Management
:
We are led by a
highly-experienced
management team knowledgeable in immunotherapy for the treatment of cancer. Our
management team has access to our
internationally recognized Scientific Advisory Board whose members are
thought-leaders in their respective areas. Our subsidiarys Chief Scientist,
Professor Yehuda Shoenfeld, M.D., FRCP, is a world-recognized immunologist and
the innovator primarily responsible for much of our IgG-based technology
development and know-how.
Corporate History
We
were incorporated under the laws of the state of Delaware on October 6, 1998
under the name of San Jose International, Inc. We engaged in several business
models and acquisition plans, until in June 2004, approximately 27% of our then
outstanding shares of common stock was acquired by Zeev Bronfeld and Vered
Caplan in a private transaction. Shortly thereafter, on August 14, 2004 we
raised approximately $900,000 in a private placement, and, pursuant to an
agreement for the purchase and sale of intellectual property between our newly
formed Israeli subsidiary, GammaCan, Ltd., and ARP Biomed, Ltd. (
ARP
),
our subsidiary completed the purchase and sale of ARPs intellectual property
on August 17, 2004 in consideration for the issuance to ARP of 12.5% of the
outstanding shares of our subsidiary. As a result, we became the owner of 87.5%
of our subsidiary which in turn owns all of the aforementioned intellectual
property consisting of IgG research and development, patents and other
intellectual property. At the same time, we also made a loan of $800,000 from
the proceeds of the private placement to the subsidiary to finance its new
business. On August 19, 2004, we changed our name to GammaCan International,
Inc.
On
December 13, 2007, we entered into a Share Purchase Agreement made as of
November 26, 2007 with ARP. The Share Purchase Agreement provides that, subject
to fulfillment of certain closing conditions, including the receipt of an
Israeli tax ruling, ARP will sell to us 12.5% of the issued and outstanding
shares of our subsidiary such that at closing we will own 100% of the issued
and outstanding shares of our subsidiary. In consideration for such sale, we
agreed to issue to ARP, at closing, 2,697,535 shares of our common stock, a
warrant to acquire 1,123,973 shares of our common stock and an additional
warrant to acquire 449,589 shares of our common stock. Both warrants are
exercisable for five years at an exercise price equal to the average last sales
price of our common stock during the sixty trading days prior to November 26,
2007. The warrants are subject to adjustment for, among other things, stock
splits, stock dividends, distributions and reclassifications. In the case of
the warrant to acquire 1,123,973 shares, if there is a change of control (as
defined therein), then subject to certain restrictions, the warrant shall be
deemed exercised in full and no exercise price shall be payable by the holder.
The securities (and underlying securities) to be issued under the Share
Purchase Agreement will also be subject to a separate lock up agreement and
registration rights agreement upon issuance.
In
connection with the Share Purchase Agreement, ARP and our subsidiary agreed to
enter into an amendment of the agreement for the purchase and sale of
intellectual property from ARP, which amendment specifically delineates clarity
of title and related issues to certain intellectual property sold under the
original agreement.
Background
Current Approaches to Cancer Therapy
Cancer
is a malignant condition which starts in a cell of a specific organ in the
body. If left untreated, the cancer will grow in size, affect the organ, and
ultimately spread (metastasize) to other
organs throughout the body where it will also grow and affect the vital
function of the organs to which it has spread. Malignant cancers are ultimately
terminal because they affect vital organ function. The rate at which these
events occur depends on the natural course of the specific cancer, host factors
such as the general health of the patient, his or her age, the ability of his
or her immune system to deal with the cancer, and other factors.
4
In
general and whenever possible, primary cancers are surgically removed,
particularly if the tumor has not spread beyond the site where it originated.
In most cases excision will be curative if the cancer has not spread (e.g. such
is the case with early stage melanomas). For some cases, adjuvant chemo and/or
radiation therapy may be indicated, even when the primary tumor does not appear
to have spread elsewhere. Once the cancer has spread beyond its primary site, a
variety of therapeutic options are available depending on the location and
extent of metastases and the natural history of the cancer. Patient factors
also play a role. Therapeutic options can be one or more of the following:
Further surgical removal;
Chemotherapy the use of drugs designed to destroy
cancer cells;
Radiotherapy the use of radiation to kill the
cancer. Radiation may be administered externally (e.g. x-ray) or via a drug
that targets the cancer (brachytherapy);
Hormonal therapy Some cancers are hormone-sensitive
(e.g. prostate and breast);
Immunotherapy the use of drugs such as antibodies or
cancer vaccines that attack the cancer immunologically; and
Combinations of any of the above.
More
recently, the use of antibodies plus chemotherapy has emerged as a promising
approach to treat cancers.
Use of Immunotherapy in Cancer Treatment
Cancer
develops from a single abnormal cell. Most individuals immune systems
recognize the cancer cell as a foreign invader and destroy it. Under certain
conditions, however, when the individuals immune system is inadequate or when
the cancerous cell fools the immune system into treating the cell as normal
tissue, the cancerous cell will multiply unchecked and over time cancer will
develop. Because of the importance of the immune system in protecting against
cancer in the natural state, there has been extensive research dedicated to
enlisting immunological approaches to treat cancer. These may be summarized as
follows:
Immunoglobulin
or Antibody-Based Treatments
Antibodies
are plasma-derived proteins (also called immunoglobulins) that bind or interact
with one specific (unique) target. The body synthesizes antibodies to destroy
and eliminate any cell or organism that bears (expresses) the target to which
the immunoglobulin is specific. After the antibodies have bound to their targets,
immune cells (B and T cells and macrophages) effect the destruction of the
target cell and remove the debris.
Scientists
have harnessed the bodys tools and are now able to make antibodies against
virtually any target. Antibodies are manufactured outside the body, usually in
cell lines, in large manufacturing
plants. These antibodies are generally monoclonal - and may affect the cancer
in a variety of ways:
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A
monoclonal antibody may attack the tumor cell itself. An example of such a
drug is Herceptin trastuzumab (it binds to the HER-2 receptor which is
over-expressed in cancerous breast tissue), used in the treatment of certain
patients with breast cancer;
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The
antibody may react against a substance that is secreted by the tumor to
enhance its own cancerous capabilities (for example to stimulate the
formation of new blood vessels). Avastin bevacizumab (it targets VEGF, a
growth factor that stimulates blood vessel formation or angiogenesis), used
to treat colon and other cancers, is an example of such a drug;
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The
antibody may attack a target central to the modulation of the immune system.
