Similar Biological Medicinal Products insulins somatropin granulocyte colonystimulating factors (G CSFs) erythropoeitcstimulating agents(esas) interferons low molecular weight heparins follitropins CAVEAT: similar biological medicinal product includes a broad spectrum of products biotechnology derived therapeutic proteins, vaccines, blood derived products, monoclonal antibodies, gen and cell therapy, etc Pharmaceuticals. 2012;5: Biosimilar medicinal products. European Medicines Agency

10 Clinical Efficacy and Tolerability for EMA approved Applications of Biosimilars Generic Epoetin Filgrastim Reference Brand Epoetin alfa (Eprex, Epogel, Procrit, Erypo ) Neupogen Biosimilar Brand Significant Biophysical Difference Significant Clinical Variation Clinical Efficacy Tolerability Pharmacology HX575 (Binocrit, Epoetin, Alfa Hexal, Abseamed ) YES NO NO NO Epoetin zeta (Retacrit, Silapo ) YES YES YES YES Nivestim NO NO NO NO Zarzio, Filgrastim Hexal NO NO NO NO XM02 (TevaGrastim, Biograstim, Filgrastim Ratiopharm, Ratiograstim ) NO NO NO NO Clin Ther. 2012;34:

11 Epoetin α (Eprex ) From 1998 to 2003: incidence of Ab mediated pure red cell aplasia (PRCA) in CKD patients with anemia being treated with Eprex (Johnson & Johnson) Nephrol Dial Transplant. 2005;20(6):vi3 vi9.

12 Epoetin α (Eprex ) Cumulative PRCA cases from 1997 to 2002 Replaced the human serum albumin as a stabilizer with glycine and polysorbate 80 Made the subcutaneous route a contraindication Nephrol Dial Transplant. 2005;20(6):vi3 vi9.

13 Immunogenicity Posttranslational modification Higher order structure Aggregation Route of administration Stabilization agents Genetic background of patients Frequency and duration of administration Nephrol Dial Transplant. 2005;20(6):vi3 vi9.

14 Indication extrapolation European Medicines Agency Based on overall evidence of comparability Must achieve quality, non clinical and clinical comparability must be achieved o Offering pivotal evidence demonstrating comparability based on pharmacodynamics and supportive relevant data to support extrapolation to all claimed clinical indications o Antigen receptor(s) o Mechanism(s) of action Food and Drug Administration Meets 351(k) requirements and offers sufficient justification for extrapolating data Target/receptor(s) Binding, dose/concentration response and pattern of molecular signaling upon engagement of target/receptors Relationship product structure and target/receptor interactions Location and expression of target/receptors Pharmacokinetics and bio distribution of the product in different patient populations European Medicines Agency. Consensus Information Paper. What you need to know about Biosimilar Medicinal Products Guidance for Industry on Biosimilars: Q&As Regarding Implementation of the BPCI Act of 2009: Questions and Answers Part I. Food and Drug Administration

15 Zarzio Experience in Europe Study Design Objective Study Population Outcomes Results Conclusion Pooled analysis of five post approval observational studies of biosimilar G CSF (Zarzio ) Assess real world clinical practice setting of Zarzio use N=1,301 patients Cancer types: Breast (42%), Lung (16%), Lymphoma/leukemia (15%) Febrile neutropenia risk: >20% risk (36%), 10 20% risk (40%) Prophylaxis: primary (57%), secondary (27%) Occurrence of severe and febrile neutropenia while receiving Zarzio prophylaxis 2.2% patients experienced febrile neutropenia episode 8.5% patients experienced severe (ANC <500/μL) neutropenia Occurrence of severe or febrile neutropenia in this analysis was within the range of that observed in previous studies of originator G CSF product. Zarzio appears to be effective for the prevention of chemotherapy induced neutropenia in clinical practice. Support Care Cancer. 2013;21:

16 Zarzio Experience in Europe Safety Estimated exposure to Zarzio is ~4.5 million patient days One study reported 8% bone pain (similar occurrence with originator product) Immunological response No neutralizing antibodies detected in Zarzio clinical trials No reports cited during the ongoing pharmacovigilance of Zarzio in clinical use Cost Savings London region of United Kingdom: est. 1 million Pounds from 2011 to 2010 Southern Health Care region of Sweden: net savings of 2 million Krona Support Care Cancer. 2013;21:

