Ustekinumab for the treatment of psoriasis: An evidence update

Zenas Z N Yiu, MBChB, BSc, MRCP and Richard B Warren, MBChB, PhD, MRCP

Dermatology Centre, Salford Royal NHS Foundation Trust, The University of Manchester,

Manchester Academic Health Science Centre, NIHR Manchester Biomedical Research

Centre, Manchester, United Kingdom.

Disclosure:

RBW has received research grants from Abbvie, Pfizer, Novartis and Leo, and reports

personal fees from AbbVie, Amgen, Boehringer Ingelheim Pharma, Celgene, Janssen-Cilag,

Leo, Lilly, Novartis, Pfizer, and Xenoport. ZZNY has no conflicts of interest to disclose.

Correspondence: Richard B Warren, MBChB, PhD, MRCP;

richard.warren@manchester.ac.uk

DOI: https://doi.org/10.12788/j.sder.2018. 040

Abstract

Ustekinumab is an interleukin-12/23 inhibitor used for the treatment of moderate-to-severe

psoriasis. Here, we review new evidence since ustekinumab was licensed for relative

efficacy in comparison with other biologic therapies from head-to-head randomized

controlled trials and network meta-analyses for the treatment of psoriasis. We also review

1

observational data emerging from psoriasis registries reporting the effectiveness and safety

of ustekinumab. Overall, new evidence suggests that ustekinumab has a favorable balance

between efficacy/effectiveness, safety, and tolerability and should remain a first-line biologic

therapy option for patients with severe psoriasis at present.END ABSTRACT

2

SUBIntroduction

The introduction of ustekinumab as a treatment option for patients with moderate-to-severe

psoriasis represented a major step forward at its time of launch. In contrast to tumor necrosis

factor inhibitors, ustekinumab was the first biologic therapy to specifically modulate what is

now recognized as the pivotal cytokine pathway of pathogenesis of psoriasis, the T-helper

17 pathway, paving the way for subsequent research, introduction, and testing of the

interleukin (IL)-17 and -23 inhibitors.

Since ustekinumab was licensed, several other biologic therapies for psoriasis have

been launched. These include secukinumab, ixekizumab, and brodalumab, which are IL-17

inhibitors, and tildrakizumab and guselkumab, which are IL-23 inhibitors. In some instances,

these therapies have been evaluated directly against ustekinumab in head-to-head

randomized controlled trials (RCTs), showing direct superiority in terms of efficacy. With

these newer therapies pushing the boundaries, however, what role does ustekinumab play in

the treatment ladder for psoriasis now and in the near future? Here, we review the new

clinical trial evidence since the pivotal licensing phase III trials were published. We also

review and appraise the emerging observational data reflecting the increasing experience

with using ustekinumab for the treatment of psoriasis in the real world. Based on the clinical

evidence accumulated thus far, we will suggest the place of ustekinumab in the expanding

treatment ladder for severe psoriasis now and in the future.

SUBEfficacy: From systematic reviews, network meta-analyses, and new head-to-

head randomized clinical controlled trials

Since the pivotal licensing trials of ustekinumab for psoriasis, PHOENIX 1 and 2,1,2 were

published, further RCTs have helped researchers place the relative efficacy and safety of

ustekinumab in comparison to other treatments for severe psoriasis (Table 1). Two major

network meta-analyses (NMAs) have been published to aid these comparisons. NMAs help

clinical decision-making by connecting a network of evidence together, enabling relative

3

comparisons of all available interventions to be made. In a comparison against other biologic

therapies, methotrexate, and placebo,3 ustekinumab had a higher probability of achieving

clear or nearly clear disease, and a reduction in Psoriasis Area and Severity Index (PASI)

score of at least 75% (PASI 75) at week 12 to 16, compared with placebo, methotrexate,

etanercept, and adalimumab, but it had a lower probability compared with secukinumab,

ixekizumab, and infliximab. However, ustekinumab was ranked the best in having the lowest

probability of withdrawal due to adverse events compared with the same treatments. In a

hierarchical cluster analysis considering efficacy (clear or nearly clear) and tolerability

(withdrawal due to adverse events) jointly, ustekinumab was clustered with adalimumab and

secukinumab as having both high efficacy and tolerability. This NMA included head-to-head

trials such as the ACCEPT trial comparing ustekinumab to etanercept,4 data from

ustekinumab arms from AMAGINE-2 and AMAGINE-3 comparing brodalumab to

ustekinumab,5 and the CLEAR trial comparing secukinumab to ustekinumab,6 enriching and

enabling these comparisons to be made (Table 1).

