WHICH PLACE WILL BIOSIMILARS

FIND IN THE MANAGEMENT OF IBD?

SHARING THE DUTCH EXPERIENCE

Geert D’Haens MD, PhD

AMC Amsterdam

CONFLICTS OR INTEREST

Abbvie: research support, lecture fee, consultant; Ablynx: consultant; Actogenix:consultant; Amakem: consultant; Amgen: consultant; AM Pharma: consultant;AstraZeneca: consultant; BMS: consultant; Boerhinger Ingelheim: consultant;Cosmo: consultant; Elan: consultant; Ferring: consultant, research support,lecture fee; DrFALK Pharma: research support, lecture fee; Celgene: consultant ;Celltrion: consultant; Centocor/Jansen Biologics: consultant, research support,lectur;e fee; Engene: consultant; Galapagos: consultant; Giuliani: lecture fee;GivenImaging: research support, consultant; GSK: consultant, research support,consultant; Hospira: consultant; Immunic Therapeutics: consultant; Lycera:consultant; Medimetrics: consultant; Millenium/Takeda: consultant, researchsupport, lecture fee; Mitsubishi Pharma: consultant; MSD: consultant, researchsupport, lecture fee; Mundipharma: consultant; Novonordisk: consultant;Norgine: lecture fee; Otsuka: consultant, lecture fee; Pfizer: consultant; Photopill:research support; PDL: consultant; Prometheus laboratories: consultant,research support; Receptos: consultant; Robarts Clinical Trials: ScientificDirector, research support; Salix: consultant; Sandoz: consultant; Setpoint:consultant; Shire: consultant, lecture fee; TEVA: consultant; Tigenix: consultant;Tillotts: consultant, lecture fee; Topivert: consultant; UCB: consultant, lecture fee;Versant: consultant; Vifor: consultant, lecture fees.

GOLIMUMAB

ADALIMUMAB

INFLIXIMAB

CERTOLIZUMAB

Farfan-Portet Eur J Health Econ 2014

MARKET PENETRATION OF BIOSIMILARS

What does the GI community know

about biosimilars (survey 2014) ?

Knowledge of biosimilars• Web based questionnaire - 307 responders

• 68% worked in a University Hospital

• 87% autonomously prescribe mAb since >2 years.

How would you best define a monoclonal antibody (mAb) biosimilar? This is…

19.3%

69.5%

7.5% 3.6%

A copy of a biological agent,

whose patent is expired, which is

identical to the originator(a

generic of a biological)

A copy of a biological agent,

whose patent is expired, which

closely resembles but is not equal

to the originator

A copy of a biological agent,

whose patent is expired, which is

based on the originator and is as

similar to it that adalimumab is

similar to infliximab (like a new

member of the anti-TNF class)I do not know

43.2%

67.1%

14.6%

9.6%

89.4%

6.6%

6.3%

0% 25% 50% 75% 100%

They can work differently from the originator

They can have a different immunogenicity patternthan the originator

Neurotoxicity can be higher than the originator

They can be used safely despite allergic reactions tothe originator

They will be less expensive than the originator

There will be larger indications than for theoriginator (indication extrapolation)

They are identical, so there are no additional issues

What could be issues or advantages of a mAb biosimilar?

(more than one answer possible)

Do you think mAb biosimilars have different feature(s) compared to the other available biosimilars

(erythropoietin. growth factors. etc.)?

62.4%

53.7%

65.1%

10.1%

0%

10%

20%

30%

40%

50%

60%

70%

Monoclonalantibodies are morecomplex than other

biosimilars thushigher risks of being

not similar enough

They require moreaccurate

postmarketingpharmacovigilance

They require well-designed trials withvalidated endpoints

in each medicalspecialty

There are nodifferences withother biosimilars

Confidence in Biosimilars

5.0%

7.7%

26.3%

28.3%

32.7%

Totally confident

Very confident

Enough confident

A little confident

Not confident at all

The data in the IBD field

Jung YS. J Crohns Colitis. 2015

Jung YS. J Crohns Colitis. 2015

Conclusion:

CT-P13 had comparable efficacy, safety, and interchangeability

with its originator in IBD. Further prospective studies with long-term follow-up

duration are needed to confirm biosimilarity of CT-P13.

Jung YS. J Crohns Colitis. 2015

Adult Crohn’s diseasetreatment of moderately to severely active Crohn’s disease, in adult patients who have not responded despite a full

and adequate course of therapy with a corticosteroid and/or an immunosuppressant; or who are intolerant to or have medical contraindications for such therapies.

treatment of fistulising, active Crohn’s disease, in adult patients who have not responded despite a full and adequate course of therapy with conventional treatment (including antibiotics, drainage and immunosuppressive therapy).

