The Potential Utility of Tildrakizumab: an Interleukin-23 Inhibitor for the Treatment of Psoriasis

Abstract

Introduction

The approved biologic therapies are effective for the treatment of psoriasis, but have limitations. Tildrakizumab has a different mechanism of action and is a humanized immunoglobulin G1κ that binds to the p19 subunit of IL23.

Areas covered

Phase I, II and III clinical trials investigated the pharmacokinetics, efficacy, safety and immunogenicity of tildrakizumab for patients with psoriasis. The mean half-life of tildrakizumab is between 20.2 to 28.2 days. Tildrakizumab achieved a PASI 75 of 66% and 74% at week 16 for the doses of 100mg and 200mg respectively in a phase IIb randomised clinical trial (RCT), and PASI 75 of 61%/64% and 62%/66% at week 12 for 100mg and 200mg respectively in two phase III RCTs. Frequently associated adverse events include headache and upper respiratory tract infection.

Expert opinion

By recent standards tildrakizumab has relatively modest efficacy, possibly due to a less intensive dosing regimen. Head-to-head RCTs in comparison with current therapies such as ustekinumab and secukinumab respectively are needed to understand its relative efficacy. In addition, trials in patients who have failed multiple biologics and patients with psoriatic arthritis would be helpful. The low frequency of injections in the tildrakizumab maintenance regimen may encourage adherence and aid persistence.

Key words

Biologic therapies, Interleukin 23p19, MK-3222, Tildrakizumab, Psoriasis

1 Introduction

Psoriasis is a chronic inflammatory skin condition affecting between approximately 1 to 8.5% of the population1, with the incidence of disease varying between 78.9 and 230 per 100,000 person-years1. Disease severity can vary from one or two small areas on the body to whole body coverage, and manifests as erythematous, raised and well-demarcated plaques with adherent silvery scales (Figure 1). Psoriasis can affect people of all ages, has an equal gender preponderance, and has a profound and long-lasting psychosocial impact on patients2, 3. Psoriasis is also associated with a debilitating and destructive inflammatory arthritis called psoriatic arthritis (PsA), with the prevalence of PsA in psoriasis patients estimated to be between 7% and 24%4.

1.1 Biologic therapies and unmet needs

The emergence of biologic therapies has transformed the care of patients with severe psoriasis. The tumour necrosis factor α inhibitors (TNFI) etanercept, infliximab, adalimumab; the interleukin(IL)12/23 p40 subunit inhibitor ustekinumab; and the interleukin(IL)17-A inhibitors secukinumab and ixekizumab are approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of psoriasis and offer patients a choice of treatments that vary in terms of efficacy, tolerability, safety profile and dosing regimen. With the exception of ixekizumab, which is undergoing review at present, all of the above biologic therapies are also recommended by the National Institute of Health and Care Excellence (NICE) for psoriasis in the UK.

These treatments have some important limitations. There is an around 50% probability that patients stop their first-line biologic therapy (combined estimate for etanercept, infliximab, adalimumab or ustekinumab) within three years, with the primary reason due to the loss of treatment effectiveness5. Certain treatments have been associated with important adverse events such as serious infection6, 7 from real-world data and cardiovascular events8 from clinical trial data. There is around 27% non-adherence to TNFIs in patients with rheumatoid arthritis9 and 16.8% non-adherence to biologic therapies in patients with psoriasis10. Although the newer IL-17 inhibitors have a higher efficacy, they are associated with different concerns such as candidiasis or exacerbation of inflammatory bowel disease11, and injections are also relatively frequent. Any new biologic therapy will need to improve on these limitations, and/or be more effective in order to offer patients with psoriasis a genuine choice.

Tildrakizumab is a subcutaneously administered humanized immunoglobulin G1κ that specifically binds to the p19 subunit of IL23. Here, we will present the pharmacokinetics of the therapy, assess the evidence for the efficacy and safety of the drug, and make an informed opinion as to the potential position of tildrakizumab in the psoriasis treatment pathway. The MEDLINE, EMBASE, Cochrane Central Register of Clinical Trials, ClinicalTrials.gov and EU Clinical Trials Register were searched using the terms “tildrakizumab” OR “MK-3222”.

