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B. L. Bartlett, MD1; M. N. Moody, MPH2; S. K. Tyring, MD, PhD, MBA1,3

1. Center for Clinical Studies, Houston, TX, USA
2. The University of Texas Medical School at Houston, Houston, TX, USA
3. Department of Dermatology, University of Texas Health Sciences Center, Houston, TX, USA

ABSTRACT

Psoriasis is a common chronic inflammatory skin disease that is mediated, in part by the body’s T-cell inflammatory response mechanisms. Further insight into the pathogenesis of the disease and the role of various cytokines, particularly interleukin(IL)-12 and IL-23, has led to advances in the treatment of this disease. A relatively new class of drugs that inhibit these interleukins is being developed and studied. Current data regarding the efficacy of these agents show they may have the potential to become the new clinical gold standard for biologic therapy to treat psoriasis.

Key Words:
IL-12; IL-23; ustekinumab; psoriasis

The Role of IL-12 & IL-23 in the Pathogenesis of Psoriasis

Psoriasis is a chronic skin disease affecting approximately 2%-3% of the general population and is mediated, at least partially, by the body’s T-cell inflammatory response mechanisms. Two interleukins (IL) in particular, IL-12 and IL-23, have been specifically implicated as key players in the pathogenesis of psoriasis secondary to their role in linking the innate and adaptive immune responses.1 IL-12 and IL-23 are composed of the p40 subunit, which is common to both, as well as the unique subunits, p35 and p19, respectively. The individual subunits facilitate the distinctive biological actions of each molecule. IL-12 functions to induce and sustain TH1 immune responses leading to the secretion of interferon (IFN)-ã and the homing of T cells to the skin via the induction of cutaneous lymphocyte antigen (CLA), whereas, IL-23 functions to maintain chronic autoimmune inflammation via the induction of IL-17, regulation of T memory cells, and direct activation of macrophages.1-4

Support for IL-12 and IL-23 Involvement in Psoriasis

Through various approaches, a plethora of studies involving transgenic mice, the human genome, and samples from human psoriatic lesions support the hypothesis that IL-12 and IL-23 have a significant role in the disease process. According to the genome-wide association study (GWAS) conducted by Cargill et al., an association exists between psoriasis and the genes for IL-12 and IL-23. This finding was reproduced by Smith et al. in a study of approximately 600 patients with psoriasis. Additionally, scrapings from psoriatic lesions have exhibited not only increased levels of IL-12 and IL-23, but also higher levels of their downstream effectors, including CLA+ T-cells, IFN-ã, and IL-17.1,4 Recent findings indicate that people with genetic over-expression of this common p40 subunit have a greater risk for the development of psoriasis, and that psoriatic lesions contain high levels of IL-12, IL-23 and their downstream effectors. In light of these findings, further investigation has been directed towards illustrating not only their specific role in its pathogenesis, but also whether direct inhibition may play an integral role in its treatment.1-3

Mechanism of Action

Both IL-12 and IL-23 bind to the b1 receptor of T cells and natural killer cells via their shared p40 subunit.1,7 This new class of drugs has been designed to function by binding with high affinity to the p40 subunit, thus preventing its binding at the receptor and the subsequent downstream signaling. Currently, at least 2 drugs exist in this class: the first is CNTO-1275 (ustekinumab), which is being developed by Centocor and ABT-874, which is being developed by Abbott.1,2 Both drugs, given as subcutaneous injections, are fully human monoclonal antibodies targeting the shared p40 subunit of IL-12 and IL-23. An oral version of these drugs was introduced by Synta Pharmaceuticals as STA-5326, but this version failed in Phase II clinical trials for the treatment of psoriasis; it is still being tested for the treatment of rheumatoid arthritis and common variable immunodeficiency.8

Advantages of IL-12/IL-23 Inhibitors

Four double-blinded, placebo controlled trials, 3 evaluating CNTO-1275 and 1 evaluating ABT-874, have shown that both drugs are very effective in the treatment of psoriasis. These studies all used 3 universal criteria to delineate an adequate response:

  1. Psoriasis Area and Severity Index (PASI), which combines assessments of the extent of body surface involvement and the severity of desquamation, erythema, and plaque induration
  2. Physician’s Global Assessment (PGA), which rates the patient’s psoriasis relative to baseline
  3. Dermatology Quality of Life Index (DQLI), which is a 10 item questionnaire to assess the patient’s perspective on how psoriasis is affecting his or her own quality of life.

The Four Studies

Krueger et al.3 evaluated the efficacy of 4 dosing regimens of CNTO-1275:

  • one 45mg dose
  • one 90mg dose
  • 4 weekly 45mg doses
  • 4 weekly 90mg doses.

At least 75% improvement from the baseline PASI was seen in more than 50% (54%-81%) of subjects at 12 weeks in all 4 treatment arms. A higher dose of drug correlated with a higher percentage of subjects with a PASI-75 or better. This degree of improvement was seen in only 2% of those who received placebo. With regards to the PGA and DQLI, all active-treatment groups significantly improved when compared with the placebo group.