17 Biosimilars Pathway in the US Federal Food, Drug, and Cosmetic Act (FFDCA) Oversight includes small molecule drugs, biologics (E.g., hormones), and medical devices Hatch Waxman Amendments to the FFDCA Established the Abbreviated New Drug Application (ANDA) process; pathway for approving generic small molecule drugs Public Health Service Act (PHS) Consolidated legislations relating to public health services Are Biosimilars the Same as Generics? NABP 109 th Annual Meeting

18 Tbo filgrastim (Granix ) Injection 2009 TEVA filed for Biologics License Application 2012 FDA approved Granix for only 1 of 5 Neupogen indications 2013 Patient infringement suit: TEVA cannot market its product before Nov 2013 How to manage similar follow on biologicals? Am J Health Syst Pharm. 2013;70:

19 Comparative Property of Originator Filgrastim and Tbo filgrastim Property Amgen G CSF Teva G CSF Brand Name Neupogen Granix Generic Name Filgrastim Tbo filgrastim Application type BLA BLA Indications 1. Cancer patients receiving myelosupressive chemotherapy 2. Patients with AML receiving induction/ consolidation chemotherapy 3. Cancer patients receiving bone marrow transplant 4. Patients undergoing peripheral blood progenitor cell collection and therapy 5. Patients with severe chronic neutropenia 1. Cancer patients receiving myelosuppressive chemotherapy Recombinant DNA structure r methug CSF r methug CSF Molecular Weight 18,800 daltons 18,800 daltons Protein length 175 amino acids 175 amino acids Expression system E. coli E. coli Dosages 300 mcg, 480 mcg 300 mcg, 480 mcg Storage forms Vial and syringe (both PF) Syringe (PF) Storage conditions 2 to 8 C 2 to 8 C Biosimilars: Balancing the Promise with the Realities of Practice. Novation Tbo filgrastim package insert. Teva Pharmaceuticals USA; Neupogen (filgrastim) package insert. Amgen; 2012.

20 Biosimilars Pathway in the US Biologics Price Competition and Innovation Act (BPCI Act) Passed as part of the Patient Protection and Affordable Care Act (PPACA) to modify the PHSA Established an abbreviated licensure pathway for biological products shown to be biosimilar to or interchangeable with an FDA licensed reference product Food and Drug Administration Safety and Innovation Act (FDASIA) Provides user fees to FDA (prescription drugs, medical devices, generic drugs, and biosimilars) and determine timelines for review Are Biosimilars the Same as Generics? NABP 109 th Annual Meeting

21 Biosimilars Approval Pathway Biologics License Application (BLA) Biologics 351(a) Biosimilars 351(k) Demonstrated safety and efficacy No clinically meaningful differences on safety and efficacy Interchangeability Expected to produce the same clinical result as the reference product in any given patient, AND would not impact safety and efficacy when used more than once (alternating or switching with or from the reference biologic product) Are Biosimilars the Same as Generics? NABP 109 th Annual Meeting

22 The Evidence in Totality Clinical Animal Studies Clinical Immunogenicity Clinical Knowledge Human PK and PD Structural and Functional Characterization Biosimilar Guidance Webinar. FDA CDER

23 Draft Guidance from the FDA

24 Filgrastim sndz (Zarxio ) FDA Approved: March 6, st biosimilar FDA approved under the 351(k) pathway Sandoz s highly biosimilar product to Amgen s filgrastim (Neupogen ) Indications: approved for the same indications as Neupogen [1] Chemotherapy induced febrile neutropenia, [2] acute myeloid leukemia, [3] cancer patients receiving bone marrow transplant, [4] peripheral blood progenitor cell collection and engraftment, [5] severe chronic neutropenia Available dosage form: prefilled syringes Administration route: intravenous or subcutaneous Labeling has dilution instructions for intravenous use FDA Oncologic Drugs Advisory Committee Meeting

25 Zarxio s Totality of Evidence Capitalized on indication extrapolation allowed by 351(k) o US approved version Neupogen data o EU approved version of Neupogen data Sandoz conducted two new clinical studies o Phase I pharmacokinetics / pharmacodynamics study in healthy volunteers o Phase III trial comparing efficacy of EP2006 to US approved version of Neupogen in breast cancer patients Clinical Animal Studies Clinical Immunogenicity Clinical Knowledge Human PK and PD Structural and Functional Characterization FDA Oncologic Drugs Advisory Committee Meeting

