Interchangeability, Switching and Substitution of Biotherapeutics: Clinical Issues and Challenges

Interchangeability, Switching and Substitution of Biotherapeutics: Clinical Issues and Challenges Dr. Freddy José Faccin Lazo, M.D. Global Biotherapeutics Head Global Medical Affairs Abbvie

Overview Introduction and Definitions Analytical Considerations Clinical Considerations The Immunogenicity Switching Challenge Clinical Evidence on Non-Medical Switching: A Review Pharmacovigilance and Patient Management In a World With Multiple Biosimilars Conclusions

Treating patients with Biotherapeutics: Definitions US FDA: An interchangeable biologic product, in addition to meeting the biosimilarity standard, is one that is expected to produce the same clinical result as the reference product in any given patient 1 Interchangeability EU: The medical practice of changing one medicine for another that is expected to achieve the same clinical effect in a given clinical setting and in any patient 2 Regulatory term Transitioning/switching Physician-controlled action: single transition of patients from a reference product to a biosimilar 2 Substitution Pharmacist action: dispensing one medicine for another equivalent and interchangeable medicine at the pharmacy level without consulting the prescribing physician 2 1. FDA Information for consumers (biosimilars). Available at: http://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/therapeuticbiologicapplications/biosi milars/ucm241718.htm; 2. European Commission. Consensus Information Paper What you need to know about Biosimilar Medicinal Products, 2013

Medically relevant switching TNF, tumor necrosis factor Evidence-based recommendation Patients treated with biologic therapy, who have an inadequate response or an intolerable AE, should be switched to a different biologic agent for clinical reasons 1 3 1. Singh et al. Arthritis Rheumatol 2016;68:1 26; 2. Smolen et al. Ann Rheum Dis 2014;73:492 509; 3. Dignass et al. J Crohns Colitis 2010;4:28 62;

Non-medical switching (NMS) What is NMS? Switching of biologics among patients with well-tolerated, adequate therapy 1 3 What motivates NMS? Potential for cost-savings and/or procurement policies 1 4 Patient preference 1,2 What types of NMS occur? Across different agents from the same class 2,6 From a reference product to its biosimilar or vice versa 1. Rubin et al. ECCO 2015, Barcelona, P354; 2. Gibofsky et al. AMCP 2015, San Diego, Poster; 3. Liu Y et al. ISPOR 2015, Philadelphia, PHS26; 4. Morgan et al. Open Medicine 2009;3:131 9; 5. Declerck. GaBi J 2012;1:13 6; 6. Van Assche et al. Gut 2012;61:229 34

Biosimilar Development: What Can Be Minimized With Acceptable Risk? 1. FDA Guidance for Industry. Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product. HHS FDA/CDER/CBER, Feb 2012; 2. EMA CHMP Guideline on similar biological medicinal products, 30 Oct 2005; 3. Health Canada: Guideline for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics, March 2010; 4. WHO Guidelines on Evaluation of Similar Biotherapeutic Products, 2009

Aggregate Analysis Enables the Degree of Similarity to be Assessed 1,2 Tier 1: Statistical equivalence Tier 2: Quantitative numerical comparison Tier 3: Qualitative comparative assessment Quality attribute Criticality Relevant for Amino acid sequence Very high Efficacy, safety, immunogenicity Potency Very high Efficacy, safety Target binding Very high Efficacy, safety Protein concentration Very high Efficacy Subvisible particles High Immunogenicity Oxidised variants High Efficacy Higher order structure High molecular weight variants/aggregates High High Truncated variants Low None Norleucine Very low None Deamidation Very low None Efficacy, immunogenicity Immunogenicity 1. Adapted from: Kozlowski. FDA; European Generic Medicines Association Biosimilar Medicines - International Symposium London, UK, April 26, 2013; 2. FDA Oncologic Drugs Advisory Committee Meeting. ZARXIO (filgrastim) Advisory Committee Briefing Materials. January 7, 2015

Biosimilarity Index to Quantify Similarity: Medical Community The International Psoriasis Council suggests guidelines for standardization of pre-clinical assessments of emerging biosimilars through the development of a biosimilar index 1 1. Blauvelt A et al. British J Derm Oct 2015; doi:10.1111/bjd.14267

