Anavex Life Science’s press release touting a phase 3 win for a Rett syndrome drug read very much like the famous doge meme that took the internet by storm several years ago. The company claimed “very large” and “large” wins on the main and secondary endpoints.
There’s just one problem. The company changed the trial from a phase 2 to a phase 3 and edited those endpoints on the FDA's clinical trials database just 14 days ago. Very wow.
Anavex CEO Christopher Missling, Ph.D., however, told Fierce Biotech in a statement that, "there was never a change of endpoints," and said the late changes on the database should not be relied upon as evidence of a change to the study protocol. More on that later.
The New York biotech touted the late-stage win Tuesday morning for Anavex2-73, or blarcamesine, in Rett syndrome, a genetic neurodevelopmental disorder that occurs mostly in girls and causes severe impairments in speech, mobility, breathing and other aspects of life.
Anavex2-73, a once-daily oral liquid treatment, was being tested in the phase 3 Avatar trial in adult female patients. Anavex said the therapy beat placebo on the main and secondary goals. The primary endpoint was a dose-dependent change on a rating scale of Rett syndrome behavior, which evaluates patients’ neurobehavioral symptoms related to quality of life. These measures include general mood, breathing problems, hand behaviors, repetitive face movements, body rocking and more.
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On this measure, Anavex’s therapy spurred a “statistically significant and clinical meaningful improvement” of 72.2% compared to 38.5% in the placebo arm, the company said. This effect size, according to Anavex, was “very large.”
The secondary endpoints relied on a different scale for rating anxiety and emotional behavior in Rett patients. Anavex said that 52.9% of patients taking Anavex2-73 saw improvement compared to 8.3% on placebo. This effect was deemed “large” by Anavex.
So let’s back up to what Anavex originally listed as the trial's goals. According to the FDA’s clinical trials database, the study was edited beginning Jan. 18 from a phase 2 to a phase 3—a major advancement that puts the therapy closer to registration with the FDA.
Missling said the phase change happened after the success of an earlier mid-stage trial in Rett syndrome that finished up before Avatar. The company decided to elevate to phase 3, "which is a more rigorous study with a higher bar." The earlier trial had safety as an endpoint, with a limited cohort of patients being included in a pharmacokinetic assessment cohort.
"The informal reporting of this upgrade, which is not mandatory, on a third party website ‘clinicaltrials.gov’ and hence should not be relied upon, was done late—giving the wrong impression of a late change of trial endpoints, which was factually not the case," Missling said.
Before the edits, Anavex was evaluating Anavex2-73’s efficacy using a main goal of plasma concentration at seven weeks and the pharmacokinetic activity of the drug. These goals are crucial to determining how a drug works in the body.
Endpoints can certainly be changed once a trial has already commenced. But introducing goals that were not prespecified can introduce bias into the study and compromise scientific integrity. Any changes should be made carefully—and done independently to any data that has already been acquired in the study.
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The updated goals similarly evaluated patients after seven weeks on the study drug. The study first began in May 2019, and the primary completion is listed as September 30, 2021, on the clinical trials database.
The pharmacokinetic measures and plasma concentrations slid into the secondary goals, and the anxiety assessment was added. The new main goal is the drug exposure-dependent response on the Rett behavior scale.
A secondary endpoint was also updated, which was originally looking for a change from baseline to the end of treatment on a scale measuring improvement. This was revised to measure improvement based on the drug’s exposure-dependent response. The number of participants was also upped from 33 to 36 during last month’s changes.
The company did not report how the drug fared on the original main endpoint in the Tuesday release. Anavex shares plunged 18% to $10.70 as investors sorted through the confusing news and considered the impact of the trial changes. Investors questioned whether the new goals were a meaningful way to show Anavex2-73's effect.
Based on the results of the now-phase 3 study and an earlier phase 2, Anavex plans to engage with the FDA about an approval pathway for Anavex2-73. The therapy has fast track, rare pediatric disease and orphan drug tags from the FDA, which means it could be up for an accelerated approval—if the agency is fine with the last-minute trial changes.
Editor's Note: This story was updated on Feb. 2, 2022, to include commentary from Anavex CEO Christopher Missling.