2014年11月25日,诺华单抗药物Cosentyx(secukinumab,曾用名AIN457)获欧盟批准生产,Cosentyx曾在系统治疗中作为主要手段用于治疗患有中到重度斑块状牛皮癣的成年患者。
Infections In the placebo-controlled period of clinical studies in plaque psoriasis (a total of 1,382 patients treated with Cosentyx and 694 patients treated with placebo for up to 12 weeks), infections were reported in 28.7% of patients treated with Cosentyx compared with 18.9% of patients treated with placebo. The majority of infections consisted of non-serious and mild to moderate upper respiratory tract infections, such as nasopharyngitis, which did not necessitate treatment discontinuation. There was an increase in mucosal or cutaneous candidiasis, consistent with the mechanism of action, but the cases were mild or moderate in severity, non-serious, responsive to standard treatment and did not necessitate treatment discontinuation. Serious infections occurred in 0.14% of patients treated with Cosentyx and in 0.3% of patients treated with placebo (see section 4.4). Over the entire treatment period (a total of 3,430 patients treated with Cosentyx for up to 52 weeks for the majority of patients), infections were reported in 47.5% of patients treated with Cosentyx (0.9 per patient-year of follow-up). Serious infections were reported in 1.2% of patients treated with Cosentyx (0.015 per patient-year of follow-up). Neutropenia Neutropenia was more frequently observed with secukinumab than with placebo, but most cases were mild, transient and reversible. Neutropenia <1.0-0.5x109/l (CTCAE Grade 3) was reported in 18 out of 3,430 (0.5%) patients on secukinumab, with no dose dependence and no temporal relationship to infections in 15 out of 18 cases. There were no reported cases of more severe neutropenia. Non-serious infections with usual response to standard care and not requiring discontinuation of Cosentyx were reported in the remaining 3 cases. Hypersensitivity reactions In clinical studies, urticaria and one case of anaphylactic reaction to Cosentyx were observed (see also section 4.4). Immunogenicity Less than 1% of patients treated with Cosentyx developed antibodies to secukinumab up to 52 weeks of treatment. About half of the treatment-emergent anti-drug antibodies were neutralising, but this was not associated with loss of efficacy or pharmacokinetic abnormalities. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard. 4.9 Overdose No cases of overdose have been reported in clinical studies. Doses up to 30 mg/kg (approximately 2000 to 3000 mg) have been administered intravenously in clinical studies without dose-limiting toxicity. In the event of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment be instituted immediately. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Immunosuppressants, interleukin inhibitors, ATC code: L04AC10 Mechanism of action Secukinumab is a fully human IgG1/κ monoclonal antibody that selectively binds to and neutralises the proinflammatory cytokine 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 occurring cytokine that is involved in normal inflammatory and immune responses. IL-17A plays a key role in the pathogenesis of plaque psoriasis and is up-regulated in lesional skin in contrast to non-lesional skin of plaque psoriasis patients. Pharmacodynamic effects Serum levels of total IL-17A (free and secukinumab-bound IL-17A) are initially increased in patients receiving secukinumab. This is followed by a slow decrease due to reduced clearance of secukinumab-bound IL-17A, 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. Clinical efficacy and safety The safety and efficacy of Cosentyx were assessed in four randomised, double-blind, placebo-controlled phase III 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 Cosentyx 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 and 8% were biologic failures (6% were anti-TNF failures, and 2% were anti-p40 failures). Approximately 15 to 25% of patients in phase III studies had psoriatic arthritis (PsA) at baseline. Psoriasis Study 1 (ERASURE) evaluated 738 patients. Patients randomised to Cosentyx 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. Psoriasis Study 2 (FIXTURE) evaluated 1,306 patients. Patients randomised to Cosentyx 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 randomised to etanercept received 50 mg doses twice per week for 12 weeks followed by 50 mg every week. In both Study 1 and Study 2, patients randomised to receive placebo who were non-responders at Week 12 then crossed over to receive Cosentyx (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 Cosentyx self-administration via the pre-filled syringe. 