Novel Drug Promising for Life-Threatening Rett Syndrome in Kids

Pauline Anderson

April 08, 2019

A new medication for the core signs and symptoms of Rett Syndrome (RTT), a life-threatening, neurodevelopmental condition, shows promise in children and adolescents, results of a new phase 2 study suggest.

Findings from the randomized controlled trial shows trofinetide was safe, well-tolerated drug and demonstrated clinically relevant improvements in a range of RTT symptoms, including disruptive behavior, breathing problems, and repetitive movements, compared with placebo.

There are still hurdles to overcome, including completion of a phase 3 study that ACADIA Pharmaceuticals will lead. But if all goes well, a new drug application could be in the works within 2 to 3 years, study investigator Nancy E. Jones, PhD, vice president of Clinical Development at Neuren Pharmaceuticals, told Medscape Medical News.

"If approved by the FDA, trofinetide could be the first medication available that targets improvement across the core symptoms of this debilitating condition," she added.

The study was published online March 27 in Neurology.

Life-Threatening Disorder

An earlier study in adolescents and adults that compared placebo with trofinetide at 35 mg/kg or 70 mg/kg twice per day showed that the higher dose led to improvement in a wide range of manifestations of the disease.

This new study, which included younger subjects who took the drug for a longer period of time — with some at the highest dose of 200 mg/kg — expands the drug's safety, tolerability, and efficacy profile.

RTT is a life-threatening neurodevelopmental disorder affecting an estimated 1 in 10,000–15,000 girls. It's characterized by loss of expressive language and purposeful hand use, and impaired or absent ambulation. In addition to severe motor deficits, girls with RTT have autonomic, gastrointestinal, and other systemic symptoms.

Neurobehavioral impairments include anxiety-like behaviors, disruptive behavior, and mood dysregulation.

The condition is related to mutations on the MECP2 gene, which codes for methyl-CpG binding protein-2 (MECP2). Evidence suggests that MECP2 is expressed in neurons and glial cells.

"In Rett syndrome, synapses are too few and underdeveloped due to insufficient formation and maturation of dendrites resulting from impaired neuronal protein synthesis and excessive pruning by overactive microglia," said Jones.

There are currently no approved or effective pharmacotherapies for RTT symptoms.

Trofinetide is a synthetic analog of the amino-terminal tripeptide of insulin-like growth factor 1 (IGF-1), which occurs naturally in the brain.

 "Evidence shows that in addition to reducing inflammation, trofinetide may restore neurotrophic function, normalize microglial phenotype, and increase long-term potentiation, or LTP, which is a measure of synaptic strengthening that could affect learning and memory", said Jones.

Multicenter Study

The new phase 2, double-blind study included 82 girls ages 5 to15 years (mean age 9.7 years, mean weight 26.1 kg, 94% white) at 12 US sites.

Of these, 62 participants were randomly assigned to placebo twice a day for 14 days, followed by placebo or 1 of 3 doses of trofinetide (50, 100, or 200 mg/kg twice a day) for 42 days. An additional 20 participants were later randomly assigned to 200 mg/kg or placebo twice a day also preceded by 14 days of placebo.

Trofinetide and placebo were administered as a strawberry-flavored liquid either orally or via gastrostomy tube. Participants were blindly up-titrated to their assigned dose based on a predefined dosing schedule.

Participants had a posttreatment visit about 10 days after the end of treatment.

Researchers used the following measures to test efficacy:

  • Caregiver-completed Rett Syndrome Behaviour Questionnaire (RSBQ)

  • Clinician-administered RTT Domain Specific Concerns (RTT-DSC)-Visual Analog Scale

  • Clinician-administered Clinical Global Impression-Improvement (CGI-I) scale

  • Caregiver-completed Top-3 Caregiver Concerns Visual Analog Scale

  • Clinician-administered RTT Motor Behavioral Assessment (MBA).

The authors note that the RSBQ is the most widely used behavioral instrument in RTT, in part because of its disorder specificity and its reliability and validity for the RTT pediatric population.

This measurement has also shown sensitivity to interventions and correlations with functioning and quality of life in RTT.

"The RSBQ could more properly be labeled as a 'neurobehavioral' measure since it includes RTT features that are modulated rather than triggered by behavior (e.g., breathing problems). Thus, the RSBQ is an instrument suitable for assessing multiple core RTT features, similar to the MBA," the authors note.

Dose-Dependent Response?

