briakinumab for the treatment of plaque psoriasis

Briakinumab for the Treatment of Plaque PsoriasisPawel Traczewski1 and Lidia Rudnicka1,2,3

1 Department of Dermatology, CSK MSWiA, Warsaw, Poland

2 Polish Academy of Sciences, Warsaw, Poland

3 Faculty of Health Sciences, Warsaw, Medical University, Warsaw, Poland

Contents

Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

2. Interleukin (IL)-12 and IL-23 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

2.1 Structure and Function of IL-12 and IL-23 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

2.2 The Role of IL-12 and IL-23 in Psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

3. Pharmacological Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

3.1 Drug Discovery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

3.2 Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

3.3 Pharmacokinetics and Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

4. Briakinumab in the Treatment of Psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

4.1 Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

4.2 Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

4.3 Quality of Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

5. Approval Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Abstract Psoriasis is a chronic inflammatory skin disorder affecting approximately 2% of individuals worldwide.

An improved understanding of the pathogenesis of psoriasis has led to the development of targeted biologic

therapies. Briakinumab (ABT-874) is a recombinant human antibody that blocks the biological activity of the

cytokines interleukin (IL)-12 and IL-23 through their shared subunit p40. IL-12 and IL-23 are keymediators

in T-cell differentiation and have been shown to play a significant role in maintaining inflammation and

abnormal keratinocyte function in psoriasis patients through development and stimulation of Th1 and Th17

subsets, respectively. In one phase II and four phase III studies (including two 52-week trials), the Psoriasis

Area and Severity Index (PASI)-75 score at weeks 12 and 52 was achieved by at least 80.6% and 66.2%(p< 0.001) of patients receiving more than one dose of briakinumab every 4 weeks, respectively, with high

proportions of patients achieving PASI-90 and PASI-100 scores (at least 55.4% and 28.8%, respectively;

p< 0.001). These studies indicate safety and tolerance of briakinumab therapy for patients with moderate-to-

severe chronic plaque psoriasis. In one clinical trial, therapy was associated with increased incidence of major

cardiac events. Available results from two briakinumab trials show its positive impact on health-related

quality of life. However, the manufacturer has now withdrawn the application in the EU and US.

1. Introduction

Psoriasis is a chronic, inflammatory disease, characterized

by abnormal epidermal differentiation and hyperproliferation.

It is a kind of autoimmune disorder that is caused by abnormal

activity of both B cells and T cells. Its pathogenesis involves

environmental (exposure to infections, pollutants), geographic,

and genetic factors; it occurs in half of the siblings of persons

REVIEWARTICLEBiodrugs 2012; 26 (1): 9-20

1173-8804/12/0001-0009/$49.95/0

ª 2012 Adis Data Information BV. All rights reserved.

with psoriasis when both parents are affected.[1] The average

prevalence of psoriasis in adults is estimated at 2%, although it

varies widely in different parts of the world and among different

ethnic groups.[1-4] Psoriasis occurs slightlymore often inwomen

than inmen. Plaque psoriasis is themost common form, affecting

80–90% of patients. Patientsmay also experience extracutaneous

manifestations commonly including nail involvement in 50% and

psoriatic arthritis in up to 20% of patients.[1]

The most commonly used evaluation tool of disease activity

in clinical trials is the Psoriasis Area and Severity Index (PASI).

PASI encompasses assessment of erythema, infiltration, and

desquamation in four body regions (head, trunk, upper and

lower extremities). Severity parameters are measured on a scale

from 0 (no symptoms) to 4 (verymarked symptoms) and overall

score ranges from 0 to 72. For patients with severe psoriasis, at

least 75% improvement in the PASI score is typically consid-

ered to be a clinically meaningful improvement and is widely

accepted as the treatment goal. The term ‘PASI-75’ corre-

sponds to a decrease in PASI score of 75%. Similarly, PASI-90

is a 90% improvement in the PASI score.[5]

The therapeutic repertoire for patients with moderate-to-

severe psoriasis has expanded significantly in recent years,

mainly due to a better understanding of the immunologic basis

of psoriasis. Psoriasis was previously considered primarily a

result of aberrant CD4 T-helper 1 (Th1)-mediated immune

responses that affected keratinocytes.[6,7] Interleukin (IL)-12,

which is the primary cytokine responsible for the activation and

differentiation of naive T-cells into CD4 Th1 cells, was con-

sidered one of the potential therapeutic targets and anti-p40

medications were initially designed to alter the activity of this

pathway. However, recent research has highlighted the possi-

bility of other mechanisms of anti-p40 antibodies. The finding

that there is significantly more IL-23 in the psoriatic plaques

than IL-12 led to the hypothesis of blocking IL-23 as a pre-

dominant effect of these medications.[8,9] The rationale for

targeting both IL-12 and IL-23 was further supported by the

present understanding of complex interactions of immune cells

in the skin. It was observed that IL-23 activates naive T-cells to

differentiate into the newly described population of Th17 cells,

which in turn produce two critical cytokines, IL-17 and IL-22,

which may be associated with the immune-mediated functional

aberrations of keratinocytes resulting in clinical symptoms of

psoriasis.[9-11]

Ustekinumab, the first anti-p40 human monoclonal anti-

body, is an approvedmedication formoderate-to-severe plaque

psoriasis. Briakinumab, the second biologic agent with a similar

mechanism of action, was previously investigated in Crohn’s

disease, rheumatoid arthritis, and multiple sclerosis, but there

are no active studies in these diseases at present.[12] Its phase II

and phase III clinical trials in patients with psoriasis showed

generally favorable efficacy and safety results.[13,14] However,

the manufacturer has withdrawn its marketing applications in

the EU and US for the treatment of psoriasis[15] (see section 5).

