Subscribe to eTOC

CNS Annual Meeting

Wednesday, October 30, 2019

CHARLOTTE, NC—The GABA-receptor agonist gaboxadol produced clinician-assessed global improvement in adults and adolescents with Angelman syndrome, according to findings presented here at the annual meeting of the Child Neurology Society.

Based on the results, the researchers have started a phase 3  trial of the drug in a cohort that will include much younger patients.

In the current study, researchers enrolled 88 patients aged 13 to 49 from 11 sites in the US and one in Israel; 78 completed the trial. To be eligible, the children and adults had to be ambulatory and able to take the oral study drug. The Ovid Therapeutics-funded trial, known as STARS, is the first industry-sponsored trial in Angelman syndrome, according to Cesar Ochoa-Lubinoff, MD, associate professor of pediatrics at Rush University, who presented the data.

Because there are no instruments tailored specifically for Angelman syndrome, researchers used the Clinical Global Impressions-Improvement (CGI-I) scale to assess patients. This measure, they said, is an appropriate endpoint because it can capture a variety of improvements—which is suitable given the disease's heterogeneity and varying natural history.

Researchers found that 66.7 percent of patients receiving the drug improved on the CGI-I at 12 weeks, compared with 39.3 percent on placebo—a significant difference of 27.4 percent (p= 0.02). The overall score for those taking gaboxadol once a day was 3.0 on the 7-point scale. This score is defined as "minimally improved."

The score of placebo patients was 3.79—closer to the 4.0 score of "no change." Patients who were dosed twice a day performed worse than those who received once-a-day dosing, with a score of 3.58. Patients with improved CGI-I scores also showed trends to improvement in sleep, motor abilities, and behavior. These scores did not rise to significant levels, the researchers said, but they suggested that the global improvement tool is reflecting real change in the overall condition.

"The STARS exploratory efficacy endpoint using CGI captured a significant global improvement," Dr. Ochoa-Lubinoff said. "STARS demonstrated the clinical benefit of gaboxadol in patients with Angelman syndrome."

Fever, rash, and seizure were among the more frequent adverse events in the patients on active drug, but overall it seemed to be well-tolerated, researchers reported.

Dr. Ochoa-Lubinoff said the results support "further development of gaboxadol and the continued exploration of using CGI-I as an endpoint for clinical trials in Angelman syndrome."

A phase 3 trial is planned to include 15 sites and 60 patients ages 2 to 12, using CGI as the primary outcome; secondary outcomes will include sleep parameters—measured by actigraphy and a sleep diary—as well as communication, motor, behavior, and other domains using the Vineland Adaptive Behavior Scale.

Commenting on the study, Donald Gilbert, MD, FAAN, a pediatric neurologist and professor of pediatrics at Cincinnati Children's Hospital Medical Center, noted the relatively modest clinical effect seen in the study.

"Statistical significance and clinical impact are not the same thing—you need statistical significance but you want the magnitude of the impact to be large," said Dr. Gilbert, who moderated the session in which the data were presented. "It's curious that the group that only got nighttime dosing did better than the group that got twice-a-day dosing."

Still, he added, the drug is worth exploring, given the limited options for this disorder.

Dr. Gilbert said he is encouraged that the phase 3 includes much younger patients, since early treatment is so important in these patients. He added that he understood why the earlier phase included older patients, since the drug has previously been seen to have adverse effects.

"I think they were probably forced to try it out in adults as they're a less vulnerable population."

Dr. Ochoa-Lubinoff has received research support from Ovid Therapeutics. Dr. Gilbert had no competing interests.

Link Up for Related Information:

Kolevzon A, Bird LM, Burdine RD, et al. Abstract 3.1. Topline results from a phase 2 adult and adolescent Angelman syndrome clinical trial: A randomized, double-blind, safety and efficacy study of gaboxadol (Ov101). J Am Acad Child Adolesc Psychiatry 2018;57(10):Suppl S182.

Wednesday, October 30, 2019

CHARLOTTE, NC—A longer lag time to continuous EEG placement is associated with a longer duration of seizures in children with refractory status epilepticus, according to findings presented here at the annual meeting of the Child Neurology Society.

Those who did not have EEG placement within five hours had significantly longer seizure duration than those who had placement before the five-hour mark, said Dmitry Tchapyjnikov, MD, assistant professor of pediatrics and neurology at Duke University Medical Center, who presented the findings.

The findings were based on data from 121 patients in the Pediatric Status Epilepticus Research Group; for the study, tertiary centers from around the US gathered data prospectively from an observational cohort of children admitted from 2011 to 2017. They had convulsive seizures at onset, with seizures persisting after at least two anti-seizure medications, one of which had to be a non-benzodiazepine anti-seizure drug or requiring a continuous infusion.

