Biosimilars for IBD Dr Vipul Jairath MBChB DPhil MRCP NIHR Clinical Lecturer Nuffield Department of Medicine University of Oxford John Radcliffe Hospital

Biopharmaceuticals help treat severe diseases RHEUMATOID ARTHRITIS First RCT of a biological agent in 1994. Now 9 approved biological agents for RA DIABETES Synthetically made Human insulin was made available in the 1980’s. Before then, it was made from cows and pigs. HIV/AIDS Some antiretroviral therapies like Infuvirtide (Fuzeon) prevent the virus from infecting cells while others treat HIV-related anemia. IBD Infliximab first biological agent approved in 1998. Biopharmaceuticals are originator medicinal products derived from living organisms (bacteria, yeasts or cells) using biotechnology. There are a host of compounds including coagulation factors, erythropoeitins, growth hormones, insulins, interferon's, interleukins and monoclonal antibodies as compounds made from living cells and this differs from synthetic chemical compounds. These include many agents such as and also biologics such as anti-TNF agents. CANCER Several biologics including this image of Trastuzumab (a monoclonal antibody) treat cancers. 2

Biologicals are different to small molecule drugs Size: Larger, more complex, heterogeneous structure Manufacture: Made from unique cell lines under precise conditions using exacting steps to yield a consistent product. Highly sensitive to manufacturing conditions. Small alterations can cause large changes in immunogenicity profile Drift: Change with time. An unintended change over time which require regulatory and manufacturing control Stability: Biologicals are sensitive to light, heat, denaturing or degradation Mono-clonally antibodies are structurally the most complex of all of these agents.. A recap to put the rest f the talk into context. 90% of all biologics made from 3 cell lines – e coli, yeast and ovarian hamster cells There is batch variability in biologics- all biological agents undergo manufacturing changes over time and these must be reviewed and accepted by regulatory authorities Minor manufacturing changes can lead to dramatic alterations in the products efficacy or A/E profile Synthetic chemical drugs are made from mixing a series of known compounds in a predictable series of reactions to consistently produce the same end product, 3

Biologics are larger than small molecule drugs

A highly complex manufacturing process Design the gene sequence Place gene sequence inside a vector Place vector inside a specific cell Fermentation – cells produce the protein defined by the vector Purification – removing the impurities Highly complex protein with 3 or 4 levels of structure IgG1 antibody >1000 amino acids ~150,000 daltons >20,000 atoms The Process is the Product 5

Increasing use and cost of biologics 2010 - biologics fastest growing segment of pharmaceutical revenue ; expanding indications, utilisation, pipeline 2012 - 32% of all products in drug development and worldwide sales of $142 billion Biologic firms spend 1/3 of revenue on R&D Greater R&D costs than chemical drugs Annual price rises for biologics far exceed rate of inflation This is big pharma! All of these things of course translate into higher costs for consumers – much more expensive than conventional chemical drugs Cost of biologics rising almost 10-15% per year over the past 4 years far greater than the consumer price index over the same corresponding years which is in the order of 2-3% So we are using more of them, there are many in development and they are costing us more. 6

The driving force for biosimilar development 7

What are Biosimilars? In principle the biologic medicines’ equivalent of generics EMA definition ..” a biosimilar medicine is a biological medicine that is similar to another biological medicine that has already been authorised for use. They can consist of small molecules such as human insulin or complex molecules such as monoclonal antibodies EMA: Demonstrate similarity based on quality characteristics, biological activity, safety and efficacy based on a comprehensive comparability exercise US FDA: A product highly similar to the reference product without clinically meaningful difference in safety, purity and potency Canada: A biologic that enters market subsequent to version previously authorized in Canada with demonstrated similarity to a reference biologic 8