2. Interleukin (IL)-12 and IL-23

2.1 Structure and Function of IL-12 and IL-23

IL-23 is a heterodimeric cytokine composed of a p19 subunit

and p40 subunit (40-kDa heavy chain) and was discovered in

2000.[12] The formation of biologically active IL-23 requires the

synthesis of both p19 and p40 subunits within the same

cell.[12,16] IL-23 is expressed predominantly by activated den-

dritic cells and phagocytic cells (monocytes, macrophages, and

neutrophils). The p40 subunit binds to IL-12Rb1, which is also

a subunit of IL-12 receptor, and the p19 subunit binds to a

unique receptor subunit, IL-23R.[17]

IL-12 shares with IL-23 the p40 subunit which is linked by

a disulfide bridge to 35-kDa light chain (known as p35 or

IL-12a), which has an overall sequence identity of approx-

imately 40% with the p19 subunit of IL-23.[12] IL-12 was first

discovered in 1989. p35 is homologous with other single-chain

cytokines, whereas p40 is homologous with the extracellular

domain of members of the hematopoietic cytokine receptor

family. IL-12, similarly to IL-23, is predominantly produced by

dendritic cells and phagocytes in reaction to microbial stim-

ulation. Production of p35 is a rate-limiting step and requires co-

expression of p40 for secretion of biologically active IL-12.[12,16]

The effects of IL-12 and IL-23 on the immune response are

related, but distinct (see figure 1). Whereas IL-12, required in

antimicrobial responses for intracellular pathogens, primarily

stimulates naive T cells’ differentiation into Th1CD4+ cells andproduction of interferon (IFN)-g, IL-23 preferentially stim-

ulates survival and proliferation of a unique set of CD4+ cells,

named Th17. IFNg produced by IL-12-activated Th1 cells

plays a dual role suppressing the differentiation of Th17 cells

while also stimulating macrophage function.[16] Th17 cells are

characterized by production of the pro-inflammatory mediator

IL-17, a critical regulator in the establishment and perpetuation

of autoimmune inflammatory response, IL-6, IL-1, and tumor

necrosis factor (TNF)-a. IL-17 was shown to play a key role in

mediating inflammation and in pathogenesis of several auto-

immune diseases, including psoriasis, Crohn’s disease, and

multiple sclerosis.[18] Increased expression of IL-23 and IL-12

was detected in patients with rheumatoid arthritis, psoriasis,

and Crohn’s disease.[16]

10 Traczewski & Rudnicka

ª 2012 Adis Data Information BV. All rights reserved. Biodrugs 2012; 26 (1)

Both IL-12 and IL-23 bind to the b-1 receptor of T cells and

natural killer cells via their shared p40 subunit.[19] The discov-

ery of a common p40 subunit in IL-12 and IL-23 explained why

clinical response during treatment with a monoclonal antibody

directed against IL-12 is also associated with inhibition of IL-23

function.[18]

2.2 The Role of IL-12 and IL-23 in Psoriasis

IL-12 and IL-23 were shown to play a significant role in

maintaining inflammation and abnormal keratinocyte prolif-

eration in psoriasis and the process of joint destruction in

psoriatic arthritis.[20-22] Both IL-12 and IL-23 are characterized

by markedly increased expression (with more evident increase

of IL-23 secretion) in psoriatic skin lesions compared with

normal-looking skin in these patients.[23,24] Th17 and Th1 cells,

differentiated upon stimulation by IL-23 and IL-12, respectively,

are predominant in psoriasis and contribute to vasodilation,

white-blood-cell recruitment, and keratinocyte proliferation.[9]

In vitro studies demonstrated that IL-12 induces prolifera-

tion and differentiation of CD4-naive T cells to Th1 and NK

cells, and activates NK cells, which produce the proin-

flammatory cytokines involved in maintaining inflammation in

psoriasis.[25-29] These cytokines include TNFa, a key cytokine

in the pathogenesis of psoriasis and the acknowledged target

for biological therapy.

Experiments showed abnormally high expression of IL-23

p40 and p19mRNA inmonocyte-derivedmature dendritic cells

from patients with psoriasis.[24] IL-23 promotes survival and

proliferation of Th17 cells. Cytokines IL-17 and IL-22 pro-

duced by Th17, acting in synergy with IL-19, IL-20, and IL-24,

produced by IL-20-activated resident macrophages, in turn

stimulate keratinocyte proliferation, which enables further, in-

creased proliferation of epidermal cells in psoriasis lesions.[11,18]

3. Pharmacological Properties

3.1 Drug Discovery

Briakinumab (ABT-874) is a recombinant, fully human, IgG1

monoclonal antibody designed to target the common p40 sub-

unit of IL-12 and IL-23.[30] Its structure is indistinguishable from

that of normal human IgG antibodies, with the only difference

being in the IL-12 p40-specific antigen-binding region. It mini-

mizes the risk of human anti-foreign protein constituents. Bria-

kinumab was initially isolated by screening three separate single-

chain variable fragment phage display libraries of antibodies to

IL-12 derived from human lymphoid cells. Target affinity was

improved by mutagenesis of the complementarity-determining

regions (CDRs) of both the heavy (H) and light (L) chains. The

resulting V regions were assorted and further modified by in-

dividuallymutating specific contact positions. Briakinumabbinds

with high affinity to the soluble forms of IL-12 and IL-23.[31]

