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^99mTc-EC-G (Oncology)

The first radiodiagnostic product based on EC Technology is 99mTc - labeled glucosamine (“99mTc-EC-G”), a universal metabolic imaging agent that can diagnose hyper metabolic activity in cancer cells. It will be the first 99mTc labeled sugar analogue developed for use in functional imaging. The only universal metabolic imaging agent in current use is 18F-DG (“FDG”) which requires a cyclotron to produce the positron emitting radioisotope fluorine-18 (“18F”) and the use of a PET camera to acquire the images. 99mTc-EC-G will be made available in a “shake and shoot” cold kit which will simplify and reduce the preparation time for administration of the agent. 99mTc is a readily available radioisotope (can be cost effectively produced on-site with a 99mMo-generator), has a six hour half-life, is imaged on a standard SPECT (gamma) camera, yields 73% lower radio-active energy than 18F, and will give the radiologist or nuclear physician the flexibility to perform staged or time phased imaging. The patient cost of a 99mTc-EC-G imaging procedure should be appreciably less than the cost of a FDG-PET procedure.

The Phase I clinical trial study for 99mTc-EC-G was conducted at The University of Texas M.D. Anderson Cancer Center. The clinical study involved imaging patients with non-small cell lung cancer (NSCLC) by comparing 99mTc-EC-G scans with FDG-PET scans. The Phase II clinical trial evaluating the imaging agent for diagnosing NSCLC and determining the extent of the disease (metastatic cancer) should be completed during the 4th Quarter 2008.

99mTc-EC-G localizes in cells undergoing rapid regeneration. It is incorporated in the cells’ DNA and is involved in protein and cell membrane synthesis. FDG undergoes phosphorylation and is trapped rather than metabolized by the cell. One of the advantages of 99mTc-EC-G is that it does not get taken up by macrophages associated with inflamed tissue. Inflammation surrounding the tumor site generally occurs following chemo or radiation therapy. Because FDG gets involved in the inflammatory process, the diagnostic accuracy for post therapy assessment of patients is considerably impaired when performing the study with FDG-PET. Sample images from our clinical trials are below:

^99mTc-EC-G (Cardiology)

In addition to use in oncology, 99mTc-EC-G is being evaluated as a functional imaging agent for use in cardiac imaging. A canine cardiac study is currently ongoing at the University of Virginia. The company plans to amend the existing IND to initiate a Phase II/III cardiology clinical trial to evaluate combination imaging using a myocardial perfusion imaging (MPI) agent and 99mTc-EC-G to diagnose the presence of ischemia in patients that have recently experienced a cardiac event.

Events such as ischemia cause the heart to change from its normal metabolite free fatty acid to glucose. Regions of the heart affected by ischemia that use glucose as their metabolic energy source as well as regions that experienced an Acute Cardiac Event but have viable myocardium should localize 99mTc-EC-G.

The Company believes that combination imaging (dual isotope imaging) using an MPI agent in combination with 99mTc-EC-G could be very effective for diagnosing and assessing ischemia while eliminating the need for attenuation correction or a rest study. Additional applications using combintion imaging could include: assessment of ischemia in women who are symptomatic for heart disease but have an equivocal MPI stress study; diagnosing and staging CHF; determining the presence and extent of cardiotoxicity in patients receiving chemotherapy. Sample images from the clinical trial follow:

^99mTc-EC-Metronidazole)

^99mTc-EC-metronidazole ("99mTc-EC-MN") is being evaluated as a cellular hypoxia targeting agent for oncology and as a functional imaging agent to assess neurological disease. Plans are to submit an IND application to the FDA to start a Phase I clinical trial for stroke in the 1st quarter 2009. The Company believes that 99mTc-EC-MN will be able to help differentiate between hemorrhagic and ischemic stroke. The following is an example of how 99mTc-EC-MN can be used in patients who have suffered a stroke. A collaborative study conducted in South Korea on patients who had suffered ischemic stroke to the brain evaluated the relationship between neurological outcome and uptake of 99mTc-EC-MN in peri-infarcted regions of the brain. 99mTc-EC-MN was used to identify hypoxic (absence of oxygen) tissue. When used in conjunction with 99mTc-ECD, a blood flow perfusion agent, 99mTc-EC-MN was found to be useful in determining the most appropriate therapy in patients within the first 48 hours following symptoms for a stroke. The agent will provide the neurologist important information on the best therapy to optimize salvageable tissue and thus the benefits from tissue rescue therapy. The results of the 99mTc-EC-MN study were published in the cardiology journal Stroke. 34(4):982-986,2003.

The above images are of two patients who have suffered infarct damage to the right side of the brain. The left image for each patient is an MRI image which shows the area affected.The center image shows the area of normal perfusion using 99m Tc labeled ECD, a perfusion agent. The far right image shows the area of the brain (outlined in yellow) that indicates hypoxic tissue within the impacted region.

