Drug Delivery Technologies

TRANSDRUG®

Scientific Papers

Doxorubicin Transdrug®

Lead Product: 10 mg vial lyophilized doxorubicin polyisohexylcyanoacrylate nanoparticles

Rational:

• Overcome resistance by bypassing Multi Drug Resistance (MDR) mechanisms
• Doxorubicin Transdrug® delivers ion pairs into the cytoplasm
• Blinds the different pumps involved in drug resistance (P-gp, MRP) to doxorubicin
• Direct targeting of cells or tissues
• Controlled release for prolonged activity

• Hepatocellular Carcinoma (HCC - primary liver cancer) via the intra-arterial route of administration

Development Status:

• Phase I/II Clinical Study in the EU completed
• Awarded Orphan Drug Status in the EU
• Awarded Orphan Drug Status in the U.S
• Phase II/III in the EU ongoing
  

Transdrug® Technology

Cancer resistance, whether it relates to spontaneous or acquired resistance, has become a serious problem in cancer treatment, and multi-drug resistance (MDR) at present is the main cause of chemotherapy treatment failure. For instance, about 60% of all breast cancer patients develop resistance after chemotherapy.

The MDR problem becomes obvious when after several cycles of chemotherapy some tumor cells, including in particular those associated with hepatocellular carcinoma, can become resistant to the chemotherapeutic agent, which results in a loss of their response to further therapy.

One of the underlying molecular rationales for MDR is the up-regulation of a family of transmembrane transporter proteins, particularly the ATP-dependent P-glycoprotein (Pgp) that is the product of the MDR-1 gene. The Pgp "pump" actively decreases the intracellular concentration of a therapeutic agent, such as the taxanes, vinca alkaloids, anthracyclines or platinium derivatives, by pumping the agent out shortly after it has entered the cell and stopping the agent from exerting its therapeutic function.

BioAlliance has developed a proprietary technology using PIHCA (poly-iso-hexyl-cyanoacrylate), a proprietary polymer to formulate a number of anti-cancer drugs in nanoparticulate form. In the human body, those drug-loaded nanoparticles are translocated into the cancer cell where they can elicit their known anti-cancer activity. Hence the name of the technology: Transdrug®.

Transdrug®, which bypasses MDR mechanisms, is capable of restoring the sensitivity of cancer cells, overcoming resistance in cancer therapy, and thereby filling a very important therapeutic gap in cancer treatment.

Other approaches and strategies have been attempted to overcome MDR and address various mechanisms leading to resistance in cancer treatment. There is increasing evidence that mechanisms in addition to P-gp/MRP do contribute to the MDR phenotype in human malignancies. These mechanisms may cause efflux of active drugs and/or intracellular redistribution of drugs (which lead to cardiac toxicity), thus limiting the efficacy of selective P-gp/MRP modulators and their future utilization in cancer therapy (R. Advani).

Competitors in the field of cancer drug resistance include:

• Liposomal Drug Delivery Systems: several liposomal formulations have been approved (doxorubicin and daunorubicin) for the treatment of ovarian cancer and Kaposi sarcoma. Those liposomes are unable to overcome resistance (P. K. Working)
  
  
• Polymer Conjugates: where anthracyclines (for example) are covalently linked to the polymer, forming a new chemical entity developed as anthracycline analogues (P.A. Vasey)
  
  
• MDR Reversal Agents: designed to specifically interfere with active pumps. These agents however may generate serious (cardiac) side effects (E. Solary)
  

Nevertheless, Transdrug® has shown the ability to restore anti-cancer chemotherapy efficacy in resistant cancer cells in various experimental models and is now in clinical studies to investigate this ability in human subjects.

Essential Properties

Doxorubicin Transdrug® is a PIHCA polymer used in nanoparticular form containing the active cancer drug doxorubicin. This unique and proprietary technology was developed by Professor Patrick Couvreur of the School of Pharmacy at the University of Paris XI (CNRS) and a leading expert in the field of nanoparticles.

