Going for gold

Pharma competes to develop patient friendly formulations for chemotherapy drug

Paclitaxel is a widely used chemo-therapy drug for fighting advanced tumours and metastases. It was launched by Bristol-Myers Squibb as Taxol in the 1990s and its sales peaked at over $1bn in the early 2000s. Following this, the drug went off-patent and was open to generic competition.

A range of firms are now trying to tap into the market for paclitaxel by developing new formulations that are more tolerable and easier to administer. These co-called supergenerics offer pharma firms product differentiation, patent protection and branding opportunities.

Why reformulate?
Paclitaxel is cytotoxic to cells that rapidly divide, hence its effectiveness against tumour cells. It is, however, also active against healthy tissues and organs that have a high proportion of actively dividing cells, for example, bone marrow or hair follicles. Such side effects limit the amount and frequency of drug administration. The standard paclitaxel preparation is formulated with castor oil and ethanol to enhance its solubility in the blood.

To ameliorate severe allergic reactions caused by the solvent, the patient must be pretreated with antihistamines and steroids. Solvent-based paclitaxel also requires special preparation and administration as the solvent can leach plasticisers from standard PVC infusion sets. Additionally, it can take from three to 24 hours to administer a single treatment.

Not a smooth road In September, Sonus Pharmaceuticals revealed that it was suspending development of its new paclitaxel formulation, Tocosol Paclitaxel. This product eliminated the need for a toxic solvent by using vitamin E to dissolve paclitaxel and allowed for intravenous administration within 15 minutes. It was expected this formulation would cause less damage to peripheral nerves (peripheral neuropathy) and hence be more tolerable. Sonus simply had to prove that its product was as effective as standard solvent-based paclitaxel.

Unfortunately, results from a $50m phase III clinical trial showed that the new product had less antitumour efficacy in patients with advanced breast cancer. More surprisingly, it did not show a benefit in peripheral neuropathy. Sonus is now attempting to find out what went wrong. Bayer Schering Pharma, which provided half of the funding for the phase III trial, is rumoured to wish to end its relationship with Sonus.

Route to success
There is one firm that has had success with its reformulation of paclitaxel and a number of other are companies not far behind. Abraxis Bioscience developed a product called Abraxane that comprises paclitaxel bound to a human protein called albumin. This protein is able to carry paclitaxel to tumours throughout the body, without the need for solvent or premedication. This allows for increased doses to be administered over 30 minutes using standard intravenous tubing.

In a pivotal phase III study for metastatic breast cancer, higher doses of paclitaxel could be administered with Abraxane, resulting in a near double increase in tumour response rates, compared with solvent-based paclitaxel.

Abraxane was approved and launched for advanced breast cancer in the US in 2005 and has subsequently been approved and launched in Canada.

The product is currently undergoing regulatory review in the EU for this indication. Abraxane is marketed in the US under a co-promotion agreement between Abraxis BioScience and AstraZeneca. Abraxis also expects to begin phase III clinical development for malignant melanoma and non-small cell lung cancer before the end of 2007. Total sales of Abraxane were $174.9m in 2006.

More to come
Cell Therapeutics is conducting late-stage clinical development with its solvent-free formulation ñ paclitaxel poliglumex (Xyotax). This product consists of paclitaxel linked to a water-soluble biodegradable glutamate polymer, which can be administered without solvents and premedications. It can be infused over 10 to 20 minutes through standard intravenous infusion sets and at higher doses than solvent-based paclitaxel. When bound to the polymer, paclitaxel is rendered inactive, potentially sparing normal tissue from exposure to high levels of unbound, active paclitaxel and its associated toxicities.

The size of the polymer ensures that it is preferentially taken up by the more permeable tumour vasculature. Once in the tumour environment, Xyotax enters cancer cells through endocytosis. The paclitaxel then releases from the polymer and becomes active. Cell Therapeutics is currently conducting phase III clinical trials for ovarian and non-small cell lung cancer, and expects to make its first regulatory filing for Xyotax in the EU during the first half of 2008.

Novartis has obtained the worldwide rights to commercialise Xyotax, except in Japan and certain other Asian markets. Lehman Brothers has given Xyotax a probability of success rating of 50 per cent and are expecting US sales to peak at $343m in 2011.

There are also a number of companies developing liposomal formulations of paclitaxel. These products utilise lipid molecules to encapsulate particles of paclitaxel, thereby making the drug soluble and removing the need for chemical solvent and premedication. Oasmia Pharmaceuticals is conducting a phase III clinical development with its liposomal product OAS-PAC-100 (Paclical) in Eastern Europe. However, market launch in the EU and US is said to be several years away. MediGene is conducting phase II trials with its product, EndoTAGTM-1, for advanced pancreatic and breast cancer. Results from these studies are expected in 2008 and 2009 respectively. Additionally, NeoPharm's liposomal candidate, LEP-ETU, is expected to enter phase II clinical trials for breast cancer in 2008.

Despite the significant advantages that these new paclitaxel formulations offer, they may play only a relatively short-term role in the treatment of cancer. More innovative and targeted cancer therapies are dominating company pipelines and will someday replace the use of cytotoxic compounds like paclitaxel.

The author
Pipeline was written by Ben Benson-Cooper of Adis International, using data derived from Adis Clinical Trials Insight and R&D Insight. For further information on Adis services, please contact Camille Scot-Smith on +44 (0)20 7981 0733