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 Cosentyx self-administration via the pre-filled pen. In both Study 3 and Study 4, patients randomised to Cosentyx 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 randomised 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 Cosentyx 150 mg or 300 mg doses at Weeks 0, 1, 2, 3, 4, 8 and 12 and then were randomised 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 randomised 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 Tables 2 and 3). The 300 mg dose provided improved skin clearance particularly for “clear” or “almost clear” skin across the efficacy endpoints of PASI 90, PASI 100, and IGA mod 2011 0 or 1 response across all studies with peak effects seen at Week 16, therefore this dose is recommended. Table 2 Summary of PASI 50/75/90/100 & IGA⃰ mod 2011 “clear” or “almost clear” clinical response in Psoriasis Studies 1, 3 and 4 (ERASURE, FEATURE and JUNCTURE)
** p values versus etanercept: p=0.0250 Cosentyx was efficacious in systemic treatment-naive, biologic-naive, biologic/anti-TNF-exposed and biologic/anti-TNF-failure patients. Improvements in PASI 75 in patients with concurrent psoriatic arthritis at baseline were similar to those in the overall plaque psoriasis population. Cosentyx was associated with a fast onset of efficacy with a 50% reduction in mean PASI by Week 3 for the 300 mg dose. Figure 1 Time course of percentage change from baseline of mean PASI score in Study 1 (ERASURE) 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). Mean decreases (improvements) in DLQI from baseline ranged from -10.4 to -11.6 with secukinumab 300 mg, from -7.7 to -10.1 with secukinumab 150 mg, versus -1.1 to -1.9 for placebo at Week 12. These improvements were maintained for 52 weeks (Studies 1 and 2). Forty percent of the participants in Studies 1 and 2 completed the Psoriasis Symptom Diary©. For the participants completing the diary in each of these studies, statistically significant improvements at Week 12 from baseline compared to placebo in patient-reported signs and symptoms of itching, pain and scaling were demonstrated. Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Cosentyx in plaque psoriasis in paediatric patients aged from birth to less than 6 years (see section 4.2 for information on paediatric use). The European Medicines Agency has deferred the obligation to submit the results of studies with Cosentyx in plaque psoriasis in paediatric patients aged from 6 years to less than 18 years (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Absorption Following a single subcutaneous dose of 300 mg as a liquid formulation in healthy volunteers, secukinumab reached peak serum concentrations of 43.2±10.4 µg/ml between 2 and 14 days post dose. Based on population pharmacokinetic analysis, 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 initial weekly dosing during the first month, time to reach the maximum concentration was between 31 and 34 days based on population pharmacokinetic analysis. On the basis of simulated data, 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. Population pharmacokinetic analysis suggests that steady-state is reached after 20 weeks with monthly dosing regimens. Compared with exposure after a single dose, the population pharmacokinetic analysis showed that patients exhibited a 2-fold increase in peak serum concentrations and area under the curve (AUC) following repeated monthly dosing during maintenance. Population pharmacokinetic analysis showed that secukinumab was absorbed with an average absolute bioavailability of 73% in patients with plaque psoriasis. Across studies, absolute bioavailabilities in the range between 60 and 77% were calculated. Distribution The mean volume of distribution during the terminal phase (Vz) following single intravenous administration ranged from 7.10 to 8.60 litres in plaque psoriasis patients, suggesting that secukinumab undergoes limited distribution to peripheral compartments. Biotransformation The majority of IgG elimination occurs via intracellular catabolism, following fluid-phase or receptor mediated endocytosis. Elimination Mean systemic clearance (CL) following a single intravenous administration to patients with plaque psoriasis ranged from 0.13 to 0.36 l/day. In a population pharmacokinetic analysis, the mean systemic clearance (CL) was 0.19 l/day in plaque psoriasis patients. The CL was not impacted by gender. Clearance was dose- and time-independent. The mean elimination half-life, as estimated from population pharmacokinetic analysis, was 27 days in plaque psoriasis patients, ranging from 18 to 46 days across psoriasis studies with intravenous administration. Linearity/non-linearity The single and multiple dose