**4.1.2 Clinical efficacy**

The first phase II trial was performed in 320 patients with moderate-to-severe plaque psoriasis who were randomized to receive one of four subcutaneous dosing regimens of ustekinumab (one 45 mg dose, one 90 mg dose, 4-weekly 45 mg doses, or 4-weekly 90 mg doses) or placebo (Krueger et al, 2007). At week 12, a PASI 75 was achieved by 52%, 59%, 67%, and 81%, respectively, of the aforementioned groups, compared to 2% of placebo patients. Other measures of clinical outcome, including DLQI and Physician's Global Assessment (PGA) showed significant improvements in responders compared with placebo patients at both weeks 12 and 24. Two important clinical trials for the assessment of ustekinumab efficacy and safety are PHOENIX-1 and PHOENIX-2. Both are large-scale, randomized, placebo-controlled phase III trials designed to evaluate the efficacy and safety of ustekinumab in patients with moderate-to-severe plaque psoriasis over a period of five years. In the PHOENIX-1 study, 766 patients were randomized to subcutaneous injections of 45 mg or 90 mg of ustekinumab at weeks 0 and 4 and then every 12 weeks, or placebo at weeks 0 and 4, with crossover to ustekinumab at week 12 (Leonardi et al, 2008). At week 12, a PASI 75 was achieved by 67.1%, 66.4%, and 3.1% of patients receiving 45 mg, 90 mg or placebo, respectively. Results at week 28 demonstrated durable effects of ustekinumab with 71.2% and 78.6% of patients treated with 45 mg or 90 mg achieving or maintaining a PASI 75 score. Patients that achieved PASI 75 were re-randomized to maintenance ustekinumab or withdrawal from treatment at week 40. A PASI 75 response was better maintained in patients receiving maintenance ustekinumab than in those who were withdrawn from

Biotech on the Rise: The Treatment of Psoriasis with Biological Drugs 343

Briakinumab is a recombinant fully human IgG1 monoclonal antibody directed against the shared p40 subunit of IL-12 and IL-23 (Kimball et al, 2008). Due to its binding to the aforesaid cytokines, briakinumab causes a decrease in secretion of IL-6, IL-12, INF- and TNF, as demonstrated in patients with Crohn's disease (Ding et al, 2008). In a phase II study, 180 patients suffering from psoriasis were treated with placebo or briakinumab at one of the following doses: one 200 mg dose at week 0, 100 mg eow for 12 weeks, 200 mg weekly for 4 weeks, 200 mg eow for 12 weeks, 200 mg weekly for 12 weeks. At week 12, an improvement in PASI 75 was reported for all briakinumab-treated groups compared with placebo (Kimball et al, 2008). The retreatment efficacy and the long-term safety of briakinumab through 48 weeks have been evaluated by the same authors (Kimball et al, 2009). Kimball et al. reported that the efficacy of briakinumab was higher in the first 12 weeks compared with the re-treatment phase, although more patients showed a PASI 75 response during this period. The most frequent adverse events observed during the treatment with briakinumab were injection site

In the last decade, the detailed comprehension of the molecular mechanisms involved in psoriasis has led to the development of new biological drugs, such as monoclonal antibodies, recombinant proteins and small RNA drugs, which are currently under

IL-17 is a pro-inflammatory cytokine produced by Th17 T cells, one of the key players in the pathogenesis of psoriasis. Due to its role in psoriasis, IL-17 is a new emerging target for

AMG 827 is a fully human IgG2 anti IL-17 receptor monoclonal antibody investigated in phase II trials for psoriasis, rheumatoid arthritis and Crohn's disease (Amgen, 2011). Preliminary data from a small study showed that psoriatic patients treated with 700 mg AMG 827 IV had a significant improvement in terms of histopathological features and PASI

AIN457 is a recombinant fully human anti-IL-17 monoclonal antibody that selectively binds and neutralizes IL-17. The efficacy and safety of AIN457 has been evaluated in a phase II trial (Jancin, 2009) which enrolled 36 patients suffering from chronic plaque psoriasis. A PASI 75 response was observed in 44% of patients receiving 3 mg/kg AIN457 IV compared with 9% of placebo group. AIN457 is currently undergoing phase II studies for psoriasis, psoriatic arthritis and rheumatoid arthritis and a phase III study for uveitis (Novartis, 2010). LY2439821 is a new humanized IgG4 anti-IL-17 monoclonal antibody in a phase II trial for

IL-22 is a pro-inflammatory cytokine produced by both Th17 and a new group of T cells known as Th22 cells; Th22 cells are known to induce epidermal hyperplasia and dermal

psoriasis and rheumatoid arthritis (Eli Lilly and Company, 2011).

reactions, upper respiratory infections and nasopharyngitis.

evaluation for psoriasis and/or psoriatic arthritis.

