The landscape for glioblastoma (GBM) treatment, a rare yet devastating brain tumor, is beginning to shift as novel therapeutic strategies emerge after two decades of clinical failures. Companies like Merck and Kazia Therapeutics are pioneering new approaches, sparking renewed hope for patients facing this aggressive cancer.
The Glioblastoma Challenge
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults, characterized by a dismal five-year survival rate of less than 5%. The lack of successful new therapies since the approval of Merck’s temozolomide in 1999 has made GBM a formidable challenge.
John Friend, CEO of Kazia Therapeutics, noted the difficulty in targeting glioblastoma, stating, "We’ve seen really no benefits whatsoever of any assets in over 20 years."
Past failures, such as Bristol Myers Squibb’s Opdivo and AbbVie’s Depatux-M, led many companies to avoid glioblastoma research. However, recent advancements in understanding tumor biology and therapeutic technologies are attracting renewed interest and investment.
Small Molecules Take the Lead
Vanessa Almendro, co-founder of the Brain Tumor Investment Fund, believes small molecules will remain at the forefront of glioblastoma treatment due to their well-understood mechanisms. This is evidenced by Merck's recent acquisition of Modifi Biosciences for $30 million upfront, with potential milestone payments reaching $1.3 billion. Modifi is developing orally delivered small molecules that target cancer cells by modifying DNA, particularly in cells lacking the MGMT protein.
Kazia Therapeutics is also advancing paxalisib, an oral, small molecule PI3K inhibitor, through Phase II/III trials. Paxalisib is designed to cross the blood-brain barrier (BBB), a significant hurdle in treating GBM. Phase II/III study data indicated that paxalisib is most effective in patients with newly diagnosed unmethylated GBM, showing a 33% improvement in overall survival.
Kazia plans to meet with the FDA to discuss potential approval pathways for paxalisib in newly diagnosed GBM patients.
Black Diamond Therapeutics is developing BDTX-1535, an epidermal growth factor receptor (EGFR) inhibitor, for glioblastoma. Given that over 50% of GBM patients express EGFR alterations, BDTX-1535 represents a promising targeted therapy. Following a Phase I trial, Black Diamond is recruiting for a Phase 0/I study in patients with recurrent GBM.
Cell and Gene Therapies: A Promising Frontier
CAR T-cell therapy is emerging as a potential breakthrough for brain cancer. Carl June, a pioneer in CAR T-cell therapy, predicts FDA-approved CARs for glioblastoma within five years.
Penn Medicine researchers, backed by Gilead subsidiary Kite, reported positive results from a Phase I trial using a "dual target" CAR T-cell therapy aimed at EGFR and interleukin-13 receptor alpha 2 in recurrent GBM patients. MRI scans showed reduced tumor sizes in all six patients 24 to 48 hours after intrathecal administration, with sustained reductions in a subset of patients. While neurotoxicity was observed, it was manageable.
CorriXR Therapeutics is addressing drug resistance by targeting the tumors’ NRF2 pathway through gene therapy, aiming to overcome resistance to standard treatments.
Harnessing the Immune Response
Glioblastoma-induced immunosuppression is being targeted with therapeutic vaccines. Researchers at Roswell Park Comprehensive Cancer Center are developing SurVaxM, a vaccine that stimulates T cells and produces antibodies to target the survivin protein on tumor cells. A Phase II study showed a median progression-free survival of over 12 months with SurVaxM, compared to four months with standard care, and an overall survival increase from 15 months to over 30 months.
At the NCI Center’s Neuro-Oncology Branch, researchers are developing a personalized vaccine from patient-derived tumor cells treated with radiation and mixed with an immune response booster. This vaccine aims to eliminate residual tumor cells after chemotherapy or convert "cold" tumors into "hot" ones, making them susceptible to checkpoint inhibitors.
Market Growth and Future Outlook
The GBM market, valued at nearly $3 billion, is projected to reach $5.7 billion by 2033, driven by the growth of targeted therapies and immunotherapies. This growth reflects the increasing investment and innovation in glioblastoma research.
Deborah Moorad, CEO of CorriXR, believes the technology is finally catching up to the long-standing interest in glioblastoma, stating, "We’re going to see more [investment] moving forward. People are being bold."