26 Phase I: Study 109 Design Study Population Cross over study Health Volunteers Intervention Outcomes Primary: Pharmacokinetic and pharmacodynamic (ANC count) equivalence Secondary: CD34 + cell count, safety, immunogenicity, and local tolerance (Bioequivalence margins of %) Presentation to the Oncologic Drugs Advisory Committee. Sandoz

27 PK Equivalence Zarxio demonstrates pharmacokinetic equivalence with respect to FDA equivalence margins Presentation to the Oncologic Drugs Advisory Committee. Sandoz

28 PD Equivalence Zarxio demonstrates pharmacodynamic equivalence with respect to FDA equivalence margins Presentation to the Oncologic Drugs Advisory Committee. Sandoz

29 PD equivalence: Multiple Dose Studies Presentation to the Oncologic Drugs Advisory Committee. Sandoz

30 Phase III: Study 302 Design Non inferiority study Study Population 138 breast cancer patients receiving myelosuppressive chemotherapy Treatment regimen (TAC chemotherapy) in each cycle Intervention Outcomes Primary efficacy: non inferiority in the mean duration of severe neutropenia (DSN) Safety: incidence, occurrence, and severity of adverse events, local tolerability of injection site, and systemic tolerance Special interest: immunogenicity (anti rhg CSF antibody formation) Presentation to the Oncologic Drugs Advisory Committee. Sandoz

31 Primary Efficacy: Duration of Severe Neutropenia Non inferiority is established between Zarxio and Neupogen Presentation to the Oncologic Drugs Advisory Committee. Sandoz

32 Safety: Adverse Drug Effects Presentation to the Oncologic Drugs Advisory Committee. Sandoz

33 Immunogenicity RIP: radioimmunoprecipitation assay to assess binding antibodies NAB: assesses neutralizing antibodies Presentation to the Oncologic Drugs Advisory Committee. Sandoz

34 Biosimilarity of filgrastim sndz (Zarxio ) Reference Product Analytical Data Animal Studies Clinical Studies Mechanism of Action Conditions of Use Route of Administration, Dosage form, and Strength US licensed Neupogen Physicochemical and functional similarity PD, toxicity, toxicokinetics, and local tolerance was confirmed in 5 animal studies Relevant data collection in 174 healthy volunteers, 388 breast cancer patients, 121 health stem cell donors No qualitative differences in the MOA in neutropenia of different origins Same indications as Neupogen Same route of administration, dosage form, and strength as Neupogen The Pink Sheet. 2015; #

35 Litigation Patent Infringement? Sandoz v. Amgen Biosimilar applicant shall provide to the reference product sponsor a copy of its biologics license and manufacturing information within 20 days of FDA s acceptance of the application for review 03/19/15: Northern District of California denied Amgen s request for a preliminary injunction to block Sandoz s launch of filgrastim sndz (Zarxio ) The Pink Sheet. 2015; #

36 Biosimilar Naming Rules World Health Organization (WHO) Proposes a compromise of using the current system for choosing International Nonproprietary Names (INNs) with adding on a four letter code at the end of the drug name European Medicines Agency (EMA) Biosimilars carry the same nonproprietary name as the reference product Food and Drug Administration (FDA) Placeholder nonproprietary name until guidance is issued Add four letters to the end of the biosimilar nonproprietary name United States Pharmacopeia (USP?) Does Zarxio meet the criteria for the filgrastim monograph? The Pink Sheet. 2015; # INN Working doc. WHO. 2014;

37 Interchangeability Dosage form presentation differences? E.g., filgrastim sndz s (Zarxio ) needle guard spring mechanism and unmeasurable doses less than 0.3 ml (+) decreases chances of needle sticks ( ) excludes certain populations such as pediatrics FDA s Purple Book The Pink Sheet. 2015; # a0ae 41b5 a744 28c41889fce8

38 FDA s Purple Book Lists biosimilar and interchangeable biological products Date of licensing a biological product under 351(a) of PHS Act 351(k)(7): Product exclusivity, biosimilar status or interchangeability status Degree of Similarity? Not similar Similar Highly similar Highly similar with a fingerprint like similarity

39 State Laws Notification Requirements Generic Pharmaceutical Association Notify the prescriber when a biologic product is substituted for a biosimilar product 8 states have enacted statutes so far, 23 have states have considered legislation Other issues: Interoperability between pharmacy records and medical records? Communicating through EHRs? State Laws and Legislation Related to Biologic Medications and Substitution of Biosimilars. National Conference of State Legislatures. 2014

