Nearly two decades of innovative research and clinical trials culminated in the FDA approval of a pill that gives fresh hope to low-grade glioma patients
For neuro-oncologist Elizabeth Maher, M.D., Ph.D., the pictures are worth a thousand words.
And then some.
In the lobby of UT Southwestern’s Cancer Care Outpatient Building, two of Dr. Maher’s patients are smiling and posing with their first doses of a newly approved drug that slows the growth of their brain tumors. The breakthrough medication, called vorasidenib, was approved by the Food and Drug Administration (FDA) in August 2024.
For Lauren Manlapig, 32, a schoolteacher from Dallas, Tulia Fogli, 49, a mother of three from Oklahoma, and thousands more like them who face the ticking clock of a low-grade glioma diagnosis, the medication represents time in a bottle.
Suspended above Lauren and Tulia's family in the photos is a white fiberglass sculpture titled Infinite Energy of the Universe, a graceful and curving reminder of the nearly 20-year arc of discovery – and all the people it took to make moments like these possible. Physicians and physicists, radiologists and researchers, all played a role. So did dreamers and donors such as the family of Bill Miller, longtime supporters of UTSW and Dr. Maher’s research. They donated the sculpture to honor his memory and inspire the art of healing.
In two simple snapshots, Dr. Maher sees a remarkable story of science and survival – one that would never have happened if not for the “frontier mentality” that defines UT Southwestern and the world’s other foremost academic medical centers.
Elizabeth Maher, M.D., Ph.D., Professor of Neuro-Oncology, has led UT Southwestern's research into understanding and treating low-grade gliomas.
It’s a story filled with amazing discoveries, including complex genetic signatures and a key biomarker that helped crack the code of low-grade gliomas. Powerful equipment – a 7 Tesla (7T) MRI machine. And some unlikely heroes, not the least of which were regulators from UT Southwestern’s Institutional Review Board (IRB) whose job it is to review research and mitigate risks.
And then there is the vital role that patients themselves have played in furthering the cause – hundreds of people like Bernie Silva, who faithfully attended six years of bimonthly appointments, participated in a long-term clinical trial, filled out a daily journal, and never missed an MRI scan or lab test. These unsung heroes of science have helped tip the scales in what has been, by all accounts, a lopsided battle against brain cancer over the past two decades.
Perhaps that’s why Dr. Maher said she is feeling downright “giddy” these days.
“Not only can I tell my patients that there is a treatment I can prescribe right now that can extend their survival by years, not just months,” she said, “but I can also tell them that they can go to bed at night knowing there are a lot of people here at UT Southwestern and all around the world who are invested in getting us to the next treatment. And the next one after that.”
Mutant enzymes and a new biomarker
Glioblastoma is one of the deadliest and most recalcitrant cancers. It has a five-year survival rate of just 6.9%, according to the National Brain Tumor Society. For years, scientists struggled to gain ground in the battle against this aggressive and fatal disease.
Then in 2008, geneticists discovered a clue in a mutated gene that encoded isocitrate dehydrogenase (IDH), a key enzyme that aided in sugar metabolism and homeostasis. A DNA sequencing study revealed that this genetic quirk was present in a subset of glioblastoma patients, and scientists observed in these individuals a more subdued and slow-growing subtype of brain tumor: a low-grade glioma that was recognized as a more latent stage of glioblastoma.
“They reviewed the findings and found that the survival rate was dramatically better in patients who had this mutation,” explained Dr. Maher, who has done extensive work in this field, including developing her own lab tool to study individual tumor cells. “It led to a greater focus on these low-grade glioma patients, who had a significantly better prognosis.”
As a result, interest in IDH and its subtypes – IDH1 and IDH2 – intensified, and researchers soon found a way to track its metabolic activities.
“The mutant enzymes formed an oncometabolite called 2-hydroxyglutarate, or 2HG, which accumulates and disrupts cellular processes,” said Dr. Maher, Professor of Internal Medicine and Neurology at UT Southwestern. “It caught the attention of the leading cancer metabolism experts in the world. The goal was then to develop a drug that would target this protein and block the cancer-causing pathways.”
