Trial Information

Phase III, Randomized, Crossover, Double-Blind, Placebo-Controlled Trial Evaluating the Safety and Efficacy of PectaSol-C Modified Citrus Pectin on PSA Kinetics in Prostate Cancer in the Setting of Serial Increases in PSA

This study on the effect of PectaSol-C Modified Citrus Pectin (MCP) with subjects selected
on the basis of documented PC post local therapy, and biochemical relapse, with linear
progression of at least 3 PSA tests in at least 3 months. After initial screening, treatment
{4.8 grams (6 capsules) three times a day away from meals} will continue for 12 months
provided patients are showing benefit and tolerating the therapy well. In the initial six
months of treatment two randomized groups of equal number will receive either blinded MCP or
the blinded placebo. At six months a crossover to the opposite treatment will occur and
continue for the duration of six more months. Patient tolerability of MCP will be assessed
by comparing the results of weekly self-assessment diaries with baseline assessments.

Prostate cancer is the most common cancer among men, except for non melanoma skin cancer. It
is the second leading cause of cancer related death in men. About 33% of prostate cancer
patients treated with primary therapy (surgery or radiation) will recur in the form of non
metastatic biochemically relapsed prostate cancer (BRPC-M0). In these patients, PSA is
rising while scans are negative for metastasis. Recent surveys demonstrated that
approximately 40% of prostate cancer patients use various complementary and alternative
medicine modalities as a component of therapy. Currently, there is no standard treatment for
biochemical failure with proven benefits. Patients are being encouraged to enroll in
clinical trials to help establish standards of care. Studies have shown that in 80% of
patients with BRPC-M0, PSA will rise by at least 25% every 6 months.

Native pectin is a complex carbohydrate soluble fiber. Dietary fibers, such as pectin, have
been shown to have positive effects on a wide spectrum of pathological conditions. Their
positive influence on human health is explained by their antioxidative, hypocholesterolemic,
and anticancer effects. MCP is composed of short, slightly-branched, carbohydrate chains
derived from the soluble albedo fraction of citrus fruit peels, which have been altered by
decreasing the molecular weight and degree of esterification using pH, temperature, and a
controlled enzymatic process. This specific modification is critical as it allows for the
absorption of MCP into the circulatory system and ensures its targeted bioactivity
throughout the body. MCP is relatively rich in galactose and thus antagonizes the binding
protein galectin-3 which results in suppression of cancer cell aggregation, adhesion, and
metastasis. MCP acts as a ligand for galectin-3, which plays a major role in tumor formation
and progression. It has been shown using a combination of fluorescence microscopy, flow
cytometry, and atomic force microscopy, that pectin galactan specifically binds to the
recombinant form of human galectin-3.

