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Cerdelga（eliglustat）为戈谢病患者一个重要新治疗选择，Cerdelga是一种强效、高度特异性神经酰胺类似物抑制剂
近日，赛诺菲（Sanofi）口服戈谢病药物Cerdelga（eliglustat）近日获欧盟批准，用作特定1型戈谢病（Gaucher disease）成人患者的一线口服疗法。在美国，Cerdelga于2014年8月获得FDA批准。Cerdelga不适用于经基因检测（CYP2D6）证实对Cerdelga代谢更快或代谢速度不确定的少数患者。赛诺菲计划从2015年开始陆续将Cerdelga推向欧盟成员国市场。
目前，酶替代疗法（ERT）是戈谢病的标准治疗方案，患者需终身定期（每2周注射一次）接受静脉输注。业界预测，Cerdelga作为首个口服治疗药物，将完全颠覆当前依赖注射型药物的戈谢病市场格局，成为1型戈谢病群体的一个重要新治疗选择。
赛诺菲花了足足15年时间，终于研制成功首个口服戈谢病药物Cerdelga，该药的临床项目，是有史以来在戈谢病群体中开展的最大规模临床项目，涉及29个国家约400例患者。III期项目中，Cerdelga在2个试验中均成功稳定了病情：其中一项安慰剂对照研究在初治患者中开展，另一项研究则证明了Cerdelga对酶替代疗法Cerezyme的非劣效性
Cerdelga是一种强效、高度特异性神经酰胺类似物抑制剂，靶向葡萄糖神经酰胺合成酶（glucosylceramide synthase， GCS），能够降低葡萄糖神经酰胺的产生。Cerdelga适用于肝脏药物代谢酶细胞色素P450 2D6（CYP2D6）代谢基因型为弱代谢（poor metabolizers，PMs）、中等代谢（intermediate metabolizers，IMs）、快代谢（extensive metabolizers，EMs）的1型戈谢病成人患者的长期治疗，但不适用于超速代谢者（ultrarapid metabolizers，UMs）。
Cerdelga的获批，对戈谢病群体是一个大好消息，无论从科学和临床角度来看，该药作为一种一线口服药物，已被证明具有积极的风险/利益属性。酶替代疗法（ERT）能够降解沉积在细胞中的脂肪沉积物并会引起各种症状，而Cerdelga则能够直接抑制脂肪沉积物在细胞中的积累。
戈谢病（Gaucher Disease）是一种常染色体隐性遗传所造成的葡糖脑苷脂沉积症，主要是因编码葡萄糖脑苷酯酶(glucocerebrosidase) 的结构基因突变，导致该酶缺乏，致使巨噬细胞内的葡萄糖脑苷脂不能被进一步水解而堆积在溶酶体中，导致细胞失去原有的功能。这些病理性细胞在人体器官中的浸润会造成骨骼、骨髓、脾脏、肝脏和肺部的病变。目前，全球仅有1万名戈谢病患者，美国患者总数约为6000人。
New Drugs Online Report for eliglustat
Information
Generic Name: eliglustat
Trade Name: Cerdelga
Synonym: Genz 112638
Entry Type: New molecular entity
Development and Regulatory status
UK: Approved (Licensed)
EU: Approved (Licensed)
US: Approved (Licensed)
UK launch Plans: Available only to registered users
Actual UK launch date:
Comments
Jan 15: European Commission grants Marketing Authorization for Cerdelga® (Eliglustat) oral therapy for Gaucher Disease Type 1 [16].
23/01/2015 09:26:19
Nov 14: EU positive opinion for eliglustat for long-term treatment of adults with Gaucher disease type 1, who are CYP2D6 poor metabolisers, intermediate metabolisers or extensive metabolisers [15].
21/11/2014 12:09:34
Aug 14: Approved by the FDA for the long-term treatment of adult patients with the Type 1 form of Gaucher disease. Cerdelga is expected to be available to patients within a month [14].
20/08/2014 19:03:37
Dec 13: Filed in the US. The FDA grants Priority Review status [13].
12/12/2013 10:48:55
Nov 13: Filed in the EU [12].
03/12/2013 14:06:31
Jun 12: Licence applications for eliglustat have not yet been filed [8].
03/09/2012 15:48:09
Apr 10: EU filing anticipated H1 2012 (7)
12/04/2010 10:47:17
Two PIII studies started in 2009: ENCORE (Aug) and ENGAGE (Oct) [4].
