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2023 Rett Syndrome Year in Review: Expert Discussion on What’s New

  • Authors: David Lieberman, MD, PhD; Shannon Standridge, DO, MPH
  • CME Released: 11/14/2023
  • Valid for credit through: 11/14/2024, 11:59 PM EST
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This activity is intended for neurologists, pediatricians, and other clinicians who treat patients with Rett syndrome.

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    • Regulatory updates for emerging therapies studied for the management of Rett syndrome
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    • Summarize new data for the diagnosis or management of Rett syndrome


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  • David Lieberman, MD, PhD

    Child Neurologist
    Instructor of Neurology, Harvard Medical School
    Director, Comprehensive Rett Syndrome Clinic
    Department of Neurology
    Boston Children’s Hospital
    Boston, Massachusetts


    David Lieberman, MD, PhD, has the following relevant financial relationships:
    Consultant or advisor for: ACADIA Pharmaceuticals Inc.; Neurogene; Taysha Gene Therapies
    Research funding from: ACADIA Pharmaceuticals Inc.; Anavex Life Sciences Corp.

  • Shannon Standridge, DO, MPH

    Professor of Pediatrics and Child Neurology
    University of Cincinnati College of Medicine
    Director, Vinaya Rett Syndrome and Related Spectrum Disorders Clinic
    Cincinnati Children’s Hospital Medical Center
    Cincinnati, Ohio


    Shannon Standridge, DO, MPH, has the following relevant financial relationships:
    Consultant or advisor for: ACADIA Pharmaceuticals Inc.; Zogenix, Inc. (former)
    Speaker or member of speakers bureau for: Greenwich Pharmaceuticals (former)


  • Pakinam Aboulsaoud, PharmD

    Senior Medical Education Director, Medscape, LLC


    Pakinam Aboulsaoud, PharmD, has no relevant financial relationships.

  • Anne M. Sendaydiego, PharmD

    Medical Education Director, WebMD Global, LLC


    Anne M. Sendaydiego, PharmD, has no relevant financial relationships.

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  • Amanda Jett, PharmD, BCACP

    Associate Director, Accreditation and Compliance, Medscape, LLC


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This activity has been peer reviewed and the reviewer has no relevant financial relationships.

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2023 Rett Syndrome Year in Review: Expert Discussion on What’s New

Authors: David Lieberman, MD, PhD; Shannon Standridge, DO, MPHFaculty and Disclosures

CME Released: 11/14/2023

Valid for credit through: 11/14/2024, 11:59 PM EST


Activity Transcript

David Lieberman, MD, PhD: Hello, I'm David Lieberman, Child Neurologist and Director of the Comprehensive Rett Syndrome Clinic in the Department of Neurology at Boston Children's Hospital in Massachusetts. Welcome to this program titled, "2023 Rett Syndrome Year in Review: Expert Discussion on What's New." Joining me today is Dr Shannon Standridge, Professor of Pediatrics and Child Neurology at the University of Cincinnati College of Medicine and Director of the Vinaya Rett Syndrome and Related Spectrum Disorders Clinic at Cincinnati Children's Hospital in Ohio. Welcome, Shannon.

Shannon Standridge, DO, MPH: Hi, David. Thanks for having me.

Dr Leiberman: So just as background, Rett syndrome is a rare neurodevelopmental disorder that causes severe cognitive and physical impairment. It was originally described in 1966 by Dr Andreas Rett and published in German originally, and then moved to English literature in 1983 when more people learned about Rett syndrome.

Over the decades since, significant progress has been made in describing the natural history and establishing diagnostic criteria for Rett syndrome. However, until recently, there were no FDA-approved agents for the treatment of Rett syndrome.

In this program, we're going to discuss the most recent and clinically impactful updates on the diagnosis and treatment of Rett syndrome. Shannon, can you tell us a little bit about the current thoughts on epidemiology of Rett syndrome?

Dr Standridge: Sure, I'm happy to.

As you already mentioned, Rett syndrome is a rare neurodevelopmental syndrome, often now being referred to as a developmental encephalopathy, along with other rare genetic neurodevelopmental disorders with similar characteristics.

