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Biosimilars 2017: What We Need to Know

Miguel Regueiro, M.D.Professor of Medicine

IBD Clinical Medical Director

Senior Medical Lead, Specialty Medical Homes

University of Pittsburgh Medical Center

Disclosures

Consultant:

• Abbvie

• Amgen

• Janssen

• Miraca laboratories

• Pfizer

• Takeda

• UCB

Research Grants:

• Abbvie

• Janssen

• Takeda

What will biosimilars mean for us?

In the last decade we were finally getting comfortable with biologics – now come along the biosimilars

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Why even have this talk?

Why not stick with what we know and love!

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Annual Revenue Due to Adalimumab

https://www.bloomberg.com/news/articles/2016-01-29/abbvie-revenue-gains-as-top-drug-humira-sales-continue-rising, Accessed Feb 5, 2017

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One approach to healthcare costs is similar to Themos’s car

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Maybe we can get away with...

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“It is likely that biosimilars will be widely used for the treatment of

IBD due to their cost savings and comparable efficacy.”

Papamichael et al. Review article: pharmacological aspects of anti-TNF biosimilars in inflammatory

bowel diseases.

AP&T 20159

Inflammatory Bowel Diseases. 22(10):2513-2526, October 2016.

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A Critical Review of Biosimilars in IBD: The Confluence of

Biologic Drug Development, Regulatory Requirements, Clinical Outcomes, and Big

Business.Ha, Christina; Kornbluth, Asher

Biosimilars: Confusion

• Are They Generics?

• How Similar Can They Be?

• Were They Tested in Humans Prior To Approval?

• Will They Get “Blanket Approval” For All Indications?

• Will Prescribers Control What Patients Get?

• How Much Cheaper Will They Be?

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Biosimilars• Biosimilars are a similar copy of an originator biologic

therapy. NOT GENERICS. The originator is also sometimes called “the reference product” or “innovator.”

What should be the same? What is different?

Strength

They are NOT an identical copy in every way (glycosylation may differ)

Route of administration

Effectiveness

Safety profile

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TNF Concentration and AntiDrug Antibody SimilarPapamichael 2015

TNF Concentration Similar between BSM and Reference in Healthy Controls Chingcuanco 2016

TNF Concentration Similar between BSM and Reference in AS and RA

Chingcuanco 2016

August 2016

What are the clinical efficacy data comparing a Biosimilar to Reference antiTNF? Note: no comparative studies in IBD, all data extrapolated from AS/RA

No Clinical Efficacy Difference between BSM and Reference antiTNF in AS or RA

Indication

Indication 1

Indication 2

Indication 3

Indication 4

Indication 6

Indication 6

Biosimilars Can be Extrapolated to Other Indications• Comparison studies of a biosimilar that show equivalent efficacy and safety to

the originator in ONE INDICATION may be EXTRAPOLATED to all indications for the originator

Adapted from: US Biologics Price Competition and Innovation Act of 2009

EXAMPLE: biosimilar infliximab that works equally well in rheumatoid arthritis can be extrapolated and receive FDA approval without any additional studies for Crohn’s disease, ulcerative colitis, ankylosing spondylitis, psoriasis and psoriatic arthritis.

• Mechanism of action• Pharmacokinetics• Immunogenicity• Toxicities

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Interchangeable Biosimilars

• “Interchangeable” designation of biosimilars may allow for free exchange with originator biologics with no greater risk of adverse effects or diminished efficacy

• Statute allows pharmacy substitution of interchangeable biosimilars without prescriber intervention

• Subject to each state’s laws and regulations governing drug

• FDA determines whether a biosimilar is interchangeable or not

– Requires studies of cross-over between originator and biosimilar

Adapted from: US Biologics Price Competition and Innovation Act of 2009

“….patients who developed Anti-Drug Antibody to either infliximab or CT-P13 will not benefit from switching to the other drug…..”