1.2 The role of Interleukin-23 in psoriasis and inflammation

The IL-23/17 pathway is crucial in the pathogenesis of psoriasis11. IL-23 is a heterodimeric cytokine composed of two subunits, p40 and p19 12. The p40 subunit is shared with IL-12, and is the target of ustekinumab, an effective treatment for psoriasis, while the p19 subunit is

specific to IL-23. Both mouse and human studies have shown that IL-23, and not IL-12, is critical in the development of inflammatory conditions such as psoriasis13-15. In particular, levels of both p19 and p40 subunits, but not p35 which is specific to IL-12, were found to be raised in lesional skin in patients with psoriasis16.

IL-23, which is primarily produced by macrophages and dendritic cells, is responsible for the development and differentiation of Th17 cells, enhancing the expression of IL-17A and IL-17F along with other pro-inflammatory cytokines such as tumour-necrosis factor-α 17. On the other hand, IL-12 has important roles in the differentiation of Th1 cells, B cells, natural killer cells and haematopoietic progenitors, playing a part in both the adaptive and innate immunity and is required for an optimal interferon-γ response during infections18. It stands to reason that a strategy to inhibit p19 and not p40 would simultaneously target inflammation and preserve the effect of IL-12 in the immunological defense of infection.

1.3 Overview of competitor compounds

There are three inhibitors of IL-23 under investigation at present for the treatment of psoriasis, tildrakizumab, guselkumab and risankizumab. Guselkumab, an IL-23p19 specific inhibitor, at a dose of 100mg is statistically superior for PASI 90 (73.3% vs 49.7%) at week 16 for the treatment of psoriasis as compared to adalimumab in a phase III19 clinical trial, while 3 phase III studies for this drug for the treatment of psoriasis, one against placebo only (ClinicalTrials.gov ID NCT02325219), one against adalimumab (ClinicalTrials.gov ID NCT02207244) and one against ustekinumab (ClinicalTrials.gov ID NCT02203032) are underway. A phase I study assessed the efficacy of risankizumab, another specific IL-23p19 inhibitor, for psoriasis20, while several studies are underway (ClinicalTrial.gov ID NCT02672852, NCT01577550, NCT02596217) with two head-to-head studies against ustekinumab (ClinicalTrial.gov ID NCT02684370, NCT02054481) and one against adalimumab (ClinicalTrial.gov ID NCT02694523).

What are the differences between tildrakizumab and the above biologic therapies, and does it have potential to provide patients with psoriasis a valuable additional choice?

2 Pharmacokinetics, metabolism and effects on the skin

A phase I study by Zandvliet et al. investigated the pharmacokinetics of tildrakizumab in healthy Caucasian (n=19), Japanese (n=22) and Chinese (n=12) subjects21. The dose-normalised area under the curve (AUC ∞) geometric mean, a representation of the total drug exposure over time, was 1275.24 μgxday/mL (95% CI 1074.21, 1513.90) in Caucasians and 1366.80 μgxday/mL (95% CI 1151.34, 1622.59) in Japanese subjects for the dose of 200mg given subcutaneously (S/C). The maximum concentration (Cmax) was 29.83 μg/mL (95% CI 24.42, 36.44) and 37.88 μg/mL (95% CI 31.01, 46.27) for the same treatment in Caucasians and Japanese subjects respectively. In dose-normalised analyses (across doses of 50mg, 200mg and 400mg S/C), the mean half-life (t1/2) was between 26.3, 28.2, 24.5 days, with a median time to maximum concentration (Tmax) at 6.04, 13.0, 6.03 days for Caucasian, Chinese and Japanese subjects respectively.

Another phase I multiple-dose randomised, placebo-controlled study by Kopp et al. investigated tildrakizumab in 77 patients with psoriasis and conducted histological, immunohistochemical and gene expression analyses of lesional skin22. The mean t1/2 from this study was reported to be between 20.2 and 26.9 days.