3.2 Pharmacodynamics

The functional activities of briakinumab were measured

in vitro, in vivo, in animal models (murine and primates), and in

clinical studies.[16,19] Briakinumab in vitro was shown to inhibit

the binding of radiolabeled IL-12 to the IL-12R on phytohe-

magglutynin (PHA)-activated lymphoblasts as well as prolif-

eration of IL-12-stimulated, PHA-activated lymphoblasts.[32]

Because briakinumab does not cross-react with rodent

IL-12, a substitute approach using amatched antibody directed

against murine IL-12 p40 was developed in order to model the

effect of briakinumab in mice. The compound, C17.15, has

binding and neutralization characteristics for mouse IL-12/23that are similar to those of briakinumab.[16,19] In amousemodel

of experimental trinitrobenzene sulfonic acid-induced colitis,

single doses of C17.15 decreased IFNg secretion from CD4+T cells and IL-12 production from macrophages. The effect of

briakinumab on IL-12 in cynomolgus macaques has also been

tested.[33] Intravenous administration of briakinumab in mon-

keys prevented leucopenia and thrombocytopenia associated

with human IL-12 administration, suppressed neopterin (a

marker of monocyte activation in response to IFNg), and re-

sulted in minimal complement fixation and activation. In all

experimental models, briakinumab was able to reduce the in-

flammatory reaction and no antibody-dependent cytotoxicity

was demonstrated.[19]

NaiveT cells

Th17 Th1

IL-23 IL-12

IL-17, IL-6, IL-22IL-1, TNFα TNFα, IFNγ

IL-23 IL-12

Chronic inflammation

⎧ ⎪ ⎪ ⎪ ⎪ ⎨ ⎪ ⎪ ⎪ ⎪ ⎩ ⎧ ⎪ ⎪ ⎪ ⎨ ⎪ ⎪ ⎪ ⎪ ⎩

Intracellular microbial responseTumor suppressionChronic inflammation

IFNγ

Maturedendritic

cells

Maturedendritic

cells

Fig. 1. Role of interleukin (IL)-23 and IL-12 in the development and

stimulation of Th17 and Th1 cells and in the inflammatory process.[14,16]

IFNg = interferon-g; TNFa= tumor necrosis factor-a.

Briakinumab for the Treatment of Plaque Psoriasis 11


In vivo results in humans have also shown that briakinumab

reduces inflammation. In a clinical trial of patients with Crohn’s

disease, treatment with briakinumab was associated with de-

creased secretion of IL-12, IL-6, IFNg, and TNFa, but not

IL-10 and IL-18. The magnitude of change in cytokine secre-

tion wasn’t dose-dependent.[19,34]

3.3 Pharmacokinetics and Metabolism

There have been two phase I studies in healthy volunteers

investigating the tolerability, safety, and pharmacokinetics of

briakinumab.[19] A double-blind, randomized, placebo-controlled,

crossover study evaluated four different briakinumab doses by

intravenous and subcutaneous administration in 64 healthy

male subjects. Both maximum serum concentration and the

area under the concentration-time curve values increased line-

arly with increasing doses. The volume of distribution at steady

state and clearance were independent of dose. Briakinumabwas

primarily distributed within the vascular space and had a pro-

longed terminal half-life of approximately 8–10 days following

a single IV dose of 1.0–5.0mg/kg. The time to maximum con-

centration for briakinumab was observed to be between 3 and

4 days. The absolute bioavailability of briakinumab was 42%and 63% following subcutaneous and intravenous administra-

tion, respectively.[16,19,35] Data on repeated infusions, available

only from experiments on animalmodels, indicated no systemic

accumulation of briakinumab with maintenance dosing. The

subcutaneous bioavailability of briakinumab was 60.7% in

males and 49.1% in females and did not change with repeated

dosing in cynomolgus macaques.[19]

4. Briakinumab in the Treatment of Psoriasis

4.1 Efficacy

There was one phase II study with two extension phases[30,36]

and four phase III studies[37-41] investigating the efficacy and

safety of briakinumab therapy in patients with moderate-to-

severe plaque psoriasis (see table I). The phase III studies began

in late 2007 and 2008 and have been completed recently.

A phase II, double-blind, placebo-controlled, dose-finding

study with two extension phases[30,36] (see figure 2) was con-

ducted to evaluate the preliminary efficacy and safety of bria-

kinumab in patients with moderate-to-severe chronic plaque

psoriasis. During the initial 12-week phase, a total of 180 sub-

jects were randomized to one of five study arms: subcutaneous

briakinumab 200mg injected once at week 0, 100mg every

other week for 12 weeks, 200mg weekly for 4 weeks, 200mg

every other week for 12 weeks, 200mg weekly for 12 weeks, or

placebo. The majority (74.4%) of patients were male, 92.2%were White, and 28.9% of patients had a history of psoriatic

