valiltramiprosate (ALZ-801) / Alzheon, GSK - LARVOL DELTA

Hippocampal Atrophy on Magnetic Resonance Imaging as a Surrogate Marker for Clinical Benefit and Neurodegeneration in Early Symptomatic Alzheimer's Disease: Synthesis of Evidence from Observational and Interventional Trials. (PubMed, CNS Drugs) - "These trials included four amyloid antibodies (aducanumab, lecanemab, donanemab, and gantenerumab) and one oral anti-oligomer agent (valiltramiprosate). HV on standardized vMRI is sensitive to anti-amyloid treatments, demonstrating strong correlations between slowed hippocampal atrophy and slowed cognitive decline. Data from over 23,000 subjects over three decades support HV as a surrogate marker for predicting clinical benefit in early symptomatic AD."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders

Alzheon Announces Peer-Reviewed Publication Providing Evidence for Hippocampal Volume as Surrogate Marker for Clinical Benefit and Neurodegeneration in Early Alzheimer’s Disease (Businesswire) - "Predictive biomarker: HV atrophy closely tracks cognitive decline in both observational and interventional data, making HV a reliable and sensitive marker of disease progression; Therapeutic sensitivity: Multiple clinical studies, including those evaluating lecanemab, donanemab, and valiltramiprosate/ALZ-801, have shown that interventions slowing cognitive decline are also associated with reduced hippocampal atrophy. These findings highlight the responsiveness of hippocampal volume to therapeutic intervention; Clinical relevance: The analysis established a hippocampal volume preservation threshold of ≥40 mm³ that correlates with significant cognitive improvement at the Mild Cognitive Impairment (MCI) stage, underscoring hippocampal volume as a potential regulatory endpoint for early Alzheimer’s disease."

Real-world evidence • Alzheimer's Disease

Alzheon to Present Multiple Clinical, Neuroimaging and Modeling Results for Oral Valiltramiprosate/ALZ-801 from Phase 2 and 3 Studies at CTAD Conference in San Diego, December 1-4, 2025 (Businesswire) - "Valiltramiprosate demonstrates potential as the first oral disease-modifying agent to slow Alzheimer’s pathology, indicated by both clinical and volumetric MRI data. Nine posters showcase consistent benefits of oral valiltramiprosate in carriers across clinical outcomes and brain integrity measures....Precision medicine approach supported by valiltramiprosate’s favorable safety in high-risk APOE4 carriers."

Clinical data • Alzheimer's Disease

The Role of Lipoprotein and Gut Microbiome in Alzheimer's Disease: A Review of Novel Findings and Potential Applications. (PubMed, Curr Alzheimer Res) - "Novel therapies targeting lipoproteins, such as ALZ-801 and IDOL inhibitors, show promise in preclinical and clinical trials...Interventions, like probiotics, GV-971, and polyphenols, demonstrate efficacy in restoring microbial balance and mitigating cognitive decline...Integrating insights into lipoprotein biology and gut microbiota dynamics may offer transformative potential for AD treatment, emphasizing combinatorial approaches to modulate these interconnected pathways. Further research is warranted to elucidate mechanistic links and translate preclinical findings into clinical applications."

Journal • Alzheimer's Disease • CNS Disorders • Inflammation • Metabolic Disorders • APOE

Alzheon Announces Peer-Reviewed Scientific Publication of Results from Pivotal APOLLOE4 Phase 3 Trial of Oral Valiltramiprosate/ALZ-801 in APOE4/4 Homozygous Individuals with Early Alzheimer’s Disease (Businesswire) - "'The primary clinical outcome was not achieved in the overall population of the APOLLOE4 trial, however, prespecified analyses demonstrated nominally statistically significant and clinically meaningful cognitive and functional benefits in patients at the MCI stage.'...'The pre-specified MCI group also showed large, consistent, and significant slowing of atrophy across multiple brain regions, together with reduced water diffusivity consistent with slowing of neurodegeneration, a key hallmark of AD.'....Importantly, valiltramiprosate treatment was associated with a favorable safety profile, showing no increased risk of amyloid-related imaging abnormalities (ARIA), comprising brain edema and microhemorrhage, and no observed symptomatic ARIA."."

P3 data • Alzheimer's Disease

Clinical Efficacy, Safety and Imaging Effects of Oral Valiltramiprosate in APOEε4/ε4 Homozygotes with Early Alzheimer's Disease: Results of the Phase III, Randomized, Double-Blind, Placebo-Controlled, 78-Week APOLLOE4 Trial. (PubMed, Drugs) - P3 | "The APOE4/4 Early AD population did not show significant clinical efficacy at 78 weeks but showed significant brain atrophy slowing. Prespecified analyses at the MCI stage showed nominally significant slowing of clinical decline with significant hippocampal atrophy slowing. Oral valiltramiprosate may provide a favorable benefit-risk profile and simple treatment paradigm for homozygotes with MCI. These results will inform the design of future MCI trials."

