Tildrakizumab
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Tildrakizumab, sold under the brand name Ilumya among others, is a
monoclonal antibody A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodie ...
designed for the treatment of immunologically mediated inflammatory disorders. It is approved for the treatment of adults with moderate-to-severe
plaque psoriasis Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by patches of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small localized patches to complete b ...
in the United States and in the European Union. Tildrakizumab was designed to block
interleukin-23 Interleukin 23 (IL-23) is a heterodimeric cytokine composed of an IL-12B (IL-12p40) subunit (which is shared with IL-12) and an IL-23A (IL-23p19) subunit. IL-23 is part of the IL-12 family of cytokines. The functional receptor for IL-23 (the ...
(IL-23), a
cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
that plays a key role in managing the
immune system The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as Tumor immunology, cancer cells, Parasitic worm, parasitic ...
and
autoimmune disease An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated tha ...
.


Medical use

Tildrakizumab was approved by the
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
in March 2018, and the
European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...
in September 2018, for the treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy. 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.


History

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. Originally developed by
Schering-Plough Schering-Plough Corporation was an American pharmaceutical company. It was originally the U.S. subsidiary of the German company Schering AG, which was founded in 1851 by Ernst Christian Friedrich Schering. As a result of nationalization, it becam ...
, this drug became part of Merck's clinical program, following that company's acquisition of Schering-Plough in 2009. In September 2014
Sun Pharmaceutical Sun Pharmaceutical Industries Limited (Trade name, d/b/a Sun Pharma) is an Indian Multinational corporation, multinational pharmaceutical company headquartered in Mumbai. It manufactures and sells Pharmaceutical formulation, pharmaceutical formu ...
acquired worldwide rights to tildrakizumab for use in all human indications from Merck in exchange for an upfront payment of 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. In 2016, Sun Pharmaceutical signed a licensing agreement with the pharmaceutical company
Almirall Almirall, S.A. is a Spanish pharmaceutical company dedicated to medical dermatology, with headquarters in Barcelona, founded in 1944. In 2023, the company generated total revenues of €898.8 million and was the leading European company in medi ...
for marketing tildrakizumab in Europe. As of March 2014, the drug was in phase III clinical trials for
plaque psoriasis Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by patches of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small localized patches to complete b ...
. The two trials enrolled nearly 2000 participants. 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. 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.


Mechanism of action

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. Recent research has found the IL-23/Th17 pathway to be crucial for the pathogenic mechanisms of psoriasis, 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. 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. 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 Keratinocytes are the primary type of cell found in the epidermis, the outermost layer of the skin. In humans, they constitute 90% of epidermal skin cells. Basal cells in the basal layer (''stratum basale'') of the skin are sometimes referre ...
immune activation, and tissue inflammation inherent in psoriasis.


Administration

Tildrakizumab is available as a single-use, pre-filled syringe and is administered via
subcutaneous injection Subcutaneous administration is the insertion of medications beneath the skin either by injection or infusion. A subcutaneous injection is administered as a bolus (medicine), bolus into the subcutis, the layer of skin directly below the dermis and ...
.


Clinical trials

Tildrakizumab has been studied in around 1,800 participants in two double-blind, randomized and controlled phase-III trials, titled reSURFACE 1 and reSURFACE 2, followed by a four-year extension period. In the reSURFACE trials, a significantly higher proportion of participants receiving tildrakizumab achieved
PASI Pasi may refer to: * Pasi (caste), a Hindu caste of northern India * Pasi (film), ''Pasi'' (film), a 1979 Tamil film * Pasi (given name) * Pasi (surname), a surname of the Pasi community * Pasi, Papua New Guinea, a settlement near the coast of San ...
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. Tildrakizumab was also proven to have superior efficacy to etanercept, an effective anti-TNFα treatment for psoriasis, with a significantly higher proportion of participants achieving PASI 75 and PASI 90 at weeks 12 and 28. After 3 years of continued treatment with tildrakizumab, response levels were well maintained in week 28 responders: approximately 68% of participants 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).


Side effects

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. Tildrakizumab has proven to be a well-tolerated treatment in the long term. The most common (≥ 1%) side effects associated with tildrakizumab treatment are upper respiratory infections, headache, gastroenteritis, nausea, diarrhoea, injection site pain, and back pain. In the reSURFACE 1 and 2 clinical trials, the overall incidence of side effects was low and comparable to placebo. Specifically, the incidence of severe infections, malignancies, and
major adverse cardiovascular events Major adverse cardiovascular events (MACE, or major adverse cardiac events) is a composite endpoint frequently used in cardiovascular research. Despite widespread use of the term in clinical trials, the definitions of MACE can differ, which makes ...
was low and similar to that of placebo and etanercept treatment groups.


Approvals and indications

In March 2018, it was approved by the
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
for the treatment of moderate-to-severe plaque psoriasis as an injection for subcutaneous use in the United States. In September 2018, it was approved by the
European Commission The European Commission (EC) is the primary Executive (government), executive arm of the European Union (EU). It operates as a cabinet government, with a number of European Commissioner, members of the Commission (directorial system, informall ...
for the treatment of adults with moderate-to-severe chronic plaque psoriasis who are candidates for systemic therapy.


References

{{Authority control Monoclonal antibodies Drugs developed by Merck & Co.