Tildrakizumab

Last updated

Tildrakizumab
Monoclonal antibody
Type Whole antibody
Source Humanized (from mouse)
Target Interleukin 23 (IL23)
Clinical data
Trade names Ilumya
Other namesTildrakizumab-asmn
AHFS/Drugs.com Monograph
MedlinePlus a618026
License data
Pregnancy
category
  • AU:B1
Routes of
administration 		Subcutaneous
ATC code
Legal status
Legal status
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
Formula C6426H9918N1698O2000S46
Molar mass 144436.68 g·mol−1

Tildrakizumab, sold under the brand name Ilumya among others, is a monoclonal antibody designed for the treatment of immunologically mediated inflammatory disorders. [4] It is approved for the treatment of adults with moderate-to-severe plaque psoriasis in the United States and in the European Union. [2] [3] [5]

Contents

Tildrakizumab was designed to block interleukin-23 (IL-23), a cytokine that plays a key role in managing the immune system and autoimmune disease. [6] [7]

Medical use

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 adults 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]

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. [8]

Originally developed by Schering-Plough, this drug became part of Merck's clinical program, following that company's acquisition of Schering-Plough in 2009. [9]

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. [10] [11] In 2016, Sun Pharmaceutical signed a licensing agreement with the pharmaceutical company Almirall for marketing tildrakizumab in Europe. [11]

As of March 2014, the drug was in phase III clinical trials for plaque psoriasis. The two trials enrolled nearly 2000 participants. [12] [13]

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. [14] 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. [15]

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. [3]

Recent research has found the IL-23/Th17 pathway to be crucial for the pathogenic mechanisms of psoriasis, [7] 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. [6]

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. [16] [6] [7] [17]

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] [17]

Administration

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

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, [14] followed by a four-year extension period. [14]

In the reSURFACE trials, a significantly higher proportion of participants 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. [14] [15] 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. [14] 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). [15]

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. [6] [16]

Tildrakizumab has proven to be a well-tolerated treatment in the long term. [15] [16] 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. [14] [16] Specifically, the incidence of severe infections, malignancies, and major adverse cardiovascular events was low and similar to that of placebo and etanercept treatment groups. [14]

Approvals and indications

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. [5]

In September 2018, it was approved by the European Commission for the treatment of adults with moderate-to-severe chronic plaque psoriasis who are candidates for systemic therapy. [18]

Related Research Articles

<span class="mw-page-title-main">Psoriasis</span> Non-contagious skin disease

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 body coverage. Injury to the skin can trigger psoriatic skin changes at that spot, which is known as the Koebner phenomenon.

<span class="mw-page-title-main">Infliximab</span> Biopharmaceutical drug for autoimmune disorders

Infliximab, a chimeric monoclonal antibody, sold under the brand name Remicade among others, is a medication used to treat a number of autoimmune diseases. This includes Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, and Behçet's disease. It is given by slow injection into a vein, typically at six- to eight-week intervals.

Etanercept, sold under the brand name Enbrel among others, is a biologic medical product that is used to treat autoimmune diseases by interfering with tumor necrosis factor (TNF), a soluble inflammatory cytokine, by acting as a TNF inhibitor. It has US Food and Drug Administration (FDA) approval to treat rheumatoid arthritis, juvenile idiopathic arthritis and psoriatic arthritis, plaque psoriasis and ankylosing spondylitis. Tumor necrosis factor alpha (TNFα) is the "master regulator" of the inflammatory (immune) response in many organ systems. Autoimmune diseases are caused by an overactive immune response. Etanercept has the potential to treat these diseases by inhibiting TNF-alpha.

Alefacept is a genetically engineered immunosuppressive drug. It was sold under the brand name Amevive in Canada, the United States, Israel, Switzerland and Australia. In 2011, the manufacturers made a decision to cease promotion, manufacturing, distribution and sales of Amevive during a supply disruption. According to Astellas Pharma US, Inc., the decision to cease Amevive sales was neither the result of any specific safety concern nor the result of any FDA-mandated or voluntary product recall. On the other hand, usage of Amevive was associated with a certain risk of development systemic diseases such as malignancies. This drug was never approved for the European drug market.

<span class="mw-page-title-main">Biological therapy for inflammatory bowel disease</span>

Biological therapy, the use of medications called biopharmaceuticals or biologics that are tailored to specifically target an immune or genetic mediator of disease, plays a major role in the treatment of inflammatory bowel disease. Even for diseases of unknown cause, molecules that are involved in the disease process have been identified, and can be targeted for biological therapy. Many of these molecules, which are mainly cytokines, are directly involved in the immune system. Biological therapy has found a niche in the management of cancer, autoimmune diseases, and diseases of unknown cause that result in symptoms due to immune related mechanisms.

Ustekinumab, sold under the brand name Stelara among others, is a monoclonal antibody medication used for the treatment of Crohn's disease, ulcerative colitis, plaque psoriasis and psoriatic arthritis, targeting both IL-12 and IL-23. It is administered either by intravenous infusion or subcutaneous injection. The antibody targets a subunit of human interleukin 12 and interleukin 23, which are naturally occurring proteins that regulate the immune system and immune-mediated inflammatory disorders. Ustekinumab is a fully human IgG1κ monoclonal antibody that binds to the p40 subunit of interleukin 12 and 23, thereby preventing them from binding to the IL 12Rβ1 receptor expressed on the surface of immune cells. By doing so, ustekinumab prevents the activation of the Th1 and Th17 cytokine pathways, which are central to the pathology of plaque psoriasis, psoriatic arthritis and Crohn's disease. Ustekinumab was developed by Centocor Ortho Biotech.

