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A Review of Investigational Therapies for Rett Syndrome

  • Authors: Jeffrey Neul, MD, PhD; Cary Fu, MD
  • CME Released: 1/13/2023
  • Valid for credit through: 1/13/2024, 11:59 PM EST
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Target Audience and Goal Statement

This activity is intended for neurologists, pediatricians, and primary care physicians.

The goal of this activity is for learners to be better able to discuss investigational therapies in development for Rett syndrome.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Investigational therapies being studied for the management of Rett syndrome


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  • Jeffrey Neul, MD, PhD

    Professor of Pediatrics, Division of Neurology, Pharmacology, and Special Education
    Annette Schaffer Eskind Chair and Director
    Vanderbilt Kennedy Center
    Vanderbilt University Medical Center
    Nashville, Tennessee


    Jeffrey Neul, MD, PhD, has no relevant financial relationships.

  • Cary Fu, MD

    Assistant Professor of Pediatrics
    Division of Pediatric Neurology
    Medical Director, Vanderbilt Rett Syndrome Clinic
    Vanderbilt University Medical Center
    Nashville, Tennessee


    Cary Fu, MD, has the following relevant financial relationships:
    Consultant or advisor for: ACADIA Pharmaceuticals Inc.


  • Pakinam Aboulsaoud, PharmD

    Senior Medical Education Director, Medscape, LLC


    Pakinam Aboulsaoud, PharmD, has no relevant financial relationships.

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    Associate Director, Accreditation and Compliance, Medscape, LLC


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A Review of Investigational Therapies for Rett Syndrome

Authors: Jeffrey Neul, MD, PhD; Cary Fu, MDFaculty and Disclosures

CME Released: 1/13/2023

Valid for credit through: 1/13/2024, 11:59 PM EST


Since this program has been recorded, the FDA has approved trofinetide oral solution indicated for the treatment of Rett syndrome in adults and pediatric patients 2 years of age and older [Trofinetide [prescribing information] Approved 2023. Revised March 2023].


Dr Jeffrey Neul (:00):

Hello, I'm Dr Jeffrey Neul, Director of the Vanderbilt Kennedy Center and Professor of Pediatrics, Pharmacology, and Special Education at the Vanderbilt University Medical Center in Nashville, Tennessee. Welcome to this podcast series titled Bringing Focus to the Diagnosis and Management of Rett Syndrome. Today joining me is Cary Fu. Dr Fu, could you please introduce yourself?

Dr Cary Fu (0:25):

Sure. Thank you, Jeff. I'm Dr Cary Fu. I'm the Medical Director of the Rett Syndrome Clinic at Monroe Carell Jr. Children's Hospital at Vanderbilt, and an Assistant Professor of Pediatrics at Vanderbilt University Medical Center.

Dr Jeffrey Neul (0:38):

Excellent. Thank you so much, Cary, for joining us today. Today's episode is titled A Review of Investigational Therapies for Rett Syndrome. So let's get started. So Cary, now I understand that really there's been a big advance in the development of ideas for therapies for Rett Syndrome, really going back to development of animal models and starting to test things. And now we're seeing clinical trials that are going on in Rett Syndrome or even being planned in Rett Syndrome. So it's kind of an exciting time. So maybe we could talk about some of the trials that have been going on and then maybe about what might be coming in the future. So if we could start maybe with one of the drugs that has been under clinical trials, which is called trofinetide, and you could tell us a little bit about what trofinetide is, why it's being looked at in Rett Syndrome, and what it might do in terms of a mechanism, and what the study results have been showing us.

Dr Cary Fu (1:52):

Yeah, sure, Jeff. Definitely very exciting times. Trofinetide is a synthetic analog of the amino terminal tripeptide cleavage product of insulin-like growth factor 1. So this is actually a naturally occurring cleavage product that has been synthetically modified with the methyl group just to make it more orally bioavailable. [2:20] And so this is what is called trofinetide. And mechanistically, we don’t know exactly how it works, but what it does, we have seen in preclinical models that it can increase the amount of IGF-1 in the brain, it improves synaptic function, restores synaptic structure, and then also appears to have a role in modulating inflammatory microglia, and then a reactive astrocytosis. So possibly an anti-inflammatory role.


And in studies, in preclinical models in Rett Syndrome mouse models, it was treatment with the terminal tripeptide was shown to improve several Rett Syndrome relevant symptoms including motor dysfunction, abnormal breathing patterns, irregular heart rate, and also extended the lifespans of these Rett Syndrome mice. And so these very encouraging preclinical data gave rise to subsequent 2 different phase 2 trials. One in an older cohort of women with typical Rett Syndrome and another in a pediatric cohort of girls with typical Rett Syndrome, that both demonstrated favorable safety and tolerability, and then also had signals of efficacy that were very encouraging.


And then of course subsequently this led to a very pivotal phase 3 trial in girls and women between the ages of 5 and 20 with typical Rett Syndrome. It was a placebo controlled trial treated with trofinetide vs placebo for 12 weeks, that has not yet been published but has top level results and has been presented at conferences, that has shown statistically significant improvements in both of the co-primary endpoints. There was a caregiver assessed rating scale [inaudible 00:04:44] the Rett Syndrome behavior questionnaire, and then a clinician assessed score called the Clinical Global Impression of Improvement, that again, both had statistically significant improvements over placebo. And then there was also a secondary endpoint that was met that was another caregiver rated assessment of the ability to communicate that was also statistically significant in the trofinetide group compared to placebo. And it was also very well tolerated. And the most common treatment of urgent adverse event with trofinetide was gastrointestinal in nature involving mainly diarrhea that was mostly mild or moderate and then some vomiting, but overall fairly well tolerated.

