Key takeaways:

• The drug works by inhibiting amyloid beta oligomer formation.
• Patients with MCI taking valiltramiprosate saw a 36% decrease in plasma p-tau217 after 78 weeks, compared with a 17% increase for placebo.

Valiltramiprosate, a drug in development as a disease-modifying therapy for Alzheimer’s disease, showed rapid and sustained reduction of plasma p-tau217, among other clinical benefits, according to data from the developer.

Valiltramiprosate (ALZ-801, Alzheon) is taken orally and acts as a small-molecule inhibitor of amyloid oligomer formation, according to information presented at Alzheimer’s Association International Conference 2026. The drug’s effects in mild cognitive impairment (MCI) AD subjects were correlated with cognitive testing results and vMRI measures of hippocampal volume and cortical thickness, said John Hey, PhD, chief scientific officer at Alzheon.

“The important findings with p-tau217/amyloid beta 42 is that these biomarkers now enable physicians to identify these patients earlier and therefore bring potential therapeutic options to them earlier,” Hey told Healio. “In the case of valiltramiprosate, what we’re seeing is that we’re getting these effects short term after dosing.”

The phase 3 APOLLOE4 trial examined the drug’s effects on APOE4/4 homozygotes with early Alzheimer’s disease. APOE4/4 homozygotes face the highest risk for Alzheimer’s disease, develop the disease earlier than other carriers, develop more aggressive forms and have the greatest unmet need in terms of safe and effective treatments, Hey said. APOLLOE4 was the largest phase 3 interventional trial exclusively examining APOE4/4 homozygous subjects.

How it works

Valiltramiprosate, which works by inhibiting amyloid beta oligomer formation and amyloid aggregation upstream from tau hyperphosphorylation, has the potential to be used as an alternative or as a complement to existing antibody treatments for Alzheimer’s disease, according to Hey.

If antibody treatments can be thought of as removing bricks of amyloid from a wall in the brain or blood vessels, valiltramiprosate works upstream of that process, preventing the bricks from being laid down in the first place, Hey said.

“The earlier you start the treatment, the better the effect,” Hey said. “What we have is a picture emerging that our drug ... is kind of preventing this sequence of events that leads to more and more damage and progression of brain atrophy.”

The multi-center, double-blind study randomly assigned 325 participants to placebo (n = 162) or 265 mg of valiltramiprosate twice a day (n = 163), stratified by MCI or mild Alzheimer’s disease. Participants were monitored over the course of 78 weeks.

At baseline, the participants with early Alzheimer’s disease assigned to the valiltramiprosate group had a mean plasma p-tau217 concentration of 0.6436 pg/mL, while the placebo group had a mean concentration of 0.6226 pg/mL.

After 26 weeks, the mean plasma p-tau217 concentration for the valiltramiprosate group dropped under 0.6 pg/mL, while the mean concentration for the placebo group rose to nearly 0.7 pg/mL (P = .021). These measurements were sustained through week 78, with the valiltramiprosate group rising slightly to 0.6 pg/mL and the placebo group rising to about 0.76 pg/mL (P = .011).

The drug had an even more pronounced effect in participants with MCI, Hey said. At baseline, those assigned to the valiltramiprosate group had a mean plasma p-tau217 concentration of 0.6885 pg/mL, while the placebo group had a mean concentration of 0.5237 pg/mL.

At week 78, the mean concentration for the valiltramiprosate group was about 0.45 pg/mL, a 36% decrease, while the mean concentration for the placebo group rose by 17% to about 0.6 pg/mL (P = .02).

The more prominent effect in the MCI group is likely because of fast Alzheimer’s disease progression in APOE4/4 homozygous AD subjects, Hey said.

“If you intervene in a pathway that prevents the formation of toxic oligomers, and that is driving the disease progression, or at least contributing largely to the disease progression, the earlier you start the treatment, the better the efficacy outcome,” he said.

As an oral drug, valiltramiprosate is absorbed quickly into the blood and with high brain penetration, which Hey said is reflected in the data.

“The onset of the effects are very quick because valiltramiprosate is a small molecule that reaches peak blood levels in about two weeks of daily dosing,” he said. “In all those studies, you see that we’re getting reduction with early onset.”

In the trial, valiltramiprosate did not meet the primary clinical endpoint in cognitive slowing, but it did produce meaningful improvements in cognition and function in pre-specified MCI subjects, according to the researchers.

For participants with MCI, valiltramiprosate reduced hippocampal atrophy by 26% (P = .004).

Hey and colleagues also found positive correlations between changes in baseline plasma concentration and the drug’s effects on cognition and volumetric brain imaging (vMRI).

The correlation was significant for the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (r = 0.28; P = .0392), the Clinical Dementia Rating-Sum of Boxes scale (r = 0.38; P = .0049), hippocampal volume (r = –0.35; P = .0129), cortical thickness (r = –0.337, P = .0178) and whole brain volume (r = –0.31; P = .0293).

In participants with MCI, the difference between the valiltramiprosate and placebo groups in plasma neurofilament light (NfL) concentration was not significant at baseline, but it became significant by week 78, according to the presentation. At that time, NfL concentration was greater than 18 pg/mL in the placebo group and about 16 pg/mL in the valiltramiprosate group (P = .0321).

Also of note

Antibody treatments work by removing amyloids, which Hey said can lead to amyloid-related imaging abnormalities (ARIA), especially in APOE4/4 homozygotes. In the Phase 3 clinical trial, there was no increase in ARIA for patients treated with valiltramiprosate, Hey said.

“By preventing that laying down of more bricks, if you will, it maintains the health, or it has less of an impact on the blood vessels,” he said.

About 20% of patients treated with valiltramiprosate experienced mild nausea in the clinical trial, which Hey said was associated with a local effect after taking the dose, and wore off with time without long-term effects. Taking the drug with food also mitigated the nausea, he said.

“It’s not a direct irritation to the GI system because we have long-term toxicology data that shows there are no other system effects,” Hey said. “We think it’s sort of an activation of a local neural response to the drug that causes short nausea event in a very small percentage of subjects.”

In the future, Hey said he and his colleagues plan to extend the study into APOE4 heterozygotes, which he said behave similarly to homozygotes but have a more delayed onset of the disease with same underlying disease process.

Future research also needs to examine how valiltramiprosate works as a complement when used in combination or a maintenance therapy with anti-amyloid antibody treatment, Hey said.

“We’ve done a lot of analysis, and we believe because we’re not adding any of the safety risks to antibodies, that we can get benefit to adding that for patients that maybe want to come off an antibody or while on an antibody,” Hey told Healio. “Those studies need to be done for sure, but when we do complete analysis, we believe there is likely to be some added or synergy benefit because both drugs are working at a different stage of the amyloid cascade pathway.”

For more information:

John Hey, PhD, can be reached at neurology@healio.com.