**7.3.2 Ustekinumab (CNTO1275)**

252 Psoriasis

group (74.6 and 82.8% vs. 6.8%) (Ortonne et al., 2007). The most frequently reported adverse events comprised headache, nasopharyngitis and pruritus. The frequency of adverse events was similar across all three groups. However, serious adverse events were more common in the 400-mg group (7.0%) than in the 200-mg group (3.3%) and in the placebo-group (1.7%) (Ortonne et al., 2007). According to the data from the phase II study, PASI 75 results and side effects were comparable with those observed in patients treated with the approved TNF- blockers adalimumab and infliximab. So far, no phase III studies or studies in

In 2003, alefacept and efalizumab were the first biological agents to be approved by the Food and Drug Administration (FDA) for the treatment of psoriasis (Pathirana et al., 2009). In the European Union, only efalizumab was approved for the psoriasis therapy (Pathirana et al., 2009). In 2009, efalizumab was withdrawn from the market in Europe and the United

Alefacept, a recombinant dimeric fusion protein, is made up of the terminal portion of leukocyte function antigen-3 (LFA-3). It binds to extracellular human CD2 and the Fc portion of human immunoglobulin IgG1 (Sugiyama et al., 2008). Alefacept blocks signalling between LFA-3 on antigen presenting cells and the CD2 molecule on T cells (primarily

Subsequently, the activation and proliferation of CD45RO+ T cells, which account for approximately 75% of T lymphocytes in psoriatic lesions, are inhibited. Furthermore, alefacept decreases the number of pathogenic T cells by binding CD2 on CD45RO+ T cells to the FcgIII receptor on natural killer cells, resulting in granzyme-mediated apoptosis of T cells (Gordon et al., 2003; Sobell et al., 2009; Sugiyama et al., 2008). Using a dosage of 15 mg alefacept administered intramuscularly QW, PASI 75 scores at week 12 were found to range between 21 and 35% (Gordon et al., 2003; Pathirana et al., 2009; Sugiyama et al., 2008). Recently, patients receiving alefacept in combination with MTX were shown to improve significantly in ACR 20 at week 24 compared with patients treated with MTX and placebo

Briakinumab and ustekinumab are both IL-12/IL-23 antagonists. Whereas briakinumab is currently under investigation for the psoriasis treatment in several phase III studies, ustekinumab was recently approved by the EMEA for the therapy of chronic plaque

Briakinumab is a recombinant fully human, IgG1 Moab targeting the shared p40 subunit of IL-12 and IL-23 (Kimball et al., 2008b). It binds to soluble forms of IL-12 and IL-23, leading to a decreased secretion of pro-inflammatory cytokines: IL-12, IL-6, IFN- and TNF-, as

States (EMEA, 2009; Food and Drug Administration [FDA], 2009).

alone (54% vs. 23%; *P* < 0.001) (Mease et al., 2006a).

**7.3 IL-12/IL-23 antagonists** 

**7.3.1 Briakinumab (ABT874)** 

shown in CD patients (Ding et al., 2008).

patients with PsA have been conducted.

**7.2 T-cell modulators** 

**7.2.1 Alefacept** 

CD45RO+).

psoriasis.

Ustekinumab is a human monoclonal antibody binding with high affinity to the p40 subunit of IL 12 and IL 23 and therefore inhibiting the binding to specific receptor (IL-12Rb1) expressed on various cells.

In a phase I study, patients with constant 70% PASI improvement at weeks 8, 12 and 16 shown significant decreases in mRNA expression of different cytokines (IL-8, IL-18 and IFN-) as early as week 1 (*P* < 0.05), whereas, in patients without PASI improvement, no significant reduction of cytokine mRNA expression was observed(Wittig, 2007).

The pharmacokinetics of ustekinumab were assessed in different studies (A. B. Gottlieb et al., 2007; Kaufmann et al., 2004; Wittig, 2007): after a single subcutaneous injection, ustekinumab was slowly absorbed into the systemic circulation (mean Tmax about 12 days) and was afterwards slowly eliminated from the circulation (mean t1/2 around 20 days) (A. B. Gottlieb et al., 2007; Wittig, 2007).