The potentially viable tissue is the difference between the abnormal MRI illuminated area (left) and the hypoxic region on the right. The upper image set is consistent with an ischemic stroke which should be treated with TPA, a blood thinning agent to relieve the hypoxia to the brain.. The lower image set is consistent with a hemorrhagic stroke (bleeding into the brain) which should not be treated with TPA to prevent further bleeding. This information is useful to the neurologist for determining the type of stroke, the most appropriate therapy, and to assess the prognosis for the patient.

The company also believes that 99mTc-EC-MN will be effective in measuring tumor hypoxia and thus will provide the medical oncologist with useful and important information on selection of therapy. Whether a tumor is hypoxic is important in the decision to give the patient external radiation treatment. This potential application will be pursued following the neurological study

¹⁸⁷Re-EC-G

The company is developing a cold metallic chemotherapeutic agent, 187Re-EC-G, which has been evaluated in pre-clinical studies as a stand-alone therapeutic agent for the treatment of non-Hodgkin’s lymphoma. A successful SCID mice study recently completed demonstrated good tolerance and therapeutic effectiveness. One of the advantages of this agent will be that it is a target specific therapeutic that uses EC-G to deliver the cold metallic Re into the DNA of metabolically active cancer cells (inrtranuclear) Another advantage is that EC-G does not normally localize in the brain or heart. This should reduce the potential adverse effects to either organ including cardiotoxicity.

187Re-EC-G should provide an alternative chemotherapy option for medical oncologists in the treatment of various cancer types to include NHL. Assuming that clinical endpoints are achieved in clinical studies expected to start by the 2nd quarter 2009, 187Re-EC-G should provide clinical equivalent efficacy commonly associated with other chemotherapy alternatives (such as Rituxan). The Company is completing the cGMP 187Re-EC-G kits with J-Star Research (New Jersey) and is preparing to start the final phase of the preclinical study. This will be followed by the filing of an IND with the FDA to start clinical trials. The current plan is for the clinical trial protocol to compare 187Re-EC-G with Rituxan in the treatment of lymphoma. Clinical studies of other indications will follow.

In-Situ Hydrogel

In-Situ Hydrogel is a high yield radio/chemotherapy delivery system that enables the physician to treat inoperable or surgically nonresectable tumors. The following are several advantages of In-Situ Hydrogel:

The hydrogel complex will contain both a therapeutic radionuclide (i.e. ,¹⁸⁸Re) and a chemotherapeutic drug. Upon direct injection into the tumor mass, the proprietary hydrogel complex encapsulates the radionuclide and chemotherapeutic drug. The radioactive decay of the radionuclide remains trapped within the hydrogel complex while the chemotherapeutic drug is slowly released. This results in minimal impact to healthy surrounding tissue thus significantly reducing adverse toxicity normally associated with systemic chemotherapy agents or external beam radiation.
Could be considered as an alternative to brachytherapy with the advantage of providing uniform therapy to the entire tumor mass such as in prostate cancer.

The choice of ¹⁸⁸Re as the therapeutic radionuclide has the advantage of a comparatively short half-life (17 hours) which would permit repeat doses of therapy if necessary. Brachytherapy (seed implant therapy) is administered only once which can be a drawback if the implant seeds migrate thus failing to resolve the presence of the prostate tumor. The Company is planning to complete preclinical studies by mid-2009 and start clinical trial studies by the 4th quarter 2009.

¹⁸⁸Re-EC-G

The second radiotherapeutic agent being developed from EC Technology is 188Re-EC-G. One of the key attributes of 188Re-EC-G is that (like 187Re-EC-G) it also functions intranuclear where the compound is taken up into the cell nuclei and translocated into the DNA. This should make the radiotherapy especially effective. Diagnostic imaging with 99mTc-EC-G in combination with using 188Re-EC-G for therapy is a good illustration of how molecular imaging can be used to assess the efficacy of “target specific therapy”.The advantage of target specific therapy is that it targets all metabolically active cancer sites (both primary and metastatic) independent of the location in the body. This differs from “image-guided therapy” which only targets cancers which are visualized by either radiological or nuclear techniques.

188Re-EC-G is a very different form of radiation therapy than traditional external beam radiation which has been a staple cancer therapy for decades. Historically, with external beam radiation therapy, it was difficult to avoid impacting healthy tissue surrounding the tumor, thus causing unwanted adverse effects from the treatment. In addition, it has been difficult to provide a high enough dose of radiation for especially large cancers, such a mesothelioma, due to toxicity. More recently, Intensity Modulated Radiation Therapy (IMRT) has been developed to reduce the impact to surrounding healthy tissue as well as provide for more intense doses of radiation to the targeted area. Another form of radiotherapy, brachytherapy (radioactive seed implant therapy), has gained widespread acceptance but is used mainly as a treatment option for prostate cancer,.Further, it’s application is limited to large tumors which are visualized radiographically. Alternatively, 188Re-EC-G is administered systemically and localizes in all metabolically active cancer sites. Since it’s localization is intranuclear, the beta particle decay of the 188Re kills cancer cells from inside the tumor and creates minimal adverse damage to surrounding healthy tissue.

