Vintafolide 属于长春花类生物碱类似物，由叶酸和细胞毒药物去乙酰基长春碱单酰肼(DAVLBH)组成。叶酸成分使DAVLBH优先作用于表达叶酸受体的肿瘤细胞，通过抑制微管组装和细胞分裂而起作用。

        Vintafolide与多柔比星脂质体(PLD)联合应用较单用PLD可改善铂类抵抗卵巢癌患者的PFS。常见的副作用为乏力、口炎、中性粒细胞减少、贫血、恶心、手足综合征、便秘、皮疹和外周感觉神经炎。Vintafolide获批的适应证为“与PLD联合用于治疗所有靶病变表达叶酸受体的铂类耐药成年卵巢癌患者。

        同一天，人用医药产品委员会(CHMP)还建议批准医用产品Folcepri(etarfolatide，一种靶向叶酸的分子显像剂)和Neocepri(叶酸)上市，作为伴随诊断检测产品，应用单光子发射体层摄影(SPECT)、CT 或磁共振成像(MRI)成像，了解叶酸受体状态，以选择适合应用vintafolide的患者。

        Folcepri 和Neocepri 在2012 年9 月10日被授予孤儿医用产品称号，Folcepri活性成分etarfolatide由叶酸和99Tc螯合肽组成，与很多肿瘤包括卵巢癌表面表达的叶酸受体结合。以99Tc放射标记后，用于SPECT成像，以检测表达叶酸受体的肿瘤细胞。Folcepri的副作用为瘙痒，并不常见。Neocepri 活性成份为叶酸，在99Tc-etarfolatide SPECT成像前注射，可以减少多数正常非靶组织如小肠、肝、肾、脾的非特异背景，提高成像质量。

On 20 March 2014, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a conditional marketing authorisation for the medicinal product Vynfinit, intended for the treatment of adult patients with platinum-resistant ovarian cancer who express the folate receptor on all target lesions. Folate receptor status should be assessed by a diagnostic medicinal product approved for the selection of adult patients for treatment with vintafolide, such as Folcepri (see Summary of Opinion on Folcepri).

Vynfinit was designated an orphan medicinal product on 9 February 2012. The applicant for this medicinal product is Endocyte Europe, B.V.

Vynfinit is to be available as a 2.5 mg powder for solution for injection. The active substance of Vynfinit is vintafolide, which belongs to the therapeutic group ‘vinca alkaloid and analogues’ (L01CA06). Vintafolide consists of folic acid and the cytotoxic agent desacetylvinblastine hydrazide (DAVLBH). The folic acid component enables DAVLBH to be delivered preferentially to cancer cells expressing folate receptors. Once delivered inside cancer cells, DAVLBH is released from vintafolide and acts by inhibiting microtubule assembly and arresting cells in mitosis.

The benefits with Vynfinit are its ability, in combination with pegylated liposomal doxorubicin (PLD), to improve progression-free survival in patients with platinum-resistant ovarian cancer when compared with treatment with PLD alone. The most common side effects are fatigue, stomatitis, neutropenia, anaemia, nausea, palmar-plantar erythrodysaesthesia, constipation, rash and peripheral sensory neuropathy.

A pharmacovigilance plan for Vynfinit will be implemented as part of the marketing authorisation.

The text for the approved indication is as follows: "Vynfinit in combination with pegylated liposomal doxorubicin (PLD) is indicated for the treatment of adult patients with platinum resistant ovarian cancer (PROC) who express the folate receptor (FR) on all target lesions. Folate receptor status should be assessed by a diagnostic medicinal product approved for the selection of adult patients for treatment with vintafolide, using single photon emission computed tomography (SPECT) imaging, in combination with Computed Tomography (CT) or Magnetic Resonance Imaging (MRI)". Vynfinit is to be prescribed by physicians experienced in chemotherapy treatment.

Detailed recommendations for the use of this product will be described in the summary of product characteristics (SmPC), which will be published in the European public assessment report (EPAR) and made available in all official European Union languages after the marketing authorisation has been granted by the European Commission.     

详细的说明在   http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/002571/WC500163558.pdf

New Drugs Online Report for vintafolide
Information
Generic Name: vintafolide  
Trade Name: Vynfinit 
Synonym: EC145 
Entry Type: New molecular entity  
 
