New Interleukin-23 Pathway Inhibitors in Dermatology

New Interleukin-23 Pathway Inhibitors inDermatologyUstekinumab, Briakinumab, and Secukinumab

Marta Kurzeja,1 Lidia Rudnicka1,2 and Malgorzata Olszewska3

1 Department of Dermatology, Central Clinical Hospital of Ministry of Internal Affairs and Administration, Warsaw, Poland

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

3 Department of Dermatology, Warsaw Medical University, Warsaw, Poland

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113

1. Literature and Data Sources. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114

2. Interleukin (IL)-12 and the IL-23 Pathway. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114

3. The Role of IL-12, IL-23, and T helper-17 (Th17) Lymphocytes in Psoriasis and other Skin Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114

4. Ustekinumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115

4.1 Inhibition of IL-12 and IL-23 Activity with Ustekinumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115

4.2 Clinical Applications of Ustekinumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115

4.2.1 Ustekinumab in Psoriasis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116

4.2.2 Ustekinumab in Psoriatic Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118

4.3 Safety of IL-12/IL-23 Inhibition with Ustekinumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118

5. Briakinumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119

6. Secukinumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120

7. Other Biologic Drugs Targeting the IL-23 Pathway. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121

8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122

Abstract Interleukin (IL)-23 is an important regulator of T helper-17 lymphocytes, which influence the cutaneous

immune system by production of IL-17 and several other proinflammatory cytokines. This pathway has

been recently linked to the pathogenesis of psoriasis and numerous other skin diseases. A newly developed

biologic drug, ustekinumab (CNTO-1275), which targets the p40 subunit of IL-12 and IL-23, was approved

by the US FDA and the European Medicines Agency in 2009 for the treatment of moderate to severe

psoriasis. Administered as subcutaneous injections of 45mg at weeks 0 and 4, and then every 12 weeks,

ustekinumab produces a 75% improvement in the Psoriasis Area and Severity Index (PASI) in 66.4–75.7%of patients and aDermatologyLifeQuality Index (DLQI) score of 0 or 1 in 55–56% of patients after 12weeks

of therapy. A recent clinical trial also indicates the possible efficacy of ustekinumab in psoriatic arthritis.

The proportion of patients who had at least one adverse event through 12 weeks in clinical studies was

51.6–57.6% in the ustekinumab group and 50.4% in the placebo group. Serious adverse events were observed

in 1.4–1.6% of patients treated with ustekinumab and in 1.4% of patients receiving placebo. Injection-site

reactions occurred in 1–2% of patients and 5% of patients developed anti-ustekinumab antibodies. Further

studies are needed to evaluate the long-term efficacy and safety of ustekinumab.

Another biologic drug that targets the samemolecules, briakinumab (ABT-874), has recently had its approval

application withdrawn in the US and Europe to conduct further analysis and clinical trials. The company plans

resubmission at a later date. Other IL-23 pathway inhibitors in the pipeline include anti-p19 monoclonal

antibody and apilimod (STA-5326), which interfere with IL-23 activity, as well as secukinumab (AIN-457),

LY-2439821, and AMG-827, which exhibit their activity at other targets of the IL-23 pathway.

REVIEWARTICLEAm J Clin Dermatol 2011; 12 (2): 113-125

1175-0561/11/0002-0113/$49.95/0

ª 2011 Adis Data Information BV. All rights reserved.

Interleukin (IL)-23 is an important regulator of T helper

(Th)-17 lymphocyte proliferation and activity. IL-23, Th17

lymphocytes, and cytokines produced by these lymphocytes

form a pathway, which significantly contributes to the

pathogenesis of psoriasis and several other skin diseases.

Newly developed biologic drugs, which target molecules in

this pathway, show significant promise for the treatment of

psoriasis.

Ustekinumab (CNTO-1275) was developed as a fully

human, IgG1k monoclonal antibody directed against p40, a

protein subunit shared by IL-12 and IL-23,[1,2] to treat psoria-

sis.[2-4] The rapid development in this field may be illustrated by

the fact that a first phase I study, showing the potential clinical

efficacy and safety of an IL-12p40 antibody in psoriasis, was

published in 2004.[5] A double-blind, placebo-controlled, phase

II trial that estimated the safety profile and effectiveness of an

IL-12/IL-23 monoclonal antibody in treating psoriasis was

published in 2007.[6] In 2008 the results of two large, random-

ized, controlled, phase III studies were published[1,7] and uste-

kinumab was approved by the US FDA and the European

Medicines Agency (EMA) in 2009.[8] Another biologic drug

that targets the same molecules, briakinumab (ABT-874), is

currently in the approval process for psoriasis. Other IL-23

pathway inhibitors are in the pipeline. This article reviews

current knowledge about this group of drugs.

1. Literature and Data Sources

Literature searches included exploration of MEDLINE/PubMed, EMBASE, EBSCO, and SCOPUS. These databases

were searched for scientific literature published from 1 January

1990 to 10 January 2011. Search terms included ‘interleukin 23’,

‘interleukin 12’, ‘interleukin 17’, ‘Th17’, ‘CNTO 1275’, ‘ustekinu-

mab’, ‘briakinumab’, ‘secukinumab’, ‘ABT-874’, ‘anti-p19mAb’,

‘apilimod mesylate’, ‘STA-5326’, ‘AIN457’, ‘LY2439821’,

‘LY2525623’, and ‘AMG827’.

