Background
Sentinel lymph node imaging is now widely used in the staging of breast cancer and melanoma. This procedure has been developed to assist physicians in locating the sentinel node (the first lymph node in a chain of lymph nodes that are located close to the primary tumor) and determining the presence or absence of cancer within the lymphatics. It is being studied for various other malignancies spread via the lymphatic system cancers, including head and neck, lung, prostate and colorectal. However, in these cancers the sentinel nodes are often more difficult to access and to assess.
It has further been shown that indiscriminate removal (lymphadenectomy) of the lymph nodes does not improve survival, is expensive and often leads to undesirable side effects. N1177-sq is a subcutaneous injectable agent for use with CT In imaging cancer extension in the lymphatic system. It is administered into suspected sentinel nodal areas (unlike the procedure with ordinary lymphography agents which are usually administered between the toes for distribution around the body). As a contrast agent for use with CT, the subcutaneous administration of N1177 serves as a minimally invasive, fast, lower cost procedure to both locate and diagnose disease in sentinel nodes with all cancers that spread via the lymphatic system.
NSI’s strategy will be to find a suitable institutional / corporate partner for N1177-sq with whom we will jointly develop the technology and to whom we expect to license or sell the product outright
Combining CT with Lymphography
According to RadioGraphics Magazine, “Conventional lymphography has long been the method of choice for imaging the lymphatic system. However, the number of lymphographic studies performed in oncology centers has declined markedly since the introduction of cross-sectional imaging techniques, especially computed tomography (CT). Therefore, levels of expertise in both performing lymphography and interpreting lymphograms are falling. The unique ability of lymphography to demonstrate derangements of the internal architecture of normal-sized lymph nodes can be valuable and makes it more accurate than CT in evaluation of some lymphomas (especially Hodgkin’s disease) and genitourinary malignancies. In fact, lymphography and CT are complementary rather than mutually exclusive techniques for the staging of some lymphomas and genitourinary malignancies."
“In addition, lymphography opacifies the lymphatic channels and therefore may be a valuable tool for detection of lymphatic fistulas or lymphatic leakage. Finally, lymphography helps guide subsequent therapy in patients with lymphomas, genitourinary malignancies, or disorders of lymphatic flow.”
Prior Studies with N1177-sq
Three separate Phase 1 clinical trials were conducted to evaluate the safety, tolerance, pharmacokinetics, and imaging properties of several doses of N1177-sq when administered subcutaneously to healthy adult male and female subjects. Each subject was monitored before and for varying lengths of time (up to 100 days) after the administration of N1177-sq for signs of adverse tolerance to the material. Safety evaluation included a complete battery of blood chemistry tests, 12-lead electrocardiogram, physical examinations, vital sign measurements, and questioning the subject. CT scans of lymphatics draining the site of injection (feet, thigh or anterior chest wall) were obtained up to 24 hours after injection. No clinically significant change requiring intervention was noted in any laboratory test value, vital sign measurement, or electrocardiographic interval. CT scans obtained after the injection of N1177-sq indicated a generally dose-related increase in lymphatic node enhancement. Over time, sequential nodes in the basin/chain were enhanced indicating node-to-node transfer of N1177-sq.
This all suggests that N1177-sq has the potential to offer a safe and accurate, non-invasive assessment of the lymph nodes regional to various carcinomas. These include cancers that target such areas as lung, breast, prostate, melanoma, uterine, cervical, head and neck.
N1177-sq Competitive Landscape / Current Technology
Growth of PET Procedure Volume, and Sales of Fluorodeoxyglucose (FDG)
PET procedures in 2004 reached 1 million, with procedure volume increasing 37%. By 2010, PET procedure volume is expected to rise to 3.2 million. Approval of new indications in oncology have added to procedure volume as well as expanded use of PET in lung cancer, breast cancer, colon cancer, lymphoma and melanoma. Although the dominant focus of PET is still on oncology, cardiology applications have increased. The introduction of PET-CT with multi-slice configurations suitable for cardiac imaging has stimulated sales of FDG (used with PET to demonstrate areas of increased glucose metabolism). FDG sales of $270 million in 2004 were up 34% from $202 million in 2003. These sales are expected to reach $795 million by 2010, despite the diminishing price per dose for FDG.
[Source: BIO_TECH REPORT #220].
Lymphotrophic Magnetic Resonance Imaging (LMRI)
Lymphotrophic magnetic resonance imaging (LMRI) represents another approach to visualizing the extension of cancers into the lymphatic system. In LMRI superparamagnetic iron-oxide nanoparticles are injected intravenously and are retained by macrophages in lymph nodes.
[M.G. Harisinghani, R. Weissleder, Sensitive Noninvasive Detection of Lymph Node Metastases, PLoS Medicine, December 2004, Volume 1, Issue 3 e66].
The New Drug Application (NDA) for one LMRI product, Combidex (Advanced Magnetics), is under review. This agent has shown some promise in the staging of prostate cancer. Overall, LMRI has a sensitivity of 83%, a specificity of 77% and an accuracy of 80%. There are, however, some important differences between the use of N1177-sq and CT and LMRI, such as:
· CT possesses superior spatial resolution that is 5-fold greater than that of MR imaging.
· CT possesses superior temporal resolution so that entire segments can be scanned in a single breath hold.
NSI will actively pursue a partnering arrangement to complete the development of N1177-sq for use in lymphotrophic CT (LCT). This development was initiated by Nycomed and demonstrated that N1177-sq can be used to detect visualize lymph nodes.
Phase 1 clinical trials conducted with the current formulation demonstrated safety by subcutaneous and peritumoral injections. The current IND # 50,714 continues to be maintained on an active status, and supplemental data is added to the files at the FDA via the annual reports.
Competitive Advantages of N1177-sq in LCT
Preclinical and clinical data indicate that N1177 is:
· Safe – No significant side effects and well tolerated
· Effective – Highlights healthy nodes and identifies diseased nodes with higher sensitivity and specificity than currently achieved by other techniques
And provides
· Added value – More accurate staging guiding election of appropriate therapy
· A technique that is easy to use – can be used with all available CT equipment
Rationale for LCT clinical studies with N1177-sq
In several animal models the imaging efficacy and pharmacokinetics of N1177 were studied following subcutaneous administration. N1177 was taken into the lymphatics and translocated to the lymph nodes. The iodine in N1177 resulted in enhanced nodal imaging with x-rays, such as in CT. These studies have shown effective nodal imaging along chains of nodes draining specific subcutaneous sites in normal and disease-bearing animals.
