Industry leading biomarker, brain preservation and clinical benefits following 24 months of treatment in phase II trial of oral ALZ 801 (valiltramiprosate) in patients with early Alzheimer’s disease

ALZ 801 (valiltramiprosate) is an investigational oral disease-modifying therapy in Phase III development for the treatment of Early AD. In mechanism of action studies, ALZ 801 fully blocked the formation of neurotoxic soluble beta amyloid (Abeta) oligomers at the Phase III clinical dose. Oral ALZ 801 has shown potential for robust clinical efficacy in the highest-risk and most fragile late-onset Alzheimer’s population – patients with two copies of the apolipoprotein e4 allele (APOE4/4 homozygotes), and favorable safety with no increased risk of vasogenic brain edema. This population is the focus of Alzheon’s pivotal 78-week APOLLOE4 Phase III trial, which is now fully enrolled and topline data is expected in the third quarter of 2024.

The open-label, multicenter, single-arm Phase II biomarker trial evaluated biomarker effects, clinical efficacy, and safety of ALZ 801 tablet in 84 Early AD patients, who carry either one or two copies of the e4 allele of apolipoprotein E gene (APOE3/4 heterozygotes and APOE4/4 homozygotes, respectively) and showed positivity for amyloid and tau biomarkers in cerebrospinal fluid (CSF). APOE4 genotype, the leading risk factor for AD after aging, is associated with a several-fold higher brain burden of neurotoxic amyloid oligomers, and APOE4 carriers represent two thirds of the Alzheimer’s patient population.

Elevation of phosphorylated tau (p-tau) levels in plasma is a sensitive and specific marker of neuronal stress and brain injury in AD and is considered a highly reliable core biomarker of disease pathology. P-tau is produced by neurons as a reaction to formation of neurotoxic beta amyloid oligomers, the key driver of AD pathology and neurodegeneration. P-tau181 levels rise with onset of AD symptoms and with the clinical deterioration of patients and have been shown to fall in response to clinically effective anti-amyloid disease modifying treatments in Alzheimer’s.

Study subjects were treated with ALZ 801 265 mg tablet once daily for two weeks and twice daily thereafter over a 104-week treatment period. At baseline, study subjects were 52% female, with mean age 69 years, MMSE 26 (range 22-30), and 70% having mild cognitive impairment (MCI). In November 2022, Alzheon reported positive study results from a pre-specified analysis following 52 weeks of treatment with ALZ 801. An ongoing long-term extension of the trial evaluates ALZ 801 for an additional 52 weeks of treatment for a total of 156 weeks. The current analysis at 104 weeks is the study’s primary completion date, with plasma p-tau181 being the primary outcome and hippocampal volume the primary imaging outcome.

A total of 70 subjects completed the Week 104 visit and 68 subjects provided evaluable plasma for biomarker assays and were included in this primary analysis. In this population, ALZ 801 achieved a statistically significant 27% reduction from baseline in plasma p-tau181 (p=0.015) at Week 13 that was sustained and significant through the remainder of the treatment period. At Week 52, ALZ 801 achieved a statistically significant 43% reduction in plasma p-tau181 (p<0.009) and at week 104 a 31% reduction was observed (p><0.045). plasma abeta42 levels decreased throughout the treatment period, reaching a statistically significant 4% reduction from baseline (p><0.042) at week 104, while the reduction in plasma abeta40 levels stabilized at 52 weeks at a new homeostatic level. all analyses of plasma biomarkers were performed at the laboratory of professor kaj blennow at the university of gothenburg in molndal, sweden, and audited according to good laboratory practice.

On measurements of hippocampal volume (HV), subjects treated with ALZ 801 demonstrated a statistically significant 28% reduction of hippocampal atrophy at Week 104 (p<0.015) compared to the external control of matched early ad subjects from the alzheimer’s disease neuroimaging initiative (adni). adni is a longitudinal observational multicenter study of mci, ad, and healthy individuals. real-world evidence analyses were performed against matched adni controls based on apoe4 genotype, age, gender, and disease stage, following the recent fda guidance from august 2023 on the use of real-world data and real-world evidence to support regulatory decision-making for drugs and biological products.