The PHOENIX 1 and 2 trials9,10 also evaluated the efficacy of CNTO-1275 by considering 2 treatment arms:

  • one 45mg dose at week 0 and week 4, followed by one 45mg dose every 12 weeks
  • one 90mg dose in the same dosing schedule.

Both trials illustrated improvement of at least 75% from baseline in more than 50% of both CNTO-1275 arms (66.4% and 63.1% in the 45mg arms, and 66.4% and 72% in the 90mg arms). In the PHOENIX 1 trial, patients who had achieved a satisfactory PASI-75 by weeks 28 or 40 were then rerandomized to a withdrawal vs. maintenance phase. Those who received the maintenance dose did much better than those who were withdrawn.9 Furthermore, in both PHOENIX trials, after the primary efficacy data was collected at week 12, patients originally allocated to the placebo arm were again randomized into either 45mg or 90mg dosing every 12 weeks. The results of these crossover randomizations paralleled those of the original treatment groups.

Kimball et al.2 conducted a similar study evaluating the efficacy of 5 dosing regimens of ABT-874:

  • one 200mg dose at week 0
  • 100mg every other week for 12 weeks
  • 200mg weekly for 4 weeks
  • 200mg every other week for 12 weeks
  • 200mg every week for 12 weeks.

Ninety percent of the patients in the ABT-874 multiple-dose arms exhibited improvement of at least 75% from baseline vs. only 3% in the placebo group.

These studies exhibited a dose-response phenomenon, and response rates declined across all dosages after treatment was discontinued for more than 12 weeks.3 Additional support for this drug class as a treatment option for psoriasis includes a short response latency and sustainable efficacy. Response time for both drugs was very rapid, measured by PASI-50 at week 2 and PASI-75 by week 4.2,9,10 The PHOENIX 1 trial continued for a total follow-up time of 76 weeks, and the PHOENIX 2 trial for 52 weeks, illustrating that maintenance dosing every 8-12 weeks ensures a sustained response.
This further indicates that IL-12 and IL-23 inhibitors have the potential to provide a treatment regimen that is not only successful but also convenient.12
Data further showed that maximum effects were reached by week 20, and that response rates had stabilized by week 28. They were successfully maintained throughout the remainder of the study at the dosage frequency of 1 dose (either the 45mg or 90mg originally assigned) every 8-12 weeks.9,10

Disadvantages of IL-12/IL-23 Inhibitors

For studies using CNTO-1275, there were no significant differences in adverse events (AEs) between the treatment groups and placebo groups.3,9,10 However, for ABT-874, Kimball et al.2 reported a higher percentage of AEs in the treatment group vs. the placebo group.2
Patients receiving any dose of ABT-874 were significantly more likely to experience an AE than those in the placebo group, 36.1% vs. 10%, respectively. The AEs in the ABT-874 treated group were most commonly related to reactions at the injection site (erythema, pruritus, and irritation), but also included nasopharyngitis (12.0%) and upper respiratory tract infections (10.7%), followed by bronchitis and viral infection (both 2.7%). The incidences of other AEs were not statistically significantly different in the ABT-874 treatment group compared with placebo-treated patients.

The most commonly encountered AE was infection, which, surprisingly, did not show a significant dose-related trend. One major difference noted between CNTO-1275 and ABT-874 was the rate of AEs at the injection site. Such events occurred at a much higher frequency with ABT-874. Injection site reactions occurred in 16.7% of patients in the study arms treated with ABT-8742 vs. only 1.2%-2% in the CNTO-1275 studies.3,9,10 In all 4 studies the occurrence of adverse injection reactions among the placebo groups was 0%-2%. The development of antibodies to the drugs also remains a concern with these treatments.


Krueger et al.3 reported AEs in 51 of 64 patients (79%) in the treatment group vs. 46 of 64 patients (72%) in the placebo group (p=0.19). Three of these patients (4%) developed antibodies to CNTO-1275. AEs leading to hospitalizations and discontinuation of treatment occurred in 3 patients in the treatment group vs. 1 in the placebo group (p=0.69). Among the patients in the groups receiving treatment who experienced a serious AE, 2 of them were hospitalized for infections (1 for cellulitis and 1 for pneumonia).

The PHOENIX 1 trial9 reported AEs in 54% of patients in either treatment arm and in 48% of patients in the placebo arm. Of the patients who were getting CNTO-1275, 5.1% developed antibodies to this formulation. Serious AEs occurred in 1.2% of treatment groups vs. 0.8% in the placebo group.

The PHOENIX 2 trial10 reported AEs at an equal frequency among the treatment and placebo arms, both measuring in at approximately 50%. Twelve percent of patients developed antibodies to CNTO-1275. For the most part, these antibodies were found to be neutralizing. Serious AEs occurred in 2% of treatment groups vs. 0% in the placebo group.

