Biopharma Takes on Deadly Brain Cancer After Decades of Failure

The tide could be turning for a rare but devastating brain tumor called glioblastoma. While the past two decades have been a wasteland of clinical failures, new therapeutic forays from Merck, Kazia Therapeutics and other companies are sparking hope for patients.

While considered a rare cancer, glioblastoma multiforme (GBM) is also the most common and aggressive primary brain tumor in adults. The five-year survival rate is less than 5% and, despite continued efforts, the wait has been long for new successful therapies.

“Glioblastoma has been a very, very challenging target to hit,” John Friend, CEO of Kazia Therapeutics, told BioSpace, adding that there have been no truly successful new therapeutics for the indication since Merck’s temozolomide was approved in 1999. “We’ve seen really no benefits whatsoever of any assets in over 20 years.”

In 2017, Bristol Myers Squibb’s Opdivo failed to improve overall survival in a Phase III trial over Genentech’s Avastin. Two years later, in 2019, a Phase III failure of its experimental gene therapy for GBM sent Tocagen’s stock tumbling, ultimately ending in a reverse merger with Forte Biosciences. Also in 2019, an independent data monitoring committee recommended AbbVie stop a Phase III study of its antibody-drug conjugate Depatux-M in GBM after an interim analysis revealed a lack of survival benefit.

These failures and others have led a lot of pharma and biotech companies to shy away from glioblastoma, Friend said.

However, there has been a recent uptick in investor and drugmaker interest in neuro-oncology. Biopharma pipelines are progressing with investigational small molecules, immunotherapies and oncolytic viruses that could change the course of this killer disease. Among the furthest along is Kazia with its brain penetrant P13K small molecule, while many earlier-stage programs, including those owned by Merck and Black Diamond Therapeutics, continue to make their way to and through the clinic.

What’s exciting today, said Vanessa Almendro, co-founder of the Brain Tumor Investment Fund, is that there “is starting to be an understanding of the risks and the opportunities in the space.” She compared it to where melanoma was 20 years ago when subtypes came on the scene to guide therapeutic decisions.

“Today we can subtype these indications,” Almendro told BioSpace. “We are starting to understand how to better match therapy modalities to the right patient in clinical trials.”

As therapeutic technologies advance, Almendro predicted that small molecules will still be at the forefront for glioblastoma. “That’s the modality we understand best,” she said.

This hypothesis gained traction in October when Merck entered the GBM ring, scooping up Modifi Biosciences for $30 million upfront with milestone payments potentially equaling $1.3 billion. Modifi is developing a new class of orally delivered small molecules aimed at killing cancer cells via DNA modification, with potential in glioblastoma.

DNA repair defects are a hallmark of tumor cells and a major driver of therapeutic resistance. Modifi’s temozolomide-based drug MOD-246 aims to eradicate cancer via DNA repair pathways—in glioblastoma’s case, by targeting cells that lack the MGMT protein. Investigational New Drug–enabling studies are underway with clinical trials expected to begin in 2025.

Further along in development is Kazia’s paxalisib, an oral, small molecule inhibitor originally developed by Genentech. Currently in Phase II/III trials, paxalisib inhibits the action of PI3K, a key controller of cell growth and division active in many forms of cancer. While PI3K has been an established therapeutic target for years in breast cancer and lymphomas, Friend said the challenge with glioblastoma has always been bypassing the blood brain barrier (BBB). Paxalisib is designed to cross the BBB.

Data from a Phase II/III study in July helped identify the specific subset of patients for which the drug is most effective. Friend explained that a high level of methylation on the promoter region of the MGMT protein signifies a better response to temozolomide and improved survival rates. The median survival rate for unmethylated patients is less than half that of methylated patients—12 months versus 26 to 28 months—meaning paxalisib is showing most benefit in the patients with the worst prognoses. Early treatment is also important. While patients with recurrent disease showed no benefit in the trial, newly diagnosed unmethylated patients showed a 33% improvement in overall survival.

Kazia will meet with the FDA in December to discuss potential pathways to approval for paxalisib in newly diagnosed patients with GBM.

Meanwhile, Black Diamond Therapeutics is developing an epidermal growth factor receptor (EGFR) inhibitor, BDTX-1535, for glioblastoma. Over 50% of GBM patients express one or more oncogenic epidermal growth factor receptor alterations, according to the company, making it a potential target for EGFR inhibitors. Following a completed Phase I trial, Black Diamond is recruiting a Phase 0/I study for patients with recurrent GBM prior to a planned resection.

Carl June, the father of CAR T cell therapy, predicted earlier this year that CAR Ts will be a breakthrough therapy for brain cancer. “I think about five years down the line, we’re going to have FDA-approved CARs for glioblastoma,” he said in a statement from his institution, UPenn’s Perelman School of Medicine. And indeed, progress is being made toward that end.

Backed by Gilead subsidiary Kite, researchers at Penn Medicine shared results in March from an ongoing Phase I trial of six patients with recurrent glioblastoma treated with a “dual target” CAR T aimed at EGFR and interleukin-13 receptor alpha 2. It was the first time a CAR T cell therapy with two targets was administered to patients with GBM. MRI scans 24 to 48 hours after intrathecal administration showed reduced tumor sizes in all six patients. The reductions have been sustained out to several months later in a “subset of patients,” Penn reported.

A concern with CAR T therapy, particularly when delivered to the brain, is neurotoxicity. In the Penn trial, researchers reported neurotoxicity in all six patients that was substantial but manageable.

“Cell therapies are likely to be the next frontier,” Almendro said. Despite the challenges and complicated manufacturing, “this is where we think the field is going,” she said.

Meanwhile, CorriXR Therapeutics is tackling drug resistance by targeting the tumors’ NRF2 pathway through gene therapy. A genetic knockout to NRF2 can alleviate the issues that cause resistance to the standard of care, CorriXR CEO Deborah Moorad explained.

“We’re not just adding more drug on top of something,” she told BioSpace. “We’re truly looking at how we can take that DNA of the tumor apart and effectively treat the patient.”

The company is taking its asset into IND-enabling studies for cancer of the oral cavity first, with glioblastoma planned as its second target.

Though located in the brain, glioblastoma causes widespread immunosuppression. Some researchers and companies are turning to therapeutic vaccines in an attempt to achieve an immune response to the tumors.

Researchers at Roswell Park Comprehensive Cancer Center are developing a vaccine called SurVaxM that stimulates CD4 and CD8 T cells to home in on the survivin protein on tumor cells. SurVaxM also helps produce antibodies to attack tumor cells. In a Phase II study, patients treated with the vaccine achieved a median of over 12 months of progression-free survival versus four months for those on standard of care. Overall survival increased from 15 months with standard of care to over 30 months for those treated with SurVaxM. A Phase IIb study is underway at the cancer center.

Separately, at the NCI Center’s Neuro-Oncology Branch, a team of researchers is developing a vaccine from tumor cells collected from the patient during surgery. The cells are treated with radiation in the lab until they can no longer grow but are not dead, and mixed with a second component that boosts immune response. The vaccine could potentially be used after chemotherapy to remove residual tumor cells or to convert “cold” tumor cells into “hot” ones to make them susceptible to checkpoint inhibitors, according to the scientists.

The GBM market is currently valued at just under $3 billion and is expected to reach $5.7 billion by 2033, according to Precedence Research. The report revealed that revenue over the last four years has dropped for surgical treatment as targeted therapy and immunotherapies have grown.

Moorad said she believes the interest has been there all along for glioblastoma. “The technology is just kind of catching up. We’re going to see more [investment] moving forward,” she said. “People are being bold.”