The terminal half-life (t1/2) was dose dependent and was found to range from 14.9 ± 4.6 days (0.27 mg·kg-1 dose group) to 28.6 ± 9.3 days (2.7 mg·kg-1 dose group) (A. B. Gottlieb et al., 2007). Similar results were also observed for t1/2 by Kaufman (Kaufmann et al., 2004), ranging from 18.5 ± 3.6 in the 0.3-mg group to 25.9 ± 3.7 in the 1.0-mg group. An increase of Cmax and AUC was observed with superior dosages (A. B. Gottlieb et al., 2007; Kaufmann et al., 2004).

placebo).

The Role of Immune Response and the Impact of Biological Drugs in Psoriasis Patients 255

placebo group. Patients receiving maintenance therapy up to week 76 significantly better sustained PASI 75 than patients randomized to the drug withdrawal group (*P* < 0.0001).

The design of the Phoenix 2 study closely resembles that of the Phoenix 1 trial (Papp et al., 2008). Of the 1230 patients, 409 patients were randomized to receive ustekinumab 45 mg, 411 to receive ustekinumab 90 mg and 410 to receive placebo at weeks 0 and 4. The efficacy analysis at week 12 revealed the following results for the three groups. The primary endpoint was achieved in 66.7% of the ustekinumab 45-mg group, 75.7% of the ustekinumab 90 mg and 3.7% of the placebo group (*P* < 0.0001 for both ustekinumab 45 and 90 mg vs.

Quality of life was significantly improved in the patients treated with ustekinumab compared with the placebo groups (*P* < 0.0001) in both Phoenix trials. Patients randomized to maintenance therapy in the Phoenix 1 study were able to sustain improved DLQI scores until the end of the study, whereas in patients withdrawn from the study drug, the DLQI

In a randomized active-controlled, parallel three-arm trial (ACCEPT trial), ustekinumab (45 and 90 mg, respectively) was compared versus the anti-TNF- etanercept (50 mg twice weekly) (C. E. M. Griffiths et al., 2008). The primary endpoint of the study was PASI 75 at week 12. 903 patients were randomized in 3 treatment-arms as follows: 347 patients received etanercept 50 mg subcutaneously twice weekly, 209 patients received ustekinumab 45 mg subcutaneously at weeks 0 and 4, and 347 patients received ustekinumab 90 mg subcutaneously at weeks 0 and 4. PASI 75 at week 12 was achieved by 56.8% of patients in the etanercept group, by 67.5% in the ustekinumab 45-mg group and 73.8% in the ustekinumab 90-mg group. A greater proportion of patients receiving ustekinumab (45 or 90 mg) achieved PASI 75 when compared with the etanercept group (*P* = 0.012 for ustekinumab 45 mg, *P* < 0.001 for ustekinumab 90 mg). Interestingly, PASI 75 values at week 12 in patients receiving etanercept were better than those published in previous

The table 4 resume the major results obtained using the briakinumab and ustekinumab in

About the major side effects of treatments with ustekinumab; in the phase I studies, no serious adverse events were reported (A. B. Gottlieb et al., 2007; Kaufmann et al., 2004). Adverse events included headaches, abdominal pain and common cold symptoms. Adverse events were comparable in the phase II studies between ustekinumab and placebo groups (79% vs. 72%) (G. G. Krueger et al., 2007). Serious adverse events in patients treated with ustekinumab were infections (2 patients), myocardial infarctions (2 patients), a cerebrovascular accident (1 patient), non-melanoma skin cancer (2 patients) and prostate

In the placebo group, one patient had a basal cell carcinoma and one patient experienced aggravation of his psoriasis requiring hospitalization. In the PsA trial conducted by Gottlieb, the following serious adverse events were reported in the ustekinumab groups: syncope (1 patient), respiratory tract infection (1 patient), haemorrhage (1 patient), stroke (1 patient), congestive heart failure/myocardial infarction/hypertension (1 patient), chest pain (1

deteriorated again (Leonardi et al., 2008; Papp et al., 2008).

studies (Leonardi et al., 2008; Papp et al., 2008).

psoriasis treatments.

cancer (1 patient).