It is estimated that 1 in every 10,000 to 15,000 girls born will have Rett syndrome. This means that there is an estimated 15,000 girls and women in the United States alone being affected by Rett syndrome and approximately 350,000 women worldwide.

Dr Leiberman: Shannon, we have some recent data from an administrative database study that provided some interesting points on health-related costs. Can you elaborate?

Dr Standridge: These are some newer, cost-related utilization data that I'd like to share with our listeners.

While it's new and we still have a lot more to learn, it's important. It helps us to start to understand the cost of Rett syndrome care and management. So, over the last few years, studies have started to be performed analyzing this healthcare resource utilization and cost data, as well as treatment patterns of patients with Rett syndrome in the United States.

Using medical claims and prescription data, over the period of the study, it was found that the incidence rate of all-cause health-related utilization was 44.43 visits per patient per year. And the Rett-related health-related utilization made up 47% of all-cause health-related utilization data.

This means all-cause healthcare costs were 40,326 dollars per patient per year, and specifically, the Rett-related healthcare costs compromised 45% of this all-cause healthcare costs.

Interesting, but not hard to believe, the rates of this health-related utilization was generally higher among the pediatric patients vs our adult patients.

That's typically what we see in our clinical care. I think you would agree, David.

I think so. I mean, pediatric patients make up a larger chunk of our patients in the Rett Clinic.

Dr Leiberman: Shannon, let me ask, let's shift focus a bit and discuss the use of biomarkers in the evaluation and management of Rett syndrome. As novel agents for the treatment of Rett are being developed, it's becoming more important to identify biomarkers that will be able to objectively assess early treatment responsiveness, and ultimately, treatment efficacy.

Can you review the most recent developments in the use of electrophysiologic biomarkers in patients with Rett syndrome?

Dr Standridge: Absolutely.

While this is a more specialized type of conversation regarding biomarkers and Rett syndrome, it's very important because we're absolutely starting to learn the value of looking for biomarkers to help us track our management or our therapy and our efficacy of how we're managing our patients.

Individuals with Rett syndrome often present with abnormalities on neurophysiologic measures, such as electroencephalogram (EEG) and evoked potentials.

In a recent report that involved electrophysiologic studies performed in participants from a Natural History Study that was done from 2017 to 2021 involving 2 developmental encephalopathies, both Rett syndrome and CDKL5-deficiency disorder, these studies showed that visual-evoked potential amplitudes were reduced compared to typical developing participants.

Also, it was interesting that the the data showed that in Rett syndrome, the visual-evoked potential amplitude attenuation negatively correlated with clinical severity, which may open the door for us to use as biomarker of, brain function in individuals with, Rett syndrome.

Particularly with CDKL5-deficiency disorder, the auditory-evoked potential amplitudes were more attenuated in those with greater clinical severity. Again, these findings suggest that the negative correlation of lower-evoked potentials in individuals with greater or more severe clinical severity would be objective measures of brain function within Rett syndrome as well as in CDKL5-deficiency deficiency disorder.

Along those lines, in a recent published manuscript from 2023, also involving participants from Natural History Study from 2017 to 2021, evoked potentials were characterized into additional developmental encephalopathies, MECP2 duplication syndrome and in FOXG1 syndrome. Then these potentials were compared across these 2 encephalopathies as well as the CDKL5-deficiency disorder and Rett syndrome encephalopathies to understand how evoked potentials compared across these 4 groups, and if and how these evoked potentials might someday serve as biomarkers of clinical severity for these related developmental encephalopathies.

You can see that by this slide here with the visual-evoked potential amplitude, it was attenuated in individuals with MECP2 duplication syndrome compared to those with typically developing groups.

So, overall, this study revealed that the visual-evoked potential attenuation in participants with Rett syndrome, CDKL5-deficiency disorder, and in MECP2 duplication syndrome, that they were attenuated when compared to typically developing participants.

The information learned here, as we're sharing with you all today, in these recent manuscripts, needs to still be refined and studied further,but we're starting to understand just how we as clinicians and researchers might be able to use these objective measures, such as these evoked potentials to gauge or track clinical severity or response to therapy someday. I think that's pretty exciting because we will have objective markers that we may be able to track to help us in our endeavors of improving one's quality of life and treatment and management.

