A new, experimental drug is helping to the change the lives of people with the genetic condition Fragile X – which often causes autism and intellectual disability, and for which, until now, there had been no treatment.
One of them is American Jason Mazzola (24) who for 22 years, needed constant supervision, lived with disabling anxiety, and struggled to answer even simple questions.
NPR reports that Mazzola’s life started to change when he started taking the experimental drug called zatolmilast in May 2023.
His mother, Lizzie Mazzola, said zatolmilast has transformed her son.
“I have a different child,” she said. “He gets himself to work, he walks downtown, gets his haircut, gets lunch. He wouldn’t have done any of that before.”
Other parents of children with Fragile X are also reporting big changes with zatolmilast.
Those anecdotes are supported by data. A 2021 study of 30 adult male participants with Fragile X found that taking zatolmilast for 12 weeks improved performance on a range of memory and language measures.
Now, two larger studies are under way that will determine whether zatolmilast becomes the first drug approved by the US Food and Drug Administration to treat Fragile X.
Brain, interrupted
Mazzola realised early on that her son was falling behind. “He could hardly talk by three,” she said. “At four he started to put some words together, but really wasn’t talking in sentences.”
Genetic tests revealed the cause: Fragile X.
The inherited condition affects the X chromosome, making one segment appear fragile or broken. This anomaly blocks production of a protein that’s important to brain development. The result can be autism, ADHD, anxiety, sensory sensitivity, and a range of intellectual disabilities.
For Jason, many of these symptoms were severe. Like many people with Fragile X, his IQ was in the 40s, and he was often paralysed by anxiety.
Jason’s twin sister, Jessica, also has Fragile X, but the symptoms are absent or much milder.
That’s often true of females with the condition. They typically benefit from having two X chromosomes, one of which is unaffected.
So while Jessica went on to college, Jason was still barely able to converse, even with his parents.
Repurposing Alzheimer’s drug
By the time Jason was a teenager, scientists had begun studying the link between Fragile X and an enzyme that plays a role in memory and cognitive impairment.
Much of the funding for this research came from the FRAXA Research Foundation, a group founded by the parents of a child with Fragile X.
FRAXA-funded researchers knew there were drugs that could tweak the enzyme in a way that might help a Fragile X brain work better. But the drugs all had side effects that made them unsuitable for people.
Then one day FRAXA got a call from Tetra Therapeutics, a small drug company in Michigan.
“They had this drug in clinical trials for Alzheimer’s disease,” recalled Dr Michael Tranfaglia, FRAXA’s co-founder and medical director.
“They wanted to explore the possibility of using their drug in Fragile X.”
That made sense because the drug targeted the same enzyme FRAXA had been studying and it didn’t seem to cause the side effects that had ruled out similar drugs.
The next stop for Tetra was Dr Elizabeth Berry-Kravis, a professor at RUSH University Medical Centre in Chicago. For nearly three decades, Berry-Kravis had been studying the way Fragile X affects brain development, and was receiving funding from FRAXA.
So she got a visit from a Tetra executive.
“Mark Gurney, who was the head of the company at the time, came to my office and said, ‘Hey, you’ve been waiting for a drug for 28 years, and we’ve got a drug,’ ” Berry-Kravis recalled.
A flurry of research showed that zatolmilast worked in fruit flies and mice with Fragile X. The 2021 study of 30 male adults extended the promising results to people.
“We saw an improvement in their memory and their vocabulary and their ability to read,” Berry-Kravis says.
The next step was to have Berry-Kravis oversee a pair of larger studies – one in males from nine to 17, the other in males from 18 to 45. The studies started in 2022, with funding from the Japanese drug company Shionogi, which had acquired Tetra.
Mazzola decided to enrol Jason, who was now in his 20s. She was optimistic about zatolmilast, despite having witnessed the failure of other promising drugs for Fragile X
“It just seemed different,” she said. “It was affecting their cognition and IQ scores.”
At first, his parents didn’t know whether their son was getting zatolmilast or a placebo.
Within a few weeks, though, Jason did something remarkable: He walked into his father’s home office and started a conversation.
“My husband said, ‘He has to be on the drug. He’s never done that’,” Mazzola said.
Jason is still taking the drug, and still improving. He has a job washing dishes at a local assisted living facility. He helps his mother coach high school field hockey and lacrosse, and plays a mean game of golf with his father.
A scientific verdict on the drug will come when the study is completed, probably in 2025.
Study details
Inhibition of phosphodiesterase-4D in adults with fragile X syndrome: a randomised, placebo-controlled, phase 2 clinical trial
Elizabeth Berry-Kravis, Mark Harnett, Scott Reines, Melody Reese, Lauren Ethridge, Abigail Outterson, Claire Michalak, Jeremiah Furman & Mark Gurney
Published in Nature Medicine on 29 April 2021
Abstract
The goal of this study was to determine whether a phosphodiesterase-4D (PDE4D) allosteric inhibitor (BPN14770) would improve cognitive function and behavioural outcomes in patients with fragile X syndrome (FXS). This phase 2 trial was a 24-week randomised, placebo-controlled, two-way crossover study in 30 adult male patients (age 18–41) with FXS. Participants received oral doses of BPN14770 25 mg twice daily or placebo. Primary outcomes were prespecified as safety and tolerability with secondary efficacy outcomes of cognitive performance, caregiver rating scales and physician rating scales. The study met the primary outcome measure since BPN14770 was well tolerated with no meaningful differences between the active and placebo treatment arms. The study also met key secondary efficacy measures of cognition and daily function. Cognitive benefit was demonstrated using the National Institutes of Health Toolbox Cognition Battery assessments of Oral Reading Recognition (least squares mean difference +2.81, P = 0.0157), Picture Vocabulary (+5.81, P = 0.0342) and Cognition Crystallised Composite score (+5.31, P = 0.0018). Benefit as assessed by visual analog caregiver rating scales was judged to be clinically meaningful for language (+14.04, P = 0.0051) and daily functioning (+14.53, P = 0.0017). Results from this study using direct, computer-based assessment of cognitive performance by adult males with FXS indicate significant cognitive improvement in domains related to language with corresponding improvement in caregiver scales rating language and daily functioning.
NPR article – Fragile X held him back. An experimental drug is helping him break free (Open access)
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