Using intravenous (IV) doses of 3mg/kg (n=10) and 10mg/kg (n=7) and placebo (n=5), biopsies were taken around 9-12 weeks after baseline (i.e. 1-4 weeks after the last dose). Tildrakizumab significantly reduced both epidermal thickness and Ki67, a marker of cell proliferation, as well as epidermal, vascular and inflammatory cell infiltrate parameters as measured by a histopathological psoriasis severity score23. Epidermal CD4+, CD8+ T cells, dermal myeloid dendritic cells, plasmacytoid dendritic cells, CD15+ neutrophils numbers all significantly decreased following administration with tildrakizumab. The higher dose of 10mg/kg significantly decreased the gene expression of various markers of inflammation including S100A7, LCN2, CCL20 and CXCL8/IL-8.

3 Clinical efficacy

3.1 Phase I study

The second part of the phase I study by Kopp et al. was dedicated to the investigation of the clinical efficacy of tildrakizumab22. This compared tildrakizumab at doses of 3mg/kg (n=15) and 10mg/kg (n=14) against placebo (n=20) given at weeks 0, 4 and 8. Tildrakizumab achieved a PASI 75 and PASI 90 of 66%/47% for 3mg/kg dose and 93%/71% for the 10mg/kg dose in part 2 at week 16, while a mean placebo-corrected reduction in PASI score between 50-80% at week 16 across doses of 0.05 to 10mg/kg was achieved across all parts of the study.

It was unclear what the percentage of patients on placebo achieving PASI 75 was, with no significance testing reported. It should also be noted that the planned enrolled number of 40 was powered for a placebo-corrected change in PASI of 30, rather than for differences in PASI 75 or 90. Efficacy outcome was designated as a secondary objective, with the primary endpoint of placebo-corrected percentage change in PASI at day 112 (week 16). Although not explicitly stated, this was a single centre study from Austria. Selection and information bias was minimised with central computer randomisation and blinding of subject and investigator. Attrition bias was difficult to assess due to the low number of participants, while discontinued numbers from all three parts were presented pooled together. Data from one of the figures (Figure 1b) shows 2 patients dropped out of the study by day 112, with no drop-outs reported in the active treatment arms.

3.2 Phase II study

A phase IIb study on the efficacy of tildrakizumab24 reported 355 adults randomised to receive two administrations of subcutaneous tildrakizumab at doses of 5mg (n=42), 25mg (n=92), 100mg (n=89), 200mg (n=86) and placebo (n=46) at baseline and week 4. At the primary endpoint of week 16, designated at the end of part 1 of the study, the PASI 75 responses for 100mg and 200mg (intended doses to be taken forward to phase III studies) were 66% and 74% respectively, with PASI 90 of 39% and 52% respectively. A secondary endpoint of PASI 75 week 12 was 61% and 72% for the doses of 100mg and 200mg respectively, showing a near maximum onset of action at week 12, while 97% of PASI 75 responders on 100mg and 200mg at week 16 had a PASI 75 at week 52 in part 2 of the study.

This was a multi-centre study carried out in the US, Canada, Japan and Europe. The study recruited more participants than the required sample size, calculated with >90% power for a difference of 40% in PASI 75 between placebo and tildrakizumab, assuming a conservative

estimate of 10% placebo response rate. Most of the patients (~80%) were biologic-naïve. Randomisation and allocation was done centrally via the internet, which should reduce selection bias if random sequencing was performed. All investigators and participants were blinded apart from the medication preparer and the accountability monitor, but the analysts were unblinded at week 16, with detection bias therefore a potential for endpoints after this time. There were no obvious differences to attrition in part 1 apart from 4 withdrawing consent in the placebo arm as compared to no subjects withdrawing consent in the two active doses of 100mg and 200mg arms. However, 12 subjects withdrew due to treatment failure from the tildrakizumab 100mg arm in part 2 (7.8%), which may be a selection of PASI 75 non-responders at week 16 who do not go on to achieve treatment response.

