Beginning a New Era of Precision Alzheimer’s Therapeutics
By Helen Albert
To really bring a precision medicine approach to the world of Alzheimer’s therapeutics, it is important to consider genetics. Although Alzheimer’s is a multifactorial disease with different features contributing to its onset, certain genetic mutations or variants can increase or decrease a person’s risk of developing the condition.
For example, there are three major alleles of the apolipoprotein E (APOE) gene: E2, E3, and E4. E3 is the most common, with an estimated frequency around the world of 78%, whereas E2 and E4 are less common, with estimated worldwide frequencies of 8% and 14%, respectively. The E4 allele is linked to significantly increased risk for Alzheimer’s disease, particularly in homozygotes (2–3% population), who have two copies of the allele. In contrast, E2 carriers have significantly reduced risk of developing the condition.
APOE4 homozygotes appear to be at particular risk of ARIA if given anti-amyloid beta antibodies such as lecanemab and are therefore currently not eligible for these therapies. This makes them a group with a particularly high unmet treatment need, given their up to 15-fold increased risk of developing Alzheimer’s over the general population.
Alzheon, a biotech company based in Massachusetts, is developing a small molecule treatment (ALZ-801) for people who carry the E4 allele, focusing initially on APOE4 homozygotes. “These patients decline very rapidly once they start showing symptoms, so it’s a very fragile population that we’re trying to help out,” explained Alzheon chief of staff, Adem Albayrak.
ALZ-801 is a prodrug of a previously tested compound known as tramiprosate or homotaurine, which originally comes from seaweed. Tramiprosate reached Phase III trials but did not show enough efficacy to be approved. However, it did show beneficial effects in APOE4 carriers, prompting the development of ALZ-801. The potential therapy is currently being tested in a Phase III trial, which is due for a read-out this year.
“The data we saw in the Phase II study gave us confidence to start building out our commercial capabilities. We’re starting to focus on the regulatory submission, so when the data reads out, we can quickly and efficiently get to the FDA and file for potential approval,” said Albayrak. “We’re trying to prepare the company so we can make it available for patients as quickly as possible if it reads out the way that we’re hoping.”