Interesting results.
Monday May 20, 7:30 am Eastern Time
Press Release
SOURCE: American Pharmaceutical Partners, Inc.
American Pharmaceutical Partners Presents Phase II Trial Results in Metastatic Breast Cancer for ABI-007, a Novel Protein-Engineered Nanoparticle Form Of Leading Cancer Agent Paclitaxel
- Study results presented at 38th Annual Meeting of the American Society for Clinical Oncology (ASCO):
- ABI-007 appears to be well tolerated up to 300 mg/m2 without the need for steroid pre-medication and a reduced need for G-CSF support
- At 300 mg/m2 ABI-007 showed an 88% first-line response rate in metastatic breast cancer and 61% overall response rate, substantially higher than previously reported
- ABI-007 showed activity in breast cancer patients who had progressed despite previous TAXOL(R) therapy
- A novel mechanism of paclitaxel nanotransport was revealed
LOS ANGELES and ORLANDO, Fla., May 20 /PRNewswire-FirstCall/ -- American Pharmaceutical Partners, Inc. (Nasdaq: APPX - News) announced the results of Phase II safety and efficacy trials of ABI-007, a novel protein-engineered nanoparticle form of the leading cancer compound, paclitaxel, on Saturday, May 18, at the 38th Annual Meeting of the American Society for Clinical Oncology (ASCO) in Orlando, FL. Scientists at that meeting also revealed for the first time ABI-007's novel mechanism of paclitaxel transport, utilizing circulating red blood cells as storage vehicles and increasing tumor intra-cellular availability of the active parent molecule, paclitaxel. ABI-007 is under clinical drug development to establish its safety and efficacy and currently is not approved by the FDA, and no representations are made to imply any safety and efficacy attributes of this compound.
"The results from this Phase II study provide clinical evidence that ABI- 007 has the potential to be an important advancement in taxane therapy for the treatment of metastatic breast cancer and other solid tumors," said Patrick Soon-Shiong, M.D., chairman and chief executive officer of APP. "It is exciting to find clinical corroboration of our earlier studies in mouse tumor models that ABI-007 appears to be very active in the treatment of solid tumors. Without the presence of the toxic solvent cremophor, the potential exists for the parent paclitaxel molecule to enter the cell at higher levels where it may exert its anti-tumor effect. Evidence also suggests ABI-007 may provide a novel mechanism for the nanotransport of paclitaxel resulting in increased intracellular availability of the drug.
"Data from the Phase II multi-center study showed a statistically significant dose-response effect of ABI-007 at 300 mg/m2 as a front-line therapy for patients with metastatic breast cancer with a response rate of 88% and that even at this high dose the drug appears to be well tolerated," continued Soon-Shiong. "In addition, because the patients treated with ABI- 007 in the Phase II study were not exposed to the toxic cremophor solvent presently used in current branded and generic formulations of paclitaxel, they did not require pre-treatment with steroids or G-CSF, and tolerated higher doses of paclitaxel than those available from the current formulations as they are approved. This increased dose, in addition to the improved intracellular availability, may have important clinical implications that raise the potential for maximizing the use of paclitaxel in the treatment of solid tumors."
ABI-007 -- A Unique Mechanism of Action
ABI-007 is a proprietary, cremophor-free, albumin-based nanoparticle of paclitaxel, the active ingredient in TAXOL, the world's leading selling cancer-fighting agent marketed by Bristol-Myers Squibb.
Recent research has shown that ABI-007, which is approximately 1/100th the size of a single red blood cell (RBC), acts as a novel biologic nanotransporter for hydrophobic drugs such as paclitaxel by making use of the properties of albumin, resulting in an increased and prolonged intracellular availability of the chemotherapeutic agent. In addition, it is believed that the efficient penetration of RBCs by ABI-007 suggests that the RBC may also serve as a secondary storage depot for paclitaxel and that the RBC then delivers paclitaxel to cells through a sustained-release mechanism, with prolonged activity of the parent molecule.
