New Drug Updates: Biosimilars

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1 Objectives New Drug Updates: Biosimilars Christopher Allen, PharmD, BCOP Supervising Pharmacist, Infusion Therapy UAB Hospital September 30, 2016 Describe current information concerning approval of biosimilar projects List currently available biosimilar products Examine factors that should be considered for a biosimilar's inclusion into your institution's medication-use process Identify potential differences in available biosimilars and reference products that may affect the medication use process (technicians) Page 2 Disclosure Statement Drug Expenditures in 2015 Christopher Allen reports that he has no financial relationships with any commercial supporters or providers Products not yet approved by the Food & Drug Administration may be discussed during this presentation. In 2015, biological products represented (in terms of overall expenditures) Eight of the top 25 drugs overall (~$40 billion) 7 with + growth Nineteen of the top 25 drugs in clinics, including the top 9 (~$26.5 billion) 17 with + growth Fifteen of the top 25 drugs in nonfederal hospitals, including the top 6 (~$8.7 billion) 11 with + growth Antineoplastic agents and biologicals rank #1 and #5, respectively, by expenditures in nonfederal hospitals Projected increases of ~12%, ~16%, and ~11%, respectively Page 3 plications/therapeuticbiologicapplications/ucm htm. July 7, 2016 (accessed August 13, 2016). Schumock GT, et al. Am J Health Syst Pharm. 2016; 73(14): Page 4 How did we get to this point? Potential Growth in Biosimilars? 1984 Drug Price Competition and Patent Term Restoration Act (Hatch-Waxman Act) 2010 Biologics Price Competition and Innovation (BPCI) Act 351(k) Biosimilar application U.S. Patent Expiration Date Adalimumab (Humira ) December 2016 Etanercept (Enbrel ) 2012/2028 Infliximab (Remicade ) 2018 Pegfilgrastim (Neulasta ) Expired Interferon beta-1a (Avonex / Rebif ) Expired Rituximab (Rituxan ) September 2016 Bevacizumab (Avastin ) 2019 Epoetin alfa (Epogen / Procrit ) Expired Trastuzumab (Herceptin ) 2019 Lucio, SD, et al. Am J Health Syst Pharm. 2013; 70(15): Page 5 September 30, 2011 (accessed August 13, 2016). May 17, 2013 (accessed August 13, 2016). Page 6

2 Regulatory Definition of a Biosimilar Biosimilar Manufacturing An Impossible Copycat Process Food and Drug Administration (U.S) A biological product that is highly similar to the reference product notwithstanding minor differences in clinically inactive components and for which there are no clinically meaningful differences in terms of safety, purity and potency April Mellstedt, H, et al. Ann Oncol. 2008; 19(3): (accessed August 13, 2016). Lucio, SD, et al. Am J Health Syst Pharm. 2013; 70(15): (accessed August 13, 2016). Page 7 June 2005 (accessed August 25, 2016). Page 8 FDA Guidelines for Demonstrating Biosimilarity A Stepwise Approach Totality of the Evidence What s the Difference? Comparative process, not a demonstration of therapeutic equivalence! Structure Function Animal Toxicity Human Pharmacokinetics / Pharmacodynamics Clinical Immunogenicity Clinical Safety and Effectiveness The FDA reserves the right to determine if more data is needed (or less in some cases!) Totality-of-the-evidence approach 8.pdf. April 2015 (accessed August 13, 2016). Page 9 Accessed August 30, Page 10 FDA Biosimilar Specifications Naming of a Biosimilar Biosimilar Product Specification Formulation Delivery device/container Routes of administration Indications Strength Comparison with Reference Product May be different May be different May obtain licensure for fewer than all routes of administration for which reference product is licensed May obtain licensure for fewer than all indications for which reference product is licensed Must be the same WHO & FDA Biosimilar identified by international nonproprietary name (INN) + four letter suffix EMA Biosimilar & reference product share INN JMCP 2016 Pharmacists prefer INN + suffix for biosimilars, but would be more confident in substituting interchangeable products if INN shared 1.pdf. April 2015 (accessed August 13, 2016). Page 11 August 2015 (accessed August 25, 2016). October 2015 (accessed August 25, 2016) February 28, 2014 (accessed August 25, 2016). Tomaszewski D. J Manag Care Spec Pharm. 2016: 22(8): Page 12

