So, here we go- Why was Rett syndrome chosen for Trofinetide trials. Contrary to what most people think, Trofinetide was not developed for Rett syndrome. A quick google search reveals that it was first developed for stroke, but the focus seems to have quickly changed to TBI.
The US Army, in conjunction with Walter Reed Army Hospital, funded initial development for NNZ-2566 (Trofinetide) Here is an excerpt from the Intrepid-2566 website (It’s no longer up now that the trial is over)
“Over the past 10 years, the incidence of traumatic brain injury (TBI) experienced by armed forces personnel in the conflicts in Afghanistan and Iraq has increased significantly over that seen in previous wars. TBI is a leading cause of battlefield death and long term disability. It is estimated that upwards of 60%* of all combat related casualties that are admitted to Walter Reed Army Medical Center or Bethesda Medical Center may be suffering from some level of brain injury. Increased attention and funding has been given to ways of protecting service members from TBI, to improving medical care and resources for recovery following a TBI, and for research into new drugs and other approaches to treat TBI. To advance the care and treatment of TBI patients, the military conducts research and collaborates with many public and private organizations to investigate the potential usefulness of new medicines to improve recovery. NNZ-2566 is one such drug and in addition to the early work on NNZ-2566 that was undertaken by scientists at the US Army’s research laboratories, the US Army has further supported the testing of this drug in TBI by awarding two grants to help complete of the INTREPID-2566 study.”
This study ended after 10 years; while it had no effect on mortality, those that received NNZ-2566 and survived were better off than those that did not. As I recall there were limitations that were discovered during this trial, by that I mean factors that were found which impacted the effectiveness of NNZ-2566 and this is why trials are so necessary. First, the dosage was miniscule compared to what is being used in trials today. Secondly, it was given by IV, this caused dilution and because most patients were given diuretics, the medication was flushed out of their system. Thirdly, even though the trial was double blind, the control group had less severely affected soldiers than the drug group. You can read about the trial-here.
Meanwhile, Autism came up on the NNZ-2566 radar. And here comes the crux of why Rett syndrome and Fragile X are the two disorders currently being trialed with Trofinetide. There are two aspects (there may be more, but these are the two that are obvious and are easy to explain) of Trofinetide that are the foremost reasons why it might be helpful in Autism and Autism Spectrum Disorders.
Autism has been linked to inflammation in the brain and Trofinetide has anti-inflammatory properties. However, the real key, imo, is in the dendrites of nerve cells. Dendrites are the fingerlike, out-branching extensions of nerve cells. They act sort of like a telephone line conference call- receiving information and relaying it to its cell’s body and then out the other side to the next cell. The space between each cell’s dendrites is called the synaptic space. Trofinetide has been shown to normalize the number and length of dendrites. The length and number of dendrites is affected in autistic people. There are two subsets of this example. One in which there are too many dendrites and one in which there are too few.
In this video of a lecture given by Dr. Snape, he goes into how Rett syndrome and Fragile X mimic these two subsets; Rett syndrome representing the “too few” and Fragile X representing the “too many” subsets and are therefore the optimal trial subjects. These are essentially control groups for autism. This is a phenomenal discovery. Not only are the disorders themselves control groups, but given that Rett syndrome occurs primarily in females and Fragile X occurs more often in males, the trials are also gender specific and so are also controls for gender as well. And that is how and why Rett syndrome became one of the two disorders that were chosen to trial!
Given these two major properties of Trofinetide (anti-inflammatory for the brain and normalizer of dendrites) it is easy to extrapolate the number of disorders that may benefit from its use.
Next week…what are the different FDA designations assigned to Trofinetide and what they mean for our children.