Medicinal chemists at the pharmaceutical company Agios were able to piece together the mutant enzyme’s structure and manufacture a synthetic replica, a drug they called ivosidenib. This was the first step that would eventually lead to a second drug, vorasidenib.
At the same time, U.S. researchers, including a group at UT Southwestern, focused on 2HG as a diagnostic and prognostic biomarker because its presence could help predict patient outcomes.
All they needed was a way to safely and accurately detect 2HG levels in the brain.
The power of imaging and innovation
The first big breakthrough came in 2010, when Changho Choi, Ph.D., former Associate Professor of Radiology at UT Southwestern’s Advanced Imaging Research Center (AIRC), began experimenting with a new technique using a 7T MRI machine, an ultra-high-powered research scanner that provides unparalleled precision and clarity. UT Southwestern acquired the massive 7T MRI in 2007 – it was one of only five in the country at the time. It was more than twice the strength of the most powerful MRI in clinical practice, which is 3T. The 7T MRI helped Dr. Choi, now a Research Professor of Radiology and Radiological Sciences at Vanderbilt University, develop an investigative protocol that measured the chemical signature of 2HG to assess and track cancer development in patients. He then refined his technique and adapted it for use with the 3T MRI, which is more widely accessible and FDA-approved for clinical use.
Dr. Maher and Changho Choi, Ph.D., developed an investigative protocol that measured the chemical signature of 2HG to assess and track cancer development in patients.
The real test came with a phase one clinical trial of ivosidenib, the first iteration of the IDH inhibitor. UTSW’s maverick team of researchers wanted to see if the drug could effectively pass through the blood-brain barrier, the body’s neuroprotective mechanism against harmful substances, and reach the tumor to suppress it. But before they could find out, they would need to earn buy-in from UTSW’s IRB – the regulatory body charged with ensuring that not only was the clinical trial safe but also that it could reap untold benefits.
“There were discussions about ending the trials in IDH-mutant gliomas entirely. But we said, ‘Wait a minute. We have evidence that the drug is getting into the brain and hitting its target – just not in the participants we expected.’”
Elizabeth Maher, M.D., Ph.D.
“The IRB was totally focused on pursuing great science,” Dr. Maher said. “They understood we needed to see the brain better, so the IRB partnered with us to get this project off the ground and, later again, to expand access outside the trials and get it into the hands of even more patients.”
Once the phase one clinical trial was approved, the UTSW researchers enrolled a group of eligible high-grade glioblastoma patients with the IDH mutation, whose blood-brain barriers were more compromised.
“Logically, it followed that the drug had a better chance of working in these patients, and we wanted to hit the most aggressive tumors,” Dr. Maher explained, “but we also enrolled some patients with low-grade gliomas into the trial.”
After receiving baseline scans of their tumors, each patient returned for regular MRIs every two months after beginning the drug.
The results were unexpected, to say the least.
“Early in the process, it became clear that the high-grade patients didn't respond at all, which meant the cancer was at a stage that the IDH mutant enzyme was no longer a factor,” Dr. Maher explained. “It nearly ended the trial.”
But the UTSW research team noticed something else. The 2HG levels in low-grade glioma patients actually decreased. In the experimental imaging scans, the proof was definitive: The drug could safely cross the blood-brain barrier and block the cancer-causing mutant enzyme.
It was a game-changing moment.
"Prior to that, there were discussions about ending the trials in IDH-mutant gliomas entirely. But we said, ‘Wait a minute. We have evidence that the drug is getting into the brain and hitting its target – just not in the participants we expected,’” Dr. Maher said. “UT Southwestern was the only investigative team in the multicenter trial that had the imaging capability and the results that proved the drug was acting exactly as designed – and our ability to do that research directly led to the next steps along the path that resulted in the FDA approval of vorasidenib.”