The analysis showed trofinetide to be safe and well-tolerated at all doses. There were no deaths and only one participant (in the 200 mg/kg twice/day group) withdrew from the study (she had increased mild gastroesophageal reflux, moderate diarrhea, and mild vomiting, which resolved after discontinuation).

The most common adverse events (AEs) across all treatment groups were diarrhea (27%), vomiting (15%), upper respiratory tract infection (11%), and pyrexia/fever (10%). Most AEs were mild or moderate in intensity and not considered related to the study drug.

There were four serious AEs in 3 participants, all of which were deemed not related to the study medication and had resolved by the end of the study.

Objective assessments, including laboratory assessments and vital signs, "did not reveal any systematic pattern of clinical detriment," the authors write.

As for efficacy, the study showed statistically significant evidence of clinical improvement for the 200 mg/kg twice/day dose of trofinetide vs placebo on assessments completed by both clinicians and caregivers. These included RSBQ (total score, P = .042), CGI-I (overall clinical status, P = .029), and RTT-DSC (most concerning aspects of RTT identified by clinicians, P = .025).

The RSBQ and RTT-DSC data suggest improvements across a range of symptoms, including repetitive behaviors, breathing problems, mood abnormalities/disruptive behavior, seizures, and ambulation impairment.

Improvements in the area of ambulation included being able to walk unassisted or improving on a particular motor milestone. For example, some girls were able to walk farther than they could before, or were better able to climb stairs.

Despite the variability in the relatively small cohort, researchers found a correlation between drug exposure and magnitude of changes in response to treatment.

The relative consistency of effects in this study provides "additional confidence that the results of the previous study were not simply attributable to chance," the authors write.

Clinically Meaningful Improvement

Even though there was only a short treatment period and a relatively small population, investigators found statistically significant and clinically meaningful improvement, said Jones.

"Taken together with the findings from the previous study," she said, "it highlights trofinetide's potential as a much-needed treatment for Rett syndrome, a condition that has such a profound impact on patients and their families."

Current treatment strategies for RTT include managing each patient's individual symptoms, such as epilepsy and constipation.

"These approaches are often unsatisfactory and have only a limited effect on function," Jones said.

Although clinicians may use medicines approved for other conditions to relieve some features of RTT, these drugs also don't address the underlying disorder, said Jones.

Nonmedication strategies typically involve multiple specialists with diverse areas of expertise.

"The standard of care typically includes aggressive physical, occupational, and speech therapies, as well as targeted approaches to frequent nutrition problems, orthopedic concerns such as scoliosis and limb contractures, and gastrointestinal dysfunction," Jones added.

To obtain regulatory approval, these new findings will need to be confirmed by a longer, 12-week, phase 3 trial in a larger population, to be initiated later this year.

This will be followed by a 9-month, open-label extension study for an eventual total follow-up of 1 year, said Jones.

In addition to RTT, trofinetide has been evaluated in phase 2 studies of traumatic brain injury and Fragile X syndrome. As an investigational drug, trofinetide has not yet been approved for use in any clinical population.

Disease-Modifying Effect?

Commenting on the study for Medscape Medical News, Nicholas Johnson, MD, vice chair of research, Department of Neurology, Virginia Commonwealth University, Richmond, said the study was well designed and the results promising.

The investigational drug "appears to have a strong effect on the outcome measures" that were assessed, said Johnson.

With a neurodevelopmental disorder like RTT, it can be challenging to identify appropriate outcome measures to use during a clinical trial, he said.

"This group should be commended for taking the time before the clinical trial to develop outcome measures that suit their population," Johnson said. "These provided a window into the disease that would not have been available with things like MRI or other outcome measures."

RTT is not only devastating, but can be life threatening, especially when it comes to seizures. And while the study found that the impact of the drug on seizures did not quite reach statistical significance, "there was a trend or hint of efficacy that needs to be followed and replicated in a larger study; it's still promising," said Johnson.

Researchers have been investigating IGF-1-like molecules for some time now, and the current compound "makes a lot of rational sense", said Johnson.

This study does not address whether trofinetide has a real disease-modifying effect, but future longer and larger studies should determine if that's the case, said Johnson.

The clinical trial was sponsored by Neuren Pharmaceuticals and funded by Neuren Pharmaceuticals and Jones is an executive of Neuren Pharmaceuticals. Johnson has disclosed no relevant financial relationships.

Neurology. Published online March 27, 2019. Abstract

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