Clinical trials
Advances in understanding of Rett syndrome have led to many therapies in clinical trials, several of which show promise.
Trofinetide. One of the most promising targets for downstream therapy, mentioned earlier, is IGF-1, which was the target of a successful phase 3 clinical trial, LAVENDER (sponsored by Acadia Pharmaceuticals).35,36 This trial studied trofinetide, a synthetic IGF-1 analog that inhibits neuroinflammation, restores glial function, corrects synaptic deficiencies, and regulates oxidative stress response.12,37,38 Initial results from phase 2 and phase 3 trials indicate improved scores for treated patients in the Rett syndrome Behaviour Questionnaire (RSBQ) and Clinical Global Impression–Improvement (CGI-I) scores, while also showing improvements in the Communication and Symbolic Behavior Scales Developmental Profile Infant–Toddler Checklist–Social composite score.36,39
The most common adverse events seen with trofinetide were diarrhea and vomiting.
Acadia Pharmaceuticals has filed for approval of a new drug application for trofinetide with the Food and Drug Administration, for which the company has been granted Fast Track Status and orphan drug designations. Most (95%) subjects in the phase 3 LAVENDER trial elected to continue taking trofinetide in the subsequent open-label Lilac and Lilac-2 extension studies.36 A current open-label phase 2/3 trial is recruiting patients 2 to 5 years of age to evaluate trofinetide.40 It is expected that, in the near future, this could be a drug given to Rett patients as an FDA-approved treatment.
Blarcamesine. Another small molecule drug, blarcamesine (also known as ANAVEX2-73), a sigma-1 receptor agonist, produced promising results in phase 2 clinical trials in adult Rett syndrome patients. The drug is in a phase 2/3 clinical trial for pediatric Rett syndrome patients (sponsored by Anavex Life Sciences).41-43
Phase 2 results indicated statistically significant and clinically meaningful improvement in RSBQ and CGI-I scores with blarcamesine. Improvement was initially observed within 4 weeks after the start of treatment and was sustained throughout the study. The drug was shown to be well tolerated, with minimal adverse effects; no serious adverse events were recorded. These results were observed in adult patients, demonstrating that improvements in Rett syndrome are possible even after regression.
Blarcamesine activates the sigma 1 receptor, which is pivotal to restoring cellular homeostasis and restoring neuroplasticity – deficiencies of which have been linked to autophagy and glutamate toxicity. The drug has also been explored as a potential treatment for other neurological disorders.44-47 Improvements in blarcamesine-treated patients further correlated with lower levels of glutamate in cerebrospinal fluid, which is a Rett syndrome biomarker, supporting the proposition that behavioral improvements were due to drug intervention.48,49 The phase 2 trial was modified into a phase 3 trial and additional endpoints were added.41-43
All patients in the phase 2 adult trial elected to continue in the extension study.
Based on these promising data, Anavex is pursuing an approval pathway for adult patients, while continuing dosage optimization phase 2/3 trials and recruitment for a pediatric trial.42,43
Is the future about gene therapy?
TSHA-102 (miniMECP2). Taysha Gene Therapies is developing a promising gene therapy, TSHA-102, for Rett syndrome, and is aiming to begin phase 1/2 clinical trials in 2022.50 The technology for this therapy relies on the delivery of a fragment of MECP2 (known as miniMECP2), which is regulated by a built-in microRNA regulator (miR-responsive auto-regulatory element, or miRARE) to help ameliorate MECP2 dosage toxicity. (Overexpression of MECP2 is toxic to neurons, which has made traditional [so to speak] gene replacement therapy difficult in Rett syndrome: Levels of MECP2 need to be tightly regulated, and the Taysha microRNA technology regulates levels of miniMECP2, thus reducing toxicity.)