A second recent Cochrane systematic review and NMA compared all systemic

treatments for psoriasis.7 At the time of review, evidence for IL-23 inhibitors tildrakizumab

and guselkumab, but not risankizumab, were available for inclusion. This NMA found that

ustekinumab had a higher probability of achieving PASI 90 at week 12 to 16 compared with

tildrakizumab, adalimumab, itolizumab, infliximab, etanercept, tofacitinib, apremilast,

ponesimod, alefacept, fumaric acid esters, ciclosporin, methotrexate, and acitretin and

considered all trials irrespective of dose and duration of treatment. Where possible, the

outcomes were evaluated at the end of induction therapy and at the end of maintenance

therapy. It found that ustekinumab had a lower probability of achieving the same outcome

compared with ixekizumab, secukinumab, brodalumab, guselkumab, and certolizumab.

Although the authors concluded that there were no clear differences between the treatments

for safety profile of serious adverse events, methotrexate, ciclosporin, infliximab,

certolizumab, alefacept, apremilast, and fumaric acid esters had a lower probability of

4

serious adverse events compared with ustekinumab. The authors recommended caution in

interpretation of this data due to the low number of serious adverse events, as well as

conclusions based on low to very low or moderate certainty evidence for this outcome. The

authors concluded that ustekinumab, along with infliximab and certolizumab, appeared to

have the best trade-off between efficacy and tolerability. This NMA also included the same

head- to- head RCTs including involving ustekinumab as the previous NMA.

SUBOther head-to-head RCTs

Since the cut-off for the literature search for the two NMAs, three more head-to-head RCTs

involving ustekinumab in the treatment of psoriasis have been published involving

ustekinumab in the treatment of psoriasis, with congruent results (Table 1). IXORA-S is a

phase III study comparing ixekizumab to ustekinumab with the primary endpoint of PASI 90

at week 12.8 The RCT found that ustekinumab had a lower PASI 90 response (n = 70;

42.2%) at week 12 compared with ixekizumab (n = 99; 72.8%), with a response difference of

32.1% (97.5% confidence interval [CI], 19.8%-44.5%). There were no significant differences

in serious adverse events between the 2 treatment arms. A phase II trial of 166 patients

compared risankizumab, an IL-23 inhibitor, with ustekinumab, with a primary endpoint of

PASI 90 at week 12.9 This trial found that ustekinumab had a lower PASI 90 response (n =

40; 40%) compared with risankizumab (n = 83; 77%), with again little significant difference in

serious adverse events between the comparators. It is likely that the choice of 12 weeks as a

primary endpoint may be too early for ustekinumab to achieve its potential overall efficacy.

Finally, NAVIGATE is a phase III RCT comparing guselkumab, another IL-23 inhibitor, with

ustekinumab in patients with inadequate response to ustekinumab.10. Ustekinumab was

shown to have a lower immunoglobulin AInvestigator’s Global Assessment (IGA) 0/1

response 16 weeks after randomization (0.7 ± 1.3 versus 1.5 ± 1.6; P ≤ 0.001) as well as a

lower PASI 90 response (22.6% versus 48.1%; P ≤ 0.001) compared with guselkumab,

although this response is an unfair comparison for ustekinumab given the preselected nature

of the population. Safety of ustekinumab is also difficult to assess in this trial given that a

5

prerandomization open-label phase would have pre-selected out patients with early adverse

events to ustekinumab.

SUBSummary from update of trial data

Since ustekinumab was approved and made available on the market, new IL-17 and IL-23

inhibitors have emerged with higher efficacy for the treatment of psoriasis. However, two

recent NMAs have both concluded that ustekinumab has a favorable trade-off between

efficacy and tolerability. This is highly important as because utility and tolerability, along with

efficacy, are crucial factors for patients and are likely to aid adherence to medication.

