Interleukin inhibitors. ATC code:
Pharmacology: Mechanism of action (MOA):
Secukinumab is a fully human IgG1 antibody that selectively binds to and neutralizes the proinflammatory cytokinc interleukin-17A (IL-17A). Secukinumab works by targeting IL-17A and inhibiting its interaction with the IL-17 receptor, which is expressed on various cell types including keratinocytes. As a result, secukinumab inhibits the release of proinflammatory cytokines, chemokines and mediators of tissue damage and reduces IL-17A-mediated contributions to autoimmune and inflammatory diseases. Clinically relevant levels of secukinumab reach the skin and reduce local inflammatory markers. As a direct consequence treatment with secukinumab reduces erythema, induration, and desquamation present in plaque psoriasis lesions.
IL-17A is a naturally occuring cytokine that is involved in normal inflammatory and immune responses. IL-17A plays a key role in the pathogenesis of plaque psoriasis. Increased numbers of IL-17A producing lymphocytes and innate immune cells and increased levels of IL-17A have been found in the blood and affected skin of patients with plaque psoriasis. IL-17A is highly up-regulated in lesional skin in contrast to non-lesional skin of plaque psoriasis patients.
IL-17A also promotes tissue inflammation, neutrophil infiltration, bone and tissue destruction, and tissue remodeling including angiogenesis and fibrosis.
Serum levels of total IL-17A (free and secukinumab-bound IL-17A) are increased due to reduced clearance of secukinumab-bound IL-17A within 2 to 7 days in patients receiving secukinumab, indicating that secukinumab selectively captures free IL-17A which plays a key role in the pathogenesis of plaque psoriasis.
In a study with secukinumab, infiltrating epidermal neutrophils and various neutrophil associated markers that are increased in lesional skin of plaque psoriasis patients were significantly reduced after one to two weeks of treatment.
Pharmacokinetics (PK): Absorption:
Following a single subcutaneous dose of either 150 mg or 300 mg in plaque psoriasis patients, secukinumab reached peak serum concentrations of 13.7 ± 4.8 μg/mL or 27.3 ± 9.5 μg/mL, respectively, between 5 and 6 days post dose.
After the initial weekly dosing during the first month, the time to reach the maximum concentration was between 31 and 34 days.
Peak concentrations at steady-state (Cmax,ss) following subcutaneous administration of 150 mg or 300 mg were 27.6 µg/mL and 55.2 μg/mL, respectively. Steady-state is reached after 20 weeks with monthly dosing regimens.
Compared with exposure after a single dose, patients exhibited a 2-fold increase in peak serum concentrations and AUC following repeated monthly dosing during maintenance.
Secukinumab is absorbed with an average absolute bioavailability of 73%.
The mean volume of distribution during the terminal phase (Vz) following a single intravenous administration ranged from 7.10 to 8.60 L in plaque psoriasis patients suggesting that secukinumab undergoes limited distribution to peripheral compartments.
Secukinumab concentrations in interstitial fluid in the skin of plaque psoriasis patients ranged from 28% to 39% of those in serum at 1 and 2 weeks after a single subcutaneous dose of 300 mg secukinumab.
Mean systemic clearance (CL) was 0.19 L/d in plaque psoriasis patients. Clearance was dose- and time-independent, as expected for a therapeutic IgG1 monoclonal antibody interacting with a soluble cytokine target, such as IL-17A.
The mean elimination half-life was estimated to be 27 days in plaque psoriasis patients. Estimated half-lives in individual plaque psoriasis patients range from 17 to 41 days.
The single and multiple dose pharmacokinetics of secukinumab in plaque psoriasis patients were determined in several studies with intravenous doses ranging from 1 x 0.3 mg/kg to 3 x 10 mg/kg and with subcutaneous doses ranging from 1 x 25 mg to multiple doses of 300 mg. Exposure was dose proportional across all dosing regimens.
Elderly patients: Of the 3,430 plaque psoriasis patients exposed to Fraizeron in clinical studies, a total of 230 were 65 years of age or older and 32 patients were 75 years of age or older.
Based on population PK analysis, clearance in elderly patients and patients less than 65 years of age was similar.
Patients with renal and hepatic impairment: No pharmacokinetic data are available in patients with hepatic or renal impairment.
Psoriasis: The safety and efficacy of Fraizeron were assessed in four randomized, double-blind, placebo-controlled phase 3 studies in patients with moderate to severe plaque psoriasis who were candidates for phototherapy or systemic therapy [ERASURE, FIXTURE, FEATURE, JUNCTURE]. The efficacy and safety of Fraizeron 150 mg and 300 mg were evaluated versus either placebo or etanercept. In addition, one study assessed a chronic treatment regimen versus a 'retreatment as needed' regimen [SCULPTURE].
Of the 2,403 patients who were included in the placebo-controlled studies, 79% were biologic-naive, 45% were non-biologic failures, 8% were biologic failures, 6% were anti-TNF failures, and 2% were anti-p40 failures. Baseline disease characteristics were generally consistent across all treatment groups with a median baseline Psoriasis Area Severity Index (PASI) score from 19 to 20, IGA mod 2011 baseline score ranged from "moderate" (62%) to "severe" (38%), median baseline Body Surface Area (BSA) ≥27 and median Dermatology Life Quality Index (DLQI) score from 10 to 12. Approximately 15 to 25% of patients in phase III studies had psoriatic arthritis (PsA) at baseline.
Psoriasis Study l (ERASURE) evaluated 738 patients. Patients randomized to Fraizeron received 150 mg or 300 mg doses at weeks 0, 1, 2, and 3, followed by the same dose every month starting at week 4. Patients randomized to receive placebo who were non-responders at week 12 were then crossed over to receive Fraizeron ( either 150 mg or 300 mg) at weeks 12, 13, 14, and 15, followed by the same dose every month starting at week 16. All patients were followed for up to 52 weeks following first administration of study treatment.
