Hematopoiesis product: PG2

PG2 in blood cell recovery

The destruction of blood cells is a common liability of many cancer therapies, including both chemotherapy and radiation therapy.

These therapies, while killing cancerous cells, unfortunately, kill some normal cells as well, notably precursors to white blood cells, red blood cells and platelets (WBCs, RBCs, PLTs).  This destruction often leaves the patient extremely vulnerable to infection, prone to bleeding, and anemia leading to a necessary delay in the administration of the next chemotherapy cycle.  In fact, many of these patients may die from these complications of therapy rather than succumbing to the cancer itself.  Also, many leading oncologists believe that if it were possible to administer higher doses and/or more frequent cycles of chemotherapy or radiation therapy, more patients could be cured of cancer than is possible today.

Thus, it would be extremely important to have drugs used in conjunction with cancer therapy, which protect or accelerate development of the blood cells.

The biotechnology industry has produced several valuable blood cell growth factors.  Erythropoietin (EPO) stimulates the formation of new red blood cells.  Granulocyte colony stimulating factor (G-CSF) restores some key white blood cells.

Platelet renewal remains an unmet medical need, although two proteins, IL-11 (approved) and thrombopoietin (in development) hold some promise.  Of course, it is not certain these two new agents will prove safe and effective.  While the blood cell growth factors G-CSF and EPO have been extremely beneficial for cancer patients  (and patients on renal dialysis who suffer from anemia), they share a major limiting liability -- as proteins they are very expensive.

To seek material from the TCM pharmacopoeia with hematopoietic activity Pharmagenesis, Inc. screened 21 TCM plants.  A number of plants show promise, however, one particular plant was chosen for more extensive research because of its broad spectrum of stimulating activity.

Resulting from this effort is PG2, which stimulates, in mice, the growth of white blood cells lines and there are hints that it also stimulates red blood cells and platelets lines in a myelosuppression model.  PG2 will be administered intravenously, whereas products in the pipeline hold promise of oral activity.

Mechanism of action

The mechanism of action of PG2 has not been yet fully elucidated.  Many animal pharmacology studies were conducted to establish the effect of PG2 on the hematopoiesis system.  In both chemotherapy and radiation therapy induced myelosuppression animal models, PG2 is effective in the restoration of granulocyte, erythrocyte, and platelet counts to normal level.  In separate ex vivo studies it was established that PG2 is effective in the stimulation of mouse splenocyte proliferation, which is very predictable so that it is utilized as an internal control for the bioactivity assay for quality control purposes.  Further studies suggest that PG2 may have an effect on the more primitive progenitor cells of hematopoeisis.  The granulocyte, erythrocyte and platelet are lineage-committed mature blood cells.  In order to restore all three cell lines in models of myelosupression, PG2 must exert an effect on a cell that is lineage uncommitted, or in other words a multilineage progenitor cell that may be closely related to a hematopoeitic stem cell.  Recent animal studies suggest that PG2 may be able to mobilize hematopoeitic stem cells.

NDA Clinical Trial in China

The NDA clinical trial conducted in China has shown that PG2 is effective in the restoration of granulocytes in chemotherapy-induced myelosuppression.  However the effect observed in the PG2 treated patients tends to be more sustained and not as exaggerated as that observed in the G-CSF treated group.  The granulocyte count increased in a linear fashion to normal levels by day 4 and never exhibited an overshoot as in case of G-CSF.  The graduated response is consistent with a site of action more removed from the target cell population.  Hence, if PG2 were to stimulate a stem cell or a primitive progenitor cell into commitment for a particular lineage, transformation over time must take place before the mature blood cell will be formed.

Another clinical observation made during the clinical trial is the improvement of Qi (TCM term for life energy or life force) and the quality of life scores (Karnowsky Index).  Unlike granulocyte counts, the patients who responded noticed this effect immediately.  The timing of the response suggests that a different mechanism is in operation.  Numerous publications have attempted to link the effect of Qi with the Hypothalamus-Pituiatary-Adrenal Cortex Axis.  It is suggested in those reports that Qi as described by the Traditional Chinese Medicine may be the effect of some neuroendocrine agent such as endorphin, cortisol, ACTH, etc.  With PG2 being effective in the stimulation of production of numerous cytokines such as G-CSF by the human peripheral mononuclear cells, it is possible that PG2 may also stimulate the production of one or more of those neuroendocrine hormones.  Investigation of the mechanism of action of PG2 is one of the objectives of Pharmagenesis, Inc.