Factors driving biosimilar development Looming expiration of patents Technological innovation in biomanufacturing Better selection of high producing cell lines Less costly bioreactors Improved production yields, time and lower costs Global socioecomomics Mounting cost pressures on government budgets Desire to increase access to patients Regulatory initiatives EMA in 2006 FDA 2009 Canada, Japan, Korea Particularly in national heath systems and the cost to third party payers References: 1. Calo-fernandez B. Pharmaceuticals 201:5(12);1393-1408 9

The “Patent cliff”: A driving force behind biosimilar development These are the top ten selling biologics in 2010- humira is the leading one All of these are by definition “Blockbuster drugs” – any prescription drug which generated more than $1 billion in revenue annually. Solid bars represent market exclusivity and yellow is the patent cliff – many of these patents will expire in the next 5 years and this is therefore one of the major drivers for biosimilar development. The cliff refers to the clustering of numerous patented biologics expirations between 2011-2019. The expiry of patents and the mounting cost pressures to private and public third party payers and the desire to improve patient access through decreased drug costs is a driver for the biosocial industry. This is big pharma! 2012 - 32% of all products in drug development and worldwide sales of $142 billion All of these things of course translate into higher costs for consumers – much more expensive than conventional chemical drugs Cost of biologics rising almost 10-15% per year over the past 4 years far greater than the consumer price index over the same corresponding years which is in the order of 2-3% So we are using more of them, there are many in development and they are costing us more. References: 1. Calo-fernandez B. Pharmaceuticals 201:5(12);1393-1408

Biosimilars: Similar ≠ Same Biosimilars manufactured by different manufacturers will differ from the innovative product and each other They are not generic biologics They use a different host cell to develop the biosimilar The active ingredient of the biosimilar can only resemble as best possible that of the original biologic How an innovator makes its biologic can never be copied to the last details since it is a trade secret. Recognised in EMA guidance (CHMP/437/04) “Due to the complexity of biotechnology derived products the generics approach is scientifically not appropriate for these products” The innovator product remains a trade secret – there is no obligation to divulge this even after patent expiry 11

Biosimilars will differ slightly from the original For example different cell lines may result in differences in the glycosylation or pegylation patterns. Oxidation and aggregation differences can alter their 3-D structure. 12

Differences can lead to unwanted immunogenicity Product Change Consequence Eprex (epoetin alfa ) New formulation Changed albumin to synthetic detergent Leaching or organic compounds from rubber stoppers in syringes Neutralization of drug and endogenous protein Immune response against erythroblasts Pure red cell aplasia (200 cases) HX575 (biosimilar for epoetin alfa) New indication Immunogenic aggregates induced by tungsten from supplier of syringes Neutralizing antibodies to EPO in 2/337 subjects Pure red cell aplasia in one subject After a manufacturing modification of a subcutaneously administered innovator epoetin (Eprex®), a dramatic increase in the incidence of pure red cell aplasia (PRCA) occurred from 1998-2003 such that over 200 cases were reported in chronic renal failure.(25) This epidemic was later attributed to the replacement of human serum albumin as a stabilizer by the synthetic detergent polysorbate 80 and glycine, which enhanced leaching of organic compounds from rubber stoppers in the drug syringes. These substances acted as an adjuvant resulting in an immune response against membrane – bound erythroblasts in the bone marrow that caused red cell aplasia. More recently, in an investigational clinical trial comparing the subcutaneously administered biosimilar epoetin alfa HX575 and Eprex® in 337 patients, two cases of neutralizing antibodies were reported.(27) Evidence suggests that tungsten contamination during the manufacturing of the syringes mediated epoetin aggregation that resulted in antibody formation, a phenomenon that might cause PRCA There are many normal examples of no adverse effect 13

How similar is “similar” If we can’t make an identical product, how similar does it need to be and what do we need to know about the product and this is the challenging part These are difficult and challenging questions to answer as I will outline over the next few slides. Over the next few slides I will talk What do we need to know? How much “similarity” do we need 14