arthritis. At baseline, the mean body surface area involvement

was 25%, and the mean PASI score was 18.8. The primary

outcome measure was the proportion of subjects achieving a

75% improvement in the PASI score at week 12. There was a

statistically significantly greater proportion of patients ach-

ieving PASI-75 at week 12 between all treatment groups when

compared with placebo (200mg once, 63%; 100mg every other

week for 12weeks, 93%; 200mgweekly for 4weeks, 90%; 200mg

every otherweek for 12weeks, 93%; 200mgweekly for 12weeks,

90%; placebo, 3%; p< 0.001). Over 90% of patients receiving

more than one dose of briakinumab achieved a PASI-75 re-

sponse by 12 weeks and over 97% achieved at least a PASI-50

response (p < 0.001).After the initial 12-week treatment phase, all medication was

discontinued and patients entered a 36-week, single-blinded,

observation/retreatment extension phase (see figure 2).[36] Those

patients who had met the primary endpoint of a ‡PASI-75

response at week 12 (n = 130; one placebo) were eligible for

retreatment. 40 non-responders (<PASI-75 response) were moni-

tored but not eligible for retreatment. Patients who lost response

after week 12 and through week 36, defined as a reduction of

PASI below 50% (n = 58; all briakinumab), received retreat-

ment with the same dosing regimen as originally assigned in the

first randomized treatment phase.The retreatment lasted 12weeks.

Most of the patients (n = 72) were able to maintain response

(at least PASI-50 score) until week 36 and were not retreated.

Amajority of patients (55–94%) in all treatment arms were able

to achieve a PASI-75 response 12 weeks after reinitiation of

briakinumab therapy.

Patients (n = 105) who achieved at least a PASI-75 response

at week 12 of initial treatment and actively participated in

the observation/retreatment phase were allowed to enter the

60-week, open-label, extension phase (see figure 3).[36] Patients

who lost PASI-50 response compared with baseline during that

phase of the study were retreated with either one dose of bria-

kinumab 200mg or two doses of briakinumab 200mg weekly

based on their dosing regimen in the initial 12-week phase of the

study. Patients who experienced subsequent loss of PASI-50

response occurring within <12 weeks of the previous retreat-

ment were retreated again with the same dosing regimen. Re-

treatment could be repeated up to five times (the majority of

patients were retreated three times, with only a small number

of patients retreated four or five times) until week 56 of the

open-label extension phase. The proportion of patients who

achieved PASI-50 (92.5% after first retreatment with two doses



Table

I.Clinicaltrialsofbriakinumabin

plaquepsoriasis

Study

Studydesign

Primary

endpoint

Dosage(n)

Efficacy,PASI-

75(%

patients)

Safety

Kim

balletal.[30]

Randomized,double-blind,place

bo-

controlled,multicenter,phaseIItrial;n=180

Percentageof

patients

achieving

PASI-75atwk12

One200mgdoseat

wk0(30)

63

Themost

commonAEwasinjectionsite

reaction;themost

commoninfectio

usAEwas

nasopharyngitisandupperrespiratory

tract

infectio

n

Noseriousinfectio

usAEs

100mgevery

otherwkfor

12wk(30)

93

200mgwklyfor4wk(30)

90

200mgevery

otherwkfor

12wk(30)

93

200mgwklyfor

12wk(30)

90

Placebo(30)

3

Kim

balletal.[36]

Observatio

n/re

treatm

entofpatients

who

achievedPASI75in

theabove

phaseIItrial.

Treatm

entw

ithbriakinumabwasdiscontinued,

andpatients

wholostresponse(PASI<5

0)

duringwk12–36receivedretreatm

entwiththe

samedosingregim

en;n=130

Percentageof

patients

reaching

PASI-75atwk12

ofretreatm

ent

One200mgdoseat

wk0(11)

55

AEsoccurring‡5

%in

atleastonetreatm

ent

groupin

descendingorderthroughwk48:

nasopharyngitis,injection-sitereaction,upper

respiratory

tractinfectio

n,headache,

hypertension,arthralgia

100mgevery

otherwkfor

12wk(16)

94

200mgwklyfor

4wk(13)

69

200mgevery

otherwkfor

12wk(12)

75

200mgwklyfor

12wk(6)

83

Kim

balletal.[36]

60-w

k,open-label,extensionphaseofthe

initialp

haseIItrial.Patients

whoachievedat

least

aPASI-75responseatwk12ofinitial

treatm

entandactivelyparticipatedin

the

observation/re

treatm

entphaseandlostPASI-

50responsewere

retreatedwithoneortwo

dosesofbriakinumab200mg,dependingon

theinitialdose.P

atientswhosubsequentlylost

response£1

2weeksafterretreatm

entwere

retreatedagain

(upto

5cycles);n=105

Onlyseco

ndary

endpoints,i.e.PASI-

50,PASI-75,PASI-

90,12wkafter

retreatm

ent,

PGAscores,safety

200mg/wk·1(58)

46.9

(1cycle)

16.7%

ofpatients

experiencedtreatm

ent-

emergentAEs;29.2%

experience

dinfectio

ns.

Most

commonAEswere

nasopharyngitis,

upperrespiratory

tractinfectio

n,injectionsite

reactions,andhypertension.Threeserious

AEsoccurred;noseriousinfectio

ns

200mg/wk·2(47)

57.5

(1cycle)

Gordonetal.[37]

PhaseIII,52-w

k,double-blind,place

bo-

controlled,two-phase(inductio

nand

maintenance)trial;n=1465

Percentageof

patients

reaching

PASI-75atwk12

200mgatwk0andwk4,

followedby100mgat

wk8(981)

80.7

ThemostcommonAEswere

nasopharyngitis,

headache,andupperrespiratory

tract

infectio

ns.IncidenceofseriousAEshigherin

Continuednextpage



Table

I.Contd

Study

Studydesign

Primary

endpoint

Dosage(n)

Efficacy,PASI-

75(%

patients)

Safety

briakinumabrecipients

thanin

placebo

recipients.Most

seriousAEswere

malignancies:mostlysquamouscellorbasal

cellskin

carcinomas.