I don't expect that we'll necessarily be using them on a day-to-day clinical basis, but certainly we'll be able to use them more likely moving forward in research protocols.

Dr Leiberman: And I would agree. I think that they're also going to be helpful to see how reproducible they are over time and track changes in our patient population.

Dr Standridge: Absolutely, because so many of the features that we're tracking and we're treating, David, they really evolve over time, and there are particular features that are more significant, typically at different ages.

Dr Leiberman: I agree.

Dr Standridge: David, in moving on, let's move from the potential use of evoked potentials someday as biological-physiologic markers. And let's really focus on the new treatments for patients with Rett syndrome.

Recently, we've had a new agent that was FDA approved for the treatment of patients with Rett syndrome 2 years and older. Can you review the data that we have for this drug, trofinetide?

Dr Leiberman: Certainly Shannon, I'll give a little bit of background to trofinetide. So, the idea to use trofinetide came from our interest in insulin-like growth factor 1 (IGF-1), which is a growth factor, and specifically, there is a tripeptide of the N-terminus of IGF-1, GPE, that has some potent effects that might be separate from the IGF-1 receptor, and trofinetide is a novel synthetic analog of GPE that allows it to be more oral bioavailable to individuals.

The drug was first used in a phase 2 study both in pediatric and adult patients and then in the phase 3 study initially of patients age 5 to 20 years inclusive with classic Rett syndrome and documented MECP2 gene mutation.

The patients were randomized 1:1 between placebo and trofinetide arms.

It was 12-week study. There were 2 co-primary efficacy endpoints. There was a parent-derived measure, the caregiver RSBQ (Rett Syndrome Behavior Questionnaire) that is a 45-item listing of symptoms of an individual with Rett that might distinguish them from someone else with intellectual disability.

And there was a Clinical Global Impressions (CGI) improvement scale a 7-point Likert scale, where 4 is in the middle and shows no change, 1 is very much improved and 7 is very much worsened. And they were scored at baseline and throughout the study. There are also some key secondary efficacy endpoints, including the CSBS (Communication and Symbolic Behavior Scales Developmental Profile), which is a social composite score that's been followed in these individuals as well.

And the RSBQ started to show some differences from baseline at the 6-week mark. And there was a small but statistically significant difference at the 12-week mark where the greater the decrease in RSBQ, the greater the improvement in the individual. So in the trofinetide-treated group, there was a 5-point reduction in the RSBQ score, whereas in the placebo group, there was a 2-point reduction.

Mirroring this, there was a small but statistically significant improvement in the Clinical Global Impression of Improvement Scale, where the placebo group was closer to 4, which was no change, so they were closer to 3.75, and the group that received trofinetide showed a score of 3.5, moving towards minimal improvement. And these were statistically significant.

And the RSBQ, subscore measures 8 domains: General Mood, Breathing Problems, Hand Behaviors, Repetitive Face Movements, Body Rocking and Expressionless Face, Nighttime Behaviors, Fear/Anxiety, and Walking/Standing, and all of these measures showed us a small trend towards improvement with trofinetide.

Dr Standridge: So, David, just to ask a few questions or to discuss with you on the RSBQ, is that something that you typically use in clinical care? I do not. I know it's more research-based.

Dr Leiberman: Right. I don't use that either in my clinical practice. I mean, I do derive a lot of input from the parents in getting their opinions on their child's progress since our previous clinic visit, and I just list those by domain, but I don't score them. And 1 problem with the RSBQ is it, although it delineates a number of behaviors, it's not a totally comprehensive picture of the patient.

Dr Standridge: Right. Right. It's very interesting. And the features that are called out by the subscores are very important and what we are managing, but to be able to use it more refined.

Right, the RSBQ has been used as an outcome measure in a number of clinical trials, but I think, as a group, we need to refine our outcome measures to make them even better.

Dr Leiberman: I just wanted to also make mention, in the LAVENDER trial, during the 12-week, double-blind, placebo-controlled portion, there were side effects seen in the trofinetide-treated group with roughly 80% of that group having diarrhea and 27% having vomiting compared to the placebo group, where 19% had diarrhea and 10% vomiting. Those numbers also increased compared to our baseline population since Rett patients tend to have constipation more than diarrhea.

