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

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

APOLLOE4: An Efficacy and Safety Study of ALZ-801 in APOE4/4 Early AD Subjects (clinicaltrials.gov) - P3 | N=325 | Completed | Sponsor: Alzheon Inc. | Active, not recruiting ➔ Completed

Biomarker • Trial completion • Alzheimer's Disease • CNS Disorders • APOE • CSF P-tau • p-tau181

Alzheon to Present Phase 2 Biomarker Trial Results and Baseline Characteristics from APOLLOE4 Phase 3 Trial of Oral ALZ-801/Valiltramiprosate in Patients with Early Alzheimer’s Disease at Alzheimer’s Association International Conference (Businesswire) - "Alzheon, Inc...today announced its participation in the Alzheimer’s Association International Conference (AAIC) in Philadelphia, held from July 28 to August 1, 2024...'Alzheimer’s is devastating to patients and families, and we believe the data we are presenting reinforce the potential of our lead agent ALZ-801/valiltramiprosate as a first-in-class, oral disease modifying therapy that may simplify the patient journey and provide increased access. In addition to the presentations at AAIC, we look forward to the upcoming topline from our pivotal APOLLOE4 Phase 3 trial later this year.'"

Clinical • P2 data • P3 data: top line • Alzheimer's Disease • CNS Disorders

Two Peer-Reviewed Scientific Publications Describe Fluid Biomarker, Brain Preservation and Clinical Benefits Following 2 Years of Treatment in Phase 2 Trial Evaluating Oral ALZ-801/Valiltramiprosate in APOE4 Carriers with Early Alzheimer’s Disease (Businesswire) - P2 | N=84 | NCT04693520 | Sponsor: Alzheon Inc. | "This positive Phase 2 study evaluating oral ALZ-801 in APOE4 patients with early AD achieved its primary efficacy endpoint of reduction in plasma p-tau181 over two years, suggesting a robust decrease in amyloid-induced brain neurodegeneration and target engagement. A significant 31% reduction (p=0.045) in plasma p-tau181 from baseline to 104 weeks started at 13 weeks and was sustained at every visit through 104 weeks. HV atrophy was significantly reduced by 25% (p=0.0014) compared to a matched external control from ADNI-1, an observational AD study. Memory scores showed improvement from baseline at 26 weeks and thereafter showed minimal decline from baseline at 104 weeks. These cognitive effects correlated significantly with decreased HV atrophy (p=0.002)."

P2 data • Alzheimer's Disease • CNS Disorders

Analysis of Cerebrospinal Fluid, Plasma β-Amyloid Biomarkers, and Cognition from a 2-Year Phase 2 Trial Evaluating Oral ALZ-801/Valiltramiprosate in APOE4 Carriers with Early Alzheimer's Disease Using Quantitative Systems Pharmacology Model. (PubMed, Drugs) - P2 | "In this genetically defined and biomarker-enriched early AD population, the QSP analysis demonstrated a positive therapeutic effect of oral ALZ-801 265 mg BID by arresting the natural decline of monomeric CSF and plasma amyloid biomarkers, consistent with the target engagement to prevent their aggregation into soluble neurotoxic oligomers and subsequently into insoluble fibrils and plaques over 104 weeks. Accompanying the amyloid biomarker changes, ALZ-801 also stabilized the natural trajectory decline of the RAVLT memory test, suggesting that the clinical benefits are consistent with its mechanism of action. This sequential effect arresting the disease progression on biomarkers and cognitive decline was more pronounced in the earlier symptomatic stages of AD. The QSP analysis provides fluid biomarker and clinical evidence for ALZ-801 as a first-in-class, oral small-molecule anti-Aβ oligomer agent with disease modification potential in AD."

Biomarker • Journal • P2 data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Developmental Disorders • Aβ42 • CSF Aβ42 • Plasma Aβ40 • p-tau181

Effects of Oral ALZ-801/Valiltramiprosate on Plasma Biomarkers, Brain Hippocampal Volume, and Cognition: Results of 2-Year Single-Arm, Open-Label, Phase 2 Trial in APOE4 Carriers with Early Alzheimer's Disease. (PubMed, Drugs) - P2 | "The effect of ALZ-801 on reducing plasma p-tau181 over 2 years demonstrates target engagement and supports its anti-Aβ oligomer action that leads to a robust decrease in amyloid-induced brain neurodegeneration. The significant correlation between reduced HV atrophy and cognitive stability over 2 years suggests a disease-modifying effect of ALZ-801 treatment in patients with early AD. Together with the favorable safety profile with no events of vasogenic brain edema, these results support further evaluation of ALZ-801 in a broader population of APOE4 carriers, who represent two-thirds of patients with AD."

Biomarker • Journal • P2 data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Infectious Disease • Novel Coronavirus Disease • APOE • Aβ42 • Plasma Aβ40 • p-tau181

Phase 3 Trial of Oral Anti-Amyloid Agent ALZ-801/Valiltramiprosate in APOE4/4 Homozygotes with Early Alzheimer’s Disease: Baseline Characteristics and Prevalence of Comorbid Cerebral Amyloid Angiopathy (AAIC 2024) - 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."

P3 data • Alzheimer's Disease • Cardiovascular • CNS Disorders • Coronary Artery Disease • Diabetes • Dyslipidemia • Genetic Disorders • Hematological Disorders • Hypertension • Metabolic Disorders • Obesity

Plasma Biomarkers, Hippocampal Volume and Cognitive Effects of Oral ALZ-801: The Phase 2 Biomarker Study and its Long-Term Extension in APOE4 Carriers with Early Alzheimer’s Disease (AAIC 2024) - "Biomarker positive APOE4 carriers showed significant plasma p-tau 181 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 • P2 data • Alzheimer's Disease • CNS Disorders • Developmental Disorders • Aβ42 • GFAP

Low Incidence of Amyloid Related Imaging Abnormalities over 104 Weeks in a Phase 2 Study of Amyloid Anti-Oligomer Agent ALZ-801: Phase 2 Study Results in Biomarker Positive APOE4 Carriers with Early Alzheimer’s Disease (AD) (AAIC 2024) - "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."

Biomarker • P2 data • Alzheimer's Disease • CNS Disorders • Hematological Disorders • Aβ42 • CSF P-tau • p-tau181

Phase 2 Study Results of Oral ALZ-801 (Valiltramiprosate) in Early Alzheimer’s Disease Shows Potential Disease Modification Effect: 2-Year Effect on Plasma Biomarkers, Volumetric MRI, Cognition Outcomes and Clinical Benefit Analysis (AAIC 2024) - "Over 2 years, oral ALZ-801 reduced plasma p-tau 181 . 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."

Biomarker • Clinical • P2 data • Alzheimer's Disease • CNS Disorders • Aβ42