Let’s Break it Down-1

 

trofinetide

Trofinetide

So, the Rett Community has had a couple of days to digest the BIG news-Trofinetide showed clinically significant improvement in the Pediatric Trial. Then we read the announcement, full of graphs and numbers and a lot of us went… what the hell is all that?!?

 

*disclaimer, unless otherwise noted these are my opinions only.

So, lets start with this summary:

Melbourne, Australia, 22 March 2017: Neuren Pharmaceuticals (ASX: NEU) today reported top-line results for its Phase 2 clinical trial in girls with Rett syndrome aged 5 to 15.  Rett syndrome is a serious and life threatening condition caused by a gene mutation, for which there are currently no approved treatments.
Neuren’s trial was a double-blind, randomized, placebo controlled study that tested three doses of trofinetide compared with placebo in 82 subjects.  The highest dose of trofinetide achieved statistically significant clinical benefit compared with placebo for each of three syndrome-specific efficacy measures, the Rett Syndrome Behaviour Questionnaire (p=0.042), the Clinical Global Impression of Improvement (p=0.029) and the Rett Syndrome Domain Specific Concerns (p=0.025).  These measures included assessments of both clinicians and caregivers.  Clinical improvements of 15% to 16% from baseline were observed, which was considered by leading Rett syndrome physicians to be clinically meaningful, particularly in a short duration trial.  The improvement increased through to the time that treatment ceased.  This suggests that further benefit may be achieved with longer treatment duration.
These results provide strong evidence of biological activity of the high dose across multiple symptom areas, indicating the potential for disease modification rather than simply addressing isolated symptoms.  In addition, trofinetide was well tolerated and had a good safety profile in these younger subjects, with no dose-limiting effects observed.

Neuren’s trial was a double-blind, randomized, placebo controlled study that tested three doses of trofinetide compared with placebo in 82 subjects.

Double-blind means neither the parents nor the doctors know which patients received the placebo vs one of the actual dose levels.

The highest dose of trofinetide achieved statistically significant clinical benefit compared with placebo for each of three syndrome-specific efficacy measures, the Rett Syndrome Behaviour Questionnaire (p=0.042), the Clinical Global Impression of Improvement (p=0.029) and the Rett Syndrome Domain Specific Concerns (p=0.025).  These measures included assessments of both clinicians and caregivers. 

For this I went to an expert. I’ll explain the three syndrome-specific efficacy measures in the next post. So, I asked what does (p and the numbers following mean)-here’s the explanation I got:

The p-value is an indication of the confidence that you have that the result obtained was a real result and not just one that occurred by chance or dumb luck.
It’s an indication of the reliability of the results.  For therapeutic intervention studies, any p-value below 0.05 is considered statistically significant.  Another way of looking at it is to say that at p=0.05, we are 95% confident that the result is real (or alternatively, there is only a 5% chance the result was due to chance).
 
p-values don’t indicate the size of the effect (the comparison between drug and placebo on a particular measure) but just that whether what we’re seeing is a true result or simply down to chance. 
 
There is a link between p-value , the number of subjects in your sample and the clinical effect size (difference between active and placebo for your measure). Since we had small sample sizes (For placebo, n= 24 and for 200mg/kg,  n = 27) and yet we still showed statistical significance across 3 measures, must mean that the clinical effect(or benefit) was large in each of the measures.
 
As an example, if you have a 2 drugs to treat high blood pressure, one lowers your BP by, say 5mmHG and the other lowers it by 50mmHG, you need a much larger sample size to show a statistically significant effect for the first drug than you would to show a statistically significant effect for the second. In other words, it’s easier to obtain a 5mmHg drop just by random chance than it is to show a 50mmHG drop.
 
In the paragraph you mention, this means that for the RSBQ measure (for eg), there is only a 4.2%   chance the result is down to luck,  and so  on for the other measures.

 

Clinical improvements of 15% to 16% from baseline were observed, which was considered by leading Rett syndrome physicians to be clinically meaningful, particularly in a short duration trial.  The improvement increased through to the time that treatment ceased.  This suggests that further benefit may be achieved with longer treatment duration.

So, a couple of important things here. 1. With the highest dose of 200mg/kg there was a 15%-16% improvement in only 6 weeks. HUGE. That’s between 1/6 th and 1/7th improvement. In my opinion…WOW. 2. The longer they were on it, the more improved they became. That means it’s possible that an even greater improvement will be seen when participants are on it longer! This tells me that a “cap” on improvements hasn’t been seen yet, which is super exciting. Where will the “cap” be??? Don’t know yet. Exciting stuff! The third phase may give us the answers or maybe only the actual use for years will tell us if a cap is reached before “normal” or not. Exciting times we are living in, here.

These results provide strong evidence of biological activity of the high dose across multiple symptom areas, indicating the potential for disease modification rather than simply addressing isolated symptoms.  In addition, trofinetide was well tolerated and had a good safety profile in these younger subjects, with no dose-limiting effects observed.

This reads, to me, that multiple symptoms were improved per person. This leads researchers to believe that Rett syndrome’s course can be modified rather than just addressing one symptom here and there. Again, HUGE news. Trofinetide was found to be safe and no side effects and again, no dose-limiting effect (meaning a place where improvement plateaued; improvement continued throughout the entire trial).

Watch for further installments!

 

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This entry was posted in cure, Neuren Pharmaceuticals, Rett Research, Rett Syndrome, Trail to a Texas Trial, Trofinetide, Trofinetide Pediatric trial, Uncategorized and tagged , , , . Bookmark the permalink.

2 Responses to Let’s Break it Down-1

  1. Rose and Renée says:

    You rock !

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