Ongoing and completed trials were identified from the fol-

lowing registers: databases of The Cochrane Library (www.

thecochranelibrary.com), Current Controlled Trials (www.

controlled-trials.com), The US National Institutes of Health

ongoing trials register (www.clinicaltrials.gov), the Australian

and New Zealand Clinical Trials Registry (www.anzctr.org.

au), and the WHO International Clinical Trials Registry Plat-

form (www.who.int/ictrp/en/). Search terms included ‘interleukin

23’, ‘interleukin 12’, ‘interleukin 17’, ‘Th17’, ‘ustekinumab’,

‘briakinumab’, ‘ABT-874’, ‘anti-p19mAb’, ‘apilimod mesy-

late’, ‘STA-5326’, ‘AIN457’, ‘LY2439821’, ‘LY2525623’, and

‘AMG827’. The last search date was 10 January 2011.

The WHO Drug Information (www.who.int/medicines/publications/druginformation/en/) was searched to verify or

confirm International Nonproprietary Names of drugs.

The websites of the FDA, EMA, and Australian Drug

Evaluation Committee (ADEC) were inspected for current

approval status of drugs. The last search date was 10 January

2011.

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

IL-12 is a heterodimeric cytokine composed of two co-

valently linked chains with masses of 35 and 40 kDa.[9,10] IL-12

is produced by dendritic cells, skin Langerhans cells, B lym-

phocytes, and phagocytic cells.[10,11] It promotes differentiation

of naive T cells into Th1 cells. IL-12 also stimulates production

of several cytokines, including interferon (IFN)-g and tumor

necrosis factor (TNF)-a, by T lymphocytes and natural killer

(NK) cells. The cytokine also enhances the cytotoxic activity of

NK cells and CD8+ cytotoxic T lymphocytes;[12-15] these find-

ings have been obtained from in vitro experiments. Based on

findings in murine models, it has been suggested that IL-12

possesses anti-tumor activity associated with activation of

CD4+ T cells, CD8+ T cells, and NK cells.[16,17]

IL-23 shares with IL-12 the p40 subunit, which is bound to a

unique p19 subunit.[18] IL-23 is produced by activated macro-

phages and dendritic cells.[19] It plays a crucial role in in-

flammatory response against infection, as demonstrated in

in vitro studies and in animal models.[20-23] IL-23 stimulates

proliferation of a unique set of T cells, termed Th17 cells.[24]

Th17 cells are different fromboth Th1 andTh2 cells and produce

a different set of proinflammatory cytokines, including IL-6,

IL-22, TNFa and, most importantly, cytokines of the IL-17

family.[25,26] IL-17 was shown to play a key role in mediating

inflammation and in pathogenesis of several autoimmune

diseases, including psoriasis, Crohn disease, and multiple scle-

rosis in humans.[27-30] This pathway, leading to autoimmune

phenomena through IL-23, Th17 cells, and IL-17 is often re-

ferred to as the ‘interleukin 23 pathway’ or the ‘interleukin

23/17 pathway.’[31]

It is important to emphasize that IL-23 induces, via Th17,

upregulation of TNFa.[25] Thus, drugs that target IL-23 will

also partially act as TNFa inhibitors.

3. The Role of IL-12, IL-23, and T helper-17 (Th17)

Lymphocytes in Psoriasis and other Skin Diseases

In murine models, IL-12 and IL-23 were shown to play a

significant role in maintaining inflammation and abnormal

114 Kurzeja et al.

ª 2011 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2011; 12 (2)

keratinocyte proliferation in psoriasis and joint destruction in

psoriatic arthritis.[32-34]

IL-12 expression is markedly increased in psoriatic skin

lesions.[12] In in vitro studies, IL-12 has been shown to induce

proliferation and differentiation of CD4 naive T cells to Th1

and NK cells and to activate NK cells, which produce proin-

flammatory cytokines involved in maintaining inflammation in

psoriasis.[12-16] These cytokines include TNFa, a key cytokine

in psoriasis and an acknowledged target for biologic therapy.[35]

IL-23 expression is also significantly increased in the epi-

dermis within psoriatic lesions.[36,37] IL-23 messenger RNA

expression is significantly higher in lesional skin of patients

with psoriasis as compared with normal-appearing skin in these

patients.[36,37] Secretion of IL-23 by monocytes and mature

dendritic cells derived from patients with psoriasis is abnor-

mally high.[37] IL-23 promotes survival and proliferation of

Th17 cells.[22,38-41] Th17 cytokines, such as IL-17, then stimulate

keratinocyte proliferation,[23] which enables further increased

proliferation of epidermal cells in psoriasis lesions.[36]

Recent clinical studies conducted in humans emphasize the

crucial role of IL-23-stimulated Th17 cells in the pathogenesis

of several other inflammatory skin diseases, including allergic

contact dermatitis, systemic sclerosis (scleroderma), and sar-

coidosis.[21,42-46] The Th17 axis also plays a significant role in

the development of other diseases with possible cutaneous in-

volvement. These include systemic lupus erythematosus,[47,48]

rheumatoid arthritis,[49] inflammatory bowel disease,[50] and

Behcet disease.[51] Taking into consideration that IL-23-

dependent Th17 cells play a significant role in several skin

diseases, it may be hypothesized that future indications for

IL-23 pathway inhibitors may be broader than currently

documented.

