Aims

Here we describe the development of RG6102, a bispecific monoclonal antibody (mAb) construct combining the anti-beta amyloid antibody gantenerumab with a “Brain Shuttle” module that specifically binds to transferrin receptor-1 (TfR1). Active TfR1-mediated transcytosis across the blood–brain barrier may allow superior target engagement and beta amyloid clearance through faster and more widespread brain penetration.

Methods

RG6102 was characterized in vitro and in vivo including a single-dose pharmacokinetics (PK) study in non-human primates (NHP). A translational PK/pharmacodynamics (PK/PD) model was developed combining data from this PK study with beta amyloid plaque removal information from the clinically established PK/PD profile of gantenerumab, and used to inform dose selection for the first-in-human, single-ascending dose (SAD) study of RG6102 (NCT04023994).

Results

Upon intravenous administration of RG6102 in NHP, a 6- to 17-fold increase in the steady-state brain area under the curve or >30-fold C_max (peak concentration), compared with gantenerumab, was observed across different brain tissues. Preliminary SAD data incorporated in the translational PK/PD model predicted faster systemic clearance than the allometric projection. A human cerebrospinal fluid (CSF)/plasma ratio of ~0.8% was measured.

Conclusions

In preclinical NHP studies, the brain shuttle-gantenerumab construct RG6102 showed improved exposure and widespread distribution in the brain, compared with gantenerumab. Preliminary first-in-human data revealed a markedly increased CSF/plasma ratio for RG6102 compared with typical mAbs (~0.8% vs. 0.1–0.2%). Studies are underway in individuals with Alzheimer’s disease to test whether these findings translate into an enhanced pharmacodynamic effect (amyloid PET reduction) with the ultimate goal to improve clinical outcomes.

Aims

Search for effective therapies for Alzheimer’s Disease (AD) and related neurodegenerative diseases remains a significant unmet medical need, thus immunotherapeutic approaches such as single chain fragments have gained increasing interest as research tools and as pharmacological drugs in recent years, but they are limited by low expression efficiency, low binding affinity and short half life. To overcome these problems we generated a fusion protein comprising a specific anti-Aβ scFv and collagen domain of a C1QTNF protein (CD).

Methods

Anti-Aβ recombinant scFvs fused to CD were packaged in AAV and delivered to newborn CRND8 mice as well as stereotaxically injected into the hippocampus of adult CRND8 mice with preexisting pathology. Amyloid burden and Aβ levels in the soluble, SDS soluble and SDS-insoluble, Formic Acid soluble fractions were compared between various cohorts. Non –specific scFv-CD as well as CD alone served as controls.

Results

We have cloned several anti-Aβ scFv (fibril-specific, anti-Aβ42, or pan-Aβ) fused CD. We then characterized scFv-CD compared wth scFv alone in vivo. Further we tested disease-modifying potential of new scFv-CD in CRND8 mice in a prevention as well as therapeutic paradigm. ScFv-CD was more efficacious in preventing formation of amyloid plaques. Further assessment whether efficacy can be improved by functionalizing scFv-CDs is underway.

Conclusions

CD fusion increases stability and half life of scFv, while retaining its binding properties. Moreover, multimerization may increase the functional affinity of the binding domain of scFvs. Thus, our studies provide a framework for identifying an optimized immunotherapy for AD, and potentially other neurodegenerative disorders.

Aims

To evaluate the BACE inhibitor elenbecestat in early Alzheimer’s Disease (EAD).

Methods

The MissionAD program comprised two randomized, placebo-controlled phase 3 studies. Patients with EAD were randomized 1:1 to either once-daily elenbecestat (50 mg) or placebo for 24 months. The primary endpoint was CDR-SB at 24 months in the combined studies. Key secondary endpoints included AD Composite Score (ADCOMS) and amyloid PET.

