Biosimilar Monoclonal Antibodies: Experience of

Galway University HospitalsProf. LJ Egan

Disclosures• Research support from:

• MSD• AbbVie

• Unrestricted educational grants from:• Takeda• Shire• AbbVie• Hospira

Biosimilars: increasing pace of developmentScientific Advice Requested from EMA by Biosimilars Companies

Schneider et al, Nat Biotechnol 2012:30:1179-85

Biosimilar Monoclonal Antibodies EMA framework: 2012

FDA process for Biosimilar MAbs• Highly similar to originator with respect to physicochemical properties• No clinically significant differences in “most sensitive” disease• Specific regulatory pathway:

• Abbreviated licensure pathway• Needs to demonstrate “Biosimilarity”

• Biosimilar• Highly similar not withstanding minor differences in clinically inactive componentsAnd• No clinically significant differences• Not the same as interchangeability

General requirements for FDA approval• Biosimilarity• Same Mechanism of action• Analytical studies• Animal studies• Clinical studies

• Pharmacokinetic• Pharmacodynamic• Immunogenicity • Clinical efficacy in one indication

Extrapolation of indications: considerations• Mechanism of action the same?• Pharmacokinetic biodistribution the same?• Immunogenicity in different populations?• Toxicity in different populations?

Anti-TNFs on the Top of Biologicals Sales

INN EU patentexp date

US patentexp date

Biosimilars in development *

Adalimumab 2018 2016 13Etanercept 2015 2028 21Infliximab 2014 2018 9Insulin Glargine 2014 2014 5Rituximab 2013 2016 30Bevacizumab 2019 2017 14Interferon B-1a Expired Expired N/ATrastuzumab 2015 2015 N/AInsulin Aspart 2014 2019 N/AGlatiramer acet 2017 2015 N/APegfilgrastim 2015 2014 14Ranibizumab 2016 2016 2

Series10 1 2 3 4 5 6 7 8 9

8.17.37.1

6.25.9

5.355

4.94.34.34

global sales, USD bil-lion

Source: IMS MIDAS, 09/2012, IMS Patent focus, Adapted from G. Morelli, IMS Health*Rader RA, Biosimilars markets. BioProcess International 2013;11(6)suppl:16-23

Total USD67 billion

Infliximab• Chimeric mouse-human Mab• Potently and specifically

neutralizes TNFα• Dampens inflammation

• Licensed Indications• Rheumatoid arthritis• Ankylosing spondylitis• Psoriatic arthritis• Psoriasis• Ulcerative colitis• Crohn’s disease• Paediatric UC and CD

Infliximab• Problems with its use

• Expense• Life threatening infusion reactions

(rare)• Loss of response• Common side effects

• Infections• Skin reactions

• Rare side effects• CNS demyelination• Cancers (?)

Infliximab

HumanFc Region

MouseFAB Arm

Adalimumab

Certolizumab pegol

HumanFc Region

VHVL

CL

CH

CL

MouseFAB Region

HumanFAB Arm

HumanFc Region

HumanFAB Arm

Golimumab

Pharmacokinetic ProfilePLANET AS

Park et al, Ann Rheum Dis 2012;71 (Suppl 3):111

n= 221

Safety - Infections

Treatment-Emergent Infections reported for at least 1% of patients

Remsima 5 mg/kg (n = 128)

Infliximab5 mg/kg (n = 122)

Total No. of patient with infection and infestation 55 49

Bacteriuria

Cervicitis

Influenza

Nasopharyngitis

Pharyngitis

Rhinitis

Tinea pedis

Upper respiratory tract infection

Viral upper respiratory tract infection

-15 -10 -5 0 5 10 15

Number of Events

Park W et al. Ann Rheum Dis 2013

PLANET AS

Efficacy Secondary EndpointN=220

PLANET AS

Park et al, Ann Rheum Dis 2012;71 (Suppl 3):111

PLANET RA – Primary Endpoint:Equivalence by Clinical Response at Week 30

Yoo et al, Ann Rheum Dis 2012;71 (Suppl 3):359

CT-P13 Open Label Extension Trials in RA and AS

• Open label extension, all pts receiving CT-P13 • Approx. 66% entering OLE

Posters presented as late breaking abstracts at ACR 2013

CT-P13

RemicadeR

Wk 0 Wk 102

Wk 54

Double-blind Open label extension

Continue CT-P13

Switch to CT-P13

Continued CT-P13 vs Switching From Remicade to CT-P13 in PLANET-RA

Yoo et al. ACR 2013, L1

ACR20 ACR50 ACR70 ACR20 ACR50 ACR70 ACR20 ACR50 ACR700

102030405060708090

76.8

45.7

21.9

71.5

48.3

24.5

72.2

48.3

24.5

77.5

50

23.9

78.2

47.9

29.6

71.8

51.4

26.1

Wk 78 Wk 102

Perc

ent o

f pat

ient

s (%

)

Wk 52

EMA approval of biosimilar infliximabOn 27 June 2013, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for the medicinal product Inflectra (and Remsima), 100 mg powder for concentrate for solution for infusion intended for the treatment of rheumatoid arthritis, adult Crohn’s disease, paediatric Crohn’s disease, ulcerative colitis, paediatric ulcerative colitis, ankylosing spondylitis, psoriatic arthritis and psoriasis.

