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强生单抗药Sylvant获欧盟批准上市

2016-06-15 06:40:32 作者：新特药房来源：互联网浏览次数：0 文字大小：【大】【中】【小】

简介： 2014年6月9日，欧盟委员会（EC）已批准单抗药物Sylvant（siltuximab），用于HIV阴性和人类疱疹病毒-8（HHV-8）阴性的多中心型巨大淋巴结增生症（multicentric Castleman'sdisease，MCD）患者的治疗。Syl ...

关键字：注射用司妥昔单抗 siltuximab 商品名sylvant 多中心castleman氏病首个批准适应证药物重组人鼠嵌合il6结合

2014年6月9日，欧盟委员会（EC）已批准单抗药物Sylvant（siltuximab），用于HIV阴性和人类疱疹病毒-8（HHV-8）阴性的多中心型巨大淋巴结增生症（multicentric Castleman'sdisease，MCD）患者的治疗。Sylvant是欧盟批准的首个MCD治疗药物。
Sylvant是一种单克隆抗体，是IL-6拮抗剂，通过静脉输注给药，每3周一次，该药已于2014年4月获FDA批准用于相同适应症，也是FDA批准的首个MCD治疗药物。Sylvant通过靶向白介素6（IL-6）发挥作用，IL-6似乎是MCD的关键驱动因子。
Sylvant的疗效和安全性，已在一项关键性III期研究（MCD2001）中得到证实。该研究是首个在MCD患者中开展的随机III期研究，评价了siltuximab+最佳支持治疗（BSC）相对于安慰剂+BSC治疗MCD患者的疗效和安全性。研究数据表明，siltuximab+BSC治疗组有显着更多的患者取得了持续的肿瘤和对症响应（肿瘤体积减少和疾病症状减轻）（34%vs0%，p=0.0012）。
多中心型巨大淋巴结增生症（MCD）是一种罕见疾病，是由于某种类型的白细胞过度生产导致淋巴结肿大。该病可能导致各种症状，并削弱免疫系统，使之难以对抗感染。对MCD患者而言，感染会非常严重甚至可能致命。目前，在美国和欧洲，还没有药物获批用于治疗这种罕见血液疾病。
强生于2013年9月向FDA和欧洲药品管理局（EMA）提交了siltuximab治疗MCD的生物制品许可申请（BLA）和上市许可申请（MAA），此前，FDA和EMA均已授予siltuximab治疗MCD的孤儿药地位。
关于Sylvant（siltuximab）：
siltuximab是一种实验性、抗白介素6（IL-6）嵌合单克隆抗体，靶向并结合人IL-6。IL-6是由多种细胞产生的一种多功能细胞因子，如T细胞、B细胞、单核细胞、成纤维细胞和内皮细胞。MCD疾病的发病机制，牵涉受影响的淋巴结中活化B细胞内IL-6的失调或不平衡过量生产。
SYLVANT(SILTUXIMAB)INJECTABLE;INJECTION
Castleman Disease
Indicated for multicentric Castleman disease in patients who are negative for HIV and human herpesvirus-8
11 mg/kg IV q3weeks; infuse over 1 hr
Continue until treatment failure
Dosage Modifications
Renal impairment
CrCl ≥15 mL/min: No initial dosage adjustment required
End-stage renal disease: No information
Hepatic impairment
Mild-to-moderate (Child-Pugh A and B): No initial dosage adjustment required
Severe (Child-Pugh C): No information
Dosing Considerations
Do not administer with severe infection until resolved
Discontinue with severe infusion-related reactions, anaphylaxis, severe allergic reactions, or cytokine release syndromes; do not reinstitute treatment
Hematology lab tests
Perform hematology tests before each dose for first 12 months and every 3 dosing cycles thereafter
If following criteria not met, consider delaying treatment (do NOT reduce dose):
If following criteria not met, consider delaying treatment (do NOT reduce dose)
ANC: ≥1 x 10^9/L
Platelets: ≥75 x 10^9/L (before 1st dose); ≥50 x 10^9/L (retreatment criteria)
Hgb: <17 g/dL
Safety and efficacy not established
New Drugs Online Report for siltuximab
Information
Generic Name: siltuximab
Trade Name: Sylvant
Entry Type: New molecular entity
Development and Regulatory status
UK: Launched
EU: Launched
US: Approved (Licensed)
UK launch Plans: Available only to registered users
Actual UK launch date: August 2014
Comments
Aug 14: Launched in UK for treatment of multicentric Castleman´s disease in adults who are HIV-negative and human herpesvirus-8 negative. Price 100mg=£415.00; 400mg=£1661.00 [9].
22/05/2016 11:04:09
May 14: Approved in the EU [7].
09/06/2014 16:28:15
April 14: US FDA approved Sylvant (siltuximab) to treat patients with multicentric Castleman’s disease (MCD), a rare disorder similar to lymphoma (cancer of the lymph nodes). [6]
24/04/2014 09:39:42
Mar 14: EU positive opinion for siltuximab for treatment of of adults with multicentric Castleman’s disease (MCD) who are HIV negative and human herpesvirus-8 (HHV-8) negative [5].
21/03/2014 14:17:39
Siltuximab has orphan status for MCD in the EU & US [3].
04/09/2013 13:23:08