Dr Jeffrey Neul (06:07):

Was there any differences in the serious adverse events between the 2 arms?

Dr Cary Fu (06:15):

There has been no significant increase in difference in the serious adverse events between the trofinetide and placebo.

Dr Jeffrey Neul (06:26):

Okay. That’s interesting and obviously be interesting to see as this is published and what subsequently happens with the FDA decisions on the interpretations of these phase 3 results. I also know that there has been some clinical development with a compound called blarcamesine. Can you tell me a little bit about that, about the mechanism of action of this drug and what preclinical evidence has been going on and where it stands in terms of the clinical development?

Dr Cary Fu (07:14):

Yeah, Blarcamesine is a sigma-1 receptor agonist. So it activates sigma-1 receptors in the endoplasmic reticulum, which has been shown pre-clinically to attenuate oxidative stress, so potentially an anti-inflammatory role. But then also is supposed to increase the release of brain-derived neurotrophic factor, BDNF, which has been shown to be decreased in a setting of Mecp2 deficiency in mice. And then in preclinical studies of blarcamesine treatment and Rett Syndrome mouse models has demonstrated improvements in again several Rett Syndrome relevant symptom domains including the abnormal breathing and then also motor impairments in the mice. And again, the encouraging preclinical results has led to initial phase 2 trials as well as phase 3 trials in people with Rett Syndrome. And there have been signals of efficacy that have been encouraging, but thus far there's been nothing published yet.

Dr Jeffrey Neul (08:42):

All right. Thank you. And the other trials that I know have been going on in Rett Syndrome relates to ketamine, which has a broad interest beyond Rett Syndrome in a variety of neuropsychiatric disorders, being used for major treatment resistant depression. And people have been exploring it for a number of other sort of neuropsychiatric conditions. But tell us a little bit about what ketamine is and what kind of results that we’re seeing in preclinical work and why there’d be clinical development for ketamine in Rett Syndrome.

Dr Cary Fu (09:26):

Yeah, so ketamine definitely very fascinating compound when it comes to Rett Syndrome. So this is again, like you alluded to, so it’s in very common use as an anesthetic and it works by blocking. So it’s an antagonist of NMDA receptors, which are one of the main receptors that mediate excitatory neurotransmission in the brain. And a lot of the preclinical work in ketamine actually derives from those post mortem brain specimens from people with Rett Syndrome that were shown to have irregularities in NMDA receptor expression, that were subsequently recapitulated in Rett Syndrome mouse models. And then work in other disease models, pre-clinical models, also shown that ketamine has the ability to stimulate BDNF translation and then dendritic growth, which again are deficient in Rett Syndrome models.


And so again, there was promise there from this compound. And then subsequently preclinical evidence from Rett Syndrome mouse models demonstrated that sub anesthetic doses, so these are not sedating doses of ketamine, were able to improve symptoms in these model mice, including irregular breathing, movement impairments. And they were also able to extend the lifespans of these mutant mice. And then subsequently, again, on account of these encouraging preclinical data, there has been a phase 2 study of, again, orally administered, sub anesthetic doses of ketamine. That completed in November of 2021 and is currently in the ongoing data analysis phase. And so we’re eagerly awaiting the results of that trial.

Dr Jeffrey Neul (11:19):

That obviously will be interesting to see and to determine if this may be a different avenue of therapy. Shifting gears a little bit into thinking about what might be newer, either trials that are just starting or things that might be being considered from a preclinical space. I know a lot of people have been interested since back in 2007 when a group in Scotland showed that by turning the Mecp2 gene back on in an animal model, even after the animal was sick, you could rescue problems. So the promise of gene therapy has always been tantalizing. And I know that this has been something that’s been explored. So what’s going on in that space now?

Dr Cary Fu (12:16):

Yeah, definitely. I mean, I think that was very exciting development in the Rett Syndrome community, the reversal of the symptoms in mice. And again, I think this really is the next frontier I feel like in disorder management because it is potentially truly disease modifying, that giving back the gene could potentially reverse the symptoms that have accrued. [11:36] And so again, yeah, gene therapy, very exciting. And so far there's been a lot of preclinical development. And there is one company that recently started enrolling for a gene therapy looking at a AAV9, which is a very common vector delivering Mecp2 intrathecally, and that started enrolling in Canada recently. And then I'm aware of a number of other companies that are also in the process of developing other ways of delivering an active gene, such as by reactivating the inactive Mecp2 on the inactive X chromosome.

Dr Jeffrey Neul (13:35):

Yeah. Well, I mean it seems it's very exciting times to have seen, since the discovery of the gene and really understanding the disorder, having animal models, using them for preclinical testing, finding good candidates, seeing it evolve to the point that multiple clinical trials and phase 3 trials that are meeting their endpoints. And a lot of exciting prospects for even future work that really have the potential of transforming how we think about caring for Rett Syndrome. Cary, do you have anything else you'd like to add?

Dr Cary Fu (14:18):

I am, again, equally excited about the promise of these emerging therapies and I think it is, as you say, going to be transformational for these individuals that we care for and their families. And I'm very hopeful for the future.

Dr Jeffrey Neul (14:40):

Absolutely. Well Cary, thank you so much for this great discussion, and thank you all for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation.

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