Missing data was imputed with last observation carried forward in part 1 and 2 for participants who had not discontinued treatment due to lack of efficacy or had a missing PASI score at week 16. This approach favours the treatment, given that adverse events such as serious infections in the first weeks of treatment will affect whether a patient can stay on the drug and achieve PASI 75 at week 16.

The methods for the report state that the primary end point was analysed using stratification for baseline weight of ≤90kg and >90kg, as well as for prior exposure to biologic therapy for psoriasis, but this data was not available in the report. Otherwise, the report adhered to the CONSORT checklist well overall.

3.3 Phase III studies

The results from the primary end points of two phase III studies evaluating the efficacy of tildrakizumab have been published in abstract form25, while one was stopped before enrolment (ClinicalTrials.gov ID NCT01936688). reSURFACE 1 (MK-3222-010) is a 64-week RCT involving 772 patients comparing tildrakizumab at doses of 100mg (n=309) and 200mg (n=308) administered at week 0, 4 then 12 weekly thereafter with placebo (n=155). reSURFACE 2 (MK-3222-011) is a 52-week RCT involving 1090 patients comparing the efficacy and safety or tolerability of tildrakizumab at doses of 100mg (n=307) and 200mg (n=314) administered at week 0, 4 then 12 weekly thereafter against etanercept 50mg twice weekly (n=313) and placebo (n=156). Both trials measure their primary endpoints of efficacy (PASI 75) and safety (percentage of participants experiencing and/or discontinuing an AE) at week 12, and both have an optional long-term extension.

In reSURFACE 1, tildrakizumab achieved a PASI 75 response of 64% (100mg) and 62% (200mg, placebo 6%, p<0.001) at week 12, while in reSURFACE 2 tildrakizumab achieved a PASI 75 response of 61% (100mg) and 66% (200mg), which was significantly higher than etanercept (48%, p<0.05) and placebo (6%, p<0.001) at week 12. The PASI 75 response in reSURFACE 1 and reSURFACE 2 rose to >70% and >80% in both dosing arms in the respective trials at week 28, but it is unclear but likely that blinding was removed after week 12. The PASI 90 responses were between 35-40% at week 12 and 52%-60% in week 28 for tildrakizumab over the two trials. At present, there are no registered phase III studies investigating the efficacy of tildrakizumab against any other current biologic therapy, nor for the treatment of psoriatic arthritis.

4 Safety and tolerability

In the phase I study involving healthy subjects, the most frequent AEs in the study were headache (24%), upper respiratory tract infection (19%) and injection site haematoma (15%). Importantly, there was no relationship between dose and incidence or severity of AEs, suggesting that these AEs are associated with the method of administration and excipients rather than the active drug. Two subjects had serious AEs, 1 had appendicitis in the 50mg group and 1 had suicidal ideation in the 400mg group, neither of which were considered to be treatment-related.

Similar AEs were presented in the phase I study involving participants with psoriasis. 19% suffered from a headache, and 19% had an upper respiratory tract infection. 11 serious AEs were reported in 8 subjects, including fractures, cytomegalovirus infection, pulmonary embolism and convulsion. All but the convulsion event was considered to be possibly related to tildrakizumab.

In the phase IIb study, safety data was considered if participants had one dose or more of the treatment drug. The most common AEs were again headache and nasopharyngitis. Hypertension was noted in 9 participants on the active drug arm but none in the placebo arm. There were 23 participants on tildrakizumab reporting serious AEs(SAEs) over 52 weeks of treatment and 20 weeks of follow-up, with 4 SAEs reported within the initial randomized period for 308 participants.

Events considered as treatment-related included cases of bacterial arthritis, lymphoedema, melanoma, stroke, epiglottitis and knee infection. One participant on tildrakizumab died of an unknown cause, but had a raised blood alcohol level at death. One patient had a thrombotic cerebral infarction and one had a confirmed major adverse cardiovascular event (MACE) after withdrawal of treatment at week 52 from the 100mg tildrakizumab arm.

The specific rates of serious AEs in the two phase III studies in each treatment arm have not been presented.