Sep 13: Filings are based on the MCD2001 study which assessed the drug plus best supportive care (53 MCD patients) vs. placebo plus BSC (26 patients). Results of the primary study analysis have been submitted for presentation at a medical meeting later this year [3].
04/09/2013 13:22:24
Sep 13: Janssen files siltuximab with the EMA & US FDA for treatment of pts with multicentric Castleman disease who are HIV-negative & human herpes virus-8 (HHV-8)-negative [3].
04/09/2013 13:20:58
Jul 13: EU & US filings planned for 2013 to 2017 [2].
02/09/2013 14:26:23
Trial or other data
Jul 14: Pivotal PII (NCT01024036) study published in The Lancet Oncology. 79pts were randomly assigned to siltuximab (n=53) or placebo (n=26). Durable tumour and symptomatic responses occurred in 18 (34%) of 53 patients in the siltuximab group and none of 26 in the placebo group (difference 34·0%, 95% CI 11·1—54·8, p=0·0012). The incidence of grade 3 or more adverse events (25 [47%] vs 14 [54%]) and serious adverse events (12 [23%] vs five [19%]) was similar in each group despite longer median treatment duration with siltuximab than with placebo (375 days [range 1—1031] vs 152 days [23—666]). The most common grade 3 or higher were fatigue (five vs one), night sweats (four vs one), and anaemia (one vs three). Three (6%) of 53 patients had serious adverse events judged reasonably related to siltuximab (lower respiratory tract infection, anaphylactic reaction, sepsis) [8].
20/07/2014 09:57:04
Dec 13: Results presented at ASH from the pivotal PII global registration study (MCD2001) which evaluated the siltuximab + best supportive care (BSC) vs placebo + BSC in 79 patients with MCD who are HIV-negative and HHV-8-negative. 34% vs 0% of patients in the siltuximab arm and placebo arms, respectively, had a durable tumour and symptomatic response to treatment. The median time to treatment failure was not reached in the siltuximab group vs 134 days for placebo. 25% vs 0% of patients had durable complete symptom resolution, defined as 100% reduction of baseline overall symptom scores for at least 18 weeks. The safety profile was similar between siltuximab and placebo even with the duration of treatment being twice as long for those in the siltuximab arm. The most frequently reported Grade 3 or higher AEs with siltuximab were fatigue (9%), night sweats (8%), hyperkalaemia, hyperuricaemia, localized oedema, hyperhidrosis, neutropenia, thrombocytopenia, hypertension and weight increase (4% each). Interim findings from a separate long-term safety PII study (MCD2002, n=19) were also reported. At the time of analysis (Jan13), patients had been treated with siltuximab for up to 7.2 years (median 5.1 years) with no cumulative toxicity observed. All patients were alive and maintaining disease control. Abstracts of these studies have been published in Blood (http://bloodjournal.hematologylibrary.org/content/122/21.toc) [4]
09/12/2013 08:52:09
NCT01400503 a PII open-label, multicentre study to evaluate the safety of long-term treatment with siltuximab in 75 subjects with multicentric Castleman´s Disease. Patients will be either siltuximab-naive or have not progressed on siltuximab in studies C0328T03 or CNTO328MCD2001, in the opinion of the investigator. Siltuximab 11 mg/kg is given by IV infusion over 1-hour every 3 weeks. The study started in Mar 11 and is due to complete Feb 16 (primary data available Mar 15) [1].
14/12/2012 12:56:51
Evidence Based Evaluations
EMA doc
EPAR http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003708/WC500169012.pdf
References
Available only to registered users