4. Ustekinumab

4.1 Inhibition of IL-12 and IL-23 Activity with Ustekinumab

Ustekinumab is a fully human, monoclonal antibody that

blocks the activity of p40, a protein subunit shared by IL-12 and

IL-23, with high affinity and specificity.[52,53] It was shown that

ustekinumab binds to the sameD1 epitope on p40 in both IL-12

and IL-23 with identical interactions.[54]

The receptors for IL-12 and IL-23 have a common part: the

IL-12Rb1 subunit, which binds p40.[27] Ustekinumab neu-

tralizes IL-12 and IL-23 bioactivity by blocking interactions

between the shared p40 subunit and the receptor IL-12Rb1.[55]

Ustekinumab was shown to decrease messenger RNA ex-

pression of IL-12p40, IL-23p19, and IFN-g in the skin;[55] it

also inhibits IL-12- and IL-23-induced IFN-g, IL-17A, TNFa,IL-2, and IL-10 secretion.[56]

4.2 Clinical Applications of Ustekinumab

Ustekinumab is currently approved for the treatment of

moderate to severe psoriasis. The recommended dosage for

patients with plaque psoriasis is 45mg administered

subcutaneously at weeks 0 and 4, and then every 12 weeks

thereafter.[3,57,58] A higher dose of 90mg may be considered in

patients with a bodyweight >100 kg (220 lb). However, a dose of

45mg may also be administered in these patients.[3,57,58]

The rationale for these dosing recommendations is currently

being discussed. An analysis of clinical response by 10 kgweight

increments at week 28 in the PHOENIX 1 and PHOENIX 2

trials showed that 90mg is more effective than 45mg in all

patient groups with a bodyweight above 60 kg and that serum

ustekinumab concentrations are affected by weight, with lower

serum concentrations observed in heavier patients at each

dose.[59] The authors performed only one global statistical

analysis of clinical efficacy, comparing all patients £100 kgwith all patients >100kg. Based on this limited analysis, the

authors concluded that the dosing regimen of ustekinumab

based on weight is appropriate for the treatment of patients

with psoriasis.[59]

The drug is currently not approved for individuals aged

below 18 years; however, there is an ongoing phase III clinical

trial, also called the CADMUS (Controlled trial evaluating

the efficacy and safety of ustekinumab in the treatment of

ADolescent subjects with Moderate to severe chronic plaqUe-

type pSoriasis), to evaluate the safety and efficacy of usteki-

numab in adolescent patients (aged 12–18 years) with moderate

to severe plaque-type psoriasis (ClinicalTrials.gov identifier

NCT01090427).

It is suggested that areas of the skin with psoriasis lesions

should be avoided as injection sites.[57]

Intravenous administration of ustekinumab at a dosage of

4.5mg/kg at weeks 0 and 8 was successfully applied in non-

dermatologic diseases, such as Crohn disease,[60] but the intra-

venous form of the drug is neither recommended nor available

for the treatment of psoriasis. There was also an attempt to use

ustekinumab in multiple sclerosis, but it showed no efficacy

despite relatively high doses of 180mg per injection.[61]

Potential efficacy of ustekinumab in palmo-plantar pustular

psoriasis was suggested based on anecdotal observations.[62]

This indication is currently being investigated in an on-

going phase III clinical trial (ClinicalTrials.gov identifier

NCT01091051).

IL-23 Pathway Inhibitors 115


In another clinical trial (phase II, ClinicalTrials.gov identi-

fier NCT00955279), the efficacy of ustekinumab in sarcoidosis

is being investigated. Case reports showing the successful

application of ustekinumab in patients with severe recalcitrant

generalized pustular psoriasis[63] and pityriasis rubra pilaris[64-66]

were recently published. It has to be emphasized that these

are currently purely hypothetical indications and every ap-

plication requires adequate clinical data and broad safety

documentation.

4.2.1 Ustekinumab in Psoriasis

The efficacy of ustekinumab was assessed in phase II and III

double-blind, placebo-controlled, clinical trials in patients with

moderate to severe plaque psoriasis.[1,6,7] The results of these

trials are summarized in table I.

The phase II study was conducted to evaluate the efficacy

and safety of single and multiple doses of ustekinumab for the

treatment of psoriasis. The study included 320 patients with

moderate to severe plaque psoriasis. Participants were ran-

domly assigned to either one subcutaneous dose of ustekinu-

mab 45mg, one 90mg dose, four weekly 45mg doses, four

weekly 90mg doses, or placebo. At week 16, patients with a

Physician’s Global Assessment (PGA) of 3 or more (on a scale

on which 1 is best and 6 is worst) were treated with one addi-

tional injection of the originally assigned dose. Patients who

were assigned at baseline to the placebo group received one

90mg dose of ustekinumab at week 20. The endpoint was

reaching 75% clinical improvement as measured by the Psori-

asis Area and Severity Index (PASI 75) after 12 weeks of treat-

ment. This endpoint was achieved by 52% of patients treated

Table I. Main results of phase II and phase III clinical trials of ustekinumab in moderate to severe psoriasis

Study Design (no. of patients) Endpoint Dosage (no. of patients)a Results

Krueger et al.[6] Randomized, double-blind,

parallel-group, placebo-

controlled, phase II study (320)

Percentage of patients

reaching PASI 75 at wk 12

Single dose of 45mg (64) 52%

Single dose of 90mg (64) 59%

Four weekly doses of 45mg (64) 67%

Four weekly doses of 90mg (64) 81%

Placebo (64) 2%

Leonardi et al.[1] Randomized, double-blind,


controlled, phase III study (766)



45mg at wk 0 and 4 and then every 12wk (255) 67.1%


Placebo at wk 0 and 4 (255) 3.1%


reaching a PGA score 0 or 1

at wk 12



Placebo (255) 3.9%

Median change in DLQI

score at wk 12

45mg at wk 0 and 4 and then every 12wk (255) 6.0


Placebo (255) 0

Time to loss of PASI 75

(median)

Patients receiving maintenance therapy

45 or 90mg every 12wk

‡76wk

Patients withdrawn from therapy 15wk

Papp et al.[7] Randomized, double-blind,


controlled, phase III study

(1230)





Placebo (410) 3.7%


reaching PGA score 0 or 1

at wk 12



Placebo (410) 4.9%

Median change in DLQI

score at wk 12



Placebo (410) 0.5

a Number of patients given the dosage, if available.

DLQI=Dermatology Life Quality Index; PASI 75 =75% improvement in the Psoriasis Area and Severity Index score; PGA=Physician’s Global Assessment.

