^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 is expanding 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 studied 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 in the 2nd quarter of 2008 to start a Phase I clinical trial for neurological applications. The following is an example of how ^99mTc-EC-MN can be used is in neurology. 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 predicting neurological outcome in patients within the first 48 hours following ischemic stroke, thus giving the neurologist important information on whether the patient may have salvageable tissue and thus benefit 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. Slide #1 for each patient is an MRI image which shows the area effected. Slide #2 shows the infarct area using ^99m Tc labeled ECD, a perfusion agent. Slide #3 shows the area of the brain (outlined in yellow) that indicates hypoxic tissue within the impacted region. The potentially viable tissue is illuminated using ^99mTc labeled metronidazole. This information is useful to the neurologist in deference to making a decision regarding further surgical intervention 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.. 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 the clinical study expected to start in the 4th quarter 2008, 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 in early 2008. 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 will contain both a therapeutic radionuclide (i.e. ,¹⁸⁸Re) and a chemotherapeutic drug. Upon direct injection into the tumor mass, the proprietary hydrogel compound encapsulates the radionuclide and chemotherapeutic drug. The radioactive decay of the radionuclide remains trapped within the hydrogel 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 without the complications associated with seed implants ( brachytherapy). The company is planning to complete preclinical studies in 2008 and start clinical trial studies by the 3rd 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 intracellular where the compound is taken up into the cell nuclei and translocated into the DNA. This should make the radiotherapy especially efficacious. Diagnostic imaging with ^99mTc-EC-G in combination with using ¹⁸⁸Re-EC-G for therapy is a good illustration of how Molecular Imaging (99mTc-EC-G) can be used to assess the efficacy of “target specific therapy”.( ¹⁸⁸Re-EC-G) 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 but 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 intracellular,the beta particle decay of the ¹⁸⁸Re kills cancer cells from inside the tumor and creates minimal adverse damage to surrounding healthy tissue. The agent therefore accomplishes it’s intended objective which is to efficiently and effectively kill the malignant cells with minimal 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 is presently developing a 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 in the 2^nd 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.