A game changer for glioma patients
The chemists at Agios went on to develop a drug that targeted both the IDH1 and IDH2 mutations at a 10-fold higher concentration to ensure that enough of the medication crossed the blood-brain barrier. This time, the clinical trial focused on low-grade glioma patients. And once again, the MRI 2HG scans proved this new version, vorasidenib, was working as designed – knocking down 2HG levels.
Bernie Silva participated in the low-grade glioma clinical trials that led to the approval of vorasidenib. “This medication is a game changer," he said recently, "and I feel ecstatic that this could help future glioma patients."
Servier Pharmaceuticals acquired the drug and moved forward with a phase three clinical trial that specifically tested it against a placebo. The findings from that 2020 study, published in The New England Journal of Medicine and presented at the 2023 annual meeting of the American Society of Clinical Oncology (ASCO), indicated that vorasidenib significantly extended progression-free survival time, as well as time until the next treatment (usually radiation and chemotherapy), compared to a placebo. Servier’s data also revealed that the drug could reduce tumor volume by an average of 2.5% every six months and reduce seizure frequency.
Throughout the multi-trial process, UT Southwestern’s IRB stepped in on behalf of patients, again helping to ensure the promising experimental medication got into the hands of those who needed it most.
Patients such as Bernie Silva.
Bernie had been living with seizures caused by a low-grade glioma for 16 years – about once a month, on average – before he sought help from UT Southwestern in 2018. He was referred to Dr. Maher, who discovered Bernie had the IDH mutation that made him a suitable candidate for a phase one clinical trial that compared ivosidenib to vorasidenib directly. After the surgical team at UTSW removed the mass from his brain, Bernie started taking vorasidenib every day. He was evaluated bimonthly, with lab testing, electrocardiograms (EKGs), and MRI scans over the next six years. He didn’t miss a single appointment, and his health data contributed significantly to the body of evidence that proved the medication was working. Bernie’s cancer was in remission, and his seizures had stopped completely.
“This was the ideal outcome,” said Bernie, now 68. “This medication is a game changer, and I feel ecstatic that this could help future glioma patients. There are so many people who need it. Having this as an option is just incredible. You'll never understand unless you've lived it.”
In 2023, Dr. Maher received an email unlike any other in her career. The final phase three trial, comparing vorasidenib to a placebo, was ending early because preliminary data found that the benefits of treatment vastly outweighed the risks. Other trials continued to move forward, including Bernie’s phase two study, and he was able to stay on the lifesaving medication. And on Aug. 6, 2024, the FDA officially authorized the use of vorasidenib to treat low-grade gliomas after surgery in adults and children age 12 or older.
A. Dean Sherry, Ph.D., Professor Emeritus, left, and Craig Malloy, M.D., Professor and Medical Director of the Advanced Imaging Research Center at UT Southwestern, each played a key role in advancing this research.
It was a hard-won moment of victory in the world of brain cancer research.
“Over the years-long journey, we’ve had such amazing partners,” Dr. Maher reflected. “Each step was a crucial one where, had things gone differently, we might have lost out on this opportunity. But that’s the arc of the story: We were able to achieve this because of the people at UT Southwestern who came before us systematically built a culture of investing in science, of asking the right question, and boldly going after it.”
Two such instrumental figures were A. Dean Sherry, Ph.D., Professor Emeritus at UT Southwestern Medical School and former Director of Advanced Imaging Research Center, and Craig Malloy, M.D., Professor and Medical Director of UT Southwestern’s AIRC.
As the AIRC Medical Director, Dr. Malloy introduced Drs. Choi and Maher and encouraged them to collaborate on this project. Dr. Sherry had lobbied the university to invest in cutting-edge technology, including the 7 Tesla research MRI, which required a specialized facility be built to house the 24-ton scanner.
