Transave Pipeline

	Status / Phase
Product	Discovery	Preclinical	I	II	III	NDA
Arikace™ (P. aeruginosa Infections in CF)
Cisplatin Lipid Complex (Primary Lung Cancer)
Cisplatin Lipid Complex (Osteosarcoma lung metastases)
Cisplatin Lipid Complex (Bronchoalveolar carcinoma)

Arikace™ - A Potential New Weapon in the Treatment of Gram-Negative Lung Infections

Pseudomonas Infections in Cystic Fibrosis Patients

There are over 70,000 cystic fibrosis patients in the U.S. and Europe. According to the Cystic Fibrosis Foundation (Patient Registry, 2005), 85% of cystic fibrosis patients will contract Pseudomonas aeruginosa lung infections by age 18. Although improved inhaled therapies and nutrition have increased the average life expectancy of a cystic fibrosis patient to 36.8 years, compared to 31 years in the 1990's, improvements still need to be made in enhancing the efficacy of inhaled antibiotic therapy and, most importantly, the patient's quality of life.

Some cystic fibrosis patients spend almost 3-5 hours per day taking medications, including inhaled antibiotics. The current gold-standard inhaled antibiotic is administered twice daily for 28 days followed by a 28-day period "off drug." Any Inhaled treatment that may reduce the weekly treatment burden of a cystic fibrosis patient could represent a significant breakthrough in improving the patient's quality of life.

CF patients produce and build up sputum and the Pseudomonas aeruginosa infection creates a biofilm, which together act as barriers protecting the bacteria from attack. Penetration of this barrier by conventional antibiotics may be impaired and, thus, treatments may be unable to deliver effective dose levels to attack the infection. In addition, many studies have shown that drugs delivered to the lung often have a very short residence time in the lung and are cleared rapidly into the blood stream.

The proprietary liposomal technology upon which Arikace™ is based may make it possible for the antibiotic to overcome the physical barriers presented by the CF patient's own mucus and by the infection's biofilm. Transave has conducted in vitro experiments, which demonstrate that Arikace™ liposomes penetrate into both human CF sputum and the biofilm of Pseudomonas aeruginosa macro-colonies. Attaining close proximity to the bacteria may significantly enhance the antimicrobial effect of Arikace™ as secreted virulence factors from the bacteria have been found to facilitate release of drug from the Arikace™ liposomes. In other words, by causing the liposomes to leak, the drug is released where it is needed most and, thus, the bacteria participate in their own demise. It is postulated that relatively high concentrations of a drug can be delivered locally to the site of an infection thus forming the basis of the possibly enhanced efficacy of Arikace™.

The sustained-release delivery of a drug may reduce dosing frequency to one time per day or less, thereby easing a patient's treatment burden and potentially improving patient compliance. Sustained release of the antibiotic above the therapeutic level (minimal level of drug needed to kill Pseudomonas aeruginosa) may also decrease the potential for the development of resistant strains of bacteria.

The overall product profile that Transave is working to develop for Arikace™ may potentially lead to broader patient usage in the U.S. and Europe and possibly result in: (1) enhanced efficacy through biofilm penetration and facilitated release (virulence factors), (2) reduced dosing frequency, (3) decreased side effects, and; (4) decreased time for administration.

Transave's Arikace™ is locally delivered via inhalation using state of the art nebulizers that may be utilized by cystic fibrosis patients for other inhaled therapies. Transave continues to seek alternatives to the current nebulizer and compressor systems to facilitate speedier delivery of the drug with greater portability than currently available systems.

Arikace™ clinical trials are underway to assess its safety and efficacy, including potential improvements in pulmonary function (FEV-1) and reductions in bacterial load (CFU counts).

Arikace™ has been granted Orphan Drug status in both the U.S. and Europe for lung infections in CF patients that are caused by Pseudomonas aeruginosa.

Other Potential Uses

Arikace™ is also being explored for use in other potential lung infections, such as mycobacterium and bronchiectasis due to susceptible organisms.

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Cisplatin Lipid Complex - A Potential New Paradigm in the Treatment of Cancers Affecting the Lung

Systemic chemotherapy has achieved limited success in the treatment of lung cancer, with only small, incremental improvements in treatment outcomes noted over the last four decades. According to the American Cancer Society, there will be an estimated 162,460 deaths from lung cancer (90,330 men and 72,130 women) in 2006 in the United States, accounting for around 28% of all cancer deaths. Preclinical and clinical studies suggest that the limited success of systemically administered chemotherapeutics is driven by a number of factors, including poor absorption of intravenously administered drugs into the lung (0.1-1%), short pulmonary residence times of the drug, and dose-limiting systemic toxicities.

Transave's Inhaled Cisplatin Lipid Complex is one of the first attempts at localized delivery of a cancer drug to the lung for the site-specific treatment of lung cancer.

Cisplatin is a potent and widely utilized chemotherapy drug administered via the intravenous route, either alone or in combination with other drugs. However, its clinical use is limited by severe toxicities, such as neurologic toxicity, renal (kidney) toxicity, myelosuppression, nausea and vomiting.

The design of the Cisplatin Lipid Complex formulation is intended to deliver targeted concentrations of the anti-cancer agent to the tumor site, while also aiming to minimize systemic exposure and limit the toxicity seen with intravenous administration.

In the current clinical trials, Cisplatin Lipid Complex is delivered via inhalation without the need for hydration prior to treatment. This is in contrast to the standard practice of 2 hours of hydration prior to slow intravenous infusion of cisplatin (~6 hours). The inhalation route of administration for Cisplatin Lipid Complex may offer an improved route of delivery and provide an improvement in the quality of care of lung cancer patients. This remains to be demonstrated in clinical trials.

The results of a Phase IIa clinical trial in eighteen end-stage lung cancer patients was published in abstract form at the 2006 American Society of Clinical Oncology meeting. The findings suggested that Cisplatin Lipid Complex was well tolerated for up to 6 dose escalations and minimized the dose-limiting toxicities commonly seen with intravenous cisplatin administration.

Cisplatin Lipid Complex is currently in Phase II clinical trials in patients with bronchoalveolar carcinoma and in patients with lung metastases from recurrent osteosarcoma, a type of bone cancer that is most common in children and young adults.

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FUTURE PIPELINE OF PRODUCTS

Transave's Liposomal technology can be applied to virtually any molecule, including small and large molecules, as well as genes. Therefore, Transave is evaluating a number of liposomal formulations in order to build a robust pipeline of Inhaled products.

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With its innovative liposomal technology, Transave strives to create valuable later stage product candidates, a robust product pipeline and a strong intellectual property position.