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New Drugs Online Report for tilmanocept
Generic Name:
Trade Name: Lymphoseek 
Synonym: Tc 99m DTPA mannosyl dextran 
Entry Type: New molecular entity  
Development and Regulatory status
UK: Approved (Licensed) 
EU: Approved (Licensed) 
US: Launched 
UK launch Plans: Available only to registered users
Actual UK launch date:  
Mar 15: Navidea expect Norgine to begin market access work immediately in the major markets in Europe with the goal of supporting commercial launch in early 2016 [21]. 
20/03/2015 16:17:24
Mar 15: Navidea and SpePharm AG (an affiliate of Norgine BV) enter into an exclusive sublicense agreement for commercialisation and distribution of Lymphoseek 250 microgram kit in the EU. Under terms of the agreement, Navidea will receive an upfront payment of $2 million and is eligible to receive additional milestone payments up to $5 million, as well as royalties on European net sales [21]. 
20/03/2015 16:16:16
Mar 15: Lymphoseek was launched in the US in May 13 [20]. 
20/03/2015 16:13:48
Jan 15: Approved in the EU [19]. 
20/03/2015 16:08:27
Oct 14: US FDA approved expanded use of Lymphoseek for lymphatic mapping in solid tumors and adding Sentinel Lymph Node detection for breast cancer and melanoma to the approved indications. [16]  
16/10/2014 10:51:08
Sep 14: EU positive opinion for for imaging and intraoperative detection of sentinel lymph nodes draining a primary tumour in adult patients with breast cancer, melanoma, or localised squamous cell carcinoma of the oral cavity. External imaging and intraoperative evaluation may be performed using a gamma detection device [15]. 
29/09/2014 12:04:22
June 14: US FDA approved a new use for Lymphoseek: detection of squamous cell carcinoma in the head and neck region. [14] 
16/06/2014 09:31:24
March 14: Navidea presented Oral Explanations to the CHMP relating to open questions in the Lymphoseek MAA. At the conclusion of the meeting, the CHMP informed Navidea that the Committee will continue with its review of the MAA. Navidea believes the course of the review continues to be supportive of its market development plans and outlook for material revenue generation in Europe beginning in 2015. [11] 
21/03/2014 09:56:10
Feb 14: FDA has accepted the Supplemental New Drug Application (sNDA) and granted a Priority Review for the expanded use of Lymphoseek® for sentinel lymph node (SLN) detection in patients with head and neck cancer. [10] 
20/02/2014 09:42:53
Mar 13: Approved for marketing in the US for the diagnosis of breast cancer and melanoma [7].  
04/04/2013 19:47:51
Dec 12: Navidea has filed for EU marketing approval for Lymphoseek for use in general Intraoperative Mapping not restricted to any particular solid tumour type [6]. 
27/12/2012 11:04:41
Nov 12: FDA decision on approval expected by 30 Apr 2013 [5]. 
29/11/2012 10:01:36
Nov 12: Company has filed the resubmission for Lymphoseek® in response to the Complete Response Letter received in Sep 2012 [4] 
05/11/2012 09:23:22
Sep 12: The FDA has rejected the application. The company said that the problems were with a third-party contract manufacturer employed to produce Lymphoseek, and not with safety and efficacy data [3]. 
11/09/2012 18:19:14
Oct 11: NDA submitted to FDA in Aug 11 and accepted for review in Oct 11 [1]. 
24/10/2011 13:31:32
Trial or other data
Feb 15: Publication of results from PIII trial of Lymphoseek® in pts with certain head and neck cancer (squamous cell carcinoma of the oral cavity, NEO3-06; NCT00911326) [17,18].  
