Switching from Reference Biologic Medicines to Biosimilars

Transcription

1 Scientific Affairs Switching from Reference Biologic Medicines to Biosimilars Hillel P Cohen, PhD Academy of Managed Care Pharmacy - Webinar July 12, 2018

2 Biosimilars are approved biologics that have been demonstrated to be highly similar to a reference medicine Key requirements for comparability Highly similar structure and function Identical primary structure (amino acid sequence) Indistinguishable higher-order structure High quality Same biological functions Equivalent PK/PD Comparable clinical efficacy and safety Same presentation, dose (strength) and administration mode European Medicines Agency (EMA). Guideline on similar biological medicinal products. CHMP/437/04 Rev 1/2014 [online]. Available from URL: [Accessed 2016 March 18]; US Food and Drug Administration. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product Accessed 9 July Available from: 2

3 Development of a biosimilar requires a paradigm shift Standard new drug development Biosimilar development PK = Pharmacokinetics; PD = Pharmacodynamics Clinical PK/PD Non-clinical Analytical Major goal is to determine the clinical effect Clinical PK/PD Non-clinical Analytical Major goal is to determine similarity; establishment of a scientific bridge to the clinical experience of the originator Analytical methods provide the most sensitive tools to establish this scientific bridge 3

4 How similar are biosimilars and their reference medicines in biochemical structure? Amino acid sequence Primary Sequence Folding Secondary, tertiary, quaternary structure Glycosylation and related substances Identical Indistinguishable Identical structures in comparable amounts Differences are only acceptable if they are clinically not relevant Adapted from: Food and Drug Administration (FDA). Guidance on Scientific Considerations in Demonstrating Biosimilarity to a Reference Product: Guidance for Industry (April 2015). Accessed 9 July Available from URL: Figure adapted from McCamish M & Woollet G. Mabs 2011;3(2):

5 Safety & Efficacy The safety and efficacy of a biosimilar is established by studies conducted with the reference biologic as well as post-approval pharmacovigilance Safety is least understood at time of approval of the reference biologic 5

6 Can biosimilars be switched for their reference medicines? 6

7 Switching scenarios 1. Reference medicine biosimilar FDA uses the term transition for a one-time (single) switch from reference medicine to a biosimilar 2. Multiple switch RM biosimilar RM biosimilar RM biosimilar 3. Single switch: Biosimilar #1 Biosimilar #2 FDA, US Food and Drug Administration; RM, reference medicine 7

8 Some companies & groups suggest that switching may be unsafe Are You Being Asked to Switch to a Biosimilar? Then make your voice heard! 8

9 What would happen if reference medicine to biosimilar switching does NOT occur? 1. Only treatment naive patients would receive biosimilars 2. Patient access through increased competition would be threatened Switching matters because it determines the initial market for a biosimilar If a biosimilar manufacturer is blocked from the larger share of the market, it is disadvantaged in contracting with payers, being on formularies, and offering value. Availability of biosimilars to established patients (via switching) is critical for commercial success and sustainability of the biosimilar industry 9

10 Can biosimilars be used to treat patients that have already been treated with reference medicine? 1. Is this practice safe? Underlying hypothetical concern: May lead to increased immunogenicity 2. Will patients get the same benefit? Underlying position of some: Non-medical switching does not provide benefits to individuals & should be avoided if possible 10

11 Factors influencing immunogenicity Size Duration Treatment Frequency Formulation Contaminants and impurities Target and biological activity Dose Immunogenicity Route Concurrent illness Concomitant medication Product Protein sequence and Aggregation structure Protein modifications Genetic background Age Patient Disease state being treated Ratanji KD, et al. J Immunotoxicol Apr-Jun;11(2):

12 Factors influencing immunogenicity Size Duration Treatment Frequency Formulation Contaminants and impurities Target and biological activity Dose Immunogenicity Route Concurrent illness Concomitant medication Product Protein sequence and Aggregation structure Protein modifications Genetic background Age Patient Disease state being treated Ratanji KD, et al. J Immunotoxicol Apr-Jun;11(2):