Clinical • Journal • P3 data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Hematological Disorders • APOE

Sulfopropanoic acid derivatives for treating neurodegenerative disorders: a patent spotlight. (PubMed, Pharm Pat Anal) - "The confirmatory APOLLOE4 phase III trial of ALZ-801 in APOE4/4 homozygotes with early AD has been initiated. If ALZ-801 is approved, it will be among the first oral disease-modifying drugs for AD."

Journal • Review • Alzheimer's Disease • CNS Disorders

Alzheon to Present Insights into Oral Valiltramiprosate/ALZ-801 Mode of Action and Clinical Efficacy at Dedicated Symposium at Alzheimer’s Association International Conference in Toronto on July 30th, 2025 (Businesswire) - P3 | N=325 | APOLLOE4 (NCT04770220) | Sponsor: Alzheon Inc. | "Alzheon...announced it will present new data on its lead investigational product, valiltramiprosate, highlighting the differentiated mode of action that acts upstream in the amyloid pathway, blocking formation of neurotoxic amyloid oligomers that drive disease progression. Valiltramiprosate showed positive clinical and volumetric MRI effects in patients with Mild Cognitive Impairment (MCI) who carry one or two copies of the ε4 allele of the apolipoprotein E gene (APOE3/4 heterozygotes and APOE4/4 homozygotes, respectively). The first of-its-kind data will be presented in a symposium during the Alzheimer’s Association International Conference (AAIC) in Toronto, Canada...In addition, Alzheon scientists will be provide clinical and imaging analyses from the APOLLOE4 Phase 3 study of valiltramiprosate in APOE4/4 homozygotes in eight poster presentations at the conference."

P3 data • Alzheimer's Disease

APOLLOE4-LTE: Long-term Extension of Phase 3 Study of ALZ- 801 in APOE4/4 Early AD Subjects (clinicaltrials.gov) - P3 | N=163 | Active, not recruiting | Sponsor: Alzheon Inc. | N=285 ➔ 163 | Trial completion date: Jan 2026 ➔ Jan 2027 | Trial primary completion date: Dec 2025 ➔ Dec 2026

Biomarker • Enrollment change • Trial completion date • Trial primary completion date • Alzheimer's Disease • CNS Disorders

AD/PD 2025: Alzheon’s ALZ-801 shows promise for MCI but missed in mild Alzheimer’s (Clinical Trials Arena) - P3 | N=325 | APOLLOE4 (NCT04770220) | Sponsor: Alzheon Inc. | "The APOLLOE4 trial did not meet its primary endpoint, change from baseline in Alzheimer’s Disease Assessment Scale-Cognitive Subscale 13 (ADAS-Cog13). However, when evaluating just the prespecified MCI patient population, which accounted for 39% of the overall trial population, treatment with valiltramiprosate was found to be significantly effective over 78 weeks. Compared with placebo, treatment with valiltramiprosate resulted in a 52% benefit on the ADAS-Cog13 scale, with differences between the treatment group and placebo group seen from 13 weeks. In the MCI population, valiltramiprosate treatment also resulted in significant improvements in Disability Assessment for Dementia (DAD) score, and, while not statistically significant, clinically meaningful effects of valiltramiprosate were also seen across the Clinical Dementia Rating."

P3 data: top line • Alzheimer's Disease

0070: INDUSTRY SYMPOSIUM 01 (NO CME/CPD CREDIT): Inhibition of Beta Amyloid Oligomer Neurotoxicity with Oral Valiltramiprosate in APOEε4/ε4 Homozygotes with Early Alzheimer's Disease: Results of APOLLOE4 Phase 3 Trial (ADPD 2025) - "Aβ monomer aggregation into cytotoxic soluble oligomers is an initiating step in the pathogenesis of neurodegeneration. Valiltramiprosate, a potent orally bioavailable small molecule inhibitor of Aβ oligomer formation, was evaluated in homozygotes with Early AD."

P3 data • Alzheimer's Disease • CNS Disorders • Hematological Disorders • APOE

Alzheon to Present Results from Pivotal APOLLOE4 Phase 3 Trial of Oral Valiltramiprosate/ALZ-801 at Dedicated Symposium at ADPD Conference in Vienna on April 1st, 2025 (Businesswire) - "Alzheon, Inc...announced it will present topline results from the pivotal APOLLOE4 Phase 3 trial of oral valiltramiprosate/ALZ-801 in patients with early AD who carry two copies of the ε4 allele of the apolipoprotein E gene (APOE4/4 homozygotes)."