Tocilizumab, sold under the brand name Actemra among others, is an immunosuppressive drug, used for the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis, giant cell arteritis, cytokine release syndrome, COVID‑19, and systemic sclerosis-associated interstitial lung disease (SSc-ILD). It is a recombinant humanized monoclonal antibody of the immunoglobulin IgG1 subclass against the interleukin-6 receptor (IL-6R). Interleukin 6 (IL-6) is a cytokine that plays an important role in immune response and is implicated in the pathogenesis of many diseases, such as autoimmune diseases, multiple myeloma and prostate cancer. Tocilizumab was jointly developed by Osaka University and Chugai, and was licensed in 2003 by Hoffmann-La Roche.

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<span class="mw-page-title-main">Tofacitinib</span> Medication

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<span class="mw-page-title-main">Secukinumab</span> Monoclonal antibody against IL-17

Secukinumab, sold under the brand name Cosentyx among others, is a human IgG1κ monoclonal antibody used for the treatment of psoriasis, ankylosing spondylitis, and psoriatic arthritis. It binds to the protein interleukin (IL)-17A and is marketed by Novartis.

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References

  1. ↑ "Summary Basis of Decision (SBD) for Ilumya". Health Canada. 23 October 2014. Retrieved 29 May 2022.
  2. 1 2 3 4 5 6 7 "Ilumya- tildrakizumab-asmn injection, solution". DailyMed. 11 April 2024. Retrieved 2 July 2024.
  3. 1 2 3 4 5 6 7 8 "Ilumetri EPAR". European Medicines Agency. 17 September 2018. Retrieved 2 July 2024.
  4. ↑ "Statement on a Nonproprietary Name Adopted by the USAN Council—Tildrakizumab", American Medical Association.
  5. 1 2 "FDA approves Ilumya for plaque psoriasis". National Psoriasis Foundation. 22 March 2018.
  6. 1 2 3 4 Dolgin E (December 2016). "New anti-IL-23 drugs raise hopes for psoriasis plaque clearance". Nature Biotechnology. 34 (12): 1218–1219. doi:10.1038/nbt1216-1218. PMID   27926724. S2CID   205273437.
  7. 1 2 3 Galluzzo M, D'adamio S, Bianchi L, Talamonti M (May 2017). "Tildrakizumab for treating psoriasis". Expert Opinion on Biological Therapy. 17 (5): 645–657. doi:10.1080/14712598.2017.1304537. PMID   28271735. S2CID   4041245.
  8. ↑ Fotiadou C, Lazaridou E, Sotiriou E, Ioannides D (2018). "Targeting IL-23 in psoriasis: current perspectives". Psoriasis: Targets and Therapy. 8: 1–5. doi: 10.2147/PTT.S98893 . PMC   5804022 . PMID   29441315.
  9. ↑ "Merck, Schering-Plough set to complete merger [Press release]". Reuters. November 2009.
  10. ↑ "Sun Pharma and Merck & Co. Inc. Enter into Licensing Agreement for Tildrakizumab" (Press release). Merck. 17 September 2014. Archived from the original on 12 March 2015.
  11. 1 2 "Sun Pharma signs licensing pact with Spain's Almirall for tildrakizumab in Europe". Business Standard. 4 August 2016. Retrieved 3 January 2025.
  12. ↑ Clinical trial number NCT01729754 for "A Study to Evaluate the Efficacy and Safety/Tolerability of Subcutaneous Tildrakizumab (SCH 900222/MK-3222) in Participants With Moderate-to-Severe Chronic Plaque Psoriasis Followed by a Long-term Extension Study (MK-3222-011)" at ClinicalTrials.gov
  13. ↑ Clinical trial number NCT01722331 for "A Study to Evaluate the Efficacy and Safety of Subcutaneous MK-3222, Followed by an Optional Long-Term Safety Extension Study, in Participants with Moderate-to-Severe Chronic Plaque Psoriasis (MK-3222-010)" at ClinicalTrials.gov
  14. 1 2 3 4 5 6 7 Reich K, Papp KA, Blauvelt A, Tyring SK, Sinclair R, Thaçi D, et al. (July 2017). "Tildrakizumab versus placebo or etanercept for chronic plaque psoriasis (reSURFACE 1 and reSURFACE 2): results from two randomised controlled, phase 3 trials". Lancet. 390 (10091): 276–288. doi:10.1016/S0140-6736(17)31279-5. PMID   28596043. S2CID   3428803.{{cite journal}}: CS1 maint: overridden setting (link)
  15. 1 2 3 4 Reich K, Warren RB, Iversen L, Puig L, Pau-Charles I, Igarashi A, et al. (March 2020). "Long-term efficacy and safety of tildrakizumab for moderate-to-severe psoriasis: pooled analyses of two randomized phase III clinical trials (reSURFACE 1 and reSURFACE 2) through 148 weeks". The British Journal of Dermatology. 182 (3): 605–617. doi:10.1111/bjd.18232. PMC   7064936 . PMID   31218661.{{cite journal}}: CS1 maint: overridden setting (link)
  16. 1 2 3 4 Pithadia DJ, Reynolds KA, Lee EB, Liao W, Wu JJ (2019). "Tildrakizumab in the treatment of psoriasis: latest evidence and place in therapy". Therapeutic Advances in Chronic Disease. 10: 2040622319865658. doi:10.1177/2040622319865658. PMC   6691657 . PMID   31448070.
  17. 1 2 Puig L (June 2017). "The role of IL 23 in the treatment of psoriasis". Expert Review of Clinical Immunology. 13 (6): 525–534. doi:10.1080/1744666X.2017.1292137. PMID   28165883. S2CID   3267755.
  18. ↑ "Almirall: The European Commission approves Almirall's Ilumetri (tildrakizumab) for moderate-to-severe chronic plaque psoriasis" (Press release). 18 September 2018. Retrieved 23 September 2018.
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