Among a number of polymers studied, PIHCA was selected for clinical development because of its specific properties, showing in particular the highest efficacy/tolerance ratio in various animal models. PIHCA is produced from highly purified and characterized monomers, and the subsequent polymerization procedure is well defined and controlled.

Doxorubicin Transdrug® Clinical Development Program

• Phase I solid tumours: completed
• Phase I/II leukaemia: discontinued
• Phase I/II hepatocarcinoma: completed
• Phase II/III hepatocarcinoma : ongoing

In the first Phase I clinical study on refractory solid tumours, the therapeutic pathway followed with doxorubicin Transdrug® was an intravenous injection every four weeks, within a toxic dose limit of 90 mg./m2 due to the haematological side effects for which this type of product is known.

During a first Phase I/II clinical study on patients suffering from resistant leukaemia, the treatment plan called for intravenous administration over three consecutive days. This plan for repeated treatment was not suitable for the pharmacokinetic profile of this product with its extended half-life, which produced serious side effects at elevated doses (130 mg./m2 cumulatively over 2 days). These findings led to the halt (in 2001) of clinical research for a resistant leukaemia indication in situations where this pattern of three consecutive days of treatment is routine.

BioAlliance Pharma finalised another Phase I/II clinical study in June 2006 using doxorubicin Transdrug® on hepatocellular carcinoma (HCC) in 8 clinical sites in France. In this study, the drug was administered using hepatic intra-arterial administration. 20 patients were studied with five dosage levels.

Upon the conclusion of this trial, a dose of 30 mg/m2 was retained on the basis of drug tolerance and efficacy criteria for the remainder of the clinical development of doxorubicin Transdrug®.

These final results were presented at the 7th international conference of the ACOS (Asian Clinical Oncology Society- September 06): 20 patients with advanced-stage liver cancer were treated with at least one injection of doxorubicin Transdrug® via hepatic intra-arterial administration. In the sub-group of patients treated at 30mg/m2, the efficacy results of the study appear to be promising for doxorubicin Transdrug®, with an objective response rate of 16.67% after a single injection. In this regard, a study presented to the gastro-enterology meeting of the ASCO in 2006 reported an objective response rate of 4% with doxorubicin after several intravenous administrations to patients with an advanced-stage hepatocarcinoma.

Liver Cancer

Primary liver cancer (hepatocellular carcinoma - HCC) is the 5th most common cancer in the world and the third most common cause of cancer-related death. HCC with a 5 year of survival rate of less than 5% without treatment is also one of the most deadly diseases.

HCC is the most common cancer of the liver. The incidence of hepatocellular carcinoma is increasing worldwide, but striking geographical differences are observed for both risk factors and occurrence. There are an estimated 14,500 new cases of the disease diagnosed each year in the United States, over 18,300 people diagnosed each year in Europe and over 1 million people diagnosed each year in Asia. Primary liver cancer is increasing by 8% each year in Western countries. The majority of patients with HCC do not live a full year after the initial diagnosis. In addition, approximately 73,000 people are diagnosed with metastatic liver cancer in the United States each year, 175,000 people are diagnosed each year in Europe and over 280,000 people are diagnosed each year in Asia. Metastatic liver cancer is a serious disease because the liver is the site to which the majority of other cancers ultimately spread.

The incidence of HCC in developing countries is two to three times higher than in developed countries. These variations in HCC incidence have been described and suggest differences in exposure to risk factors. Chronic infection with the hepatitis B virus (HBV) and hepatitis C virus (HCV) in the aetiology of HCC is well established. In Europe, 28% of HCC cases have been attributed to chronic HBV infection and 21% to HCV infection. Other risk factor such as alcohol consumption, cigarette smoking and oral contraceptives may explain the residual variations within countries.

The difficulties in treating HCC and the high mortality associated with it are attributable to a number of factors like cirrhosis, which limits treatment options of the cancer, and also the fact that HCC is usually asymptomatic at early stages and has a great propensity for intravascular and intrabiliary extension, even when the primary tumour is small. As a result, the carcinoma is frequently at an advanced stage when discovered and most are beyond curative treatment.

