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THE NEW BIOLOGICS IN THE RHEUMATIC DISEASES

Benjamin Wang, M.D., FRCPC

Division of Rheumatology

Mayo Clinic

Jacksonville, FL

Disclosures

• None

Topics

• The Biologics Era

• Mechanisms of Action

• Biologics and the Diseases Treated

• Use and Precautions

• Biosimilars: A New Era?

The Biologics Era

• A new period of “molecular medicine”: the therapeutic use

of directed macromolecules

• The first commercial biologic: human insulin (1982, Eli

Lilly and Genentech)

• Other early drugs: tissue plasminogen activator (1987,

Genentech), erythropoietin (1983, Amgen)

• First biologics in arthritis:

• Remicade® (infliximab) [Centocor, Aug. 24, 1998]

• Enbrel® (etanercept) [Immunex, Nov. 2, 1998]

• Humira® (adalimumab) [Abbot, Dec. 31, 2002]

The result of understanding

molecular targets

Choy, E.H. NEJM 2001; 344(12):907-916.

The result of advances in manufacturing

Advanced Biotechnology

Available Anti-TNF Biologic Drugs

I. Solovic et al. Eurr Resp J 2010 36: 1185-1206

The Origin of Species (of mAbs)

The simple days are over…

ciprofloxcin

ixekizumab

Cipro®

Ick® (??)

Taltz®

Mechanisms of Action: 1)Bind the ligand (e.g. cytokine molecule)

• Etanercept (Enbrel)

• Infliximab (Remicade)

• Adalimumab (Humira)

• Certolizumab (Cimzia)

• Golimumab (Simponi)

• Ustekinumab (Stelara)

• Secukinumab (Cosentyx)

Pedersen J. World J Gastroenterol. Jan 7, 2014; 20(1): 64-77

Mechanisms of Action: 2)Block the receptor (e.g. cytokine receptor)

Anakinra (Kineret)

Tocilizumab (Actemra)

Mechanisms of Action: 3)Inhibit cell-cell signaling and activation (e.g. T cell activation)

Abatacept (Orencia)

Mechanisms of Action: 4)Cellular lysis

Samantha M. Jaglowski et al. Blood 2010;116:3705-3714

Rituximab (Rituxan)

Mechanisms of Action: 5) Block growth and differentiation factors

Stohl & Hilbert.Nature Biotechnology 30:69–77 (2012).

Belimumab (Benlysta)

Mechanisms of Action: 6)Block intracellular signaling (e.g. JAK-STAT)

Pedersen J. World J Gastroenterol. Jan 7, 2014; 20(1): 64-77

Tofacitinib (Xeljanz)

Biologics in Rheumatic Diseases -- Reference

Venuturupalli S. Immunol Allergy Clin N Am 37 (2017) 301–313.

Abbreviations: mAb-monoclonal antibody; TCZ-tocilizumab; RA-rheumatoid arthritis;PSA-psoriatic arthritis; JAK-Janus kinase

Indicates FDA approved and commercially available as of March 2018


• Abatacept (T cell signaling inhibitor) –

RA, PSA

• Anakinra (IL-1 receptor antagonist) – RA

• Ustekinumab (IL-12/23 receptor

antagonist) – Psoriasis, PSA

• Belimumab (B cell proliferation inhibitor)

– SLE

• Guselkumab (IL-23 receptor antogonist)

– Psoriasis, PSA

• Apremilast (Phosphodiesterase 4

inhibitor) – Psoriasis, PSA



Approved Biologic Therapies Drug Target Dose Prescreen Other

Rheumatoid Arthritis

Remicade ® (infliximab) TNF 3-10 mg/kg IV q4-8 wk TB, HBV, HCV with MTX

Enbrel ® (etanercept) TNF 50 mg SQ qwk TB, HBV, HCV

Humira ® (adalimumab) TNF 40 mg SQ q2wk TB, HBV, HCV Also Uveitis

Cimzia® (certolizumab) TNF 200 mg SQ q2wk OR

400 mg SQ q4wk

TB, HBV, HCV Load 400 mg SQ

at week 0, 2, 4

Simponi ® (golimumab) TNF 50 mg SQ q4wk TB, HBV, HCV

Orencia ® (abatacept) T cell 500-1000 mg IV q4wk OR

125 mg SQ qwk

TB

Rituxan ® (rituxumab) B cell 1000 mg IV q2wk x 2 HBV

Actemra ® (tocilizumab) IL-6 4-8 mg/kg IV q4wk OR

162.5 mg SQ q1-2wk

TB, HCV, HBV,

lipids

Kineret ® (anakinra) IL-1 100 mg SQ qD CBC

Xeljanz ® (tofacitinib) JAK

1,2

5 mg PO BID OR

11 mg PO qD

TB, HBV, HCV,

lymphocyte count

(>500 cells/mm3)

or abs neutrophil

count (>1000

cells/mm3),

hemoglobin level

greater than 9 g/dL

Drug Target Dose Prescreen Other

Psoriatic Arthritis: see also Enbrel, Remicade, Humira, Cimzia, Simponi, Orencia

Stelara ® (ustekinumab) IL-12/23 45-90 mg SQ q12wk TB

Cosentyx ®

(secukinumab)

