Biosimilars: Conversion, Switching, and Educating Prescribers and Patients Philip Schwieterman PharmD, MHA Director of Oncology and Pediatric Pharmacy UK HealthCare Markey Cancer and KY Children’s Hospital Lexington, Kentucky

Background Biosimilar (351(k)(4)): “Highly similar” to reference product; approved via biosimilars pathway Approved using abbreviated data for comparability BCPIA requires manufacturer meet requirements for a biosimilar: Licensing Testing Manufacturing Safety Exclusivity Labeling Describes biosimilar vs interchangeable products Communication requirements between the two companies Others Currently 16 products approved, 7 available

Patient Conversion: Interchangeable Interchangeable (351(k)): the use of a biosimilar without impacting on safety or efficacy if it is alternated or switching between the biosimilar and the innovator compared to the use of the innovator without alternation or switching A biosimilar that can be substituted for the reference without permission from prescriber More extensive data package for comparability supporting that the interchangeable biosimilar anticipated to produce same clinical effects for all the reference product’s licensed conditions No interchangeable products available Very little conversion data available, especially for therapeutic products

Patient Conversion: Immunogenicity Concerns the propensity of the therapeutic protein product to generate immune responses to itself Consequences include neutralizing antibodies or cytokine release Scientific tools for detecting immunogenicity exist, but they are not precise Clinical consequences: Loss or diminished efficacy or safety Some rare but serious adverse reactions Changes to the structure of the protein increase variation in immunogenicity How does this vary per Lot or Batch? Variations in manufacturing must be minimized FDA. Guidance for industry: immunogenicity assessment for therapeutic protein products. August 2014.

Available on the US Market? Reference Product Manufacturer Biosimilar Available on the US Market?   Interchangeable Adalimumab (Humira®) AbbVie Adalimumab-adbm (Cyltezo®) Adalimumab-atto (AmjevitaTM) Adalimumab-adaz (Hyrimoz) No Boehringer Ingelheim Amgen Sandoz Bevacizumab (Avastin®) Genentech Bevacizumab-awwb (MvasiTM) Epoetin alfa Epoetin alpha-epbx (Retacrit) Yes Pfizer Etanercept (Enbrel®) Amben Etanercept-szzs (Erelzi®) Filgrastim (Neupogen®) Filgrastim-sndz (Zarxio®) Filgrastim-aafi (Nivestym®) Infliximab (Remicade®) Jansenn Infliximab-abda (RenflexisTM) Infliximab-dyyb (Inflectra®) Infliximab-qbtx (Ixifi®) Merck Pegfilgrastim (Neulasta and Onpro® kit) Pegfilgrastim-cbqv (Udenyca®) Pegfilgrastim-jmdb (Fulphila®) Coherus Mylan Rituximab (Rituxan®) Rituximab-abbs (Truxima®) Celltrion Trastuzumab (Herceptin®) Genentech/Roche Trastuzumab-dkst (Ogivri®) Trastuzumab—pkrb (Herzuma®) Mylan/Biocon

Educating Prescribers : Clinical Assesment of Infliximab NOR-SWITCH Primary endpoint was disease worsening during 52 week follow-up 482 patients enrolled and randomized 241 to Infliximab 241 to Biosimilar Adverse events were 10% for infliximab, 9% for biosimilar Disease worsening was 26% for infliximab, 30% for biosimilar End conclusion is that biosimilar is non-inferior to reference product Jorgensen, KK et all. Switching from originator biosimilar to CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): a 52-week, randomized, double-blind, non-inferiority trial. Lancet 2017 June 10; 389(10086):2304-2316

Educating Providers: Filgrastim Sensorgram overlay of the receptor binding affinities of biosimilar and originator filgrastim, based on a surface plasmon resonance-based interaction assay using Biacore technology. RU resonance units Sorgel F, et al. BioDrugs. 2015;29:123-131

Educating Providers: Filgrastim Pharmacokinetic analysis: geometric mean filgrastim concentration–time profiles for biosimilar and US originator filgrastim Sorgel F, et al. BioDrugs. 2015;29:123-131

Educating Prescribers : Pegfilgrastim https://www.ema.europa.eu/documents/assessment-report/udenyca-epar-public-assessment-report_.pdf. Accessed January 2019

Educating Providers: Filgrastim N = 218 pts with breast cancer receiving myelosuppressive chemotherapy Filgrastim 5 µg/kg/day administered over 6 chemotherapy cycles Conclusion: biosimilar filgrastim noninferior to originator filgrastim at improving ANC counts Blackwell K, et al. Ann Oncol.. 2015;26:1948-1953

Educating Providers: Trastuzumab Rugo HS, et al. JAMA. 2017;317:37-47.

Educating Prescribers: Insurance Payer requirements: There are several brands of long-acting granulocyte colony stimulating factors (G-CSFs) on the market, including Neulasta (pegfilgrastim), Fulphila (pegfilgrastim-jmdb), and pegfilgrastim- cbqv (Udenyca).There is a lack of reliable evidence that any one brand of long-acting G-CSF is superior to other brands for medically necessary indications. Fulphila and Udenyca are the least cost brands of long-acting G-CSF to Aetna. Consequently, because the Neulasta brand of long-acting G-CSF is more costly than the least cost brands of long-acting G-CSF, and the least cost brands of long-acting G-CSF are at least as likely to produce equivalent therapeutic results, Neulasta will be considered medically necessary only if the member has a contraindication, intolerance or ineffective response to one of the least cost brands of long-acting G-CSF, Fulphila or Udenyca http://www.aetna.com/cpb/medical/data/1_99/0055.html

Educating Prescribers : Cost Savings US Health Care system Estimated cost savings of 3% annually from now to 2026 Potential of $24-$150 billion in cost savings Mulcahy AW, Hlavka JP, Case SR. Biosimilar cost savings in the United States: initial experience and future potential. Santa Monica, CA: RAND Corporation, 2017. https://www.rand.org/pubs/perspectives/PE264.html. Accessed November 30, 2017.

Educating Patients: General What is the difference between receiving a reference product and a biosimilar product? Patients and their physicians can expect that there will be no clinically meaningful differences between taking a reference product and a biosimilar when these products are used as intended. All reference products and biosimilar products meet FDA’s rigorous standards for approval for the indications (medical conditions) described in product labeling. Once a biosimilar has been approved by FDA, patients and health care providers can be assured of the safety and effectiveness of the biosimilar, just as they would for the reference product. https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm580430.htm#sub

New initation vs. continuation? Therapeutic vs. Supportive? What’s the preferred product by their health plan Potentially cheaper copay https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UCM585738.pdf Accessed Jan 2019

Educating Patients: Financial

Biosimilar Utilization: Educating Prescribers and Patients Philip Schwieterman PharmD, MHA Director of Oncology and Pediatric Pharmacy UK HealthCare Markey Cancer and KY Children’s Hospital Lexington, Kentucky