pharmacokinetics of secukinumab in plaque psoriasis patients were determined in several studies with intravenous doses ranging from 1x 0.3 mg/kg to 3x 10 mg/kg and with subcutaneous doses ranging from 1x 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 Cosentyx 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 pharmacokinetic analysis with a limited number of elderly patients (n=71 for age ≥65 years and n=7 for age ≥75 years), clearance in elderly patients and patients less than 65 years of age was similar. Patients with renal or hepatic impairment No pharmacokinetic data are available in patients with renal or hepatic impairment. The renal elimination of intact Cosentyx, an IgG monoclonal antibody, is expected to be low and of minor importance. IgGs are mainly eliminated via catabolism and hepatic impairment is not expected to influence clearance of Cosentyx. 5.3 Preclinical safety data Non-clinical data revealed no special risks 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 were considerably higher than the predicted average serum concentration expected in psoriatic patients at the highest clinical dose. Antibodies to secukinumab were detected in only one of the exposed animals. No non-specific tissue cross-reactivity was observed when secukinumab was applied to normal human tissue. Animal studies have not been conducted to evaluate the carcinogenic potential of secukinumab. In an embryofoetal 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 maximum effective dose in terms of IL-17A suppression and activity (see section 4.6). 6. Pharmaceutical particulars 6.1 List of excipients Trehalose dihydrate L-histidine L-histidine hydrochloride monohydrate L-methionine Polysorbate 80 Water for injections 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life 18 months 6.4 Special precautions for storage Store in a refrigerator (2°C - 8°C). Do not freeze. Store the syringes in the original package in order to protect from light. Store the pens in the original package in order to protect from light. 6.5 Nature and contents of container Cosentyx 150 mg solution for injection in pre-filled syringe Cosentyx is supplied in a pre-filled 1 ml glass syringe with a FluroTec-coated plunger stopper, staked 27G x ½″ needle and rigid needle shield of styrene butadiene rubber assembled in a passive safety device of polycarbonate. Cosentyx is available in packs containing 1 or 2 pre-filled syringes. Cosentyx 150 mg solution for injection in pre-filled pen Cosentyx is supplied in a single-use pre-filled syringe assembled into a triangular-shaped pen with transparent window and label (SensoReady pen). The pre-filled syringe inside the pen is a 1 ml glass syringe with a FluroTec-coated plunger stopper, staked 27G x ½″ needle and rigid needle shield of styrene butadiene rubber. Cosentyx is available in packs containing 1 or 2 pre-filled pens. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling Cosentyx 150 mg solution for injection is supplied in a single-use pre-filled syringe or pen for individual use. Do not shake or freeze the syringe or pen. The syringe or pen should be taken out of the refrigerator 20 minutes before injecting to allow it to reach room temperature. Prior to use, a visual inspection of the pre-filled syringe or pen is recommended. The liquid should be clear. Its colour may vary from colourless to slightly yellow. You may see a small air bubble, which is normal. Do not use if the liquid contains easily visible particles, is cloudy or is distinctly brown. Detailed instructions for use are provided in the package leaflet. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Novartis Europharm Limited Frimley Business Park Camberley GU16 7SR United Kingdom 8. Marketing authorisation number(s) Cosentyx 150 mg solution for injection in pre-filled syringe EU/1/14/980/002 EU/1/14/980/003 Cosentyx 150 mg solution for injection in pre-filled pen EU/1/14/980/004 EU/1/14/980/005 9. Date of first authorisation/renewal of the authorisation 15.01.2015 10. Date of revision of the text Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. 欧盟和美国先后批准银屑病治疗首个一线生物药Cosentyx(secukinumab,曾用名AIN457) 首个一线生物药Cosentyx(secukinumab) 1月19日,诺华公司的Cosentyx(secukinumab)赢得欧洲批准,成为用作中度至重度斑块样银屑病成人患者一线治疗的首个IL-17(白介素-17)抑制剂。 根据这家瑞士制药巨头称:此类患者此类患者从此有了一种新的一线生物治疗药作为选择。目前市场上用于这种疾病的其它生物制剂都作为二线药物。 “近一半的银屑病患者不满意目前的治疗,包括生物治疗,”诺华制药部门负责人David Epstein称Cosentyx作为一线全身用药可为患者提供“达到(银屑病斑块)清除或几乎清除的更佳机会”。 该药物的临床试验显示在12周治疗后达到很高的皮肤清洁至几乎清洁的比例,优于安进公司的Enbrel(Etanercept for Injection,注射用依那西普/恩利)和强生公司的Stelara(ustekinumab,优特克单抗)。 Cosentyx在美国的审批结果预计将于今年年初出炉,但种种迹象表明前景乐观:去年10月,FDA的皮肤科和眼科药物咨询委员会已一致建议批准。 不出所料,就在获得欧盟批准之后2天,美国FDA于1月21日也对Cosentyx做出了批准决定。 |