Although there are no approved therapies available for cancer, there are
several products in late stage development including anti-CTLA4 antibodies
(Antegren natalizumab targets a receptor in the Integrin family and is
approved for the treatment of multiple sclerosis).
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We
are developing immunoglobulin or antibody-based therapies. We use more than one
antibody, which we understand enhances our product vis-à-vis the others
discussed above. Moreover, we harvest IgG from human donors, which we think
makes our IgG-based therapy safer than others.
Our donors are considered healthy and are extensively screened for possible
diseases or contaminants.
Immunoglobulins
are also used in combination with chemotherapeutic drugs as an adjuvant
therapy. We are active in developing this approach as well.
Cell-Based Therapies
There
are two basic approaches to this therapy. The first involves harvesting the
patients own immune or other cells, manipulating them outside the body and
then returning them to the patient as an anti-cancer therapy. A second approach
involves taking established immune or other cells and giving them to a cancer
patient. Clinical and commercial development of cell-based therapies has been
challenging and there are no commercial products in the market at present.
Tumor Vaccinations
This
is the use of tumor extracts or other substances related to the tumor to induce
the patients immune system to act against the tumor. Such vaccines would work
in a manner similar to any other vaccine (e.g. rubella, varicella) except that
the target is an internal invader, the cancer, rather than an external
pathogen such as a virus. To date, only two cancer vaccines are commercially
available (Melacine, sold by GlaxoSmithKline in Canada to treat melanoma and
Mercks Gardasil® human papilloma virus vaccine to prevent cervical cancer)
.
We are also pursuing novel ways to
leverage our knowledge of the immune system, IgG biology, and the cellular
immune response in order to develop cancer vaccines.
Immune Modulators
Small
stretches of nucleic acids have been shown to be
immunostimulatory
. These molecules affect the innate immune
response by means of so called pattern recognition receptors. Several
therapies based on this concept are in clinical development.
6
Stage III and Stage IV Melanoma
Melanoma
is a serious skin cancer that originates from the transformation (e.g.,
conversion from normal cells to cancerous cells) of melanocytes, the skins
pigment (melanin) producing cells. In 2002, the American Joint Committee on
Cancer (AJCC) published a revised staging system for melanoma comprising five
different stages of the degree of the disease (Stages 0 through IV).
Current
therapies for melanoma, especially those available for the treatment of Stage
III and Stage IV metastatic melanoma, are unsatisfactory. Chemotherapy, with
or without the addition of biologics, have improved survival only slightly,
if at all, and the overall prognosis in these patients is poor. Interferon
(IFN), interleukin-2 (IL-2) and dacarbazine are the most commonly prescribed
therapeutics for the treatment of Stage III and Stage IV melanoma. Their
efficacy is moderate and these drugs are plagued by significant side effects.
Newer therapies, including monoclonal antibodies and vaccines, are still in
development stage. Accordingly, new approaches for the treatment of melanoma
are being actively pursued and metastatic melanoma remains a major unmet
medical need.
According
to the American Cancer Society (ACS):
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there were
62,160 new cases of melanoma diagnosed in the U.S. during 2006; and
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the
incidence of melanoma in the U.S. has doubled since 1973 and has doubled
around the world as well.
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If
recognized early, melanoma is curable by surgery alone. Most new cases are, in
fact, cured surgically. For Stage 0, simple excision is 100% effective. For
Stage I melanoma, surgery is also almost 100% effective.
Melanoma
can be a particularly aggressive cancer. Although melanoma accounts for only 4%
of all skin cancers, it accounts for 80% of all skin cancer deaths. Once the
disease has spread, the prognosis worsens dramatically. There have been no
significant advances in improving the survival of patients with advanced
melanoma (Stages II to IV) in the ten last years and limited success in
improving their quality of life. We are committed to developing better and
safer immune-mediated approaches to treat melanoma and other cancers.
We
believe that the U.S. melanoma market will continue to grow significantly in
the next few years as a result of:
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ozone depletion;
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increased
exposure to the sun; and
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population
growth in the sunbelt.
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Market
researchers estimate the number of melanoma cases will grow from 731,000 cases
in 2004 to over 1,000,000 cases in 2010.
According
to Navigant Consulting, the worldwide melanoma market is expected to double
from $265 million in 2004 to over $600 million in 2009. Experts estimate that
it will exceed $1 billon in 2010. The U.S. accounts for close to 50% of the
worldwide melanoma market.
7
Intravenous Immunoglobulin (IgG)
Intravenous
immunoglobulins are manufactured from human plasma. More than 12 million liters
of source plasma are collected annually in the U.S. Virtually all this plasma
is collected from paid donors.
The
plasma industry has existed for more than 50 years and has developed
substantial experience and know-how in methods to attract, recruit and retain
donors. The industry recruits individuals to donate plasma for the manufacture
of standard plasma products as well as other individuals who agree to be
immunized prior to the donation of plasma for the production of specific
immunoglobulin preparations (e.g., rabies immune globulin, Rh immune globulin,
hepatitis B immune globulin, etc.). This also includes recruiting specific
patients whose plasma contains commercially valuable constituents, particularly
for use as control reagents in the diagnostic field and for research (e.g.,
patients with anti-mitochondrial antibodies, patients with various
hyperglobulinemic syndromes, etc.).
Plasma
for manufacture into
plasma derivatives
is
collected by
plasmapheresis
. This
is a process where the donor is connected to a machine for about 40 minutes.
The machine extracts plasma, and returns the bloods cellular components to the
donor automatically. Plasma collected by this approach is termed
source plasma
. On average, about 800 to
850 mls of plasma are harvested per donation. Donors may donate twice per
week and are monitored with an FDA-mandated series of tests with every donation
which includes a plasma protein determination and testing for transmissible
diseases. There is substantial literature going back more than 30 years
indicating that regular plasmapheresis donors suffer no ill effects from this
activity.
Strategy
Our
business objective is to become a recognized leader in the development of
immunotherapy and related approaches to treat cancer. We intend to pursue our
objective by implementing the following key strategies:
Market
Introduction of VitiGam Through Its Designation as an Orphan Drug
In
August of 2007, we received Orphan Drug Status
by the FDA VitiGam for the treatment of Stage IIB to Stage IV metastatic
melanoma. Orphan Drug Status is granted by the FDA to promote the development
of drugs for diseases affecting fewer than 200,000 people in the U.S. Orphan
Drug Status provides us with the following:
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seven year
period of market exclusivity;
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waiver of
fees required for FDA filings and registrations; and
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tax
incentives for up to 50% of clinical development costs.