116 Kurzeja et al.


with one 45mg dose, 59% treated with one 90mg dose, 67%treated with four weekly 45mg doses, and 81% treated with

four weekly 90mg doses. In the placebo group, 2% of patients

achieved PASI 75 at week 12, which is statistically significantly

less (p < 0.001) compared with each ustekinumab dose.[6]

The randomized, double-blind, placebo-controlled, phase

III, PHOENIX 1 trial was carried out in 766 patients with

moderate to severe plaque psoriasis, who received ustekinumab

45mg (255 patients) or 90mg (256 patients) at weeks 0 and 4

and then every 12 weeks or placebo (n = 255) at weeks 0 and 4.

The patients who initially received placebo were randomly as-

signed to crossover: half to ustekinumab 45mg and half to

ustekinumab 90mg at week 12. Patients taking ustekinumab

who achieved PASI 75 at weeks 28 and 40 were re-randomized

to continue maintenance treatment with ustekimumab or were

withdrawn from treatment until loss of response. The primary

endpoint was reaching PASI 75 after 12 weeks of treatment.

This primary endpoint was achieved by 171/255 (67.1%)

patients receiving ustekinumab 45mg, 170/256 (66.4%) patients

treated with ustekinumab 90mg, and 8/255 (3.1%) of patients

receiving placebo, which is statistically significantly less

(p < 0.001) compared with each ustekinumab dose.[1]

Another phase III clinical trial, the PHOENIX 2 study was a

double-blind, placebo-controlled, multicenter trial that in-

cluded 1230 patients with moderate to severe plaque psoria-

sis.[7] At baseline, patients underwent randomization to receive

ustekinumab 45mg (409 patients) or 90mg (411 patients) by

subcutaneous injection at weeks 0 and 4 and every 12 weeks or

placebo (410 patients) at weeks 0 and 4 with subsequent

crossover to ustekinumab 45mg or 90mg at week 12. At week

28, partial responders (PASI >50 to <70) who had initially re-

ceived ustekinumab were re-randomized to continue receiving

the drug every 12 weeks or to receive intensified dosing every

8 weeks. The primary endpoint was achieving PASI 75 at week

12. The endpoint was achieved by 66.7% of patients receiving

45mg and 75.7% of patients receiving 90mg, compared with

3.7% receiving placebo (p < 0.0001 for the 45mg dose efficacy vs

placebo; p < 0.0001 for the 90mg dose efficacy vs placebo). The

complete clearance of psoriatic skin lesions (PASI 100) after

12 weeks was observed in 18.1%, 18.2%, and 0.0% of patients,

respectively (p < 0.0001 for ustekinumab vs placebo). Onset of

improvement in ustekinumab-treated patients was observed in

the second week after the first ustekinumab injection, whereas

PASI 75 response rate achieved the maximum at week 20

(74.9% in patients receiving 45mg and 83.5% in patients re-

ceiving 90mg per injection).

At week 28, 22.7% of patients receiving ustekinumab 45mg

and 15.8% of patients receiving ustekinumab 90mg every

12weeks showed partial response, without achieving PASI 75. In

the PHOENIX 2 trial it was assessed whether dosage in-

tensification (from injections administered every 12 weeks to the

same dose administered every 8 weeks) in the group of partial

responders would improve efficacy. Improvement of skin re-

sponse was assessed by the number of visits between weeks 40

and 52 atwhich patients achieved PASI 75 and by the proportion

of patients achieving PASI 75 response rates at week 52.

In the 45mg group, dosage intensification (administration of

ustekinumab every 8 weeks) did not result in greater efficacy.

By contrast, dosage intensification in the partial responders

receiving ustekinumab 90mg (administration every 8 weeks)

resulted in an improvement of skin response rate in terms of the

number of visits at which patients achieved PASI 75 response

(mean of 1.58 visits in patients with no dosage intensification vs

2.63 visits in the group of patients who received ustekinumab at

increased frequency; p= 0.014). PASI 75 response rates were

68.8% in patients with dosing every 8 weeks vs 33.3% in patients

with dosing every 12 weeks (p = 0.004).Patients who achieved PASI 75 at week 28 and continued

treatment had sustained response until week 52.

Patients with lower efficacy of treatment had higher body-

weight, higher severity of disease, and higher incidence of

psoriatic arthritis. Antibodies against ustekinumab were found

more often in partial responders (12.7%) than PASI 75 res-

ponders (2.0%). Serum drug concentrations were two to three

times lower in the partial responders compared with patients

who achieved PASI 75, with amean of 0.14 (standard deviation

[SD] 0.19) mg/mL in partial responders versus 0.39 (SD 0.34)

mg/mL in PASI 75 responders in the 45mg group and 0.34 (SD

0.36) mg/mL versus 0.72 (SD 0.66) mg/mL in the 90mg group.[7]

The authors indicated an association between serum drug

concentrations of ustekinumab and clinical response.[7]

It may be concluded that studies carried out up to now dem-

onstrate that treatment with ustekinumab results in signif-

icant improvement of moderate to severe psoriasis. Efficacy, as

measured by PASI 75 at week 12, is comparable to or slightly

higher compared with other biologic drugs that are FDA ap-

proved for psoriasis.[1,6,7,67-69] There are still no long-term,

large-scale studies and knowledge about long-term efficacy and

safety is needed.

A growing body of evidence is rapidly accumulating about

the efficacy of diverse biologic drugs in psoriasis treatment.

