Since joining the Indiana University School of Medicine in 2018, Kathryn Nevel, MD, has spearheaded several clinical trials that aim to improve the quality of life and find better treatments for patients with neurological disorders.
Nevel, an assistant professor of clinical neurology, most recently served as the principal investigator for a clinical trial of mirdametinib, a drug for both children and adults to treat neurofibromatosis type 1 (NF1) and plexiform neurofibromas.
Affecting about 1 in 3,500 people in the United States, NF1 is a genetic condition that causes changes in skin pigment and tumors to grow on nerve tissue. Plexiform neurofibromas are non-cancerous tumors that develop along nerves and are commonly associated with NF1.
Nevel co-authored a paper published in the Journal of Clinical Oncology with results of the study, which led to the drug receiving approval from the Food and Drug Administration in February.
This is the first FDA-approved therapy for adults with NF1 and plexiform neurofibromas.
"I was thrilled with the approval," said Nevel, a board-certified neurologist and neuro-oncologist at Indiana University Health who specializes in the care of patients with primary and metastatic brain and spinal cord tumors. "I am fortunate to say that the patients who I treated on this study had received benefit from this drug."
About 30-50% of people with NF1 will develop a plexiform neurofibroma, Nevel said.
Dependent on the size, location and growth rate of the tumors, plexiform neurofibroma symptoms include disfigurement, pain, numbness, difficulty moving, trouble breathing and changes in eyesight.
"These large tumors can be a significant cause of morbidity, and in some cases, can be life threatening," said Nevel, a member of the IU School of Medicine's Multidisciplinary Neurofibromatosis Clinic, the only clinic for comprehensive care of neurofibromatosis patients in Indiana.
"There are people who have large plexiform neurofibromas that are near vital structures or impact nerve function, and in some cases are near important blood vessels or their airway. Our ability to treat these tumors traditionally has been through surgical removal, but in many cases, it isn’t possible due to the high risks."
Improving the standard of care
While a MEK inhibitor — a type of drug that blocks proteins, which help control cell growth — called selumetinib was approved by the FDA in 2020 for pediatric patients ages 2 years and older, Nevel said therapeutic treatments for adults with NF1 who have symptomatic, inoperable plexiform neurofibromas was limited.
"We hoped this new MEK inhibitor could be effective in adults because that patient population was not included in the landmark study of selumetinib that led to its approval in children," said Nevel, who led the mirdametinib clinical trial study site in Indianapolis at the IU School of Medicine. "Secondly, we wanted to evaluate if this similar but different MEK inhibitor, mirdametinib, was better tolerated."
The overall results of this multicenter, single-arm study were successful as 41% of adult patients (out of 58) and 52% of pediatric patients (out of 56) experienced at least a 20% reduction in tumor volume. Patients also experienced significant improvements in pain severity, pain interference and overall health-related quality of life.
"Notably in the study, there were many patients who had what we called deep responses, meaning a tumor volume reduction of 50% or more," Nevel said. Several adult and children patients experienced tumor shrinkage of 75% or more.
"Our ultimate goal — and this is true in any area of medicine — is prevention. We hope to one day prevent these tumors from forming in the first place," said Nevel, noting that there isn’t a cure for NF1. "The second-best thing is being able to offer a therapy that’s effective and well-tolerated to someone who already has the disease that requires treatment."
Additional clinical studies underway
As long-term follow up with patients continues for the mirdametinib study across all sites, additional research at the IU School of Medicine is underway for patients with NF1 and plexiform neurofibromas.
Nevel is the co-chair of a newly opened study on HLX-1502, an oral medication that was initially identified through an artificial intelligence drug discovery platform that predicts treatments using libraries of currently available drugs and gene expression data.
IU School of Medicine's researcher Steven D. Rhodes, MD, PhD, assistant professor of pediatrics, and D. Wade Clapp, MD, the Richard L. Schreiner Professor of Pediatrics and chair of the Department of Pediatrics, examined the drug in pre-clinical models and found there was signs of efficacy, Nevel said.
"That led to developing this into a clinical trial that will include multiple sites across the country," Nevel said. "The hope is that this drug will be an effective therapy that can shrink these tumors and make people feel better with minimal side effects or toxicity."
Rhodes, a pediatric oncologist and co-director of the Neurofibromatosis Multidisciplinary Program at the IU Melvin and Bren Simon Comprehensive Cancer Center, serves as the site principal investigator for the study at IU, which is currently enrolling participants with NF1 ages 16 and older with progressive and/or symptomatic plexiform neurofibromas.
"It's rewarding to be a part of a group of really smart, dedicated physicians, researchers, and scientists who are collaboratively trying to find better treatments for people with this condition," Nevel said. "We are dedicated to finding new, well tolerated therapies to help shrink tumors and ultimately improve patients’ overall quality of life. I'm delighted to be able to be a part of that work."