Mechanisms of Action of TNF inhibitors in Different Pathogenic Conditions Do we fully understand how biologic therapies exert their effects? 1-5 Binding of soluble TNF Avidity, affinity Binding to membrane-tnf Apoptosis Reverse signaling? Binding to Fc receptors Part of mode of action Elimination, recycling (half-life) Other(s)? 1. Miletich et al. mabs 2011;3:318 325; 2. Tracey et al. Pharmacol Ther 2008;117:244 279; 3. Vos et al. Inflamm Bowel Dis 2012;18:401 408; 4. Vos et al. Gastroenterology 2011;140:221 230; 5. Kuo & Aveson. mabs 2011;3:422 430; 6. Lee et al. AAPS 2014;16:22 26

What is the Primary Concern? Immunogenicity Protein or Carbohydrate Exposure Immune Tolerance 4 Prevention of an immune response against a particular antigen Desired State: Immune Equilibrium & Stability of Response New Tolerance Equilibrium Modification of Protein or Carbohydrate Potential for Immunogenicity 1. Change to different drug 2. Drug Modification Primary loss of response Secondary loss of response Type-I hypersensitivity Type-III hypersensitivity 1. Chamberlain P.D., Biosimilars, 2014: 23-43; 2.Shankar et al. AAPS 2014;16:658 73; 3. Scott B et al, The journal of Clinical Pharmacology DOI:I 002/jcph.339; 4. National Inst. Allergy and Infect. Dis Accessed 3/22/2016. http://www.niaid.nih.gov/topics/immunesystem/pages/immunetolerance.aspx

Mechanisms to Evaluate Clinical Switching 1 Reference drug Biosimilar Reference drug Biosimilar Reference drug Biosimilar Transition study Substitution study (single switch) Interchangeability study (multiple switches) demonstration of interchangeability should require testing of repeated switches between the reference product and the biosimilar Drug switching takes place when a patient is transitioned from one biopharmaceutical to another or from a reference biopharmaceutical to its biosimilar Figure: Study design to compare the efficacy of reference drugs and biosimilars. Switching, as has been carried out in clinical trials of some biosimilars, is compared with substitution involving single or multiple switches, as potential study designs to support the FDA designation of interchangeability. Switch studies are not required for approval by the EMA A switch study demonstrating no loss of efficacy nor increase in risk would support the transition under consideration 1. Dörner & Kay. Nat Rev Rheumatol 2015; doi:10.1038/nrrheum.2015.110 [Epub ahead of print]

Induction of the Immune Response According to the Prime-Boost Effect Persistent presence of an antigen induces an initial immune response followed by tolerance 1 It is well established that conventional B cells and T cells are anergized when an antigen is constantly present 2 Conversely, intermittent presence of an antigen (or epitope) promotes a persistent immune response that is similar to that seen in vaccination and vaccine recall 1 1. Schaeverbeke et al. Rheumatology 2015; [Epub ahead of print]; 2. Pradeu et al. Nat Rev Immunol 2013;13:764 9

Foundation of the Immune Prime-Boost Response

Measuring High Order Structure (HOS) of Biologics Antibody Array Enzyme-Linked Immunosorbent Assay (ELISA) The 3D conformation of a biologic protein is an important factor in its function 1,2 However it can often be difficult to define precisely using current physiochemical analytical technology 1,2 Antibody-array technology was developed to characterize HOS of mabs: 2 Measures epitope exposure and compares conformational status of biosimilar to reference product Antibody arrays can detect subtle changes not detected by any other analytical technologies 2 More than 30 polyclonal antibodies cover an entire mab Thereby measuring its surface-epitope distribution systematically and sensitively 2 1. CBER/CDER. Guidance for Industry Scientific Considerations in Demonstrating Biosimilarity to a Reference Product Feb 2012; 2. Wang et al. BioProcess International 2014;12:32 7

