has a ‘virtual’ Development organization.
General reasons for this strategy include drug development is costly and
a high-risk activity, return on investment is years away, and Pharmagenesis
intellectual property is based on multiple different product candidates.
Most importantly, it
is our strategy to develop the ‘best medicines’ from TCM and thus far that
includes low molecular weight single chemical entities and large molecular
weight mixtures. TriptoSar and
WilGraf are low molecular weight examples and, PG2 and PG2-2000 are high
molecular weight examples. These
product opportunities require different facility capabilities and staff
expertise for active pharmaceutical ingredient manufacture.
Likewise, we have both intravenous and oral formulations for drug
products that also require personnel and facilities. For example, TriptoSar is an intravenous formulation and
WilGraf is an oral formulation.
Thus our development process strategy was to hire consultants for all development activities (see Management section) and employ vendors with requisite knowledge and experience. In other words, we focus on our core technologies and what we do best and outsource Development via consulting teams and vendors.
TriptoSar in cancer
Cancer is the second
leading cause of mortality in the United States.
There is an unmet need for drugs with efficacy as single agents that can
also be used in combination with current therapy to enhance responses.
Pharmagenesis, Inc. compound PG490-88 shows promise to be such an agent.
TriptoSar (PG490-88Na i.v. formulation) is a patented
semisynthetic prodrug of PG490 that is an active compound isolated from a
Chinese plant traditionally used to treat autoimmune disease.
TriptoSar is Pharmagenesis, Inc. lead NCE for worldwide development in
cancer treatment via a mechanism of inducing apoptosis.
An investigation into its mechanism of action revealed that PG490 suppresses T lymphocyte activation by inhibiting the activation of transcription factors and transcriptional activation.
severe limitations, and new approaches are needed to successfully increase the
efficacy of anti-cancer treatment while reducing toxic side effects.
One of the more attractive concepts in cancer therapy is the induction of
apoptosis, or programmed cell death, in tumor cells.
Apoptosis is a controlled physiologic process accomplished by the
activation of constitutive cellular death machinery.
PG490 induces apoptosis in a variety of human tumor cell lines in
vitro, including lung, breast, colon, prostate and lymphoid cancers.
Furthermore, in vivo administration of TriptoSar to mice bearing human tumor
xenografts produces a marked regression and even complete disappearance of
tumors. Although many chemotherapy
agents produce tumor cell killing through apoptosis, malignant cells frequently
exhibit resistance and have defects in the apoptosis induction and signaling
pathways. Despite being resistant
to the effects of conventional chemotherapy, chemoresistant human tumor cells
are sensitive to induction of apoptosis by PG490 treatment in vitro and to TriptoSar in
vivo in human tumor xenografts. Furthermore,
combination treatment including TriptoSar with a chemotherapeutic agent to which
the cells are resistant produces a greatly enhanced effect upon tumors of
chemoresistant cancer cells. CPT-11
(Camptosar®) is a camptothecin derivative approved for first-line use in
colorectal carcinoma. The
combination of TriptoSar and CPT-11 administered over a 12-day treatment course
to nude mice bearing HT-1080 fibrosarcoma tumors (Figure) produced complete
tumor regression in all treated mice by day 20, with no tumor recurrence at
least 180 days later.
pathway is apparently intact in this chemoresistant cell line, and can be
successfully activated by TriptoSar in combination with CPT-11, allowing this
drug to target cancer cells that are resistant to conventional chemotherapy
alone. Synergy was demonstrated
here between TriptoSar and CPT-11. Translation of these findings into clinical reality will allow patients
to be effectively treated with conventional chemotherapy by the addition of
TriptoSar to their treatment or by the use of TriptoSar alone.
The synergies with
chemotherapeutic agents provide a new approach to cancer treatment utilizing
TriptoSar. Each year in the United
States alone there are more than 1.4 million cases of newly diagnosed cancers,
and the combined incidence of lung, breast, prostate and colon cancer is
estimated to be more than 650,000 cases annually. The market potential
for new oncologic agents treating solid tumors is in excess of $1.0 billion in
the United States alone and triple that worldwide.
Clinical Development of TriptoSar in Cancer
Other Anti-cancer Product Leads
The work to enlarge the PG490 derivatives
family as well as to improve their pharmaceutical profile is well engaged.
