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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:
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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
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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