CombiPlex^SM/TM Technology

The Role of Drug Ratios in Combination Chemotherapy to Treat Cancer

Many forms of cancer are currently treated with combinations of individual chemotherapy agents. In developing these drug “cocktails,” clinicians typically combine agents that have non-overlapping toxicities. This makes it possible to combine different agents at their individual maximum dosing levels. While this approach has represented the standard of care in oncology for many years, it generally produces less than optimal treatment options because it fails to recognize the critical role that drug ratios can play in combination chemotherapies.

Research efforts led by Celator have shown that individual chemotherapeutic agents can interact synergistically, additively or antagonistically when combined at different ratios. Thus, the ability to identify the ratio of drugs that will produce a synergistic benefit – and a technology able to control that ratio systemically – could have a profound impact on the overall efficacy of combination chemotherapy agents used to treat millions of cancer patients each year.

Celator’s work represents the first concerted effort to understand the role that drug ratios play in combination therapy and to use advanced technology to develop new and more effective combination chemotherapies able to maintain those ratios in patients. This approach positions Celator to pursue a wide range of product development opportunities based on a portfolio of delivery technologies including liposomes, polymers and nanotechnologies.

CombiPlex and the Opportunity to Improve the Standard of Care in Oncology

The effort to develop new combination therapies with the optimal ratio of combined chemotherapy agents has faced two significant challenges. In developing these therapies, clinicians have not previously focused much attention on the role that drug ratios play. In addition, the advanced technology necessary to develop drug products able to maintain these ratios systemically was not available.

Celator’s proprietary CombiPlex technology platform has shown significant success in identifying and locking in the optimal drug ratios for combination chemotherapies. With this technology advantage, Celator is positioned to develop an expansive pipeline of new combination chemotherapies able to target cancer with enhanced efficacy.

Drug Discovery and Development at Celator

The CombiPlex technology platform positions Celator to pursue a two-stage development process for new products:

• Identify drug combinations that exhibit ratio-dependent synergistic anti-tumor activity using in vitro screening.
• Develop new combination chemotherapy formulations able to maintain the optimal synergistic drug ratio systemically

In this process, Celator identifies formulations that can deliver a synergistic drug ratio in vivo. From there, expanded preclinical studies are used to establish the therapeutic benefits of the CombiPlex formulation. This approach positions Celator to target an expansive range of product opportunities that demonstrate significant and consistent superiority in therapeutic activity compared to uncontrolled combination treatment regimens.

The CombiPlex Advantage at Work

Celator has completed extensive studies comparing regimens involving Irinotecan-HCI:Floxuridine, a combination therapy active against GI tumors. In this effort, Celator studied the ratio dependence of Irinotecan and Floxuridine in 11 cell lines by applying the Chou and Talalay algorithm.

According to the research, for Irinotecan:Floxuridine, the 1:1 molar ratio was generally synergistic, the 10:1 molar ratio generally antagonistic particularly in colorectal cell lines. Due to the disparate pharmacokinetics of these two drugs, administration of the combination as an “unbridled cocktail” would result in a range of drug ratios including antagonistic ratios leading to impaired efficacy.

Targeting the optimal 1:1 ratio for maximum synergistic benefit, Celator developed a CombiPlex formulation of Irinotecan-HCI:Floxuridine (CPX-1) designed to maintain plasma levels of the two drugs at this ratio after injection. Based on this formulation, Irinotecan-HCI:Floxuridine exhibited dramatically improved therapeutic activity in mouse models as compared to the same drug agents combined in a 1:1 ratio in free-drug cocktail therapies. (fig. 1)

The results of these studies indicate that therapeutic activity correlates with maintaining the optimal drug ratio in vivo. Based on these findings, CPX -1 was selected as Celator’s first product candidate and it is now in Phase 2 clinical development.

Drug Development Using CombiPlex

Initially the company will pursue drug development opportunities involving established agents. Building on the promise of the CombiPlex technology platform, Celator has initiated developmental studies in three areas:

• CPX-1 (Irinotecan-HCI:Floxuridine) is in Phase 2 clinical trials as a treatment for colorectal cancer.
• CPX-351 (Cytarabine-Daunorubicin) is in Phase 1 clinical trials as a treatment for acute myeloid leukemia, or AML. (fig.2)
• Platinum-based combinations are in preclinical evaluation as therapy options for a range of head and neck cancers and lung cancers.

Intellectual Property

Celator is pursuing broad patent protection for the CombiPlex technology platform. The Company currently has several additional patent applications pending worldwide. Additional pending patents cover applications related to products developed using Celator’s drug combination carrier technology. Others provide coverage related to technology extending from lipid-based carrier formulation techniques through to novel peptide, polymer and lipid-polymer hybrid technologies.

© 2005 Celator Pharmaceuticals, Inc.