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Rejected
ATC codes:
L04AC05
Indication
Psoriasis of unspecified type
ICD11 code:
EA90.Z
INN
Ustekinumab
Medicine type
Biological agent
List type
Core
Formulations
Parenteral > General injections > SC:
45 mg per 0.5 mL in vial ;
90 mg per mL in pre-filled syringe
EML status history
Application rejected in 2023
(TRS
1049)
Sex
All
Age
Adolescents and adults
Therapeutic alternatives
The recommendation is for this specific medicine
Patent information
Main patent is active in several jurisdictions. For more information on specific patents and
license status for developing countries visit www.MedsPal.org
Read more
about patents.
Expert Committee recommendation
The Expert Committee acknowledged the global burden of psoriasis and the public health need for effective treatments for this condition. To date, only topical therapies for psoriasis have been included on the Model Lists.
The Committee noted that multiple randomized trials have shown ustekinumab to be more effective than placebo in the proportion of patients achieving a PASI 75 and PASI 90 response.
The Committee noted that biological disease-modifying therapies such as ustekinumab have an important role in the management of moderate-to-severe forms of psoriasis.
The Committee noted that the network meta-analyses presented in the application demonstrated varying degrees of efficacy and toxicity among pharmacological classes and individual biological medicines in the treatment of moderate-to-severe psoriasis. The Committee considered that the optimal choice of one agent over another was not straightforward, especially when taking into account their high costs and limited availability, which are major barriers to access in low- and middle-income countries.
The Expert Committee therefore did not recommend the inclusion of ustekinumab on the EML for the treatment of severe psoriasis in adults. The Committee recommended a comprehensive review of all biological disease-modifying medicines in the treatment of moderate-to-severe forms of psoriasis be undertaken to better inform the selection of the most effective and cost-effective agents for future consideration for inclusion on the Model Lists. This review should also consider safety and feasibility of use across global settings.
Background
Ustekinumab has not previously been evaluated for inclusion on the Model Lists for this indication.
Public health relevance
According to the 2019 Global Burden of Disease study, psoriasis was reported to affect almost 41 million people globally and was responsible for 0.14% of global disability-adjusted life years (1). People with psoriasis have a reduced quality of life similar to or worse than those with other chronic diseases (2,3). A family history of psoriasis is common and genetic influences are thought to play a major role in the expression of disease. Psoriasis can present at any age but the mean age at onset for the first presentation of psoriasis ranges from 15 to 20 years, with a second peak occurring at 55 to 60 years (2,4).
Benefits
A 2017 Cochrane systematic review and network meta-analysis of 109 randomized trials (39 882 participants) compared the efficacy and safety of non‐biological systemic agents, small molecules, and biological agents in adults with moderate‐to‐severe psoriasis (5). Nineteen treatments were compared and ranked according to their effectiveness, measured by Psoriasis Area and Severity Index (PASI) 90 score, and acceptability. Ranking analysis showed ustekinumab to be ranked sixth for PASI 90 and eighth for serious adverse events, when compared with placebo. The authors noted that the most effective treatments also had more serious adverse events than other treatments. On balance, it was considered that ustekinumab, infliximab and certolizumab had the better compromise between efficacy and acceptability of the treatments evaluated. The evidence considered was limited to induction therapy, with outcomes measured between 12 and 16 weeks after randomization; longer-term outcomes were not evaluated.
An updated version of this review included 167 randomized trials (58 912 participants) (6). The updated review included seven randomized controlled trials comparing ustekinumab with placebo, and 11 randomized controlled trials comparing ustekinumab with active comparators (etanercept, secukinumab, ixekizumab, risankizumab and brodalumab). At the medicine class level, all classes of medicines performed better than placebo for the outcome of the proportion of patients achieving a PASI 90 response. Active treatment comparisons showed that biological agents, including ustekinumab, performed better than non-biological agents for the proportion of patients achieving a PASI 90 response. Overall, there was high-certainty evidence that the most effective drugs compared with placebo for achieving a PASI 90 response were infliximab, bimekizumab, ixekizumab and risankizumab. Of 20 medicines evaluated, ustekinumab was ranked ninth for PASI 90 response and thirteenth for serious adverse events.