16/02/2010 15:46:56
Two PIII studies planned to start 2H 2009 (3)
07/05/2009 19:08:14
PII trials
Trial or other data
Mar 15: RCT (n=160) published in The Lancet found oral eliglustat maintained haematological and organ volume stability in adults with Gaucher´s disease type 1 already controlled by IV enzyme replacement therapy (85% on EG and 94% imiglucerase met composite primary endpoint and met non-inferiority criteria) [19].
30/03/2015 22:23:16
Feb 15: Results from PIII ENGAGE trial evaluating Cerdelga® (Eliglustat) for treatment-naïve pts with Gaucher Disease Type 1 is published in JAMA [17,18].
18/02/2015 10:51:29
Feb 13: Top line results from the PIII Encore study presented at the 9th Annual Lysosomal Disease Network WORLD Symposium. In the multi-national, randomized, controlled, open-label study, 160 patients with Gaucher disease type 1 who had begun enzyme replacement therapy at least 3 years prior to randomization and who had reached therapeutic goals were randomized (2:1) to eliglustat or Cerezyme for 1 year. The primary efficacy endpoint of stability was a composite of pre-specified change criteria for each of the following parameters: spleen volume, haemoglobin levels, platelet counts and liver volume. To meet the endpoint, a patient had to remain stable in all 4 parameters. Eliglustat was non-inferior to Cerezyme, with the majority of patients in both groups remaining stable at 1 year (84% vs 94%). In an additional, pre-specified efficacy analysis of change in spleen volume from baseline, a mean change of -6% was observed in the eliglustat arm vs -3% in the Cerezyme arm. This analysis also met the criteria for non-inferiority. The majority of patients had normal BMD scores at study entry for total femur and lumbar spine. These scores were maintained over the 12-month study period. 2% of patients in each group discontinued treatment because of an adverse event [11].
21/02/2013 09:34:41
Jan 13: PIII results of the ENCORE study evaluating eliglustat vs. Cerezyme in patients with Gaucher disease are expected in Q1 2013 [10].
10/01/2013 08:15:57
Oct 12: Top line results reported from the PIII ENGAGE study in 40 treatment-naïve patients with Gaucher disease type 1. Patients treated with eliglustat tartrate had a statistically significant improvement in spleen size at 9 months, compared with placebo, the study’s primary endpoint. Spleen volumes decreased from baseline by a mean of 28% vs a mean increase of 2% in eliglustat and placebo treated patients, respectively (p<0.0001). All secondary endpoints were met, including improvements in Hb levels, platelet levels, and liver volumes. No serious AEs were reported in the primary analysis period and no clinically meaningful differences in the related AEs reported between the two groups [9].
02/10/2012 18:15:30
Feb 12: 4-year follow-up data from patients enrolled in the PII trial reported. The data indicate continued or stabilized improvements across all endpoints: from baseline, spleen and liver volumes decreased by a mean of 63% and 28% respectively, and haemoglobin and platelet levels increased by a mean of 2.3 g/dL and 95%, respectively.
All patients met at least 3 of the 4 haematologic and visceral therapeutic goals established for enzyme replacement therapy.
The data also indicate continued improvement in bone mineral density by DXA, with a mean T-score increase of 0.8 from baseline in the lumbar spine. The most common AEs events included viral infections (6patients), urinary tract and upper respiratory tract infections (4 patients each), and nasopharyngitis, sinusitis, arthralgia, pain in extremity, headache, increased blood pressure, abnormal nerve conduction study, abdominal pain, and diarrhoea (3 patients each). Ten drug-related adverse events, including one serious event, were reported in 8 patients [7].
09/02/2012 19:08:41
Feb 11: Three-year follow-up data from patients enrolled in the ongoing PII trial were presented at the Lysosomal Disease Network WORLD Symposium. Sustained or further improvements were observed across all endpoints. At 3-years, spleen volume and liver volume decreased from baseline by a mean of 61% and 29%, respectively; Hb increased by a mean of 2.6 g/dL and platelet count increased by a mean of 91%. All patients met at least 3 of the 4 therapeutic goals developed for haematologic and organ volume parameters. Eliglustat also had positive effects on indicators of bone disease. In the 18 patients at baseline with dark marrow in the femur visible by MRI, 5 improved by 1 year, 7 by 2 years and 10 by 3 years, with the other 8 patients remaining stable. In the 15 patients with results available at all time points, BMD in the lumbar spine showed clinically and statistically significant improvements after 1 year of treatment (T score=+0.4) which further improved after 2 years (+0.6) and were sustained after 3 years. The most common adverse events (AEs) reported in >2 patients included viral infections (6 patients), UTIs and upper RTIs (4 patients each), headache, increased bp, diarrhoea and abdominal pain (3 patients each). Eight drug-related AEs, including one serious event, were reported in 6 patients [8].
