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单抗药物Cosentyx(secukinumab,曾用名AIN457) -2015年获批上市,成为首个IL-17阻断剂
Infections In the placebo-controlled period of the clinical trials in plaque psoriasis (a total of 1382 subjects treated with COSENTYX and 694 subjects treated with placebo up to 12 weeks), infections were reported in 28.7% of subjects treated with COSENTYX compared with 18.9% of subjects treated with placebo. Serious infections occurred in 0.14% of patients treated with COSENTYX and in 0.3% of patients treated with placebo [see Warnings and Precautions (5.1)]. Over the entire treatment period (a total of 3430 plaque psoriasis subjects treated with COSENTYX for up to 52 weeks for the majority of subjects), infections were reported in 47.5% of subjects treated with COSENTYX (0.9 per patient-year of follow-up). Serious infections were reported in 1.2% of subjects treated with COSENTYX (0.015 per patient-year of follow-up). Phase 3 data showed an increasing trend for some types of infection with increasing serum concentration of secukinumab. Candida infections, herpes viral infections, staphylococcal skin infections, and infections requiring treatment increased as serum concentration of secukinumab increased. Neutropenia was observed in clinical trials. Most cases of secukinumab-associated neutropenia were transient and reversible. No serious infections were associated with cases of neutropenia. Exacerbation of Crohn’s Disease Exacerbations of Crohn’s disease, in some cases serious, were observed in clinical trials in both COSENTYX and placebo treated patients. In the psoriasis program, with 3430 patients exposed to COSENTYX there were 3 cases of exacerbation of Crohn’s disease [see Warnings and Precautions (5.3)]. Hypersensitivity Reactions Anaphylaxis and cases of urticaria occurred in COSENTYX-treated patients in clinical trials [see Warnings and Precautions (5.4)]. 6.2 Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. The immunogenicity of COSENTYX was evaluated using an electrochemiluminescence-based bridging immunoassay. Less than 1% of subjects treated with COSENTYX developed antibodies to secukinumab in up to 52 weeks of treatment. However, this assay has limitations in detecting anti-secukinumab antibodies in the presence of secukinumab; therefore the incidence of antibody development might not have been reliably determined. Of the subjects who developed antidrug antibodies, approximately one-half had antibodies that were classified as neutralizing. Neutralizing antibodies were not associated with loss of efficacy. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to COSENTYX with the incidences of antibodies to other products may be misleading. 7 DRUG INTERACTIONS Drug interaction trials have not been conducted with COSENTYX. 7.1 Live Vaccines Patients treated with COSENTYX may not receive live vaccinations [see Warnings and Precautions (5.6)]. 7.2 Non-Live Vaccines Patients treated with COSENTYX may receive non-live vaccinations. Healthy individuals who received a single 150 mg dose of COSENTYX 2 weeks prior to vaccination with a non-U.S. approved group C meningococcal polysaccharide conjugate vaccine and a non-U.S. approved inactivated seasonal influenza vaccine had similar antibody responses compared to individuals who did not receive COSENTYX prior to vaccination. The clinical effectiveness of meningococcal and influenza vaccines has not been assessed in patients undergoing treatment with COSENTYX [see Warnings and Precautions (5.6)]. 7.3 CYP450 Substrates A role for IL-17A in the regulation of CYP450 enzymes has not been reported. The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-6, IL-10, TNFα, IFN) during chronic inflammation. Thus, COSENTYX, an antagonist of IL-17A, could normalize the formation of CYP450 enzymes. Upon initiation or discontinuation of COSENTYX in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for therapeutic effect (e.g., for warfarin) or drug concentration (e.g., for cyclosporine) and consider dosage modification of the CYP450 substrate. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B There are no adequate and well controlled trials of COSENTYX in pregnant women. Developmental toxicity studies conducted with monkeys found no evidence of harm to the fetus due to secukinumab. COSENTYX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. An embryofetal development study was performed in cynomolgus monkeys with secukinumab. No malformations or embryofetal toxicity were observed in fetuses from pregnant monkeys that were administered secukinumab weekly by the subcutaneous route during the period of organogenesis at doses up to 30 times the maximum recommended human dose (MRHD; on a mg/kg basis at a maternal dose of 150 mg/kg). A pre- and postnatal development toxicity study was performed in mice with a murine analog of secukinumab. No treatment related effects on functional, morphological or immunological development were observed in fetuses from pregnant mice that were administered the murine analog of secukinumab on gestation days 6, 11, and 17 and on postpartum days 4, 10, and 16 at doses up to 150 mg/kg/dose. 8.3 Nursing Mothers It is not known whether secukinumab is excreted in human milk or absorbed systemically after ingestion. Because many drugs are excreted in human milk, caution should be exercised when COSENTYX is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness of COSENTYX in pediatric patients have not been evaluated. 