IL-17A 150-300 SQ q4wk TB

Taltz ® (ixekizumab) IL-12 80 mg SQ q4wk TB

Tremfya ® (guselkumab) IL-23 100 mg SQ q8wk TB

Otezla ® (apremilast) PDE4 30 mg PO BID TB, HBV

Ankylosing Spondylitis: see Enbrel, Remicade, Humira, Cimzia, Simponi, Cosentyx

Systemic Lupus Erythematosus

Benlysta ® (belimumab) 10 mg/kg IV q4wk None

Vasculitis

Rituxan ® (rituximab) B cell 375 mg/m2 IV qwk x 4 ANCA vasculitis

Actemra ® (tocilizumab) IL-6 162.5 mg SQ qwk GCA

Approved Biologic Therapies

Side Effects

• Actemra® (tocilizumab): infections, increased liver function tests, neutropenia, thrombocytopenia,

increase of lipid levels, and gastrointestinal perforation (rare)

• Benlysta® (belimumab): infection, hypersensitivity reactions, depression. progressive multifocal

leukoencephalopathy (rare)

• Orencia® (abatacept): Side effects: infections, increased frequency of chronic obstructive pulmonary

disease exacerbations, injection site reactions, hypersensitivity reaction

• Otezla® (apremilast): nausea, vlimiting, diarrhea, URTI

• Rituxan® (rituximab): infection, infusion reactions, cytopenias, hepatitis B reactivation. Rarely

progressive multifocal leukoencephalopathy, cardiac arrhythmias, angina

• Stelara®: infections, tuberculosis and other mycobacterial conditions, anaphylaxis, reversible

posterior leukoencephalopathy syndrome

• Taltz® (ixekizumab): Infections, tuberculosis reactivation, hypersensitivity, Inflammatory Bowel

Disease exacerbation

• TNF Inhibitors: infections, including fungal infections and tuberculosis reactivation, hepatitis B

reactivation, cytopenias, heart failure, lupus-like syndrome, non-melanoma skin cancer,

demyelinating disease (rare)

• Tremfya® (guselkumab): upper respiratory infections, headache, injection site reactions, arthralgia,

diarrhea, gastroenteritis, tinea infections, herpes simplex infections

• Xeljanz® (tofacitinib): infections, monitor labs (lymphocytes, neutrophils, hemoglobin, liver

enzymes, lipids). Rarely GI perforation

Adapted from Wolfe and Ang. Immunol Allergy Clin N Am 37 (2017) 283–299

Biosimilars in Rheumatology

• Biopharmaceuticals that replicate originator molecules using similar, but not

identical biomanufacturing processes

• Biosimilar must demonstrate no significant difference from its reference

product

• Robust analytical, toxicologic, PK/PD, and immunogenicity studies in comparison to

reference product

• Smaller comparative effectiveness clinical trial(s), which must be conducted in pts

with a disease for which the reference product is licensed

• No need to demonstrate efficacy in all indications

• No differences in safety or efficacy are expected between an approved

biosimilar and its reference product

• In Europe, the advent of biosimilars to infliximab, etanercept and rituximab

has introduced more treatment choice and led to cost reduction

Parameter Biosimilar Products Generic Drugs

Synthesis In living systems, generally with

recombinant DNA technology Chemical synthesis

Structure vs

reference product Similar Almost completely identical

Structural

complexity

Many layers of structure, including

posttranslational modification Typically simple molecular structure

Immunogenic

potential

Possible; requires testing and

pharmacovigilance monitoring

Less likely; allergic reactions can

occur

Interchangeability

with reference

product

Only when higher standard of

“interchangeable” has been met

Allowed by legislation if standards of

purity and bioequivalence have been

met

Automatic

substitution Guidance pending

Generally allowed; depends on state

law and physician preference

Nomenclature

FDA proposes unique INN (eg,

reference product with a

distinguishing 4-letter suffix that is

devoid of meaning)

INN generally same as reference

product

Why Biosimilars Are NOT Generic Biologics

Slide credit: clinicaloptions.com

Rak Tkaczuk KH, et al. Semin Oncol. 2014;41:S3-S12.