“When the AIRC was established in 2005, UTSW leadership had the vision to invest in a high-field MRI scanner for clinical studies,” Dr. Sherry said. “Although we had little direct funding to support these early clinical investigations, I believed in this new technology and continued to support these studies using AIRC funds. It is gratifying to know now, 20 years later, that UTSW and the AIRC played an instrumental role in the development of a drug that gives glioma patients worldwide new hope for survival.”
‘Like getting my life back’
Lauren Manlapig, the Dallas-based schoolteacher, was barely in her 30s when she was diagnosed with brain cancer after experiencing a seizure in June 2023. Surgeons removed as much of the cancer as they could, but she still faced an uphill battle wherein demanding treatments such as chemotherapy and radiation seemed inevitable. It wasn’t until one doctor on her medical team referred her to Dr. Maher that Lauren learned she had an IDH-1 mutation that made her a possible candidate to receive vorasidenib.
“I was on another drug, but Dr. Maher thought vorasidenib would be a better treatment for me,” said Lauren, who was subsequently approved to receive the drug, free of charge, from Servier through an FDA single patient Investigational New Drug (IND) license, which authorizes patients to receive experimental treatments outside of clinical trials.
“Dr. Maher and her team have dedicated their time and passion to this profound achievement. We congratulate them and extend our hope to the many patients who will benefit from their endeavors.””
Tricia Miller
Donor and Chair of the Arts and Interiors Committee of UTSW’s President’s Advisory Board
She began taking vorasidenib in May 2024.
“That was really exciting for me because it finally seemed like the odds were in my favor,” said Lauren, who still sees Dr. Maher regularly. “She’s reaffirmed to me that vorasidenib is doing what it needs to do, and I cry every time because this medicine gives me hope. It feels like getting my life back, which is different from how I imagined it before all this.”
Similarly, Tulia Fogli was granted access to vorasidenib under a single patient IND license. She and her husband, Michael, a cardiologist and alumnus of UT Southwestern Medical School, were blindsided in fall 2023 when doctors in Oklahoma diagnosed Tulia with a low-grade glioma after she suffered a seizure. Although surgeons tried to remove as much of the tumor as possible, the procedure left her with speech difficulties and an uncertain future.
It was around that time that Michael learned of Dr. Maher’s research, which he called a “true blessing.” The couple drove to Dallas to meet her for a consultation, and she ultimately got Tulia authorized to receive the drug.
“We put our trust in Dr. Maher and her expertise,” Michael said. And in April 2024, they got the call saying Tulia could start vorasidenib. The Foglis gathered their three sons and drove four hours through a torrential downpour to Dallas.
“We didn’t want to wait any longer,” Michael said. “I remember that trip vividly. There was just this sense of relief.”
Dr. Maher continues to push for more progress on low-grade gliomas. "I always use the analogy of the window. It is our job to keep them well, to keep this window open, and to drive the science forward so one day we cannot only halt these cancer cells but kill them completely."
The Foglis stood together in the lobby of the Cancer Care Outpatient Building and marked the moment with a photograph under Infinite Energy of the Universe, the suspended art piece dedicated to Bill Miller, a passionate supporter of Dr. Maher and her research.
“My husband was a health care professional who understood the importance of a positive experience for patients, physicians, and hospital staff,” said his wife, Tricia Miller, who serves as Chair of the Arts and Interiors Committee of UTSW’s President’s Advisory Board. “We are honored to have been able to be a part of the research that led to the development and FDA approval of vorasidenib! Dr. Maher and her team have dedicated their time and passion to this profound achievement. We congratulate them and extend our hope to the many patients who will benefit from their endeavors.”
For Dr. Maher, who has been leading the fight against brain tumors for more than two decades, the FDA approval of vorasidenib is not the final destination, but it is an important sign of progress.
“We are giving patients more time. We’re talking about years of difference,” she said. “I always use the analogy of the window. It is our job to keep them well, to keep this window open, and to drive the science forward so one day we cannot only halt these cancer cells but kill them completely. I, along with so many others, am completely invested in getting us to the next milestone.”