Anavex Life Sciences Corp (AVXL)

[Doc328]

She is also very optimistic about trofinetide for Rett:

She is a true expert on pediatric neurodevelopmental disorders, especially Fragile X. I don't know many pediatric neurologists, professionally or personally. However, I do know many thought leaders in the MS space and almost all are intelligent and most are enthusiastic -- sometimes appropriately and sometimes not. Their predictions fall flat at the same rate as non thought leader predictions. Her comments about Anavex are positive but do not substitute for data from an appropriate sized well designed study (of which the Rett Anavex study appears to be). (Neurology, the journal, often has an editorial about papers reporting novel clinical trials)

April 16, 2019; 92 (16) EDITORIAL link
Turning the tide on targeted treatments for neurodevelopmental disorders
Randi Hagerman, Roberto Tuchman

The study by Glaze et al.1 in this issue of Neurology® provides a remarkable glimpse into the future of targeted treatments for neurodevelopmental disorders. The investigators are to be commended for their well-designed clinical trial of trofinetide, an analog of the amino terminal tripeptide of the insulin-like growth factor 1, in the treatment of girls with Rett syndrome, a rare severe disabling disorder for which there is no current treatment. Their study provides Class I evidence that trofinetide is well-tolerated and effective at ameliorating specific core symptoms of Rett syndrome. This article is a positive light in a sea of negative studies for other neurodevelopmental disorders.2,–,5

The exciting new frontier of targeted treatments that have the potential to reverse neurophysiologic abnormalities in specific genetic neurodevelopmental disorders have had success in animal models; however, this promise has so far not been achieved in patients.5,6 There are many reasons for the failures of clinical trials. In addition to true lack of efficacy of the tested intervention, these include suboptimal dosing, utilization of adolescents and adults only, large placebo effects, lack of biological markers, and nonquantitative outcome measures that are not syndrome-specific.7,8 Some newer protocols have addressed these problems, including focusing on younger children to take advantage of a developmental window in which targeted treatments may have their greatest effect to reverse neurophysiologic abnormalities. Targeted treatments for neurodevelopmental disorders may require intervening during specific developmental windows, or combining both pharmacologic and behavioral–educational interventions. One example of such a study is the FX-LEARN study (NCT02920892) in children 3 to 6 years of age with fragile X syndrome; it is a controlled trial of AFQ056 (an mGluR5 antagonist) in addition to an intensive language intervention through Skype to improve expressive language.

In contrast to previous failed treatments in developmental disorders, the positive results in the present trofinetide study may have been due in part to (1) studying younger children (ages 5 to 15 years), (2) utilizing a placebo run-in, and (3) using measures developed specifically for Rett syndrome. In addition, trofinetide is a new medication with many potential mechanisms, including trophic effects, anti-inflammatory benefits, inhibition of astrogliosis and microglia activation, normalization of synaptic protein synthesis, and improvement of dendritic morphology. These benefits had been documented in animal models of Rett syndrome, where aspects of the phenotype are rescued.9 A multidimensional medication may be more likely to provide benefit when the loss of a protein, such as MECP2, has effects on many pathways. Their initial study in adults with Rett syndrome9 demonstrated limited benefits,10 but the present study focused on a younger group, a higher dose (up to 200 mg/kg bid), and longer duration of treatment. The high dose in this study demonstrated benefit and so the investigators increased the number of patients who were randomized to either placebo or this high-dose group as the study progressed. Fortunately, limiting toxicity did not occur at the high dose; all doses were well-tolerated.

We hope that this study marks the beginning of a new age of positive treatment trials for children with neurodevelopmental disorders. However, this hope for effective treatments should be tempered by the real challenges of treating less homogenous populations of children with neurodevelopmental disorders. There are many commonalities across several neurodevelopmental disorders such as upregulation of MEK-ERK and mTOR pathways, oxidative stress, mitochondrial dysfunction, imbalances between inhibition and excitation, and inflammation.11 Trofinetide may be able to address many of these, so it is possible that other neurodevelopmental disorders, such as fragile X syndrome or other identified genetic disorders associated with autism, may also benefit from this medication. Future treatment studies of neurodevelopmental disorders should strive to study well-defined populations, look for specific measurable and quantitative outcome assessments to reduce the placebo effect, and combine both pharmacologic and educational–behavioral interventions. The study by Glaze et al. may well be the first wave that turns the tide on the development of targeted treatments for neurodevelopmental disorders.