However, there are only a very limited number of studies that

compare psoriasis therapies head-to-head. One of them is a

randomized, multicenter, phase III, head-to-head study com-

paring ustekinumab with etanercept in moderate to severe

psoriasis.[70] The study involved 903 patients with chronic



plaquepsoriasis,whowere randomly assigned to receive treatment

with ustekinumab at doses of 45mg or 90mg at weeks 0 and 4 or

etanercept 50mg twice weekly for 12 weeks. PASI 75 was

achieved in 67.5% of patients receiving ustekinumab 45mg and

in 73.8% of patients receiving ustekinumab 90mg as compared

with 56.8% of patients in the etanercept group (p = 0.01 and

p < 0.001, respectively).[70-73] These results show the superiority

of ustekinumab comparedwith etanercept in achieving PASI 75

after 12 weeks of therapy. However, it has to be considered that

etanercept was first approved by the FDA in 1998, more than

10 years ago. This has allowed the collection of a significant

body of experience in a large number of patients and in long-

term therapy. In global studies approximately 20 070 patients

have been treated with etanercept compared with 2266 usteki-

numab-exposed subjects.[74,75] Thus, further large-scale, head-

to-head studies are needed to assess the long-term efficacy and

safety of ustekinumab and, if possible, more specific indications

for each biologic drug in individual patients with psoriasis.

The estimated degree of life-quality impairment associated

with psoriasis is comparable to that in othermajor diseases such

as heart disease, hypertension, diabetes mellitus, cancer, and

depression.[76,77] Beyond efficacy of ustekinumab measured by

PASI, the effect of this drug on quality of life was also eval-

uated. In phase II and III clinical trials, ustekinumab showed

efficacy in improving quality of life, as evaluated by the Der-

matology Life Quality Index (DLQI).[1,7] The DLQI is a ten-

item questionnaire assessing how skin disease affects patients’

reported quality of life. The DLQI scores range from 0 to 30;

lower scores indicate lower impairment of patient’s quality of

life, while higher scores indicate greater impairment of patient’s

quality of life.[1,7] In the phase II study, 20% of patients treated

with one ustekinumab 45mg dose, 30% treated with one uste-

kinumab 90mg dose, 42% treated with four weekly ustekinu-

mab 45mg doses, and 41% treated with four weekly

ustekinumab 90mg doses achieved a DLQI score of 0 at week

12.[6] The PHOENIX1 and PHOENIX2 phase III clinical trials

also showed improvement of quality of life in patients with

psoriasis, as assessed by the DLQI, the Short-Form 36 (SF-36),

and the Work Limitations Questionnaire (WLQ).[1,7,78]

4.2.2 Ustekinumab in Psoriatic Arthritis

IL-23 is an essential promoter of end-stage joint auto-

immune inflammation, in particular in psoriatic arthritis.[79-83]

To evaluate the possible efficacy of IL-12/IL-23 p40 inhibition

by ustekinumab in patients with active psoriatic arthritis, a ran-

domized, double-blind, placebo-controlled, multicenter, clinical

trial was carried out.[79] A total of 146 patients were randomly

assigned to receive ustekinumab (group 1, 76 patients) at weeks

0, 1, 2, and 3, followed by placebo at weeks 12 and 16, or

placebo (group 2, 70 patients) at weeks 0, 1, 2, and 3 followed by

the active treatment at weeks 12 and 16.[79] Patients were treated

with ustekinumab at a dose of either 63mg or 90mg. The pri-

mary efficacy endpoint was the proportion of patients who had

a 20% improvement from baseline in the American College of

Rheumatology (ACR) arthritis score (ACR20) at week 12.

These criteria were fulfilled by 42% of patients in the usteki-

numab group compared with 14% of patients in the placebo

group (p = 0.0002). At week 12, ACR50 was achieved by 25%and ACR70 by 11% of patients receiving ustekinumab versus

7% and 0% of placebo-treated patients, respectively. At week

12, PASI 75 was achieved by 52% of patients treated with us-

tekinumab and 5% of patients receiving placebo.[79] These

results indicate that treatment with ustekinumab may signif-

icantly reduce symptoms of arthritis and psoriatic skin lesions

in patients with psoriatic arthritis.[84]

4.3 Safety of IL-12/IL-23 Inhibition with Ustekinumab

Data regarding safety of ustekinumab are based on phase II

and III clinical trials in patients with moderate to severe plaque

psoriasis.[1,6,7] A total of 1970 individuals were treated with

ustekinumab for at least 6 months, 1285 subjects for at least

1 year, and 373 subjects for 18 months.[1,3,6,7] A total of 50.4%of patients in the placebo group, 57.6% in the 45mg group, and

51.6% in the 90mg group had at least one adverse event during

12 weeks of treatment.[3] Themost frequent adverse events were

upper respiratory tract infections, including nasopharyngitis.[2]

Adverse events that occurred in ‡1% of patients and at least

1.5-fold more frequently than in the placebo group were: diz-

ziness, back pain, myalgia, injection-site erythema, ecchymosis,

diarrhea, and pharyngolaryngeal pain. Serious adverse events

were observed in 1.4–1.6% of patients treated with ustekinu-

mab and in 1.4% of patients in the placebo group.[3] Five

patients treated with ustekinumab experienced major adverse

cardiovascular events, such as cardiovascular death, myo-

cardial infarction, or stroke. The incidence of the major ad-

verse cardiovascular events was 0.61 per 100 patient-years of

follow-up for ustekinumab-treated patients (95%CI 0.28, 1.16)

compared with 0.55 for placebo-treated patients (95% CI 0.01,

3.06).[3] The difference was not statistically significant.