Some guidelines recommend continuous EEG placement within an hour in cases of refractory status epilepticus. But in this study, many patients had a longer lag time: The median time was nine hours after seizure onset; only 4 percent had continuous EEG placement at one hour, Dr. Tchapyjnikov said.

Researchers limited the analysis to patients with a seizure duration of more than three hours. They pointed out that three hours is the median time to seizure resolution; at three hours, only about 10 percent of patients were placed for EEG, making it unlikely that EEG affected management before that time point for most patients.

They divided the cohort into two groups—those who had EEG placed before five hours and after five hours. An exploratory analysis suggested that this was when a "dramatic divergence" in seizure duration started to emerge, Dr. Tchapyjnikov explained.

Only 37 of the 121 patients had EEG placed within five hours of seizure onset: Females were significantly more likely than males to be in this group (p= .03), as well as those whose seizure onset occurred at a study hospital (p=.0005).

A central nervous system infection was significantly associated with the seizures and persistent status epilepticus at the time of EEG placement (p=.04).

Seizures resolved in about 70 percent of the children who had EEG placement by the five-hour cut-off, compared with about 50 percent of those who did not have EEG placed by that time, Dr. Tchapyjnikov said.

"There are a lot of kids who are not getting timely EEG placement, and that's happening at big academic centers that I'm sure are trying very hard to do these things quickly," he said. "We need to understand what [effect] this is having on how we care for children in refractory status epilepticus," he said.

Dr. Tchapyjnikov added that the study doesn't establish why there is a link between the delay in time to EEG placement and seizure duration. "I would suspect that there's a difference in treatment trajectory—so if you don't know if somebody is still having seizures or not because the EEG is not on, then that might affect how aggressively you're treating their seizures, which in turn might affect seizure durations."

Commenting on the study, Mary L. Zupanc, MD, FAAN, professor of neurology and pediatrics at the Children's Hospital of Orange County in Orange, CA,  pointed out that physiological changes occurring much earlier than the five-hour mark during status epilepticus make it harder to bring seizures under control. Benzodiazepines, for example, become much less effective once a patient who developed status [epilepticus] outside the hospital actually gets to the emergency department.

"The GABA receptors don't bind the benzodiazepines as tightly," she said. "That happens early, long before five hours."

"The cytotoxic edema has transpired to the point where it's going to be increasingly difficult to control status, and that may be because of ongoing injury to the brain cells," she said.

The findings point to the need for measures to hasten continuous EEG placement and for faster transport to higher levels of care. Moreover, she said, emergency physicians should be educated that the lack of a physical seizure doesn't mean status epilepticus is over.

She added, "Is there a way that we could train [staff at] outside hospitals who may not have EEG techs all the time and EMS to place a cap…or even a few electrodes, to get some data more quickly?

"That to me would be an action plan. What the feasibility [is] I can't exactly tell you, but those ought to be recommendations."

Drs. Tchapyjnikov and Zupanc had no competing interests.

Link Up for Related Information:

Fung FW, Jacobwitz M, Vala L, et al. Electroencephalographic seizures in critically ill children: Management and adverse events. Epilepsia 2019;60(10):2095–2104.

Wednesday, October 30, 2019

CHARLOTTE, NC—A nanoparticle enhanced drug delivery in a mouse model of medulloblastoma, leading to prolonged survival, researchers reported here at the annual meeting of the Child Neurology Society.

The nanoparticle targeted the endothelium in a subtype of medulloblastoma, the researchers said, holding the promise for good results with less toxicity.

Medulloblastoma is the most common kind of brain tumor in childhood, but over a third of patients are incurable even after a combined approach of surgery, chemotherapy, and radiotherapy, which can bring severe morbidities, such as cognitive deficits. The sonic hedgehog (SHH) molecular subgroup of medulloblastoma accounts for about 30 percent of the tumors. SHH-pathway inhibitors are effective, but cause secondary toxicities, including effects on bone development. A limited ability to cross the blood-brain barrier has required higher dosing, leading to greater toxicity.

Researchers at Weill Cornell Medical College packaged the SHH-pathway inhibitor vismodegib in a nanoparticle based on fucoidan, a polysaccharide that binds P-selectin, a protein overexpressed on vascular endothelial cells. When low doses of radiation are used, it can induce P-selectin expression specifically in the tumor vasculature, providing a better target for the nanoparticle—and with it, more effective and precise delivery of the drug, said Praveen Raju, MD, PhD, assistant professor of pediatrics in neurology at Weill Cornell.

