Discovering a path ahead for fragile X medicine | Spectrum
In June 2020, cannabidiol reached a well-known hurdle in Fragile X research: like many previous drug candidates, it missed its primary goal in clinical trials. Among 109 young people with Fragile X syndrome who took the drug and 101 who took a placebo, the researchers saw no significant difference in social avoidance ratings.
However, a secondary analysis included in the original design of the study offered a glimmer of hope. According to unpublished results, a subgroup of 91 participants showed a significant improvement over the same measure after treatment with the drug.
Among this group, the FMR1 gene underlying Fragile X syndrome is full of methyl groups that block its expression of the FMRP protein. In contrast, the remaining participants have only partially methylated copies of the gene and can produce more FMRP.
“Looking at methylation was pretty important to finding the subgroup that showed the most optimal response,” says Randi Hagerman, medical director of the MIND Institute at the University of California, Davis, who ran one of the study centers.
The subset’s improvements only hit the minimum threshold for a statistically significant measure – they have a p-value of 0.02 – and the results are waiting to be replicated, which is what the company doing the studies, Zynerba Pharmaceuticals, is working on. However, the design of the study reflects a fundamental shift in the way researchers are trying to advance drug development for Fragile X syndrome, one of the leading hereditary causes of intellectual disability and autism.
A number of teams working on treatments for Fragile X syndrome have turned to molecular and other biomarkers to stratify their results and increase their chances of identifying responders. They also research novel study designs and tools to analyze the results. Their efforts steer the testing of new drugs, but also spur scientists to re-examine abandoned candidates.
“There is a general feeling that because we are getting these studies wrong, we may be abandoning drugs with potential benefits,” said Leonard Abbeduto, director of the MIND Institute, who helped develop new outcome measures for Fragile-X studies.
A long-standing obstacle to drug trials in this area has been that Fragile X syndrome, like autism, is very heterogeneous. People with this condition generally have excess DNA repeats in FMR1, but vary in their FMRP expression, depending in part on the level of methylation, says Craig Erickson, associate professor of psychiatry at Cincinnati Children’s Hospital Medical Center in Ohio.
As a result, they may not respond in the same way to a drug.
To break the heterogeneity and predict drug response, researchers are studying a variety of biomarkers, sometimes in combination. For example, Erickson is leading a small study looking at how electroencephalography (EEG) signatures shift when people with Fragile X take a single dose of either acamprosate, lovastatin, or minocycline.
EEG recordings from people with fragile X syndrome are different from those from typical people, Erickson and colleagues found. At rest, for example, people with fragile X often have more high-frequency “gamma” vibrations than typical individuals. “It’s like the brain is shooting a mile a minute,” says Erickson.
But the EEG patterns vary in people with fragile X even before they take any medication: men with fragile X tend to have higher gamma oscillations than neurotypical men, while women with fragile X, for example, have lower values than neurotypical women. And some patterns track with the severity of a person’s traits, such as: B. social communication difficulties and IQ.
Erickson’s team is investigating whether any of the drugs can normalize certain EEG patterns and how these shifts are related to improvements in cognitive and behavioral parameters. The researchers are also studying blood levels of FMRP, which may similarly measure the severity of the Fragile X traits and may underlie the differences in EEG responses.
Other ongoing studies have included various arrays of biomarkers in their protocols. Among other things, a study examining the effects of the diabetes drug metformin on behavior, language and cognition in people with Fragile X syndrome is also collecting information using EEG, eye tracking and molecular tests.
Biomarkers are expected to become even more important as researchers move toward studies of gene therapy treatments for fragile X, Erickson says. Because these treatments can come with greater risks and costs, knowing beforehand who is most likely to benefit from them is critical.
Another problem plaguing fragile X studies is measuring the effectiveness of a drug. Most have relied on behavioral reports such as the Aberrant Behavior Checklist, which prompts caregivers to assess a child’s characteristics. However, parents can expect their child to improve during an exam, which can skew their ratings. For example, in several drug studies, parents have reported significant improvements even when their child takes a placebo.
“If the drug had a small effect, we would never have known,” says Elizabeth Berry-Kravis, professor of child neurology at Rush University Medical Center in Chicago, Illinois, who has led many Fragile X studies.