Prior to the use of IL-12 and IL-23 inhibitors for the treatment of psoriasis, concern arose because of unrelated studies involving people and transgenic mice with IL-12 deficiencies. Populations of people with a congenital deficiency of the IL-12 p40 subunit or the IL-12 receptor were found to have an increased susceptibility to intracellular pathogens, including tuberculosis, Toxoplasma gondii and Leishmania major, as well as defective delayed type hypersensitivity reactions. Furthermore, IL-12 plays an integral role in immunity against multiple viruses, including herpes simplex virus, vesicular stomatitis virus, and murine aquired immunodeficiency syndrome (MAIDS).7 These specific concerns have not yet been proven to be an issue in the trials, but due to the tuberculosis concern, an exclusion criterion common to all 4 studies outlined that no person with active disease would be allowed to participate. Ultimately, long-term consequences of IL-12 and IL-23 inhibitor usage beyond 76 weeks have yet to be determined as the clinical trials are very recent.

Various studies involving autoimmune diseases in non-human models have shown that targeting IL-23 alone instead of targeting both may be a better strategy.1 Specifically, a study by Chan et al. showed that direct intradermal administration into mice of IL-23 alone, but not IL-12 alone, initiates a psoriatic type reaction. This TNF-mediated spectrum of events culminates in erythema, and acanthosis with parakeratosis that is accompanied by a mixed dermal infiltrate.

Another important consideration is the cost of these drugs. Although the exact market cost has not yet been established, biologic agents tend to be very expensive, and IL-12 and IL-23 inhibitors will likely not be an exception to this trend.

Conclusions

IL-12 and IL-23 inhibitors remain on the forefront of treatment options for inflammatory diseases such as psoriasis, Crohn’s disease, multiple sclerosis, and rheumatoid arthritis. Although the current data does not provide insight into the long-term effects of these drugs, results have been extremely encouraging. In light of the current research and results, IL-12 and IL-23 inhibitors are a very promising option in the treatment of psoriasis.

While the therapeutic effects were shown to have a dose-response relationship, the AEs illustrated no such trend. Furthermore, although the rate of AEs was higher in the ABT-874 treatment groups, these events were reported to be generally tolerable, easily managed, and did not cause a significant percentage of subjects to be discontinued from the study.2 The current standard of care for psoriasis includes the use of broad spectrum anti-T-cell agents with accompanying immunosuppression,12 and often necessitates early discontinuation and subsequent psoriatic flares. With the introduction of the IL-12 and IL-23 inhibitors, there is new hope for patients battling psoriasis, as these formulations offer a favorable balance between disease treatment, resolution, tolerable side-effects, and an overall improved quality of life.

References

  1. Reddy M, Davis C, Wong J, et al. Modulation of CLA, IL-12R, CD40L, and IL-2Rá expression and inhibition of IL-12 and IL-23-induced cytokine secretion by CNTO 1275. Cell Immunol 247(1):1-11 (2007 May).
  2. Kimball AB, Gordon KB, Langley RG, et al. Safety and efficacy of ABT-874, a fully human interleukin 12/23 monoclonal antibody, in the treatment of moderate to severe chronic plaque psoriasis. Arch Dermatol 144(2):200-7 (2008 Feb).
  3. Krueger GG, Langely RG, Leonardi C, et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med 356(6):580-92 (2007 Feb).
  4. Piskin G, Sylva-Steenland RMR, Bos J, et al. In vitro and in situ expression of IL-23 by keratinocytes in healthy skin and psoriasis lesions: enhanced expression in psoriatic skin. J Immunol 176(3):1908-15 (2006 Feb).
  5. Cargill M, Schrodi SJ, Chang M, et al. A Large-scale genetic association study confirms IL-12B and leads to IL-23R as psoriasis-risk genes. Am J Hum Genet 80(2):273-90 (2007 Feb).
  6. Smith RL, Warren RB, Eyre S, et al. Polymorphisms in the IL-12â and IL-23R genes are associated with psoriasis of early onset in a UK cohort. J Invest Dermatol 128(5):1325-7 (2008 May).
  7. Torti DC, Feldman SR. Interleukin-12, Interleukin-23, and psoriasis: current prospects. J Am Acad Dermatol 57(6):1059-68 (2007 Dec).
  8. Stetsko D, Sauder DN. IL-12 and IL-23 in health and disease. Expert Rev Clin Immunol 4(3):301-3 (2008 May).
  9. Leonardi CL, Kimball AB, Papp KA, et al. Efficacy and Safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomized, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 371(9627):1665-74 (2008 May).
  10. Papp KA, Langley RG, Lebwohl M, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomized, double-blind, placebo-controlled trial (PHOENIX 2). Lancet 371(9625):1675-84 (2008 May).
  11. Chan RC, Blumenschein W, Murphy E, et al. IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis. J Exp Med 203(12):2577-87 (2006 Nov).
  12. Bartlett BL, Tyring SK. Ustekinumab for chronic plaque psoriasis. Lancet 371(9625):1639-40 (2008 May).
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