Paediatric Crohn’s diseasetreatment of severe, active Crohn’s disease in children and adolescents aged 6 to 17 years, who have not responded to

conventional therapy including a corticosteroid, an immunomodulator and primary nutrition therapy; or who are intolerant to or have contraindications for such therapies. Infliximab has been studied only in combination with

conventional immunosuppressive therapy.

Ulcerative colitistreatment of moderately to severely active ulcerative colitis in adult patients who have had an inadequate response to

conventional therapy including corticosteroids and 6-mercaptopurine (6-MP) or azathioprine (AZA), or who are intolerant to or have medical contraindications for such therapies.

Paediatric ulcerative colitistreatment of severely active ulcerative colitis in children and adolescents aged 6 to 17 years, who have had an

inadequate response to conventional therapy including corticosteroids and 6-MP or AZA, or who are intolerant to or have medical contraindications for such therapies.

IBD EMA APPROVAL

Remsima EMA/CHMP/363689/2013

BIOSIMILAR IFX FOR

‘NEW’ IBD PATIENTS

European data

Efficacy and safety of biosimilar infliximab after one year: results from a prospective nationwide cohort

K. Gecse1, Z. Vegh1, Z. Kurti1, M. Rutka2, K. Farkas2, J. Banai3, L. Bene4, B. Gasztonyi5, P. A. Golovics1, T. Kristof6, L. Lakatos7, P. Miheller8, F. Nagy9, K. Palatka10, M. Papp11, L. Lakner12, A. Patai13, A. Salamon14, T. Szamosi3, Z. Szepes9, B. Szalay15, G. T. Toth16, A. Vincze17, T. Molnar2, P. Lakatos1

1Semmelweis University, First Department of Medicine, Budapest; 2University of Szeged, First Department of Medicine, Szeged; 3Military Hospital, State Health Centre, Department of Gastroenterology, Budapest; 4Peterfy Hospital, First Department of Medicine, Budapest; 5Zala County Hospital, Second Department of Medicine, Zalaegerszeg; 6B-A-Z County and University Teaching Hospital, Second Department of Medicine, Miskolc; 7Csolnoky F. Province Hospital, Department of Medicine, Veszprem; 8Semmelweis University, Second Department of Medicine, Budapest; 9University of Szeged, First Department of Internal Medicine, Szeged; 10University of Debrecen, Institute of Medicine, Department of Gastroenterology, Debrecen; 11University of Debrecen, Institute of Internal Medicine, Department of Gastroenterology, Debrecen; 12Markusovszky Hospital, Department of Medicine and Gastroenterology, Szombathely; 13Markusovszky Hospital, First Department of Medicine and Gastroenterology, Szombathely; 14Tolna County Teaching Hospital, First Department of Gastroenterology, Szekszard; 15Semmelweis University, Department of Laboratory Medicine, Budapest; 16Janos Hospital, Department of Gastroenterology, Budapest; 17University of Pécs, First Department of Medicine, Pécs, Hungary

HUNGARY

Background

• Biosimilar infliximab CT-P13 received EMA’s positive CHMP recommendation in June 2013 for all indications of the originator product

• Since May 2014 all IBD patients in Hungary starting new infliximab treatment receive the biosimilar CT-P13

• Long-term data on the efficacy and safety of the biosimilar infliximab in IBD are lacking

Aims

to examine the efficacy and safety of CT-P13 infliximab

biosimilar in the maintenance treatment of CD and UC in a

prospective multicenter nationwide observational cohort

Patients and MethodsMonitoring strategy

BASELINE W14 W30 W54

Demographic data ✔

Medication history ✔ ✔ ✔ ✔

Clinical activityCDAI/PDAI or pMayo

✔ ✔ ✔ ✔

Biochemical activityWBC, CRP, We, albumin

✔ ✔ ✔ ✔

Endoscopic activitySES-CD or Mayo

✔ ✔

Imaging (perianal)MR or CT

✔ ✔

Trough + ADAELISA (Theradiag)

✔ ✔ ✔ ✔

Adverse events ✔ ✔ ✔ ✔

ResultsClinical remission and response

84

55

78,7

58,7

CDresponse(n=132)

CDremission(n=132)

UCresponse(n= 104)

UCremission(n=104)

