Key clinical-trial evidence for tildrakizumab

Introduction

In March 2018, tildrakizumab (Ilumya™; Sun Pharma, Mumbai, India) received US Food and Drug Administration (FDA) approval for the treatment of moderate-to-severe plaque psoriasis in patients who are candidates for systemic therapy or phototherapy. This monoclonal antibody, which selectively binds to the p19 subunit of interleukin (IL) 23 and inhibits its interaction with the IL-23 receptor, was licensed by Sun Pharma from Merck and Co. (New Jersey, USA) in 2014.

Tildrakizumab is the second approved biological therapy that selectively blocks only IL-23, a cytokine that plays a key role in plaque psoriasis.

Tildrakizumab received FDA approval based on safety and efficacy data from the Phase III reSURFACE clinical trials that compared tildrakizumab to placebo and etanercept. In both studies, tildrakizumab was linked to significant improvements versus placebo and etanercept at Week 12 as measured by the Psoriasis Area Sensitivity Index (PASI) and Physician's Global Assessment (PGA) scores.

Almirall has been granted rights to develop and commercialise the drug in Europe. Almirall filed the drug for regulatory approval with the European Medicines Agency in March 2017.

Tildrakizumab is currently not available in New Zealand.

Clinical trial evidence for tildrakizumab

The approval of tildrakizumab was based on two Phase III trials.

• reSURFACE 1 evaluated the efficacy and safety of tildrakizumab compared with placebo.
• reSURFACE 2 evaluated the efficacy and safety of tildrakizumab compared with etanercept and placebo.

reSURFACE 1

• The reSURFACE 1 study was a multicentre, double-blind, randomised, parallel-group trial.
• reSURFACE 1 included 1772 patients with moderate-to-severe psoriasis who were randomised to three treatment groups to receive either tildrakizumab 100 mg (n = 309), tildrakizumab 200 mg (n = 308), or placebo (n = 155) at Weeks 0, 4, and 16.
• At Week 12, the placebo patients were crossed over to receive either 100 mg or 200 mg tildrakizumab at Weeks 12 and 16.
• Primary endpoints were the percentage of patients in each group who achieved a 75% improvement in PASI score (PASI 75) and a PGA (Physicians Global Assessment) score of 0 or 1 with a > 2-point reduction from baseline at 12 weeks.
• At 12 weeks, a significantly greater percentage of patients in both tildrakizumab groups achieved PASI 75 and PGA score of 0 or 1 compared with placebo (PASI 75: 100 mg 64%, 200 mg 62%, placebo 6%; p< 0.001; PGA score of 0 or 1: 100 mg 59%, 200 mg 58%, placebo 7%; p < 0.001).

reSURFACE 2

• The reSURFACE 2 study included 1090 patients with moderate-to-severe psoriasis who were randomised to one of the following treatment groups: placebo, tildrakizumab 100 mg, or tildrakizumab 200 mg, at Weeks 0, 4, and 16, or etanercept 50 mg twice a week for 12 weeks followed by once weekly until Week 28.
• Co-primary end points were similar to reSURFACE 1.
• At Week 12, PASI 75 was reached by a significantly greater percentage of patients in the tildrakizumab groups compared with the placebo and etanercept groups (100 mg 61%, 200 mg 66%, etanercept 48%, placebo 6%; p < 0.0001 for comparisons of both tildrakizumab groups versus placebo; p < 0.0001 for 200 mg versus etanercept and p = 0.0010 for 100 mg vs etanercept).
• This was also the case for the proportion of patients who achieved a PGA score of 0 or 1 at Week 12 (tildrakizumab 100 mg 55%, tildrakizumab 200 mg 59%, placebo 4%; p< 0.001) and at Week 28 (tildrakizumab 100 mg 66%, tildrakizumab 200 mg 71%, etanercept 48%; p< 0.001).
• The percentage of patients with at least one adverse event in each treatment group at Week 12 was as follows: tildrakizumab 100 mg 44.3%, tildrakizumab 200 mg 49.4%, placebo 55.1%, etanercept 54.0%. One death occurred in a patient with alcoholic cardiomyopathy and hepatic steatosis in the tildrakizumab 100-mg group and the cause of death was undetermined.

Adverse reactions — the clinical trial experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data from Phase III randomised, placebo-controlled trials were pooled to evaluate the safety of tildrakizumab. The table below summarises the adverse reactions that occurred at a rate of at least 1% and at a higher rate in the tildrakizumab 100-mg group compared to placebo.

Table. Adverse reactions in ≥ 1% of subjects treated with tildrakizumab

Respiratory infections observed as an adverse reaction in patients treated with tildrakizumab include:

• Nasopharyngitis
• Upper respiratory tract infection
• Viral upper respiratory tract infection
• Pharyngitis.

Injection site reactions observed as an adverse reaction in patients treated with tildrakizumab include:

• Urticaria
• Pruritus
• Erythema
• Inflammation
• Oedema
• Swelling
• Bruising
• Haematoma
• Haemorrhage.

Adverse reactions that occurred in < 1% of the tildrakizumab group and at a higher rate than in the placebo group include:

• Dizziness
• Pain in extremities.

Cases of angioedema and acute urticaria have occurred in tildrakizumab-treated subjects in clinical trials. If a serious hypersensitivity reaction occurs, the drug should be discontinued immediately and an appropriate therapy should be initiated.

The rates of serious infections for patients in the tildrakizumab group and the placebo group were ≤ 0.3%. Treatment with tildrakizumab should not be initiated in patients with any clinically important active infection until the infection resolves or is adequately treated.

Tildrakizumab — the future potential

Phase III studies with tildrakizumab have shown great promise regarding tildrakizumab's efficacy and short-term safety. However, larger, long-term studies and evidence from everyday practice are needed to confirm these assumptions. Head-to-head randomised controlled trials in comparison with current therapies, such as ustekinumab and guselkumab, are needed to understand tildrakizumab's relative efficacy. The main advantage of tildrakizumab is that it is dosed in a maintenance regimen of 12 weeks (similar to ustekinumab), and this is likely to encourage treatment adherence.

As the understanding of the immunopathogenesis of psoriasis grows, the emphasis has turned toward more specific targets for psoriasis drugs. The IL-23/IL-17 axis is currently considered to be crucial in the pathogenesis of psoriasis.

Agents that target the p40 subunit common to both IL-12 and IL-23 (such as ustekinumab) have shown robust clinical activity. However, selectivity for IL-23p19 could offer advantages in efficacy and safety with respect to the anti-p40 blockade. Acting upstream in the IL-23/IL-17 cytokine pathway is likely to reduce the expression of multiple pro-inflammatory cytokines acting on keratinocytes, including IL-17F, IL-21, and IL-22, in addition to IL-17A.

Based on that understanding, the selective targeting of the IL-23p19 subunit has emerged as an attractive therapeutic option and led to the development of a new category of biological agents (eg, guselkumab and tildrakizumab) for the treatment of moderate-to-severe psoriasis. Safety data thus far suggest that these drugs might be devoid of some of the adverse effects of IL-17A blockade demonstrated by secukinumab and brodalumab (eg, mucocutaneous candida infections or the triggering or worsening of inflammatory bowel disease).

Biological drugs targeting these cytokines and their receptors have proven to be effective and safe in clinical trials and have offered greater efficacy than pre-existing biologicals, as evidenced by the large proportions of patients achieving not only PASI 75 but also 90% and 100% improvement in PASI score (PASI 90 and PASI 100).

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