In the clinical trial conducted by Kaufman (Kaufmann et al., 2004), 18 psoriasis patients were enrolled in four dose groups: 0.1, 0.3, 1.0 and 5.0 mg per kg to assess the clinical response and the safety of a single intravenous administration of ustekinumab. At week 12, PASI 75 was reached in 25, 50, 60 and 100% of patients respectively. In patients responding to ustekinumab treatment, the expression of pro-inflammatory cytokines and chemokines IFN-, CXCL-8, CCR2, TNF-, IL-12p40 and IL-23p19 subunits was decreased, compared with baseline levels (Reddy et al., 2007; Toichi et al., 2006).

In a second double-blind, placebo-controlled study, patients were randomized to receive either a single subcutaneous injection of 0.27, 0.675, 1.35 or 2.7 mg·kg-1 ustekinumab or placebo (A. B. Gottlieb et al., 2007). For a second time, patients treated with ustekinumab showed a dose-dependent improvement of their psoriasis. PASI 75 was achieved in 60% of the 0.27 mg·kg-1 group, 100% in the 0.675 mg·kg-1 group, 50% in the 1.35 mg·kg-1 group and 100% in the 2.7 mg·kg-1 group, but in none of the patients receiving placebo during the whole study period.

Krueger (G. G. Krueger et al., 2007) evaluated in a double-blind, placebo controlled trial, four subcutaneous dosing regimens of ustekinumab in patients with psoriasis; 320 patients were randomized to receive one of the following treatment regimens: one 45-mg dose, one 90-mg dose, four weekly 45-mg doses and four weekly 90-mg doses of ustekinumab or placebo. The primary endpoint of the study was a 75% improvement in the PASI at week 12. PASI 75 was achieved in 52% of patients receiving ustekinumab 45 mg, in 59% receiving ustekinumab 90 mg, in 67% receiving four weekly 45-mg doses and in 81% of patients receiving four weekly 90-mg doses, whereas only 2% of patients in the placebo group achieved a PASI 75.

Another placebo-controlled double blind randomized crossover study was conducted to evaluate the efficacy of ustekinumab in 146 patients suffering from PsA (A. Gottlieb et al., 2009). Patients were either randomized to receive ustekinumab 90 or 63 mg every week for 4 weeks (weeks 0–3) followed by placebo at weeks 12 and 16 (76 patients, group 1) or placebo (weeks 0–3) and ustekinumab (63 mg) at weeks 12 and 16 (70 patients, group 2). ACR 20 at week 12 (taken as the primary endpoint of the study) was achieved by 42% of patients in group 1 and by 14% in group 2 (*P* = 0.0002). Significantly more patients in group 1 achieved PASI 75 compared with group 2 in week 12 (52% vs. 5%, *P* < 0.0001). However, one should note that the dosages of ustekinumab used in the study were higher (90 and 63 mg, respectively) than those recommended for patients of normal weight (45 mg) with psoriasis (Leonardi et al., 2008).

In conclusion*,* we report the results of the two double-blind, placebo-controlled phase III studies (Phoenix 1 and Phoenix 2) in patients with psoriasis were performed parallel in USA and Europe. Primary outcome in both studies was PASI 75 at week 12 (Leonardi et al., 2008; 211,). 766 patients of Phoenix 1 trial were randomly assigned to receive either ustekinumab 45 mg or 90 mg at weeks 0 and 4 and afterwards every 12 weeks or placebo at weeks 0 and 4 and to cross over at week 12 to ustekinumab (Leonardi et al., 2008; Papp et al., 2008).