However, it should be noted that both NMAs and the head-to-head RCTs mostly report on

short-term outcomes (week 12), and interpretation of longer-term outcomes from these data

is made difficult given the lack of comparator arms in most RCTs. In our opinion,

ustekinumab may have its maximum efficacy after loading later than week 12, and there is

therefore there is the probability that this timepoint may underestimate its efficacy. The low

external validity due to stringent exclusion and inclusion criteria of RCTs also affects

interpretability of the true safety of ustekinumab and other biologic therapies in the real

world.

SUBObservational data evidence: Effectiveness

Real-world data areis extremely helpful for clinicians as because they have high external

validity, and evaluate the effectiveness of medicines, or how medicines perform in the

clinics, rather than efficacy, or how medicines perform in idealized settings. Psoriasis

treatment registries around the world help to provide this data to enable clinicians to further

scrutinize the performance of ustekinumab and other biologic therapies.11

Psoriasis Longitudinal Assessment and Registry (PSOLAR) is a large, multinational

single-sponsor prospective observational registry of patients with psoriasis on systemic

treatments. PSOLAR collects data from predominantly US dermatology centers but also

includes data from Europe and other countries. A recent study looked at effectiveness

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outcomes for patients initiating ustekinumab, infliximab, adalimumab, or etanercept, with the

Physician Global Assessment (PGA) and percent body surface area (BSA) used as outcome

measures.12 The Dermatology Life Quality Index (DLQI) was used as the health-related

quality of life score.

The study found that 1,041 patients on ustekinumab had a PGA 0/1 proportion of

57.1% at 6 months and 59.2% at 12 months. Adjusted logistic regression found that all tumor

necrosis factor (TNF) inhibitors had a lower probability of achieving a PGA score of 0/1 at 6

months although at 12 months, the equivalent estimates were nonsignificant apart from the

infliximab versus ustekinumab comparison. There was also a mean decrease of percent

BSA of −14.7 (SD 19.65) at 6 months and −16.3 (SD 18.53) at 12 months. Analysis of

covariance found that ustekinumab was significantly better at reducing percent BSA than

adalimumab and etanercept, but not infliximab, at 6 months. At 12 months, ustekinumab was

significantly better than infliximab and etanercept but not adalimumab. Regarding quality of

life, the DLQI 0/1 for ustekinumab was 47.6% at 6 months and 54.8% at 12 months. The

study report did not state whether thereis wereas any significant differences between the

treatment groups for this outcome, so it can be assumed that there was no significant

difference between ustekinumab and the other outcomes.

Although this study provides some useful comparative data, it is somewhat difficult to

interpret the raw proportions of patients achieving the outcomes becauseas the study uses a

generous per-protocol or complete case analysis approach to missing outcome data. This

means that only those with no missing outcome data are analyzed, rather than the whole

starting cohort. The study report states that the background characteristics of patients with

missing data were comparable to those evaluated, but theseis data areis not given in the

manuscript. If the missing data were not at random but associated with effectiveness and/or

quality of life, this could introduce a bias to both the raw proportions and the adjusted point

estimates. Nonetheless, assuming that missing data were missing for the same reasons for

all comparator arms (nondifferential misclassification), the adjusted relative risk estimates

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suggest that ustekinumab was more effective for treating clinical signs of psoriasis than TNF

inhibitors at 6 months but was not more effective at quality of life measures than the same

comparators. It is also notable that PSOLAR is sponsored by the manufacturers of

ustekinumab, and analysis of data is not independent.