Our own anecdotal experience with patients receiving uste-

kinumab after the FDA/EMA approval showed a more com-

mon occurrence of transient, mild cardiovascular adverse

events than indicated by clinical trials. We observed ankle and

lower leg swelling, temporary chest pain with normal ECG, or

temporary ECG changes indicative of ischemic heart disease

118 Kurzeja et al.


with no other features of ischemia or cardiac insufficiency in

31% (5/16) of patients. None of these patients had ischemic

heart disease, heart failure, or drug-related hypertension. One

(1/16, 6.2%) patient developed alopecia areata during usteki-

numab therapy.[85]

A total of 1–2% of patients receiving ustekinumab had in-

jection-site reactions. No anaphylactic or serum sickness-like

reaction to ustekinumab was observed.[3] No significant ab-

normalities in hematologic and blood chemistry tests were re-

corded. The frequency of other basic laboratory abnormalities,

including liver enzymes and renal tests, were within reference

range and comparable to placebo throughout phase II and III

clinical studies.[1,7]

Because of a higher rate of reactivation of latent tuberculosis

infection among patients treated with TNFa inhibitors and

the observation that IL-12p40 deficiency may predispose to

Mycobacterium infections in mice and in humans,[86-88] patients

who were included into ustekinumab trials were screened in

detail for tuberculosis. A history of or symptoms of active

tuberculosis were exclusion criterion. Patients with latent tuber-

culosis were accepted in the phase III psoriasis studies, if anti-

tuberculosis therapy was started before or simultaneously with

the first administration of ustekinumab.[2] A total of 68 patients

participating in phase III psoriasis studies were treated with

isoniazid for latent tuberculosis during ustekinumab therapy.

In two plaque psoriasis clinical trials[1,7] and one psoriatic ar-

thritis trial[79] no case of active tuberculosis was observed.[3]

Tuberculosis was also not observed in any of the 202 patients

treated with subcutaneous or intravenous ustekinumab for

Crohn disease.[60]

There are no recommendations indicating how often patients

receiving ustekinumab should be assessed for tuberculosis. We

believe that exclusion of tuberculosis should be recommended

for all patients qualified to receive ustekinumab, as for every

(biologic) immunosuppressive drug used in psoriasis and psori-

atic arthritis. We perform a chest x-ray and the purified protein

derivative test before initiating therapy. During therapy, the

QuantiFERON�-TB test (Cellestis Inc., Valencia, CA, USA),

and chest x-rays are carried out once a year or when symptoms

that might be suggestive of tuberculosis occur.

During the ustekinumab clinical development program, one

case of reversible posterior leukoencephalopathy syndrome

(RPLS) was observed. After receiving 12 doses of ustekinumab

over approximately 2 years, this patient presented with RPLS

symptoms: headache, seizures, and confusion. Ustekinumab

therapy was discontinued and, after adequate therapy, the pa-

tient fully recovered.[89] No patient to date has developed pro-

gressive multifocal leukoencephalopathy, which was observed

earlier in four patients treated long term with efalizumab. This

adverse event was the reason for withdrawing efalizumab[90,91]

from themarket in 2009.Mild neurologic adverse events seen in

ustekinumab clinical trials included transient headache and

vertigo.[1,7,60,79]

In clinical trials, the rate of malignancies was comparable in

placebo- and ustekinuamb-treated patients.[1,7,79] In our opin-

ion, long-term cancer consciousness should be advised for all

physicians who treat patients with ustekinumab, as cytokines

targeted by this drug may exert anti-tumor activity in mice.[80]

According to some mouse model experiments, IL-12 and IL-23

play opposite roles in carcinogenesis. IL-12 promotes anti-

tumor immunity via activation of CD4+ cells, CD8+ cells, and

NK cells, whereas IL-23 may promote tumor growth by in-

creasing angiogenesis, and reducing CD8+ cell infiltrates.[17,20]

Other data indicate that IL-12 and IL-23 suppress tumor

growth in a mouse model.[92] These effects are not yet suffi-

ciently evaluated in human studies.

5. Briakinumab

Briakinumab (ABT-874) is a fully human, anti-IL-12/IL-23monoclonal antibody directed against the common p40 sub-

unit.[93] In 2009 the name ‘briakinumab’ was accepted for ABT-

874 by the WHO.

In a randomized, placebo-controlled, phase II trial, briaki-

numab showed efficacy in the treatment and retreatment of

moderate to severe psoriasis and a favorable safety profile

(table II).[93,94] In this study, five dosage regimens of briaki-

numab were evaluated: one 200mg dose at week 0; 100mg

every other week for 12 weeks; 200mg weekly for 4 weeks;

200mg every other week for 12 weeks; and 200mg every week

for 12 weeks.[93] Among patients receiving briakinumab,

63–93% exhibited improvement of at least PASI 75 versus 3% in

the placebo group (p < 0.001 for all dosage regimens compared

with placebo).[93,94] The study showed that response was dose

related, and deterioration was seen across all dosages after

treatment was discontinued for more than 12 weeks.

Phase III clinical trials evaluating the safety and efficacy of

briakinumab in psoriasis were recently completed. The results

of these studies are currently available only in the form of

published abstracts from presentations at the American

Academy of Dermatology, European Academy of Dermatol-

ogy and Venereology and Psoriasis meetings.

A phase III, randomized, controlled study[95] was carried out

to assess the efficacy and safety of two dosage regimens of

briakinumab compared with placebo (NCT00570986). A total

of 1465 patients were enrolled. During the induction phase of



the study, patients with moderate to severe psoriasis received

briakinumab 200mg at weeks 0 and 4, followed by 100mg at

week 8, or placebo. Patients who achieved a PGA score of

‘clear’ or ‘minimal’ (PGA 0 or 1) at week 12 qualified to enter

the maintenance phase lasting 40 weeks and were re-random-

ized in a ratio of 2 : 2 : 1 to the following treatment arms: bria-

kinumab 100mg every 4 weeks, briakinumab 100mg every

12 weeks, or placebo. A higher proportion of patients treated

with briakinumab compared with placebo achieved PASI 75

(80.7% vs 4.5%) at week 12.

