Aims

A QSP Platform was developed integrating the known features of amyloid beta (Aβ) aggregation and microglia biology with the pharmacology of lecanemab to evaluate the dynamics of the modulation of Aβ aggregation cascade by the unique binding properties of lecanemab targeting aggregated Aβ species for the treatment of Alzheimer’s Disease (AD).

Methods

A reduced physiological based pharmacokinetic (PBPK) model for lecanemab interstitial fluid concentrations was coupled with a mathematical model of the Aβ aggregation based on elongation, primary and secondary nucleation, and fragmentation. Removal of Aβ peptides was modeled by microglia-dependent clearance through phagocytosis of the antibody-Aβ-complexes and modulated by selective binding affinity of lecanemab. Activation of immune cells by antibody-bound plaques in a perivascular compartment was assumed to drive ARIA-E liability.

Results

The QSP Aβ Platform predicts well the observed lifetime trajectory of Aβ species (monomers, oligomers, protofibrils, and plaque), including the effect of APOE genotype. It was qualified against observed clinical PK and biomarker (Plasma Aβ, CSF Aβ, and PET SUVr) data for lecanemab. The model characterized the temporal changes of the clinical biomarkers during lecanemab treatment, its ARIA-E incidence, and the dynamics of SUVr after termination of treatment.

Conclusions

A QSP Aβ Platform was developed and qualified using existing clinical PK and PD data from lecanemab. The model describes the lecanemab PK and the time course of Aβ species in plasma, CSF, and ISF. It is a valuable tool to explore the impact of patient baseline characteristics and treatments on amyloid dynamics.

Aims

Design an optimal amyloid-beta (Abeta) vaccine to elicit antibodies selective for toxic Abeta oligomers (ABO) without inducing potentially detrimental B or T cell reactivity to normal Abeta.

Methods

A conformational B cell epitope previously determined to elicit antibodies selective and protective against toxic ABO (cyclized HHQK peptide; Gibbs et al, Scientific Reports, 2018), was coupled to KLH as a carrier protein to provide T helper epitopes. Mice received 2 immunizations with the conjugate in 3 different adjuvant formulations (alum, Emulsigen, TriAdj). Serum titers of total IgG, IgG1 and IgG2a antibodies to the peptide epitope were measured by ELISA. T helper type 1 (Th1) and type 2 (Th2) responses to the peptide and to KLH were evaluated by ELISPOT analysis of splenic lymphocytes.

Results

A robust antibody response against the conformational peptide epitope was observed with all 3 adjuvants. Alum gave rise to a predominantly IgG1 response while Emulsigen and TriAdj produced a more comparable IgG1/IgG2a response. ELISPOT analysis showed a lack of Th1 (interferon-gamma) or Th2 (IL-5) cytokine production in response to stimulation with the ABO epitope thereby confirming that the peptide only contains a B cell epitope. T cell help was provided by the carrier and stimulation with KLH induced Th2-biased cytokine production.

Conclusions

A vaccine consisting of an ABO-restricted conformational B cell epitope conjugated to KLH for T cell help successfully induced an antibody response to the B cell epitope without eliciting a potentially inflammatory Abeta-directed T helper response. This vaccine configuration has the potential for optimal safety and efficacy.

Aims

Posiphen has been shown in animal models to reduce multiple neurotoxic proteins, restore axonal transport, lower inflammation and protect nerve cells from dying. To show that Posiphen reverses the toxic cascade and potentially shows efficacy in humans, we started two double-blind, placebo- controlled clinical phase 2a studies in AD and PD patients.

Methods

In the first part, we enrolled 14 AD and 14 PD patients (4 placebo and 10 treated with 80 mg posiphen QD for 25 +/- 2 days). We measured markers of neurotoxic proteins, axonal transport, inflammation and neurodegeneration. The second part enrolled an additional 40 PD patients with the same study design to test biomarkers and efficacy at different concentrations of posiphen.

Results

From the first part of the study, we report statistically significant improvements in ADAS-Cog 11 and WAIS coding in treated AD patients comparing to baseline. Posiphen reduced sAPPα, sAPPβ, Tau, p-Tau and improved the Ab42/40 ratio. In PD patients, we see statistically significant improvements in the WAIS coding test comparing to control and strong trends in all 4 UPDRS parts. Posiphen significantly reduced inflammation in treated patients.

We expect to finish analyzing all the remaining biomarkers of part 1 and report on the part 2 data mid October.

Conclusions

In conclusion, our data from the first 28 patients shows that Posiphen improves cognition in AD and motor function in PD as well as reverses the toxic cascade. The expected additional markers and the new part 2 data will solidify and confirm that Posiphen works in AD and PD patients.

Aims

To describe the ongoing ACT-AD study, a 26-week, randomized, double-blind, placebo-controlled study in mild-to-moderate Alzheimer’s disease (AD) with ATH-1017. ATH-1017 is a small-molecule enhancer of HGF/MET, a neurotrophic pathway impaired in AD. Neuronal MET expression is decreased in the cortex and hippocampus, which may contribute to synaptic loss, neurodegeneration, and functional decline. Enhancement of HGF/MET activity has the potential to restore neuronal connections and improve cognition. The ACT-AD study seeks to replicate and extend the previously shown improvement of ERP P300 latency, the primary endpoint and a non-invasive neurophysiological biomarker of cognitive performance.

Methods

ACT-AD has a target enrollment of 75 patients (aged 55-85, CDR 1 and 2, MMSE 14-24) in the US and Australia. Subjects are randomized 1:1:1 to placebo, 40 mg, or 70 mg dose of ATH-1017 with a once daily subcutaneous injection. In addition to ERP P300 latency and safety, ADAS-Cog₁₁, ADCS-CGIC, ADCS-ADL₂₃, COWAT, NPI, and other measures are protocoled. Summary statistics for demographic and baseline characteristics for the overall patient population are presented.