Clinical Development of PG2 in Taiwan

The Department of Health (DOH) in Taiwan has reviewed the IND file for PG2 submitted by PhytoHealth, Pharmagenesis' licensee for PG2 in Taiwan.  DOH deemed PG2 to be satisfactory to enter a clinical trial and permission was granted to PhytoHealth for the initiation of a Phase I/II clinical trial.  This trial is currently underway in Taiwan under the sponsorship of PhytoHealth and conducted at Triservice Hospital in Taipei.  This is an escalating dose protocol in cancer patients undergoing chemotherapy with neutropenia to evaluate the safety and efficacy of PG2.

Acquired Immune Deficiency Syndrome (AIDS)

Aside from the involvement of the lymphocyte cell lineages in AIDS patients, the latter also suffer from numerous abnormalities of hematopoiesis.  70 to 80% of patients develop anemia during the course of their infection.  Up to 50% with more advanced HIV-related immunodeficiency develop neutropenia.  40% of the patients develop thrombocytopenia.  Initially, it was thought that HIV infects hematopoietic stem cells as part of the AIDS pathophysiology, and that multiple lineage cytopenias develop as a consequence of this.  Recent evidence indicates, however, that the hematopoietic stem cell or CD34+ progenitor cell is resistant to infection by HIV.  In contrast, the stromal elements of the marrow microenvironment are readily infected by HIV.  These infected cells have been shown to produce decreased amounts of granulocyte colony-stimulating factor and IL-3, leading to a decreased ability to support normal hematopoiesis.

Potential PG2 usage in AIDS:  PG2 does not have the direct antiviral activity of the modern HAART (highly active antiretroviral therapy) agents.  However, PG2 may well find utility as an adjunct treatment to support the action of a HAART protocol if PG2 can act alone or in combination with another agent to restore normal hematopoiesis in AIDS patients.

PG2 appears to increase RBC, PLT and WBC counts in mice in both chemotherapy and radiation therapy models. It also increases some of the more lineage-committed progenitors of the normal hematopoiesis process, (e.g. CD34+, Kit+, Sca1+ and Lin- cells), and increases the ability of these stem cells to form colonies. The numbers of BFU/CFU-E and CFU-GM are significantly increased.

In AIDS patients, PG2 may enhance the hematopoietic capability and provide generalized support for bone marrow hematopoiesis, benefiting those patients who might otherwise develop anemia, neutropenia, or thrombocytopenia.  PG2 may, in particular, enhance and speed the recovery of hematopoietic capability in AIDS patients undergoing HAART treatment.  In addition, PG2 may enhance lymphocyte function and increase cell (e.g., CD4+) counts in AIDS patients.

PG2 for improving the quality of life, and for cachexia

Cachexia is a condition of severe malnutrition characterized by anorexia, weight loss and muscle wasting that occurs as a consequence of chronic conditions such as cystic fibrosis, cerebral palsy, cancer, AIDS, congestive heart failure, end-stage organ failure, neurological degenerative diseases, chronic obstructive lung disease, chronic liver disease, and chronic renal disease. Cachexia has repeatedly been associated with adverse clinical outcomes, and increased morbidity and mortality. The physiological, metabolic, and behavioral changes in cachexia are associated with patient complaints of weakness, fatigue, gastrointestinal distress, sleep/wake disturbances, pain, listlessness, shortness of breath, lethargy, depression and malaise. Cachexia has also been identified in patients after extensive traumatic injury and sepsis, and in aging persons with failure to thrive syndrome.

Cachexia involves immune changes, and cytokines have been identified in the development and/or progression of the cachexia-anorexia syndrome.  For example, IL-1, IL-6, IFN-g, TNF-a, and brain derived neurotrophic factor have been associated in various cachectic conditions.  Cytokines are thought to participate in the development and progression of cachexia. 

Potential PG2 usage for cachexia

In our animal model for evaluating PG2 therapy for treating myelosuppression induced by irradiation or chemotherapy, we observed that treated mice tended to look healthier and were noticeably more active. Weight analysis of these mice indicated that PG2- treated mice did not loose as much weight as did the control group.  This protection from weight loss (or recovery of weight gain) struck us as being potentially useful in the treatment of cachexia.  In fact, the results of our own PG2 clinical trials in China supported this view.  In addition to blood cell recovery, Qi (a quality of life measure long used in TCM) was found to be significantly improved in treated patients. 

Other Potential Developments

The intention of PhytoHealth is to design and conduct a multinational multicentered phase III clinical trial in South East Asia and Taiwan.  The design of this protocol is under discussion. PhytoHealth is aiming to conduct this Phase III trial such that the participating countries will accept this result as part of the registration requirement for that country.  This is a first in pharmaceutical development for all of the involved countries and therefore requires high degree of coordination in the design and conduct of this crucial trial.  There are some interests from South East Asia markets such as Malaysia and Indonesia for PG2.


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