HOS, Epitope Exposure and Immunogenicity Potential Color Change (OD 450mm) 2.0 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 HOS Comparability of Humira and Biosimilar mabs in the Constant Region Humira Batches Biosimilar Batches 1 2 3 1 2 3 24 25 26 27 28 29 30 31 Polyclonal Antibody 2/3 batches of biosimilar adalimumab indicated polyclonal increased surface-epitope exposure across all regions covered by the antibody array 1 Ab-array technology should provide a unique measurement of biosimilar mab HOS comparability and detect conformational impurity 1 HOS, high order structure 1. Wang et al. BioProcess International 2014;12:32 7

Induction of the Immune Response According to the Discontinuation Theory Persistent presence of an antigen induces an initial immune response followed by tolerance 1 It is well established that conventional B cells and T cells are anergized when an antigen is constantly present 2 Transition study Reference drug Biosimilar Interchangeability Substitution study (single (multiple switch) switches) Reference drug Conversely, intermittent presence of an antigen (or epitope) promotes a persistent immune response that is similar to that seen in vaccination and vaccine recall 1 Biosimilar 1. Schaeverbeke et al. Rheumatology 2015 [Epub ahead of print]; 2. Pradeu et al. Nat Rev Immunol 2013;13:764 9

Switching Study Design for Biosimilars and Their Reference Products 1 3 Design Randomized, controlled trials Should include at least two switches Should include appropriate control groups Size and duration Duration should be sufficient to demonstrate equivalent efficacy and to detect pre-defined safety issues or loss of efficacy Immunogenicity should always be assessed, as it can cause serious adverse events as well as drug neutralization and loss of efficacy Washout periods should be considered, particularly if there is no adequate control groups Study size should be properly calculated based on effect size and margin, calculated withdrawal rates and chosen statistical power Population For chronic diseases, should both new patients and stable treated patients be studied? Should switching studies be conducted in the most sensitive population(s)? How will interchangeability extrapolation be required/assessed/approved? 1. Lu et al. Drug Design 2013,3:1 6; 2. Endrenyi et al. Statist Med 2013;32:434 441; 3. Chow et al. Statist Med 2013;32:442 448

Patents with IBD: Patients with Crohn s disease: Switching study from Remicade to Humira SWITCH trial 1 Dose optimization or treatment interruption Switch to ADA (n=36) Continue on IFX (n=37) 47% 16% p=0.003 Treatment interruption 28% 2% p<0.01 Conclusions from the SWITCH trial Adherence to the first anti-tnf is recommended 1 Important for IBD, as there are a limited number of approved biologics for these diseases 1 a Patients switched between anti-tnfs because of a lack of efficacy or because of intolerance ADA, adalimumab; IBD, inflammatory bowel disease; IFX, inflixumab 1. Van Assche et al. Gut 2012;61:229 34

Impact of NMS across anti-tnfs on patient outcomes: a retrospective study 1 Number of office or clinic visits per patient Initial anti-tnf (NMS cohort, N=158; control cohort, N=4804) 15 10 5 0 ADA: 37.3%; 35.7% ETN: 37.3%; 51.2% IFX: 12.7%; 10.9% Office or clinic visits during follow-up 1 13.0 a 3.1 a 1.1 a 1,5 0,5 NMS 30-Day Follow-Up 90-Day Follow-Up 1-Year Follow-Up Controls CZP: 2.5%; 0.9% GOL: 10.1%; 1.4% 5,8 % of patients 75 50 25 Author conclusions Side effect or lack of efficacy leading to treatment adjustment during follow-up 1 0 16 b,c 36 b NMS Cost-related switching in medically stable patients may have unintended consequences 1 63 b 30-Day Follow-Up 90-Day Follow-Up 1-Year Follow-Up 4 9 Controls 20 1. Rubin et al. ECCO 2015, Barcelona, P354; Data source: Humedica EMR database (2007 2013): Integrates EMR data from a network of >20 provider organizations treating 30 million patients across 38 US states with broad geographic representation a p<0.001 for NMS vs controls (t test and multivariate regression); b p<0.001 for NMS vs controls (chi square test and multivariate regression); c p<0.001 for NMS vs controls (chi square test), p<0.01 (multivariate regression) Patients with autoimmune diseases: rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn s disease, and ulcerative colitis