**4.2 Briakinumab** 

**5. Perspectives** 

**5.1 Anti-interleukin 17** 

score (Russell et al, 2010).

**5.2 Anti-interleukin 22** 

biological therapy.

treatment. The median time to loss of PASI 75 in patients withdrawn from therapy was 15 weeks. The PHOENIX-2 study enrolled 1230 patients (Papp et al, 2008). Its design and results were similar to the PHOENIX-1 study: a PASI 75 was achieved by 66.7% of patients in the 45 mg group, by 75.7% in the 90 mg group, by 3.7% in the placebo group, at week 12. However, a dosing intensification was added for those subjects who did not respond fully to ustekinumab (PASI 50 to <75). At week 28, partial responders were re-randomized to continue dosing regimen every 12 weeks or to increase dosing frequency to every 8 weeks. In the 90 mg group, 22 of 33 partial responders achieved PASI 75 after increasing dosage frequency to every 8 weeks. Conversely, dosing intensification did not improve clinical outcomes in the 45 mg group. The authors concluded that intensification of dosing to once every 8 weeks with ustekinumab 90 mg might be necessary to achieve a full response in partial responders. The ACCEPT study is a randomized phase III clinical trial that directly compares ustekinumab to etanercept in 903 patients with psoriasis (Griffiths et al, 2010). Patients were randomized to receive ustekinumab 45 or 90 mg at week 0 and 4, or etanercept 50 g twice weekly for 12 weeks. At week 12 PASI 75 was achieved by 74% of the patients in the ustekinumab 90 mg group, by 68% of patients in the ustekinumab 45 mg group, and by 57% of those in the etanercept group. Patients who were unresponsive to etanercept were switched to ustekinumab, with almost a 50% response rate within the first 12 weeks. There were no significant safety differences between ustekinumab and etanercept in the ACCEPT trial. Both drugs were generally well tolerated. This head-to-head comparison clearly showed a significant superiority of ustekinumab over etanercept for the treatment of patients with moderate-to-severe psoriasis. However, this trial only evaluated 12 weeks of therapy, a short period to have an adequate comparison of the drugs, especially for their safety profiles.

#### **4.1.3 Safety**

In general, ustekinumab is well tolerated with only mild adverse events experienced in clinical trials. The most common adverse events have been equally observed between the treatment and placebo groups and included upper respiratory infections, headache, nasopharyngitis, arthralgia, back pain, and injection site reactions (Leonardi et al, 2008; Papp et al, 2008). Safety concerns exist for risks of infection and suppression of tumor immune surveillance. Individuals congenitally deficient in IL-12p40 or IL-12R1 are known to have an increased susceptibility to intracellular pathogens, including tuberculosis and salmonella (Döffinger et al, 2002). However, in the PHOENIX 1 and 2 studies only two serious infections occurred in the ustekinumab group treated with the 90 mg dose. No mycobacterial or salmonella infections were reported. The risk of malignancy did not appear to be significant. Cutaneous malignancies were reported in two patients in the PHOENIX 2 study, a squamous cell carcinoma in the placebo group and a basal cell carcinoma in the 90 mg treatment group. No malignancies were reported in the PHOENIX 1 trial. The rate of malignancies reported in ustekinumab-treated patients was comparable to the rate in the general population. Patients with psoriasis have an increased risk of cardiovascular events. In the phase II trial of ustekinumab two patients experienced myocardial infarction and one suffered a stroke (Krueger et al, 2007). However, subsequent larger phase III studies revealed no apparent increased risk of cardiovascular side effects. Further studies are needed to assess long-term ustekinumab safety in patients treated for extended periods.
