Anavex Rett hit says nothing about blarcamesine’s effect size

The white space of Rett syndrome might soon have not one but two approved therapies. At least this is the bull case for Anavex, whose blarcamesine today appeared to score a phase 3 success, just as Acadia did with trofinetide. However, close reading reveals that the Anavex study’s endpoints were changed, likely recently, and it is anyone’s guess what the FDA will say about this. The trial in question, Avatar, previously sought to show blarcamesine’s absolute effects from baseline, versus placebo, on RSBQ and CGI-I scores; but today it was revealed that these took the form of “area under the effect curve” responder analyses that, while ostensibly positive, revealed nothing about the project’s effect size. Sceptical investors, who today sent Anavex down 18%, pointed to Avatar’s clinicaltrials.gov entry, showing that the change had been made just 14 days ago, though Anavex insisted it had done this earlier. The company also claims that “statistical significance alone [is] not sufficient for determining whether an individual patient experienced a meaningful clinical benefit” – a criticism made in December of the relatively small effect sizes seen with Acadia’s trofinetide. Blarcamesine’s paediatric Rett study, Excellence, yet to read out, now apparently also uses AUC measures.

The changing endpoints of Anavex's pivotal blarcamesine studies
Trial Design Date Selected efficacy endpoint  Result
Avatar Adults, quadruple blinded vs placebo Pre Jan 18, 2022 RSBQ baseline to 7wk (secondary) Not disclosed
CGI-I baseline to 7wk (secondary)
Post Jan 18, 2022 RSBQ AUC responder analysis (primary) 72.2% vs 38.5% (p=0.037)
CGI-I AUC responder analysis (secondary) 72.2% vs 38.5% (p=0.037)
Excellence Paediatrics, quadruple blinded vs placebo Pre Sep 27, 2021 RSBQ baseline to 12wk (primary) Primary completion May 2022
RSBQ AUC responder analysis (primary)
Pre Sep 27, 2021 CGI-I baseline to 12wk (primary)
CGI-I baseline to 12wk (secondary)
Source: clinicaltrials.gov. Note: RSBQ=Rett Syndrome Behaviour Questionnaire; CGI-I=Clinical Global Impression-Improvement; AUC=area under the curve. 

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