EMA guideline on biosimilars containing mAbs Pre-clinical studies A “stepwise” approach on a case by case basis Step 1 = In-vitro studies To assess differences in binding or function Step 2 = Determination of need for in-vivo studies Usually non-human primate; if not available proceed to human studies Step 3 = In-vivo studies PK and PD of the two products should be compared Immunogenicity in animals does not predict immunogenicity in humans EMA paved the way for other regulators with its first guidance in 2006,with several subsequent versions and this is the summary of its guidance of biosimilars containing monoclonal antibodies A stepwise approach on case by case basis is recommended to decide on the choice and extent of in vitro and in vivo studies MUST GP THROUGH A VERY THOROUGH COMPARISONOF STRUCTURE AND FUCNTIONAL CHARACTERISTICS. AMINI ACID SEQUECE WILL BE THE SAME References: 1. EMA/CHMP/403543/2010; May 2012 15

EMA guideline: Clinical studies Comparative clinical studies should always be conducted. A stepwise approach is needed and extent of programme depends on evidence in previous steps Step 1 = Pharmacokinetics Encouraged to provide supportive PK data from patients AUC, Cmax, tmax, half-life, volume of distribution Conventional equivalence margin 80-125% Step 1 = Pharmacodynamics Clear dose response relationship Accepted surrogate marker and can be related to patient outcome Aim for single lowest dose in healthy population AUC is the primary parameter of interest Such that similar effect on the PD marker will ensure a similar effect on the clinical outcome variable – sufficiently sensitive PD markers often lacking, that will consistently predict clinical efficacy References: 1. EMA/CHMP/403543/2010; May 2012 16

EMA guideline: Clinical studies Step 2 = Clinical efficacy If highly sensitive PD studies cannot be performed, similar clinical efficacy should be demonstrated in adequately powered RCTs, preferably double blind equivalence trials The guiding principle is to demonstrate similar efficacy and safety compared to the reference product, not patient benefit per se, which has already been established by the reference medicinal product Step 2 = Clinical safety Type, severity and frequency of ADRs between the two products Assessment of immunogenicity Pharmacovigilance and risk management plan (e.g. registries) Clinical safety is really throughout the programme, PK, PD and clinical programme. There are many details of how they might asses immunogenicity in the guidance PV is likely to exceed routine PV and use registries or large population databases. I don't think this is mutually exclusive actually References: 1. EMA/CHMP/403543/2010; May 2012 17

FDA References: 1. FDA Biosimilar Guidance Web, Feb 15, 2012 18

Importance of clinical trials:immunogenicity and safety Omnitrope (somatropin): Innovator (genotropin- Pfizer) 60% of enrolled patients developed antibodies to Omnitrope in first phase III study High concentration of host cell protein in the host cell known to enhance antibody reaction against growth hormone Resulted in additional purification steps New phase III studies initiated Antibody levels sufficiently reduced This was a growth hormone trial EMA Approval References: 1. EMA/164541/2012 19

Importance of clinical trials: efficacy and safety Alpheon (interferon alfa-2a): Roferon-A (Roche) Differences in the qualitative and quantitative impurity profile could not lead to a similarity conclusion for Alpheon and Roferon-A Manufacturing processes not adequately validated A phase III trial demonstrated that patients using Alpheon had a higher relapse rate and higher rate of adverse events that the innovator agent This was a trial in hepatitis C. This was a phase III parallel group trial to look at the safety and efficacy enrolled approximately 225 patients in each arm, so reasonable size. Highly significant increase in relapse rates – p <0.005, could not be explained bey baseline characteristics or other aspects of the trial For all these reasons marketing authorization was not approved. EMA – Not approved References: 1. EMA/H/C/000585 20

Pharmacovigilance Clinical trials are usually too small to detect rarer AEs, especially if duration is limited Robust PV programmes can track immunogenicity and unforeseen adverse events Multiple biosimilars may be available for each innovator biologic. Assigning unique names to each biosimilar would enable: Clear prescribing and dispensing Enable tracking of adverse events to the appropriate product These are needed to supplement clinical trials Each biosimilar is different to each other and to the innovator – so cant really have the same generic name. Unique names will allow tracking to 21