13 Theoretical immunogenicity concerns Two most important concerns related to immunogenicity (apply to all biologics): 1. Neutralizing antibodies with clinical sequelae 2. Off-target immune responses Potential clinical sequelae due to altered dose Loss of efficacy (lower concentration of available therapeutic protein or increase in clearance rate) Impact on dosing levels (higher or lower doses required to elicit equivalent response) Potential formation of immune complexes May stimulate macrophages and/or may block glomeruli Independent of switching back-and-forth between an originator and biosimilar Relevant only for proteins that stimulate high levels of ADAs (i.e. proteins that do not induce ADAs do not raise this concern) Epitope spreading (aka epitope drift) Associated with long-term use Independent of switching back-and-forth between reference medicine and biosimilar Walter Reinisch and Josef Smolen. Seminars in Arthritis and Rheumatism. (2015) 44: S9-S15 European Medicines Agency. (2012) (accessed 1 July 2018) US FDA. (2014) (accessed 1 July 2018) 13

14 What is known about immunogenicity Some (but not all) therapeutic proteins are inherently immunogenic Have been assessing immunogenicity of reference for >10 years Risk factors influencing immunogenicity of reference medicine are well known (e.g. aggregates, degradates etc.) All biologics have inherent variability within a single batch and from batch to batch Additional variability introduced due to process changes has not led to immunogenicity concerns ( de facto switches ) Most anti-drug antibodies, when observed, are against the protein portion of the molecule (NOTE: structurally, the protein backbone, i.e. amino acid sequence of biosimilars and reference medicines are identical, sugar portions are highly similar) Extensive analytical head-to-head comparisons are already mandatory for biosimilars Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (accessed 9 July 2018) Available from: 14

15 Does data exist to help assess the hypothetical concerns about switching? 15

16 Published on-line on March 3, 2018 Since publication, review has been downloaded times from the publishers website 16

17 Studies comparing biosimilar with originator (with a transition event) are gaining importance Literature comparing reference medicine with a biosimilar involving a switch/transition event comprises around 14,225 patients from 90 studies 14,225 Patients 14 Indications Literature covers around 14 different disease indications There is a steady growth in literature from 1993 till 2016 Rapid growth can be seen in the year 2016 and is expected to continue to grow in the near future 17

18 Literature search was conducted to collate evidence in patients who switched from originator to biosimilar Four step targeted methodology was employed A Targeted Lit. Search B Data Classification C Data Extraction D Data Presentation Molecules assessed approved biosimilars (US or EU) & corresponding reference medicines Smaller proteins: Growth hormone, epoetin, filgrastim Larger proteins: Etanercept, adalimumab, infliximab Key Variables Type of Molecule Single vs. Multiple Switch RWE vs. RCTs Disease Indications 1 & 2 Endpoints Study (Abstract, Article, News...) Time frame: 1993 to June 30, 2017 EU, European Union; RCT, randomized clinical trial, RWE, real-world evidence 18

19 Safety, efficacy, immunogenicity, & adverse events data were compared Why Efficacy Data? Loss of efficacy may relate to neutralizing antibodies Most of the time, it is related to the drug itself Why Safety Data? Some adverse reactions may be related to immunogenicity (e.g. rash, anaphylactic reactions) Why Immunogenicity Data? Circulating anti-drug antibodies (ADAs) versus neutralizing antibodies Clinical relevance of detected levels 19

20 Citation disposition 20

21 Results of the literature review From 1993 to June 30, studies that enrolled 14,225 unique individuals 7 different molecular entities used to treat 14 diseases No reported differences in immunogenicity, safety, or efficacy in vast majority of studies (88/90) Nature & intensity of safety signals reported after switching were the same as those already known from continued use of the reference medicines Molecule Total Articles Efficacy Immunogenicity Adverse Events Large proteins: Etanercept, adalimumab, infliximab Small proteins: Somatropin, epoetin, filgrastim

