Better Preclinical Practices Would Boost Success in Clinical Setting for Rett Syndrome Therapies, Review Says

Ana Pena, PhD avatar

by Ana Pena, PhD |

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Discovery and development of therapies for Rett syndrome requires better preclinical research practices and study design to raise the chances of success in the clinic, according to a study reviewing current therapy development efforts.

The review study, “A Coordinated Attack: Rett Syndrome Therapeutic Development,” was published in the journal Trends in Pharmacological Sciences.

Repurposing Therapies

While there are no specific treatments for Rett syndrome, a large number of potential therapies have completed or are about to enter clinical trials.

Most pharmacological approaches under development seek to relieve major symptoms of the disease. Many rely on repurposing therapies that are already approved or in clinical development for other conditions that have overlapping symptoms or share molecular targets with Rett syndrome.

Gilenya (fingolimod), a medication approved to treat multiple sclerosis, recently completed a Phase 1/2 trial (NCT02061137) testing its safety and efficacy in children with Rett syndrome who are older than 6. Results have not been released yet.

Ketalar (ketamine), an approved anesthetic, is “perhaps the best example of repurposing efforts,” according to the study’s authors.

“Relative to other potential treatments, ketamine is an example of a compound whose efficacy has been demonstrated in multiple laboratories, in both male and female MeCP2-knockout mice (mouse models of Rett syndrome), and in acute and chronic dosing paradigms,” they said.

Sub-anesthetic doses of ketamine improve brain function in such models and may reduce repetitive behaviors and respiratory problems, the study said. Those positive effects remain for some time after therapy withdrawal.

A first exploratory study testing ketamine treatment for Rett syndrome was terminated earlier due to funding withdrawal (NCT02562820), but a Phase 2 clinical trial (NCT03633058) was recently launched and is currently recruiting patients in the U.S. This study will assess the safety, tolerability, and efficacy of four ascending doses of ketamine. Participants will receive, in either order, oral ketamine twice daily over five days followed by an equivalent regimen of placebo. A total of 48 patients are expected to enrol.

Despite positive preclinical results in mice, the approved antidepressant treatment desipramine (sold as Norpramin, Pertofrane, or as a generic) had no significant clinical efficacy in 36 girls with Rett syndrome, and led to several side effects in a recent European clinical trial (NCT00990691).

A Phase 2 study (NCT02715115) on trofinetide, an investigational compound initially developed for strokes, showed favorable safety and initial efficacy results in girls with Rett syndrome. Neuren and ACADIA Pharmaceuticals, which are working together this year to develop the therapy, plan to initiate a Phase 3 trial, followed by a long-term study.

Another candidate under investigation, sarizotan, was originally intended for Parkinson’s disease but is under current testing for relieving respiratory problems associated with Rett syndrome, although results from a Phase 2/3 study (NCT02790034) have not been released yet.

Improving Translation to Clinical Testing

Finding new therapeutic targets for Rett syndrome has primarily relied on identifying which genes change activity in patients’ tissues or cells. The most promising targets are then tested in preclinical animal models in the lab, using agents that disrupt the identified pathways.

However, “there is a staggering failure rate of therapeutics to cross the preclinical to clinical ‘Valley of Death,’ often despite broad and reproducible efficacy profiles in animal models,” the researchers said.

To address this issue, the National Institutes of Health, and the Rett syndrome research community and patient family organizations, such as the Rett Syndrome Research Trust and, have set a series of standards to improve the translational success of preclinical research, known as the “preclinical research in Rett syndrome” practices document.

Their recommendations include: testing a range of doses of the potential therapeutic, in both male and female mouse models that represent a variety of clinically relevant MeCP2 mutations (most Rett cases are caused by mutations in this gene); using sufficient sample sizes; incorporating clinical datasets and clinically meaningful outcome measures; and having safety and efficacy results that could be replicated across laboratories and published in peer-reviewed journals.

The choice of clinically relevant outcome measures is important, since there is still debate about how treatment response and efficacy measures in animal models can be translated to humans.

Many of the symptoms of Rett syndrome patients are difficult or impossible to measure in mouse models, including cognitive deficits due to the inability to speak and the limited use of hands. Sociability is also challenging to quantify.

Choosing outcomes that are easier to measure and/or are routinely assessed during clinical visits is likely to increase translational success. Examples include breathing abnormalities such as apnea (temporarily cessation of breathing), seizures, gait dynamics, and heart rhythm and electroencephalography abnormalities.

Responses that can be reliably measured across a patient population with varying degrees of symptom severity is also important in trial design.

The practices document is a good starting point to improve the chances of success into clinical development “but fieldwide adherence must increase,” the researchers wrote.

Scientists who take these practices into consideration when applying for research grants and during the review process will make these standards “more commonplace and financially feasible in academia,” the study stated.

Large pharma companies are quitting early-stage treatment development for Rett syndrome, so these efforts to bring promising new approaches to clinical trials are falling on the research community.