Back on track

Glioblastomas are the most common and deadliest type of primary brain tumour, afflicting an estimated 10,000 patients each year in European Union (EU) member countries.

They are a high-grade, particularly aggressive type of glioma; tumours arising from the glial tissue that supports and nourishes the brain. Glioblastomas are fast-growing, invade adjacent tissues and carry a poor prognosis.

Patients initially diagnosed with glio-blastoma present with the generalised signs of intracranial pressure including headaches, nausea, vomiting and cognitive impairment. It is also common for patients to suffer behavioural changes and seizures.

Current status
The treatment of glioblastoma remains difficult because there are no current curative therapies and the tumour is usually beyond the reach of local control when it is first detected. As a result, the treatment of patients with malignant gliomas is palliative and encompasses a multidisciplinary approach of surgical resection when feasible, followed by radiotherapy with, or without, adjuvant chemotherapy.

Adjuvant chemotherapy provides a modest but significant effect in prolonging survival when administered after surgery and radiation therapy. However, a major drawback to the use of chemotherapeutic agents for brain tumours is the blood-brain barrier, which acts to keep harmful substances out of the brain, and effectively excludes many agents from the central nervous system.

For this reason, new intra-cranial drug delivery formulations are being developed to deliver higher concentrations of chemo-therapeutic agents to the tumour cells, while avoiding the adverse systemic effects of the medications.

Time to move on
There has been no significant change in the treatment of glioblastoma for 20 years. The most commonly used chemotherapy drugs for newly diagnosed glioblastoma, given after surgery and radiation therapy, are the nitrosourea drugs: carmustine (BCNU), lomustine (CCNU), procarbazine, cisplatin and carboplatin.

However, these medicines are largely ineffective, with median survival rates for glioblastoma typically in the range of nine to 12 months, with 2-year survival rates in the range of only 8 per cent to 12 per cent.

Guilford Pharmaceuticals' Gliadel, a wafer formulation of carmustine, was approved in September 2004 in Europe for the treatment of patients with newly diagnosed glioblastomas as an adjunct to surgery and radiation.

The drug works by alkylating tumour cell DNA and RNA, causing cell death. Gliadel wafers are implanted in the tumour cavity created in the brain after surgical removal and release carmustine slowly, directly to the tumour site.

Gliadel has been shown to prolong the survival of patients significantly compared with those solely undergoing surgery. Schering-Plough's Temodal is an oral alkylating drug that was approved in June 2005 in Europe for newly diagnosed glioblastomas.

It also readily crosses the blood-brain barrier. It is administered in combination with radiation therapy, followed by six cycles of Temodal monotherapy. Results have shown significant improvement in overall survival in patients treated with Temodal and radiation therapy
compared with those treated solely with radiation therapy.

Adis International's R&D Insight lists approximately 37 drugs in either phase II or phase III trials, or that have been submitted for regulatory approval for high-grade gliomas or glioblastomas.

Coming through
Among the late-stage drugs currently in development is Peregrine Pharmaceutical's Cotara, a chimeric iodine-131-labelled monoclonal antibody that specifically targets degenerating and dead cells of human cancers.

Cotara binds to DNA in dead and dying cells that have porous nuclear and cellular membranes, which comprise up to 50 per cent of tumour mass.

Peregrine is currently conducting a phase III registrational trial of Cotara in the US, which is expected to be expanded to Europe where it has received orphan drug status for this indication.

Nycomed and Xenova are currently co-developing TransMid, a conjugate of human transferrin and a modified form of diphtheria toxin known as CRM 107.

TransMid selectively targets transferrin receptors, which are prevalent on the
surface of rapidly dividing glioblastoma cells. Once inside the tumour cell, the diphtheria toxin interferes with protein synthesis which ultimately kills the cancer cell.

A phase III pivotal trial is in progress across the EU, the US and Israel.

TransMolecular is developing TM-601-I-131, comprising a chlorotoxin molecule (a component of the venom from the giant yellow Israeli scorpion) which binds specifically to the chloride ion channels of primary gliomas, conjugated to the iodine radioisotope, I131.

TM-601-I-131 enters glioblastoma cells via the chloride ion channels and causes oxidative damage and apoptosis.

TransMolecular started a phase II study of the compound in June 2005, in the US.

German-based Antisense Pharma is also developing an antisense oligonucleotide compound called AP12009, which targets transforming growth factor-fl2 (TGFfl2). Antisense Pharma is currently conducting a phase IIb trial in Europe in high-grade glioma patients. AP12009 has received orphan drug status for this indication in Europe.

Merck's Cilengitide has demonstrated promising results in a phase I trial and is currently undergoing phase II studies in the US.

The company is collaborating with New Approaches to Brain Tumour Treatment (NABTT) group, a consortium sponsored by the National Cancer Institute. Cilengitide is a vitronectin (avfl3) inhibitor designed to inhibit angiogenesis. It has recently received orphan drug status in Europe

The Author
Pipeline is written by Teresa Wedding of Adis International, using information derived from Adis Clinical Trials Insight and R&D Insight. For more information on Adis services, contact Camille Scot-Smith on 020 7981 0733.