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We
are currently also applying for Orphan Drug Designation for VitiGam for Stage
IIB to Stage IV metastatic melanoma in the E.U. and its member states. Similar
to the FDA, the European Medicines Agency (
EMEA
) grants Orphan Drug Designation to
promote the development of drugs for diseases with a prevalence of fewer than 5 cases per 10,000 inhabitants.
If granted, Orphan Drug Designation would provide us with the following:
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ten year
period of market exclusivity;
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fee
reductions;
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protocol
assistance (scientific advice); and
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European
Community and member state specific incentives.
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Leverage Our Capabilities in
Order to Bring to Market
Novel and Improved Cancer Therapy Products
We
intend to leverage our IgG-based technology, the expertise of our development
team, and the expertise of GammaCans research and development partner, Sheba
Hospital in Tel HaShomer, and Professor Yehuda Shoenfeld, M.D., F.R.C.P., a
world renowned immunologist.
Leverage
Our Research and Development Efforts to Attract Collaborative Partners to
Assist Us
We
intend to utilize our research and development efforts to attract collaborative
partners with expertise in, and resources necessary for, clinical trials and
manufacturing. By entering into collaborative arrangements, we anticipate that
we will gain access to sales, marketing, and other resources to expedite
commercialization of our product candidates.
Continue
to Leverage Our Technology to Develop Additional Products
We
intend to build upon our technology to develop the following:
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Next generation (recombinant)
VitiGam
- VitiGam is currently manufactured as a
mixture that largely consists of IgG molecules (antibodies of the IgG type).
We anticipate that within this mixture, only a subset of IgG molecules will
be responsible for the biological activity of VitiGam. Next generation
VitiGam will be composed of
only the IgGs
required to exert the anti-melanoma effect
, thereby creating a
more effective compound. Identifying the relevant IgGs may also permit cost
reductions;
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Cancer vaccines based on
VitiGam
- An off-the-shelf cancer vaccine is
considered a silver bullet in cancer therapy. We anticipate that based on
our evolving understanding of the specific IgG molecules responsible for the
biological activity of VitiGam, we may be in a position to identify the
corresponding antigens that may be used to develop melanoma cancer
vaccines; and
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Anti-angiogenesis -
We are developing additional
novel IgG-based therapies for cancer and other diseases. These therapies
are based on the disruption of the blood supply to cells. Our scientists
have shown that several mechanisms may be involved in mediating the anti-cancer
effects of IgG-based immunotherapies. Angiogenesis is one of a number of
well known pathways to deprive cells of their blood supply.
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9
Research and Development Program
Foundational
Research
Prior
to our acquisition of ARP intellectual property by us, ARP
scientists conducted extensive pre-clinical research to test the
effectiveness of IgG immunotherapy in treating cancer. They have employed mouse
models of various types of cancers as well as various types of human cancers
introduced into these mice. They have investigated the effectiveness of IgG
treatment at various stages of disease progression, using alternative dosages
and routes of administration. These pre-clinical and preliminary experiments
have shown that IgG treatment prevents metastases and tumor recurrence for a
broad spectrum of cancers with few or no side effects.
Most
pre-clinical experiments were conducted using a standard dosage of 2.0 grams
per kilogram body weight. Additional experiments have shown that our proposed
therapy is effective with low doses of IgG representing 1% (20 milligrams per
kilogram body weight) of the standard IgG dosage. These experiments suggest
that IgG treatment could be affordably administered as a preventive measure.
IgG has been shown in mice experiments to be effective when administered
subcutaneously, intravenously, or through intra-cavitary injection. The option
of alternative routes of administration dramatically improves ease-of-use and
enables the treatment of previously untreatable conditions such as
intra-peritoneal spread (i.e. ovarian carcinoma). IgG has also been shown to be
effective when administered as a whole molecule or as a fraction.
Product
Development
Our
near term focus is to demonstrate efficacy of IgG-based cancer immunotherapy in
human clinical trials. Efficacy is the ability of a drug or other treatments to
produce the desired result when taken by its intended users. If ultimately
proven to be successful, and we can provide no assurance that it will be, we
could be well-positioned to enter into a licensing agreement with one or more
major pharmaceutical partners for late stage clinical development and/or
commercial market development and sales.
IgG
immunotherapy will require regulatory approval before being commercially
marketed for human therapeutic use. Clinical trials generally include three
phases that together may take several years to complete. Phase I clinical
studies (toxicity trials) are primarily conducted to establish the safety and
determine the maximum tolerated dose, or MTD. Phase II studies are designed to
determine preliminary efficacy and establish dosing. Phase III studies are
conducted to demonstrate therapeutic efficacy in a statistically significant
manner at the levels of optimal dose, method or route of delivery into the
body, and the schedule of administration. Once clinical trials are completed
successfully, products may receive regulatory approval. See
BusinessGovernment
Regulation
.
We
are pursuing the development of IgG-based technology to develop
therapies for the treatment of melanoma, as well as therapies directed toward
disrupting the blood supply to cancers, referred to as anti-angiogenesis
therapies.
Our
lead product candidate, VitiGam, is a first-in-class anti-cancer immunotherapy
derived entirely from the plasma of donors with vitiligo, a benign autoimmune
skin condition affecting up to two percent of the general population. We have
demonstrated that plasma from individuals with vitiligo contains anti-melanoma
activities. Based on this, we are developing VitiGam to initially address
Stage III and Stage IV melanoma and possibly earlier stages of melanoma at a
future time.
10
In
June 2007, we completed a non-FDA Phase II clinical trial designed to test the
safety and efficacy of standard IgG (collected and manufactured from general
population donors, which may have included donors with vitiligo) in patients
with prostate cancer, colon cancer and melanoma. In this trial, no serious
untoward effects of IgGs were noted. In one patient with melanoma, the cancer
remained stable or improved over eight cycles of therapy (approximately ten
months).
In
addition to the pre-clinical evidence we have accumulated using
vitiligo-derived plasma, the above observations provide further validation for
our plan to develop VitiGam.
We
plan to file an Investigational New Drug Application, or
IND
, for VitiGam in the near future with
the intent
to conduct a Phase I/II trial to evaluate VitiGam in patients with Stage III
and IV melanoma. We estimate that the costs of this Phase I/II will be
substantial and the timing of initiation of the Phase I/II trials will be based
on several major factors, including our ability to attract sufficient financing
on acceptable terms.