MCP showed anti-metastatic effects on cancer cells in multiple in vitro and in vivo studies.
MCP inhibits carbohydrate mediated tumor growth, angiogenesis and metastasis via effects on
galectin-3 function as demonstrated in an animal study on MCP's inhibition of breast and
colon cancer progression. Results demonstrated a 70.2% reduction in breast tumor growth, a
66% reduction in breast angiogenesis, and 0% breast to lung metastasis compared to 100% in
the control group; 0% colon to liver metastasis compared to 60% in the control group; and
25% colon to lymph metastasis compared to 100% in the control group. In an earlier study
oral intake of MCP had been shown to act as a potent inhibitor of spontaneous prostate
carcinoma metastasis in an animal model, demonstrating a significant 56% reduction in lung
metastases. Human cancer cell lines (LNCaP androgen dependent & PC3 androgen independent)
and mouse prostate cancer cell lines (CASP2-1 androgen dependent and CASP1-1 androgen
independent) treated with 1% MCP showed the following cytotoxicity due to induced apoptosis:
52.28% in LNCaP; 48.16% in PC3; 23.03% in CASP2-1; and 49.01% in CASP1-1.13 The effects of
MCP on cell-cell and cell-matrix interactions mediated by carbohydrate-recognition were
investigated by looking at MCP-inhibited B16-F1 melanoma cells adhesion and aggregation. MCP
was shown to inhibit anchorage-independent growth of B16-F1 cells. These results indicate
that carbohydrate-recognition by cell surface galectin-3 is involved in cell-extracellular
matrix interaction and plays a role in anchorage-independent growth as well as the in vivo
embolization of tumor cells. The modulation of the lung colonization of B16-F1 melanoma
cells by MCP was first observed in 1992 when injection of MCP significantly decreased B16-F1
experimental metastasis (greater than 90%). Galectin-3 participation in the adhesion of the
MDA-MB-435 cells to the endothelium was observed by the clustering of galectin-3 on
endothelial cells at the sites of the contact with tumor cells, suggesting its potential
functional significance for anti-adhesive therapy of cancer metastasis. The anti-metastatic
effect of MCP has also been shown in reduced liver metastasis in a dose-dependent manner.
The use of MCP in combination with the chemotherapy drug doxorubicin has demonstrated an
increased cytotoxicity effect of inducing rapid cell death in prostate cancer cell lines
DU-145 (androgen independent) through apoptosis, and in LNCaP (androgen dependant) through
cell cycle arrest (G2-M arrest). These results show promise for the use of MCP with
doxorubicin as an adjuvant to chemotherapy which may allow for lower dosage of the cancer
drug to be used with less toxicity. A human clinical pilot trial with MCP showed an increase
in prostate specific antigen doubling time, a marker of slowing the progression of prostate
cancer. Clinical research on MCP also demonstrated a significant improvement in quality of
life and stabilization of disease for patients with advanced solid tumors.

In addition to its therapeutic roles against cancer, MCP has been shown to remove toxic
metals from the body without affecting essential minerals. In a clinical study, baseline
levels of heavy metals and essential minerals were established with 24-hours urine
collection prior to oral administration of MCP. 24-hours urine collection was repeated on
days 1 and 6. Urinary excretion of lead, mercury, cadmium, and arsenic increased
significantly, essential minerals were not changed significantly and no side effects were
reported. In a hospital study in China, children with lead toxicity were given MCP. Their
blood serum levels went down while corresponding lead levels in their urine increased
significantly, without side effects.

MCP has immunostimulatory properties as demonstrated in human blood samples, including the
activation of functional NK cells against K562 leukemic cells in culture: Unsaturated
oligogalacturonic acids appear to be the immunostimulatory carbohydrates in MCP. Human blood
samples collected from healthy volunteers were incubated with increasing concentrations of
MCP and antibodies. After 24-hours, blood-antibody mix was lysed and run on a flow cytometer
using a 3-color protocol and the % of activated T-cytotoxic cell subset, B-cell, and
NK-cells, and % increase over untreated control calculated and a significant dose dependent
activation was seen. The ability of the activated NK cells to induce leukemia cell death was
analyzed by co-incubating MCP-treated lymphocytes with K562 T-cell leukemia cells and
induced leukemia cell death was determined to be greater than 50%.

MCP has been demonstrated to be protective in experimental nephropathy with modulation of
early proliferation and later galectin-3 expression, apoptosis and fibrosis by
experimentally modulating galectin-3 in folic acid (FA)-induced acute kidney injury. Mice
were pre-treated with normal or 1% MCP-supplemented drinking water one week before FA
injection. During the initial injury phase, all FA treated mice lost weight whilst their
kidneys enlarged secondary to the renal insult; these gross changes were significantly
lessened in the MCP group but this was not associated with significant changes in
galectin-3 expression. At a histological level, MCP clearly reduced renal cell
proliferation but did not affect apoptosis. Later, during the recovery phase at two weeks,
MCP-treated mice demonstrated reduced galectin-3 in association with decreased renal
fibrosis, macrophages, proinflammatory cytokine expression and apoptosis. Galectin-3
inhibition by MCP was demonstrated to block Aldosterone (Aldo) induced collagen type I
synthesis. Rats were treated with Aldo-salt combined MCP for 3 weeks. Hypertensive
Aldo-treated rats presented vascular hypertrophy, inflammation, fibrosis, and increased
aortic Gal-3 expression. MCP treatment reversed all the above effects.

MCP is affirmed as GRAS (generally regarded as safe) under the US Code of Federal Regulation
21CFR184.1588.