77,2

57,5

68,9

45,9

CDresponse(n=101)

CDremission(n=101)

UCresponse(n= 74)

UCremission(n=74)

Week 14 Week 30

Gecse KB et al. J Crohn’s Colitis 2016

Response: CD: CDAI decrease >70points or fistula drainage decrease >50%, UC: decrease in pMAYO >3 pointsRemission: CD: CDAI <150 points or no fistula drainage, UC: pMAYO <3 points

ResultsClinical remission and response

*p<0.05, compared to prior exposure

91,7

61,5

79,5

62,562,9

37,1

75

37,5

0

10

20

30

40

50

60

70

80

90

100

CDresponse(n=132)

CDremission(n=132)

UCresponse(n= 104)

UCremission(n=104)

previous anti-TNF NO previous anti-TNF YES

83,6

63

72,6

50

60,7

42,9

50

25

0

10

20

30

40

50

60

70

80

90

100

CDresponse(n=101)

CDremission(n=101)

UCresponse(n= 74)

UCremission(n=74)

previous antiTNF NO previous antiTNF YES

*

** *

*Week 14 Week 30

ResultsLong-term clinical remission and response

58,3

46,7

56,1

46,3

CD response(n=60)

CD remission(n=60)

UC response(n= 40)

UC remission(n=40)

Week 54

Response CD: CDAI decrease >70points or fistula drainage decrease >50%, UC: decrease in pMAYO >3 pointsRemission CD: CDAI <150 points or no fistula drainage, UC: pMAYO <3 points

ResultsTrough levels (ELISA)

Infl

ixim

ab t

rou

gh(µ

g/m

l)

0

5

10

15

20

25

30

Week2 Week6 Week14 Week30

CD n=66 n=55 n=90 n=61

UC n=58 n=41 n=68 n=36

CD

UC

ResultsAnti-drug antibodies (ELISA)

Baseline Week 14 Week 30

CD

IFX naive 5/110 (4.5%) 12/89 (13.5%) 14/67 (20.9%)

IFX exposed 8/32 (25.0%)* 7/23 (30.4%) * 7/15 (46.7%)*

UC

IFX naive 2/72 (2.8%) 13/66 (19.7%) 14/49(28.6%)

IFX exposed 5/15 (33.3%)* 5/14 (32.4%) 5/12 (41.7%)

ResultsAdverse events

Patient (%)

Death 1 (0.3%)

Infections• Upper respiratory tract infection• Gastroenteritis• Viral infections (influenza, herpes, varicella)• C. difficile colitis• Sepsis/invasive fungal infection• Pneumonia• Urinary tract infection• Tuberculosis

8 (2.5%)6 (1.9%)3 (0.9%)2 (0.6%)1 (0.3%)1 (0.3%)1 (0.3%)0 (0%)

Allergy• Infusion reaction• Anaphylaxis

21 (7.2%)1 (0.3%)

Others• Arthralgia• Delayed hypersensitivity• Malignancy

10 (3.1%)7 (2.2%)0 (0%)

Conclusions

• CT-P13 effectively maintains clinical remission and response in both CD and UC

• Clinical efficacy was coupled with decreased biochemical activity

• Efficacy was influenced by previous anti-TNF exposure

• Adverse event profile and rates are comparable with those of the originator

SWITCH FROM ORIGINATOR

TO BIOSIMILAR IFX

European data

• Polish paediatric study

• UK (Southampton)

• Czeck republic

• Netherlands

REPORTS ON SWITCH TO BIOSIMILARS

Polish swith study in paediatric IBD

30Sieczkowska et al., JCC 2016

Managed switch program in the UK (Southampton)

Bettey et al., ECCO 2016

99% of 143 pts agreed1 flu-like syndrome, 1 LFT

32

33

34

35

36

• GE: – Starters OK; re-starters not recommended; – Switch only in trials/projects

• Federation Medical Specialists:– New patients to start biosimilars: no objection– Switch: only controlled, preferably research; patient information

needed– No substitution

• Rheumatology:– New patients: no objections against using biosimilars– Switching in responders NOT recommended

Definition of ‘new patient’ ?? Interval ?

