Interleukin 23 Inhibitors

Pharmacokinetics

Two phase I studies in psoriasis patients have been conducted using ascending single intravenous (IV) and SC dosing to evaluate pharmacokinetics, immunogenicity, safety, and tolerability of guselkumab, both of which showed linear pharmacokinetics. Mean half-life ranged from 12 to 19 days in healthy subjects and 15 to 17 days in patients with psoriasis. The median time to achieve maximum serum concentration after a single SC dose of 100 mg was 3.2 days, with a range of 2.0 to 7.0 days.

Combined analysis of phase II and III studies found a half-life of 18.1 days with steady-state concentrations reached within 12 weeks. In this analysis, contributing factors to pharmacokinetics were assessed, including body weight, age, gender, race, disease severity and duration, comorbidities, medications, smoking status, alcohol use, and positive immune response to guselkumab. Factors affecting apparent volume of distribution included body weight, and factors affecting apparent clearance included body weight, diabetes, and race (nonwhite vs white). The most significant effect was due to body weight, however given efficacy across different body weight subgroups with 100 mg every-8-week dosing, dose adjustment based on body weight is not warranted. Moreover, variations due to diabetes and race were also deemed to be clinically insignificant.

Efficacy

Q29.5 In a randomized, double-blind, placebo-controlled phase I trial, 10 out of 14 patients who received one dose of 10 mg, 30 mg, or 100 mg achieved Psoriasis Area Severity Index (PASI)-75 through 24 weeks. Moreover, improvements were observed in epidermal thickness and numbers of CD3 ⁺ or CD11c ⁺ cells at week 1, with statistically significant reductions in epidermal thickness and T-cell counts observed at week 12 for all guselkumab dose groups compared with baseline. Guselkumab was also shown to attenuate Th17 molecular biomarkers in psoriatic skin. Specifically, serum IL-17A levels in patients responding to guselkumab were found to be reduced. A phase II study further evaluated the role of guselkumab in patients with moderate-to-severe plaque psoriasis and found significantly higher proportions of patients on guselkumab achieved Physician Global Assessment (PGA) scores of 0 or 1 as well as greater improvements in quality of life scores compared to placebo and adalimumab, respectively, at week 16.

The long-term efficacy and safety of guselkumab have been evaluated thus far in three major phase III studies in which treatment was compared with placebo and adalimumab, respectively. VOYAGE 1 consisted of an active-comparator period during which guselkumab 100 mg was compared with adalimumab (week 0–48) and a placebo-controlled period (week 0–16), respectively, after which patients taking placebo crossed over to receive guselkumab through week 48. VOYAGE 2 comprised a placebo-controlled period (week 0–16), an active comparator-controlled period (week 0–28), and a randomized withdrawal and retreatment period (week 28–72). In both studies, significantly more patients in the guselkumab treatment groups achieved the primary endpoints of Investigator’s Global Assessment (IGA) 0/1 and PASI-90 than those receiving placebo or adalimumab at week 16. NAVIGATE involved an open-label period during which patients were treated with ustekinumab (week 0–16) followed by a randomized active-treatment period during which patients who did not achieve IGA 0/1 were randomized to either initiate guselkumab or remain on ustekinumab until week 44. The patients then underwent a follow-up period (week 44–60). In this study, the primary endpoint was the number of visits at which patients achieved IGA 0/1 with at least two grade improvement from week 16 from weeks 28 to 40.

In VOYAGE 1, 91.2% of patients receiving guselkumab achieved PASI-90 compared with 73.1% in the adalimumab group and 5.7% in the placebo group at the end of the placebo-controlled period at week 16. Moreover, the percentage of patients achieving IGA 0/1 at week 16 was significantly higher in the guselkumab group compared with placebo and adalimumab, respectively. Efficacy was noted as early as week 2 compared with placebo. Significantly higher rates of responses were maintained at weeks 24 and 48 when compared with adalimumab, as measured by IGA 0/1 and PASI-90 response. At weeks 24 and 48, 50.5% of patients on guselkumab reached complete clearance (IGA 0). Additionally, at the end of the active-comparator period, the greatest responses were seen in patients who were originally randomized to placebo and then randomized to guselkumab, with approximately 80% of patients maintaining PASI-90. Guselkumab was also effective in treating difficult-to-treat areas, including the scalp, hands, and feet. Patient-reported outcomes based on Psoriasis Symptoms and Signs Diary (PSSD) and Dermatology Life Quality Index (DLQI) questionnaires demonstrated guselkumab was superior to placebo at week 16 and adalimumab at weeks 24 and 48, respectively.

In VOYAGE 2, 84.1% of patients receiving guselkumab achieved IGA 0/1 compared with 8.1% of patients receiving placebo ( P < .001) at the end of the placebo-controlled period. In terms of PASI-90 scores, guselkumab demonstrated superior efficacy as early as week 2 with 70.0% of patients in the guselkumab group achieving PASI-90 by week 16 ( P < .001 when compared with placebo). Moreover, guselkumab was superior to adalimumab by proportion of patients achieving PASI-90 and IGA 0/1 at week 16. Responders rerandomized to the maintenance group maintained better responses than those rerandomized to the withdrawal group at the end of the study (week 48). The median time to loss of PASI-90 response was 15.2 weeks (or 23 weeks after last guselkumab dose) in the withdrawal group. In patients who were nonresponders to adalimumab at week 28 and thus initiated guselkumab, the proportion of patients achieving PASI-90 reached 66.1% after 20 weeks of treatment.

In NAVIGATE, patients receiving guselkumab during the active-treatment period achieved IGA scores of 0/1 or at a significantly higher number of visits compared with the ustekinumab group (1.5 vs. 0.7; P < .001). Moreover, patients in the guselkumab group also reached PASI-90 at significantly more visits, and the mean decrease in PASI score overall was also significantly greater than in the ustekinumab group. Response rates in patients receiving guselkumab increased after the first dose, with maximum response between 32 and 36 weeks. Differences between the guselkumab and ustekinumab groups occurred as early as week 2, or 4 weeks postrandomization. At the end of the observation period, a greater percentage of patients on guselkumab achieved both PASI-90 and PASI-100 compared with the randomized ustekinumab group.

In summary, the VOYAGE 1 and 2 and NAVIGATE trials all demonstrate the efficacy of guselkumab in patients with moderate-to-severe psoriasis, especially for patients who have failed to respond to other biologics, such as adalimumab and ustekinumab. Clinical responses were evident as early as week 2 and maintained over 1 year. It has been suggested that guselkumab may have a slower mechanism of action than the IL-17 inhibitors. However, a potential benefit of guselkumab is its dosing regimen of every 8 weeks, which may be more appealing to patients, and thus, may potentially enhance adherence. However, long-term efficacy remains to be seen.