20/02/2011 16:31:50
Aug 10: The two-year follow-up results from a PII trial have been accepted for publication in the journal Blood: Improvement in hematological, visceral, and skeletal manifestations of Gaucher disease type 1 with oral eliglustat tartrate (Genz-112638) treatment: two-year results of a Phase 2 study. Blood First Edition Paper, prepublished online August 16, 2010;DOI 10.1182/blood-2010-06-293902
23/08/2010 21:50:34
Mar 10: A one-year PIII study (NCT01074944 - EDGE) will start this month. The study will evaluate the efficacy and safety of once daily vs twice daily dosing in 234 patients with Gaucher disease type 1 who have demonstrated clinical stability on twice daily dosing of eliglustat. The study is due to complete Dec 14 [6].
08/03/2010 14:34:59
Feb 10: Genzyme has begun enrollment in two global, multi-centre, PIII trials of eliglustat. The first trial, ENCORE (NCT00943111), is a randomized, open-label study for 186 adult patients with Gaucher disease type 1 designed to compare eliglustat vs Cerezyme. Adult patients who have previously received Cerezyme for ≥3 years and have reached their therapeutic goals may qualify for this trial. The second trial, ENGAGE (NCT00891202), is a randomized, double-blind, placebo-controlled study for 36 patients with Gaucher type 1 disease who have not been treated in the last 12 months. Over 30 centers in more than 20 countries are participating in these trials and both trials are expected to complete in Dec 2011. Genzyme is also initiating a trial comparing once-daily dosing of eliglustat with twice-daily dosing [4,5].
16/02/2010 16:07:57
Feb 10: Two-year follow-up data from patients enrolled in the PII trial show that continued improvements were observed across all endpoints, including bone disease. 22 of 26 study participants completed at least one year of treatment, and 20 patients completed two years. The study is continuing with 19 patients in their third year. Continued improvement was observed through 2 years in spleen volume (52% decrease vs baseline), liver volume (24% decrease), Hb levels (2.1g/dL increase), platelet count (81% increase), chitotriosidase levels (63% decrease at 18 months in the 17 patients with chitotriosidase). In addition BMD in the lumbar spine showed significant improvements (Z score = +0.60, T score = +0.56) in 16 patients with available data at baseline, 1 and 2 years. In the 18 patients with dark marrow visible on MRI at baseline, 6 improved by 1 year, an additional 2 improved by 2 years and 10 remained stable. Eliglustat was generally well tolerated. The most common Aes (>10%) included viral infections, UTIs, increased bp and abdominal pain [5].
16/02/2010 15:59:33
Current treatment for Gaucher´s disease is imiglucerase given i.v. (2)
19/03/2009 13:52:54
PII open label study results reported involving 26 patients. At 52 weeks 91% achieved the composite primary efficacy endpoint: a clinically meaningful response in at least two of three endpoints (improvements in spleen size, hemoglobin and platelet levels). (2)
19/03/2009 13:51:34
Data from the first five patients indicate that Genz 112638 may produce a rapid and meaningful impact on endpoints including reductions in spleen and liver volume and an increase in platelet counts and haemoglobin concentration.(1)
Evidence Based Evaluations
EPAR http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003724/WC500182389.pdf
NICE scope http://www.nice.org.uk/guidance/indevelopment/gid-gaucherdiseasetype1eliglustatid709/documents
NHSC/NIHR http://www.hsc.nihr.ac.uk/topics/eliglustat-for-gaucher-disease/
Other http://www.cadth.ca/media/pdf/htis/dec-2011/RC0312-000%20Gaucher%20Disease%20final.pdf
References
Available only to registered users
Category
BNF Category: Metabolic disorders (09.08)
Pharmacology: Glucosylceramide synthase inhibitors
Epidemiology: Gaucher disease is an inherited condition affecting fewer than 10,000 people worldwide [4]. It is a pan-ethnic disorder with an overall frequency of around 1 in 40,000 to 1 in 50,000 live births (all variants, including types 1, 2 and 3) (Lancet 2008;372:1263)
Indication: Gaucher's disease
Additional Details: type 1
Method(s) of Administration
Oral
Company Information
Name: Genzyme
US Name: Sanofi
Further Information
Anticipated commissioning route (England) NHSE
High cost drug list? Yes
In NICE timetable: Yes
When: Aug / 2015
Note: www.nice.org.uk/guidance/indevelopment/gid-gaucher
Implications Available only to registered users
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