@Goldfish I think there are two parts ot yesterday's "relief response". First, relief that FDA and $NEU were able to agree on the primary endpoints. Second, reversal of the recent concern that FDA staff cuts might further delay the start of the trial.

I wonder if we'll ever know the cause of the delay, and whether $NEU got what they were after or whether they had to yield to FDA reservations on agreeing the endpoints?

Your post has nailed the key point about the fact that moving to a Phase III randomised, placebo controlled, double-blind (RPCDB) trial significantly raises the bar.

I see this mostly as an issue for the VABS-3 Receptive-Raw Score, as this is based on a structured interview with the Caregiver, which I (and experts, after all, what do I know!) consider to be highly susceptible to bias. So the RPCDB trial is a much higher hurdle.

That said, the reported improvement of 7.5 from the 29.0 baseline (P=0.0001) measured in Phase 2 is a clinically meaningful gain, representing a significant real world gain in communication.

In placebo arms of RPCDB trials for severe development disorders over 3-6 months, VABS gains are typically <= 2 points (from -1 to +2) but, of course, what we don't know is how much of the positive perception is removed when the caregiver is uncertain as to whether they received the drugs.

I wouldn't be surprised if this is the endpoint where the $NEU team were focused in the FDA meeting. Given that the VABS composite score at Phase 2 was not statistically significant, I wonder whether the $NEU team had to work hard to make the case to have the communication component of the VABS Composite split out as the Endpoint. If so (and we can ask Jon, but perhaps he can't or won't say) it is a win for the $NEU team.

Because the clinician is less invested in the patient than the caregiver, clinican-bais in open label questionnaires are not as strong as for the caregiver. So, when we look at the Phase 2 result, while 16 out of 18 clinical scores were either "minimally improved", "much improved" or "very much improved", I take some comfort from the fact that 10/18 were either "much improved" or "very much improved", with my thinking being that there is a good chance that a positive bias could be at work betwee the "no change" and "minimally improved' scores.

In conclusion, I agree with your assessment, There is definitely risk here, However, despite the clear potential bias at Phase 2, the signal at Phase 2 looks reasonably healthy, so I still consider the risk for Phase 3 to be of the order of 50%. And as you make clear, the very recent experience at Opthea is a clear reminder to all of us who need reminding, that if that coin doesn't come up "heads", then your outcome is zero!

For me the "two for the price of one" thesis is very much intact, and I am reliefed at yesterday's announcement. I do consider $NEU to be valued at less than DAYBUE, and so I see this particular coin toss as having no long-term downside risk. That said, a failed Phase 3 trial result would of course lead to a nasty SP move, such is that nature of over-reactions in this space. However, on your comment regarding the SP move yesterday, if the market believed there was a 50% chance that $NEU and FDA would not agree, then the approval moved the success of NNZ-2591 from 25% back up to 50%. I think that easily warranted a $200m market cap move. In fact, by my valuation, of $24 putting $12 on DAYBUE and $12 on the rest (but let's say the lion's share is NNZ-2592 for PMS), then moving CoS of NNZ-2591 from 25% to 50% is a SP move of $3.... so more to come today?

Disc: Held

Wow. Up 18.5% today so far

Clearly other people were more worried about this agreement than I was

Also suggests that "the market" regards the value of NNZ-2591 as representing a very significant portion of the market cap. Simply agreeing endpoints with the FDA results in the market cap increasing by approx $200 million (to $1.2 billion). If you think that is justified, you would have to believe that NNZ-2591 is worth at least in the ballpark of $400 million plus, probably more