40 Biosimilar Substitution by Pharmacies Virginia H1422; Ch.412, signed 3/16/2013 Sponsor: Rep. O Bannon S.1285; Ch.544, signed 3/18/2013. Sponsor: Rep. Newman Relates to dispensing of interchangeable biosimilar biological products; permits pharmacists to dispense a biosimilar that has been licensed by the FDA as interchangeable with a prescribed biological product unless the prescriber indicates such substitution is not authorized or the patient insists on dispensing of the prescribed biological product. The pharmacist or his designee must inform the patient prior to dispensing the interchangeable biosimilar and must disclose the retail cost. The notification provisions sunset July 1, 2015 FDA must certify interchangeability Prescriber notification Patient notification Prescriber s Brand medically necessary blocks substitution Pharmacy records must be retained Posted list for interchangeable YES YES 5 days YES Prior YES (prescriber or patient) YES 2 years N/A State Laws and Legislation Related to Biologic Medications and Substitution of Biosimilars. National Conference of State Legislatures. 2014

41 Specialty Pharmacy Using pharmacy benefit type management tools effectively help promote use of biosimilars? Express Scripts Increasing the benefit from biosimilar competition (and costs) Move coverage of Amgen s Neupogen from the medical benefit to the specialty pharmacy benefit (Medical Channel Management (MCM program)) Neupogen (WAC) $ per 300 mcg/ 1 ml syringe Zarxio $???? predicted to be 20% 30% below the brand The Pink Sheet. 2015; #

42 CMS Reimbursement Medicaid The most single source drugs are subject to the 23.1% minimum drug rebate (equivalent to 13% of AMP) applicable to brands as a condition of Medicaid participation Includes covered outpatient drugs licensed under a biologics license application, and also biosimilar biological products Medicare Part B Reimburse biosimilar using the average sales price (ASP) formula Payment will initially be 106% of WAC, and then 100% of the biosimilar s ASP + 6% of reference biologic s ASP Part D Biosimilars will not be considered to be different from the reference biologic Clarifies biosimilars role for the purposes of meeting the two distinct drugs requirement for each of the categories and classes by a Part D sponsor Coverage Gap Cost Sharing: Biosimilars will not be discounted in the coverage gap or subject to Discount Program requirements The Pink Sheet. 2015; # The Pink Sheet. 2015; #

43 Formulary Analysis for P&T Committee Drug Monograph should include: Approval history of biosimilar Labeled and off label indications Brand and nonproprietary names Clinical safety and efficacy information Therapeutic interchange Existing level of adverse events with the originator product Dosage forms Use in special patient populations Economic aspects Pharmacovigilance Am J Health Syst Pharm. 2013;70:

44 Other Considerations Provider drug information references Prescription Insurance Coverage Overcoming prescriber skepticism Transitions of Care Patient educational materials Indication extrapolation

45 Order and Inventory Systems Differentiating biosimilar and reference product in CPOE, EHRs, MAR, order sets, and protocols Purchasers have appropriate information to purchase biosimilars (E.g., correct NDCs) Par levels for biosimilar and reference product Financial systems: base price, contract price, reimbursement for biosimilar vs. originator product Financial impact from the health system and patient perspectives Availability of patient assistance programs Am J Health Syst Pharm. 2013;70:

46 Conclusion The historical use of biosimilars in Europe have demonstrated substantial cost savings, in addition to established evidence in safety and efficacy. The foundation for the totality of evidence in approving of biosimilars may be established through confirmed PK and PD equivalence studies and indication extrapolation; this will continue to evolve with each new class of biosimilar agents approved. Pharmacists should be proactive in serving as resources of information for providers and patients on the safe use of biosimilars.

47 Questions?

48 Learning Assessment Question 1 What medication would meet the criteria for the BLA 351(k) pathway for biosimilar approval? a. Edoxaban b. Sofosbuvir c. Infliximab d. Chlorpheniramine

49 Learning Assessment Question 2 What is a correct statement involving filgrastim sndz s (Zarxio ) totality of evidence that helped to meet the requirements for biosimilar approval in the United States? a. The reference product was EU approved Neupogen b. Different route of administration, same dosage form, and strength of Neupogen c. No qualitative difference in the MOA in neutropenia of different origins d. Physicochemical and functional variance

50 Learning Assessment Question 3 TRUE or FALSE? In Virginia, a pharmacist or his designee must inform the patient prior to dispensing the interchangeable biosimilar and must disclose the retail cost.