8.5 Geriatric Use Of the 3430 plaque psoriasis subjects exposed to COSENTYX in clinical trials, a total of 230 were 65 years or older, and 32 subjects were 75 years or older. Although no differences in safety or efficacy were observed between older and younger subjects, the number of subjects aged 65 years and older was not sufficient to determine whether they responded differently from younger subjects. 10 OVERDOSAGE Doses up to 30 mg/kg intravenously (i.e., approximately 2000 to 3000 mg) have been administered in clinical trials without dose-limiting toxicity. In the event of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment be instituted immediately. 11 DESCRIPTION Secukinumab is a recombinant human monoclonal IgG1/κ antibody that binds specifically to IL-17A. It is expressed in a recombinant Chinese Hamster Ovary (CHO) cell line. Secukinumab has a molecular mass of approximately 151 kDa; both heavy chains of secukinumab contain oligosaccharide chains. COSENTYX Injection COSENTYX injection is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution. COSENTYX is supplied in a single-use Sensoready pen with a 27 gauge fixed ½ inch needle, or a single-use prefilled syringe with a 27 gauge fixed ½ inch needle. The removable cap of the COSENTYX Sensoready pen or prefilled syringe contains natural rubber latex. Each COSENTYX Sensoready pen or prefilled syringe contains 150 mg of secukinumab formulated in: L-histidine/histidine hydrochloride monohydrate (3.103 mg), L-methionine (0.746 mg), polysorbate 80 (0.2 mg), trehalose dihydrate (75.67 mg), and Sterile Water for Injection, USP, at pH of 5.8. COSENTYX for Injection COSENTYX for injection is supplied as a sterile, preservative free, white to slightly yellow, lyophilized powder in single-use vials. Each COSENTYX vial contains 150 mg of secukinumab formulated in L-histidine/L-histidine hydrochloride monohydrate (4.656 mg), polysorbate 80 (0.6 mg), and sucrose (92.43 mg). Following reconstitution with 1 mL Sterile Water for Injection, USP, the resulting pH is approximately 5.8. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Secukinumab is a human IgG1 monoclonal antibody that selectively binds to the interleukin-17A (IL-17A) cytokine and inhibits its interaction with the IL-17 receptor. IL-17A is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Secukinumab inhibits the release of proinflammatory cytokines and chemokines. 12.2 Pharmacodynamics Elevated levels of IL-17A are found in psoriatic plaques. Treatment with COSENTYX may reduce epidermal neutrophils and IL-17A levels in psoriatic plaques. Serum levels of total IL-17A (free and secukinumab-bound IL-17A) measured at Week 4 and Week 12 were increased following secukinumab treatment. These pharmacodynamic activities are based on small exploratory studies. The relationship between these pharmacodynamic activities and the mechanism(s) by which secukinumab exerts its clinical effects is unknown. 12.3 Pharmacokinetics Absorption Following a single subcutaneous dose of either 150 mg (one-half the recommended dose) or 300 mg in plaque psoriasis patients, secukinumab reached peak mean (± SD) serum concentrations (Cmax) of 13.7 ± 4.8 mcg/mL and 27.3 ± 9.5 mcg/mL, respectively, by approximately 6 days post dose. Following multiple subcutaneous doses of secukinumab, the mean (± SD) serum trough concentrations of secukinumab ranged from 22.8 ± 10.2 mcg/mL (150 mg) to 45.4 ± 21.2 mcg/mL (300 mg) at Week 12. At the 300 mg dose at Week 4 and Week 12, the mean trough concentrations resulted from the Sensoready pen were 23% to 30% higher than those from the lyophilized powder and 23% to 26% higher than those from the prefilled syringe based on cross-study comparisons. Steady-state concentrations of secukinumab were achieved by Week 24 following the every 4 week dosing regimens. The mean (± SD) steady-state trough concentrations ranged from 16.7 ± 8.2 mcg/mL (150 mg) to 34.4 ± 16.6 mcg/mL (300 mg). In healthy subjects and subjects with plaque psoriasis, secukinumab bioavailability ranged from 55% to 77% following subcutaneous dose of 150 mg (one-half the recommended dose) or 300 mg. Distribution 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. Intravenous use is not recommended [see Dosage and Administration (2)]. Secukinumab concentrations in interstitial fluid in lesional and non-lesional skin of plaque psoriasis patients ranged from 27% to 40% of those in serum at 1 and 2 weeks after a single subcutaneous dose of secukinumab 300 mg. Elimination The metabolic pathway of secukinumab has not been characterized. As a human IgG1κ monoclonal antibody secukinumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. The mean systemic clearance (CL) ranged from 0.14 L/day to 0.22 L/day and the mean half-life ranged from 22 to 31 days in plaque psoriasis subjects following intravenous and subcutaneous administration across all psoriasis trials. Intravenous use is not recommended [see Dosage and Administration (2)]. Dose Linearity Secukinumab exhibited dose-proportional pharmacokinetics in subjects with psoriasis over a dose range from 25 mg (approximately 0.083 times the recommended dose) to 300 mg following subcutaneous administrations. Weight Secukinumab clearance and volume of distribution increase as body weight increases. Specific Populations Hepatic or Renal Impairment: No formal trial of the effect of hepatic or renal impairment on the pharmacokinetics of secukinumab was conducted. Age: Geriatric Population: Population pharmacokinetic analysis indicated that the clearance of secukinumab was not significantly influenced by age in adult subjects with plaque psoriasis. Subjects who are 65 years or older had apparent clearance of secukinumab similar to subjects less than 65 years old. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of COSENTYX. Some published literature suggests that IL-17A directly promotes cancer cell invasion in vitro, whereas other reports indicate IL-17A promotes T-cell mediated tumor rejection. Depletion of IL-17A with a neutralizing antibody inhibited tumor development in mice. The relevance of experimental findings in mouse models for malignancy risk in humans is unknown. No effects on fertility were observed in male and female mice that were administered a murine analog of secukinumab at subcutaneous doses up to 150 mg/kg once weekly prior to and during the mating period. 14 CLINICAL STUDIES Four multicenter, randomized, double-blind, placebo-controlled trials (Trials 1, 2, 3, and 4) enrolled 2403 subjects (691 randomized to COSENTYX 300 mg, 692 to COSENTYX 150 mg, 694 to placebo, and 323 to a biologic active control) 18 years of age and older with plaque psoriasis who had a minimum body surface area involvement of 10%, and Psoriasis Area and Severity Index (PASI) score greater than or equal to 12, and who were candidates for phototherapy or systemic therapy. •Trial 1 enrolled 738 subjects (245 randomized to COSENTYX 300 mg, 245 to COSENTYX 150 mg, and 248 to placebo). Subjects received subcutaneous treatment at Weeks 0, 1, 2, 3, and 4 followed by dosing every 4 weeks. Subjects randomized to COSENTYX received 300 mg or 150 mg doses at Weeks 0, 1, 2, 3, and 4 followed by the same dose every 4 weeks. Subjects randomized to receive placebo that were non-responders at Week 12 were then crossed over to receive COSENTYX (either 300 mg or 150 mg) at Weeks 12, 13, 14, 15, and 16 followed by the same dose every 4 weeks. All subjects were followed for up to 52 weeks following first administration of study treatment. •Trial 2 enrolled 1306 subjects (327 randomized to COSENTYX 300 mg, 327 to COSENTYX 150 mg, 326 to placebo and 323 to a biologic active control). COSENTYX and placebo data are described. Subjects received subcutaneous treatment at Weeks 0, 1, 2, 3, and 4 followed by dosing every 4 weeks. Subjects randomized to COSENTYX received 300 mg or 150 mg doses at Weeks 0, 1, 2, 3, and 4 followed by the same dose every 4 weeks. Subjects randomized to receive placebo that were non-responders at Week 12 then crossed over to receive COSENTYX (either 300 mg or 150 mg) at Weeks 12, 13, 14, 15, and 16 followed by the same dose every 4 weeks. All subjects were followed for up to 52 weeks following first administration of study treatment. •Trial 3 enrolled 177 subjects (59 randomized to COSENTYX 300 mg, 59 to COSENTYX 150 mg, and 59 to placebo) and assessed safety, tolerability, and usability of COSENTYX self-administration via prefilled syringe for 12 weeks. Subjects received subcutaneous treatment at Weeks 0, 1, 2, 3, and 4, followed by the same dose every 4 weeks for up to 12 weeks total. •Trial 4 enrolled 182 subjects (60 randomized to COSENTYX 300 mg, 61 to COSENTYX 150 mg, and 61 to placebo) and assessed safety, tolerability, and usability of COSENTYX self-administration via Sensoready pen for 12 weeks. Subjects received subcutaneous treatment at Weeks 0, 1, 2, 3, and 4, followed by the same dose every 4 weeks for up to 12 weeks total. Endpoints In all trials, the endpoints were the proportion of subjects who achieved a reduction in PASI score of at least 75% (PASI 75) from baseline to Week 