Papamichael 2015 AP&T

Biosimilars for IBDInflectraTM is the first FDA approved biosimilar for inflammatory bowel disease

– Has biosimilarity to Infliximab (Remicade®)

– Not interchangeable (per regulatory)

– Studied in:

• Ankylosing Spondilitis

• Rheumatoid Arthritis

– Extrapolated to:

• Crohn’s disease (in adults and children)

• Ulcerative colitis (in adults)

– Not available yet, projected 2018

AmjevitaTM is the second FDA approved biosimilar (adalimumab) for inflammatory bowel disease

2016: The First Monoclonal Biosimilars Received US FDA Approval

• Food and Drug Administration approved biosimilar for infliximab (-dyyb) on April 5, 20161 and adalimumab (-atto) on September 23, 2016.2

• Approved for most but not all of the same indications

• Launch: “Pfizer press release 10/17/16: “Pfizer Inc. (NYSE:PFE) announced today that the company will begin shipment of INFLECTRA® (infliximab-dyyb)for injection, a biosimilar of REMICADE®1 (infliximab) to wholesalers in the United States (U.S.) in late November 2016.” 3

• Price? : “INFLECTRA will be introduced at a 15% discount to the current wholesaler acquisition cost (WAC) of REMICADE®, its reference product.”3

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1http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm494227.htm. Published April 5, 2016. Accessed August 6, 2016. 2http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm522243.htm. Published and accessed September 23, 2016. 3http://www.pfizer.com/news/press-release/press-release-detail/pfizer_announces_the_u_s_availability_of_biosimilar_inflectra_infliximab_dyyb. Published and accessed 10/17/16.

HOW HAVE BIOSIMILARSPERFORMED IN IBD?

Papamichael et al. AP&T 2015

Clinical Response 33% - 100% (most > 60%) and Remission 38% -100% (most > 65%):remember no IBD head-head BSM vs Reference

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Clinical Experience with CT-P13 in IBD: Updated Systematic Review

• 13 studies in Korea, Hungary, Czech, Norway, Netherlands, Italy involving at least 500 IBD patients who were switched from IFX to CT-P13

• Treatment persistency ranged 57%-88% at end of follow-up

• Adverse events in the range of expected

• Infusion reactions up to 6.6%

• ATI in the range of expected

Danese S et al, J Crohns Colitis 2017;11(1):26-34

Clinical Experience with CT-P13 in IBD: Prospective Study

• Prospective Italian study: PROSIT-BIO

– 547 patients

– Clinical response at 8 weeks

• 90% in anti-TNF-naïve

• 89% in previous anti-TNF

• 100% in switchers from IFX

– Loss of response (median 4 months follow up)

• 17.8% anti-TNF-naïve

• 29.1% anti-TNF-experienced

• Only 7.9% in switchers

– Infusion reactions occurred twice as often in IFX exposed if drug holiday had been >4 months

Fiorino G et al, Inflamm Bowel Dis 2017;23:233-43

Prospective Trial of Switching From Originator Infliximab to CT-P13: NOR-SWITCH

• 481 Norwegian patients with CD, UC, SpA, RA, PsA, Ps

• Stable, on IFX ≥6 months• Randomized 1:1 to continued IFX

or CT-P13 for 52 weeks• Primary endpoint: clinical

worsening– “…worsening in disease specific

composite measure or consensus between investigator and patient leading to major change in therapy”

• Non-inferiority, margin of 15%

Jorgenson KK et al, UEGW 2016 Late breaking abstract. UEGJ 2016;4(6):805-6.

Primary endpoint met: however, difference in CD subset barely missed statistical significance

Biosimilars: Study Designs

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Reference drug

Biosimilar

Transition Study1

Single Switch2

Multiple Switches1

Reference drug

Biosimilar

Reference drug

Biosimilar

1. Dörner T, Kay J. Nat Rev Rheumatol. [published online ahead of print August 18, 2015] doi:10.1038/nrrheum.2015.110. 2. 2. Clinicaltrials.gov NCT01970488. Available at: https://www.clinicaltrials.gov/ct2/show/record/NCT01970488. Accessed October 2015.