Review of switching across reference product and biosimilar epoetins, growth hormones and G-CSFs Switching types included in the review Review of 58 clinical trials and 12,039 patients who were switched 1 Switching across reference products Switching between reference products and biosimilars Limited clinical data that studied the effects of switching/transitioning of biologics 1 Most clinical trials not designed to identify switching-related AEs 1 Adequate substantive data and adequate post-marketing surveillance are required 1 Currently, no indication that switching/transitioning impacts on safety and efficacy 1. Ebbers et al. Expert Opin Biol Ther 2012;12:1473 85 AEs, adverse events

What is the Evidence for Switching From Originator to Biosimilar Monoclonal Antibodies? Compare vs. Continued Ref. Product Switch x1 or Alternating Sample Size of switched cohort (n) Duration after switch Sieczkowska J et al 1 IBD Smits L. et.al. 2 IBD Kolar M. et.al. 3 IBD Díaz Hernández 4 L, et al. IBD None Single Switch 32 8 mos (range 2-11) None Single Switch 83 16 wks None Single Switch 74 24 wks None Single Switch 72 6 mos Fiorino G. et.al. 5 IBD Park W. et.al. 8 Ank. Spon. Yoo DH et.al. 9 Rheum. Arth. Bettey et al. 6 IBD Gesce et al. 7 IBD No: Compare vs new /re-starts* Single Switch 97 6 mos No: Compare vs biosimilar Single switch 84 48 wks No: Compare vs biosimilar Single switch 142 48 wks Yes Single switch 143 Up to 16 weeks No : compare vs biosimilar Observational 1. Sieczkowska J, et al. Advanced access pub JCC 2015. DOI: 10.1093/ecco-jcc/jjv 2. Smits L, et al. ECCO 2016. Abstr DOP030 3. Kolar M, et al. ECCO 2016. Abstr DOP032 4. Díaz Hernández L, et al. ECCO 2016. Abstr P449 5. Fiorino G, et.al. DDW 2016 Oral Pres Abstr 439 (* New /re-starts include bio-naïve or previously TNFi exposed pts) 6. Bettey et al. ECCO 2016, DOP029 7. Gesce et al. ECCO 2016, DOP028 Single switch No direct switch ++ 70 (estimate ) 30 wks RCT Extensions 8. Park W, et al. Ann Rheum Dis 2016;0:1 9. doi:10.1136/annrheumdis-2015-208783 9. Yoo DH, et al. Ann Rheum Dis 2016;0:1 9. doi:10.1136/annrheumdis-2015-208786

What is the evidence for switching from reference product to biosimilar mabs? Increasing evidence Heterogeneous designs Increasing outgoing evidence on switching among reference products and biosimilars on several indications, including rheumatic diseases 1 9 Study designs vary widely Randomized, active-controlled design, single-switch studies, open-label studies without a control arm, retrospective analysis, small cohorts 1 9 Data generation need There is an evident need to generate robust data on switches and interchangeability mabs, monoclonal antibodies 1. Sokka et al, EULAR 2015, Ann Rheum Dis 2015;74(Suppl. 2): 717; 2. Jarzebicka et al, 10th Congress of ECCO, 19 21 Feb 2015, P295 3. Yoon Suk et al, 10th Congress of ECCO, 19 21 Feb 2015, P540. 4. Gesce et al. 11th Congress of ECCO, March 16-19 2016, DOP028 5. Gesce et al. JCC 2016,133-140 6. Bettey et al. 11th Congress of ECCO, March 16-19 2016, DOP029; 7. Fiorino et al. 11th Congress of ECCO, March 16-19 2016, P544; 8. Strober B, et al. 74th AAD meeting, March 4-8 2016, Abstract 2957; 9. Gooderham M, et al. 74th AAD meeting, March 4-8 2016, Abstract 2961