To address the problem, she and her colleagues validated the NIH Toolbox, a series of tests participants take on a tablet or computer, as an objective measure of cognition in people with intellectual disabilities, including those with Fragile X. They used them then, along with other reviews and biomarkers, in a cross-over study to measure how 30 men with fragile X responded to an experimental drug called BPN14770, which increases levels of a molecule involved in learning and memory.
Cognition improved significantly when the men took the drug compared to taking a placebo, the researchers reported in April. “That was a great result,” says Berry-Kravis. Not only did the NIH Toolbox help researchers avoid placebo effects, the measure may have characterized the condition better than behavioral reports. The behavior of people with fragile X varies, but everyone with the condition has cognitive difficulties, explains Berry-Kravis.
Outcome measurements like the NIH Toolbox can help reduce some of the variability that often blurs clinical trial results, says Eric Hollander, professor of psychiatry and behavioral sciences at Albert Einstein College of Medicine in New York City, who did not participate in the most recent study was involved. But “just showing an improvement in one outcome measure may not be enough,” he says. To approve a drug, researchers must also demonstrate that a shift in a person’s score on that metric is clinically meaningful.
Federal drug regulatory agencies still have to accept the NIH Toolbox as a valid outcome measure in clinical trials. Berry-Kravis and her colleagues are working to reach an agreement with the US Food and Drug Administration on what additional data needs to be collected about the measure and hope to use it in a phase 3 study with BPN14770 expected to start next year, she says.
From all of these studies, it is becoming increasingly clear that a single drug for Fragile X syndrome is unlikely to be enough. Given the many functions of FMRP, effective treatment will likely require multiple therapies that work in different ways, says Berry-Kravis. Researchers may need to research drug combinations, but for now we need to get the first drugs across the finish line, she adds.
To this end, scientists are not only testing new drugs, but also evaluating some compounds that failed in previous studies with improved tools and strategies. Among them, Berry-Kravis and her colleagues are re-evaluating AFQ056, which blocks a receptor called mGluR5. Drugs that block mGluR5 appear to reverse fragile X traits in mice, but show mixed results in humans, possibly due to problems with the way studies were conducted.
Because the drug can work best early in development, the ongoing study is tracking children ages 3 to 6, rather than adolescents and adults who have been the focus of previous studies. The team also plans to investigate whether a language learning intervention works better for people taking the drug than for people taking a placebo.
The drug is expected to kickstart a process that allows neurons to optimize the strength of their connections, says Abbeduto, who works on the study, but how much this biological shift will alter a person’s overall communication skills is unclear. The language intervention can help increase the drug’s effects and improve the team’s chances of spotting changes, he says.
Another group revitalizes arbaclofen, a drug that dampens neuronal activity by stimulating inhibitory receptors in the brain. The drug improved social behavior in a 2012 study of 63 children and adults with fragile X. However, the results did not hold up in subsequent studies – one in adolescents and adults with fragile X and one in children and adolescents with autism. The company developing the drug, Seaside Therapeutics, stopped its arbaclofen work in 2013 and later closed its business. Clinical Research Associates, a subsidiary of the Simons Foundation, the parent company of Spectrum, acquired the rights from Seaside to develop arbaclofen for Fragile X syndrome, autism and other neurodevelopmental disorders.
However, results from one stopped study suggest the drug may have worked in children and adolescents with Fragile X, says Randall Carpenter, past president of Seaside Therapeutics. Children in the study received different doses of the drug. Those who took the highest dose were, in the parents’ opinion, significantly less irritable than those who took a placebo. They also showed improvements in social avoidance, the study’s primary endpoint that narrowly missed statistical significance. Many families involved in the studies also anecdotally reported that the drug helped their children communicate and complete everyday tasks.
Carpenter and his colleagues haven’t given up. Last November, a new company that Carpenter co-founded acquired the licensing rights from Clinical Research Associates to develop arbaclofen for fragile X. The team plans to meet with the Food and Drug Administration this year to find out what the filing is for application of a new drug is required.
“These are exciting times for the field,” says Carpenter. “We’re making great strides.”
Quote this article: https://doi.org/10.53053/NICC8065