Current Treatment

A significant near term market opportunity for BioAlliance is in HCC, in the U.S., Europe, and Japan. By 2006/2007, we estimate these three markets represent a total opportunity of approximately $200 million. China also represents a significant revenue opportunity given its high incidence of HCC and enormous population with currently over 200,000 estimated cases of HCC annually.

These market estimates assume only a portion of the HCC population are immediately eligible for doxorubicin Transdrug® treatment, and recognize that the use of trans-arterial chemoembolization ("TACE") has been broadly adopted in Japan. We believe the market potential could be substantially greater because doxorubicin Transdrug® is less toxic to the liver and can be used in both earlier stage HCC, and later stage HCC where an already weakened liver cannot tolerate TACE. There is currently no alternative therapy for the HCC population whose tumors have progressed beyond surgical resection and for whom TACE is contra-indicated, including patients with impaired liver function, larger or multi-focal tumors, and portal vein thrombosis.

When a patient is diagnosed with primary liver cancer, the first treatment of choice is surgical resection to remove the entire tumor. However, due to the late stage at which this disease is diagnosed, tumors are often large in size and several in number and only 20-30% of patients qualify for surgery. In those patients that do not qualify for surgical resection, there are three alternatives for therapy, none of which are approved.

• Systemic chemotherapy (intravenous) is sometimes used but due to limited efficacy and systemic toxicity, the tolerable doses are typically ineffective.
  
  
• Two intra-arterial (IA) approaches are used: IA with lipiodol and doxorubicin has been reported and yields about a 12% response rate. This increases to 23% if mitomycin C is added to the doxorubicin and lipiodol.
  
  
• A third option is chemoembolization wherein drugs are injected IA with an embolizing agent to prevent blood flow for a short period of time, thus allowing the chemotherapeutic drugs to “dwell in the diseased lobe of the liver for 20-30 minutes before blood flow has to be restored. Unfortunately, in many patients treated in this fashion, this therapy is accompanied by post chemoembolization syndrome and 30% of these patients require extended hospital stays. To date, changes in life expectancy/survival have not been prospectively demonstrated with any of these therapies.

As indicated, there are currently no approved therapies for the treatment of HCC. The only proven potentially curative therapy for HCC remains surgical, either hepatic resection or liver transplantation. Current non-surgical treatment strategies include percutaneous ablative therapy, radiofrequency ablation, and chemoembolisation, but these therapies should only be used where surgical therapy is not possible.

The need for effective therapy and new treatment strategies in HCC management remains huge. These treatments should take into account the chemo-resistant profile of HCC, which is the main reason for treatment failure.

Cytotoxic agents have been used extensively to treat cancer since the early 1940's. However, the non-specificity of these drugs toward healthy cells in addition to cancer cells has curtailed their administration at the most therapeutic or efficacious levels. Therefore, developing a delivery system that specifically targets tumor cells, reducing toxicity to healthy cells and overcoming drug resistance, would constitute a significant advance in treating various cancers with standard chemotherapy.

Our lead product, doxorubicin Transdrug®, is designed to deliver the anthracycline drug, doxorubicin, one of the most widely prescribed therapeutic agents in cancer. As a single agent or in a combination regimen, doxorubicin has a 15-20% response rate in HCC, making it one of the more effective single agent drugs. However, a high risk of cardiac toxicity is associated with doxorubicin and limits its use as a front line treatment for non-resectable patients.

An even larger market opportunity exists for the treatment of metastatic liver tumors, which we estimate to be significantly larger than the HCC market. In order to expand the use of doxorubicin Transdrug® into this market, BioAlliance plans to conduct a Phase I/II study in patients with liver metastasis from colorectal cancer via the IV route of administration. Phase IIb studies in this indication will be initiated once the current studies in HCC have progressed to a more advanced state where safety and dosing requirements have been clearly demonstrated.

Scientific Papers