Navidea Biopharmaceuticals Inc (NAVB)

[DewDiligence]

RIGS info from 10K:

[Emphasis added by Dew]

http://www.sec.gov/Archives/edgar/data/810509/000095015204002505/l05786ae10ksb.txt

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From inception until 1998, Neoprobe devoted significant efforts and resources to the development of its proprietary RIGS technology. The RIGS system combines a patented hand-held gamma radiation detection probe, proprietary radiolabeled cancer targeting agents, and patented surgical methods to provide surgeons with real-time information to locate tumor deposits not detectable by conventional methods, and to assist in more thorough removal of the cancer. The RIGS system is designed to assist the surgeon in the more thorough removal of the cancer, thereby leading to improved surgical treatment of the patient. The targeting agents used in the RIGS process are monoclonal antibodies, labeled with a radioactive isotope that emits low energy gamma rays. The device used is a very sensitive radiation detection instrument that is capable of detecting small amounts of radiation bound to the targeting agent. Before surgery, a cancer patient is injected with one of the targeting agents which circulates throughout the patient's body and binds specifically to cancer cell antigens or receptors. Concentrations of the targeting agent are then located during surgery by Neoprobe's gamma-detection device, which emits an audible tone to direct the surgeon to targeted tissue.

RIGSCAN CR49 is an intraoperative radiodiagnostic agent consisting of a radiolabeled murine monoclonal antibody (MAb CC49). The radiolabel used is 125I, a 27 - 35 KeV emitting isotope. The MAb used in RIGSCAN CR49 is the CC49 MAb developed by the NCI and licensed to Neoprobe by the NIH. The CC49 MAb is produced from a murine cell line generated by the fusion of splenic lymphocytes from mice immunized with tumor-associated glycoprotein-72 (TAG-72) with non-immunoglobulin secreting P3-NS-1-Ag4 myeloma cells. The CC49 MAb localizes or binds to TAG-72 and shows a strong reactivity with both LS-174T colon cancer extract and to a breast cancer extract.

RIGSCAN CR49 is the biologic component for the RIGS system to be used in patients with colon or rectal cancer. The RIGS system is designed to be a diagnostic aid in the intraoperative detection of clinically occult disease. RIGSCAN CR49 is intended to be used in conjunction with other diagnostic methods, for the detection of the extent and location of tumor in patients with colorectal cancer. The detection of clinically occult tumor provides the surgeon with a more accurate assessment of the extent of disease and, therefore, may impact the surgical and therapeutic management of the patient. Clinical trials suggest that RIGSCAN CR49 provides additional information outside that provided by standard diagnostic modalities (including surgical exploration) that may aid in patient management. Specifically, RIGSCAN

CR49 used as a component of the RIGS system confirms the location of surgically suspicious metastases, evaluates the margins of surgical resection, and detects occult tumor in perihepatic (portal and celiac axis) lymph nodes.

Neoprobe conducted two Phase III studies, NEO2-14 and NEO2-13, of RIGSCAN CR49 in patients with colorectal cancer. Both studies were multi-institutional involving cancer treatment institutions in the United States, Israel, and Europe. The primary endpoint of both studies was to demonstrate that RIGSCAN CR49 detected pathology-confirmed disease that had been undetected by traditional preoperative (i.e., CT Scans) or intraoperative (i.e., surgeon's visual observations and palpation) means. That is, the trials were intended to show that the use of RIGSCAN CR49 assisted the surgeon in the detection of occult tumor. In December 1996, Neoprobe submitted applications to the European Agency for the Evaluation of Medicinal Products (EMEA) and the FDA for marketing approval of RIGSCAN CR49 for the detection of metastatic colorectal cancer.

Clinical study NEO2-14, which was submitted to the FDA in the RIGSCAN CR49 Biologic License Application (BLA), enrolled 151 colorectal cancer patients with either suspected metastatic primary colorectal disease or recurrent colorectal disease. During the FDA's review of the BLA, 109 of the enrolled patients were determined to be evaluable patients. Clinical study NEO2-13 was conducted in 287 enrolled patients with primary colorectal disease. The primary end-point for clinical study NEO2-13 was the identification of occult tumor.

NEO2-14 was the pivotal study submitted with Neoprobe's referenced BLA. Two additional studies evaluating patients with either primary or metastatic colorectal disease, NEO2-11 (a multi-center study) and NEO2-18 (a single institution study), were included in the BLA and provided supportive proof of concept (i.e., localization and occult tumor detection) and safety data. A study report for NEO2-13 was not submitted under the BLA and the FDA undertook no formal review of the study.

Following review of its applications, we received requests for further information from the FDA and from the European Committee for Proprietary Medicinal Products (CPMP) on behalf of the EMEA. Both the FDA and EMEA acknowledged that our studies met the diagnostic endpoint of the Phase III clinical study, which was to provide incremental information to the surgeon regarding the location of hidden tumor. However, both agencies wanted to know how the finding of additional tumor provided clinical benefit that altered patient management or outcome. In a series of conversations with the FDA the product claims were narrowed to the intraoperative detection of hepatic and perihepatic disease in patients with advanced colorectal cancer and patients with recurrent colorectal cancer.