Furthermore, patients initially receiving ustekinumab and reaching a PASI 75 at weeks 28 and 40 were re-randomized at week 40 to either continue therapy with ustekinumab or to withdrawal of the study drug until loss of response. Significantly more patients in both ustekinumab groups (45 and 90 mg) received a PASI 75 at week 12 compared with the

In the clinical trial conducted by Kaufman (Kaufmann et al., 2004), 18 psoriasis patients were enrolled in four dose groups: 0.1, 0.3, 1.0 and 5.0 mg per kg to assess the clinical response and the safety of a single intravenous administration of ustekinumab. At week 12, PASI 75 was reached in 25, 50, 60 and 100% of patients respectively. In patients responding to ustekinumab treatment, the expression of pro-inflammatory cytokines and chemokines IFN-, CXCL-8, CCR2, TNF-, IL-12p40 and IL-23p19 subunits was decreased, compared

In a second double-blind, placebo-controlled study, patients were randomized to receive either a single subcutaneous injection of 0.27, 0.675, 1.35 or 2.7 mg·kg-1 ustekinumab or placebo (A. B. Gottlieb et al., 2007). For a second time, patients treated with ustekinumab showed a dose-dependent improvement of their psoriasis. PASI 75 was achieved in 60% of the 0.27 mg·kg-1 group, 100% in the 0.675 mg·kg-1 group, 50% in the 1.35 mg·kg-1 group and 100% in the 2.7 mg·kg-1 group, but in none of the patients receiving placebo during the

Krueger (G. G. Krueger et al., 2007) evaluated in a double-blind, placebo controlled trial, four subcutaneous dosing regimens of ustekinumab in patients with psoriasis; 320 patients were randomized to receive one of the following treatment regimens: one 45-mg dose, one 90-mg dose, four weekly 45-mg doses and four weekly 90-mg doses of ustekinumab or placebo. The primary endpoint of the study was a 75% improvement in the PASI at week 12. PASI 75 was achieved in 52% of patients receiving ustekinumab 45 mg, in 59% receiving ustekinumab 90 mg, in 67% receiving four weekly 45-mg doses and in 81% of patients receiving four weekly 90-mg doses, whereas only 2% of patients in the placebo group

Another placebo-controlled double blind randomized crossover study was conducted to evaluate the efficacy of ustekinumab in 146 patients suffering from PsA (A. Gottlieb et al., 2009). Patients were either randomized to receive ustekinumab 90 or 63 mg every week for 4 weeks (weeks 0–3) followed by placebo at weeks 12 and 16 (76 patients, group 1) or placebo (weeks 0–3) and ustekinumab (63 mg) at weeks 12 and 16 (70 patients, group 2). ACR 20 at week 12 (taken as the primary endpoint of the study) was achieved by 42% of patients in group 1 and by 14% in group 2 (*P* = 0.0002). Significantly more patients in group 1 achieved PASI 75 compared with group 2 in week 12 (52% vs. 5%, *P* < 0.0001). However, one should note that the dosages of ustekinumab used in the study were higher (90 and 63 mg, respectively) than those recommended for patients of normal weight (45 mg) with psoriasis

In conclusion*,* we report the results of the two double-blind, placebo-controlled phase III studies (Phoenix 1 and Phoenix 2) in patients with psoriasis were performed parallel in USA and Europe. Primary outcome in both studies was PASI 75 at week 12 (Leonardi et al., 2008; 211,). 766 patients of Phoenix 1 trial were randomly assigned to receive either ustekinumab 45 mg or 90 mg at weeks 0 and 4 and afterwards every 12 weeks or placebo at weeks 0 and 4

Furthermore, patients initially receiving ustekinumab and reaching a PASI 75 at weeks 28 and 40 were re-randomized at week 40 to either continue therapy with ustekinumab or to withdrawal of the study drug until loss of response. Significantly more patients in both ustekinumab groups (45 and 90 mg) received a PASI 75 at week 12 compared with the

and to cross over at week 12 to ustekinumab (Leonardi et al., 2008; Papp et al., 2008).

with baseline levels (Reddy et al., 2007; Toichi et al., 2006).

whole study period.

achieved a PASI 75.

(Leonardi et al., 2008).

placebo group. Patients receiving maintenance therapy up to week 76 significantly better sustained PASI 75 than patients randomized to the drug withdrawal group (*P* < 0.0001).