Developmental Status
UK: Filing withdrawn 
EU: Filing withdrawn 
US: Suspended 
UK launch Plans: Available only to registered users
Actual UK launch date:  
Comments
May 14: MSD announced the withdrawal of conditional marketing authorization applications from the EMA for vintafolide and companion imaging components, imaging agent etarfolatide and intravenous (IV) folic acid. [12]
21/05/2014 11:23:51 
May 14: The Data Safety Monitoring Board of the PIII PROCEED trial has recommended that the trial be stopped because vintafolide did not demonstrate efficacy on the pre-specified outcome of Progression-Free Survival (PFS) in an interim futility. Enrolment has been suspended [11]. 
02/05/2014 21:25:27 
Mar 14: EU positive opinion for vintafolide for use in combination with pegylated liposomal doxorubicin (PLD) to treat adults with platinum resistant ovarian cancer (PROC) who express the folate receptor (FR) on all target lesions. EU positive opinions also for etarfolatide (Folcepri) and folic acid (Neocepri) - etarfolatide is used, after intravenously administered folic acid, in single photon emission computed tomography (SPECT) imaging to select adult patients with ovarian cancer suitable for treatment with vintafolide [10].
21/03/2014 14:15:53 
Jan 14: Re the pending EU conditional marketing authorization applications for vintafolide and etarfolatide, the company state that provided that they can answer questions posed by CHMP in Q1 2014, an opinion on marketing would be expected soon after [9].
02/02/2014 20:47:51 
Nov 12: EMA has accepted filings for vintafolide and its companion diagnostic imaging agent etarfolatide, for the targeted treatment of patients with folate-receptor positive platinum-resistant ovarian cancer in combination with pegylated liposomal doxorubicin [6].
28/11/2012 09:13:43 
Mar 12: Plan to file in the EU 3Q 2012 [4].
15/03/2012 19:15:31 
Mar 12: Endocyte, Inc will submit EU conditional marketing authorisation applications for EC145 for treatment of patients with folate-receptor positive platinum resistant ovarian cancer. [4]
15/03/2012 16:02:52 
Mar 12: Orphan drug status in the EU [3].
09/03/2012 16:40:40 
Apr 11: Endocyte is planning to file in the EU for conditional market authorisation for EC145 and its companion imaging diagnostic EC20 based on the results of the randomized PII PRECEDENT trial (NCT00722592) and supported by a second PII study in which EC145 was used as monotherapy (NCT00507741) [2]. 
28/04/2011 09:07:32 
 
Trial or other data
Oct 13: PII PRECEDENT study published in J Clin Oncol. The intent-to-treat population comprised 149 patients. Median PFS was 5.0 and 2.7 months for the vintafolide plus PLD and PLD-alone arms, respectively (hazard ratio [HR], 0.63; 95% CI, 0.41 to 0.96; P = .031). The greatest benefit was observed in patients with 100% of lesions positive for FR, with median PFS of 5.5 compared with 1.5 months for PLD alone (HR, 0.38; 95% CI, 0.17 to 0.85; P = .013). The group of patients with FR-positive disease (10% to 90%) experienced some PFS improvement (HR, 0.873), whereas patients with disease that did not express FR experienced no PFS benefit (HR, 1.806) [8].
16/10/2013 08:47:07
Sep 12: folic acid solution for injection granted orphan drug status for ovarian cancer. Folic acid solution for injection is used as a pre-injection for the radiodiagnostic imaging agent, etarfolatide, to select patients for whom treatment with vintafolide, is being considered. [7]
11/12/2012 15:52:02
Apr 12: Merck has bought worldwide rights to Endocyte´s vintafolide (EC145) [5].
18/04/2012 14:07:07
Apr 11: A PIII study, PROCEED (NCT01170650) is planned to start in Apr 11. It is a randomized double-blind study comparing EC145 + pegylated liposomal doxorubicin vs PLD alone in 640 women with platinum-resistant ovarian cancer. The primary outcome is progression free survival. All participants will undergo imaging with the FR-targeting diagnostic agent EC20 during screening to assess binding of EC20 to tumours. The study is due to complete May 15 [1].
28/04/2011 09:08:51
PRECEDENT (NCT00722592) is a randomized, multi-center, international PII study, which investigated EC145 + standard chemotherapy (pegylated liposomal doxorubicin (PLD)), for 122 women with platinum-resistant ovarian cancer and eva luated the utility of EC20 for patient selection. The study met its primary endpoint of improvement in progression free survival vs PLD alone. This improvement was more substantial in patients who were selected with the EC20 diagnostic. The study started in Sep 08 and is due to complete Jun 11 [1].
28/04/2011 09:08:44
 
Evidence Based eva luations
NICE scope  http://www.nice.org.uk/Guidance/InDevelopment/GID-TAG332/Documents 
EMA doc  http://www.ema.europa.eu/docs/en_GB/document_library/Application_withdrawal_assessment_repor
t/2014/08/WC500171403.pdf 
NHSC  http://www.nhsc-healthhorizons.org.uk/files/downloads/1688/2130.9bd33474.EC145.pdf 
   
References  
Available only to registered users
 Category
BNF Category: Vinca alkaloids and etoposide (08.01.04)
Pharmacology: Small molecule conjugate of folate and a potent vinca alkaloid  
Epidemiology: The target folate vitamin receptor is expressed on virtually all ovarian cancers  
Indication: Ovarian cancer 
Additional Details:  
 
Method(s) of Administration  
Intravenous 
 
Company Information
Name: Merck Sharp & Dohme 
US Name: Merck Sharp & Dohme 
 
NICE Information
In timetable: Yes  
When:  /  
Note: www.nice.org.uk/Guidance/InDevelopment/GID-TAG332 
   
   
PBR Chemotherapy is locally negotiated.
   
Implications Available only to registered users