Guselkumab is a human IgG1λ monoclonal antibody (mAb) that binds selectively to the interleukin 23 (IL-23) protein with high specificity and affinity through the antigen binding site. IL-23 is a cytokine that is involved in inflammatory and immune responses. By blocking IL-23 from binding to its receptor, guselkumab inhibits IL-23-dependent cell signalling and release of proinflammatory cytokines.
Levels of IL-23 are elevated in the skin of patients with plaque psoriasis. In patients with ulcerative colitis or Crohn's disease, levels of IL-23 are elevated in the colon tissue. In in vitro models, guselkumab was shown to inhibit the bioactivity of IL-23 by blocking its interaction with cell surface IL-23 receptor, disrupting IL-23-mediated signalling, activation and cytokine cascades. Guselkumab exerts clinical effects in plaque psoriasis, psoriatic arthritis, ulcerative colitis, and Crohn's disease through blockade of the IL-23 cytokine pathway.
Myeloid cells expressing Fc-gamma receptor 1 (CD64) have been shown to be a predominant source of IL-23 in inflamed tissue in psoriasis, ulcerative colitis, and Crohn's disease. Guselkumab has demonstrated in vitro blocking of IL-23 and binding to CD64. These results indicate that guselkumab is able to neutralise IL-23 at the cellular source of inflammation.
In a Phase I study, treatment with guselkumab resulted in reduced expression of IL-23/Th17 pathway genes and psoriasis-associated gene expression profiles, as shown by analyses of mRNA obtained from lesional skin biopsies of patients with plaque psoriasis at Week 12 compared to baseline. In the same Phase I study, treatment with guselkumab resulted in improvement of histological measures of psoriasis at Week 12, including reductions in epidermal thickness and T-cell density. In addition, reduced serum IL-17A, IL-17F and IL-22 levels compared to placebo were observed in guselkumab treated patients in Phase II and Phase III plaque psoriasis studies. These results are consistent with the clinical benefit observed with guselkumab treatment in plaque psoriasis.
In psoriatic arthritis patients in Phase III studies, serum levels of acute phase proteins C-reactive protein, serum amyloid A, and IL-6, and Th17 effector cytokines IL-17A, IL-17F and IL-22 were elevated at baseline. Guselkumab decreased the levels of these proteins within 4 weeks of initiation of treatment. Guselkumab further reduced the levels of these proteins by Week 24 compared to baseline and also to placebo.
In patients with ulcerative colitis or Crohn's disease, guselkumab treatment led to decreases in inflammatory markers including C-reactive protein (CRP) and faecal calprotectin through induction Week 12, which were sustained through one year of maintenance treatment. Serum protein levels of IL-17A, IL-22 and IFNγ were reduced as early as Week 4, and continued to decrease through induction Week 12. Guselkumab also reduced colon mucosal biopsy RNA levels of IL-17A, IL-22 and IFNγ at Week 12.
Following a single 100 mg subcutaneous injection in healthy subjects, guselkumab reached a mean (± SD) maximum serum concentration (Cmax) of 8.09 ± 3.68 mcg/mL by approximately 5.5 days post dose. The absolute bioavailability of guselkumab following a single 100 mg subcutaneous injection was estimated to be approximately 49% in healthy subjects.
In patients with plaque psoriasis, following subcutaneous administrations of guselkumab 100 mg at Weeks 0 and 4, and every 8 weeks thereafter, steady-state serum guselkumab concentrations were achieved by Week 20. The mean (± SD) steady-state trough serum guselkumab concentrations in two Phase III studies in patients with plaque psoriasis were 1.15 ± 0.73 mcg/mL and 1.23 ± 0.84 mcg/mL. The pharmacokinetics of guselkumab in patients with psoriatic arthritis was similar to that in patients with psoriasis. Following subcutaneous administration of guselkumab 100 mg at Weeks 0, 4, and every 8 weeks thereafter, mean steady-state trough serum guselkumab concentration was also approximately 1.2 mcg/mL. Following subcutaneous administration of guselkumab 100 mg every 4 weeks, mean steady-state trough serum guselkumab concentration was approximately 3.8 mcg/mL.
The pharmacokinetics of guselkumab were similar in patients with ulcerative colitis and Crohn's disease. Following the recommended intravenous induction dose regimen of guselkumab 200 mg at Weeks 0, 4, and 8, mean peak serum guselkumab concentration at Week 8 was 68.27 mcg/mL in patients with ulcerative colitis, and 70.5 mcg/mL in patients with Crohn's disease.
Following the recommended subcutaneous induction dose regimen of guselkumab 400 mg at Weeks 0, 4, and 8, mean peak serum concentration was estimated to be 27.7 mcg/mL in patients with Crohn's disease. The total systemic exposure (AUC) after the recommended induction dose regimen was similar following subcutaneous and intravenous induction.
