SPG601 found to reduce measure of abnormal brain activity in fragile X
Therapy helps normalize brain activity associated with learning, memory: Trial
A single dose of Spinogenix’s investigational oral therapy SPG601 led to significant reductions in a measure of abnormal brain activity among men with fragile X syndrome, according to top-line results from a Phase 2a trial.
Announced by Spinogenix in a company press release, the results from the placebo-controlled Phase 2a trial (NCT06413537) were also presented at the National Institutes of Health Fragile X Centers of Excellence Update earlier this month.
“I am very excited about these encouraging early phase clinical trial results with SPG601 in fragile X syndrome,” Craig Erickson, MD, chief medical advisor for Spinogenix and the trial’s principal investigator, said in an emailed statement to Fragile X News Today.
The study, conducted at the Cincinnati Children’s Hospital in Ohio where Erickson is a research director, was completed in just over three months, making it “the most rapid clinical trial I have ever been associated with in fragile X,” Erickson said. “This is important — we want to get families answers quickly — we want to use small numbers of patients in a rare disorder to quickly determine next steps for a new treatment program.”
Analyses are ongoing to prepare full study results for publication, the release stated.
Next step to test daily dosing of SPG601 in larger group of fragile X patients
With these positive results in hand, the scientist indicated the next step will be to work toward a study that tests daily dosing of SPG601 in a larger group of fragile X patients.
Fragile X is caused by FMR1 gene mutations that result in changes in brain function that drive a range of symptoms including intellectual disability, motor problems, behavioral issues, language delays, and seizures.
Among the consequences of FMR1 mutations is dysregulation of proteins that are important for the development and function of synapses, or the sites between nerve cells through which they communicate with one another. Synapses don’t mature properly in fragile X, contributing to its many neurological symptoms.
SPG601 is designed to restore more normal synapses in fragile X, and therefore ease its core symptoms, by increasing the activity of large-conductance calcium-activated potassium channels — more simply known as BK channels. These proteins are key players in synaptic function, and preclinical evidence suggests they are abnormal in fragile X.
In the U.S., SPG601 was recently granted fast track designation and had previously received orphan drug designation for fragile X. These statuses offer various incentives to accelerate a treatment’s development and regulatory review.
The Phase 2a trial, which was cleared by regulators last spring, involved 10 men with fragile X, ages 18-44. Participants were given a single dose of SPG601 (800 mg) or a placebo, taken as eight oral capsules. A week later, those given the placebo received SPG601, and vice versa.
Participants underwent an electroencephalogram, or EEG, which records the brain’s electrical activity. A main goal of the study was to evaluate whether SPG601 reduced high frequency gamma band activity, an EEG abnormality that’s associated with learning and memory problems in fragile X.
EEG signatures that reflect brain changes in fragile X
Erickson and colleagues have worked over the last decade to identify and validate EEG signatures that reflect brain changes in fragile X patients and animal models.
“We believe this gamma activity is representative of the excessive ‘noise’ that is going on a mile a minute in the fragile X brain, noise whose activity likely gets in the way [of] appropriate brain response to sounds and inhibits learning,” Erickson said.
According to the scientist, this excessive gamma activity may be associated with too many immature close-range connections between neighboring nerve cells that happen at the expense of mature connections between nerve cells that aren’t as physically near to each other.
In turn, this leads to hyperexcitability, where nerve cells are primed to fire more than normal. This is a known feature of fragile X that helps explain why patients “have over-active responses to many stimuli, such as sounds and looking at faces,” Erickson said.
Results showed SPG601 significantly reduced high-frequency gamma band activity, meeting the trial’s goal. Erickson indicated the treatment “clearly and consistently” reduced this EEG abnormality across participants.
“This is the strongest test result to date demonstrating a therapy normalizing gamma band activity, which is directly associated with learning, memory, and typical brain activity,” Erickson said in the press release.
These beneficial changes on brain electrical activity were not associated with sedation or lower reaction time, and SPG601 has been well tolerated, with no adverse events reported.
“This is an exciting milestone for SPG601 at a time when there are no approved treatments for [fragile X syndrome],” Stella Sarraf, PhD, founder and CEO of Spinogenix, said in the release. “The completion of this trial and our … Fast Track designation allow us to accelerate its development to offer a much-needed therapy that can improve patients’ quality of life in an underserved community.”
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