The British Association of Dermatologists Biologic Interventions Register (BADBIR) is

a United Kingdom and Republic of Ireland national prospective safety psoriasis registry

that,and similar to PSOLAR, recruits patients with psoriasis on systemic treatments. A study

in BADBIR investigated self-reported outcome measures of DLQI and EuroQoL-5D (EQ5D)

after 6 and 12 months of follow-up on etanercept, adalimumab, and ustekinumab.13. Out of

Aa total of 396 patients on ustekinumab, 46.8% achieved a proportion of patients with DLQI

0/1 at 6 months of 46.8% and 50.2% achieved a DLQI 0/1 at 12 months of 50.2%. Patients

on all three treatments experienced significant improvements in both the DLQI and EQ5D

scores at both timepoints. Multivariable regression modelling found that ustekinumab had no

significant difference of in odds of achieving a DLQI score of 0 or 1 as compared to

adalimumab, after adjustment of a range of potential confounders (6- months odds ratio

[OR] 0.86; 95% CI, 0.59-1.25), but etanercept had a lower odds as compared to adalimumab

(OR 0.37; 95% CI, 0.28-0.50); while none of the treatments were significantly different from

one anotherhad any significant difference in mean change in EQ-5D score from each other

after 6 or 12 months.

Similar to the previous study, there is a complete case analysis approach to

missing data, especially of the outcome. It is therefore difficult to extrapolate solely from the

percentages of patients achieving the outcomes a conclusive relative difference between

ustekinumab and the other two biologic therapies solely from the percentages of patients

achieving the outcomes, but the multivariable regression result suggests that ustekinumab

may also have a more beneficial effect for quality of life (DLQI) as compared with

etanercept.

8

The Continuous Assessment of Psoriasis Treatment Use Registry with Biologics

(BioCAPTURE) is a registry based in the Netherlands, and that contains data from

consecutive patients with psoriasis treated with biologics in one academic and eight

nonacademic centers.14 This smaller study investigated 90 treatment episodes with

ustekinumab and, in a multilevel linear regression analysis, found that a significantly higher

probability of achieving a lower mean PASI for ustekinumab compared with etanercept at 5

years (P = .019) but not adalimumab (mean PASI 5 years: ustekinumab, 4.7; 95% CI, 3.9-

5.5; etanercept, 5.9; 95% CI, 5.4-6.5). There were no significant differences in mean PASI

between the three treatments at 1 year. The per-protocol PASI 75 data areis also shown,

with a 45.3% PASI 75 for ustekinumab after 1 year of treatment and a higher probability of

achieving PASI 75 for ustekinumab compared with etanercept (P = 0.048)

Given that those who persisted on the drug after 1 year have directed the difference

between ustekinumab and etanercept in the above analysis, ustekinumab could have a

higher long-term effectiveness compared with etanercept. An alternative interpretation could

be the fact that those who have persisted and were treated with ustekinumab early (to

enable a follow-up of 5 years) have a lower mean PASI than the equivalent patients selected

on etanercept, and therefore any difference could be due to selection bias. The per-protocol

PASI 75 results are hard to interpret given the same missing data concerns as listed in the

above analysis.

SUBSummary from effectiveness data in observational studies

Although an interpretation of observational data is difficult due to the per-protocol approach

necessitated by missing outcome data, there is a suggestion that ustekinumab is superior to

etanercept for effective treatment of ness of the treatment of psoriasis when the outcome is

either objective (disease severity scores) or subjective (patient-reported quality of life

scores). However, there is less consistent evidence for a difference in treatment

effectiveness between ustekinumab and adalimumab.

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SUBDrug survival

It is now well established that ustekinumab has a higher drug survival compared with the

TNF inhibitors as a first-line therapy. Analyses in the BADBIR, PSOLAR, and BioCAPTURE

registries all found that, after adjustment for potential confounding factors, ustekinumab has

a higher drug survival as a first-line therapy compared with infliximab, etanercept, and

adalimumab as a first-line therapy.15-17 The PSOLAR registry also investigated drug survival

by different lines of therapy and found similar results, with ustekinumab having the highest

drug survival for as the a second-2nd and third3rd -line therapy. A recent study specifically

investigated second-line therapy in the BADBIR database and found similar overall drug

survival as first-line therapy, with drug survival highest at year 1 for ustekinumab (85%;, 95%

CI, 82%-87%).18. In the multivariable Cox regression model, second-line ustekinumab

therapy also had significantly higher drug survival than the etanercept or adalimumab

(hazard ratio [HR] 0.46; 95% CI, 0.33-0.64). Importantly, the discontinuation of a prior TNF

inhibitor due to lack of ineffectiveness was not associated with a higher probability of

discontinuation due to ineffectiveness of a second biologic, and therefore this therefore

suggests that ustekinumab may perform well also as a second-line biologic.

