Anavex says placebo "masked" effects of paediatric Rett drug

2024-01-02

临床结果上市批准

Anavex Life Sciences kicked off the new year with a poor readout of its paediatric Rett Syndrome candidate, driving shares down 35% when the markets opened on Tuesday. Chief scientific officer Walter Kaufmann chalked up the setback to a "high placebo response [that] may have masked the therapeutic effect" of the company's oral sigma-1 chaperone protein agonist Avanex 2-73 (blarcamesine).

While the Phase II/III EXCELLENCE trial "showed improvement" on the co-primary endpoint Rett Syndrome Behaviour Questionnaire (RSBQ), it fell short of statistical significance on the "less granular assessment" of Clinical Global Impression – Improvement scale (CGI-I), according to top-line results unveiled Tuesday. RSBQ is 45-item questionnaire for assessing multiple Rett syndrome characteristics by a patient's caregivers, whereas CGI-I uses a seven-point scoring system.

No better in ad hoc analysis

The EXCELLENCE study enrolled 92 patients with Rett syndrome between the ages of 5 through 17 years who were randomised to receive Avanex 2-73 or placebo for 12 weeks, followed by a week 16 safety visit. In an ad-hoc analysis, which used a predefined mixed-effect model for repeated measure method, the company noted that there was a greater improvement in patients who received Avanex 2-73, although the difference was a non-significant -4.61 points between the two groups.

However, Anavex Anavex highlighted the treatment's rapid onset of action, saying patients given Avanex 2-73 saw significant improvement in their condition after four weeks, as indicated by a greater reduction in RSBQ total score of -4.65 points versus a placebo. Meanwhile, the company noted that the drug's performance on the Anxiety, Depression, and Mood Scale (ADAMS) "trended favourably," and that it was associated with several benefits overall, "impacting positively" on areas such as repetitive movements, nighttime disruptive behaviours and social avoidance.

"Although data analysis is ongoing, the early conclusion is that the placebo rate could have been higher in the study due to a slight imbalance in disease severity at baseline, across the treatment arms, and the 2-to-1 drug to placebo randomisation ratio," Kaufmann said, adding "we intend to further assess the collective results and discuss with the regulatory authorities next steps."

Targeting 2024 filing in Alzheimer's

CEO Christopher Missling said the company remains "committed to the Rett syndrome and rare disease community, given also the prior successful two placebo-controlled studies in adult patients with Rett syndrome."

The company is also evaluating Anavex Anavex 2-73 in other neurodevelopmental disorders, including Fragile X syndrome, and in neurodegenerative diseases like Parkinson's. Anavex shares gained 16% recently when EU regulators said it said it could submit a marketing application for oral blarcamesine as a treatment for Alzheimer's disease. The company is aiming to submit the application as early as possible in 2024.

In September, Anavex reported Phase IIb/III data showing the drug resulted in a significant reduction of amyloid beta levels in early Alzheimer's disease, along with a decrease in brain volume loss. Commenting on the EU filing update last month, analysts at H. C. Wainwright & Co. said "blarcamesine constitutes an intriguing potential treatment option for Alzheimer's disease, [but] feedback from the EMA on its actual approvability remains to be received and accordingly we cannot predict when blarcamesine might be approved in the EU." They suggested the drug could reach the market as an Alzheimer's treatment in the US "in the 2025 time frame."

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