Although fixed-dose biologics offer convenient dosing, efficacy may be affected by weight because serum drug concentrations are inversely associated with weight. Heavier patients who use fixed-dose biologics generally have lower drug concentrations leading to reduced response rates.
The objectives of this study were to evaluate the impact of weight on ustekinumab (UST) efficacy and to determine whether weight should be considered in dose selection.
PHOENIX 1 and PHOENIX 2 were Phase 3 clinical trials that evaluated the efficacy and safety of UST in patients with moderate-to-severe plaque psoriasis (>=10% of total body surface area and Psoriasis Area Surface Index [PASI] score >=12) who were candidates for phototherapy or systemic therapy. Patients were randomized to receive subcutaneously UST 45 or 90 mg at Weeks 0 and 4 and then every 12 weeks or placebo with crossover to UST at Week 12. To examine the impact of weight on clinical response, prespecified analyses of efficacy were conducted by weight categories in 10-kg increments (e.g., 51-60 kg, 61-70 kg, etc.) after steady-state drug levels were achieved (Week 28).
Across both studies, 664 patients were randomized to the UST 45 mg group and 667 patients to the UST 90 mg group. Mean baseline body weights were 93.9 and 91.0 kg in PHOENIX 1 and 2, respectively. On the basis of the analysis by weight categories in 10-kg increments, a clear difference was evident in both studies at 100 kg, such that for the subpopulation of patients over 100 kg, PASI 75 response was approximately 20% higher in the 90 mg than in the 45 mg group (PASI 75 response rates were 74.2% [155/209] and 54.6% [107/196] for the 90 and 45 mg groups, respectively). In patients <=100 kg, response rates were similar between the groups (PASI 75 response rates were 80.8% [350/433] and 76.9% [347/451] for the 90 and 45 mg groups, respectively). These efficacy findings were paralleled by median serum UST concentrations. The median UST serum concentrations in patients weighing >100 kg who received a 90-mg dose were similar to those in patients weighing <=100 kg who received a 45-mg dose. Patient weight did not affect the safety of UST (54.7% and 54.5% of patients had greater than or equal to one adverse event in the <=100 and >100 kg weight subgroups, respectively).
Two doses of UST (45 mg for patients weighing <=100 kg and 90 mg for those weighing >100 kg) provide comparable efficacy and pharmacokinetic exposure in both heavier and lighter weight patients. This dosing approach optimizes efficacy and dosing convenience while minimizing serum drug exposure.