Pharma

The decades-long battle for better outcomes in glioblastoma

As many as two-thirds of glioblastoma patients don't respond to a central class of treatments due to a nifty DNA repair mechanism known as MGMT. DelMar Pharmaceuticals has a workaround that it hopes can extend the lives of patients in a meaningful way.

A 3-D image of a human skull and brain depicting cancer

Like all malignant brain cancers, glioblastomas are extremely difficult to treat. There’s the blood-brain barrier to contend with, the cells are diverse, there is ample blood flow to the tumor and the surrounding area is vitally important for function and survival.

The unfortunate result for patients is an extremely poor prognosis — even in 2017, explained Jeffrey Bacha, cofounder, CEO and chairman of DelMar Pharmaceuticals.

Bacha believes the lack of progress in treating glioblastomas (GBMs) has a lot to do with MGMT or O6-methylguanine DNA methyltransferase. Also known as AGT or AGAT, the gene and associated protein are crucial for genome stability, helping to realign two DNA strands when the base pairs become mismatched.

This built-in repair mechanism protects the genome from routine DNA damage. Unfortunately, when MGMT is expressed by cancer cells, it works to repair the damage doctors intentionally inflict with targeted therapeutics.

An unmethylated MGMT promoter gene will make a tumor resistant to treatment with alkylating agents such as temozolomide (TMZ), carmustine (BCNU), and lomustine (CCNU).

Numbers vary, but more than 50 percent of glioblastoma patients are believed to carry completely unmethylated MGMT, meaning they’re resistant to those front-line therapies. Bacha quotes a number as high as two-thirds, which goes a long way to explaining why patients have such a variable response.

“If you go back and look at the median survival of glioblastoma back when the original war on cancer was waged, back when Richard Nixon signed the famous paper that created the National Cancer Institute,” Bacha said in a phone interview. “The median survival for glioblastoma back then was about 15 months. Today: 15 months from diagnosis. The culprit there, now that we better understand it, is MGMT. Because if two-thirds of patients don’t respond to the primary therapy, you’ll never change the median.”

DelMar Pharmaceuticals was created around a small molecule asset, VAL-083 (dianhydrogalactitol), which works independently of MGMT. It passes through the blood brain barrier and to date has shown very manageable side effects, leaving the door open for possible combination therapy approaches.

On Thursday, the company announced the launch of a Phase II trial of VAL-083 in patients with MGMT-unmethylated, Avastin (bevacizumab)-naïve recurrent glioblastoma. DelMar plans to enroll 48 patients in the single-arm design, run at the University of Texas MD Anderson Cancer Center in Houston. Patients treated with VAL-083 will be compared to historical controls.

Jeffrey Bacha, cofounder, chairman and CEO of Del Mar Pharmaceuticals

Jeffrey Bacha, DelMar Pharmaceuticals

The publicly-listed company has also announced plans to advance VAL-083 into a pivotal randomized multi-center Phase 3 clinical trial for the treatment of GBM patients that have failed Avastin. A separate international Phase II trial is being designed for newly diagnosed GBM patients with an unmethylated MGMT promoter.

There is a big unmet need in all three patient cohorts. According to the American Brain Tumor Association, approximately 79,000 Americans will be diagnosed with brain cancer this year. Of those, glioblastomas account for approximately 15 percent.

Unfortunately, the endpoint for the studies remains a measure of survival in months. The gains are small and hard fought. But simply knowing what drugs are likely to respond can do a great deal of good. If lives can be extended for a couple of extra months, that’s worth pursuing.

VAL-083 has received orphan designation in the U.S. for the treatment of glioma, medulloblastoma and ovarian cancer. It has also been granted orphan designation in the E.U. for the treatment of malignant gliomas.

This hints at the wider potential of the drug. MGMT is expressed throughout the body and according to the company website, “Published pre-clinical and clinical data suggest that VAL-083 may be active against a range of tumor types, including lung, brain, cervical, ovarian tumors and hematologic (blood) cancers.”

The odds are stacked against DelMar based on history alone. Drugs in development for glioblastoma are particularly prone to failure. What is positive is the company’s experience getting cancer drugs over the line.

Cofounder and Chief Scientific Officer Dennis Brown also founded ChemGenex Pharmaceuticals using the same business model: Select a drug with positive historical data and shape it for a niche, underserved population.

The group ultimately won approval for omacetaxine, now sold by Teva Pharmaceuticals as an alternative treatment for CML (Synribo). When ChemGenex was acquired in 2011, Bacha said most of the team stayed together, keeping the same office in Menlo Park, California.

“The development team has done this before,” Bacha underscored.

Can the company do the same with glioblastoma and VAL-083? That remains to be seen.

Photo: Eraxion, Getty Images; DelMar Pharmaceuticals

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