5 Immunogenicity

The phase I study reported by Zandvliet et al did not fully report the method of anti-drug antibody (ADA) measurement21. 4 out of 50 subjects had detectable ADAs, with 2 considered to have neutralising ADAs that decreased tildrakizumab exposure. 8 had baseline positive ADAs that did not have any effect on the pharmacokinetic profile of tildrakizumab, and continued to have non-neutralising ADAs after treatment.

Similarly the second phase 2 study did not report the method of anti-drug antibody measurement22. 9 participants (18%) had post-treatment ADAs, with 5 showing a lower tildrakizumab exposure. This did not affect the PASI response or adverse effect profile.

The phase IIb study24 reported using an electro-chemiluminescence-based ADA bridging assay by Covance Laboratories in the US, which is a sensitive method of detecting ADAs26. It is unclear whether an acid dissociative method was utilised to further enable detection of ADAs. 46 participants (13%) had positive ADAs at baseline, while 25 (7.0%) developed ADAs after treatment. 10 (3% of the total participant population) had neutralising ADAs, while 14 participants with positive ADAs overall had reduced tildrakizumab levels and no association with AEs. The specific dosing arm that these participants were enrolled into was

not reported. It is unclear whether ADAs had any association with primary or secondary non-response.

6 Conclusion

Tildrakizumab is a specific inhibitor of IL-23p19, and targets the IL17/23 axis that is critical in the pathogenesis of psoriasis. It has a relatively long half-life and achieves maximum concentration in around a week. A full peer-reviewed publication is awaited for the two phase III studies in order to evaluate the trial methodology, dropout, and areas of probable bias and firm conclusions from the top line efficacy figures can only be drawn after that is made available. The safety data presented by the initial trials are reassuring, although further large RCTs and observational studies are needed to establish tildrakizumab’s relative safety profile, in particular investigating whether tildrakizumab increases the risk of MACEs given the present uncertainty over p40 inhibitors. There appears to be low levels of ADAs that affect drug levels and primary response, but larger and longer studies are also needed to evaluate this.

7 Expert opinion

At present, it is unclear whether tildrakizumab offers any tangible improvement over other available biologic therapies. The main advantage of tildrakizumab is that it is dosed in a maintenance regimen of 12 weeks, and similar to ustekinumab this is likely to encourage adherence and aid persistence to the drug5. The PASI 75 and PASI 90 figures achieved by tildrakizumab in the phase II and III trials so far are around the same as ustekinumab and less than the figures achieved by the IL-17A inhibitors and other p19 competitors, although direct comparisons cannot be made without a head-to-head RCT. Despite this caveat, tildrakizumab does appear to underperform against the other p19 competitors. Dosing does not affect the efficacy of the drug substantially, given the similar figures reported in the 100mg and 200mg dosing arms in the studies, but from both the phase IIb study and the unblinded part of the phase III study the maximum efficacy is achieved at week 16 rather than week 12. The higher efficacy achieved by guselkumab (73.3% PASI 90 for 100mg) at week 1619 may also be due to the fact that it is dosed 8 weekly, resulting in three doses of the drug delivered rather than two before the primary endpoint.

The choice of etanercept as the active comparator in the phase III RCT awaiting publication is inadequate, as etanercept has a lower efficacy than the other current biologic therapies. Further evaluations against ustekinumab and/or secukinumab are needed to fully evaluate the comparative efficacy of tildrakizumab. Given the increasing efficacy of biologic therapies reaching the market, these trials should be sufficiently powered to investigate minimal clinically important differences in PASI 90 instead of PASI 7511.

A RCT investigating the efficacy and safety/tolerability of tildrakizumab in both patients who have failed multiple biologics, and/or in patients with PsA are also needed. This group of patients has a large unmet need. Post-licensing investigations into the other properties of tildrakizumab, such as its risk of demyelination; serious infections such as tuberculosis; cardiovascular events in terms of effects on heart failure or associations with MACEs; suicide, and longer term effectiveness studies, will also be needed.

This evidence will inform whether physicians are likely to prescribe the drug, the likely subgroup of patients with psoriasis to benefit the most, and whether tildrakizumab will be a valuable alternative to the current biologic armamentarium in the coming years.