Injection with the nanoparticles blocked the SHH pathway in medulloblastoma in mice and prolonged survival of the mice, researchers found. Using just 0.25 Gray of radiation, nearly 50 percent of the mice injected with the nanoparticle were still alive at 40 days, while none were alive after being treated with the nanoparticle injection by itself or radiation alone (p= 0.01).

Researchers also found there was no long-bone growth toxicity in the mice treated with the nanoparticle and radiation. These mice went on to develop significantly greater femur bone length, about the same as control mice, when compared with those treated with free vismodegib (p< 0.05).

"P-selectin-targeted nanoparticles translocate the tumor blood-brain-barrier," Dr. Raju said. "P-selectin-targeted vismodegib nanoparticles enhance SHH pathway inhibition at lower doses in a [mouse model] with no bone toxicity and thus increases the therapeutic index."

Commenting on the study Scott L. Pomeroy, MD, PhD, FAAN, neurologist-in-chief and chairman of neurology at Boston Children's Hospital, said there is a huge need for better treatments for these patients.

"To irradiate the entire brain of a 3-year-old has devastating long-term effects," he said. Even among those who survive the disease, "a very small percentage of them go on and live independently as adults. They're mostly quite incapacitated. So, to have treatments that are very targeted to the disease and enable us to cut down or eliminate radiation is one of our primary objectives in this disease."

This approach is interesting, he said. "It seems like it gets into the tumor and slows its growth… and they don't see any effects on the bones. So potentially that is a differential way to get this drug to affect tumors but not affect bones by packaging them in this nanoparticle."

Dr. Pomeroy said that the drug would likely have to be given long-term to be effective, and questions remain about how long the P-selectin would continue to be expressed in the amount required. He added that, no matter the efficacy in some patients, the drug would not work for all SHH medulloblastoma patients.

"The challenge is there's a fair amount of heterogeneity of how the [SHH] pathway is activated, and [in] a significant percentage of the tumors—the activating lesion is downstream of the site where this drug inhibits—and they're resistant to the drug. So that's one of the caveats. It will not work for all of the sonic hedgehog medulloblastomas."

Link Up for Related Information:

Lou E, Nelson AC, Kool M. Differential response of SHH-expressing adult medulloblastomas to the sonic hedgehog inhibitor vismodegib: Whole-genome analysis. Cancer Biol Ther 2019;20(11):1398–1402

Wednesday, October 30, 2019

CHARLOTTE, NC—Edasalonexent, an oral small molecule drug that inhibits NF-kappa-B (NF-κB), showed an array of improvements, including function in young boys with Duchenne muscular dystrophy (DMD), according to findings presented here at the annual meeting of the Child Neurology Society.

Better treatment is needed for DMD, a rapidly progressive form of muscular dystrophy affecting males and caused by mutations to the DMD gene, said Richard S. Finkel, MD, chief of the division of pediatric neurology at Nemours Children's Health System in Orlando, FL.

Activation of NF-κB is a key factor in DMD progression involving skeletal and cardiac muscle, Dr. Finkel explained, and the oral drug is being developed both as a monotherapy and potentially in combination with other dystrophin-targeted therapies.

Thirty-one patients participated in the phase 2 trial, including 16 patients involved in a six-month off-treatment period to serve as controls. The study participants, who ranged in age from 4 to 8 years old, could not concurrently be treated with corticosteroids.

Researchers found that NF-κB target gene levels rose during the off-treatment period, but they observed a pattern of declining levels when treatment was resumed in the phase 2 study. They also found that muscle enzymes, including creatinine kinase (CK), significantly decreased with edasalonexent treatment, suggesting the drug was having a positive effect (p< 0.05 for baseline compared with weeks 12 through 72).

Five lower leg muscles showed significant improvement on MRI T2 through week 48 of the treatment period compared with the off-treatment control period (p= 0.018).

Function declined during the off-treatment period, but it stabilized during the treatment period on several tests: The North Star Ambulatory Assessment, a 17-item measure for DMD patients; the 4-stair climb, the 10-meter walk/run; and time to stand.

The drug also showed signs that it might have a cardiac benefit: The average resting heart rate significantly decreased from 99 to 92 beats per minute. The researchers noted that the heart rate reduction was more pronounced in those with a higher initial resting rate (p< 0.01)

The most common adverse events were diarrhea, upper abdominal pain, and nausea, but researchers said they tended to be mild and transient.

Growth curves for those on the drug were similar to boys without disease, Dr. Finkel said.

"It showed clinically meaningful slowing of disease progression on edasalonexent compared to the off-treatment control," Dr. Finkel said. "We saw that there were positive biomarkers such as the CK stabilization and the MRI. We showed that the drug was well-tolerated. And, finally, we feel that this data collectively supports the development of a phase 3 clinical trial."

