Yes, we have finally reached the last part of the Pediatric Trial Results. Hooray. It was quite a challenge for me and hopefully I made it understandable for everyone. I want to thank those people who explained things to me until I grasped the concept/s so that I could explain it in my own words. I want to thank the girls and their parents who were so very brave, forging ahead on to unknown waters.
*disclaimer: these are my opinions only, unless otherwise noted.
This last little bit doesn’t need a whole lot of explaining, but I don’t want to stop with the shore insight, so here we go!
Lower dose groups and pharmacokinetics
The two lower dose groups of 50mg/kg BID and 100mg/kg BID did not demonstrate evidence of efficacy. However, two important observations were confirmed by pharmacokinetic analyses: The level of efficacy measured by each of the RSBQ, CGI-I and RTT-DSC correlated with exposure to drug (which varies within dose groups). Lighter subjects experienced lower levels of drug in their blood compared with heavier subjects receiving the same dose. This was also observed in Neuren’s previous trial in older subjects as well as in the completed Phase 2 trial in Fragile X syndrome. In this younger population, the effect was that the nearly threefold increase in the highest dose compared with the previous trial resulted in significantly lower actual exposure to drug than expected. In a pivotal trial, Neuren intends to use dosing that will aim to achieve similar exposure in subjects regardless of their weight.
And what can we take away from all that? The lower doses (under 200mg/kg) did not demonstrate evidence of efficacy. In my opinion and from the fact that PRE-trial efficacy measurements had to be met, I find it unlikely that there was NO improvement, just none that reached that PRE-CLINICAL bar. So, even if a change was noticed it couldn’t be counted if 1. it just didn’t reach the bar set and 2. if it was something that wasn’t already pre-determined to be measured. They can’t just go… oh, wow, we see this change! Let’s add it into the protocol. Nope, none of that. And the same thing actually goes for the higher dose group if they saw something that was not already pre-decided as a goal.
Lighter subjects had lower levels of the drug in their blood. This was a trend seen in all three Trofinetide trials; the adult, the Fragile X (on boys), and the pediatric Rett trial. So, Neuren’s going to work on that. No worries there, they’ll get it figured out. Of course, people might be wondering why that’s so, and I don’t know. Perhaps a higher metabolism? Maybe it binds somehow to fat molecules, this is a question for someone with way more education than me! I’ll see if later I can get a suppositional answer, or maybe someone out there knows.
So, we’re pretty sure Trofinetide is working. But what good is something that works if it’s not safe? Well, good news there as well!! Super safe!!
The primary endpoint of the trial was safety in this younger population. The safety profile appears benign, with the following key observations: There were no time-dependent patterns of adverse events (AEs) and no pattern of AEs evident with initiation or cessation of treatment. The majority of AEs during double-blind treatment period were either mild or moderate in intensity. The most commonly reported AE across trofinetide treatment groups was diarrhea, which was not dose-limiting. Four serious adverse events unrelated to treatment were reported in 3 subjects. There was one discontinuation – the caregiver withdrew the subject from the study due to AEs of vomiting and diarrhea. There was no systematic pattern of objective laboratory, vital sign, fundoscopy/tonsil or ECG abnormalities.
So, basically the worst thing was some diarrhea. It is my opinion that Trofinetide may have corrected the neurogenic bowel seen in Rett syndrome and the body was unprepared for that. (This is absolutely only my opinion-it could as easily been the strawberry flavoring or some other issue. I know Katie didn’t need her laxative at all during the trial she was in, but I do not know if she got the placebo or Trofinetide) I’m sorry someone had to withdraw because of that. However, as a parent, and while you can’t count it here as an adverse effect, the fact that the girls regressed AGAIN afterwards is a terrible consequence of such a trial and one of the reasons these parents were so incredibly brave.
So, to sum up all of the last five installments:
Trofinetide improved many symptoms significantly at the 200 mg/kg dose vs placebo.
Trofinetide is safe.
There was no “cap” seen; meaning, improvement continued throughout the trial on the 200mg/kg dose.
There was a correlation between how much drug was measured in the blood and improvement; lighter girls did not have as much drug in their blood despite the high dosing level. This was observed in all three Trofinetide trials and Neuren is working on a solution.
The Natural History Study is an important data collection study and has resulted in standards that can be used in clinical trials.
It’s not mentioned here, but subsequent announcements put Phase III starting in 2018.
But, the greatest thing you can take from all of this is that….THERE IS HOPE!
Thank you to Neuren, the researchers and all those who believed before us parents ever got an inkling, you are changing our world.