7MACEoccurredin

briakinumabgroup

Placebo(484)

4.5

Percentageof

patients

reaching

PASI-75at52wk

100mgevery

4wk(298)

82.4

100mgevery

12wk(298)

46

Placebo(149)

9

Gottliebetal.[38]

PhaseIII,double-blind,double-dummy,

multicenter,randomizedstudy;n=347

Percentageof

patients

reaching

PASI-75atwk12

Briakinumab100mgatw

k

0andwk4,followedby

100mgatwk8(141)

81.9

IncidenceofAEsforbriakinumabandETN

sim

ilarandslightlyhigherthanplacebo.Low

numberofseriousAEs.Themost

frequent

treatm

ent-emergentAEsin

theactive

treatm

entgroupswere

nasopharyngitis,upper

respiratory

tractinfectio

n,injectionsite

reaction,andheadache.NoMACEacross

groups

ETN50mgtwicea

wk(138)

56.0

Placebo(68)

7.4

Stroberetal.[39]

PhaseIII,double-blind,double-dummy,

multicenter,randomizedstudy;n=350

Percentageof

patients

reaching

PASI-75atwk12

Briakinumab100mgatw

k

0andwk4,followedby

100mgatwk8(139)

80.6

IncidenceofAEsforbriakinumabandETN

sim

ilarandslightlyhigherthanplacebo.Low

numberofseriousAEs.Themost

frequently

reportedtreatm

ent-emergentAEsintheactive

treatm

entgroupswere

upperrespiratory

tract

infectio

nandnasopharyngitis.NoMACE

acrossgroups

ETN50mgtwicea

wk(139)

39.6

Placebo(72)

6.9

Reicheta

l.[40,41]

PhaseIII,52-w

k,double-blind,

active-controlledtrial;n=317

Percentageof

patients

reaching

PASI-75atwk24

Briakinumab200mgat

wk0andwk4,followedby

100mgevery

4wkfrom

wk8–48a

81.8

Themost

commonAEsin

both

treatm

ent

groupswere

nasopharyngitis,headache,

diarrhea,a

rthralgia,a

ndupperrespiratory

tract

infectio

n.Seriousinfectio

nsreportedby

4patients

inthebriakinumabgroupand

3patients

intheMTXgroup.3casesof

malignancieswere

reportedinthebriakinumab

group.NoMACEreportedin

eithertreatm

ent

group

MTX5–25mgwklyfrom

wk0–51a

39.9

Percentageof

patients

reaching

PASI-75atwk52

Briakinumab200mgat

wk0andwk4,followedby

100mgevery

4wkfrom

wk8–48a

66.2

MTX5–25mgwklyfrom

wk0–51a

23.9

aNumberofpatients

notavailable.

AEs=adverseevents;ETN=etanercept;MACE=majorcardiacevents;MTX=methotrexate;PGA=Physician’sGlobalA

ssessmentscore;PASI=

PsoriasisAreaandSeverity

Index.



of briakinumab 200mg, 92.9% after third retreatment) and

PASI-75 responses (57.5% and 35.7%, respectively) generally

decreased with each cycle of retreatment, more evidently in

patients who received a single briakinumab dose per cycle

(PASI-50: 77.6% after first retreatment, 47.6% after third re-

treatment; PASI-75: 46.9% and 19.0%, respectively). Possible

explanations for this reduced response include the abbreviated

dosing regimen used during the open-label extension and the

amount of drug received, as well as corresponding pharm-

acokinetic factors such as briakinumab concentration.[36]

A phase III, randomized, controlled study was carried out to

assess efficacy and safety of two dosing regimens of briakinu-

mab compared with placebo (see figure 4).[37] Of a total of 1465

patients enrolled, 90%were white and 68.8%weremale. During

the induction phase of the study, patients with moderate-

to-severe psoriasis were randomized to receive briakinumab

200mg at weeks 0 and 4, followed by 100mg at week 8, or

placebo. Patients who achieved a Physician’s Global Assess-

ment score of ‘clear’ or ‘minimal’ (PGA 0/1) at week 12 quali-

fied to enter the maintenance phase lasting 40 weeks and were

re-randomized 2 : 2 : 1 to one of three treatment arms: briaki-

numab100mg every 4weeks, briakinumab100mgevery 12weeks,

or placebo. Significantly greater proportions of patients treated

with briakinumab versus placebo achieved the primary endpoints

ABT-874 200 mg x 1

ABT-874 100 mg EOW

ABT-874 200 mg x 4

ABT-874 200 mg EOW

ABT-874 200 mg weekly

Placebo

PA

SI ≥

75

YES: monitored for the loss of responseNO: monitored and not retreated

12-week, double-blind, placebo-controlled phase

36-week, observation/retreatment phase

Week 0 Week 12 Week 24 Week 36 Week 48

Loss of PASI-50 response = retreatmentwith the original dose except placebogroup (200 mg EOW) for 12 weeks

⎧⎪⎪⎪⎪⎪⎨⎪⎪⎪⎪⎪⎩ ⎧⎪⎪⎪⎪⎪⎪⎪⎪⎪⎪⎪⎨⎪⎪⎪⎪⎪⎪⎪⎪⎪⎪⎩

Fig. 2. Design of initial 12-week, double-blind, placebo-controlled, phase II study with a 36-week, observation/retreatment phase.[30,36] Reproduced from

Kimball et al.[36] with permission from Elsevier. ABT-874= briakinumab; EOW= every other week; PASI=Psoriasis Area and Severity Index.