PHOENIX 1 was a randomized, double-blind, placebo-controlled phase III trial evaluating the efficacy and safety of ustekinumab in 766 adult participants with moderate to severe psoriasis (7). Participants were randomly assigned to receive ustekinumab 45 mg or 90 mg at weeks 0 and 4 then every 12 weeks thereafter, or placebo at weeks 0 and 4, followed by crossover to ustekinumab from week 12. The primary endpoint was the proportion of participants achieving PASI 75 at week 12. The proportions of participants achieving PASI 75 were 67.1%, 66.4% and 3.1% in the 45 mg, 90 mg and placebo groups, respectively. Long-term response (PASI 75 at weeks 28 and 40) was achieved by 150 and 172 participants in the 45 mg 90 mg groups, respectively. Of these, 162 participants were randomly assigned to maintenance ustekinumab and 160 to withdrawal. Participants receiving maintenance ustekinumab maintained a PASI 75 response to at least 1 year better than those who were withdrawn from treatment.
PHOENIX 2 was a randomized, placebo-controlled, double-blind, multicentre, phase III trial evaluating the efficacy and safety of ustekinumab in 1230 adult patients with moderate to severe psoriasis (8). Patients were randomly assigned to receive ustekinumab 45 mg or 90 mg at weeks 0 and 4 then every 12 weeks thereafter, or placebo. Participants achieving a partial response of between 50% and 75% improvement from baseline were re-randomized at week 28 to ustekinumab every 12 weeks or to continue dosing every 8 weeks. The primary endpoint was the proportion of patients achieving at least PASI 75 at week 12. The proportions of patients achieving the primary endpoint were 66.7%, 75.7% and 3.7% in patients receiving ustekinumab 45 mg, 90 mg and placebo, respectively. More partial responders at week 28 who received ustekinumab 90 mg every 8 weeks achieved PASI 75 at week 52 than did those who continued to receive the same dose every 12 weeks. No difference was seen in response to changes in dosing interval observed in partial responders who received ustekinumab 45 mg.
Similar results to those described above have been reported in other studies of ustekinumab in China (9), Japan (10) and Republic of Korea (11).
The application also presented summaries of the findings of other network meta-analyses (12), comparative randomized trials (13–15) and observational studies (16–18) that included ustekinumab.
Analyses of registry data have shown ustekinumab to have a higher drug survival (a marker for treatment sustainability in chronic diseases) as a first-line therapy for psoriasis compared with the tumour necrosis factor-alfa inhibitors infliximab, etanercept and adalimumab (19–21). Ustekinumab is also associated with less non-adherence to treatment (22).
Harms
Adverse events reported with the use of ustekinumab by at least 1% of treated patients include nasopharyngitis, upper respiratory tract infection, headache, fatigue, diarrhoea, back pain, pruritus, injection-site erythema and depression (23).
Adverse reactions that occurred at rates less than 1% in the controlled period of the PHOENIX 1 and PHOENIX 2 studies through to week 12 included cellulitis, herpes zoster infection, diverticulitis and injection-site reactions (7,8). Serious infections occurred in 0.3% of participants treated with ustekinumab and in 0.4% of participants given placebo (23).
Analyses of registry data assessed the risk of serious infection associated with ustekinumab and other biological agents compared with non-biological systemic therapies (24–26). In general, the findings suggested no increased risk of serious infection associated with ustekinumab.
Malignancies have been reported with the use of ustekinumab in clinical trials with 1.7% of participants reported to have malignancies excluding non-melanoma skin cancers and 1.5% reported to have non-melanoma skin cancers. Malignancies other than non-melanoma skin cancer in patients treated with ustekinumab during the controlled and uncontrolled parts of the studies were similar in type and number to what would be expected in the general United States population according to the SEER database (23).
Cost / cost effectiveness
A 2013 cost–effectiveness analysis of ustekinumab versus etanercept from a United States societal perspective found that using a 3-year time horizon, ustekinumab 45 mg dominated etanercept 50 mg. However, the incremental cost–effectiveness ratio comparing ustekinumab 90 mg with etanercept 50 mg was US$ 384 401 per quality-adjusted life year (QALY) gained, which was considered not to be cost-effective using typical willingness-to-pay thresholds (27). A 2011 cost–utility analysis from the Canadian perspective and using a 10-year time horizon also found ustekinumab 45 mg to be more cost-effective than etanercept for patients with moderate-to-severe plaque psoriasis (28). Other analyses of cost–effectiveness studies have reported similar results (29,30).
