Tildrakizumab

Tildrakizumab was approved by the Food and Drug Administration in March 2018,[2] and the European Medicines Agency in September 2018, for the treatment of moderate-to-severe plaque psoriasis in adult patients who are candidates for systemic therapy.[2][3]

Tildrakizumab is administered via subcutaneous injection. It is available as a single-dose prefilled syringe containing 100 mg of tildrakizumab in 1 ml of solution.[2][3]

The importance of IL-23 selective inhibition for the treatment of plaque psoriasis started to increase early after its identification in the year 2000, when it was found to be a crucial player in the pathogenesis of chronic immune diseases in general, and of psoriasis in particular. Based on that discovery, three monoclonal antibodies that selectively bind to IL-23p19 have been approved for the treatment of plaque psoriasis.[7]

Originally developed by Schering-Plough, this drug became part of Merck's clinical program, following that company's acquisition of Schering-Plough in 2009.[8]

In September 2014 Sun Pharmaceutical acquired worldwide rights to tildrakizumab for use in all human indications from Merck in exchange for an upfront payment of US$80 million. Upon product approval, Sun Pharmaceutical became responsible for regulatory activities, including subsequent submissions, pharmacovigilance, post approval studies, manufacturing and commercialization of the approved product.[9][10] In 2016, Sun Pharmaceutical signed a licensing agreement with the pharmaceutical company Almirall for marketing tildrakizumab in Europe.[10]

As of March 2014, the drug was in phase III clinical trials for plaque psoriasis. The two trials enrolled nearly 2000 patients.[11][12]

In 2016, tildrakizumab became the first IL-23p19 inhibitor to demonstrate positive results in Phase-3 clinical trials for the treatment of moderate-to-severe plaque psoriasis, further validating the importance of the role of IL-23 dependent pathways in psoriasis.[13] Later on, in 2019 the 3-year study results of continuous treatment with tildrakizumab were published. Given that psoriasis is a chronic disease that requires lifelong treatment, data on long-term maintenance of clinical responses and long-term safety are of special interest.[14]

Tildrakizumab is a humanized IgG1/k monoclonal antibody that selectively binds to the p19 subunit of the interleukin-23 (IL-23) cytokine and inhibits its interaction with the IL-23 receptor. IL-23 plays a critical role in modulating inflammatory and immune responses.[3]

Recent research has found the IL-23/Th17 pathway to be crucial for the pathogenic mechanisms of psoriasis,[6] with IL-23 considered the “master cytokine” since it acts at the top of the inflammatory pathway, activating the proliferation of pathogenic Th17 cells and subsequent production of proinflammatory cytokines, including IL-17.[5]

Structurally, IL-23 is a heterodimer with two subunits, p19 and p40. The p40 subunit is also shared with IL-12, a cytokine that is involved in the immune response. Treatments targeting the p40 subunit block both IL-23 and IL-12 and have been associated with an increased risk of infections.[15][5][6][16]

Tildrakizumab binds only to the p19 subunit of IL-23. Through this specific blockage, tildrakizumab inhibits the release of proinflammatory cytokines and chemokines that mediate epidermal hyperplasia, keratinocyte immune activation, and tissue inflammation inherent in psoriasis.[3][16]

Tildrakizumab is available as a single-use, pre-filled syringe and is administered via subcutaneous injection.[2][3]

The recommended dose of tildrakizumab in the United States and in the European Union is 100 mg at weeks 0, and 4 and every 12 weeks thereafter.[2][3] In the European Union, a 200 mg dose is also approved. For patients with certain characteristics (high disease burden, body weight ≥ 90 kg) the 200 mg may provide greater efficacy.[3]

Tildrakizumab has been studied in around 1,800 patients in two double-blind, randomized and controlled Phase-3 trials, titled reSURFACE 1 and reSURFACE 2,[13] followed by a 4-year extension period.[13]

In the reSURFACE trials, a significantly higher proportion of patients receiving tildrakizumab achieved PASI 75 response at week 12 and a PGA score of “clear” or “minimal”, with at least a 2-grade reduction from baseline at week 12, than those in the placebo group (p<0.0001). Response continued to increase up to week 28 and was maintained through week 52.[13][14] Tildrakizumab was also proven to have superior efficacy to etanercept, an effective anti-TNFα treatment for psoriasis, with a significantly higher proportion of patients achieving PASI 75 and PASI 90 at weeks 12 and 28.[13] After 3 years of continued treatment with tildrakizumab, response levels were well maintained in week 28 responders: approximately 68% of patients maintained PASI 90 response and 91.6%, 79.8% and 51.9% maintained an absolute PASI of <5, <3, and <1, respectively (observed-cases data).[14]

Safety differentiates anti-IL-23p19 treatments from other biologic treatments. There is a theoretical risk of infection and malignancy with the use of any immunosuppressant, including biologics. However, compared with the inhibition of other inflammatory cytokines, IL-23 targeting may only minimally impair the ability to generate a proper immune response.[5][15]

Tildrakizumab has proven to be a well-tolerated treatment in the long term.[14][15] The most common (≥ 1%) side effects associated with tildrakizumab treatment are upper respiratory infections, headache, gastroenteritis, nausea, diarrhoea, injection site pain, and back pain.[2][3] In the reSURFACE 1 and 2 clinical trials, the overall incidence of side effects was low and comparable to placebo.[13][15] Specifically, the incidence of severe infections, malignancies, and major adverse cardiovascular events was low and similar to that of placebo and etanercept treatment groups.[13]

In March 2018, it was approved by the Food and Drug Administration for the treatment of moderate-to-severe plaque psoriasis as an injection for subcutaneous use in the United States.[4] In September 2018, it was approved by the European Commission for the treatment of adult patients with moderate-to-severe chronic plaque psoriasis who are candidates for systemic therapy.[17]

• Psoriasis
• Interleukin-23
• Psoriasis Area Severity Index
• Monoclonal antibody
• Guselkumab, another experimental, IL-23-specific monoclonal antibody (FDA approved in 2017)
• Risankizumab, another experimental, IL-23-specific monoclonal antibody (FDA approved in 2019)
• Ustekinumab, a monoclonal antibody targeting both IL-12 and IL-23 and used to treat plaque psoriasis, launched in the United States under the brand name Stelara