PASI <50vs baseline

ABT-874 200 mg × 1

Yes

No

Yes

No

Monitoring and no retreatmentunless PASI <50

Loss of PASI-50 ≤12weeks after previous retreatment = repeatedretreatments with ABT-874200 mg × 1 until week 56

PASI <50vs baseline

Monitoring and no retreatmentunless PASI <50

ABT-874 200 mg × 2 Loss of PASI-50 ≤12weeks after previous retreatment = repeatedretreatments with ABT-874200 mg × 2 until week 56

ABT-874 200 mg weekly

ABT-874 200 mg EOW

Placebo

ABT-874 200 mg x 1

ABT-874 100 mg EOW

ABT-874 200 mg x 4

Week 0 Week 60Initial dose

⎧⎪⎪⎨⎪⎪⎩

Fig. 3. Design of 60-week, open-label, extension phase of initial phase II trial.[36] Reproduced from Kimball et al.[36] with permission from Elsevier.

ABT-874= briakinumab; EOW =every other week; PASI =Psoriasis Area and Severity Index.



of PGA 0/1 (76.0% vs 4.3%, respectively) and PASI-75

(80.7% vs 4.5%) at week 12 (p < 0.001). Long-term efficacy re-

sults showed higher maintenance of PGA and PASI response

rates fromweeks 12–52 in briakinumab patients versus placebo.

The study indicated the different efficacies of the two doses.

Dosing briakinumab every 4 weeks resulted in maintenance

rates of 79.2% (PGA 0/1) and 82.4% (PASI-75), while dosing

every 12 weeks resulted in rates of 41.6% and 46.0% for PGA

0/1 and PASI-75, respectively (p < 0.001). Moreover, PASI-90

was maintained in 81.5% of patients receiving briakinumab

every 4 weeks versus 40.7% of patients receiving it every

12 weeks.

Two phase III studies (figure 5) compared briakinumab to

etanercept and placebo and were very similar in design with

both being double-blind, double-dummy,multicenter studies of

12-week duration.[38,39] Participants were males and females

with moderate-to-severe plaque psoriasis. Patients (n = 347,[38]

n = 350[39]) were randomized to one of the three following

treatment arms: subcutaneous briakinumab (200mg at weeks 0

and 4 followed by 100mg at week 8), etanercept (50mg

subcutaneously twice weekly, 3–4 days apart at weeks 0, 0a, 1,

1a, 2, 2a, 3, 3a, 4, 4a, 5, 5a, 6, 6a, 7, 7a, 8, 8a, 9, 9a, 10, 10a, 11,

11a), and placebo (dosing suitable to match briakinumab or

etanercept dosing). Outcome measures in both studies were the

proportion of patients achieving a PGA 0/1 and PASI-

75/90/100 at week 12. A statistically significantly greater pro-

portion of patients in the briakinumab treatment groups in

both studies achieved a PASI-75 response at week 12 (81.9%[38]

and 80.6%[39]) as compared with placebo groups (7.4% and

6.9%) or etanercept (56.0% and 39.6%, respectively). PASI-90

(59.4%[38] and 55.4%[39]) and PASI-100 (37.0%[38] and

28.8%[39]) responses were achieved by large proportions of

patients in the briakinumab treatment groups at week 12. By

comparison, PASI-90 responses for placebo (1.5%[38] and

4.2%[39]) and etanercept (23.4%[38] and 13.7%[39]) groups in

both studies as well as PASI-100 responses for placebo (both

0%) and etanercept (7.1% and 5.8%, respectively; p < 0.001)groups were significantly lower.

A phase III, 52-week, double-blind, randomized, multi-

center, active-controlled study of 317 patients with moderate-

to-severe psoriasis compared briakinumab to methotrexate

treatment (see figure 6). The results are currently available in

the form of a conference abstract[40] and a press release.[41]

At baseline (week 0), patients were randomized 1 : 1 to receive

briakinumab or methotrexate. The briakinumab treatment

group received 200mg at weeks 0 and 4 and 100mg every

4 weeks from weeks 8 to 48. The methotrexate treatment group

received methotrexate (5–25mg weekly from weeks 0 to 51)

plus oral folate (5mg weekly from weeks 0 to 51). Primary

endpoints were the proportions of patients achieving PGA 0/1and PASI-75 at weeks 24 and 52. Briakinumabwas significantly

more effective than methotrexate over both short and long

periods. At 24 weeks, 81.8% of briakinumab patients achieved

PASI-75 compared with 39.9% of those taking methotrexate

(p < 0.001). PASI-90 clearance was achieved by 63.6% of bria-

kinumab patients versus 22.7% of methotrexate patients, while

PASI-100 was achieved by 42.2% of briakinumab patients

versus 8.6% of methotrexate patients. At 52 weeks, 66.2% of

briakinumab patients achieved PASI-75 compared with 23.9%of methotrexate patients (p < 0.001). PASI-90 clearance was

achieved by 59.7% of briakinumab patients versus 17.8% of

methotrexate patients, while PASI-100 was achieved by 45.5%of briakinumab patients versus 9.2% of methotrexate patients.