We
are developing additional novel IgG-based therapies for cancer and other
diseases. These therapies are based on the disruption of the blood supply to
cells. Our scientists have shown that several mechanisms may be involved in
mediating the anti-cancer effects of IgG-based immunotherapies. Angiogenesis is
one of a number of well known pathways to deprive cells of their blood
supply.
In
June 2007, we announced the discovery of proprietary IgG sub-fractions which
contain potent anti-angiogenic properties. These sub-fractions may be used for
treatment of disorders resulting from neovascularization (the formation of new blood
vessels or angiogenesis).
We
have established a pre-clinical development program to define and characterize
these anti-angiogenic anti-cancer fractions and to test their biological activity in
animal models. We believe that successfully developed therapies derived
from our novel IgG sub-fractions have the potential to address multi-billion
dollar markets. For example, Avastin®, also known as
Bevacizumab
, counteracts
VEGF, a growth factor which stimulates neovascularization, and is used to treat
colon and other cancers. Sales for Avastin® in 2006 were in excess of $2
billion.
We
are also contemplating conducting additional clinical trials to test new
formulations and/or combinations of IgG-based immunotherapies and to test these
formulations and/or methods for different cancers at different stages of
disease progression with varying dosages and routes of administration. To
achieve this, we may elect to partner with a pharmaceutical company to conduct
these further clinical trials, in order to attain broad-based regulatory
approval.
We
expect that it will take a number of years to receive final approval and
registration of our IgG preparation for commercial use as an anti-cancer agent.
Our strategy is to collaborate with a suitable partner to support late stage
(Phase III) clinical development, registration and/or sales for our IgG-based
cancer products.
We
have spent approximately $2.7 million through September 30, 2007 on our
research and development.
Raw Materials
IgGs
are manufactured from human plasma. More than 12 million liters of source
plasma are collected annually in the U.S. Virtually all this plasma is
collected from paid donors. The U.S. supplies the majority of the plasma needed
for the in excess of $6 billion plasma-derivatives market
worldwide. The largest producers of IgG are CSL-Behring, a subsidiary of CSL
LTD., Baxter Bioscience, a business of Baxter International Inc., and Talecris
Biotherapeutics, Inc. (formerly the plasma business of Bayer A.G.s Biological
Products business unit). In addition, there are numerous smaller suppliers
serving the market. We generally depend upon a limited number of suppliers for
our IgGs. Although alternative sources of supply for these materials are
generally available, we could incur significant costs and disruptions in
changing suppliers. The termination of our relationship with our suppliers or
the failure of these suppliers to meet our requirements for raw materials on a
timely and cost-effective basis could materially adversely affect our business,
prospects, financial condition and results of operations.
11
Patents and Licenses
To
the best of our knowledge, we are the only entity to own issued patents
covering the use of IgG-based therapies for the treatment of cancer. We have
been issued two U.S. patents that cover the use of basic IgG to treat cancers.
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U.S. Patent 5,562,902, Immunotherapeutic Method of
Treating Cancerous Disease by Administration of Intravenous Immunoglobulin
claims the use of intravenous IgG or fragments to inhibit melanoma
metastasis. The claims further recite the intracavitary and subcutaneous
administration of intravenous IgG or fragments to inhibit tumor metastasis.
The patent was issued on October 8, 1996.
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U.S. Patent 5,965,130, Immunotherapeutic Method
of Treating Cancerous Disease by Administration of Gamma Globulins
claims the use of 2g/kg bodyweight/month to inhibit the growth of a primary
tumor or metastases. The claims further recite the intracavitary and
subcutaneous administration of intravenous IgG or fragments to inhibit tumor
metastasis. The patent was issued on October 12, 1999.
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In
December 2006, we filed two Continuations in Part (
CIPs
) to
these patents. The first CIP is titled
Administration of Gamma Globulins to Treat
Metastatic Melanoma
and builds on the pre-clinical work conducted
at GammaCan and substantiates these findings with data from our non-FDA
clinical trials. The second CIP is titled
Administration
of Gamma Globulins to Treat Cancer
and provides experimental data
supporting the use of IgG-based therapy for colorectal cancers.
Consistent
with a strategy to seek protection in key markets worldwide, we have been
issued or are prosecuting national counterparts to our issued U.S. patents.
We
have filed two additional U.S. patent applications that cover both composition
of matter and methods for using IgG manufactured from donors with Vitiligo
(VitiGam) and its use in melanoma. The prosecution of these and related
patents is taking place in the U.S. and worldwide.
We
have also filed one additional U.S. patent application covering novel IgG
sub-fractions with potent anti-angiogenic properties. In June 2007, we
discovered that IgGs contain sub-fractions with potent anti-angiogenic
properties which may have application in disorders of neovascularization (the
formation of new blood vessels), including cancer and other diseases. We
anticipate that this discovery may be developed into broad-based cancer
therapies and other therapies that address non-cancer disorders.
We
have also filed a patent application for the utilization of IgG
therapy as a potential treatment of Avian Influenza.
Our
patent strategy is as follows:
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Aggressively protect all current and future technological developments to
assure strong and
broad protection by filing patents and/or continuations in part as
appropriate;
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Protect
technological developments at various levels, in a complementary manner,
including the base technology, as well as specific applications of the
technology; and
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Establish
comprehensive coverage in the U.S. and in all relevant foreign markets in
anticipation of future commercialization opportunities
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We
believe that our success will depend in part on our ability to obtain patent
protection for our intellectual property. Our patent coverage includes a wide
range of matters including but not limited to: a novel method of administering
to a mammal a preparation of IgG for inhibiting tumor metastasis, for treating
primary tumors, and for a broad spectrum of cancerous diseases. Our patents
will both expire in November 2014.
We
believe anyone selling IgG for treatment of cancer is subject to these patents.
However, the validity and breadth of claims in medical technology patents
involve complex legal and factual questions and, therefore, may be highly
uncertain. No assurance can be given that any patents based on pending patent
applications or any future patent applications by us will be issued, that the
scope of any patent protection will exclude competitors or provide competitive
advantages to us, that any of the patents that have been or may be issued to us
will be held valid if subsequently challenged or that others will not claim
rights in or ownership of the patents and other proprietary rights held or
licensed by us. Furthermore, there can be no assurance that others have not
developed or will not develop similar products, duplicate any of our technology
or design around any patents that have been or may be issued to us. Since
patent applications in the United States are maintained in secrecy for the
initial period of time following filing, we also cannot be certain that others
did not first file applications for inventions covered by our pending patent
applications, nor can we be certain that we will not infringe any patents that
may be issued to others on such applications.