Several years ago, the FDA approved the first two radioimmunotherapeutic agents - Zevalin (developed by Biogen IDEC) and Bexxar (developed by Corixa that is now part of GlaxoSmithkline). Zevalin is comprised of a CD-20 monoclonal antibody (ibritumomab) that is first radiolabeled with 111In for dosimetry imaging and then labeled with 90Y for radiotherapy. The CD-20 monoclonal antibody attaches to the outer surface of the tumor membrane. It is unable to penetrate inside the tumor due to its molecular weight, thus the position of the therapeutic radioisotope results in a killing radius that impacts both healthy as well as malignant cells. Bexxar is also a CD-20 monoclonal antibody; however, the antibody is labeled with 131I for therapy. Bexxar occupies the same space in the market as Zevalin for the treatment of non-Hodgkin’s lymphoma. With both Zevalin and Bexxar, the radioisotopes have a long half-life (eight days for 131I and 2.7 days for 90Y). By contrast, 188Re has a half-life of 17 hours and a penetration of almost a centimeter that will allow the radiopharmaceutical to effectively treat even large tumors. Localization of the . 188Re directly in the cell’s nucleus should significantly increase the killing power of the agent compared to the extra cellular localization of both Zevalin and Bexxar and should also provide minimal damage to surrounding healthy tissue. To determine the proper dose of 188Re to administer, the patient will first receive 99mTc-EC-G and dosimetry estimates obtained using a SPECT or SPECT/CT camera. The advantage of using 99mTc to perform the dosimetry is that 99mTc and 188Re are part of the same family of isotopes and should yield more accurate dose information. Further, 188Re-EC-G will not suffer the limited application (NHL) that confront both Zevalin and Bexxar since the proposed agent will be efficacious for treatment of all metabolically active cancer types and will be more economical per dose.

N₄Technology

^99mTc-N₄-Tyrosine is a diagnostic imaging agent being developed for the diagnosis and assessment of Parkinson’s and Huntington’s disease. Also, 99mTc-N4-Tyrosine will be studied as a diagnostic imaging agent to assess EGFR tyrosine kinase activity in tumor cells. The goal is to determine whether a patient will benefit from tyrosine kinase therapy. The Company has entered intoa pre-clinical study collaboration agreement with a major pharmaceutical company. The collaboration agreement will, among other things, focus on potential clinical imaging applications in neurological diseases. Cell>Point will supply all GMP material. The pharmaceutical company will contribute the animal models and will fund the pre-clinical research. In addition, the pharmaceutical company will retain the right to publish the results of its pre-clinical research work. Cell>Point will have unfettered rights to the imaging applications that are identified by the research work.

^99mTc-EC-Guanosin

^99mTc-EC-guanosin is a new DNA marker that is incorporated into DNA/RNA syntheses. The radiopharmaceutical compound will initially be evaluated as a target specific agent for brain and prostate cancer. The company plans to submit an IND application to the FDA by the 3rd quarter 2009 for authorization to commence a Phase I clinical trial study.

¹⁸⁸Re-EC-Guanosin

The Company has made a decision to move forward with the radiothrapeutic form of EC-guanosin. Potential clinical applications include brain and prostate cancers.

A unique feature of EC conjugated to guanosin is that the compound does not cross the blood-brain barrier unless there is a breakdown in the barrier such as that caused by a brain lesion. The first clinical trial will evaluate whether 188Re-EC-guanosin can be an effective targeted radiotherapeutic for the treatment of certain brain tumors. The specific targeted application will be for adult brain tumors which are not considered candidates for surgical excision or external beam radiotherapy.

The second clinical trial will focus on the treatment of prostate cancer. Currently, there are two different approaches to radiation treatment, one being external beam radiation and the other is brachytherapy. About 30% of those patients electing to receive treatment for their prostate cancer receive one or both of these forms of radiation treatment. 188Re-EC-Guanosin represents an alternative form of radiation treatment for this disease. It has the advantage of being target specific (localizes in the prostate cancer cells) and therefore treats the cancer directly. This differs from extertnal beam radiation which can cause significant residual damage to tissue surrounding the prostate gland including the bladder and bowel.

Brachytherapy has disadvantages to include the fact it typically can only be administered to the patient once and the radioactive seeds can migrate out of the intended target area causing damage to normal tissue and consequently decreasing treatment to the tumor mass.

Beta Cell Technology

^99mTc-DTPH-Glipizide is being evaluated as a beta cell specific diagnostic agent for the early detection and assessment of pancreatic cancer. In addition, the Company will determine whether this technology has potential applications for early diagnosis of diabetes or pancreatitis.

The Company and a major pharmaceutical company are exploring a collaboration involving beta cell technology. The collaboration agreement will, among other things, focus on potential clinical imaging applications. Cell>Point will supply all GMP material. The pharmaceutical company will contribute the animal models and will fund the pre-clinical research. In addition, the pharmaceutical company will retain the right to publish the results of its pre-clinical research work. Cell>Point will have unfettered rights to the imaging applications that are identified by the research work.