Available results of clinical phase II and phase III trials in-

dicate briakinumab (PASI-75 in 80.6–93% of patients at week

12 with more than one dose) has a similar efficacy in moderate-

to-severe psoriasis to TNFa inhibitors infliximab (PASI-75 in

80–88% of patients at week 10), adalimumab (PASI-75 in

ABT-874 200 mg (weeks 0, 4) then 100 mg at week 8

Placebo at weeks 0, 4, 8

ABT-874 100 mg every 4 weeks




Placebo every 4 weeks

Placebo every 4 weeks

Week 0 Week 12 (re-randomization if PGA 0/1)

PA

SI-

75, P

GA

0/1

Week 52

PA

SI-

75, P

GA

0/1

Fig. 4. Design of a phase III study comparing two dosing regimens.[37]

ABT-874= briakinumab; PGA=Physician’s Global Assessment score;

PASI=Psoriasis Area and Severity Index.

Screening ≤28 days

PA

SI-

75, P

GA

0/1

ABT-874 200 mg weeks 0, 4then 100 mg week 8

ETN 50 mg 2×/week through week 11

Placebo

Week 0 Week 12

Fig. 5. Design of two phase III briakinumab (ABT-874) vs etanercept (ETN)

vs placebo studies.[38,39] Reproduced from Strober et al.[39] with permission

from John Wiley & Sons Ltd. PGA=Physician’s Global Assessment score;

PASI =Psoriasis Area and Severity Index.



53–80% of patients at week 12), and another p40 inhibitor,

ustekinumab (PASI-75 in 66.4–75.7% of patients at week

12),[14,42] with efficacy superior to TNFa inhibitor etanercept

and immunosuppressant methotrexate.

4.2 Safety

In the phase II trial,[30] adverse events (AEs) that were at

least possibly related to the study drug were significantly more

frequent in briakinumab-treated patients as compared with the

placebo group (see table I). Injection-site reaction was the most

common AE in patients receiving any dose of briakinumab

(16.7%). Infectious AEs occurred in 34.7% and 23.3% of

patients treated with briakinumab and placebo, respectively.

Nasopharyngitis and upper respiratory tract infections were

the most frequent infectious AEs. No opportunistic or serious

infections, including salmonellosis or mycobacterial infec-

tion, were identified. Two cases of malignancy were reported:

a non-melanoma skin cancer in one of the treatment arms and

an ovarian cancer in the placebo arm. No cardiovascular or

hematologic complications were described. Most of these

patients were followed for 48 weeks, throughout the retreat-

ment phase.[36] Injection-site reaction continued to be the most

common AE (19.3%). Incidence of infections increased in

patients receiving briakinumab (41.3%), while it did not change

in the placebo group (23.3%). No other cases of malignancies

were reported within the period of the study. In the open-label

extension phase,[36] 16.7% of patients experienced treatment-

emergent AEs and 29.2% experienced infections. The most

common AEs were nasopharyngitis, upper respiratory tract

infection, injection-site reactions, and hypertension. Three se-

rious AEs that were observed were chest discomfort, chest pain,

and dyspnea; obesity; and meningioma.

A prematurely terminated, phase II study performed in

patients with Crohn’s disease[34] also showed that the most

frequent AE was injection-site reaction, which was usually mild

and did not require any treatment. Patients were followed for

18 weeks. Two patients, among 63 receiving briakinumab,

discontinued the study because of an AE: one had a local in-

jection reaction and the other had a small-bowel dysplastic

adenoma. No serious infections or AEs attributed to briaki-

numab were reported. The most common laboratory abnor-

malities in patients in the treatment arms were hyperuricemia,

hypoglycemia, and hyperamylasemia. Three patients presented

with anti-drug antibodies.

Results of the phase III studies in psoriasis generally cor-

roborated earlier findings. In the phase III trial comparing two

dosing regimens,[37] the most common AEs reported in patients

in the induction phase and in those receiving briakinumab

through 52 weeks were nasopharyngitis (10.6%), headache

(6.6%), and upper respiratory tract infections (10.4%). Per-

centages of injection-site reactions weren’t given. Serious AEs

occurred in 2% of patients receiving briakinumab in the in-

duction phase and in 3% of patients in the maintenance phase

(33 in total). Percentages of serious AEs in placebo recipients

were 1.2% and 1.3%, respectively. Most serious AEs were ma-

lignancies with themajority (10 out of 14; 71%) being squamous

cell or basal cell skin carcinomas. A total of sevenmajor cardiac

events (MACE), defined as myocardial infarction, stroke, or

cardiovascular death, occurred in the briakinumab group (no

MACE events were observed in patients receiving placebo).

In two phase III studies[38,39] comparing briakinumab to

etanercept and placebo, safety of the two active treatments was

similar, with a slightly higher percentage of AEs than placebo.