Cremophor-induced Limitations
Although an effective anti-cancer agent, the cremophor-based formulations such as TAXOL present serious side effects, including neuropathy (temporary and sometimes permanent nerve damage), hair loss, anemia (loss of red blood cells), neutropenia (loss of white cells, with risk of infection), and aching muscles and joints. Most of these side effects arise from the use of cremophor, which is used to ensure paclitaxel is solubilized for intravenous injection. In addition to toxicities, the use of cremophor often requires pre-treatment of the patient with steroids and growth factor (G-CSF) support. Taken together, these factors can significantly limit dosing with this cremophor-based formulation, thereby reducing the potential of paclitaxel therapy.
While the toxic side-effects and limitations of cremophor paclitaxel formulations are well known, scientists have only now begun to recognize that the cremophor solvent may create a more serious impediment to realizing the maximal potential of paclitaxel by entrapping paclitaxel within hydrophobic cores of cremophor micelles in the plasma. According to Alex Sparreboom, Ph.D., Head, Laboratory of Pharmacology, Rotterdam Cancer Institute, "We have shown in our clinical studies that the entrapment effect of cremophor is dependent on its concentration. Thus, increasing doses of cremophor solutions of paclitaxel can actually worsen the entrapment effect, leading to higher toxicities but none of the potential benefits of higher doses of paclitaxel, since much of the active molecule is unavailable to the intra-cellular space, where it is needed to act. We, and recently other scientific groups, have independently confirmed this phenomenon of the entrapment effect by cremophor which may have significant clinical implications for patients receiving cremophor-based paclitaxel and which previously has not been well recognized and understood."
ABI-007 -- Positive Phase II Clinical Results in Metastatic Breast Cancer
Nuhad K. Ibrahim, M.D., from the University of Texas MD Anderson Cancer Center, presented results from two multi-center Phase II studies comparing the safety and efficacy of two doses of ABI-007 given as mono-therapy in 106 patients with metastatic breast cancer. The studies evaluated doses of 175 mg/m2 in 43 patients and 300 mg/m2 in 63 patients, administered once every three weeks without steroid pre-medication or growth factor (G-CSF) support.
Results of the Phase II studies demonstrate that ABI-007 is apparently well tolerated at high doses of 300 mg/m2, administered over 30 minutes without the need for steroid pre-medication and G-CSF support (the FDA- approved dose of cremophor-based formulation such as TAXOL is 135-175 mg/m2). At the 300 mg/m2 dose, ABI-007 was very active in metastatic breast cancer with an 88% first-line response rate and a 61% overall response rate (defined as complete disappearance or greater than 50 percent shrinkage of the tumor mass). In addition, patients who had prior taxane exposure had a 22% response rate to ABI-007 and one patient with taxane resistance exhibited a complete response.
When given at the dose equivalent to the current FDA approved dose for cremophor-based formulations, 175 mg/m2, ABI-007 showed a 50% first-line response rate and a 51% overall response rate. At that dose, it was shown that ABI-007 could be given without steroids. No evidence of severe neuropathy reported.
Status of Development
Preclinical development of ABI-007 began in 1992, and clinical studies were initiated in 1998. To date, over 300 patients have received ABI-007 as mono-therapy in three Phase I and two Phase II clinical trials for a variety of solid tumors to determine safety, dose ranges and efficacy. A multi-center Phase III clinical trial comparing treatment with ABI-007 to TAXOL in patients with metastatic breast cancer is currently underway. In addition, a Phase II trial is underway to explore a weekly dosing regimen of ABI-007 in patients with metastatic breast cancer in which taxane therapy has failed. APP has secured the North American marketing and manufacturing rights for ABI-007 from American BioScience, Inc., which is responsible for conducting the clinical studies of ABI-007.
About American Pharmaceutical Partners, Inc.
American Pharmaceutical Partners, Inc. (APP) is a specialty drug company that develops, manufactures and markets injectable pharmaceutical products, focusing on the oncology, anti-infective and critical care markets. The company is one of the largest producers of injectables, with more than 100 generic products in more than 300 dosages and formulations. APP has acquired the exclusive North American rights to manufacture and market a proprietary injectable oncology product (ABI-007), currently in advanced clinical trials and being studied in a variety of cancers. For more information, visit APP's Web site at www.appdrugs.com . |