Psoriasis Study 2 (FIXTURE) evaluated 1,306 patients. Patients randomized to Fraizeron received 150 mg or 300 mg doses at weeks 0, 1, 2, and 3, followed by the same dose every month starting at week 4. Patients randomized to etanercept received 50 mg doses twice per week for 12 weeks followed by 50 mg every week. Patients randomized to receive placebo who were non-responders at week 12 then crossed over to receive Fraizeron (either 150 mg or 300 mg) at weeks 12, 13, 14, and 15, followed by the same dose every month starting at week 16. All patients were followed for up to 52 weeks following first administration of study treatment.
Psoriasis Study 3 (FEATURE) evaluated 177 patients using a pre-filled syringe compared with placebo after 12 weeks of treatment to assess the safety, tolerability, and usability of Fraizeron self-administration via the pre-filled syringe. Patients randomized to Fraizeron received 150 mg or 300 mg doses at weeks 0, 1, 2, and 3, followed by the same dose every month starting at week 4. Patients were also randomized to receive placebo at weeks 0, 1, 2, and 3, followed by the same dose every month starting at week 4.
Psoriasis Study 4 (JUNCTURE) evaluated 182 patients using a pre-filled pen compared with placebo after 12 weeks of treatment to assess the safety, tolerability, and usability of Fraizeron self-administration via the pre-filled pen. Patients randomized to Fraizeron received 150 mg or 300 mg doses at weeks 0, 1, 2, and 3, followed by the same dose every month starting at week 4. Patients were also randomized to receive placebo at weeks 0, 1, 2, and 3, followed by the same dose every month starting at week 4.
Psoriasis Study 5 (SCULPTURE) evaluated 966 patients. All patients received Fraizeron 150 mg or 300 mg doses at weeks 0, 1, 2, 3, 4, 8 and 12 and then were randomized to receive either a maintenance regimen of the same dose every month starting at Week 12 or a ''retreatment as needed" regimen of the same dose. Patients randomized to "retreatment as needed" did not achieve adequate maintenance of response and therefore a fixed monthly maintenance regimen is recommended.
The co-primary endpoints in the placebo and active controlled studies were the proportion of patients who achieved a PASI 75 response and IGA mod 2011 'clear' or 'almost clear' response versus placebo at Week 12 (see Table 1 and Table 2). The 300 mg dose provided improved skin clearance across efficacy endpoints of PASI 75/90/100, and IGA mod 2011 'clear' or 'almost clear' responses across all studies with peak effects seen at week 16, therefore this dose is recommended. (See Table 1 and Table 2.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
Fraizeron was efficacious in biologic-naive, biologic/anti-TNF-exposed and biologic/anti-TNF-failure patients.
Fraizeron was associated with a fast onset of efficacy as shown in the figure as follows with a 50% reduction in mean PASI by week 3 for 300 mg (see figure).
Click on icon to see table/diagram/image
All plaque psoriasis phase III studies included approximately 15 to 25% of patients with concurrent psoriatic arthritis at baseline. Improvements in PASI 75 in this patient population were similar to those in the overall plaque psoriasis population.
In the placebo controlled studies 1 and 2 in the subset of psoriatic arthritis patients, physical function was assessed using the HAQ Disability Index (HAQ-DI). In these studies, patients treated with 150 mg or 300 mg Fraizeron showed greater improvement from baseline in the HAQ-DI score (mean decreases of -27.5% and -50.2% at week 12) compared to placebo (-8.9%). This improvement was maintained up to week 52.
Quality of Life/Patient reported outcomes: Statistically significant improvements at week 12 (Studies 1-4) from baseline compared to placebo were demonstrated in the DLQI (Dermatology Life Quality Index), these improvements were maintained for 52 weeks (Studies 1 and 2).
Statistically significant improvements at week 12 from baseline compared to placebo (Studies 1 and 2) in patient reported signs and symptoms of itching, pain and scaling were demonstrated in the validated Psoriasis Symptom Diary.
Non-clinical safety data [NCO]:
Non-clinical data revealed no special hazard for humans based on tissue cross-reactivity testing, safety pharmacology, repeated dose and reproductive toxicity studies performed with secukinumab or a murine anti-murine IL-17A antibody.
Since secukinumab binds to cynomolgus monkey and human IL-17A, its safety was studied in the cynomolgus monkey. No undesirable effects of secukinumab were seen following subcutaneous administration to cynomolgus monkeys for up to 13 weeks and intravenous administration up to 26 weeks (including pharmacokinetic, pharmacodynamic, immunogenicity and immunotoxicity (e.g. T cell dependent antibody response and NK cell activity) evaluations). The average serum concentrations observed in monkeys after 13 weekly subcutaneous doses of 150 mg/kg are 48-fold higher than the predicted average serum concentration expected in psoriatic patients at the highest clinical dose. The exposure multiples are even higher when the average serum concentration from the 26 weeks intravenous toxicology study in cynomolgus monkeys are taken into consideration. Antibodies to secukinurnab were detected in only one out of 101 animals. No non-specific tissue cross-reactivity was demonstrated when secukinumab was applied to normal human tissues.
Animal studies have not been conducted to evaluate the carcinogenic potential of secukinumab.
In an embryofetal development study in cynomolgus monkeys, secukinumab showed no maternal toxicity, embryotoxicity or teratogenicity when administered throughout organogenesis and late gestation.
No undesirable effects of a murine anti-murine IL-17A antibody were seen in fertility and early embryonic development and pre- and postnatal development studies in mice. The high dose used in these studies was in excess of the maximally effective dose in terms of IL-17A suppression and activity (see Use in Pregnancy & Lactation).