We
also rely on trade secrets and unpatentable know-how that we seek to protect,
in part, by confidentiality agreements. Our policy is to require our employees,
consultants, contractors, manufacturers, outside scientific collaborators and
sponsored researchers, board of directors, technical review board and other
advisors to execute confidentiality agreements upon the commencement of
employment or consulting relationships with us. These agreements provide that
all confidential information developed or made known to the individual during
the course of the individuals relationship with us is to be kept confidential
and not disclosed to third parties except in specific limited circumstances. We
also require signed confidentiality or material transfer agreements from any
company that is to receive our confidential information. In the case of employees,
consultants and contractors, the agreements provide that all inventions
conceived by the individual while rendering services to us shall be assigned to
us as the exclusive property of our company. There can be no assurance,
however, that all persons who we desire to sign such agreements will sign, or
if they do, that these agreements will not be breached, that we would have
adequate remedies for any breach, or that our trade secrets or unpatentable
know-how will not otherwise become known or be independently developed by
competitors.
Our
success will also depend in part on our ability to commercialize our technology
without infringing the proprietary rights of others. Although we have conducted
freedom of use patent searches, no assurance can be given that patents do not
exist or could not be filed which
13
would have an
adverse affect on our ability to market our technology or maintain our
competitive position with respect to our technology. If our technology
components, products, processes or other subject matter are claimed under other
existing United States or foreign patents or are otherwise protected by third
party proprietary rights, we may be subject to infringement actions. In such
event, we may challenge the validity of such patents or other proprietary
rights or we may be required to obtain licenses from such companies in order to
develop, manufacture or market our technology. There can be no assurances that
we would be able to obtain such licenses or that such licenses, if available,
could be obtained on commercially reasonable terms. Furthermore, the failure to
either develop a commercially viable alternative or obtain such licenses could
result in delays in marketing our proposed technology or the inability to
proceed with the development, manufacture or sale of products requiring such
licenses, which could have a material adverse effect on our business, financial
condition and results of operations. If we are required to defend ourselves
against charges of patent infringement or to protect our proprietary rights
against third parties, substantial costs will be incurred regardless of whether
we are successful. Such proceedings are typically protracted with no certainty
of success. An adverse outcome could subject us to significant liabilities to
third parties and force us to curtail or cease our development and
commercialization of our technology.
Partnerships and Collaborative Arrangements
We
anticipate that we will enter into strategic relationships for plasma
collection and for the manufacture of VitiGam. There is considerable
specialized expertise associated with the collection and manufacture
(fractionation) of plasma products. There are also significant expenses,
capital expenditures and infrastructure involved in the manufacture of plasma.
We believe that working together with strategic partners will expedite product
formulation, production and approval.
On
December 13, 2005, our subsidiary, GammaCan Ltd., entered into a Research and
Licensing Agreement (the
Research and Licensing Agreement
)
with Tel HaShomer Medical Research Infrastructure and Services LTD. (
THM
),
pursuant to which our subsidiary agreed to provide THM with $200,000 in funding
for THM to conduct a research project relating to the mechanism of action for
intravenous IgG, hyper-immune intravenous IgG and use of intravenous IgG as an
anti-cancer treatment. To date, our subsidiary paid a total of $200,000 to THM
under this agreement. Pursuant to the Research and Licensing Agreement, THM has
granted our subsidiary an exclusive worldwide license to any resulting technology
and know-how as described in the above mentioned agreement.
On
December 23, 2007, our subsidiary entered into an Amendment of the Research and
Licensing Agreement (the
Amendment
) with THM. The Amendment reduces the license fees payable
under the Research and Licensing Agreement and clarifies, among other things, the nature of research activities pursuant
to the Research and Licensing Agreement. Further, the research period under the Research and Licensing
Agreement has been extended for a two year period, commencing January 1, 2007,
and the research funding for this period totals $500,000.
In
connection with this Amendment, we will issue to THM a five year warrant to
acquire 500,000 shares of our common stock exercisable, commencing December 31,
2008, at $0.40 per share. In addition, within 30 days of the acceptance by the
FDA of each new IND application that results from work pursuant to a research
project (excluding INDs pertaining to VitiGam), we will issue to THM a warrant
to acquire 250,000 shares of our common stock at an exercise price equal to the
closing price of our common stock on the date of issuance of such warrant. The
warrants are subject to adjustment for, among other things, stock splits, stock
dividends, distributions and reclassifications.
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In
October 2006, we entered into a strategic agreement with Life Therapeutics,
Inc. (
Life
) for the purpose of
collecting source plasma from individuals with Vitiligo. Under the agreement,
Life will be responsible for the collection, storage, quality control,
import/export, delivery, and supply of plasma to us in such amounts as required
to complete Phase I and Phase II clinical trials for VitiGam. Life is a
U.S./Australian company that specializes in niche therapeutic hyperimmune
products. Life currently operates 13 plasma collection centers in eight
American states and has considerable experience recruiting and collecting hard
to find plasma donors. Life is headquartered in Atlanta, Georgia and operates
facilities in the U.S. and in Australia. In the event that Life, for any
reason, fails to provide us with its total required plasma for the timely
initiation and completion of Phase I and Phase II clinical testing for
VitiGam, we will have the unrestricted right to acquire plasma from other
sources. We recognize the importance of having access to sufficient plasma for
the clinical development of VitiGam as well as for commercial sale. Life and GammaCan have been approved for
a $1 million dollar grant for VitiGams Phase I and Phase II clinical program
by the BIRD Foundation, an Israeli Government non-profit organization that
promotes U.S./Israeli joint programs.
On
September 6, 2007, we entered into an agreement for the purchase and sale of
blood plasma with DCI Management Group, LLC (
DCI
). Under the
terms of the agreement, DCI will collect plasma from vitiligo donors at DCI
operated FDA-approved, IQPP certified donor centers for the manufacture of
VitiGam. The entry into this agreement is part of our revised strategy to
assure a continued and uninterrupted supply of Vitiligo plasma for the clinical
development and long-term commercial sale of VitiGam as we gear up to submit
an Investigational New Drug Application (IND) for VitiGam.