SUBAdherence

One of the factors byin which ustekinumab is thought to encourage drug survival is a

favorable 12-weekly dosing regimen. A study of a subset of patients in the BADBIR cohort

investigated medication non-adherence, classified into intentional and unintentional non-

adherence.19. Only 11 out of 160 (7.3%) of patients on ustekinumab were classified as

nonadherent, compared to 52 out of 331 (16.4%) of those prescribed either etanercept or

adalimumab. Part of this is due to the fact that ustekinumab is often nurse-administered in

the United Kingdom, compared with self-administration for etanercept and adalimumab.

SUBPharmacogenetics

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Moving on from overall markers of treatment response or adherence, there is a growing

interest in personalized medicine, where in which an individual’s characteristics direct

treatment choice in order to maximize the probability of treatment effectiveness and also

avoid adverse effects. Although clinically the individual tailoring of therapies is central to the

art of medicine, the advent of the availability of big data enables utilization of “omics” data to

objectively personalize treatment options.20

Pharmacogenetics is a field of intense interest for psoriasis biologic therapies at the

moment.21 A recent systematic review identified several candidate genetic predictors. Three

out of five studies identified the presence of the human leukocyte antigen (HLA)-Cw6 allele

as a predictor for higher response rates to ustekinumab.22 One study also found a higher

response rate with a TT genotype for rs763780 in the IL17F gene,23, while another found

associations with higher efficacy with ustekinumab for two variants in the ERAP1 gene

(rs26653 and rs151823) in patients with psoriasis.24 Further research to identify relevant

genetic markers for ustekinumab is needed, and it is likely that genetics will play a

supporting role amongst other clinical and “omic” predictors that, together, will explain more

of the variability in treatment response and hence thus allow for accurate prediction.

SUBSerious infection

There have now been several studies utilizing registry data to assess the risk of serious

infection associated with ustekinumab compared with non-biologic systemic therapies. The

PSOLAR registry investigated the following three populations of patients on ustekinumab: an

overall (including prevalent) population of 3,474 patients on ustekinumab with a follow-up of

5,923 person-years (median follow-up 1.6 years), an incident population of 1,519 patients

with a follow-up of 2,489 person-years (median follow-up 1.4 years), and a biologic-naïve

population of 376 patients with a follow-up of 585 person-years (median follow-up 1.4

years).22 They reported a crude incidence rate of 8.3 per 1,000 person-years for the overall

population, but the crude incidence rates were not reported for the other two populations. In

11

an adjusted Cox regression, ustekinumab was found to have an HR of 0.96 (95% CI, 0.56-

1.65), 1.26 (95% CI, 0.66-2.42), and 1.29 (95% CI, 0.43-3.87) for the respective overall,

incidence, and biologic-naïve populations when compared to a group of patients on acitretin

and/or phototherapy. The Spanish Registry of Adverse Events Associated With Biologic

Drugs in Dermatology ( BIOBADADERM r)egistry, a smaller single- country registry,

reported a crude incidence rate of 5.9 per 1,000 person-years in 560 patients and 1,194

person-years of follow-up.23 This gave an adjusted HR of 0.75 (95% CI, 0.18-3.13) when

compared to methotrexate. All patients were incident users of ustekinumab, and no separate

estimate was given for the biologic-naïve population in this registry. Finally, the authors were

involved in a study utilizing the BADBIR database, and we found a crude incidence rate of

15.1 per 1,000 person-years in 994 biologic-naïve patients and 2,256 person-years of follow-

up (median follow-up 2 years).24 We found an adjusted HR of 0.92 (95% CI, 0.60-1.41)

comparing against a cohort on any nonbiologic systemic therapy and an adjusted HR of 1.22

(95% CI, 0.75-1.99) comparing against methotrexate. It is therefore reassuring that, despite

the different comparators and use of different types of ustekinumab starters in the different

analyses of registry data across the world (ie, incident, prevalent, biologic-naïve), the relative

risk of serious infection for ustekinumab was consistent and was not shown to be elevated.