The design of the Phoenix 2 study closely resembles that of the Phoenix 1 trial (Papp et al., 2008). Of the 1230 patients, 409 patients were randomized to receive ustekinumab 45 mg, 411 to receive ustekinumab 90 mg and 410 to receive placebo at weeks 0 and 4. The efficacy analysis at week 12 revealed the following results for the three groups. The primary endpoint was achieved in 66.7% of the ustekinumab 45-mg group, 75.7% of the ustekinumab 90 mg and 3.7% of the placebo group (*P* < 0.0001 for both ustekinumab 45 and 90 mg vs. placebo).

Quality of life was significantly improved in the patients treated with ustekinumab compared with the placebo groups (*P* < 0.0001) in both Phoenix trials. Patients randomized to maintenance therapy in the Phoenix 1 study were able to sustain improved DLQI scores until the end of the study, whereas in patients withdrawn from the study drug, the DLQI deteriorated again (Leonardi et al., 2008; Papp et al., 2008).

In a randomized active-controlled, parallel three-arm trial (ACCEPT trial), ustekinumab (45 and 90 mg, respectively) was compared versus the anti-TNF- etanercept (50 mg twice weekly) (C. E. M. Griffiths et al., 2008). The primary endpoint of the study was PASI 75 at week 12. 903 patients were randomized in 3 treatment-arms as follows: 347 patients received etanercept 50 mg subcutaneously twice weekly, 209 patients received ustekinumab 45 mg subcutaneously at weeks 0 and 4, and 347 patients received ustekinumab 90 mg subcutaneously at weeks 0 and 4. PASI 75 at week 12 was achieved by 56.8% of patients in the etanercept group, by 67.5% in the ustekinumab 45-mg group and 73.8% in the ustekinumab 90-mg group. A greater proportion of patients receiving ustekinumab (45 or 90 mg) achieved PASI 75 when compared with the etanercept group (*P* = 0.012 for ustekinumab 45 mg, *P* < 0.001 for ustekinumab 90 mg). Interestingly, PASI 75 values at week 12 in patients receiving etanercept were better than those published in previous studies (Leonardi et al., 2008; Papp et al., 2008).

The table 4 resume the major results obtained using the briakinumab and ustekinumab in psoriasis treatments.

About the major side effects of treatments with ustekinumab; in the phase I studies, no serious adverse events were reported (A. B. Gottlieb et al., 2007; Kaufmann et al., 2004). Adverse events included headaches, abdominal pain and common cold symptoms. Adverse events were comparable in the phase II studies between ustekinumab and placebo groups (79% vs. 72%) (G. G. Krueger et al., 2007). Serious adverse events in patients treated with ustekinumab were infections (2 patients), myocardial infarctions (2 patients), a cerebrovascular accident (1 patient), non-melanoma skin cancer (2 patients) and prostate cancer (1 patient).

In the placebo group, one patient had a basal cell carcinoma and one patient experienced aggravation of his psoriasis requiring hospitalization. In the PsA trial conducted by Gottlieb, the following serious adverse events were reported in the ustekinumab groups: syncope (1 patient), respiratory tract infection (1 patient), haemorrhage (1 patient), stroke (1 patient), congestive heart failure/myocardial infarction/hypertension (1 patient), chest pain (1

The Role of Immune Response and the Impact of Biological Drugs in Psoriasis Patients 257

However, as Th1 and Th17 blockade by ustekinumab might impair cell-mediated immunity, normal KCs host immunity and defence against malignancies, close monitoring in patients on long-term treatment with ustekinumab seems to be appropriate (O'Neill & Kalb, 2009). In the ACCEPT trial, serious adverse events have been observed in 1.2% of patients in the etanercept group, 1.9% in the ustekinumab 45-mg group and 1.2% of patients in the ustekinumab 90 mg group respectively. These included 4 patients in each treatment group: etanercept group: abdominal pain, bacterial meningitis, nephrolithiasis, rotator cuff syndrome; 45-mg ustekinumab group: alcoholic pancreatitis, chest pain/hypertension, psychotic disorder, breast cancer; ustekinumab 90-mg group: urosepsis/renal failure, uveitis, appendicitis and gastroenteritis from food poisoning (C. E. M. Griffiths et al., 2008).