The researchers recently completed enrollment in the phase 3 trial enrollment across 40 sites and data are expected in about a year, he said.

Commenting on the study, Ann H. Tilton, MD, FAAN, professor of neurology and pediatrics and section chair of child neurology at Louisiana State Health Science Center in New Orleans, said the drug is a breakthrough because it casts a wider net than the other newly developed drugs that have only targeted individual mutations.

"This is a novel new DMD drug, which is oral and is shown in the initial studies to affect multiple associated abnormalities—because this is a huge gene there can be multiple different types of deletions and of different sizes," Dr. Tilton said.

Also important, she said, is that "it might make a difference in the heart."

"I think this is innovative and it's much easier and less expensive in the delivery (than other drugs that are intravenous)," Dr. Tilton said. "If it can truly meet all those parameters—which are biochemical, measurement by imaging, and measurement of function—it is exciting but we will just have to wait for the phase 3 trial and see what happens."

She said she will be curious about the cost of the drug, especially considering the duration of treatment that will be needed: "This is probably a lifelong therapy."

Dr. Finkel is a principal investigator in clinical trials for Catabasis, which provided funding for the study; he also serves as an advisory board member for Catabasis.

Link Up for Related Information:

Finanger E, Vandenborne K, Finkel RS, et al. Phase 1 study of edasalonexent (CAT-1004), an oral NF-κB inhibitor, in pediatric patients with Duchenne muscular dystrophy. J Neuromuscul Dis 2019;6(1):43–54.

Tuesday, October 29, 2019

CHARLOTTE, NC—Hemorrhagic transformation (HT) occurred in nearly 25 percent of patients with cardioembolic arterial ischemic stroke who were treated with antithrombotic therapy, according to findings presented here at the annual meeting of the Child Neurology Society.

The study aimed to better clarify the safety of the therapy in children with cardiac disease who have a stroke. The risk for stroke is heightened in these children—132 in 100,000 compared to two to eight per 100,000 in the general pediatric population, said Elizabeth Pulcine, MD, MSc, assistant professor at the Hospital for Sick Children in Toronto, who presented the findings.

A retrospective study on a cohort that was enrolled prospectively from 2003 to 2017 at her center found that 20 of the 82 neonates and children—or 24.4 percent—experienced HT. This condition was symptomatic in five of the children within 15 days of their stroke, with a median time to HT of four days. The children ranged in age from full-term neonates up to those younger than 18 years old at the time of their diagnosis; to be included, they had to have a primary diagnosis of congenital or acquired heart disease.

About 60 percent of the children had cyanotic heart disease, with a much smaller percentage having acyanotic heart disease, cardiomyopathy or myocarditis, infective endocarditis, primary arrhythmia, and rheumatic heart disease.

Researchers found that 19 of 66 children experienced HT while on anticoagulant therapy alone and one of nine were taking both antiplatelet and anticoagulant therapy. None of the five who were on antiplatelet therapy alone and neither of the two who were treated with IV plasminogen activator experienced HT.

Arterial ischemic stroke recurred in 13.4 percent—11 of 82 patients—which was lower than previously reported rates that approached 30 percent, Dr. Pulcine said. Researchers found that those with univentricular physiology of the heart were significantly less likely to undergo HT (p= 03).

"Further optimization of antithrombotic therapy to prevent stroke recurrence particularly in those with univentricular physiology… is warranted," Dr. Pulcine said.

E. Steve Roach, MD, FAAN, professor of neurology at Dell Medical School at the University of Texas at Austin, said the study provides useful insight on the management of these patients.

"Congenital heart disease is the most common risk factor for ischemic stroke in children," he said. "Antithrombotic therapy is commonly administered to children with embolic stroke due to congenital heart disease in an effort to prevent additional strokes. While this approach seems intuitive, we have limited information about the safety and efficacy of antithrombotic therapy."

"This study is retrospective, but the cohort is large enough to provide useful insight into treatment complications," he added. "Some of the children experienced hemorrhagic transformation after receiving an antithrombotic, but the rate of transformation did not increase in patients who also received an antiplatelet agent."

He said the researchers "do not fully address the treatment effectiveness or long-term outcome in these children, and this information will be needed in order to really assess whether antithrombotic therapy is effective. Nevertheless, having more information about its safety in children is extremely valuable."

Link Up for Related Information:

Jain P, Haller C, Pulcine E, et al. A child with a stroke, drug-refractory epilepsy and congenital heart disease: Can a hemispherectomy be safely performed between staged cardiac procedures? Childs Nerv Syst 2019;35(7):1245–1249.