Thanks for the tag @SSilverstein. This will take some work to...

Thanks for the tag @SSilverstein. This will take some work to explain, so apologies for the long response.

Visual Field Assessment is completed by using the Humphrey Visual Field (HVF). In IIH, the key outcome for visual field testing Perimetric Mean Deviation(PMD). The pivotal Wall et al 2014 trial that the FDA Neurology/Opthalmology is likely usin

The paper reports two things:
1. Acutely post lumbar puncture - Improvement in Attention and Executive Function.
2. Chronic post improvement in ICP - Improvement in verbal short term memory.

These cognitive changes lead to inaccurate Visual Field Assessment due to false positives and negatives, visual field index and test duration.

Why does Inaccurate Visual Field Assessment matter?

If cognitive impairment in IIH patients affect the accuracy of performing a Visual Field Assessment on them - this means that using Perimetric Mean Deviation(PMD) will be an unreliable primary outcome in IIH.

This makes sense - Invex's Phase II did not show a statistically significant result in Visual Field(PMD) but it did show a significant result in Visual Acuity(LOGMAR). Similarly, the pivotal Wall et al 2014 trial did not show a clinically significant improvement in Visual Field(PMD) of at least -2dB.

This is important because even if Invex run a perfect Phase III, they're leaving the Inaccurate PMD outcome to chance and the Phase 3 could flop.

How does this affect the Regulatory Interactions for Invex?

The FDA Neurology/Ophthalmology has been stubborn in their scientific advice that Invex use Visual Field(PMD) as the key vision outcome.

The company curiously spent the last year resisting pursuing any other outcome apart for PMD as the primary vision outcome for the FDA. Initially we assumed it was because Exenatide wasn't effective in 12 weeks in the Phase II, but now we learn that a more compelling reason is because Sinclair/Invex know that PMD is an unreliable measure of visual function.

Where does Invex go from here?
The FDA is widely known for its obstination, and despite Invex publishing this seminal work, it seems unlikely that they will shift from their requirement for Vision Field(PMD) or another measure of Vision such as Visual Field. We do not know if they presented this information in the package to the FDA earlier this year.

Invex has a few options from here.

They can persist with PMD, and hope that Presendin over 12 months is so powerful that it produces a significant outcome despite the inaccuracy of the endpoint in measuring the comparator. They can push for the Visual Function(LOGMAR), which the FDA may want 1 or 2 trials with this. They can try the Best Corrected Visual Acuity(BCVA) which Opthea have used successfully for Wet AMD.

They can try a different outcome like cognition, but there's so many confounding factors like Depression, OSA, Headache severity etc and the cognitive changes are subtle, and blunt to simple cognitive testing.

Take Home Messages

Seminal piece of work that finally explain why Invex desperately don't want the PMD as the vision outcome. It could go belly up if we use the PMD Outcome measure.

Invex needs to pivot to another outcome measure of Vision that is acceptable to the FDA. This explains why they'll need to take some time to formulate the regulatory strategy with the FDA and will likely see the EMA trial start first due to the simplicity of a negotiated endpoint and trial design.

I'm a fan of Sinclair - she's the world leader and Key Opinion Leader in IIH. Invex shareholders are getting her scientific talent in protecting our capital for a pittance.