SUBMalignancy

In contrast to infection, the risk of malignancy associated with ustekinumab is not as well

established. A recent systematic review25 identified only one study investigating the risk of

malignancy in patients on ustekinumab—an open-label extension of combined safety data

from four large RCTs.26 The standardized incidence ratios (SIRs) did not show an increased

risk of malignancies overall (excluding nonmelanoma skin cancer; SIR, 0.98; 95% CI, 0.74-

1.29) or across a range of specific cancers, including prostate, melanoma, colorectal,

lymphoma, and breast cancers. Since the systematic review was published, the PSOLAR

has published a nested case-control analysis with 252 cases of malignancy and 1,008

controls.27 The primary analysis including exposure within 12 months did not show any

12

increase in the risk of malignancy for any length of exposure (≥3 to <12 months of exposure:

OR 1.12; 95% CI, 0.63-2.01; ≥12 months: OR 0.98; 95% CI, 0.63-1.53) although the CIs

were wide.

SUBSummary from observational studies

As real-world evidence for biologic therapies in the treatment of psoriasis has gradually

emerged over time, ustekinumab has been shown to be a drug with favorable effectiveness

and safety profile. In our opinion, ustekinumab has several properties that give it a high real-

world utility. The regular dosing regimen of 12 weeks in conjunction with drug administration

by nurses helps encourage good adherence and a high drug survival as a first- or second-

line biologic drug. The licensed higher dose of 90 mg for patients over 100 kg also helps

both effectiveness and drug survival given that BMI is a predictor for drug discontinuation

due to ineffectiveness in multiple-registry drug survival studies.15,16 Data from psoriasis

registries are consistent in showing that ustekinumab does not have an elevated risk of

serious infection compared to the nonbiologic systemic therapies, while early data on the risk

of malignancy areis also promising. Further observational data areis needed, however, to

fully understand the true risk of malignancy associated with ustekinumab, and to assess

other safety outcomes.

SUBConclusion

It is undeniable that the IL-17 and IL-23 inhibitors have a higher efficacy when compared

head-to-head with ustekinumab. However, there are several reasons why ustekinumab

should remain a first-line biologic option. Two large meta-analyses have both concluded that

trial data show that ustekinumab strikes a good balance between efficacy and tolerability.

There is a substantial body of evidence from observational studies to indicate that

ustekinumab is effective, safe, and associated with high drug survival and adherence.

Importantly, no observational evidence has suggested the emergence of any new adverse

event signal after 9 years of use in the clinic. Coupled with favorable drug administration and

13

a weight-based dosing profile, we believe that ustekinumab should remain a first-line option

for patients until further real-world and trial evidence are is available for IL-23 inhibitors. It is

a particularly important option for patients who are more concerned about safety of

treatments over other aspects, such asfor example the onset of action or the probability of

obtaining complete clearance.

14

TABLE 1 Summary of efficacy outcomes from new RCTs involving ustekinumab since

the drug was licensed

Trial Phase Primary

endpoint

PASI 90 for

ustekinumab

PASI 90 for comparator

ACCEPT III Week 12 36.4% (45

mg); 44.7%

(90 mg)

Etanercept; 23.1%

AMAGINE-2 III Week 12 PASI 100

22.0%

PASI 100

Brodalumab 26.0% (140

mg); 44.0% (210 mg)

AMAGINE-3 III Week 12 PASI 100

19.0%

PASI 100

Brodalumab 27.0% (140

mg): 37.0% (210 mg)

CLEAR III Week 16 57.6% Secukinumab; 79.0%

IXORA-S III Week 12 42.2% Ixekizumab; 72.8%

Risankizumab

trial

II Week 12 40.0% Risankizumab; 77.0%

NAVIGATE III Week 16 after

randomization

22.6% Guselkumab; 48.1%

Abbreviations: PASI, Psoriasis Area and Severity Index; RCT, randomized controlled trial.

15

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