P3 data: top line • Alzheimer's Disease

APOLLOE4-LTE: Long-term Extension of Phase 3 Study of ALZ- 801 in APOE4/4 Early AD Subjects (clinicaltrials.gov) - P3 | N=285 | Active, not recruiting | Sponsor: Alzheon Inc. | Enrolling by invitation ➔ Active, not recruiting

Biomarker • Enrollment closed • Alzheimer's Disease • CNS Disorders

Alzheon Announces Two New Scientific Papers Ahead of APOLLOE4 Phase 3 Trial Topline Symposium at ADPD Conference in Vienna on April 1st, Marking 15 Pathbreaking Peer-Reviewed Publications from Alzheon (Businesswire) - "Topline of APOLLOE4 Phase 3 Evaluating Valiltramiprosate/ALZ-801 Will be Presented at Dedicated Symposium at ADPD Conference in Vienna on April 1st, 2025; Publication in Journal of Prevention of Alzheimer’s Disease Highlights Challenges of Immunotherapies, Calling on Stakeholders to Prepare for Emerging Treatments Including Valiltramiprosate; Publication in Clinical Pharmacokinetics Demonstrates Favorable Pharmacokinetic Properties of Valiltramiprosate, an Investigational Oral Disease-Modifying Therapy for Treatment of Early Alzheimer’s Disease."

Clinical data • P3 data: top line • PK/PD data • Alzheimer's Disease

ALZ-801 prevents amyloid β-protein assembly and reduces cytotoxicity: A preclinical experimental study. (PubMed, FASEB J) - "ALZ-801 can inhibit Aβ42 aggregation by preventing both nucleus formation and fibril elongation, while promoting large globular oligomer formation, and can significantly reduce LMW-Aβ42-induced cytotoxicity. These findings underscore the potential of ALZ-801 as an effective DMT for APOE ε4 homozygous patients with AD."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • APOE • Aβ42

Clinical Pharmacokinetics of Oral ALZ-801/Valiltramiprosate in a 2-Year Phase 2 Trial of APOE4 Carriers with Early Alzheimer's Disease. (PubMed, Clin Pharmacokinet) - P2 | "The steady-state PK profile of oral ALZ-801 in subjects with early AD was not affected by sex, APOE genotype, age, BMI, concomitant use of AChEI, or tablet lot. The inverse relationship of plasma exposures of tramiprosate and 3-SPA, but not ALZ-801, versus eGFR is consistent with renal clearance as the primary route of elimination for tramiprosate and 3-SPA (active moieties), and with the efficient conversion of ALZ-801 prodrug to the active moieties after dosing. These results demonstrate that ALZ-801 displays favorable PK properties without evidence of interactions with demographic characteristics and support its development as an oral disease-modifying treatment for AD."

Journal • P2 data • PK/PD data • Alzheimer's Disease • CNS Disorders • APOE

Sulfonic acid functionalized β-amyloid peptide aggregation inhibitors and antioxidant agents for the treatment of Alzheimer's disease: Combining machine learning, computational, in vitro and in vivo approaches. (PubMed, Int J Biol Macromol) - "Several functionalized sulfonic acid molecules have been reported, including tramiprosate prodrug, which is currently in clinical trial III and exhibits a good response in mild to moderate AD patients...H-HPA-NSA arrested elongation phase of Aβ aggregation in kinetic study at a lower concentration (10 μM), while B-PEA-MBSA reduced the intensity of stationary phase at a dose of 100 μM. Thus, based on the outcomes, it can be suggested that B-PEA-MBSA and H-HPA-NSA can prevent β-amyloid aggregation with mild to moderate AD."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • CNS Tumor • Neuroblastoma • Oncology • Solid Tumor • Aβ42

Alzheon Announces Appointment of Renowned Investor and Financial Executive Muneer A. Satter to Board of Directors (Businesswire) - "APOLLOE4 Topline Presentation at Valiltramiprosate Symposium at Alzheimer’s Disease Parkinson’s Disease (ADPD) Conference in Vienna in April 2025..."

P3 data: top line • Alzheimer's Disease • CNS Disorders

Biomarkers. (PubMed, Alzheimers Dement) - "Biomarker positive APOE4 carriers showed significant plasma p-tau181 and Aβ42 effects, with promising HV effects that correlated with cognitive benefit. Sustained long term benefits on these outcomes over 2.5 years could support disease modification with a continued favorable safety profile of ALZ-801. Correlations of plasma biomarkers to long-term clinical and imaging outcomes provides valuable insights into ALZ-801 effects in AD."

