binant fully human monoclonal immunoglobulin IgG2 antibody that binds with high affinity to human IL-17RA and blocks the biological activities of the pro-inflammatory cytokines IL-17A, IL-17F, IL-17A/F heterodimer and IL-25, resulting in inhibition of the inflammation and clinical symptoms associated with psoriasis. IL-17RA is a protein expressed on the cell surface and is a required component of receptor complexes utilized by multiple IL-17 family cytokines. IL-17 family cytokine concentrations have been reported to be increased in psoriasis. IL-17A, IL-17F and IL-17A/F heterodimer have pleiotropic activities including the induction of pro-inflammatory mediators such as IL-6, GROα, and G-CSF from epithelial cells, endothelial cells and fibroblasts that promote tissue inflammation. Blocking IL-17RA inhibits IL-17 cytokine-induced responses resulting in normalization of inflammation in the skin.
Pharmacodynamic effects
Elevated levels of IL-17A, IL-17C and IL-17F gene expression are found in psoriatic plaques. Elevated levels of expression of IL-12B and IL-23A, the genes for the two subunits of IL-23, an upstream activator of IL-17A and IL-17F expression, are also found in psoriatic plaques. Treatment with Kyntheum in psoriasis patients has been shown to decrease levels of IL-17A and markers of cell proliferation and epidermal thickness in lesional skin biopsies to non-lesional skin biopsy levels up to 12 weeks post-treatment.
Clinical efficacy and safety
The efficacy and safety of Kyntheum was assessed in 4373 adult plaque psoriasis patients across three multinational, randomised, double-blind, phase 3, placebo-controlled clinical trials (AMAGINE-1, AMAGINE-2, and AMAGINE-3). AMAGINE-2 and AMAGINE-3 were also active comparator (ustekinumab)-controlled. All three trials included a 12-week placebo-controlled induction phase, a double-blind duration of 52 weeks, and an open-label long-term extension.
Patients enrolled were candidates for systemic therapy, including phototherapy, biologic and non-biologic systemic therapies. Approximately 21% of patients had a history of psoriatic arthritis. Approximately 30% of patients had previously received a biological and 12% of patients were biological failures.
Patients were predominantly men (69%) and white (91%), with a mean age of 45 years (18 to 86 years), of these 6.1% were >65 years of age and 0.3% were >75 years of age. Across treatment groups, the baseline Psoriasis Area Severity Index (PASI) score ranged from 9.4 to 72 (median: 17.4) and baseline involved body surface area (BSA) ranged from 10 to 97 (median: 21). Baseline static Physician Global Assessment (sPGA) score ranged from “3 (moderate)” (58%) to “5 (very severe)” (5%).
AMAGINE-1 was conducted in 661 patients. The trial included a 12-week double-blind, placebo-controlled induction phase followed by a double-blind withdrawal and retreatment phase up to 52 weeks. Patients randomised to Kyntheum received 210 mg or 140 mg at Week 0 (day 1), Week 1, and Week 2 followed by same dose every 2 weeks. At Week 12, patients originally randomised to Kyntheum who achieved sPGA success (0 or 1) were re-randomised to receive either placebo or continued Kyntheum at their induction dose. Patients originally randomised to placebo and those who did not meet the criteria for re-randomisation received Kyntheum 210 mg every two weeks beginning at Week 12. Retreatment was available at or after Week 16 for patie |