3 Audience Response Question #1 Which of the following details MUST be identical when comparing a biosimilar product to its reference product? a. Labeled indications b. Routes of administration c. Strength d. Formulation THE CURRENT BIOSIMILAR PRODUCT LANDSCAPE Page 13 Page 14 Filgrastim-sndz (Zarxio ) Filgrastim-sndz (Zarxio ) Approval Data FDA approval: March 6, 2015 Key differences: Approved for 5 of the 6 indications that Neupogen carries Not labeled to increase survival in patients acutely exposed to myelosuppressive doses of radiation Available only as prefilled syringes Supported by evaluations of analytical similarity and animal studies of pharmacodynamics and toxicity Preclinical study - Sörgel F, et al. Compared biosimilar filgrastim, U.S. reference product, and E.U. reference product Protein structure and bioactivity highly similar Pharmacokinetic and pharmacodynamics parameters bioequivalent No observed differences in safety or immunogencity Filgrastim-sndz (Zarxio ) [package insert]. Princeton, NJ: Sandoz, Inc.; March 6, 2015 Filgrastim (Neupogen ) [package insert]. Thousand Oaks, CA: Amgen, Inc.; (accessed August 13, 2016). March 6, 2015 Sörgel, F, et al. BioDrugs. 2015; 29(2): (accessed August 13, 2016). Page 15 Page 16 Filgrastim-sndz (Zarxio ) Approval Data Filgrastim Biosimilars The European Experience Clinical study Blackwell K, et al. Conducted in 218 women with breast cancer receiving TAC x 6 cycles (docetaxel, doxorubicin, cyclophosphamide) Randomized 1:1:1:1 Biosimilar, Reference, Biosimilar-Reference or Reference- Biosimilar (alternating with each cycle) Hospitalization due to febrile neutropenia, incidence of infections, depth of/time to ANC nadir, and time to ANC recover equivalent; higher number of patients with FN with biosimilar (but within expected variability) No observed differences in safety profile Currently, there are 8 branded biosimilar filgrastim products approved for use in the European Union 2010 EORTC Guidelines for the Use of G-CSF Filgrastim biosimilars are an acceptable treatment option (Grade A recommendation) Recommends that clinicians identify products by brand name to ensure there are no changes in treatment without informing the physician and patient Pooled data from 5 post-approval studies of Zarxio Among 1,302 patient, rates of febrile neutropenia (2.2%) and severe neutropenia (8.5%) were comparable to previous studies of reference filgrastim Blackwell, K, et al. Ann Oncol. 2015; 26(9): Page 17 Aapro, MS, et al. Eur J Cancer. 2011; 47(1): Gasćon, P, et al. Support Care Cancer. 2013; 21(10): Page 18

4 Infliximab-dyyb (Inflectra ) Approval Data FDA approval: April 5, 2016 Key differences: Approved for 7 of the 8 indications that Remicade carries Not labeled for pediatric ulcerative colitis due to orphan drug exclusivity Initial application (2014) rejected due to residual uncertainty regarding differences in bioactivity and immunogenicity, which were addressed in the follow-up application Supported by evaluations of analytical similarity and animal studies of pharmacodynamics and toxicity Preclinical study Park W, et al. Compared biosimilar infliximab, U.S. reference product, and E.U. reference product Pharmacokinetic parameters bioequivalent No observed differences in safety Additional PK/PD data reported as highly similar in larger clinical studies comparing biosimilar infliximab to the E.U. reference product; safety profiles and immunogenicity were comparable April 5, 2016 (accessed August 13, 2016). Page 19 April 5, 2016 (accessed August 13, 2016). Park, W, et al. Expert Rev Clin Immunol. 2015; 11(S1): S Park, W, et al. Ann Rheum Dis. 2013; 72:10: Yoo, DH, et al. Ann Rheum Dis. 2013; 72(10): Page 20 Approval Data Rheumatoid Arthritis Approval Data Ankylosing Spondylitis Clinical study Yoo DH, et al. Conducted in 606 patients with active rheumatoid arthritis despite methotrexate therapy Randomized 1:1 Biosimilar infliximab or E.U. reference product 3 mg/kg at weeks 0, 2, 6, and then every 8 weeks ACR20 responses at week 30, secondary endpoints - comparable Results at 54 weeks, and at 2 years (after switching to biosimilar) - comparable Clinical study Park W, et al. Conducted in 250 patients with active ankylosing spondylitis Randomized 1:1 Biosimilar infliximab or E.U. reference product 5 mg/kg at weeks 0, 2, 6, and then every 8 weeks Primary endpoint was PK evaluation ASAS20/ASAS40 responses at week 30, other secondary endpoints comparable Results at 54 weeks - comparable Yoo, DH, et al. Ann Rheum Dis. 2013; 72(10): Yoo, DH, et al. Arthritis Res Ther. 2016; 18: 82. Yoo, DH, et al. Ann Rheum Dis Apr 29 [Epub ahead of print]. Page 21 Park, W, et al. Ann Rheum Dis. 2013; 72:10: Park, W, et al. Arthritis Res Ther. 2016; 18: 25. Page 22 Barriers to Market Availability? Biosimilars Walking a Fine Line? August 1, 2016 (accessed August 14, 2016). August 5, 2016 (accessed August 25, 2016). Traynor, K. Am J Health Syst Pharm. 2016; 73(10): 604, October 28, 2015 (accessed August 14, 2016). April 7, 2016 (accessed August 14, 2016). July 13, 2016 (accessed August 25, 2016). April 12, 2016 (accessed August 14, 2016) August 17, July 29, 2016 (accessed Augsut 30, 2016). Page 23 (accessed August 25, 2016). Page 24