Limitations of the evidence for switching from reference product to biosimilar mabs Data mostly comes from abstracts, posters and/or oral presentations from medical/scientific congresses 1 7 What do the data provide? Cohorts may provide clinically relevant important information, particularly on cumulative experience with the use of biosimilars in real life, including limited switching/transitioning data from the reference product to its biosimilar Potential limitations Number of therapy switches; open label, retrospective design, highly heterogeneous patient populations 1 7 Interpret with caution Available data may not represent final results We await final data from these cohorts and from well-designed studies 1. Sokka et al, EULAR 2015, Ann Rheum Dis 2015;74(Suppl. 2): 717; 2. Jarzebicka et al, 10th Congress of ECCO, 19 21 Feb 2015, P295 3. Yoon Suk et al, 10th Congress of ECCO, 19 21 Feb 2015, P540. 4. Gesce et al. 11th Congress of ECCO, March 16-19 2016, DOP028 5. Gesce et al. JCC 2016,133-140 6. Bettey et al. 11th Congress of ECCO, March 16-19 2016, DOP029; 7. Fiorino et al. 11th Congress of ECCO, March 16-19 2016, P544

Overview Introduction and Definitions Analytical Considerations Clinical Considerations The Immunogenicity Switching Challenge Clinical Evidence on Non-Medical Switching: A review Pharmacovigilance and Patient Management In a World With Multiple Biosimilars Conclusions

Reference product biologics today Uniquely identified and differ in structure 1 7 Have different mechanisms of action 7 Undergo the same full clinical development pathways required for regulatory approval 8 1. Humira SPC, November 2015, https://www.medicines.org.uk/emc/medicine/21201; 2. Enbrel SPC, December 2015, https://www.medicines.org.uk/emc/medicine/3343; 3. Remicade SPC, October 2015, https://www.medicines.org.uk/emc/medicine/3236; 4. Cimzia SPC, December 2015, http://www.medicines.org.uk/emc/medicine/22323; 5. Simponi SPC, May 2015, https://www.medicines.org.uk/emc/medicine/23766; 6. Orencia SPC, December 2015, https://www.medicines.org.uk/emc/medicine/27216; 7. Timlin H, et al. Expert Opin Biol Ther 2014;14:893 904; 8. EMA. Clinical trials in human medicine. Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/general_content_000489.jsp&mid=wc0b01ac058060676f

Looking towards the future: number of biologics in inflammatory/rheumatic disease will increase substantially The Present Future Established Current reference products + + new reference >36 biosimilars products 1 (new MoA) >36 biosimilars 1 The Market Will Be Complex 1. Dörner T, Kay J. Nat Rev Rheumatol 2015;11:713 24

Many New Biosimilar Entrants Present a Potential Complex Multi-Switch Scenario Reference product One biosimilar Two biosimilars Four biosimilars

Switching Between Several Biologics A biological product may not be evaluated against more than 1 reference product. 1 If A=B and A=C, does B=C follow? Reference Product A Biosimilar B Comparability studies are performed between a biosimilar and its reference product, but studies between one biosimilar and another are not done; two separate biosimilars may have been compared to the same reference but not between themselves. 2 A C B Biosimilar C, D, Thus, switching between biosimilars is not desirable and there needs to be some way of distinguishing between one SBP and another and between the reference product. 2 1. FDA Biologics Price Competition and Innovation Act of 2009, HR 3590:686-703; 2. 56th Consultation on INN for Pharmaceutical Substances, Geneva: WHO, 2013, INN working document 13.335

Non-medical Switching, Pharmacovigilance and Patient Management 1,2 Post-marketing surveillance of the new and complex emerging biologics market is critical NMS practice may increase the risk of misattribution of AEs, especially if the onset of the adverse reaction is delayed To avoid misattribution of adverse reactions, physician s and patient s awareness of the drug prescribed to the patient should be maximized 1. Vermeer NS et al. Expert Opin Drug Saf 2015;14:63 72; 2. Casadevall N et al. New Engl J Med 2002;346:469 75

Conclusions Reference product biologics and their biosimilars are very important treatment options for multiple diseases and have the potential to expand the possibilities for our patients The prescribing doctor needs to be in control of what their patients are receiving to improve the chances for an effective pharmacovigilance NMS between different biologics and even between versions thereof is an emerging field and highlights a need for further study Pharmacovigilance is critical; it may enable adverse effects or any other possible drug-related problems in clinical practice to be: DETECTED ASSESSED UNDERSTOOD PREVENTED

Obrigado! Gracias! Thank you! freddy.faccin@abbvie.com