Glioblastoma Start-Ups Get Specific

For start-ups developing novel and risky medicines to treat glioblastoma, a rare, invasive form of brain cancer, the Pfizer/Avant deal was a watershed moment: It signaled the vigorous interest of a pharmaceutical behemoth in a disease where patients number in just the tens of thousands. The positive effects are likely to be felt in executive suites of biotechs developing therapeutics for this grievous disease.

Novel treatments for this invasive brain cancer offer patients hope--and their developers potential profits.

As adverse side effects or potential safety signals trigger increasing regulatory scrutiny of primary care drugs, large pharmaceutical companies have increasingly looked to obtain—either via licensing deals or acquisitions—access to specialty drugs, particularly in the area of oncology where high unmet medical need and a dearth of treatments offer the promise of an easier path to market. This spring, for instance, Takeda Pharmaceutical Co. Ltd. spent $8.2 billion to acquire Takeda Oncology to obtain rights to bortezomib (Velcade), while Bristol-Myers Squibb Co. ponied up $235 million for Kosan Biosciences Inc., adding two new classes of drugs, epithilones and Hsp90 inhibitors, to its stable of cytotoxic oncology medicines. [See Deal] [See Deal]

Pfizer Inc. has been on its own oncology dealmaking odyssey. In addition to announcing the formation of its new oncology business unit at the American Society of Clinical Oncology’s annual meeting in late May, the company has inked licensing or acquisitions deals with Five Prime Therapeutics Inc., Celldex Therapeutics Inc.’s Celldex Therapeutics, Serenex Inc., CovX Research LLC, and Coley Pharmaceutical Group Inc. since November 2007. [See Deal] [See Deal] [See Deal] [See Deal] [See Deal] Of these partnerships, perhaps the most interesting is the April tie-up with Avant, a licensing agreement worth up to $440 million plus royalties for the biotech’s novel cancer vaccine, CDX-110, currently in Phase II trials for glioblastoma multiforme (GBM).

For start-ups developing novel and risky medicines to treat this rare, invasive form of brain cancer, the Pfizer/Avant deal was a watershed moment: it signaled the vigorous interest of a pharmaceutical behemoth—both intellectually and economically--in a disease where patients number in just the tens of thousands. The positive effects are likely to be felt in executive suites of biotechs such as Peregrine Pharmaceuticals Inc. and TransMolecular Inc., companies actively looking for partners for their respective mid-stage glioma treatments, Cotara and TM-601. "There’s a broadening interest among Big Pharma and Big Biotech in terms of partnering," claims E. Michael Egan, TransMolecular’s CEO. "As in other treatment areas, it’s a matter of looking for the next opportunity," he says.

For patients, family members, and neuro-oncologists an uptick in interest by the industry’s largest players is also welcome news. Although the National Institutes of Health is currently sponsoring more than 250 experimental trials for adult glioma patients, in many cases the drugs currently being tested were developed first for other types of cancer and are being tried almost as an afterthought, notes Russell Pieper, MD, a neuro-oncologist at the University of California, San Francisco.

Glioblastomas, which affect about 10,000 Americans annually, are one of the most formidable kinds of cancer oncologists currently treat. Survival time is measured in months not years: most patients succumb within 14 months of their diagnosis. That’s partly because the tumors form long fingers that infiltrate the speech and cognition centers of the brain, making surgical removal of the entire growth virtually impossible. Moreover, the protective blood-brain barrier prevents adequate delivery of tumor-killing drugs capable of mopping up remaining cells post-surgery.

Up until 2005, the gold-standard approach to combating glioblastoma was a decades old treatment: surgery to remove the bulk of the tumor, followed by insertion of a polymer wafer that melts to release a chemotherapeutic carmustine (Gliadel). That year researchers published a landmark study in the New England Journal of Medicine showing that, in combination with radiation, the DNA synthesis and cell growth inhibitor temozolomide (Temodar), which is marketed by Schering-Plough Corp., extended life to two years in 26% of patients compared with 10% of patients receiving radiation alone. Although statistically significant, the results were cold comfort to many glioblastoma patients and their families. "Unfortunately, it’s still true that for many patients, there aren’t many good [treatment] options," says Pieper.