Following subcutaneous maintenance dosing of guselkumab 100 mg every 8 weeks or guselkumab 200 mg every 4 weeks in patients with ulcerative colitis, mean steady-state trough serum guselkumab concentrations were approximately 1.4 mcg/mL and 10.7 mcg/mL, respectively.
Following subcutaneous maintenance dosing of guselkumab 100 mg every 8 weeks or guselkumab 200 mg every 4 weeks in patients with Crohn's disease, mean steady-state trough serum guselkumab concentrations were approximately 1.2 mcg/mL and 10.1 mcg/mL, respectively.
Mean volume of distribution during the terminal phase (Vz) following a single intravenous administration to healthy subjects ranged from approximately 7 to 10 L across studies.
The exact pathway through which guselkumab is metabolised has not been characterised. As a human IgG mAb, guselkumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.
Mean systemic clearance (CL) following a single intravenous administration to healthy subjects ranged from 0.288 to 0.479 L/day across studies. Mean half-life (T1/2) of guselkumab was approximately 17 days in healthy subjects and approximately 15 to 18 days in patients with plaque psoriasis across studies, and approximately 17 days in patients with ulcerative colitis or Crohn's disease.
Population pharmacokinetic analyses indicated that concomitant use of NSAIDs, AZA, 6-MP, oral corticosteroids and csDMARDs such as MTX, did not affect the clearance of guselkumab.
The systemic exposure of guselkumab (Cmax and AUC) increased in an approximately dose-proportional manner following a single subcutaneous injection at doses ranging from 10 mg to 300 mg in healthy subjects or patients with plaque psoriasis. Serum guselkumab concentrations were approximately dose proportional following intravenous administration in patients with ulcerative colitis or Crohn's disease.
The pharmacokinetics of guselkumab in paediatric patients have not been established.
No specific studies have been conducted in elderly patients. Of the 1 384 plaque psoriasis patients exposed to guselkumab in Phase III clinical studies and included in the population pharmacokinetic analysis, 70 patients were 65 years of age or older, including 4 patients who were 75 years of age or older. Of the 746 psoriatic arthritis patients exposed to guselkumab in Phase III clinical studies, a total of 38 patients were 65 years of age or older, and no patients were 75 years of age or older. Of the 859 ulcerative colitis patients exposed to guselkumab in Phase II/III clinical studies and included in the population pharmacokinetic analysis, a total of 52 patients were 65 years of age or older, and 9 patients were 75 years of age or older. Of the 1 009 Crohn's disease patients exposed to guselkumab in Phase III clinical studies and included in the population pharmacokinetic analysis, a total of 39 patients were 65 years of age or older, and 5 patients were 75 years of age or older.
Population pharmacokinetic analyses in plaque psoriasis, psoriatic arthritis, ulcerative colitis, and Crohn's disease patients indicated no apparent changes in CL/F estimate in patients ≥65 years of age compared to patients <65 years of age, suggesting no dose adjustment is needed for elderly patients.
No specific study has been conducted to determine the effect of renal or hepatic impairment on the pharmacokinetics of guselkumab. Renal elimination of intact guselkumab, an IgG mAb, is expected to be low and of minor importance; similarly, hepatic impairment is not expected to influence clearance of guselkumab as IgG mAbs are mainly eliminated via intracellular catabolism. Based on population pharmacokinetic analyses, creatinine clearance or hepatic function did not have a meaningful impact on guselkumab clearance.
Clearance and volume of distribution of guselkumab increases as body weight increases, however, observed clinical trial data indicate that dose adjustment for body weight is not warranted.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeat-dose toxicity, toxicity to reproduction and pre- and post-natal development.
In repeat-dose toxicity studies in cynomolgus monkeys, guselkumab was well tolerated via intravenous and subcutaneous routes of administration. A weekly subcutaneous dose of 50 mg/kg to monkeys resulted in exposure (AUC) values that were at least 23 times the maximum clinical exposures following a dose of 200 mg given intravenously. Additionally, there were no adverse immunotoxicity or cardiovascular safety pharmacology effects noted during the conduct of the repeat-dose toxicity studies or in a targeted cardiovascular safety pharmacology study in cynomolgus 38 monkeys.
There were no preneoplastic changes observed in histopathology evaluations of animals treated up to 24 weeks, or following the 12-week recovery period during which active substance was detectable in the serum.
No mutagenicity or carcinogenicity studies were conducted with guselkumab.
Guselkumab could not be detected in breast milk from cynomolgus monkeys as measured at post-natal day 28.
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