We
have engaged INC Research to assist us in conducting our clinical trials. INC
Research is a therapeutically focused contract research organization engaged in
conducting global Phase I - Phase IV clinical development programs in
therapeutic areas including oncology. INC Research is headquartered in Raleigh,
North Carolina and has 24 offices with a presence in 36 locations worldwide.
We
have also engaged BioSolutions Services, LLC (
BioSolutions
) for various
projects to assist us with the commercialization of our anti-cancer
immunotherapy to treat metastatic cancer. The first project relates to
regulatory consulting services to be provided by BioSolutions in connection
with the application for an IND with the FDA for VitiGam.
Government Regulation
The Drug and Therapeutic Product Development
Process
The
FDA requires that pharmaceutical and certain other therapeutic products undergo
significant clinical experimentation and clinical testing prior to their
marketing or introduction to the general public. Clinical testing, known as
clinical trials
or
clinical studies
, is
either conducted
internally by life science, pharmaceutical, or biotechnology companies or is
conducted on behalf of these companies by contract research organizations.
The
process of conducting clinical studies is highly regulated by the FDA, as well
as by other governmental and professional bodies. Below we describe the
principal framework in which clinical studies are conducted, as well as
describe a number of the parties involved in these studies.
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Protocols.
Before commencing human clinical studies, the sponsor of a new drug or
therapeutic product must submit an investigational new drug application, or
IND, to the FDA. The application contains what is known in the industry as a
protocol
. A protocol is the blueprint for
each drug study. The protocol sets forth, among other things, the following:
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who must be
recruited as qualified participants;
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how often to
administer the drug or product;
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what tests
to perform on the participants; and
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what dosage
of the drug or amount of the product to give to the participants.
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Institutional
Review Board
. An institutional review board is an
independent committee of professionals and lay persons which reviews clinical
research studies involving human beings and is required to adhere to guidelines
issued by the FDA. The institutional review board does not report to the FDA,
but its records are audited by the FDA. Its members are not appointed by the
FDA. All clinical studies must be approved by an institutional review board.
The institutional review boards role is to protect the rights of the
participants in the clinical studies. It approves the protocols to be used, the
advertisements which the company or contract research organization conducting
the study proposes to use to recruit participants, and the form of consent
which the participants will be required to sign prior to their participation in
the clinical studies.
Clinical
Trials
. Human clinical studies or testing of a
potential product are generally done in three stages known as Phase I through
Phase III testing. The names of the phases are derived from the regulations of
the FDA. Generally, there are multiple studies conducted in each phase.
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Phase I
. Phase I studies involve testing
a drug or product on a limited number of healthy participants, typically 24
to 100 people at a time. Phase I studies determine a products basic safety
and how the product is absorbed by, and eliminated from, the body. This phase
lasts an average of six months to a year;
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Phase II
. Phase II trials involve
testing up to 200 participants at a time who may suffer from the targeted
disease or condition. Phase II testing typically lasts an average of one to
two years. In Phase II, the drug is tested to determine its safety and
effectiveness for treating a specific illness or condition. Phase II testing
also involves determining acceptable dosage levels of the drug. If Phase II
studies show that a new drug has an acceptable range of safety risks and
probable effectiveness, a company will continue to review the substance in
Phase III studies.
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Phase III
. Phase III studies involve
testing large numbers of participants, typically several hundred to several
thousand persons. The purpose is to verify effectiveness and long-term safety
on a large scale. These studies generally last two to three years. Phase III
studies are conducted at multiple locations or sites. Like the other phases,
Phase III requires the site to keep detailed records of data collected and
procedures performed.
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New
Drug Approval.
The results of the clinical trials are
submitted to the FDA as part of a new drug application (
NDA
).
Following the completion of Phase III studies, assuming the sponsor of a potential
product in the United States believes it has sufficient information to support
the safety and effectiveness of its product, it submits an NDA to the FDA requesting
that the product be
approved for marketing. The application is a comprehensive, multi-volume filing
that includes the results of all clinical studies, information about the drugs
composition, and the sponsors plans for producing, packaging and labeling
the product. The FDAs review of an application can take a few months to
many years, with the average review lasting 18 months. Once approved, drugs and
other products may be marketed in the United States, subject to any conditions
imposed by the FDA.
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Phase
IV
. The FDA may require that the sponsor conduct
additional clinical trials following new drug approval. The purpose of these
trials, known as Phase IV studies, is to monitor long-term risks and benefits,
study different dosage levels or evaluate safety and effectiveness. In recent
years, the FDA has increased its reliance on these trials. Phase IV studies
usually involve thousands of participants. Phase IV studies also may be
initiated by the company sponsoring the new drug to gain broader market value
for an approved drug. For example, large-scale trials may also be used to prove
effectiveness and safety of new forms of drug delivery for approved drugs.
Examples may be using an inhalation spray versus taking tablets or a
sustained-release form of medication versus capsules taken multiple times per
day.
Biologics
License Application.
Once clinical trials are
completed and the results tabulated and analyzed, a Biologics License
Application (
BLA
) is submitted
to the FDA. The application presents to FDA reviewers the entire history or the
whole story of the drug product including animal studies/human studies,
manufacturing, and labeling/medical claims. Before the FDA applies its
scientific technical expertise to the review of the application, it will decide
if the application gets a priority review or a standard review.
This classification determines the review timeframe. A priority review is for
a drug that appears to represent an advance over available therapy, whereas,
a standard review is for a drug that appears to have therapeutic qualities
similar to those of an already marketed product. Generally, an advisory committee
(the Oncology Drug Advisory Committee, ODAC) will review the BLA and make a
recommendation to the FDA. This outside advice is sought so that the FDA will
have the benefit of wider expert input. The FDA usually agrees with advisory
committee decisions but they are not binding.
The
FDA takes action on the BLA after their review is complete. There are three
possible actions to be taken by the review team:
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Approved
This indicates to a company that it may now market in the U.S.;
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Not
Approved This tells a company that the product may not be marketed in
the U.S. and is accompanied by a detailed explanation as to why; or
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Approvable
This indicates that the FDA is prepared to approve the application upon the
satisfaction of certain conditions. These drug products may not be legally
marketed until the deficiencies have been satisfied, as well as any other
requirements that may be imposed by the FDA.