But that may be starting to change. As researchers learn more about the underlying biology of GBM, they are developing experimental treatments, including cell-based immunotherapies such as Avant’s CDX-110, Northwest Biotherapeutics Inc.’s DCVax-Brain, and Sangamo BioSciences Inc.’s ZFP-TF; peptide molecules such as TransMolecular’s TM-601; and RNA interference medicines such as SG-1311 and PTD-DRBD from [SanoGene Therapeutics Inc.] and Traversa Therapeutics Inc., respectively, both profiled in this issue. (Also see "SanoGene Therapeutics Inc." - Scrip, 1 Jul, 2008.) (Also see "Traversa Therapeutics Inc" - Scrip, 1 Jul, 2008.) Antibodies that block tumor angiogenesis, especially Genentech Inc.’s bevacizumab (Avastin) are also being investigated. (See Exhibit 1.)

The goal is to improve upon the so-called cytotoxic medicines of the past, whose cell-killing powers lay waste to healthy and cancerous cells alike. This next generation of products promises to be exquisitely specific for glioblastoma cells; moreover, scientists believe they are beginning to have the ability to design treatments based on the specific genetic profile of a patient’s tumor. Given the complexity of glioblastoma biology and the tumor’s ability to develop resistance to treatments, most neuro-oncologists believe a cocktail approach that targets multiple biological pathways will become the regimen of choice.

Inhibiting the VEGF pathway, which plays a key role in tumor blood vessel formation, either directly via antibodies such as Avastin or indirectly via other tyrosine kinase inhibitors in the signal transduction cascade, is an approach many experts in the field are monitoring closely. From a biological perspective, inhibiting the VEGF pathway makes "tremendous sense since gliomas are very vascularized tumors," says Patrick Wen, MD, a neuro-oncologist with Dana-Farber Cancer Institute and Brigham and Women’s Hospital. At this year’s ASCO meeting, Genentech presented results from its Phase II BRAIN study comparing Avastin alone to Avastin plus irinotecan in patients with recurrent glioblastoma multiforme. Median overall survival rates were 9.2 months in the Avastin arm versus 8.7 months in the combination arm, compared with the historical control of 6 months. Perhaps more importantly, 43% of GBM patients treated with Avastin alone and 50% treated with the Avastin/irinotecan combination saw no progression of their disease for at least six months. Genentech plans to file an sBLA in GBM in the second half of the year.

Calling such data "encouraging," Wen notes "the benefit from Avastin is still modest." UCSF’s Pieper agrees. "Anti-angiogenesis benefits a subset of patients, but it doesn’t look like it will be a magic bullet," he says. He and many other clinicians are interested in cancer vaccines that trigger the body’s T-cells to kill tumor cells. And Avant’s CDX-110 immunotherapy, which is designed to induce an immune response in cells carrying a variant of the EGFR gene, seems to be generating the lion’s share of the interest. In an on-going Phase II trial in roughly two dozen patients, Duke University clinicians administered monthly doses of their cancer vaccine in conjunction with temozolomide following surgical removal of the tumor and radiation. Data presented at ASCO showed overall survival increased from 14.3 months to 33.1 months, while time to progression—defined as the period in which the tumor’s growth remains under control—lengthened from 6.4 months to 16.6 months. Based on data from this and another small Phase II trial, Pfizer in-licensed the drug in April. According to Tom Davis, MD, SVP and CMO at Avant, the Pfizer tie-up "validates this vaccine and the idea that immunotherapy might work."

Beyond cancer vaccines, researchers are also looking to deploy short interfering RNAs as GBM therapeutics, provided that biotechs can solve the delivery challenges associated with the approach. In 2005, Both Traversa and SanoGene have exciting preclinical data in mice. Traversa has developed a warhead with siRNAs against the EGFR and Akt-2 kinase genes. When this compound is injected into mice, it doubles life expectancy from 14 to about 30 days. SanoGene, meanwhile, is using RNAi to block the activity of serum protease and metalloprotease genes.

One of the hallmarks of glioblastoma is its invasiveness. Clinicians such as Wen believe that a critical component of any future therapy will include agents that not only target the primary tumor but also block its ability to infiltrate the surrounding brain tissue. Here the science is only at the earliest stages, but already one company, Pharmaxon SA (Also see "Pharmaxon SA" - Scrip, 1 Jul, 2008.), profiled in this issue, has developed a neural cell mobility inhibitor called PR-22G that blocks cell migration in vitro and limits GBM proliferation in animal models.

As compounds such as Pharmaxon’s PR-22G or SanoGene’s SG-1311 advance into human trials, it seems likely that big pharmaceutical and biotech companies will be monitoring the data closely, following Pfizer’s lead as they look for valuable in-licensing opportunities. Given the continued unmet medical need associated with GBM, such products are likely to command premium price tags and a smoother regulatory path, even if they provide modest improvements on existing therapies. As far as patients are concerned, any new drug that extends life will be a blessing.

Ellen Foster Licking