Tildrakizumab

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Tildrakizumab
Monoclonal antibody
TypeWhole antibody
SourceHumanized (from mouse)
TargetIL23
Names
Trade namesIlumya, Ilumetri
Other namesTildrakizumab-asmn
Clinical data
Drug classMonoclonal antibody[1]
Main usesPlaque psoriasis[1]
Side effectsBack pain, headache, infection, nausea[2]
Pregnancy
category
  • AU: B1
  • US: N (Not classified yet)
Routes of
use
Subcutaneous injection
External links
AHFS/Drugs.comMonograph
US NLMTildrakizumab
MedlinePlusa618026
Legal
License data
Legal status
Chemical and physical data
FormulaC6426H9918N1698O2000S46
Molar mass144436.68 g·mol−1

Tildrakizumab, sold under the brand name Ilumya among others, is a monoclonal antibody used to treat plaque psoriasis.[1] In the United Kingdom use is only recommended in severe disease that has not responded to other treatments.[2] It is given by injection under the skin.[3]

Common side effects include back pain, headache, infection, and nausea.[2] Other side effects include angioedema and pain at the site of injection.[1] Use in the months before and during pregnancy is not recommended.[2] It works by blocking interleukin-23 (IL-23), a cytokine.[1]

Tildrakizumab was approved for medical use in the United States and Europe in 2018.[3][1] In the United Kingdom it costs the NHS about £3,250 per dose as of 2021.[2] This amount in the United States costs about 15,300 USD.[4]

Medical use

It is used to treat moderate-to-severe plaque psoriasis in adult patients who are candidates for systemic therapy.[5][6]

Dosage

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.[5][6]

It is given at a dose of 100 mg at weeks 0, and 4 and every 12 weeks thereafter.[5][6]

In the European Union, a 200 mg dose is also approved for people with certain characteristics (high disease burden, body weight ≥ 90 kg) the 200 mg may provide greater efficacy.[6]

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.[7][8]

Tildrakizumab has proven to be a well-tolerated treatment in the long term.[9][8] The most common (≥ 1%) side effects associated with tildrakizumab treatment are upper respiratory infections, headache, gastroenteritis, nausea, diarrhoea, injection site pain, and back pain.[5][6] In the reSURFACE 1 and 2 clinical trials, the overall incidence of side effects was low and comparable to placebo.[10][8] Specifically, the incidence of severe infections, malignancies, and major adverse cardiovascular events was low and similar to that of placebo and etanercept treatment groups.[10]

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.[6]

Recent research has found the IL-23/Th17 pathway to be crucial for the pathogenic mechanisms of psoriasis,[11] 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.[7]

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.[8][7][11][12]

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.[6][12]

History

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.[13]

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.[14]

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.[15]

Originally developed by Schering-Plough, this drug became part of Merck's clinical program, following that company's acquisition of Schering-Plough in 2009.[16]

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.[17][18] In 2016, Sun Pharmaceutical signed a licensing agreement with the pharmaceutical company Almirall for marketing tildrakizumab in Europe.[18]

As of March 2014, the drug was in phase III clinical trials for plaque psoriasis. The two trials enrolled nearly 2000 patients.[19][20]

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.[10] 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.[9]

Research

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,[10] followed by a 4-year extension period.[10]

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.[10][9] 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.[10] 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).[9]

References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 "Tildrakizumab-asmn Monograph for Professionals". Drugs.com. Retrieved 4 October 2021.
  2. 2.0 2.1 2.2 2.3 2.4 BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. p. 1327. ISBN 978-0-85711-369-6.CS1 maint: date format (link)
  3. 3.0 3.1 "Ilumetri". Retrieved 4 October 2021.
  4. "Ilumya Prices, Coupons & Patient Assistance Programs". Drugs.com. Retrieved 4 October 2021.
  5. 5.0 5.1 5.2 5.3 ILUMYA™ Prescribing Information.
  6. 6.0 6.1 6.2 6.3 6.4 6.5 6.6 ILUMETRI® Summary of Product Characteristics. Almirall, July 2019.
  7. 7.0 7.1 7.2 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.
  8. 8.0 8.1 8.2 8.3 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.
  9. 9.0 9.1 9.2 9.3 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.
  10. 10.0 10.1 10.2 10.3 10.4 10.5 10.6 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.
  11. 11.0 11.1 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.
  12. 12.0 12.1 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.
  13. "FDA approves Ilumya for plaque psoriasis". National Psoriasis Foundation. March 22, 2018.
  14. "Almirall: The European Commission approves Almirall's ILUMETRI® (tildrakizumab) for moderate-to-severe chronic plaque psoriasis". Retrieved 23 September 2018.
  15. 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.
  16. "Merck, Schering-Plough set to complete merger [Press release]". Reuters. November 2009.
  17. "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.
  18. 18.0 18.1 Bureau, BS B2B (28 July 2016). "Sun Pharma signs licensing pact with Spain's Almirall for tildrakizumab in Europe". Business Standard. BS B2B Bureau.
  19. 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
  20. 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

External links

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