22 Count Switching evidence in larger proteins was dominated by infliximab mabs 3, 6% 4, 7% Evidence Types Study Types 46, 85% Infliximab Etanercept 1, 2% Adalimumab Rituximab mabs 1 1 Journal Article Abstract Letter Poster RCT RWE Evidence in large proteins was dominated by infliximab studies with 46 publications We included peer-reviewed journal articles, conference abstract/ posters, and letters to collate relevant evidence More RWE studies were conducted as compared to RCTs involving Infliximab molecule mabs, monoclonal antibodies; RCT, randomized clinical trial; RWE, real-world evidence 22

23 Patient counts in large protein studies across disease indications Patient Counts across Disease Indications 16% Rheumatoid Arthritis (RA) 2% 0% 1% 1% 2% 4% 12% 37% Inflammatory Bowel Disease (IBD) Plaque Psoriasis (PsO) Crohn's Disease (CD) Spondyloarthritis (SpA) Healthy Volunteers (HV) Rheumatic Diseases Ankylosing Spondylitis (AS) 25% Ulcerative Colitis (UC) Combined Indications Rheumatoid arthritis patients represented the largest group (37%) in terms of patient numbers Inflammatory bowel disease, Crohn s disease and ulcerative colitis patients taken together represented around 30% of the entire patient population Remaining 33% of the population included patients suffering from plaque psoriasis, spondyloarthritis, ankylosing spondylitis, psoriatic arthritis, and other diseases 23

24 No. of Articles ADA & NAB levels in large protein studies across disease indications In an extensive literature search, we found 24 studies reporting ADA data (From 1993 to June 30, 2017) Evidence include RWE studies such as NOR- SWITCH, DANBIO Registry, Eir-Switch and observational studies from countries like Italy, Norway, Finland, Ireland & the Netherlands Evidence with ADA Data Diverse methods were used to assess ADAs such as validated radio-immunoassay, ELISA, electroluminescence assay etc. Hence reported ADA rates may vary depending on the type of assay used ADA and NAB levels were found to be comparable at baseline and at the end of study across disease indications ADA, anti-drug antibody; AS, ankylosing spondylitis; IBD, inflammatory bowel disease, NAB, neutralizing antibodies; PsO psoriasis Disease RA AS IBD PsO Disease Indication Base & End of Study Comparable ADAs Comparable ADAs May not be generalized due to small sample sizes Higher & comparable ADA levels as compared to other diseases 24

25 No. of Articles Percentage TAEs & TSAEs in large protein studies across disease indications 39 articles reported data on TAEs/ TSAEs (from year 1993 to June 30, 2017) Evidence with TAE & TSAE Switch vs. Reference comparison was reported in 33% studies (N=13/39), while cohort design was employed in 62% (N=24/39) (mainly IBD indication) SAEs were reported as Nil (0%) in 33% of the articles (N=13/39) Abstracts (N=2) reported comparable AE data with no details IBD CD PsO AS RA Disease Indications 1 1 SpA HV 4 Combined Indications Percentage of TAEs and TSAEs in switch & reference arms were comparable across disease indications AS, ankylosing spondylitis; CD, Crohn s disease; IBD, inflammatory bowel disease, PsO psoriasis; SpA, spondyloarthritis, TAE, treatment associated adverse events; TSAEs, treatment associated serious adverse events 25

26 IBD CD UC PS RA AS Spondyloarthritis RA, PsA, SpA No. of Articles Efficacy data in large protein studies across disease indications 36 articles reported efficacy data Switch vs. Reference comparison was reported in 33% studies (N=12/36), while cohort design was employed in 67% (N=24/36) (mainly IBD indication) Efficacy was comparable in maintenance vs. switched groups or was maintained before and after switching event in cohort design Study with a partial negative results (Kang et al. 2015) was small making it difficult to generalize Evidence with Efficacy Data Disease Indications AS, ankylosing spondylitis; CD, Crohn s disease; IBD, inflammatory bowel disease, PS psoriasis; PsA, psoriatic arthritis; RA, rheumatoid arthritis; UC, ulcerative colitis 26

