James Garner, CEO of Kazia Therapeutics, is feeling positive about one of his company’s drug candidates. The product, GDC-0084, is a treatment for patients with glioblastoma, the most common and aggressive form of brain cancer. Despite the seriousness of the ailment, patients have not seen much advancement in treatments over the past decade. Making matters worse is the fact that the five-year survival rate is only three percent. Garner believes GDC-0084 offers real hope for those patients.
“The product was conceived and developed as a brain cancer drug,” says Garner. “Since it was designed for that purpose, researchers from the very beginning were able to ask themselves what the drug would need to do to be successful. One of the things they took a close look at was the blood-brain barrier.”
The blood-brain barrier is a protective mechanism of the brain. Garner notes it is a filtering mechanism of the capillaries that carries blood to the brain and spinal cord that will block the passage of certain substances. He notes this is the reason why most drugs administered to patients do not get into the brain.
“I used to work in multiple sclerosis and it was a real challenge to get drugs to the brain to treat the disease,” he states. “The same is true when treating brain cancer. Most cancer drugs do not get into the brain. Obviously, if you're treating brain cancer, you want to be able to get the drug into the brain because that is where the cancer resides.”
Crossing The Blood-Brain Barrier
GDC-0084, designed by Genentech and licensed to Kazia a little over a year ago, was specifically designed to reach the brain. Genentech performed complex biochemistry to ensure the drug would cross the barrier into the brain, which was demonstrated in animal data. Garner notes the drug was studied in three animal species and there is even some human data Kazia received from Genentech. A Phase 1 study confirmed the drug would reach the brain.
The drug is a capsule consumed by patients once per day. That makes dosing of patients easy and convenient. A Phase 2 study will help determine how long patients should take the drug, but Garner states it could potentially be two years.
“Right now, the life expectancy of a newly diagnosed patient with brain cancer is 12 to 15 months,” says Garner. “Our starting premise will be that if a patient is doing well while on our drug, there may be no reason to take them off it. Thus far, the drug seems to be safe and well tolerated in patients.”
The current treatment available to patients is ineffective in two-thirds of patients who receive it. That treatment works by damaging DNA, a mechanism prominent in many cancer drugs. Unfortunately, many patients with this form of brain cancer have genetics that allow their DNA to be repaired very quickly. That serves to cancel out the DNA damaging effect of the drug.
“The problem with that treatment is it doesn't work for the majority of patients,” says Garner. “The tumor is, in effect, immune or impervious to the effect of the drug. For patients with this type of brain cancer, researchers can tell which patients the treatment will work on. That makes it easy to identify those for whom the treatment will not be effective.”
Treatment Requires An Adaptive Approach
The Phase 2 trial currently being prepared by Kazia will utilize an adaptive approach. Certain information that emerges during the trial will influence the operation of the study. Specifically, the beginning component of the Kazia trial will look at dosing levels and determine if dosing can be increased for patients.
“The Genentech Phase 1 trial studied a particular dose, but we believe, in the population we’re looking at, that we may be able to dose a bit higher and a bit differently,” states Garner. “There's some work in the early part of a study that looks to optimize the dose. The information we obtain will then be used to influence dosing in the main part of the study. Results could also impact the size of the study.”
Garner notes the dosing adjustments are neither extreme nor trivial, but he does believe they are necessary and will not present a risk to patients. He states the industry has learned a great deal about how to run this type of trial. The technology involved, as well as the expertise of researchers, is fairly well established. Kazia also had discussions with the FDA last year where the company shared information on what it was trying to accomplish. Garner says the regulator was able to provide useful feedback, which has since been integrated into the design of the study.
A Partnership Between Large And Small
Kazia is a small company headquartered in Australia. Genentech is a Big Pharma company on the U.S. west coast. For the two companies to come together and strike an agreement on GDC-0084 presented some challenges for Kazia.
“There was certainly a huge amount of work involved being that we are a small company,” states Garner. “One benefit we had is that our team is made up of several individuals who were formerly with Big Pharma companies. One of our directors served as a SVP at Eli Lilly for 36 years. My own background includes time spent with both Sanofi and Takeda. So although we are a small company, our team has an impressive track record with Big Pharma.”
Kazia became aware of the asset as a result of a former Genentech team member who is now based in Australia. Garner notes the process by which he became aware of the drug was rather serendipitous. Genentech never really shopped the drug in the open market. After becoming aware of it from the former team member, Kazia worked with her to pursue the licensing opportunity.
“It is not unusual for a drug to go through several companies before finally getting to market,” says Garner. “Companies always have different strategies, priorities, and circumstances. These kinds of deals are not uncommon. In this instance we were able to convince Genentech that we would be a good custodian for GDC-0084.”
The trial will get its start at the University of Oklahoma, one of the participating sites in the Phase 1 study. The population of glioblastoma patients is greatest in the U.S. and many of the experts in this field are also based in the states. Eventually the study will grow to a number of different hospitals in Australia, Europe, and possibly Asia. It is expected to recruit around 228 patients.
“This is a niche area of cancer,” Garner adds. “Some of the real-world experts in the disease are US-based. If we want to work with the people who know the disease best, and those who are on the front line of clinical research in this area, that tends to lead us towards the U.S. We also need to make sure we get it right. The last thing we want to do is conduct a study in a remote part of the world and then find it doesn't fit with what the FDA is expecting. The U.S. accounts for about 50 percent of the world oncology market. Australia is only about 1.6 percent of the global market. That is something we had to consider.”
Because of the poor prognosis for this disease, and the high unmet need of patients, there is the possibility of Kazia gaining accelerated approval from the FDA. That would allow the treatment to be approved and launched without a full Phase 3 trial. Although accelerated approval is a discussion to be had with the FDA at the conclusion of the trial, Garner notes the Phase 2 study was designed to try and maximize the possibility of that result. “If the drug performs as we hope it will, we think there is a good chance it can be launched after Phase 2,” he says. “A confirmatory Phase 3 study may then be performed while the drug is on the market.”