European Crohn’s and Colitis Organization:Position statement on biosimilar medications

GUH response• Can biosimilar IFX provide advantages for our patients and hospital?

• Rheumatoid patients already on infliximab?• Rheumatoid patient starting infliximab?

• IBD patients?• Concerns that no published data on use of biosimilar infliximab in IBD

• What are the cost implications of adopting biosimilar infliximab for some or all of our patients at GUH?

GUH• Tertiary referral centre for the west of

Ireland• Extensive use of biological drugs across a

host of indications• Chronic inflammatory diseases

• Inflammatory bowel disease• Inflammatory arthritis• Psoriasis

• Cancer• Haematological• Solid tumours

• Administration setting• Outpatient infusions unit • Haematology/Oncology day ward

• Increasing cost of biological drugs

GUH Drug and Therapeutics committee

Galway University Hospitals (GUH)

Drug and Therapeutics Committee

Terms of Reference

Title

The committee will be known as the Galway University Hospitals Drug and Therapeutics Committee

 Purpose and Objectives of the Committee.

To ensure the safe, rational and cost-effective use of medicines in GUH.

Introduction of Biosimilar monoclonal antibodies in practice: Issues• Chequered history of biosimilar recombinant proteins

• Eprex recombinant erythropoietin• Pure red cell aplasia

• Efficacy long term• Safety long term• Supply• Pharmacovigilence• Extrapolation of indications• Physician autonomy• Impact on cost savings due to vial sharing

GUH Drug and Therapeutics committee: Introduction of Biosimilar Medicines Policy

TITLE: Policy for the Use of Biosimilar Medicines in Galway University Hospitals

REFERENCE NO: CLN-PHAR/UCH-091 REVISION NO: 1

OWNER: Andrew Barber AUTHOR: Tom Walsh, Andrew Barber

APPROVED BY: Andrew Barber Page 1 of 6

EFFECTIVE FROM: 6th March 2014 REVIEW DATE: 6th March 2016

GUH Biosimilar Medicines Policy• Purpose

• The purpose of this policy is to provide guidance and a standardised methodology for the safe introduction and use of licensed biosimilar medicines in GUH. It is important that clinicians should have confidence when prescribing biosimilars for all their licensed indications

GUH Biosimilar Medicines Policy: checklist

Yes NoIs the biosimilar under consideration licensed by the EMA/IMB for its intended indication?

Is there at least one published (or submitted) randomised comparative clinical study, using hard clinical outcomes that demonstrates equivalence with the reference product?

Was human safety (including immunogenicity) data required and provided for the biosimilar’s approval?

Is the clinician/specialist satisfied based on the totality of evidence, that the biosimilar has demonstrated similarity in nature to the reference product, in terms of quality, efficacy and safety?

Have the full projected savings/costs for the hospital been assessed and outlined for the DTC?

Are prescribers aware that prescribing of biosimilars is by brand (or trade) name only?

Will the reference product remain available to clinicians if needed in exceptional circumstances?

Is Pharmacy satisfied with the post-licensing surveillance requirements of the new product?

Is Pharmacy satisfied with the supply arrangements for the new biosimilar?

Is Pharmacy satisfied with the new product packaging, labelling and patient/product information?

Introduction of Biosimilar Infliximab at GUH• Rheumatology Patients

• Consultants satisfied with Switch data• Patients asked for agreement to switch• All (approximately 40) agreed• All switched to biosimilar infliximab in 2014

Introduction of Biosimilar Infliximab at GUH• Inflammatory bowel disease patients

• Consultants not confident in lack of data on IBD patients• Agreed to start new infliximab patients on biosimilar for a trial period• No obvious problems arose• Continued since• No patients switched from the originator

GUH: Use of biological drugs in chronic inflammatory bowel disease• Current usage data

IBD 2015 2014 2013 2012 2011 vials vials vials vials vialsREMICADE 100MG 1729 1973 1669 1442 1219INFLECTRA 100MG 695 88

Total 2424 2061 1669 1442 1219

RHEUMATOLOGY vials vials vials vials vialsREMICADE 100MG 16 145 663 633 694INFLECTRA 100MG 1079 706

Total 1095 851 663 633 694

OVERALL 3519 2912 2332 2075 1913

GUH: Use of biological drugs in chronic inflammatory bowel disease• Results of biosimilar infliximab at GUH

• Too few patients to detect differences in • Efficacy• Safety

• Subsequent recommendation of approval of biosimilar infliximab for all 7 indications by FDA advisory panel

• Subsequent adoption of biosimilar infliximab by several other Irish hospitals

• Subsequent approval for funding by Irish private health insurers

Conclusions• Successful introduction of biosimilar infliximab at GUH• Different approach for rheumatic and IBD patients based on

availability of clinical data• Key role of prescribing consultants• Supported by a policy adopted by the hospital Drug and Therapeutics

committee• Pharmacovigilance maintained• Increased usage of infliximab