5 What s in the Pipeline? What s in the Pipeline? Reference Product Adalimumab (Humira ) Bevacizumab (Avastin ) Cetuximab (Erbitux ) Epoetin alfa (Procrit, Epogen ) Infliximab (Remicade ) Rituximab (Rituxan ) Trastuzumab (Herceptin ) Biosimilar Developer Sandoz/Novartis, Amgen, Pfizer, Biogen, Samsung Bioepis/Merck Amgen, Pfizer, Samsung Bioepis/Merck Amgen Sandoz/Novartis Sandoz/Novartis, Amgen, Samsung Bioepis/Merck Sandoz/Novartis, Amgen, Pfizer Amgen, Pfizer, Samsung Bioepis/Merck Others in development Tocilizumab, golimumab, abatacept What about biosimilar insulins? insulin glargine (Basaglar ), MK Accessed August 25, April 1, 2016 (accessed August 25, 2016). Accessed August 25, Accessed August 25, April 17, 2015 (accessed August 25, 2016). Biosimilar_Brief_March_2016.pdf. March 2016 (accessed August 25, 2016). April 19, 2016 (accessed August 25, 2016). Page 25 Page 26 What to Consider When Reviewing Biosimilars for Formulary Inclusion Safety & Efficacy Manufacturer Considerations Hospital & Patient Factors KEY CONSIDERATIONS IN BIOSIMILAR REVIEW Product characteristics Clinical data Immunogenicity Pharmacovigilance for safety concerns Medication availability History of shortages or recalls Handling practices Supply chain security Anti-counterfeit protection Packaging and labeling Product storage Product administration Interchangeability Variety (extrapolation) of indications Product naming Information technology support Economic considerations Patient education Page 27 Page 28 Safety & Efficiacy Manufacturer Considerations Key Questions Key Questions Does the clinical data (pre-approval, post-approval, international) available support the indications for which the biosimilar has been approved and is being considered for formulary inclusion? What about use of the biosimilar in offlabel indications? How will your health system address pharmacovigilance concerns regarding potential differences in immunogenicity and other adverse effects? Will the manufacturer be able to maintain a reliable supply and adequate production of the biosimilar to meet demand for its anticipated usage? Does the manufacturer have a recent history of shortages or recalls that would decrease your health system s confidence in the biosimilar s availability? Page 29 Page 30

6 Hospital & Patient Factors Interchangeability Key Questions Are there any differences in packaging, shelf life, storage requirements or routes of administration between the biosimilar and reference product? How should interchangeability of the biosimilar be addressed? Will the biosimilar being reviewed be included on formulary for all indications for which the reference product is approved, if different? How will the naming of the biosimilar affect adverse event reporting/tracking and its inclusion in your health system s IT systems? What cost factors, besides acquisition cost, should be considered? The biological product is biosimilar to the reference product, can be expected to produce the same clinical result as the reference product in any given patient, and the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch. Impact of state substitution laws? Page 31 (accessed August 13, 2016). August 1, 2016 (accessed 2016 Aug 14). Page 32 Interchangeability Interchangeability The Shift is On CVS Health s 2017 formulary management strategy Filgrastim-sndz (Zarxio ) replacing filgrastim (Neupogen ) Insulin glargine (Basaglar ) replacing insulin glargine (Lantus ) Chingcuanco F, et al. Systematic review of clinical data for biosimilar and reference TNF- inhibitors Biosimilarity supported by pharmacokinetic and adverse effect variable as well as major clinical efficacy endpoints Despite the paucity of studies, the existing evidence supports the biosimilarity and interchangeability of these newly developed TNF- inhibitor products, especially for the treatment of patients with RA. August 1, 2016 (accessed 2016 Aug 14). Page 33 August 3, 2016 (accessed August 29, 2016). Accessed August 29, 2016 Chingcuanco, F, et al. Ann Intern Med. August 2, 2016 [Epub ahead of print]. Page 34 Resources for Pharmacists Audience Response Question #2 FDA s Purple Book FDA Website Information on Biosimilars ASHP Resource Center on Biosimilars Partnership between 8 pharmacy-related associations Filgrastim-sndz (Zarxio ) is considered interchangeable by the Food & Drug Administration. a. True b. False ogicapplications/biosimilars/ucm htm. July 19, 2016 (accessed August 14, 2016). cbiologicapplications/biosimilars/default.htm. May 10, 2016 (accessed August 14, 2016). Accessed August 14, Accessed August 29, Page 35 Page 36

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