The effect on drug acquisition costs after the introduction of biosimilar molecules of both ustekinumab and biological comparators will affect the cost–effectiveness.
WHO guidelines
WHO guidelines for the treatment of psoriasis are not currently available.
Availability
Ustekinumab is reported to be widely available in the countries where it is marketed. The patent for the innovator brand of ustekinumab will expire in September 2023 and a number of biosimilar products are in trial and development.
1. Global Burden of Disease database [internet]. Seattle, WA: Institute for Health Metrics and Evaluation; 2019 (https://vizhub.healthdata.org/gbd-results/, accessed 6 October 2023).
2. Langley RG, Krueger GG, Griffiths CE. Psoriasis: epidemiology, clinical features, and quality of life. Ann Rheum Dis. 2005;64(Suppl 2):ii18–23; discussion ii4–5.
3. Bhosle MJ, Kulkarni A, Feldman SR, Balkrishnan R. Quality of life in patients with psoriasis. Health Qual Life Outcomes. 2006;4:35.
4. Global report on psoriasis. Geneva: World Health Organization; 2016 (https://apps.who.int/iris/handle/10665/204417, accessed 6 October 2023).
5. Sbidian E, Chaimani A, Garcia-Doval I, Do G, Hua C, Mazaud C, et al. Systemic pharmacological treatments for chronic plaque psoriasis: a network meta-analysis. Cochrane Database Syst Rev. 2017;12(12):CD011535.
6. Sbidian E, Chaimani A, Garcia-Doval I, Doney L, Dressler C, Hua C, et al. Systemic pharmacological treatments for chronic plaque psoriasis: a network meta-analysis. Cochrane Database Syst Rev. 2022;5(5):CD011535.
7. Leonardi CL, Kimball AB, Papp KA, Yeilding N, Guzzo C, Wang Y, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet. 2008;371(9625):1665–74.
8. Papp KA, Langley RG, Lebwohl M, Krueger GG, Szapary P, Yeilding N, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet. 2008;371(9625):1675–84.
9. Zhu X, Zheng M, Song M, Shen YK, Chan D, Szapary PO, et al. Efficacy and safety of ustekinumab in Chinese patients with moderate to severe plaque-type psoriasis: results from a phase 3 clinical trial (LOTUS). J Drugs Dermatol. 2013;12(2):166–74.
10. Igarashi A, Kato T, Kato M, Song M, Nakagawa H. Efficacy and safety of ustekinumab in Japanese patients with moderate-to-severe plaque-type psoriasis: long-term results from a phase 2/3 clinical trial. J Dermatol. 2012;39(3):242–52.
11. Tsai TF, Ho JC, Song M, Szapary P, Guzzo C, Shen YK, et al. Efficacy and safety of ustekinumab for the treatment of moderate-to-severe psoriasis: a phase III, randomized, placebo-controlled trial in Taiwanese and Korean patients (PEARL). J Dermatol Sci. 2011;63(3):154–63.
12. Jabbar-Lopez ZK, Yiu ZZN, Ward V, Exton LS, Mohd Mustapa MF, Samarasekera E, et al. Quantitative evaluation of biologic therapy options for psoriasis: a systematic review and network meta-analysis. J Invest Dermatol. 2017;137(8):1646–54.
13. Reich K, Pinter A, Lacour JP, Ferrandiz C, Micali G, French LE, et al. Comparison of ixekizumab with ustekinumab in moderate-to-severe psoriasis: 24-week results from IXORA-S, a phase III study. Br J Dermatol. 2017;177(4):1014–23.
14. Papp KA, Blauvelt A, Bukhalo M, Gooderham M, Krueger JG, Lacour JP, et al. Risankizumab versus ustekinumab for moderate-to-severe plaque psoriasis. N Engl J Med. 2017;376(16):1551–60.
15. Langley RG, Tsai TF, Flavin S, Song M, Randazzo B, Wasfi Y, et al. Efficacy and safety of guselkumab in patients with psoriasis who have an inadequate response to ustekinumab: results of the randomized, double-blind, phase III NAVIGATE trial. Br J Dermatol. 2018;178(1):114–23.
16. Strober BE, Bissonnette R, Fiorentino D, Kimball AB, Naldi L, Shear NH, et al. Comparative effectiveness of biologic agents for the treatment of psoriasis in a real-world setting: results from a large, prospective, observational study (Psoriasis Longitudinal Assessment and Registry [PSOLAR]). J Am Acad Dermatol. 2016;74(5):851–61.e4.
