Development

Development strategy

Pharmagenesis, Inc. 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.

Anti-cancer products: TriptoSar and other candidates

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.

Chemotherapy has 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.

The apoptosis 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

a)    Further Development in Collaboration with PFM

In collaboration with Pharmagenesis, Inc., Pierre Fabre Medicament (“PFM”) will assume responsibility for worldwide clinical development of TriptoSar.  PFM has designed an ambitious development plan consisting of multiple Phase I and Phase II trials in various tumor types and using a number of dosing regimens, including combination chemotherapy.  The first European clinical trial commenced in 2003 using drug supplied by Pharmagenesis, Inc.

b)    First part of phase I in the US

Pharmagenesis, Inc. conducted the first part of a clinical trial of TriptoSar (PG490-88Na for Injection) in cancer patients at two centers in the United States.  The trial is an open-label, dose-escalation Phase I safety study in patients with advanced solid tumors who failed standard therapy.  The objectives of the trial are to determine the maximum tolerated dose, assess the safety profile, and evaluate antitumor activity of the drug.  Patients are treated with TriptoSar in 4-week cycles consisting of three weekly intravenous injections followed by a 1-week rest period. To date, 15 patients have been treated for up to 5 cycles. No toxicities clearly attributable to study drug have been observed.

Other Anti-cancer Product Leads

The SAR of compounds related to PG490 is under investigation with compounds isolated from the plant, synthetic derivatives and analogues. 

Derivatives

The work to enlarge the PG490 derivatives family as well as to improve their pharmaceutical profile is well engaged.

Prodrugs

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).


Immune Suppression Products: WilGraf and other candidates

Introduction

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.

WilGraf 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.

Market Overview

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

a)    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.

Immunosuppressive 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.

b)    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.


Other Candidates

a)    PG27

PG27, a refined fraction extracted from a plant, is active as an immunosuppressive agent in vitro and in vivo. 

PG27 demonstrates activity in several in vivo models of disease.  The extract suppresses autoimmune disease and inflammation in the collagen-induced arthritis mouse model and inhibits the induction and development of GVHD in allogeneic bone marrow transplantation.  PG27 suppresses rejection and extends survival of rat heart allografts, and suppresses rejection, preserves the function and extends the survival of rat kidney allografts, and shows synergy when combined with cyclosporin.  PG27 suppresses rejection and extends survival of hamster heart xenografts when used in combination with cyclosporin.

PG27 may be used to treat several types of autoimmune diseases (possibly including rheumatoid and/or osteoarthritis, with a large market potential).  PG27 shows activity in a mouse model of rheumatoid arthritis, suppressing the induction of autoimmune disease and inhibiting inflammation.  The development strategy for PG27, which is planned for licensing in portions of the Far East, will be for autoimmune diseases like rheumatoid arthritis.

b)    Other derivatives

There are already two other identified small molecules with immune suppression activity.  They both reduce viability in Jurkat T lymphoid cells and suppress IL-2 production by stimulated Jurkat cells.

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