18/02/2015 10:39:57
Jun 14: Results from combined analyses from three pivotal PIII clinical studies: two PIII studies in pts with breast cancer and melanoma (melanoma, n=153; breast cancer, n=148) and one PIII study in pts with head and neck squamous cell carcinoma (n=83) announced. Lymphoseek sensitivity for sentinel lymph node mapping was consistent across the tumor type studies, regardless of whether surgery was conducted on the same day as, or on the day after injection of Lymphoseek; 99% sensitivity for both. [13] 
12/06/2014 10:09:19
Apr 14: In Oct 13 final results from US-based PIII trial of Tc 99m tilmanocept in pts with head and neck squamous cell carcinoma announced (NCT00911326). The primary endpoint (identification of pts with cancerous lymph nodes) was met, as well as all other pre-specified study endpoints. In view of positive top-line results released in April 13, the study´s Data Safety Monitoring Committee recommended closing the study early; the company formally closed the trial in Aug 13. [12] 
02/04/2014 11:24:25
Mar 13: Top-line results from the interim analysis of PIII trial NEO3-06 demonstrated that Lymphoseek met the primary efficacy endpoint of accurately identifying sentinel lymph nodes (SLNs) in pts with squamous cell carcinoma of the head or in the mouth, as compared to the removal of all lymph nodes during multiple level nodal dissection surgery of the head and neck. Of the over 80 pts enrolled in the NEO3-06 trial, 39 pts were determined to have pathology-positive lymph nodes. Results demonstrated that of these 39 pts, Lymphoseek accurately identified 38, for an overall False Negative Rate (FNR) of 2.56%, which was statistically significant (p=0.0205) and met the statistical threshold for success of the primary endpoint [9].  
05/04/2013 08:35:00
Mar 13: The study, “Comparative Evaluation of [99mTc] Tilmanocept for Sentinel Lymph Node Mapping in Breast Cancer Patients: Results of Two PIII Trials,” was published in the current online edition of the journal Annals of Surgical Oncology [DOI 10.1245/s10434-013-2887-8] [8] 
25/03/2013 17:00:39
Oct 12: “Combined Analysis of Phase III Trials Evaluating [99mTc]Tilmanocept and Vital Blue Dye for Identification of Sentinel Lymph Nodes in Clinically Node-Negative Cutaneous Melanoma,” published early online in Annals of Surgical Oncology [DOI 10.1245/s10434-012-2612-z].  
11/10/2012 08:52:18
Jun 12: Abstract of a meta-analysisof PIII trials for Intraoperative lymphatic mapping (ILM) of lymph nodes in breast cancer, compared to standard of care techniques has been published in conjunction with ASCO in the Journal of Clinical Oncology Online 2012; e21066; The novel receptor targeted (CD206) 99mTc-labeled tilmanocept versus the currently employed Tc99m-sulfur colloid in intraoperative lymphatic mapping (ILM) on key performance metrics in breast cancer” [2]. 
06/06/2012 13:54:48
Lymphoseek has undergone study in two prospective open-label non-randomised PIII studies (NEO3-05 and NEO3-09; NCT01106040 and NCT00671918) in >300 patients with either breast cancer or melanoma. The primary was the concordance on a lymph node count basis of Lymphoseek with vital blue dye. Lymphoseek met all primary and secondary endpoints across both studies [1]. 
24/10/2011 13:31:52
Used in Intraoperative Lymphatic Mapping (ILM). ILM with a radiopharmaceutical identifies the first lymph node to receive lymphatic flow from the primary tumour site. The node is removed and analyzed for the presence of malignant cells. By locating the lymph node prior to surgery, a smaller incision and lymph node dissection can be employed. Lymphoseek is a radiotracer that accumulates in lymphatic tissue by binding to a mannose binding protein that resides on the surface of dendritic cells and macrophages. It has a diameter of about 5 nm, which is smaller than current agents used for targeting lymphoid tissue. This permits enhanced diffusion into lymph nodes and blood capillaries, resulting in a rapid injection site clearance.  
24/10/2011 13:31:43
Evidence Based Evaluations
EPAR  http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002085/WC500180050.pdf 
NHSC/NIHR  http://www.hsc.nihr.ac.uk/topics/lymphoseek-for-lymphatic-mapping-and-sentinel/ 
Available only to registered users
BNF Category:
Non BNF (50)
Pharmacology: Radionuclide imaging enhancer. Must be radiolabelled before administration to the patient.  
Epidemiology: In patients with breast cancer, melanoma, HNSCC, and multiple other solid tumor cancers, the ability to identify whether the cancer has spread greatly influences patients’ outcomes and future treatment [19].  
Indication: Cancer 
Additional Details: diagnosis of solid tumours 
Method(s) of Administration
Peri-tumoural and peri-lymphatic 
Subcutaneous injection 
Company Information
Name: Norgine 
US Name: Neoprobe Corporation 
Further Information
Anticipated commissioning route (England) NHSE 
High cost drug list? Awaiting Update
Implications Available only to registered users