Ann: Investor Presentation, 14 March 2023, page-20

Now that Daybue is approved, I'm wondering (hottod) what options this gives Acadia in getting approval for Fragile X. Do they, for example have to do the traditional phase 3 trial or can they go down an alternative route.

Mr_Cod, I don’t know the answer and I don’t think there is a definitive answer.

But some facts to consider:

• Fragile X is overseen by the FDA’s Division of Psychiatry whereas Rett syndrome is overseen by one of the two Divisions of Neurology.
• The Division of Psychiatry is reputed to be “more difficult” than the Division of Neurology.
• Post-Phase 2 Fragile-X advice Neuren received from the FDA was that another Phase 2 trial was required before a pivotal Phase 3 trial.
• Of course, those requirements might differ now that trofinetide has received FDA approval in another indication. I would think that an sNDA application would now be used but am unclear how that would change data requirements.
• Ultimately, Acadia would now need to sit down with the FDA to discuss further clinical/ regulatory requirements.
• Another factor to be considered by Acadia is the competitive landscape in Fragile X. Mid-last year, Tetra Therapeutics launched Phase 2B/3 trials in Fragile-X – 2 x 150 patient trials + extension trial which I would presume they hope to use as pivotal trials. Tetra’s previous (successful) Phase 2 trial results can be seen here.
• Neuren also needs to consider that Clause 5.4(d) of the trofinetide licence agreement requires Neuren to contribute 50% of any Phase 2 development costs over an unspecified amount. However, any development beyond that is to be funded solely by Acadia.