**3.1.2 Clinical efficacy**

A series of clinical trials showed significant improvement in the PASI score in patients treated with alefacept. The first multicenter, randomized, controlled phase II trial was conducted in 229 patients who received alefacept 0.025, 0.075 and 0.150 mg/kg IV or placebo weekly for 12 weeks, with a 12-week follow-up (Ellis & Krueger, 2001). Patients achieved a reduction in PASI by 38%, 53% and 53%, respectively, compared with 21% reduction by placebo. A significant improvement in quality of life was also reported, and long-term follow-up showed a sustained response for a median of 10 months (Ellis & Krueger, 2001).

Two phase III clinical trials showed similar results (Krueger et al, 2002; Lebwohl et al, 2003). In these trials, patients with chronic plaque psoriasis received a once-weekly administration of alefacept IV or IM for 12 weeks, with a 12-week follow-up. In the first study (Krueger et al, 2002), a total of 553 patients was randomized to receive 7.5 mg of IV alefacept or placebo, while in the second trial (Lebwohl et al, 2003) 507 patients were treated with 10 or 15 mg of IM alefacept or placebo. Both trials showed a significant clinical improvement in psoriatic patients: a PASI 75 was achieved by 28% in IV-treated patients compared to 8% in placebotreated patients, and by 28% and 33% in 10 or 15 mg IM-treated patients, respectively, compared to 13% in the placebo group. Most responder patients maintained a 50% or greater reduction in PASI in the follow-up period. Other studies have been performed to investigate alefacept efficacy and safety in the long-term treatment of plaque psoriasis. Treatment of up to 5 courses provided incremental efficacy in responders, while maintaining the safety profile (Menter et al, 2006; Roberts et al, 2010). Although these studies are limited by the decreasing number of patients over multiple treatment courses or the lack of appropriate controls, but do they suggest that multiple courses of alefacept are well tolerated and maintain clinical improvement in responder patients.

Biotech on the Rise: The Treatment of Psoriasis with Biological Drugs 341

cell responses, including CD4+ T cell differentiation toward the Th1 phenotype, while IL-23 leads to Th17 differentiation, regulates T memory cells, and activates macrophages to maintain chronic autoimmune inflammation (Aggarwal et al, 2003; Trinchieri, 2003). Ustekinumab prevents the interaction of these cytokines with the IL-12Rβ1 receptor, neutralizing their immune-mediated responses. A single administration of anti-IL-12p40 demonstrated significant changes in psoriatic skin lesions after 2 weeks, including the reduction of a type 1 cytokine (IFN-) and chemokines (IL-8, IFN--inducible protein-10, and

Ustekinumab was approved by the FDA in September 2009 for the treatment of adult patients with moderate-to-severe plaque psoriasis who are candidates for phototherapy or systemic therapy (Centocor Ortho Biotech, 2009). Early-stage clinical trials have also

Ustekinumab is administered by subcutaneous injections at the recommended dose of 45 mg for patients who weigh ≤100 kg and 90 mg for those who weight ≥100 kg, at week 0 and then at week 4, followed by one injection every 12 weeks as maintenance treatment (Centocor Ortho Biotech, 2009). Clinical response to ustekinumab is associated with serum ustekinumab concentration and patient body weight. Two phase III clinical trials demonstrated that efficacy of the 45 and 90 mg doses of ustekinumab was similar in patients weighing ≤100 kg, while the 90 mg dose was more effective than the 45 mg dose in patients

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

MCP-1), and a decrease of TNF and infiltrating T cells (Toichi et al, 2006).

weighing >100 kg (Leonardi et al, 2008; Papp et al, 2008).

**4.1.1 Administration** 

**4.1.2 Clinical efficacy** 

demonstrated its therapeutic potential in psoriatic arthritis (Gottlieb et al, 2009).

Several studies evaluated the effect of alefacept in combination with other therapies, including topical agents, methotrexate, cyclosporine, acitretin, systemic retinoids, or phototherapy (Krueger et al, 2008). The results suggest that the combination of alefacept with other psoriasis therapies is efficacious and well tolerated but larger studies are needed to confirm these results and evaluate long-term effects.