Based on a large series of studies, that we discuss in the different paragraphs, current evidence indicates the importance of T cells during psoriasis pathogenesis and demonstre that T cell expansion precedes the development of typical psoriatic changes; the more reasonable conclusion is that psoriasis is the outcome of an inappropriate T cell-based activation event, together with a defect in KCs, whose combination results in the full

Once recognized the primary role of T cells in psoriasis pathogenesis, several biological therapies have been developed and proposed to counteract immune T response. These treatments consist in blocking the actions of several T cell cytokines that play a key role in sustain the pathogenesis of early and late events of psoriasis, e.g. anti-IL23 and anti-TNF-. So far, considering published data from the clinical trials, the new biological agents have been shown to be efficient treatment options for patients suffering from psoriasis and the

These new biological agents seem to have proven a good risk/benefit ratio. As psoriasis is considered a life-long disease and no causal therapy for the disease is yet available, longterm studies on safe and efficacious treatments are needed and are of major importance.

Taking into account the possibility that uncommon adverse events or events occurring during long-term exposure to these drugs might emerge in the future (e.g. the development of progressive multifocal leukoencephalopathy in long-term patients treated with efalizumab), vigilant and careful post-marketing surveillance in patients treated with

We thank Dr. Elena Niccolai for editorial support and Dr. Chiara Della Bella for the artworks. We wish to thank Istituto Superiore di Sanità, and Italian Ministry of University

Abel, E. A., DiCicco, L. M., Orenberg, E. K., Fraki, J. E., & Farber, E. M. (1986). Drugs in exacerbation of psoriasis. *J Am Acad Dermatol,* 15, 5 Pt 1, (Nov 1986), 1007–22.

**8. Conclusion** 

psoriatic phenotype.

major comorbidities disease-associated, primarily PsA.

biological agents is strongly recommended.

and Research for their support of our studies.

**9. Acknowledgment** 

**10. References** 

patient), gastric ulcer haemorrhage/abdominal pain/back pain (1 patient) and basal cell carcinoma (1 patient) respectively (A. Gottlieb et al., 2009). Two serious infections occurred during the placebo-controlled phase of the two large phase III trials: one case of cellulitis and one case of herpes zoster (both in the ustekinumab 90-mg group) (Ding et al., 2008; Ortonne et al., 2007).

During the placebo-controlled phase of the Phoenix 2 study, a squamous cell carcinoma in a patient in the placebo group and a basal cell carcinoma in a patient in the ustekinumab 90 mg group were observed (Ding et al., 2008). Comparing patients on maintenance therapy with patients randomized to the withdrawal group in Phoenix 1 study did not reveal an increased infection rate between the two groups (Ortonne et al., 2007).


B = Briakinumab; E = Etanercept; U = Ustekinumab; RDBPC = Randomized Double-Blind Placebo Controlled Trial

Table 4. Efficacy of anti- IL-12/IL-23 in the psoriasis cure

However, as Th1 and Th17 blockade by ustekinumab might impair cell-mediated immunity, normal KCs host immunity and defence against malignancies, close monitoring in patients on long-term treatment with ustekinumab seems to be appropriate (O'Neill & Kalb, 2009). In the ACCEPT trial, serious adverse events have been observed in 1.2% of patients in the etanercept group, 1.9% in the ustekinumab 45-mg group and 1.2% of patients in the ustekinumab 90 mg group respectively. These included 4 patients in each treatment group: etanercept group: abdominal pain, bacterial meningitis, nephrolithiasis, rotator cuff syndrome; 45-mg ustekinumab group: alcoholic pancreatitis, chest pain/hypertension, psychotic disorder, breast cancer; ustekinumab 90-mg group: urosepsis/renal failure, uveitis, appendicitis and gastroenteritis from food poisoning (C. E. M. Griffiths et al., 2008).