Table 1 – Planned and completed clinical trials of tildrakizumab

Study name/report Indication Phase Completed (Y/N)

Patients Trial details Main results/outcome

Zandvliet et al, International Journal of Clinical Pharmacology and Therapeutics, 201521

Healthy subjects

I Y 59 Pharmaco-kinetics in healthy Japanese, Caucasian and Chinese subjects

AUC geometric mean 1275.24 μgxday/mL Caucasians, 1366.80 μgxday/mL Japanese for 200mg S/C. t 1/2 24.5-28.2 days

Kopp et al, Nature, 201522

Psoriasis I Y 77 Three-part randomized, placebo-controlled, sequential multiple-dose study

PASI 75 66% for 3mg/kg, 93% for 10mg/kg at week 16

Papp et al, British Journal of Dermatology, 201524 (MK-3222-003, NCT01225731)

Psoriasis IIb Y 355 Three-part randomised, double-blind trial

PASI 75 66.3% for 100mg S/C, 74.4% for 200mg S/C at week 16

reSURFACE 1/MK-3222-01025 (NCT01722331)

Psoriasis III Y 772 Randomised, placebo-controlled, double-blind study

PASI 75 64% for 100mg, 62% for 200mg S/C at week 12

reSURFACE 2/ MK-3222-01125

(NCT01729754)

Psoriasis III Y 1090 Randomised, double-blind study against active comparator etanercept and placebo

PASI 75 61% for 100mg, 66% for 200mg S/C at week 12

MK-3222-012(NCT01936688)Withdrawn prior to enrolment

Psoriasis III N Not available

Randomised, double-blind study against active comparator etanercept and placebo

Not available

Table 2 – Dosing information and key efficacy data from the primary endpoint of the major clinical trials involving biologic therapies for psoriasis.

Adalimumab Etanercept Infliximab Ixekizumab Ustekinumab Secukinumab TildrakizumabDosing Loading dose

80 mg S/C; 40 mg S/C every other week thereafter

50 mg S/C once weekly

5 mg/kg IV infusion at 0, 2, 6 weeks, then every 8 weeks thereafter.

Loading dose 160 mg S/C, 80 mg every 2 weeks until week 12;80 mg every 4 weeks thereafter

45 mg (90 mg if >100kg), S/C, followed by a 45 mg (90 mg) dose 4 weeks later, and then every 12 weeks thereafter.

300 mg S/C weeks 0, 1, 2 and 3, monthly dosing from week 4

100mg/200mg at weeks 0, 4 then 12 weekly thereafter

Efficacy PASI 75 71% at week 16 27

PASI 75 34% at week 1228

PASI 75 80% at week 10 29

PASI 75 89.7%/87.3% at week 16 30

PASI 75 66.7% at week 12 31

PASI 75 77.1%/81.6% at week 12 32

PASI 75 61/64% 100mg; 62/66% 200mg at week 1225

Figure 1 – A patient with severe psoriasis, manifested by widespread, bilateral erythematous plaques

Figure 2 - Interleukin(IL)-23 is responsible for the development and differentiation of Th17 cells, enhancing the expression of IL-17A and IL-17F along with other pro-inflammatory cytokines that activate keratinocytes and perpetuate the inflammatory cascade. Tildrakizumab inhibits the p19 subunit of IL-23, acting to halt the inflammatory Th17 pathway.

Drug summary box

Drug name TildrakizumabPhase (for indication under discussion) Phase III results pendingIndication PsoriasisPharmacology description and mechanism of action

Inhibitor of the p19 subunit specific to interleukin 23

Route of administration SubcutaneousChemical structure Humanized immunoglobulin G1Pivotal trial(s) MK-3222-003 (Papp et al, BJD 2015) ,

reSURFACE 1, reSURFACE 2 (full results not available yet)

References

Reference Annotation

22. *This Phase I RCT is the first reported trial to establish the efficacy of Tildrakizumab in patients with psoriasis24 ** A phase II RCT published in the British Journal of Dermatology showing the efficacy and safety of Tildrakizumab.

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