Clinical Development

Historic

Metastatic cancer patients treated with the Angiostatic Cocktail in compassionate use cases and an earlier clinical trial from 2001 through 2003 elicited successful and objective clinical responses. Four of eight compassionate use patients, where individual doctors administered Angiogen’s protocol and were responsible for ethics approval, exhibited positive results from the Angiostatic Cocktail, with some marked tumor necrosis. In an initial Phase I trial, at a low and controlled dose, the Angiostatic Cocktail was well tolerated and two out of five patients experienced an improvement in tumor serum markers (CA19-9 and PSA in colon and prostate cancer respectively).

A 14 year-old girl suffering from Ewing’s Sarcoma, the second most common type of bone cancer typically occurring between the ages of 10 and 20, was initially unresponsive to either chemotherapy or radiation therapy. Treatment options typically involve chemotherapy, radiation therapy, surgical intervention or a combination of the three. The images below are of the tumor prior to the patient receiving the Angiostatic Cocktail; 6 weeks after beginning the Angiostatic Cocktail, where the tumor had begun to liquefy; and week 12, where there was no radiological evidence of disease. This patient remained free of cancer for seventeen months following cessation of the Angiostatic Cocktail. The cancer did relapse and the patient chose to defer further treatment. Soon thereafter, she succumbed to her disease. A PBS program was aired on January 1, 2001, featuring this case.

A second patient was initially responsive to chemotherapy for his prostate cancer (months 6-12), as can be seen by the low PSA levels below. However, at month 12, even with continued chemotherapy, the PSA levels began to rise. The Angiostatic Cocktail of tPA/Captopril, 6 hr. C.I., daily x 5 days, was administered at month 15 and repeated every 2 weeks. Shortly thereafter, the PSA levels again dropped significantly. This patient continued treatment for several months before voluntarily discontinuing further treatment.

A clinical study of tPA and mesna was completed at Northwestern University utilizing groups of patients with refractory cancer. Cohorts of patients received a fixed dose of mesna (the free-sulfhydryl donor) and escalated doses of tPA. The higher dose cohort showed a significant increase in the plasma level of Angiostatin4.5 (AS4.5) as well as Angiostatin-related Protein (ARP), another, novel angiogenesis inhibitor. The figure below shows the increased levels of AS4.5 and ARP following the administration of the Angiostatic Cocktail and that the effect was dose dependent. At the dose of 6 mg/hr of tPA, the levels of Angiostatin4.5 increased by over two-fold.

Clinical Development / Present

Angiogen is currently conducting Phase I clinical trials necessary for FDA approval in collaboration with Genentech and Northwestern University. The trial involves patients who have otherwise failed cancer therapy. The present and ongoing Phase I trial has reinforced the earlier positive data, with most of Cohort Group I completing treatment and two patients exhibiting partial tumor necrosis. Results from cohort group I have proven incontrovertibly that the Angiostatic Cocktail generates Angiostatin4.5 with minimal side effects.

Angiogen expects to treat approximately twenty patients during the current Phase I trial. The trial consists of three cohort groups, with successive groups receiving escalated dosages to assist Angiogen in determining the optimal amount of drug necessary to generate sufficient amounts of Angiostatin4.5 to inhibit angiogenesis. Cohort group I has received plasminogen activator dosages of 5 mg/hr, 7.5 mg/hr and 10 mg/hr for six hours per day, five days a week, every other week. Cohort group II will receive plasminogen activator dosages of 7.5 mg/hr, 10 mg/hr and 15 mg/hr for six hours per day, five days a week, every other week. Angiogen expects to see escalated generation of Angiostatin4.5 and a concomitant increase in anti-tumor activity as doses escalate.

Angiogen is also treating transgenic mice (mice with human plasminogen) in parallel with the human trials. Three cohort groups have been treated: (i) a group with no treatment; (ii) a group receiving chemotherapy; (iii) a group receiving the Angiostatic Cocktail, which elicited in the best results in the study. The rodent studies are helpful in allowing for the validation and development of the Angiostatic Cocktail in a more efficient manner than can be achieved in human cancer patients. In the next round of rodent studies, Angiogen will use the Angiostatic Cocktail and chemotherapy adjunctively.