17. Iskandar IYK, Ashcroft DM, Warren RB, Lunt M, McElhone K, Smith CH, et al. Comparative effectiveness of biological therapies on improvements in quality of life in patients with psoriasis. Br J Dermatol. 2017;177(5):1410–21.
18. Zweegers J, Groenewoud JMM, van den Reek J, Otero ME, van de Kerkhof PCM, Driessen RJB, et al. Comparison of the 1- and 5-year effectiveness of adalimumab, etanercept and ustekinumab in patients with psoriasis in daily clinical practice: results from the prospective BioCAPTURE registry. Br J Dermatol. 2017;176(4):1001–9.
19. Warren RB, Smith CH, Yiu ZZN, Ashcroft DM, Barker J, Burden AD, et al. Differential drug survival of biologic therapies for the treatment of psoriasis: a prospective observational cohort study from the British Association of Dermatologists Biologic Interventions Register (BADBIR). J Invest Dermatol. 2015;135(11):2632–40.
20. Zweegers J, van den Reek JM, van de Kerkhof PC, Otero ME, Kuijpers AL, Koetsier MI, et al. Body mass index predicts discontinuation due to ineffectiveness and female sex predicts discontinuation due to side-effects in patients with psoriasis treated with adalimumab, etanercept or ustekinumab in daily practice: a prospective, comparative, long-term drug-survival study from the BioCAPTURE registry. Br J Dermatol. 2016;175(2):340–7.
21. Menter A, Papp KA, Gooderham M, Pariser DM, Augustin M, Kerdel FA, et al. Drug survival of biologic therapy in a large, disease-based registry of patients with psoriasis: results from the Psoriasis Longitudinal Assessment and Registry (PSOLAR). J Eur Acad Dermatol Venereol. 2016;30(7):1148–58.
22. Thorneloe RJ, Griffiths CEM, Emsley R, Ashcroft DM, Cordingley L. Intentional and unintentional medication non-adherence in psoriasis: the role of patients’ medication beliefs and habit strength. J Invest Dermatol. 2018;138(4):785–94.
23. Presribing information. STELARA (ustekinumab) injection, for subcutaneous or intravenous use. Silver Spring, MD: United States Food and Drug Administration; 2016 (https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761044lbl.pdf, accessed 6 October 2023).
24. Kalb RE, Fiorentino DF, Lebwohl MG, Toole J, Poulin Y, Cohen AD, et al. Risk of serious infection with biologic and systemic treatment of psoriasis: results from the Psoriasis Longitudinal Assessment and Registry (PSOLAR). JAMA Dermatol. 2015;151(9):961–9.
25. Dávila-Seijo P, Dauden E, Descalzo MA, Carretero G, Carrascosa JM, Vanaclocha F, et al. Infections in moderate to severe psoriasis patients treated with biological drugs compared to classic systemic drugs: findings from the BIOBADADERM Registry. J Invest Dermatol. 2017;137(2):313–21.
26. Yiu ZZN, Smith CH, Ashcroft DM, Lunt M, Walton S, Murphy R, et al. Risk of serious infection in patients with psoriasis receiving biologic therapies: a prospective cohort study from the British Association of Dermatologists Biologic Interventions Register (BADBIR). J Invest Dermatol. 2018;138(3):534–41.
27. Villacorta R, Hay JW, Messali A. Cost effectiveness of moderate to severe psoriasis therapy with etanercept and ustekinumab in the United States. Pharmacoeconomics. 2013;31(9):823–39.
28. Pan F, Brazier NC, Shear NH, Jivraj F, Schenkel B, Brown R. Cost utility analysis based on a head-to-head Phase 3 trial comparing ustekinumab and etanercept in patients with moderate-to-severe plaque psoriasis: a Canadian perspective. Value Health. 2011;14(5):652–6.
29. Chi CC, Wang SH. Efficacy and cost-efficacy of biologic therapies for moderate to severe psoriasis: a meta-analysis and cost-efficacy analysis using the intention-to-treat principle. BioMed Res Int. 2014;2014:862851.
30. Rouse NC, Farhangian ME, Wehausen B, Feldman SR. The cost-effectiveness of ustekinumab for moderate-to-severe psoriasis. Expert Rev Pharmacoecon Outcomes Res. 2015;15(6):877–84.