NEU (ASX) Importance of the trial results &amp; challenges

Originally posted by Noda ↑

Reviewing the results a few of things stand out to me.

The results show clinical benefit to the subjects, but I don't think the results show anywhere near the full potential of the treatment. The trial methodology is very much geared to measure symptomatic relief via the traditional drug model. The key take out for Trofinetide is that it "targets mechanisims underlying the disorder rather than a symptomatic medication". Surely this mode of action is less immediate than a traditional drug that alters the operation of natural systems. Trofinetide is stimulating self repair of the brain structure, not masking symptoms by turning stuff on or off.

On such a short trial this makes the results even more outstanding in my view. It also explains that after 54 days improvement is still improving linearly - the trial was far from complete from an improvement standpoint. With a drug model we would expect rapid change in measurable results, followed by a flat line. The duration is set to confirm tolerability in the safety profile. Trofinetide does not suit this method that well, it is stimulating natural repair mechanisms that take time, but it also explains the high degree of safety. Imagine what 180 or 360 days might look like vs placebo. I think a pivotal study will offer even better results.

MBA was improved but not statistically significantly enough to show clinical benefit, this was also the case in the first trial at 70mg/kg. It may be that this mechanism is more time dependent than dose dependent. Is the action of Trofinetide to repair the brain going to take longer then 54 days to be statistically significant? I would suggest - quite possibly.

The key issue raised is the variability of blood concentration. Lighter subjects showed lower concentration than heavier ones. I would be most interested to see the data of improvement grouped by blood concentration rather than oral dosage mg/kg. What does this tell us? Do the higher blood concentration patients show higher improvement? I think this data is important to understand - hopefully we see something in an investor presentation at some stage.

Dosage was 200mg/kg , therefore lighter participants were given less Trofinetide than heavier ones. A 30kg girl would receive 50% more than a 20kg girl. Maybe a straight dosage of 6g twice daily would reduce this variance. Or is the lower blood concentration an issue of metabolism? What is the variability of blood concentration in girls of the same weight?

The issue of blood concentration also featured in the TBI trial where it was noted the clearance rate was far higher than healthy volunteers - potentially due to IV fluids. With the low dose and high clearance rate, blood concentration was low and showed no clinical benefit.

Adjusting dosage for blood concentration could be the key element to maximising the results, not necessarily long term, but for a short time period where we are trying to measure statistical significance in a specific window.

Even with the variance in blood concentration they showed clinical benefit, optimising the dosage can only improve performance. It is also apparent that the improvement from Trofinetide had not flat lined at 54 days so we have not seen full potential - that's why I think the results are outstanding.

I would expect Big Pharma to be all over this. They will have the resources to sort this all out in phase 3 and bring an optimised treatment to market.

Expand

Noda nailed it. I can see why Jon is over in the USA with Dr T. They will be getting calls flat out from big pharma.

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