This long-term, 52-week efficacy study showed that admin-

istering briakinumab every 4 weeks resulted in PASI 75 main-

tenance in 82.4% of patients compared with 46.0% in the group

receiving briakinumab every 12 weeks.[95]

Two other phase III studies (ClinicalTrials.gov identifier

NCT00691964 with 347 participants and NCT00710580 with

340 participants), which both compared briakinumab with

etanercept and placebo, were carried out.[96,97] Briakinumab

was administered at the dose of 200mg at weeks 0 and 4 fol-

lowed by 100mg at week 8, and etanercept was administered at

a dose of 50mg subcutaneously twice weekly. A statistically

significantly greater proportion of patients in the briakinumab

treatment group achieved a PASI 75 response at week 12 in

both studies (81.9% and 80.6%, respectively) compared with

placebo (7.4% and 6.9%, respectively) or etanercept (56.0% and

39.6%, respectively). PASI 90 was achieved in 59.4% and 55.4%of patients receiving briakinumab compared with 1.5% and

4.2% in patients receiving placebo, and 23.4% and 13.7% in

patients receiving etanercept, respectively.[96,97]

Results of the phase III, 52-week, double-blind, randomized,

multicenter, active controlled trial comparing the efficacy of

briakinumab with methotrexate were presented at the European

Academy of Dermatology and Venereology Meeting in 2010.[98]

In this study, patients were randomized in a 1 : 1 ratio to receive

briakinumab (200mg at weeks 0 and 4, followed by 100mg every

4 weeks during weeks 8–48) or methotrexate at a dosage that was

presented as 5–25mgweekly (with no detailed information about

the methotrexate dosing regimen given). A total of 317 patients

were enrolled in the study. At week 24, PASI 75 was achieved by

81.8% of briakinumab-treated patients versus 39.9% of metho-

trexate-treated patients (p< 0.001). At week 52, 66.2% of bria-

kinumab-treated patients achieved PASI 75 compared with

23.9% of methotrexate-treated patients (p< 0.001). It has to be

emphasized that the results of phase III clinical trials have not

yet been published in peer-reviewed journals. According to

media information, the manufacturer, Abbott Laboratories

(IL, USA), has recently withdrawn the application for approval

for briakinumab in the US and Europe.[99]

6. Secukinumab

Secukinumab (AIN-457) is a fully human IgG1k monoclonal

anti-IL17 antibody that selectively neutralizes IL-17A.[100] In 2009

the name ‘secukinumab’ was accepted for AIN-457 by theWHO.

Results of randomized, proof-of-concept clinical trials

with secukinumab were performed in patients with chronic

plaque-type psoriasis (n = 36), rheumatoid arthritis (n = 52),and chronic noninfectious uveitis (n = 16).[100] Patients received

Table II. Main results of phase II clinical trials of briakinumab (ABT-874) in moderate to severe psoriasis

Study Design (no. of patients) Endpoint Dosage (no. of patients)a Percentage

Kimball et al.[93] Randomized, double-blind,

placebo-controlled, multicenter,

phase II trial (180)

Percentage of

patients reaching

PASI 75 at wk 12

One 200mg dose at wk 0 (30) 63

100mg every other wk for 12wk (30) 93

200mg weekly for 4wk (30) 90

200mg every other wk for 12wk (30) 93

200mg weekly for 12wk (30) 90

Placebo (30) 3

Kimball et al.[94]b Retreatment of patients who achieved

PASI 75 in the above phase II trial.

Treatment with study drug was

discontinued, and patients who lost

response (<PASI 50) during wk 12–24

received retreatment with the same

dosing regimen (130)

Percentage of

patients reaching

PASI 75 at wk 12 of

retreatment

One 200mg dose at wk 0 55

100mg every other wk for 12wk 94

200mg weekly for 4wk 69

200mg every other wk for 12wk 75

200mg weekly for 12wk 83

Placebo 3

a Number of patients given the dosage, if available.

b Conference abstract data.

PASI 50= 50% improvement in the Psoriasis Area and Severity Index score; PASI 75=75% improvement in the Psoriasis Area and Severity Index score.

120 Kurzeja et al.


secukinumab twice at doses of 3-10mg/kg, given intravenously

3 weeks apart. Secukinumab treatment induced clinically rele-

vant responses of variable magnitude in every patient group.

The rates of adverse events, including infections, were similar

in the secukinumab and placebo groups.[100] Currently there is

an ongoing dose-ranging, phase II trial of secukinumab in

patients with moderate to severe chronic plaque-type psoriasis

(ClinicalTrials.gov identifier NCT01071252). The efficacy of

three different doses (25mg, 75mg, and 150mg) of secukinu-

mab administered subcutaneously monthly or as a single ad-

ministration (25mg) in patients with moderate to severe

chronic plaque-type psoriasis is being evaluated with respect to

PASI 75 achievement, compared with placebo. Estimated en-

rolment is 80 patients and the estimated primary completion

date is April 2011.

Another phase II clinical trial (ClinicalTrials.gov identifier

NCT00941031) is currently ongoing. The estimated enrollment

is 396 patients and the estimated primary completion date is

March 2011.

In another phase II clinical trial, efficacy of secukinumab is

being evaluated in adults with psoriatic arthritis (Clinical-

Trials.gov identifier NCT00809614). In this study, two doses of

secukinumab 10mg/kg are being administered 3 weeks apart.

This study is expected to be completed in 2011.

7. Other Biologic Drugs Targeting the IL-23 Pathway

Apilimod (STA-5326) is a novel, oral, small-molecule com-

pound that selectively inhibits the production of the IL-12

family of proteins.[101] Apilimod inhibits the expression of genes

encoding the p40 subunit of IL-12 and IL-23 by selective in-

hibition of c-Rel translocation.[101]

Conference discussions indicate that phase II clinical trials

for psoriasis were not encouraging, and indicated clinical ben-

efit only at higher doses and after prolonged administration. To

our knowledge the results of these trials were not published in a

peer-reviewed journal.

