Alzheon Alzheimer's hopes dented by trial readout

 Alzheon has been left sifting through the data of a failed Alzheimer's disease trial for crumbs of evidence that its oral therapy may have some efficacy.

The top-line results of the APOLLOE4 trial showed that valitramiprosate (ALZ-801) was unable to slow down cognitive decline in Alzheimer's patients with two copies of the APOE4 gene (homozygotes) compared to placebo.

The APOE4 allele, present in approximately 10%-15% of people, increases the risk of Alzheimer's and also lowers the age of onset. Having one copy of the gene can increase a patient's risk two- to three-fold, while two copies can increase it by 12 times.

The new data comes more than a decade after Alzheon reported negative phase 3 results with an older form of the drug called tramiprosate. Despite that setback, signals in the data in APOE4 homozygotes encouraged the company to press ahead with the clinical development of a new prodrug form of the drug – developed by Bellus Health – which has a longer half-life than its parent and can be dosed once daily.

All these years later, the APOLLOE4 study has ended in disappointment, as valitramiprosate did not meet the primary endpoint of slowing cognitive decline as assessed by the ADAS-Cog13 scale in people with early Alzheimer's and mild cognitive impairment (MCI), although the company said there was a trend towards improvement compared to placebo.

That non-statistically significant numerical advantage was the pattern for almost all the study's secondary endpoints – including other scales measuring cognitive function (CDR-SB and MMSE) and a scale measuring disability (DAD) – but the control group performed better on a measure of activities of daily living (A-IADL).

Like many Alzheimer's candidates ALZ-801 targets beta-amyloid, which forms the characteristic plaques that are seen in the brains of people who develop the disease, but works higher up the pathway than the two currently approved, antibody-based amyloid-directed drugs – Eisai/Biogen's Leqembi (lecanemab) and Eli Lilly's Kisunla (donanemab) – which have to be delivered via a needle.

The modest efficacy seen in trials of Leqembi and Kisunla cannot disguise the litany of failures in late-stage testing for earlier amyloid-targeting drugs – with dozens dropping by the wayside over the years – and, in many of those cases, companies looked to results in a subpopulation of patients as they tried to chart a way forward with their programmes.

Alzheon is considering a similar move, pointing to "nominally statistically significant and clinically meaningful cognitive benefits compared to placebo in ADAS-Cog13, as well as functional benefits, in a prespecified group of patients who could benefit from early intervention," according to its chief medical officer Susan Abushakra.

"A precision medicine approach is key to addressing the needs of Alzheimer's patients who have the APOE4/4 genotype, and we are committed to this patient population," she added.

For now, Alzheon hasn't revealed its plans for the programme but said it plans to publish the APOLLOE4 trial data in a peer-reviewed publication.

https://pharmaphorum.com/news/alzheon-alzheimers-hopes-dented-trial-readout