Editor

Even its name is ugly: glioblastoma multiforme. More often known as GBM, the swiftly lethal form of brain cancer leaves patients with few treatment options. For longer-lasting survival, they have none - a grim fact that makes the indication especially appealing to cash-hungry drug developers.

GBM could be hugely lucrative. In the U.S., the disease strikes 8,000 to 10,000 new patients every year, and the numbers will grow with the percentage of elderly people in the population. Sen. Edward Kennedy (D-Mass.) was diagnosed last year.

Until recently, the best drug was Kenilworth, N.J.-based Schering-Plough Corp.'s Temodar (temozolomide), which won FDA approval for GBM in the spring of 2005. Used with radiation and afterward, Temodar was shown to extend the life of newly diagnosed patients by 14.6 months, compared to 12.1 months with radiation alone. Annual sales of the oral chemotherapy, used in first-line GBM and in relapsed anaplastic astrocytoma (another form of brain cancer), have passed the billion-dollar mark annually.

But now there's Avastin (bevacizumab), too, from South San Francisco-based Genentech Inc., cleared under accelerated approval last month by the FDA for single-agent therapy against refractory GBM. The vascular endothelial growth factor inhibitor made in the U.S. by Genentech (now part of Roche AG), already approved for metastatic colorectal and non-small-cell lung cancers as well as metastatic breast cancer, sold about $4.62 billion last year.

"In the U.S., physicians are very high on Avastin," said Ramya Kollipara, analyst with Decision Resources. Overseas, enthusiasm is somewhat less - but there's nothing better, at least not yet. Her firm forecasts 12.6 percent annual growth through 2012 in therapies for glioma, of which GBM is the most malignant form, with sales climbing to nearly $1.4 billion.

Through 2017, annual market growth will slow to 5.7 percent, with sales of more than $1.8 billion, Kollipara predicts. That amount will include Avastin sales of more than $932 million, accounting for more than half of the total glioma market. Temodar use will decline only slightly over Decision Resources' 10-year study period (starting in 2007), because of its use in combination with emerging agents, but sales will fall to $329 million in 2017 because of generic competitors.

In GBM, Avastin represents "a first step," said James Vredenburgh, a neuro-oncologist at Preston Robert Tisch Brain Tumor Center at Duke University, who has been involved in trials with the drug. Since a decade or so ago, when vascular endothelial growth factor was found to be implicated in cancers, many companies have started working on anti-VEGF drugs.

"Avastin was the first, and a lot of us were skeptical," Vredenburgh said, especially since the compound is an antibody. Global Phase III trials with Avastin in newly diagnosed GBM have just begun, he said. Also targeting the VEGF receptor is London-based AstraZeneca's oral Recentin (cediranib), which has reached Phase III trials.

Today, developers aplenty are pursuing their slice of the GBM market pie, with still more therapies using various mechanisms pushing toward approval. The need remains great. GBM is hot.

Data tumbled forth at last week's annual meeting of the American Society of Clinical Oncology. Among the stars was the GBM vaccine CDX-110, for which New York-based Pfizer Inc. and partner Celldex Therapeutics Inc., of Needham, Mass., provided an update on newly diagnosed patients' survival in the Phase II trial. The trial's principal investigator is John Sampson, also from Duke. With CDX-110, the idea is to get rid of stem cells expressing EGRFvIII for better results to follow-on therapy, and progress with CDX-110 represents something of a comeback for cancer vaccines in general. (See BioWorld Today, June 2, 2009.)

CDX-110 would be used in combination with Temodar in newly diagnosed patients. So would Darmstadt, Germany-based Merck KGaA's cilengitide, an integrin antagonist at the Phase III stage. But the Pfizer/Celldex drug will only be useful in about 30 percent of patients, Vredenburgh told BioWorld Insight. He's more excited about XL184 from Exelixis Inc., of South San Francisco, and New York-based partner Bristol-Myers Squibb Co., which also had Phase II data at ASCO. The small-molecule tyrosine kinase inhibitor garnered good results in previously treated GBM patients.

Little News, Big Bounce

So strong is the GBM fever that Peregrine Pharmaceuticals Inc., of Tustin, Calif., provided only a vague update in a press release ahead of ASCO on its Phase II GBM compound. Wall Street responded by boosting the stock almost 60 percent. (See BioWorld Today, May 29, 2009.)

Peregrine said enrollment was almost finished in the second Phase II trial with Cotara, which consists of an antibody attached to a radioactive molecule, and interim data will be reported at the Society of Nuclear Medicine's annual meeting in mid-June. Some GBM patients from early experiments have lived more than 8.5 years after therapy. Survival otherwise averages about six months after the disease recurs.

Kollipara said the Peregrine compound is "a little tough to call" and may face challenges in delivery, though it seems to be moving along well enough so far. Vredenburgh agreed, but praised the approach. "It always confused me that we treat GBM patients systemically," he said, since the tumor only spreads in the brain. "We should treat it locally." Peregrine deploys a convection-enhanced delivery, developed by the National Institutes of Health, which directs Cotara to the tumor by using a catheter to bypass the blood-brain barrier and target the tumor site.

Radiolabeled antibodies may be the key to GBM - or one of them, Vredenburgh said, predicting that VEGF and other growth factors will be important as targets. Another is Neuradiab, with which Bradmer Pharmaceuticals Inc., of Toronto, is conducting Phase III trials, suspended in March while the company mulls strategic alternatives.

Neuradiab was developed at Duke, where researcher Hai Yan recently discovered mutations in two genes - isocitrate dehydrogenase 1, gene 1 and 2 (IDH1 and IDH2) - that could turn into targets as well. As described in a paper he co-authored in The New England Journal of Medicine Feb. 19, Yan and his colleagues found IDH1 mutations in more than 70 percent of astrocytomas and olidgodendrogliomas, as well as in secondary GBM. Those without the IDH1 mutation had similar mutations in the closely-related IDH2 gene, and these mutations decreased IDH enzymatic activity.

It all means IDH mutations are probably important in the start of malignant gliomas, and could mean especially good news for personalized medicine, as therapies are carefully tailored to tumor subtypes. Today, all GBM patients are considered the same.

"We don't want to over-treat or under-treat patients," Yan told BioWorld Insight, especially not with heavy-duty cancer therapies that can have serious side effects. "Now, we can clearly distinguish two different animals [in the tumor subtypes]," he said, which could translate into more options for patients and give the patient options - though this is far from certain.

"First things first," Yan said. "We have to know the relevance of this mutant gene product, and figure out what kind of pathways are involved. Based on the pathway and metabolite profile, we'll screen drugs." Whether the finding is clinically relevant will not be known for "several years," he said.

Meanwhile, other firms - and universities - crank along with a variety of approaches. Ascenta Therapeutics Inc., of Malvern, Pa., has AT-101 in Phase II trials. An oral pan-Bcl-2 inhibitor (including Bcl-2, Bcl-xL, Bcl-w, and Mcl-1), AT-101 yielded positive outcomes in a 56-patient GBM study reported last month by the University of Alabama at Birmingham.

AT-101 is made from cottonseed. Scientists are trying anything that might work against GBM, "the worst of all malignancies," Vredenburgh said. The need is so great that Phase III trials are hard to recruit. "Patients are not willing to accept a placebo or standard of care," he said. "They demand that [experimental] therapy."

Randy Osborne can be reached at randy.osborne@ahcmedia.com.