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The
drug approval process is time-consuming, involves substantial expenditures of
resources, and depends upon a number of factors, including the severity of the
illness in question, the availability of alternative treatments, and the risks
and benefits demonstrated in the clinical trials.
Orphan
Drug Act.
The Orphan Drug Act provides incentives to
develop and market drugs (
Orphan Drugs
) for rare disease conditions
in the United States. A drug that receives Orphan Drug designation and is the
first product to receive FDA marketing approval for its product claim is
entitled to a seven-year exclusive marketing period in the United States for
that product claim. A drug which is considered by the FDA to be different than such FDA-approved
Orphan Drug is not barred from sale in the United States during such exclusive
marketing period even if it receives approval for the same claim. We can
provide no assurance that the Orphan Drug Acts provisions will be the same at
the time of the approval, if any, of our products.
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Orphan
Drug Designation.
The E.U. offers a range of
incentives to encourage the development of orphan drugs for rare disease
conditions in the E.U and its member states. A drug that receives orphan drug
designation and is the first product to receive EMEA marketing approval for its
product claim is entitled to a ten-year exclusive marketing period in the E.U
and its member states for that product claim. A drug which is considered by the
EMEA to be different than such EMEA-approved orphan drug is not barred from
sale in the E.U and its member states during such exclusive marketing period
even if it receives approval for the same claim. We can provide no assurance
that the above provisions will be the same at the time of the approval, if any,
of our products.
Other Regulations
Various
federal and state laws, regulations, and recommendations relating to safe
working conditions, laboratory practices, the experimental use of animals, and
the purchase, storage, movement, import, export, use, and disposal of hazardous
or potentially hazardous substances, including radioactive compounds and
infectious disease agents, used in connection with our research are applicable
to our activities. They include, among others, the United States Atomic Energy
Act, the Clean Air Act, the Clean Water Act, the Occupational Safety and Health
Act, the National Environmental Policy Act, the Toxic Substances Control Act,
and Resources Conservation and Recovery Act, national restrictions on
technology transfer, import, export, and customs regulations, and other present
and possible future local, state, or federal regulation. The extent of
governmental regulation which might result from future legislation or
administrative action cannot be accurately predicted.
Competition
Competition in General
Competition
in the area of biomedical and pharmaceutical research and development is
intense and significantly depends on scientific and technological factors.
These factors include the availability of patent and other protection for
technology and products, the ability to commercialize technological
developments and the ability to obtain governmental approval for testing,
manufacturing and marketing. Our competitors include major pharmaceutical,
medical products, chemical and specialized biotechnology companies, many of
which have financial, technical and marketing resources significantly greater
than ours. In addition, many biotechnology companies have formed collaborations
with large, established companies to support research, development and commercialization
of products that may be competitive with ours. Academic institutions,
governmental agencies and other public and private research organizations are
also conducting research activities and seeking patent protection and may
commercialize products on their own or through joint ventures. We are aware of
certain other products manufactured or under development by competitors that
are used for the treatment of the diseases and health conditions that we have
targeted for product development. We can provide no assurance that developments
by others will not render our technology obsolete or noncompetitive, that we
will be able to keep pace with new technological developments or that our
technology will be able to supplant established products and methodologies in
the therapeutic areas that are targeted by us. The foregoing factors could have
a material adverse effect on our business, prospects, financial condition and
results of operations. These companies, as well as academic institutions,
governmental agencies and private research organizations,
also compete with us in recruiting and retaining highly qualified scientific
personnel and consultants.
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Competition
within our sector itself is increasing, so we will encounter competition from
existing firms that offer competitive solutions in cancer treatment. These
competitive companies could develop products that are superior
to, or have greater market acceptance, than the products being developed by us.
We will have to compete against other biotechnology and pharmaceutical
companies with greater market recognition and greater financial, marketing and
other resources.
Our
competition will be determined in part by the potential indications for which
our technology is developed and ultimately approved by regulatory authorities.
In addition, the first product to reach the market in a therapeutic or
preventive area is often at a significant competitive advantage relative to
later entrants to the market. Accordingly, the relative speed with which we, or
our potential corporate partners, can develop products, complete the clinical
trials and approval processes and supply commercial quantities of the products
to the market are expected to be important competitive factors. Our competitive
position will also depend on our ability to attract and retain qualified
scientific and other personnel, develop effective proprietary products, develop
and implement production and marketing plans, obtain and maintain patent
protection and secure adequate capital resources. We expect our technology, if
approved for sale, to compete primarily on the basis of product efficacy,
safety, patient convenience, reliability, value and patent position.
Competition for VitiGam
We
anticipate VitiGam to be a competitive anti-melanoma drug because of its
anticipated efficacy and safety profile. Treatment options for Stage III and
Stage IV melanoma comprise three drugs from major drug classes as follows:
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Antineoplastics Antineoplastics include chemotherapeutics (alkylating
agents, antimetabolites and antimitotic agents) that are administered
intravenously or orally. Generally speaking, they have significant toxicity
associated with severe side effects to the patient. Antineoplastics are
typically used to treat Stage IV melanoma.
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Immunomodulators Substances that suppress, stimulate or boost the immune
system. These have some efficacy (10% to 20%), with side effects that are
moderate compared to antineoplastics.
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Vaccines
Preparations that aim at coaxing the patients immune system to mount an
immune response against the tumor.
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Because
of the paucity of safe and effective therapies to treat late stage melanomas,
so called off-label use of drugs is common and physicians typically use
antineoplastics approved for other cancers in treating melanoma.
Antineoplastics
and immunomodulators account for 80% of the treatment for Stage III and Stage
IV melanoma. Interferon (IFN), interleukin-2 (IL-2) and dacarbazine are the
most commonly prescribed therapeutics in these categories.
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Schering
Corporations INTRON® A (Interferon alfa-2b, recombinant) dominates the
melanoma market with a 46% market share;
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Chirons PROLEUKIN® (aldesleukin,
recombinant human interleukin-2, rhIL-2) commands approximately 28% of
the total melanoma market; and
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Bayers DITCDOME (dacarbazine,
alkylating agent) accounts for 9%.
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The
majority of the remaining 17% of the market is comprised of a group of
antineoplastics that are sold by Bristol Myers Squibb, Daiichi, Eli Lilly, and
Roche. GlaxoSmithKline is currently the only company selling a melanoma
vaccine.
Scientific Advisory Board
We
maintain a scientific advisory board consisting of internationally recognized
scientists who advise us on scientific and technical aspects of our business.