On cognitive scales, Rey Auditory Verbal Learning Test (RAVLT) and Digit Symbol Substitution Test (DSST), patients treated with ALZ 801 demonstrated a consistent improvement at Week 26 and remained stable and above baseline through the 104-week treatment period. On the RAVLT Total Score, which combines effects on immediate and delayed recall tests, patients treated with ALZ 801 demonstrated a statistically significant 24% improvement (p<0.0001) at week 104 compared to matched adni subjects.

“The sustained reduction in plasma p-tau181 combined with the decrease in rate of hippocampal atrophy as well as the stabilization of cognition over 2 years is consistent with a disease modifying action in Alzheimer’s patients. These early p-tau181 effects are enabled by the robust 40% brain penetration of ALZ 801 compared to an approximately 1% brain penetration of plaque-clearing anti-amyloid antibodies. As p-tau181 is primarily of brain origin and is actively cleared from brain into plasma, the significant lowering of p-tau181 in response to ALZ 801 treatment validates the drug’s target engagement and mechanism of action in the brain,” said John Hey, PhD, Chief Scientific Officer of Alzheon. “To put these effects into context, trials with currently approved anti-amyloid antibodies showed a 24-32% reduction in cognitive decline over 1.5 years, while patients treated with ALZ 801 demonstrated cognitive gain from baseline status and maintained their cognitive skills through and beyond same time period. These well-differentiated results position ALZ 801 to potentially become the first oral agent that can slow or even stop and prevent Alzheimer’s pathology in patients and healthy individuals at risk for the disease.”

ALZ 801 treatment demonstrated significant correlations at Week 104 between effects on volumetric MRI outcomes and 3 cognitive scales, including the Mini-Mental Status Examination (MMSE), suggesting that cognitive gain from baseline status and maintenance of cognitive skills are a result of preservation of brain structures from neurodegeneration and atrophy: i. Hippocampal volume versus RAVLT Total Score: r=0.44, .p=0.0002. ii. Hippocampal volume versus MMSE: r=0.43, p=0.0003.iii. Hippocampal volume versus DSST: r=0.38, p=0.002. iv. Cortical thickness versus RAVLT Total Score: r=0.35, p=0.004. v. Cortical thickness versus MMSE: r=0.58, p<0.0001. vi.cortical thickness versus dsst: r="0.55,".

Consistent with the prior safety database of over 2,800 AD patients, ALZ 801 demonstrated a favorable safety profile in the Phase III trial, showing no events of vasogenic brain edema (amyloid-related imaging abnormalities, or ARIA) in APOE4 carriers. Common adverse events experienced in more than 10% of participants were COVID infection, mild nausea, and decreased appetite.

“These positive results represent the latest evidence supporting the promise of ALZ 801, expanding upon other key discoveries made by Alzheon scientists over the past decade. The significant effect on plasma p-tau181, combined with hippocampus volume preservation and clinical stabilization after 24 months of treatment, supports the disease modifying action of ALZ 801 in patients with Alzheimer’s disease,” said Susan Abushakra, MD, Chief Medical Officer of Alzheon. “We have developed a differentiated agent in terms of its mechanism of action, which acts upstream on the same pathway as the currently approved anti-amyloid antibodies and that translates to promising and meaningful efficacy, as well as decrease in brain atrophy, easy oral administration and a favorable safety profile that obviates the need for frequent monitoring for brain edema and microhemorrhage. ALZ 801 tablet is well positioned to become the first oral disease-modifying AD treatment approved for slowing and even halting cognitive decline, and we are very encouraged by these results and the potential for a life-changing impact on the lives of Alzheimer’s patients and their families.”