The objective of the small molecule new leads prodrug program is to identify a backups. A candidate prodrug is defined as one that is completely converted in human plasma to PG490 in less than 48 hours and is chemically stable in water and buffer for greater than 8 hrs. (greater than 90% of the prodrug remaining).
Although the immune system is one of the body's natural defense
mechanisms, there are many clinical situations where suppressing certain
elements of the immune response is therapeutically beneficial.
Thus there are several diseases for which immunosuppressive drugs are the
preferred therapy, and there is a variety of agents with clinical utility in the
suppression of the immune system. The
Fujisawa drug, FK506, Prograf, is used as standard therapy and prophylaxis in
transplantation. Any new drug that
can complement or enhance the effects of FK506 would
be an important addition to transplant medicine.
has been evaluated alone and in combination with FK506 in prevention of
transplant rejection, and the promising results demonstrate remarkable potential
for WilGraf and other PG490 derivatives. The
clinical disease targets for the immune suppression drug discovery program are
the rejection of solid organ transplants, autoimmune diseases such as rheumatoid
arthritis, and graft-vs.-host disease (“GVHD”) associated with the
transplantation of allogeneic bone marrow, and activity has been demonstrated in
animal models of these disorders.
The refined plant extract, PG27, with PG490 as the major active
component, has shown efficacy as single agent therapy in several solid-organ
transplant animal models. In
combination therapy with cyclosporin, PG27 has allowed reduction in the
cyclosporin dose while demonstrating enhanced efficacy.
Note that cyclosporin (Sandimmune, Novartis) is the "gold
standard" of therapy and prophylaxis in transplantation, with worldwide
sales of approximately $1.0 billion.
There are approximately 20,000 organ transplant procedures annually in the U.S. alone and virtually all receive cyclosporin in spite of its side effect.
In 1994, 3000 people in the United States died while on a waiting
list for a donor organ, and currently there is considerable effort to make
animal organs a viable means of extending those lives in hopes of finding an
appropriate human donor. Assuming a
price of $10,000 for a course of therapy, the market potential is $30 million in
the U.S., twice that globally, and many times this amount if xenotransplantation
moves more into the mainstream of medical practice and animal hearts can one day
replace human hearts in transplantation.
Bone marrow transplant is often the only hope for survival of
patients suffering from certain types of cancer, but there is a desperate need
for new drugs to treat the patients whose transplanted bone marrow turns against
them with life-threatening consequences. With 5000 new bone marrow transplant patients annually in the
United States (double this number worldwide) and a $5,000 annual cost of
therapy, the global market potential today is $50 million. The unusual
effectiveness of WilGraf in preclinical animal studies of graft-host-host
disease suggests possible fast track approval of WilGraf for this indication.
In the United States
there are 2.5 million people with rheumatoid arthritis and up to 25 million
people with osteoarthritis. The
market potential is between $25 and $30 billion. Sales projections in a very competitive market like the
United States range from $200 to 300 million.
Additionally, the market potential is significant in the other autoimmune
or inflammatory diseases that may be amenable to treatment with PG27, WilGraf,
and the PG490 prodrugs or the PG490 derivatives.
WilGraf in immune suppression
When incubated in
human plasma, WilGraf reduces viability in Jurkat T lymphoid cells and
suppresses IL-2 production by stimulated Jurkat cells.
The suppression of T lymphocyte activation, proliferation and cytokine
production by PG490 supports the use of WilGraf as an immunosuppressant.
agents like cyclosporin and FK506 suppress conventional immune responses but not
those enhanced by costimulation. PG490
effectively suppresses responses involving costimulation, which contributes to
complex immune responses like xenograft rejection and GVHD.
WilGraf has shown activity in animal transplantation, preventing rat
heart allograft rejection when used alone.
WilGraf demonstrates a promising extension of allograft survival when combined with
FK506. This agent also suppresses
the induction and development of GVHD in allogeneic bone marrow transplantation.
Clinical Development of WilGraf
The strategy for the
development of WilGraf will be as an oral formulation for prevention of kidney
transplant rejection, and would also be expected to be used in combination with
an immunosuppressant like FK506.
A limited option agreement with a one year duration was in operation with Fujisawa until September 30, 2003 to allow limited investigation of pharmacokinetics, toxicology and efficacy of WilGraf.
Fujisawa signed on September 4, 2003 to extend the option agreement for two years.