NETHERLANDS

Switching from Remicade® to Remsima® SECURE Study (Netherlands)

Study Design & Objective• Open-label switch study in 120 patients with CD (n=40), UC (n=40), RA (n=40) in

patients in stable remission on maintenance IFX

Primary endpoint• Maintained serum concentrations of IFX• Immunogenicity (Ab against IFX)• Maintained remission (clinical & biomarkers) Disease Worsening over 6 months after

Population• 120 patients, 40 in each indication in RA, UC, CD

3

IFX

CT-P13

6 months 6 months

Switching from Remicade® to Remsima®NOR-SWITCH Study (Norway)

Study Design & Objective• Randomized, double-blind, parallel group study to assess if CT-P13 is non-inferior to

infliximab (INX) in patients who have been on stable INX treatment for at least 6 months

Primary endpoint• Disease Worsening over 6 months after switching over from INX to CT-P13• Worsening in composite scores or consensus between patients and physicians.• Estimated to occur in 30% over 52 weeks• Non-inferiority margin ± 15%

Population• 500 patients randomized, 100 in each indication (20% withdrawals) in RA, SpA, PsA,

UC, CD and Psoriasis patients

3

IFX

CT-P13

IFX

6 months 6 months

Relevant scientic questions

that remain unanswered

Oligosaccharide

Fab – antigen binding

Fc – effector functions

FcRn

FcγR, C1q

Ligand binding

IgG structure and function

Jefferis R. Arch Biochem Biophys 2012;526:159–66 Kozlowski, S, et al. Adv Drug Deliv Rev 2006;58:707–72 Harris RJ. Dev Biol (Basel) 2005;122:117–27

Potential post-translational modifications

● Pyroglutamyl peptides

● Deamidation

● Methionine oxidation

● Glycation

● Glycosylation; Mannose, G0, G1, G1, G2

● Sialylation

● C-terminal lysine, (K)

FcγR: Fcγ receptor; FcRn: neonatal Fc receptor

IMMUNOGENICITY

How is Immunogenicity Assessed?

Only clinical studies are appropriate for detecting immunogenicity

Current analytical methods or animal models cannot accurately predict human immunogenicity

Lack of international standardization of assays and references makes it impossible to compare results from different test laboratories

Comparison of immunogenicity can only be performed via comparative clinical studies and not by comparison of or to historical data

It would be preferable to use a single assay that measures binding of ADAs, using inhibition by the biosimilar and reference product to detect ADAs that recognize novel epitopes on the biosimilar

43

Development of Anti-Drug Antibodies to Adalimumab Over Time

Bartelds GM, et al. JAMA 2011

Median Adalimumab Concentration Over Time

45Bartelds GM, et al. JAMA. 2011

MANUFACTURING DRIFT

Interchangeability and Independent Product Manufacturing Changes

• Even small changes can have a large impact.1

• Independent changes made by different manufacturers could causeconvergence, divergence or neither in their profiles over time2-3

• Post-marketing comparative biosimilarity validation not required 4

• A reason some regulators do not endorse interchangeability3,5

Highly Similar

ConvergenceOR

Divergence OR

NeitherReference product

Biosimilar

Reference Product “A”

Biosimilar “C”, “D”, ….

Biosimilar “B”

A biological product may not be evaluated against more than ONE reference product.1

BEYOND SINGLE SWITCHES...

1. Biologics Price Competition and Innovation Act of 2010.

2.WHO 56th Consultation on International Nonproprietary Names for Pharmaceutical Substances; Executive Summary Geneva, 15‐17 Apr il 2013

B

C

A

“Comparability studies are performed between a biosimilar and its reference product, but studies between one biosimilar and another are not done; two separate biosimilarss may have been compared to the same reference but not between themselves.”2

“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

Interchangeability & Substitution / External Materials / November 2014

COMMONLY VOICED QUESTIONS REGARDING BIOSIMILARSImmunogenicity:

- Analytical data cannot predict immunogenicity- Issues re: methodology used to detect Abs

Safety:- manufacturer may not have assessed differences between attributes biosimilarvs originator- subtle changes may have profound effects on immunogenicity

Trial sensitivity:- appropriate statistics/margins to capture clinically relevant differences in phase 3 trials ?

Extrapolation:- safety and efficacy data transferable to other indications ?- different effects/distribution of mAbs in different tissues ? - role of other confounding factors eg. co-medication ?- different safety profiles in different populations ?

Stability:- what if originator and biosimilar drift apart over time ?

CONCLUSIONS: BIOSIMILARS IN IBD

- A number of scientifically relevant questions remain unanswered and challenging.

- Budget impact will probably be too important so that these concerns will not slow BS penetration.

- Some centres have started to switch ahead of changes in the guidelines.

- New, safer, more potent drugs may overtake the anti-TNF markets and hence limit budgetary consequences of biosimilar advent (Stelara, Entyvio, Xeljanz)