We should have mentioned that the trofinetide-related diarrhea, it was reversible. So when the dose was either decreased or stopped, the diarrhea abated and they returned to baseline.

Dr Standridge: David, why is this study, why is it important today?

Dr Leiberman: That's a great question, Shannon. So up till now, we have mostly symptomatic treatment for Rett patients. So, if they have epilepsy, we treat them with antiepileptics, if they have gastrointestinal (GI) disturbances, we treat them with laxatives for constipations or medications for reflux, but we don't actually have medications that treat the actual core features of Rett syndrome that give rise to its definition.

The regression in hand function, the regression in communication, the hand stereotypies, and the gait difficulties.

What some medications like trofinetide offer some patients is the ability to see some improvements in communication, hand function gross motor function, or a decrease in hand stereotopies.

And amongst my patients, those who've taken trofinetide I've heard from families that their child is more alert and engaged with the environment and they're more interested in communication. And I think those are, important, areas to explore and families are seeking trials with this medication at this time.

The medication might be worth a try in patients with Rett syndrome when the parents feel that the potential improvements could outweigh the potential risks that their child would have with the increased risk of diarrhea and vomiting.

So, you know, patients could try this medication for a number of weeks, you know, by 12 weeks you would expect to see differences from baseline as was found in the double-blind, placebo-controlled trial, and the clinician and the family can decide together whether that medication trial should continue or not based on progress of that child during treatment.

Dr Standridge: Something that I'd like to add David, is that, it can take a while for effects to be seen, if we are titrating the medicine slowly in order to try to avoid side effects. I found that it may take longer than what was the timing that was seen in the trials just based on time-to-goal therapy.

And yes, I think having that conversation with the family regarding ongoing trial with the medication based on the side effects vs the benefits is absolutely helpful as do with any of our medications and any of our treatments today with Rett syndrome, but even more important with the FDA-approved specific Rett therapy today.

Dr Leiberman: Yeah, I can also say that there is a publication that was put out recently on ways to mitigate some of the side effects of diarrhea and vomiting that you see withtrofinetide

So, that, is another tool that a clinician can have at hand to help manage treatment.

Dr Standridge: Absolutely.

David, there's another agent, blarcamesine, that is in later stages of clinical development, which is another exciting opportunity in Rett syndrome.

What data do we have regarding blarcamesine for the treatment of patients with Rett syndrome?

Dr Leiberman: Thanks for asking, Shannon. So, blarcamesine is a sigma 1 receptor agonist and a muscarinic receptor modulator. The sigma 1 receptor is an integral membrane protein involved in cellular homeostasis, which targets restoration of neuroplasticity and response to inflammation and cellular stress.

This compound was used in an adult population of Rett patients 18 to 45 years of age in this initial study, where they looked at the RSBQ and the CGI as co-primary outcome measures, and they looked at the Anxiety, Depression, and Mood Scale, the ADAMs, as a secondary outcome measure.

The ADAMs is an instrument used to assess anxiety-, depression-, and mood-related problems in individuals with intellectual disabilities. So the patients had to be stable on their medications, including any antiepileptic medication.

The RSBQ showed a 14-point improvement at 7 weeks after dose initiation in the placebo-controlled trial, and the ADAMs showed a 12.9-point improvement at 7 weeks with these 2 measures being statistically significant.

That was the AVATAR trial. The EXCELLENCE trial is a phase 2/3, double-blind, randomized, placebo-controlled trial in patients 5 to 17 years of age. This was conducted in England and in Australia.

Dr Standridge: And the study enrollment has been completed, but we have not heard word yet of the outcome from this, and the AVATAR trial is complete, and we are waiting for the publication of the final results of this study. I'm looking forward to getting those results, just because to have more tools in our toolbox as clinicians, it would be extraordinary, right, to try to start managing more of the particular disease-related management as opposed to just general symptomatic management would be amazing. And to, as I said, have more ways to do that.

