A poliovirus cancer treatment designed by Duke medical researchers was awarded rare "breakthrough therapy" status by the Food and Drug Administration last week to speed up its approval for market use.
The FDA's recognition follows Phase 1 clinical trials of the therapy, which have been occurring since 2012 and are held at Duke's Preston Robert Tisch Brain Tumor Center. Medical researchers have found a 20 percent three-year survival rate in patients with glioblastoma—a particularly aggressive form of brain cancer—who received the poliovirus therapy, compared to a historical 4 percent survival rate. Dr. Darell Bigner, director of the Preston Robert Tisch Brain Tumor Center, said that the team of researchers will meet with the FDA within 60 days to discuss the next steps for future trials, and that they hope to expand the trials to several hundred patients.
“Breakthrough status means that we can work with the highest levels in the FDA to develop the most efficient clinical trial and pathway to fully evaluate the safety and efficacy of the genetically modified poliovirus for treating recurrent glioblastoma,” Bigner said in a press release Monday.
Dr. Maciej Mrugala, chief of the Division of Neuro-Oncology at the University of Washington’s School of Medicine, explained that glioblastoma is currently one of the most difficult human cancers to treat.
“For one, the location of the tumor in the brain is behind the blood-brain barrier, which makes it very difficult for a lot of chemotherapeutics to penetrate the brain," Mrugala said. "It is also very difficult to surgically remove its tumor. And finally, even if we can treat [glioblastoma] successfully for a while, it very quickly develops resistance and that has to do with the activation of multiple pathways in the cancer cell.”
The development of PVS-RIPO, the synthetic form of the live polio vaccine administered as a treatment in these trials, was spearheaded by Dr. Matthias Gromeier, professor of neurosurgery, molecular genetics and microbiology and medicine. In a "60 Minutes" broadcast Sunday, Gromeier explained that the PVS-RIPO has been shown to infect glioblastoma tumors, signaling the immune system to destroy the tumor. MRI tests from the clinical trials—led by principal investigator Dr. Gordana Vlahovic, associate professor of medicine—showed no tumor in three surviving patients and only residual neurological traces of a tumor in a fourth patient.
Gromeier explained during the "60 Minutes" segment that initial tests with the poliovirus platform in the laboratory indicated that the treatment could also be successful in targeting “lung cancers, breast cancers, colorectal cancers, prostate cancers, pancreatic cancers, liver cancers [and] renal cancers," though this has not yet been tested.
“We do not have good comparative information on the immune reactivity among different types of cancer,” Bigner wrote in an email, adding that he cannot yet confidently predict the effectiveness of PVS-RIPO in other human cancers. “That is information that we will be gathering in the future.”
Some members of the medical community, however, remain skeptical of the FDA’s recognition of the trial. Dr. Bruce Chabner, director of clinical research at Massachusetts General Hospital and former director of the National Cancer Institute’s Division of Cancer Treatment, said in a MedPage Today article that he believed the study’s initial results did not address many critical aspects of cancer therapy, such as the safe dosage of the poliovirus platform and the mechanism through which it works. He added that “it is premature to draw any conclusion but ‘possibly interesting’ from what was presented.”
Bigner wrote that the team remains cautious in evaluating the results of the Phase 1 Trial.
“Breakthrough status does not at all mean that the FDA is near final approval of the agent,” he wrote. “I made it abundantly clear in my remarks that I did not want to give false hope to anyone, and that I did think in my lifetime we would see major advances, but did not at all promise we were near FDA approval.”
One of the primary goals designated by the FDA for a Phase 1 clinical trial is establishing a baseline dosage for a new drug or treatment. The team experimented with different doses of the poliovirus, significantly lowering the dose of the poliovirus when a patient had an overpowering immune response. Bigner added in his email that the poliovirus treatment team is still evaluating other dosage options, including "checkpoint inhibitors," a growing class of drugs that help activate a person’s immune system.
“There are future trials being planned with...checkpoint inhibitors, in which three different dose levels will be evaluated and lower doses will be evaluated in the pediatric brain tumor population,” Bigner wrote. “Additional follow-up will help us [decide] whether the current -1 dose level is the optimal dose.”
Adam Feuerstein, a senior columnist at TheStreet, pointed out in a Tweet that breakthrough therapy status was similarly given to the drug rindopepimut—another form of immunotherapy—for glioblastoma treatment led by Celldex Therapeutics, Inc., but it was later discontinued after a failed Phase 3 trial.
Bigner wrote that the failed glioblastoma trials involving the drug rindopepimut—some of which included Duke medical faculty—were not similar to this treatment.
“All of us were involved to some extent in the rindopepimut trial,” he wrote. “That trial failed not because of the lack of success of rindopepimut, but because the control arm lived six months longer than usual. The design of rindopepimut is so different from the poliovirus that the design characteristics [of these trials] have had to be quite different from one another.”
Mrugala, who was also part of the previous rindopepimut trials, explained that he felt both cautious and optimistic about recent findings with Duke’s poliovirus treatment.
“This is a very exciting product,” he said. “But I think we have to be very careful in how we interpret the data shown with these patients. I would be very cautious at this point in time to make any claims that this is the new cure for glioblastoma because we’ve really only had a handful of patients that have been treated and very few patients that have had a long term response.”