The most common AEs in patients receiving briakinumab were

nasopharyngitis (7.2% in both studies), upper respiratory tract

PA

SI-

75, P

GA

0/1

PA

SI-

75, P

GA

0/1

Loss of response (PGA >0/1 at week 24 or PASI <50 and PGA >3 after week 24) = discontinuation from study

ABT-874 200 mg (weeks 0, 4)then 100 mg every 4 weeks

ABT-874 100 mgevery 4 weeks

MTX 5−25 mg weekly MTX 5−25 mg weekly

Week 0 Week 24 Week 52

Fig. 6. Design of phase III briakinumab (ABT-874) vsmethotrexate (MTX) study.[40,41]PGA=Physician’sGlobal Assessment score;PASI = the Psoriasis Areaand Severity Index.



infections (6.5%[38] and 7.2%[39]), and injection site reactions

(5.8%[38] and 3.6%[39]). SeriousAEs in those trials were reported

in 2.9%[38] and 1.4%[39] of briakinumab patients; skin malig-

nancies (n = 2) weren’t classified as serious AEs in the second

trial. Patients treated with monoclonal antibody briakinumab

experienced four malignancies (colon cancer, malignant mela-

noma in situ, and basal cell and squamous cell skin carcinomas).

One serious infection occurred in a briakinumab patient (viral

infection).[38] No MACE were reported in either trial.

In the phase III study comparing briakinumab to metho-

trexate,[40,41] the most common AEs in both treatment groups

were nasopharyngitis, headache, diarrhea, arthralgia, andupper

respiratory tract infection. Three cases of malignancies were

reported in the briakinumab group. Serious infections occurred

in 2.6% (n = 4) of the patients in the briakinumab group and in

1.8% (n = 3) of the patients in the methotrexate group. No

MACE were reported in either treatment group.

4.3 Quality of Life

The impact of briakinumab treatment on health-related

quality of life (HR-QOL) has been assessed in phase III stud-

ies.[43,44] The results of the briakinumab vs placebo[43] and

briakinumab vs etanercept vs placebo[44] trials, presented at the

2010 Congress of the European Academy of Dermatology and

Venerology, showed significant improvements in briakinumab-

treated patients compared with etanercept and placebo. In both

studies, the HR-QOL outcomes included the Dermatology Life

Quality Index (DLQI), visual analog scales for plaque psoriasis

(VAS-Ps) and psoriatic arthritis (VAS-PsA)-related pain, and

Short Form-36 Health Survey Mental Component summary

(MCS) and Physical Component summary (PCS) scores. Ad-

ditionally, in one of the trials,[43] total activity impairment

(TAI) was assessed using Work Productivity and Activity

Impairment Questionnaire: Psoriasis. Percentages of patients

with improvement at or above the minimum clinically im-

portant difference (MCID) response were compared. In the

first of two trials[43] treatment with briakinumab gave sig-

nificantly greaterMCID response rates at week 12 than placebo

for all outcomes (e.g. DLQI, 78.1% vs 19.4%; TAI, 51.4% vs

15.3%). After re-randomization, week-52MCID response rates

were significantly greater for briakinumab every 4 weeks than

for every 12 weeks in all outcomes except for psoriatic arthritis-

related pain. Both briakinumab groups had significantly

greater MCID response rates than placebo for all outcomes

(e.g. DLQI, 81.1% vs 71.1% vs 49.3%; TAI, 56.9% vs 45.1% vs

31.0%). Mean improvements in all outcomes were significantly

greater for briakinumab than placebo at week 12 and for

briakinumab every 4 weeks than every 12 weeks or placebo at

week 52. In one study,[44] significantly greater MCID response

rates were observed with briakinumab versus etanercept or

placebo forMCS (43.4% vs 30.6% or 20.6%) and versus placebo

only for DLQI (81.5% vs 38.1%), PCS (45.0% vs 28.6%), VAS-

PsA (69.2% vs 28.6%), and VAS-Ps (56.6% vs 25.8%) scores.

5. Approval Process

Applications for marketing authorization for briakinumab

were submitted to the US Food and Drug Administration

(FDA) and European Medicines Agency (EMA) in 2010.

However, the approval process is expected to be delayed due to

the recently announced withdrawal of the marketing applica-

tions to the FDA and EMA prior to the organizations’ review

and decision.[15,45] In its official letter to the EMA, the manu-

facturer stated that its decision to withdraw the application was

based on the views of the rapporteurs in their day 80 assessment

reports that additional new data and analyses would be re-

quired for a favorable opinion, but those could not be generated

within the timeframe allowed in the centralized procedure.[15] It

should be noted that increased risk of MACE in briakinumab

patients observed in one of the phase III studies[37] may have

affected themanufacturer’s decision and could be a factor in the

approval process. The company plans to conduct further anal-

ysis and clinical trials and evaluate next steps, including re-

submission at a later date.[15,46]

6. Conclusion

Although the therapeutic options for patients withmoderate-

to-severe psoriasis have expanded in recent years, there is still a

great need for highly efficacious and safe agents. Briakinumab,

an anti-p40 monoclonal antibody, is one of the new promising

biologic agents. The recently announced results of phase III

trials and previous observations suggest that its efficacy profile

is at least comparable to the most effective currently available

biological treatments, and superior to immunosuppressive

therapy with methotrexate. However, the detected increased

incidence of MACE in briakinumab patients in one phase III

trial casts doubt on treatment safety, and this needs to be fur-

ther evaluated in clinical studies.

Acknowledgments

No sources of funding were used to assist in the preparation of this

review. The authors have no conflicts of interest that are directly relevant

to the content of this review.



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Correspondence: Dr Pawel Traczewski, Department of Dermatology, CSK

MSWiA, ul. Woloska 137, 02-507 Warsaw, Poland.

E-mail: [email protected]



briakinumab for the treatment of plaque psoriasis

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