Biosimilars today 35 biosimilar antibodies in RCTs in the EU at end of 2012 18 biosimilars have been granted marketing authorisation With variable uptake across Europe June 2013 EMA CMPH recommended two biosimilar infliximab products for EU marketing Celltrion’s Remsima© Hospira’s Inflectra© Vast majority of these are EPOs, GHs, insulins Now just awaiting the European Commission's decision is due any day now in September 2013 Its use in IBD was extrapolated from rheumatology trials Interesting – in RA lower dose of IFX (3mg versus 5mg in IBD); monotherapy is more often used in IBD compared to RA. Immunomodulators reduce the risk of developing neutralizing antibodies against anti-TNFs This approval accors indication is a landmark case – anks spond, RA, ps 22

PLANETAS STUDY: CT-P13 Objectives: To compare the pharmacokinetics of biosimilar and innovator infliximab (CT-P13 Remsima® and Remicade®) in patients with active ankylosing spondylitis (AS). Secondary endpoints evaluated safety, efficacy and immunogenicity. Methods: 250 patients randomized in 1:1 ratio to 5mg/Kg at weeks 0, 2, 6 and q8 upto week 30 Primary endpoint of PK equivalence at steady state at weeks 22 and 30 (AUC and Cmax) Equivalence margin of 80-125% for the 90% CIs 23

PLANETAS STUDY: CT-P13 Clinical, safety and immunogenicity profile were also all very similar in exploratory secondary analyses Conclusion: CT-P13 bioequivalent and INX equivalent in terms of AUC and Cmax in patients with active AS Park W et al. Ann Rheum Dis 2013 Oct; 72 (10): 1605-12 24

PLANETRA RCT: CT-P13 Objectives: Randomised, double-blind, parallel-group RCT to demonstrate equivalence in safety and efficacy of CT-P13 compared with IFX when co-administered with methotrexate in patients with active rheumatoid arthritis Methods: Parallel group equivalence trial Anticipated response rates in E and C of 50% Equivalence margin of 15%, 80% power, α 0.05, needs 584 patients to reject H0 (-d, d) 606 patients randomized in 1:1 ratio to 3mg/Kg at weeks 0, 2, 6 and q8 upto week 30, with weekly methotrexate Primary endpoint of equivalence for ACR20 at week 30 Conducted in 100 sites in 19 countries across europe, asia, latin america and the middle east. Worth noting that not only is this a different condition, but also the doses are different as it the routone co-prescription of MTx 25

PLANETRA RCT: CT-P13 Clinical, safety and immunogenicity profile were also all very similar in exploratory secondary analyses Yoo D H et al. Ann Rheum Dis 2013;72:1613-1620 26

PLANETRA RCT: CT-P13 50% developed ADA at week 30 Post goc analyses showed no differences in efficacy in those with ADA or not. Conclusion: 60.9% vs. 58.6% in ITT (95% CI -6 to 10%) and 73.4% vs. 69.7% in PP (95% CI -4% to 12%) for CT-P13 and IFX Yoo D H et al. Ann Rheum Dis 2013;72:1613-1620 27

Biosimilars today In June 2013 EMA recommended that CT-P13 be granted MA for the marketing authorisation and extrapolated for all 6 indications of Remicade RA, AS, PsA, PsO, adult and paediatric CD and UC Once MA granted, it is the responsibility of individual EU member states to develop their own processes regarding the prescription, delivery and use of biosimilars ABPI has launched recommendations where action is needed by regulators, HTA agencies, NHS commissioners and professionals who prescribe or dispense biosimilars This is known as extrpolation of indications The extrapolation is to other indications even if that indication wasnt specifically tested during clinical development of the biosimilar. This approval across indication is a landmark case – anks spond, RA, ps The EMA position in this is that there are no pharmacokinetic or safety issues specific to IBD, so this extrapolation is warranted. 28