The FDA determined during its review of the BLA review that the clinical studies of RIGSCAN CR49 needed to demonstrate clinical utility in addition to identifying additional pathology confirmed disease. In discussions between Neoprobe and the agency, an FDA driven post hoc analysis plan was developed to limit the evaluation of RIGSCAN CR49 to patients with hepatic and perihepatic disease with known metastasis to the liver. Findings of "occult" disease and subsequent changes in patient management (i.e., abandoning otherwise risky hepatic resections) in this limited population would serve as a measure of patient benefit. The FDA's analysis of the patients enrolled in NEO2-14 matching the limited criteria was evaluated with a determination to confirm the surgical resection abandonment outcome. The number of evaluable patients in this redefined patient population was deemed too small by the agency and the lack of pre-stated protocol guidance precluded consistent sets of management changes given similar occult findings. The number of evaluable patients for any measure of clinical utility, therefore, was too small to meet relevant licensing requirements and the FDA ultimately issued a not approvable letter for the BLA on December 22, 1997, describing certain clinical and manufacturing deficiencies. Neoprobe also withdrew its application to the EMEA in November 1997.

We developed a clinical response plan for both agencies during the first half of 1998. However, following our analysis of the regulatory pathways for approval that existed at that time, we determined that we did not have sufficient financial resources to conduct the additional studies requested and sought to identify others with an interest in continuing the development process.

Over the last several years, we have held preliminary discussions with several parties potentially interested in continuing the RIGS development; however, only one of those discussions resulted in an arrangement that attempted to restart the development of RIGS. During 2000, we executed and amended an agreement with OncoSurg Ltd. (OncoSurg, formerly NuRIGS Ltd.), that provided OncoSurg with an option exercisable through December 31, 2001 to license the RIGS technology for use in the diagnosis and treatment of colorectal cancer. During 2001, OncoSurg conducted pre-clinical testing and sponsored a Phase I physician's Investigational New Device (IND) clinical trial for colorectal cancer using a second-generation humanized version of our RIGSCAN CR49 antibody. However, OncoSurg did not exercise its option to continue development at the end of 2001 due to a lack of funding which we believe is unrelated to the pending clinical results of the current Phase I trial. The physician-IND researchers reported favorable results of the Phase I trial during fourth quarter of 2003.

We recently obtained results of a third party's survival analysis suggesting that RIGSCAN CR49 may be predictive of, or actually contribute to, a positive outcome when measuring survival of the patients that participated in our original BLA studies. The data or its possible significance was unknown at the time of the BLA review given the limited maturity of the follow-up experience. The data includes publication by some of the primary investigators involved in the Phase III RIGS trials who have independently conducted survival follow-up analyses to their own institution's RIGS trial patients with apparently favorable results relating to the long-term survival prognosis of patients who were treated with RIGS. In addition, we have recently learned that the FDA has held the BLA originally filed with the FDA in 1996 open. Based primarily on these pieces of information, we requested, and have been granted, a meeting with the FDA to discuss the possible next steps for evaluating the survival related to our previous Phase III clinical trials as well as the possible submission of this data, if acceptable, as a prospective analysis in response to questions originally asked by the FDA in response to our original BLA. Our meeting with the FDA has been scheduled for April 15, 2004.

If our plan for evaluating the survival data is received positively, we intend to engage the services of a clinical research organization (CRO) to review these survival findings related to all evaluable patients from our Phase III primary and metastatic colorectal cancer clinical trials. The analysis of this data may answer some of the questions raised by the FDA in response to our original application; however, the RIGSCAN CR49 drug has not been produced for several years and we believe it is likely we would have to perform some additional work related to ensuring the drug cell line is still viable and submit this data to the FDA for their evaluation before approval could be considered. [The “bridge” study.] Neoprobe is in the process of initiating discussions with established biologic manufacturing organizations to determine the costs and timelines associated with the production of commercial quantities of the CC49 antibody. In addition, we will need to establish a process for radiolabeling the CC49 antibody in order to meet the regulatory needs for the RIGSCAN CR49 product. At this time, we have not examined the possible steps towards a similar re-invigoration of the process for approval with the EMEA. We intend to re-evaluate that situation once the approval process with the FDA has been clarified.

We are encouraged by the recent developments regarding RIGS and believe that a positive outcome from our upcoming meeting with the FDA could represent a dramatic turnaround in the development for RIGS. We believe we would need to obtain additional funding and/or identify a development partner in order to carry out all the activities necessary for commercialization. We do not have any agreements in place or pending with third parties that would ensure the continued development of the RIGS process beyond the FDA meeting scheduled for April 15th and the completion of the survival analysis being proposed to the FDA at the April 15th meeting. In addition, even if we are able to make such arrangements on satisfactory terms, we believe that the time required for continued development, regulatory approval and commercialization of a RIGS product would likely be a minimum of two years before we receive any significant product-related royalties or revenues. However, we cannot assure you that we will be able to complete definitive agreements with a development partner for the RIGS technology and does not know if a partner will be obtained on a timely basis on terms acceptable to us, or at all. We cannot assure you that the FDA or the EMEA will approve our RIGS products for marketing, or that any such products will be successfully introduced or achieve market acceptance. See Risk Factors.
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