Key evidence from clinical trials for tildrakizumab

Introduction

In March 2018, tildrakizumab (Ilumya ™; Sun Pharma, Mumbai, India) received approval from the United States Food and Drug Administration (FDA) for the treatment of moderate to severe license plate psoriasis in patients candidates for systemic therapy or phototherapy. Is monoclonal antibody, which selectively binds to the p19 subunit of interleukin (IL) 23 and inhibits its interaction with IL-23 receiver, 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 It plays a key role in plaque psoriasis.

Tildrakizumab received FDA approval based on safety and effectiveness data from Phase III reSURFACE clinical trials comparing tildrakizumab with placebo and etanercept. In both studies, tildrakizumab was associated with significant improvements over placebo and etanercept at week 12, as measured by the psoriasis area sensitivity index (PASI) and Global Physician Assessment (PGA) scores.

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

Tildrakizumab is not currently available in New Zealand.

Evidence from clinical trials for tildrakizumab

Tildrakizumab approval was based on two phase III trials.

• RESURFACE 1 evaluated the efficacy and safety of tildrakizumab compared to placebo.
• RESURFACE 2 evaluated the efficacy and safety of tildrakizumab compared to etanercept and placebo.

RESOURCE 1

• The reSURFACE 1 study was multicenter, double-blind, randomized, parallel group trial.
• reSURFACE 1 included 1772 patients with moderate to severe psoriasis who were randomized to three treatment groups to receive tildrakizumab 100 mg (n = 309), tildrakizumab 200 mg (n = 308), or placebo (n = 155) at weeks 0. , 4 and 16.
• At week 12, placebo patients were crossed over to receive 100 mg or 200 mg of tildrakizumab at weeks 12 and 16.
• Primary The end points were the percentage of patients in each group who achieved an improvement of the 75% in the PASI score (PASI 75) and a PGA (Physicians Global Assessment) score of 0 or 1 with a reduction> 2 points of base at 12 weeks.
• At 12 weeks, a significantly higher percentage of patients in both tildrakizumab groups achieved a PASI 75 and PGA score of 0 or 1 compared to 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).

RESOURCE 2

• The reSURFACE 2 study included 1090 patients with moderate to severe psoriasis who were randomized 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 a week until week 28.
• The coprimary endpoints were similar to reSURFACE 1.
• At week 12, PASI 75 was achieved by a significantly higher percentage of patients in the tildrakizumab groups compared to the placebo and etanercept groups (100 mg 61%, 200 mg 66%, etanercept 48%, placebo 6%; p <0.0001 for comparisons of both groups of tildrakizumab 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 it was as follows: tildrakizumab 100mg 44.3%, tildrakizumab 200mg 49.4%, placebo 55.1%, etanercept 54.0%. One death occurred in a patient with alcoholism. 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 highly variable conditions, adverse reaction The rates observed in clinical trials of one drug cannot be directly compared with the rates in clinical trials of another drug and may not reflect the rates observed in practice.

Data from Phase III randomized placebo-controlled trials were pooled to assess the safety of tildrakizumab. The following table summarizes 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 infection of the upper respiratory tract
• Pharyngitis.

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

• Urticaria
• Pruritus
• Erythema
• Inflammation
• Edema
• Swelling
• Bruising
• Hematoma
• Hemorrhage.

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

• Dizziness
• Limb pain.

Cases of angioedema and acute Hives have occurred in subjects treated with tildrakizumab in clinical trials. Yes a serious hypersensitivity A reaction occurs, the drug should be discontinued immediately, and appropriate therapy should be started.

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

Tildrakizumab: the future potential

Phase III studies with tildrakizumab have shown great promise regarding the short-term efficacy and safety of tildrakizumab. However, larger long-term studies and evidence from daily practice are needed to confirm these assumptions. Direct randomized controlled trials compared to current therapies such as ustekinumab and guselkumab are needed to understand the relative efficacy of tildrakizumab. The main advantage of tildrakizumab is that it is dosed on a 12-week maintenance regimen (similar to ustekinumab), and this is likely to promote adherence to treatment.

Like understanding the immunopathogenesis As psoriasis grows, the emphasis has turned toward more specific goals for psoriasis medications. The IL-23 / IL-17 axis is currently considered crucial in the Pathogenesis psoriasis

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

Based on that understanding, selective selection of the IL-23p19 subunit has become an attraction 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. The safety data thus far suggests that these drugs may be exempt from some of the adverse effects of IL-17A blockade demonstrated by secukinumab and brodalumab (eg. mucocutaneous candida infections or the trigger or worsening of inflammatory bowel disease).

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