The scientific advisory board meets periodically to review specific projects
and to assess the value of new technologies and developments to us. In
addition, individual members of the scientific advisory board meet with us
periodically to provide advice in particular areas of expertise. The scientific
advisory board consists of the following members, information with respect to
whom is set forth below: David Sidransky; Richard Spritz, M.D.; Yoseff Yarden M.D., Ph D.; Lynn M.
Schuchter M.D.; and Pearl E. Grimes M.D.
David
Sidransky, M.D.
Dr. Sidransky is the Director of
the Head and Neck Cancer Research Division at Johns Hopkins University School
of Medicine. In addition, he is Professor of Oncology, Otolaryngology-Head and
Neck Surgery, Cellular & Molecular Medicine, Urology, Genetics, and
Pathology at Johns Hopkins University and Hospital. Dr. Sidransky is certified
in Internal Medicine and Medical Oncology by the American Board of Medicine. He
has served as a Director of Imclone since January 2004. He is a founder of
several private biotechnology companies and has served on the scientific
advisory boards of many private and public companies including MedImmune,
Telik, Roche and Amgen. He was formerly on the Board of Scientific Counselors
at the NIDCR and is currently a member of the Recombinant DNA Advisory
Committee at the National Institute of Health (NIH). Dr. Sidransky is a member
of numerous editorial boards. He has over 250 peer-reviewed publications, has
contributed more than 40 cancer reviews, and also has numerous issued
biotechnology patents. He has been the recipient of many awards and honors, including
the 1997 Sarstedt International Prize from the German Society of Clinical
Chemistry, the 1998 Alton Ochsner Award Relating To Smoking and Health by the
American College of Chest Physicians, and the 2004 Hinda and Richard Rosenthal
Award from the American Association of Cancer Research.
Richard
Spritz, M.D.
Dr. Spritz is the Director Human Medical
Genetics Program and Professor of Pediatrics, Biochemistry and Molecular
Genetics at the University of Colorado Health Science Center. Prior to his
tenure at the University of Colorado, Dr. Spritz served as Professor of Medical
Genetics and Pediatrics at the University of Wisconsin. Among his numerous
accomplishments, Dr. Spritz sits on the Medical Advisory Board of Vitiligo
Support International, is a member of the Council of the PanAmerican Pigment
Cell Society, and has chaired a number of NIH Committees. He has for many years
served on various national research advisory committees and for the March of
Dimes Birth Defects Foundation. He has published over 170 peer-reviewed papers
and receives ongoing research support from the NIH, specifically for studies of
the genetics of human pigmentation and autoimmune disorders. Dr. Spritz holds
an M.D. from Pennsylvania State University, was a Resident in Pediatrics at the
Childrens Hospital of Philadelphia, and was a Fellow in Human Genetics at the
Yale University School of Medicine. Dr. Spritz has received many honors and
awards, including the first Annual Research Award from the Society for
Pediatric Dermatology, the Vitiligo and Melanocyte Biology Research Achievement
Award from the American Skin Association, the Tanioku Memorial Lectureship from
the Japanese Society for Investigative Dermatology, and the Alumni Fellow Medal
from Pennsylvania State University.
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Yoseff
Yarden M.D., Ph D.
Dr. Yarden is professor in the Department of
Biological Regulation at the Weizmann Institute of Science in Rehovot. He
received his B.Sc. in Biology and Geology (cum laude) at the Hebrew University
in Jerusalem in 1979, and his Ph.D. at the Weizmann Institute in 1985. Dr.
Yardens research career has been devoted to understanding the role of the EGFR
family of growth-factor receptors and EGF-like growth factors in human cancers.
He has been involved in many crucial developments in this field, including
isolating the EGFR, isolating several neuregulins, establishing the pivotal
role of receptor dimerization in transmembrane signaling, understanding the
role of HER2 in signal transduction and tumor development, and resolving the
process of ligand-induced degradation of oncogenic receptors.
Lynn
M. Schuchter M.D.
Dr. Schuchter is Director of the
Abramson Cancer Center at the University of Pennsylvania and is a world
renowned hematologist and oncologist. Her published research and focus of
investigative clinical trial activity is melanoma and breast cancer. Dr.
Shuchters research has led to the development of leading-edge approaches to
melanoma therapy.
Pearl
E. Grimes M.D.
Dr. Grimes is nationally and internationally
recognized for her work on pigmentary disorders. She lectures worldwide on
pigmentary disorders including Vitiligo, Melasma, and post-inflammatory
hyperpigmentation. Dr. Grimes is the past Assistant Editor of the Journal of
the American Academy of Dermatology, and has served on the Editorial Board of
the Journal of Clinical Dermatology, Practical Dermatology, and Skin &
Allergy News. Dr. Grimes is presently a contributing editor to Cosmetic
Dermatology. As founder of The Vitiligo and Pigmentation Institute of Southern
California and its ongoing research program, Dr. Grimes mission is to provide
cutting edge therapies to patients suffering from Vitiligo and other pigmentary
disorders. She has authored over 100 publications and abstracts and is a member
of: The American Academy of Dermatology; the American Society of Dermatological
Surgery; the American Dermatological Association; Society of Investigative
Dermatology; Dermatology Foundation; and the International Pigment Cell
Society. Dr. Grimes is a graduate of Washington University in St. Louis,
Missouri and completed her Dermatology Residency at Howard University Hospital
in Washington, D.C.
Employees
We
have been successful in retaining the experienced personnel involved in our
research and development program. In addition, we believe we have successfully
recruited clinical/regulatory, quality assurance and other personnel needed to
advance through clinical studies or have engaged the services of experts in the
field for these requirements. As of September 30, 2007, we employed eight
individuals and engaged the services of several consultants. Of our employees,
three were senior management, three were engaged in research and development
work, and the remaining in administration work.
Facilities
Our
principal executive offices are located in approximately 1337 square feet of
office space in Kiryat Ono, Israel. The lease commenced on August 10, 2006 and
lasts for a period of 36 months. The aggregate annual base rental for this space
is $26,827. Since June 8, 2006, we have been leasing a suite in New York
for the use of our CEO. The lease agreement was renewed on June 6, 2007 for
a period of 12 months and the aggregate annual base rental for this space
is $24,000. We believe that our existing facilities are suitable and adequate
to meet our current business requirements. In the event that we should require
additional or alternative facilities, we believe that such facilities can
be obtained on short notice at competitive rates.
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