27 Multiple switch studies Three published studies One each for biosimilars of filgrastim, etanercept and adalimumab Not designed to meet FDA interchangeability expectations (as outlined in the Draft Guidance) Blackwell K, Gascon P, Krendyukov A et al. Annals Oncology (2018) 29:244-9 Griffiths CEM, Thaci D, Gerdes S, Arenberger P, Pulka G, Kingo K et al. Br J Dermatol. (2017)176: Blauvelt A, Lacour J-P, Fowler JF, Weinberg JM, Gospodinov D, Schuck E, et al. Br J Dermatology (2018) doi: /bjd

28 Zarxio (filgrastim-sndz) multiple switch study design EP2006, development code for Zarxio (filgrastim-sndz); d, day; dsn, duration of severe neutropenia Zarxio is a registered trademark of Novartis AG 28

29 Erelzi (etanercept-szzs) multiple switch study design GP2015, development code for Erelzi (etanercept-szzs); wk, week Erelzi is a registered trademark of Novartis AG 29

30 Antibodies to reference medicines cross-react with biosimilars Three studies demonstrated that: Antibodies created against reference medicine infliximab will also react towards biosimilar infliximab and vice versa Antibody formation to biosimilar and originator infliximab are dose dependent in an identical manner Antibodies are formed to the same specific regions of biosimilar and originator molecules ( epitopes ) Therefore: Biosimilarity extends to immunogenicity as well other parameters Experimental evidence that if a patient stops responding or has an allergic-type reaction to the originator, they will have the same response to biosimilar infliximab. This is critical evidence of why failoriginator-first policies are dangerous for patients!! Ben-Horin S, Yavzori M, Benhar I, et al. Gut (2016) 65:1132 Goncalves et al. Alimentary Pharmacology & Therapeutics (2018) DOI: /apt Ruiz-Arguello, et al., Ann Rheum Dis (2016) 75: Avalere: Use of Step Through Policies for Competitive Biologics Among Commercial US Insurers. May 17,

31 Two studies posed concerns about switching from originator to biosimilars Author Yazici Y. et al (2016) Kang et al. (2015) Publication ACR-ARHP 2016 Abstract Number: 2,240 Dig Dis Sci (2015) 60: Study type Turkish health insurance database Case series at Dongguk University Ilsan Hospital (South Korea) Sample size Switch Patients: n=148; Originator IFX: n=2,870 Switching study 5% switched to CT-P13; n=148 out of 3,018 patients. 82% drop-out rate among the patients that switched (went back to originator) Indications AS, PsA, PS, CD, UC, RA CD, UC Conclusions Analysis: Switching from IFX to CT-P13 was infrequent. High % (82%) of CT-P13 discontinuation was a concern. Switch Patients: n=9; Originator IFX: n=8 53% switched to CT-P13; n=9 out of 17 patients. 1 switched patient reported a loss of efficacy. CT-P13 may have biosimilarity and interchangeability with its originator in IBD. A large, randomized, double-blind, prospective study is needed. Yazici et al. (2016) found a 82% dropout rate in patients that were switched compared to a 38% in patients that remained continuously on the originator medicine. Similar high drop-out rates were not detected in any of the other >40 infliximab switching studies Difficult to draw conclusions about loss of efficacy (a subjective measure) in 1 patient from Kang et al. (2015) AS= ankylosing spondylitis;; CD=Crohn s disease; IFX=infliximab; PS=psoriasis; PsA=psoriatic arthritis; RA=rheumatoid arthritis; UC=ulcerative colitis 31

32 Biosimilar to biosimilar switching No published data Anecdotal evidence only Kaiser Permanente switching of growth hormones from different manufacturers Poland: National tenders led to switching of different growth hormones year over year Hungary: National tenders led to switching of different filgrastims year over year 32

