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

2. Biopharmaceuticals help treat severe diseases
RHEUMATOID ARTHRITIS
First RCT of a biological agent in 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

3. 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

4. Biologics are larger than small molecule drugs

5. 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

6. Increasing use and cost of biologics
biologics fastest growing segment of pharmaceutical revenue ; expanding indications, utilisation, pipeline
% 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

7. The driving force for biosimilar development7

8. 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

9. 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); 9

10. The “Patent cliff”: A driving force behind biosimilar development
These are the top ten selling biologics in 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
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!
% 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);

11. 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

12. 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

13. 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 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

14. 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

15. 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

16. 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 %
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

17. 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

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

19. 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

20. 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

21. 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

22. 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

23. 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 % for the 90% CIs 23

24. 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): 24

25. 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

26. 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: 26

27. 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: 27

28. 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

29. 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. 29

30. 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. 30

31. 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

32. 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: NCT 32

33. 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