Biomarker • Journal • Developmental Disorders • Aβ42 • GFAP • p-tau181

Drug Development. (PubMed, Alzheimers Dement) - "The Phase 2 APOE4-carrier population with positive CSF biomarkers showed low incidence of microhemorrhage (8%) over 2 years, all asymptomatic, with no siderosis or ARIA-E. This 265 mg BID ALZ-801 dose showed significant target engagement and promising cognitive effects in this study. These data suggest a low risk of ARIA with ALZ-801 in APOE4 carriers with Early AD."

Journal • Alzheimer's Disease • CNS Disorders • Hematological Disorders • Aβ42 • CSF P-tau • p-tau181

Drug Development. (PubMed, Alzheimers Dement) - "Over 2 years, oral ALZ-801 reduced plasma p-tau181. Cognitive stabilization correlated with reduced brain atrophy, showing treatment benefit compared to external controls. Cohen's d values for hippocampal volume and cognition suggest strong clinical benefit. No ARIA-E/vasogenic edema was detected. These biomarker results support the disease-modifying effects of ALZ-801 in Early AD with promising clinical efficacy and favorable safety in APOE4 carriers. A Phase 3 78-week trial in APOE4/4 homozygotes Early AD (EAD) is ongoing with results expected in 2024."

Journal • Aβ42 • p-tau181

Developing Topics. (PubMed, Alzheimers Dement) - P3 | "ALZ-801 showed no ARIA-E in prior AD studies allowing its evaluation in the high-risk APOE4/4 homozygotes. This pivotal APOLLOE4 Phase 3 trial of ALZ-801 enrolled homozygous APOE4/4 subjects with higher CAA burden than anti-amyloid antibody trials. The APOE4/4 CAA subjects were older with more advanced AD and higher rates of CAD and antiplatelets use than non-CAA subjects, which may increase brain edema and microhemorrhage risk, requiring heightened vigilance with anti-amyloid antibodies. If this Phase 3 trial is positive, ALZ-801 could become a potentially safer alternative to anti-amyloid antibodies for this population. The Phase 3 results are expected in 3Q 2024."

Journal • Alzheimer's Disease • Cardiovascular • CNS Disorders • Coronary Artery Disease • Diabetes • Dyslipidemia • Genetic Disorders • Hematological Disorders • Hypertension • Metabolic Disorders • Obesity

New Alzheon Peer-Reviewed Scientific Publication Describes Study Design and Baseline Characteristics from APOLLOE4 Phase 3 Trial of Oral ALZ-801/Valiltramiprosate in APOE4/4 Homozygous Individuals with Early Alzheimer’s Disease (Businesswire) - "Alzheon, Inc...announced a new scientific publication describing its APOLLOE4 Phase 3 study, the first Phase 3 trial focused on AD patients carrying two copies of apolipoprotein ε4 allele (APOE4/4 homozygotes), a population with pressing unmet medical need for effective and safe treatments....This population is the focus of the pivotal 78-week APOLLOE4 Phase 3 trial, with topline data expected in late 2024.... APOLLOE4 is a Phase 3 randomized, double-blind, placebo-controlled, parallel-arm, multicenter study of 78-week duration, enrolling APOE4/4 individuals at the early symptomatic stages of AD, which include MCI and Mild AD dementia per Alzheimer’s Association clinical criteria. After two stages of screening, patients aged 50-80 years, with Mini-Mental State Examination score ≥22, CDR-G=0.5 or 1 and RBANS-delayed memory ≤85, with stable medical conditions and no exclusionary findings on brain MRI were enrolled."

Clinical protocol • P3 data: top line • Alzheimer's Disease • CNS Disorders

Network Pharmacology Identifies Intersection Genes of Apigenin and Naringenin in Down Syndrome as Potential Therapeutic Targets. (PubMed, Pharmaceuticals (Basel)) - "Moreover, molecular docking studies included positive control drugs, such as lamellarin D, valiltramiprosate, benserazide, and TK216, which exhibited binding affinities ranging from -5.5 to -8.9 kcal/mol. Future studies should focus on in vivo validation, clinical trials, and exploring combination therapies to fully harness the therapeutic potential of these compounds for managing DS. This study underscores the promising role of network pharmacology in identifying novel therapeutic targets and agents for complex disorders like DS."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Developmental Disorders • Genetic Disorders

APOLLOE4 Phase 3 study of oral ALZ-801/valiltramiprosate in APOE ε4/ε4 homozygotes with early Alzheimer's disease: Trial design and baseline characteristics. (PubMed, Alzheimers Dement (N Y)) - "APOLLOE4 is the first disease-modification AD trial focused on APOE ε4/ε4 homozygotes. Oral ALZ-801 has the potential to be the first effective and safe anti-amyloid treatment for the high-risk APOE ε4/ε4 population."

Clinical • Journal • P3 data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Hematological Disorders • APOE