CAN WE SWITCH FROM ONE TO THE OTHER?

A multi-centre double-blind, parallel-group RCT will investigate the safety

and efficacy of switching from innovator infliximab to CT-P13

compared with continued treatment with infliximab in patients with RA, AS, CD, UC, psoriatic arthritis and plaque

psoriasis until week 52 (NOR-SWITCH study – ClinicalTrials.gov NCT02148640)

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NOR-SWITCH (Jørgensen, et al. abstract LB15)Presented at UEGW (Vienna) 2016

• Phase IV multi-indication prospective non-medical switch study in Norway by Norwegian govt. – 52w randomized, double blind non inferiority study

• RESULTS:– Primary outcome: disease worsening at 12 months

• Remicade 53/202 (26.2%) vs. CT-P13 61/206 (29.6%)

– Anti-drug antibodies:

• Remicade 7.1%

• CT-P13 7.9%

Remicade

CT-P13 (Inflectra/Remsima)

Week 52

Remicade CT-P13

CD (n=155) 14 (21.%) 23 (36.5%)

UC (n=93) 3 (9.1%) 5 (11.9%)

Disease Worsening

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Concluding statement from recent systematic review in the Annals of Internal Medicine:

“Preliminary evidence supports the biosimilarity and interchangeability of biosimilar and reference TNF inhibitors.”

Infliximab: Remicade® indications not included in biosimilar Inflectra™ FDA approval

FDA Indication Remicade® Inflectra™

Adult Crohn’s Disease Yes Yes

Pediatric Crohn’s Disease Yes Yes

Adult Ulcerative Colitis Yes Yes

Pediatric Ulcerative Colitis Yes No

Adult Rheumatoid Arthritis Yes Yes

Adult Ankylosing Spondylitis Yes Yes

Adult Psoriatic Arthritis Yes Yes

Adult Plaque Psoriasis Yes Yes

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http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm494227.htm. Published 4/5/2016; accessed September 235 2016.http://www.remicade.com/shared/product/remicade/prescribing-information.pdf. Revision 10/2015; Accessed September 25, 2016

Adalimumab: Humira® indications not included in biosimilar Amjevita™ FDA approval

FDA Indication Humira Amjevita

Adult Crohn’s Disease Yes Yes

Pediatric Crohn’s Disease Yes No

Adult Ulcerative Colitis Yes Yes

Adult Rheumatoid Arthritis Yes Yes

Juvenile Idiopathic Arthritis Yes Yes

Adult Ankylosing Spondylitis Yes Yes

Adult Psoriatic Arthritis Yes Yes

Adult Plaque Psoriasis Yes Yes

Hidradenitis Suppurativa Yes No

Adult Uveitis Yes No

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http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm522243.htm. Published and accessed September 23, 2016.http://www.rxabbvie.com/pdf/humira.pdf. Revision 7/2016; Accessed September 25, 2016

www.ncsl.org, accessed 2/7/17

State variations on: Prescriber notification Patient notification “Medically Necessary” Pharmacy records

Biosimilars in 2017• Are extrapolation data (AS and RA) ok? Probably

• Is it ok to start a biosimilar in an antiTNF naïve patient? Yes

• Is it ok to switch from the innovator drug to a biosimilar in someone doing well? Yes, but will UC and CD be different?

– Will pharmacies be able to switch to a biosimilar automatically? Not in USA (at this time)

• Will there be issues of immunogenicity? Yes, same as reference product

• Will a biosimilar be cheaper? How much? And will innovator meds reduce price? That’s the $1,000,000,000 question!!!!

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…..We probably shouldn’t take this approach to biosimilars…...

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