Results

The first 67 enrolled patients have a mean(SD) age of 71.9 (7.2), of whom 54% are female and 46% male, and 91% are white. Mean (SD) baseline MMSE score is 19.2 (3.0), with a minimum of 14 and a maximum of 24. ApoE4 carriers make up 56% of the population, with 44% as non-carriers. Data will be updated once enrollment is complete.

Conclusions

Enrolled subjects represent an appropriate population to evaluate the treatment effects of ATH-1017 on ERP P300.

Aims

T3D-959 is a novel (non-amyloid/non-tau-directed) new chemical entity aimed at improving dysfunctional brain glucose energy and lipid metabolism in Alzheimer’s disease (AD). To validate and expand upon observed efficacy signals in a Phase 2a trial, a larger and longer Phase 2 clinical trial is in progress, powered to measure significant differences versus placebo in outcome measures of cognition and function and assessments of multiple biomarkers of disease.

Methods

The ‘PIONEER’ Study is assessing three T3D-959 dose strengths vs. placebo. The trial is randomizing 256 AD patients dosed q.d., for 24-weeks. Eligible patients are 50-90y, have mild to moderate AD with a CDR-SB >3.0 and MMSE of 14-26. Co-primary outcome measures include ADAS-Cog11 and ADCS-CGIC. Secondary outcome measures include DSCT and change in plasma Aβ 42/40 ratio. Exploratory outcome measures include the effect of T3D-959 on absolute regional and whole brain CMRgl using FDG-PET, on plasma metabolomic, lipidomic and proteomic biomarkers, including NfL total tau, p-tau217, and p-tau181.

Results

Enrollment in PIONEER commenced in March 2021 and is ongoing [See ClinicalTrials.gov identifier NCT04251182].

Conclusions

The etiology of AD remains unknown. Brain metabolic dysfunction as causation is underserved in AD research. The PIONEER study fills this gap and supposes that aberrant glucose and lipid metabolism in AD causes protein misfolding which causes formation of plaques, tangles and promotes inflammation. The PIONEER Study will determine the clinical efficacy and safety profile of T3D-959 in individuals with mild to moderate AD. PIONEER is supported by NIA/NIH, under award R01AG061122 and by the Alzheimer’s Association’s Part the Cloud Gates Partnership Grant Program.

Aims

Additional analysis of data from the GAIN trial, a large Phase 2/3 randomized, double-blind, placebo-controlled clinical trial in mild-moderate AD testing the efficacy and safety of the oral small-molecule atuzaginstat, a novel P. gingivalis virulence factor inhibitor.

Methods

The Phase 2/3 GAIN trial (NCT03823404) completed enrollment in November 2020. 643 subjects (aged 55-80; mild-moderate AD with MMSE 12-24) were randomized 1:1:1 to one of two doses of atuzaginstat (40mg or 80mg BID) or placebo for 48 weeks.

Results

Baseline data show that the 643 randomized subjects are typical of a mild-moderate AD population: 57% female, 64% ApoE4 carriers, 50% mild (MMSE = 19-24) and 50% moderate (MMSE 12-18). 70% were from the United States and 30% from Europe. 74% of subjects received symptomatic AD co-medications. Topline data indicated efficacy of both doses of atuzaginstat in prespecified P. gingivalis infected populations. Changes in P. gingivalis DNA in saliva correlated significantly with outcomes on multiples scales, including ADAS-Cog, CDR-SB, and MMSE. New analyses will be shared.

Conclusions

Enrollment of the GAIN trial was completed in November 2020, and topline data announced in October 2021. The GAIN trial provided further support that P. gingivalis is a novel driver of disease in an easily identified population comprising approximately 50% of the mild to moderate patients. Atuzaginstat slowed cognitive decline in Alzheimer’s disease with P. gingivalis by approximately 50% on ADAS-cog. Additional analyses are pending and will be shared.

Aims

E2814 is a novel anti-tau therapeutic monoclonal antibody (mAb) that inhibits the propagation of pathological tau species by binding to the microtubule binding region (MTBR). This study evaluated safety, pharmacokinetics (PK), immunogenicity and target engagement (TE) of single and multiple doses of E2814.

Methods

This randomized, placebo-controlled, Phase 1 study evaluated 3 single ascending doses (SAD) and 2 multiple ascending doses (MAD) in healthy adults. Subjects (n=8/cohort) received single or multiple (every 4 weeks) 1-hour IV infusions of E2814 (or placebo). PK was characterized in blood and CSF samples. TE was evaluated in CSF by measuring E2814-bound and free MTBR-tau proxy peptide concentrations (MTBR-tau354 and MTBR-tau299 containing epitopes in R4 and R2, respectively).

Results

E2814 has an adequate single and multiple dose safety profile. No dose limiting events were observed. E2814 exposures (C_max, AUC) increased in a dose-related manner. E2814 acumulation index on multiple dosing (R_ac=1.5) was consistent with its elimination half-life (22 days). The serum-to-CSF ratio was 0.2%. TE was dose related and sustained over time with maximum TE levels of 45% and 76% in the SAD and 47% and 62% in the MAD for MTBR-tau354 and MTBR-tau299, respectively. In the SAD, 2 out of 24 subjects had transient low level anti-drug antibody (ADA) titers by the last study day; no post dose ADA were detected in the MAD.

Conclusions

E2814 presented an adequate safety, PK and immunogenicity profile in healthy adults. Increase in TE was dose-related and sustained. These results support further development of E2814 as a disease-modifying therapy for AD.