Olech E. Semin Arthritis Rheum. 2016;45:S1-S10.

http://www.clinicaloptions.com/

Critical Attributes for Biosimilarity

Lot-to-lot variability of critical quality attributes must be assessed and

controlled to ensure consistent product quality

High-Quality Biosimilar Not a Biosimilar

Similar

Acceptable

differences

Difference with

critical

or unknown impact

Process-

related

impurities

Higher

order

structure Biological

function

Particles

and

aggregates

Primary

structure

Product purity

Stability

95 attributes similar

2 acceptable differences

0 critical differences

87 attributes similar

7 acceptable differences

3 critical differences

Process-

related

impurities

Higher

order

structure Biological

function

Particles

and

aggregates

Product purity

Stability

General

properties

and

excipients

Primary

structure

Slide credit: clinicaloptions.com FDA. Overview of biosimilar products. 2016.

General

properties

and

excipients


Immunology Biosimilars in the United

States

Biosimilar Approval

Date

Reference

Product Rheumatologic Indications

Infliximab-dyyb

Infliximab-abda

2016

2017 Infliximab

Rheumatoid arthritis

Ankylosing spondylitis

Psoriatic arthritis

Plaque psoriasis

Adalimumab-atto 2016 Adalimumab


Juvenile idiopathic arthritis


Psoriatic arthritis

Plaque psoriasis

Etanercept-szzs 2016 Etanercept


Juvenile idiopathic arthritis


Psoriatic arthritis

Plaque psoriasis


1. Infliximab-dyyb [package insert]. 2016. 2. Infliximab-abda [package insert]. 2017.

3. Adalimumab-atto [package insert]. 2016. 4. Etanercept-szzs [package insert]. 2016.


NOR-SWITCH: Switch to Infliximab-dyyb for Multiple Indications

Remission

61 61

Disease

Worsening*

100

80

60

40

20

0

Pts

With E

ndpoin

t at

Wk 5

2 (

%)

26 30

Treatment Difference: -4.4%

(95% CI: -12.7% to +3.9%) Treatment Difference: 0.6%

(95% CI: -7.5% to +8.8%)

Infliximab (n = 202)

Infliximab-dyyb (n = 206)

53/202 61/206 123/202 126/206

*Primary endpoint.

n/N =

• 52-wk randomized, double-blind

phase 4 trial in pts with RA, SpA,

CD, Ps, PsA, or UC on stable

infliximab for ≥ 6 mos

• Primary endpoint: disease

worsening during 52-wk follow-up

• Prespecified non-inferiority margin:

15%

• Result: Switching from infliximab to

infliximab-dyyb noninferior to

continued treatment with infliximab

Slide credit: clinicaloptions.com Jørgensen KK, et al. Lancet. 2017;[Epub ahead of print].


VOLTAIRE-RA phase III randomised equivalence study of

adalimumab biosimilar BI 695501 and Humira

reference product

Cohen SB et al. Ann Rheum Dis 2018 epub ahead of print.. doi:10.1136/annrheumdis-2017-212245

Reference

Biologic

Drug

Class

~ Patent

Exp.

Date

Indication Biosimilars With Phase III

Clinical Trials

Rituximab[1-3] CD20

inhibitor 2016

Lymphoma;

RA

BCD-020 equivalent PK/PD,

efficacy, safety in iNHL

CT-P10 equivalent PK/PD, efficacy,

safety, immunogenicity in RA

RTXM83 equivalent PK, safety in

DLBCL

Adalimumab[2-

4]

TNF-α

inhibitor 2022*

Autoimmune

diseases

BI695501 accepted for FDA review

Multiple others registered/under

way

Infliximab[2-4] TNF-α

inhibitor 2018*

Autoimmune

diseases Multiple registered/under way

Biosimilars Currently in the Pipeline for

Rheumatologic Conditions

*Ongoing patent litigation.


1. Rugo HS, et al. Cancer Treat Rev. 2016;46:73-79. 2. Stevenson JG, et al. Ann

Pharmacother. 2017;[Epub ahead of print]. 3. Panesar K. US Pharm. 2016;41:26-29. 4. Goel

N, et al. Rheumatology. 2017;56:187-197.


Potential Scenarios: Incorporation of Biosimilars Into

Clinical Practice

• Gradual introduction of biosimilars only in patients newly starting a

biologic

• Instant switching to biosimilars for patients currently receiving a

biologic

• Switching due to loss of response or adverse events with a biologic

• Switching between the biosimilar and the reference drug on an

alternating basis, depending on pharmacy supply and drug product

availability

• In the United States, the complexity of drug pricing and distribution

through Pharmacy Benefit Managers does not guarantee easier

access or significantly lower cost (Fleischmann, Arthritis Rheum 2018)



Summary

• Biologics are now a well-established form of drug therapy

using a variety of targeting molecules based on the

knowledge of the mechanisms of disease

• As molecular pathways become clearer, more directed

treatments will emerge

• Biologics for diseases of immunity and inflammation are

highly efficacious and share similar side effects

• Biosimilars are molecules manufactured in the same

principle of their parent originator drugs – they hold the

promise of providing greater access, equal efficacy and

safety, and lower cost

[email protected]

Thank you

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