12 and treatment success (clear or almost clear) on the Investigator’s Global Assessment modified 2011 (IGA). Other evaluated outcomes included the proportion of subjects who achieved a reduction in PASI score of at least 90% (PASI 90) from baseline at Week 12, maintenance of efficacy to Week 52, and improvements in itching, pain and scaling at Week 12 based on the Psoriasis Symptom Diary©. The PASI is a composite score that takes into consideration both the percentage of body surface area affected and the nature and severity of psoriatic changes within the affected regions (induration, erythema and scaling). The IGA is a 5-category scale including “0 = clear” “1 = almost clear”, “2 = mild”, “3 = moderate” or “4 = severe” indicating the physician’s overall assessment of the psoriasis severity focusing on induration, erythema and scaling. Treatment success of “clear” or “almost clear” consisted of no signs of psoriasis or normal to pink coloration of lesions, no thickening of the plaque and none to minimal focal scaling. Baseline Characteristics Across all treatment groups the baseline PASI score ranged from 11 to 72 with a median of 20 and the baseline IGA score ranged from “moderate” (62%) to “severe” (38%). Of the 2077 plaque psoriasis subjects who were included in the placebo-controlled trials, 79% were biologic-naïve (have never received a prior treatment with biologics) and 45% were non-biologic failures (failed to respond to a prior treatment with non-biologics therapies). Of the patients who received a prior treatment with biologics, over one-third were biologic failures. Approximately 15% to 25% of trial subjects had a history of psoriatic arthritis. Clinical Response The results of Trials 1 and 2 are presented in Table 2. Table 2 Clinical Outcomes at Week 12 in Adults with Plaque Psoriasis in Trials 1 and 2
Table 3 Clinical Outcomes at Week 12 in Adults with Plaque Psoriasis in Trials 3 and 4
PASI 90 response at Week 12 was achieved with COSENTYX 300 mg and 150 mg compared to placebo in 59% (145/245) and 39% (95/245) versus 1% (3/248) of subjects, respectively (Trial 1) and 54% (175/327) and 42% (137/327) versus 2% (5/326) of subjects, respectively (Trial 2). Similar results were seen in Trials 3 and 4. With continued treatment over 52 weeks, subjects in Trial 1 who were PASI 75 responders at Week 12 maintained their responses in 81% (161/200) of the subjects treated with COSENTYX 300 mg and in 72% (126/174) of subjects treated with COSENTYX 150 mg. Trial 1 subjects who were clear or almost clear on the IGA at Week 12 also maintained their responses in 74% (119/160) of subjects treated with COSENTYX 300 mg and in 59% (74/125) of subjects treated with COSENTYX 150 mg. Similarly in Trial 2, PASI 75 responders maintained their responses in 84% (210/249) of subjects treated with COSENTYX 300 mg and in 82% (180/219) of subjects treated with COSENTYX 150 mg. Trial 2 subjects who were clear or almost clear on the IGA also maintained their responses in 80% (161/202) of subjects treated with COSENTYX 300 mg and in 68% (113/167) of subjects treated with COSENTYX 150 mg. Among the subjects who chose to participate (39%) in assessments of patient reported outcomes, improvements in signs and symptoms related to itching, pain, and scaling, at Week 12 compared to placebo (Trials 1 and 2) were observed using the Psoriasis Symptom Diary©. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied COSENTYX Sensoready pen: •NDC 0078-0639-41: Carton of two 150 mg/mL (300 mg dose) Sensoready pens (injection) •NDC 0078-0639-68: Carton of one 150 mg/mL single-use Sensoready pen (injection) COSENTYX prefilled syringe: •NDC 0078-0639-98: Carton of two 150 mg/mL (300 mg dose) single-use prefilled syringes (injection) •NDC 0078-0639-97: Carton of one 150 mg/mL single-use prefilled syringe (injection) The removable cap of the COSENTYX Sensoready pen and prefilled syringe contains natural rubber latex. Each Sensoready pen and prefilled syringe is equipped with a needle safety guard. COSENTYX vial (for healthcare professional use only): •NDC 0078-0657-61: Carton of one 150 mg lyophilized powder in a single-use vial (for injection) 16.2 Storage and Handling COSENTYX Sensoready pens, prefilled syringes and vials must be refrigerated at 2ºC to 8ºC (36ºF to 46ºF). Keep the product in the original carton to protect from light until the time of use. Do not freeze. To avoid foaming do not shake. COSENTYX does not contain a preservative; discard any unused portion.
诺华的Cosentyx(TM)被欧盟批准用于中、重度银屑病一线治疗 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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COSENTYX(secukinumab)injection简介：
单抗药物Cosentyx(secukinumab,曾用名AIN457) -2015年获批上市,成为首个IL-17阻断剂2015年1月21日，美国食品和药品监管局(FDA)批准Cosentyx (secukinumab)治疗有中度至严重斑块性银屑病成年。银屑病是一 ... 责任编辑：admin |
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