I was wondering if you could tell us more about gene therapy and the development that is underway for the management of patients with Rett syndrome.

Dr Leiberman: Certainly, Shannon. I want to start off by saying that one hurdle to get over in gene therapy for Rett syndrome is gene dosage and that's because too little MECP2 gives Rett syndrome, but too much MECP2 is something we find in an MECP2 duplication syndrome, and these patients are also very much impacted by their disorder, also have problems with epilepsy and motor functions.

So, we're looking to these new methods of gene therapy that help to control the expression of the transcript so that the MECP2 levels are controlled.

I'll talk first about TSHA-102. So they use an AAV9 virus, which is very good at bringing their gene therapy into the nervous system.

This transcript is a self complimentary compound that has a mini MECP2 gene and a miRNA-responsive autoregulatory element (miRARE), and this miRARE, it constrains how much expression you get in a cell because they utilize microRNA that are dependent on MECP2 levels in the cell.

So, in wild-type animals, if you give them this TSHA-102 treatment, they don't show any toxicity, because the transcript is not expressed in those cells. If you, inject into the knockout pups, they live much longer than the ones who did not receive the virus.

They just were vehicle treated.

In the knockout mouse, they looked at an aggregate Bird score, which is a score that shows how much impact there was behaviorally in terms of motor function and behavior. And there was improvement with a TSHA-102 over several timepoints.

And the improvement was reflected in a significant delay in the onset of severe gait and limb abnormalities.

There is a REVEAL trial of TSHA-102 that was launched in Canada in women with Rett, 18 and older. It is a phase 1/2, open-label, randomized, dose-escalation, and dose-expansion study.

So far, I believe 2 adult women have been injected, and it's an intrathecal injection, and we're waiting for some more results from those studies.

Dr Standridge: Absolutely. I'm really excited.

Tell us more about the other option, the other genetic study that is ongoing right now.

Dr Leiberman: Certainly, NGN-401 delivers full-length copies of the MECP2 gene using an AAV9 vector It has a different construct. It is a full-length MECP2 gene. It has an expression attenuation via construct-tuning method, which is a microRNA that binds to the MECP2 messenger RNA, so that excess transcript is not expressed and you can constrain the amount of expression in any cell.

The design ensures the microRNA regulates the transgene and demonstrates a lack of off-target effects. There was a a study done in the male knockout mouse showing a dose-dependent improvement in survival and an improvement in the Rett-like phenotype on the Bird score. Again, we're looking at motor, gait, and breathing abnormalities, and when tested in female heterozygous mice did not show toxicity. The Expression Attenuation via Construct Tuning (EXACT) circuit is what enables these mice to do well for those who were just given the AAV9 with the MECP2 gene, but without the EXACT circuit. The mice did not live more than 2 or 3 weeks. But if given the virus with the full construct, they lived several weeks longer.

There is a phase 1/2 trial that has been launched in the United States, looking at girls age 4 to 10, with classic Rett syndrome who will be studied in this open-label design.

Dr Standridge: David. I mean, it's just pretty amazing that you and I are having conversation in 2023 regarding the possibility and actually the reality now of the genetic therapy that is being studied in patients with Rett syndrome.

Dr Leiberman: Yeah, I mean, what's amazing about gene therapy is that it's, you know, actually replacing the gene that's dysfunctional in Rett syndrome. And we know that gene is a transcription regulator. So it increases the transcription of some genes and depresses the transcription of other genes.

And it's a large number of genes, which makes it a very difficult target to hit pharmacologically, but using gene therapy, you know, you can recapitulate the function of the gene and, hopefully, see improvements in a number of areas, for our patients.

Dr Standridge: I mean, it's just amazing that you and I are discussing this along with the newly approved FDA treatment trofinetide specifically for Rett syndrome and the up and coming other potential drug therapies specifically for Rett syndrome. It's an exciting space to be at today and having more tools in our toolbox to help our patients and improve their quality of life.

And, you know, just how the families are enjoying the lives of those of their loved ones is really something I'm looking forward to. I know you are too.

Dr Leiberman: Yes, I totally agree. Shannon, thank you for this great discussion, and thank you for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation.

This transcript has not been copyedited.

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