ABPI position statement on Biosimilars May 2014 All biologicals/biosimilars should be prescribed by brand name Ensures safety, PV and traceability requirements Automatic substitution is not appropriate. A biologic medicine including a biosimilar must only be substituted under the direct supervision and consent of the prescribing physician Patients should be kept fully informed about their medication and should be consulted if any changes to their treatment is made “..switching should not be based on cost alone. Physicians should base their decisions on appropriate evidence” This is known as extrpolation of indications The extrapolation is to other indications even if that indication wasnt specifically tested during clinical development of the biosimilar. This approval across indication is a landmark case – anks spond, RA, ps ABPI biosimilars positioning paper. http://www.abpi.org.uk/our-work/library/medical-disease/pages/1040514 29

ABPI position statement on Biosimilars May 2014 The SmPC of a biosimilar should clearly indicate the source of information contained within it, such as relevant data from its clinical development programme and clinical data derived from the originator or reference biological Biosimilars should be subject to health technology assessments processes in the UK Tenders which are undertaken involving biological medicines should not seek to source a single product only Extrapolation of indications for biosimilars should be evaluated by regulators on a case by case basis Summary of product characteristics ABPI biosimilars positioning paper. http://www.abpi.org.uk/our-work/library/medical-disease/pages/1040514 30

ECCO position statement Stance against automatic extrapolation of indications A biosimilar proven effective for one indication may not necessarily be so for a second indication for which the innovator has been shown to be effective Specific evidence obtained in IBD should be required to establish efficacy and safety. Efficacy in IBD cannot be predicted by that in other conditions such as RA Effect of immunomodulators need ccoutinf for when assessing the impact of biosimailr evidence in IBD Important not to extrapolate from other indications e.g just because it is effective in rheumatology. Efficacy in IBD cant be predicted from efficacy in rheumatoid arthritis and we have seen examples of this in innovator biologics; one good example of this is the drug etanaracept or abacept. Gut References: 1. Danese, S. ECCO position statement:The use of biosimilar medicines for IBD; JCC Jul 2013 31

Trials in IBD? NOR-Switch study A randomized, double-blind, parallel-group study to evaluate the safety and efficacy of switching from innovator infliximab to biosimilar infliximab compared with continued treatment with innovator infliximab in patients ulcerative colitis, crohn's disease, rheumatoid arthritis, psoriatic arthritis, and chronic plaque psoriasis E = Infusions of biosimilar infliximab (Remsima) with same dose and frequency as pre-inclusion treatment with innovator infliximab (Remicade) C = Continued infusions of innovator infliximab (Remicade) with same dose and frequency as prior to inclusion Effect of immunomodulators need ccoutinf for when assessing the impact of biosimailr evidence in IBD Important not to extrapolate from other indications e.g just because it is effective in rheumatology. Efficacy in IBD cant be predicted from efficacy in rheumatoid arthritis and we have seen examples of this in innovator biologics; one good example of this is the drug etanaracept or abacept. Gut ClinicalTrials.gov identifier: NCT02148640 32

Challenges/Questions that lie ahead We will be prescribing them, with a 20-30% cost reduction Are gastroenterologists sufficiently convinced about efficacy/immunogenicity of biosimilars in IBD? Are there sufficient scientific grounds to warrant a comparative effectiveness trial in IBD? If so, who is going to pay for and recruit to such a study (NI/equivalence trials >>1000 patients)? How will we monitor use/PV (registry?) Multi-professional engagement with stakeholders to produce a framework to guide their use for IBD within each country Effect of immunomodulators need ccoutinf for when assessing the impact of biosimailr evidence in IBD Important not to extrapolate from other indications e.g just because it is effective in rheumatology. Efficacy in IBD cant be predicted from efficacy in rheumatoid arthritis and we have seen examples of this in innovator biologics; one good example of this is the drug etanaracept or abacept. Gut 33