Table III. Drugs that target molecules in the interleukin (IL)-23 pathwaya

Drug name Mechanism of action Stage of clinical development References Most recent

ClinicalTrials.

gov identifiers

Ustekinumab

(CNTO-1275)

Human mAb targeting

IL-12/IL-23 p40 subunit

Approval for psoriasis in 2009

Phase II study for psoriatic arthritis completed

Phase III studies for psoriatic arthritis, palmo-plantar

pustular psoriasis, adolescent patients with

psoriasis, and phase II trial for sarcoidosis all

ongoing

2-4,69 NCT00267956

NCT00870285

NCT01091051

NCT00955279

NCT01090427

Briakinumab (ABT-874) Human mAb targeting

IL-12/IL-23 p40 subunit

Phase II study for psoriasis completed

Phase III studies for psoriasis completed

93-98 NCT00292396

NCT00570986

Anti-p19 mAb mAb targeting IL-23 p19

subunit

Phase I study completed 103

LY-2525623 mAb targeting IL-23 Phase II study in psoriasis terminated 103 NCT01018810

Apilimod (STA-5326) Small molecule

– inhibition of IL-12/IL-23p40 subunit production

Phase II trial in psoriasis completed 102 NCT00642629

Secukinumab (AIN-457) mAb targeting IL-17 Phase II studies in psoriasis and psoriatic arthritis

ongoing

100 NCT00941031

NCT01071252

NCT00770965

NCT00805480

NCT00809614

LY-2439821 mAb targeting IL-17 Phase II study for psoriasis ongoing 103 NCT01107457

AMG-827 Human mAb targeting

IL-17 receptor

Phase II study for psoriasis ongoing 103 NCT00975637

NCT01101100

a For drugs that have been evaluated for a dermatologic indication only, this indication is provided in the table. In case of drugs that have not been evaluated for

a dermatologic indication, the table incorporates the non-dermatologic indication that was evaluated.

IL= interleukin; mAb =monoclonal antibody.



A randomized, double-blind, placebo-controlled trial of oral

apilimod in the treatment of Crohn disease failed to show

statistically significant benefit over placebo.[102]

LY-2439821, a humanized anti-IL-17 monoclonal antibody,

is another drug that interferes with the IL-23 pathway.[103]

LY-2439821 administered in a phase I clinical trial in 77 patients

in intravenousdosagesof 0.06, 0.2, 0.6, and2.0mg/kgevery2weeksfor a total of five doses (added to conventional oral therapy) im-

proved the signs and symptoms of rheumatoid arthritis, with no

strong adverse safety signal noted.[104] The drug was not evaluated

in skin diseases, such as psoriasis. A phase II clinical trial of LY-

2439821 administered subcutaneously in patients with moderate to

severe psoriasis (ClinicalTrials.gov identifier NCT01107457) is

currently ongoing. The study is expected to be completed in 2011.

AMG-827 is a fully human, monoclonal antibody that binds

to and blocks signaling via the IL-17 receptor. AMG-827 is now

in phase II clinical trials for moderate to severe psoriasis, ad-

ministered as 210mg subcutaneous injections (ClinicalTrials.

gov identifier NCT01101100).[103]

LY-2525623 is an anti-IL-23 antibody that was investigated

in a phase II trial to evaluate clinical activity, safety, tolerability,

pharmacokinetics, pharmacodynamics, and immunogenicity in

adults with plaque psoriasis. This trial was terminated in 2010.

According to information provided by Eli Lilly and Company,

the trial was terminated ‘‘for several reasons, including com-

plexities in development of LY2525623, but not because of

safety concerns’’ (NCT01018810).

Other biologic drugs that target the molecules IL-23, Th17

lymphocytes or IL-17 are currently under investigation. These

include, according to company press releases and patent appli-

cations, suchmolecules as AZ17, a bispecific Th17 antagonist that

inhibits the differentiation and effector function of human Th17

cells (ALLOZYNE� Inc., Seattle, WA, USA), an anti-IL23-p19

humanmonoclonal antibody (Schering Corporation [nowMerck

& Co, Inc., Whitehouse Station, NJ, USA]), a monoclonal anti-

body fragment that specifically binds to and inhibits the activity of

IL-17 (ScheringCorporation [nowMerck&Co, Inc.,Whitehouse

Station, NJ, USA]), and antagonists to IL-17A, IL-17F, and IL-

23-p19 (ZymoGenetics, Inc., Seattle, WA, USA).

A summary of currently investigated inhibitors of the IL-23

pathway is provided in table III.

8. Conclusion

IL-23 pathway inhibitors are a new group of biologic drugs

for the treatment of psoriasis and psoriatic arthritis. The safety

and efficacy of a number of these drugs was confirmed in

phase I, II, and III clinical trials.[105,106] Further studies should

be carried out to confirm the long-term efficacy and safety

of ustekinumab, briakinumab (ABT-874), and other drugs in

this group. Before these results are available we should remain

vigilant for potential complications due to the complex nature

of cytokine pathways downregulated by these drugs.

Taking into consideration the ubiquitous participation of

IL-23, Th17 lymphocytes, and IL-17 in cutaneous inflammatory

processes, it is likely that the list of possible indications for

IL-23 pathway inhibitors may broaden and the number of these

drugs may increase over time.

Acknowledgments

Wewould like to thankMsAgnieszkaKrynicka for her secretarial help.

No sources of funding were used to prepare this review. The authors have

no conflicts of interest directly that are relevant to the content of this review.

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Correspondence: Prof. Lidia Rudnicka, Department of Dermatology,

CSK MSWiA, Woloska 137, 02507 Warsaw, Poland.

E-mail: [email protected]



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New Interleukin-23 Pathway Inhibitors in Dermatology