Acadia, page-114

My notes on the Lilac trial results, as disclosed by Acadia yesterday. And a reminder - I'm not an expert!

Efficacy

• As stated by Acadia, these results showed sustained and continued improvement for participants on both the RSBQ and CGI-I measures.
• The greater improvement in the group switching across from placebo provides further validation of efficacy.
• This is exactly what you would want to see in a much longer extension trial – confirmation of the efficacy results seen in the main trial + continued improvement.

Safety and Tolerability

• As stated by Acadia, these results were consistent with those seen in Lavender.
• Importantly, no new safety or tolerability issues arose in the longer extension trial.
• The diarrhoea rate had a small decline and the vomiting rate was similar (note that a 10% vomiting rate and 40% reflux rate is standard for Rett patients).
• Notably, all adverse events were issues of tolerability rather than safety.

Lilac 1 Extension Trial Discontinuation Rate

A 46% discontinuation rate did seem high to me so I did some research and found....

• The average discontinuation rate in main clinical trials is 30% and rising.
• In several (Phase 3) trials in back pain where the opioids oxycodone and tapentadol were compared, discontinuation rates were 50%+.
• In an extension trial of antidepressants in youth, the median rate of discontinuation was 45%, with the most cited reasons being "administrative issues" or "unknown".
• Notably, if the impact of Covid is removed, the Lilac 1 extension trial discontinuation rate is not dissimilar to that seen in the average clinical trial.
• When compared with average clinical trial discontinuation rates and when the massive challenges and disruption Rett families face during trial participation is taken into account, the discontinuation rate seems much less surprising.

Conclusion

I don’t see any real cause for concern from the safety and tolerability and discontinuation data. Further, the efficacy results seen over the longer term treatment period nicely support the efficacy findings of the shorter, main Lavender trial.