33 Conclusions of the review There is a large body of published evidence for biologic medicines evaluating the impact of switching from reference medicines to biosimilars that assesses immunogenicity, efficacy, and safety. The great majority of studies did not report differences in safety, efficacy, or immunogenicity after a single switch event compared to patients that were not switched. Overall, the results suggest a low risk of either a safety concern or a loss of efficacy after switching to a biosimilar. The extensive data collected to date suggest that the act of switching from a reference medicine to a biosimilar is not inherently dangerous, and that patients, healthcare professionals, and the public should not assume that it is problematic. Results provide reassurance to healthcare professionals and the public that the risk of immunogenicity-related safety concerns or diminished efficacy is unchanged after switching from a reference biologic to a biosimilar medicine. 33

34 Additional reviews 34

35 Cohen at al. is consistent with other literature reviews of biosimilar switching 1. Ebbers et al. The safety of switching between therapeutic proteins. Expert Opinion Biol Therapy (2012) 12: studies of smaller proteins: somatropin, epoetin & filgrastim 2. Gisbert and Chaparro. Switching from an originator anti-tnf to a biosimilar in patients with inflammatory bowel disease: Can it be recommended? A systematic review. Gastroenterol Hepatol. (2018) (recently published on-line) studies of infliximab reference to infliximab biosimilar 3. Moots et al. Switching between reference biologics and biosimilars for the treatment of rheumatology, gastroenterology, and dermatology inflammatory conditions: Considerations for the clinician. Curr Rheum Rep (2017) 19: studies of larger proteins: adalimumab, etanercept, infliximab and rituximab 4. McKinnon et al. Biosimilarity and interchangeability: Principles and Evidence: A systematic review. BioDrugs (2018) 32: switching studies No safety or efficacy concerns identified 35

36 A different type of review... Inotai and colleagues identified all studies that raised the possibility of safety concerns after switching 58 papers (12 empirical papers, 5 systematic reviews and 41 non-empirical papers) Reviewed the publications to determine if any data is provided The implied risk of negative clinical consequences of switching from an originator biologic to a biosimilar is not substantiated by convincing clinical evidence. Inotai et al. (2017) Expert Opinion Biol Ther 17:

37 The Cohen et al. review was challenged by Janssen, manufacturers of Remicade (infliximab) Remicade is a registered trademark of Janssen Pharmaceuticals 37

38 Exchange on the editorial pages of Drugs (published May 21, 2018) 38

39 Challenges asserted by Pires et al. Data has limitations and was over-interpreted: 1. Diversity in studies limits ability to draw conclusions 2. Several switching studies showed higher drop-out rates among biosimilar recipients 3. A large study was omitted that revealed very high drop-out rates 4. The three multiple switch studies did not establish interchangeability 5. Product differences due to manufacturing process changes are not de facto switches because they were implemented as per ICH guidance 39

40 Bottom line of Pires et al. More studies are needed. 40

41 Rebuttal by Authors Reply 1. Diversity in products, endpoints, study design is a great strength as 88/90 publications drew the same conclusions 2. Each study that reported elevated drop-out rates in biosimilar recipients also attributed them to subjective patient factors. In those same studies there was no difference in objective measurements It is inappropriate to select specific data points while ignoring the totality of evidence from the same study. 3. The large study that was omitted was in fact a replicate analysis of the same data set from another study A key principle of the review was that individual patients were only counted once. As a result the publication with the replicate analysis was not included in the review 4. The multiple switch studies were conducted to answer a scientific question and were not designed to support an interchangeability designation 5. Patients are often exposed to drug product with differences in critical quality attributes due to manufacturing process changes Even if the process changes were implemented in compliance with ICH guidances, intellectual honesty requires us to acknowledge that these patients were subjected to de facto switches 41

42 Bottom line of the Authors Reply It is incorrect to presume that there may be a problem with switching and that further study is necessary, or to impose a data burden on biosimilars not applied to other biologics, especially when there is no credible basis for such a request. A total of 90 studies with 14,225 patients is larger and provides stronger evidence than any individual study could be expected to provide. 42

43 Conclusions 1. The risk of immunogenicity-related safety concerns or diminished efficacy is unchanged after switching 2. The act of switching is not inherently dangerous 3. Patients, healthcare professionals, and the public should not assume that switching from reference medicine to a biosimilar is problematic 43

44 Thank you very much for your attention. Any questions?? 44