Results

Following recommendation of the elenbecestat DSMB, the studies were terminated early due to an unfavourable risk-benefit ratio. 2209 patients were treated (elenbecestat:1101;placebo:1108) and 189 had a 24-month CDR assessment. No differences were observed in least squares (LS) mean [SE] change from baseline in CDR-SB at 24 months (elenbecestat: 1.99 [0.146]; placebo: 2.17 [0.142]; LS mean difference [95% CI]: -0.17 [-0.57, 0.22]). For ADCOMS at 24 months, no differences were observed in LS Mean (SE) change from baseline (elenbecestat: 0.23 [0.015]; placebo: 0.24 [0.014]; LS mean difference [95% CI]: -0.02 [-0.06, 0.02]). LS mean (SE) change from baseline in amyloid PET centiloids at 24 months was -5.02 (2.046) for elenbecestat and 7.81 (2.500) for placebo (LS mean differences [95% CI] was –12.83 [-18.79, -6.88], nominal p<0.001). Incidence of adverse events were similar between groups with lymphopenia, rash, dizziness, weight loss, and abnormal dreams occurring more frequently with elenbecestat.

Conclusions

There was no evidence of a treatment effect on CDR-SB or ADCOMS for elenbecestat in the early terminated MissionAD studies.

Aims

To assess the use of cerebrospinal fluid (CSF) biomarkers as a valid alternative to positron emission tomography (PET) for amyloid confirmation by conducting a concordance analysis using data from EMERGE (NCT02484547) and ENGAGE (NCT02477800).

Methods

EMERGE and ENGAGE were randomized, double-blind, placebo-controlled, global Phase 3 studies of aducanumab. Participants were 50-85 years old and met clinical criteria for mild cognitive impairment due to Alzheimer’s disease or mild Alzheimer’s disease dementia, with a baseline Mini-Mental State Examination score of 24-30 (inclusive) and a CDR global score of 0.5. All enrolled participants had amyloid pathology detected by amyloid PET (visual read) during screening. Participants received an intravenous injection of high-dose aducanumab, low-dose aducanumab, or placebo, randomized 1:1:1, monthly for 18 months. Concordance between CSF biomarkers (amyloid beta [1-42], amyloid beta [1-40], phosphorylated tau [181], total tau, and applicable CSF biomarker ratios; Lumipulse® G immunoassay) and amyloid PET at screening was examined. Positive percent agreement (sensitivity), negative percent agreement (specificity), and overall percent agreement (OPA) using the cutoff value maximizing the Youden J index per biomarker or ratio were determined.

Results

A total of 350 participants (n=308 positive; n=42 negative) provided CSF samples at screening and were included in the analysis. For the CSF Abeta₄₂/Abeta₄₀ ratio, the observed sensitivity of 94%, specificity of 88%, and OPA of 94% in EMERGE and ENGAGE were equivalent to approved PET tracers (sensitivity, 88%-98%; specificity, 80%-95%).

Conclusions

These analyses demonstrate robust concordance between CSF biomarkers and PET amyloid results in EMERGE and ENGAGE.

Aims

To investigate the efficacy of monoclonal antibodies against Amyloid-beta (Aβ) in Alzheimer’s disease (AD).

Methods

Pubmed, Web of Science and ClinicalTrials.gov were searched for phase III randomized controlled trials (RCTs) and random-effects meta-analyses were performed.

Results

Seventeen RCTs (12,585 patients) were included. Monoclonal antibodies improved the cognitive outcomes ADAS-Cog {SMD = -0.06 [95% CI (-0.10; -0.02), I²= 0%]} and MMSE {SMD = 0.05 [95% CI (0.01; 0.09), I²= 0%]}, but did not improve the cognitive/functional measure CDR-SOB.

Antibodies decreased PET amyloid {SMD = -1.02 [95% CI (-1.70; -0.34), I²= 95%]} and CSF p181-tau {SMD = -0.87 [95% CI (-1.32; -0.43), I² = 89%]}, but increased ARIA risk {RR = 4.30 [95% CI (2.39; 7.77), I²= 86%]}. Antibody effects on reducing PET amyloid SUVR were correlated with their effects on decreasing (improving) ADAS-Cog (r = 0.66, p = 0.02)

In subgroup analysis by drug, Aducanumab improved ADAS-Cog, CDR-SOB, ADCS-ADL, and decreased amyloid PET SUVR and CSF p181-tau. Solanezumab improved ADAS-Cog and MMSE, and increased (improved) CSF Aβ_1-40. Bapineuzumab, Gantenerumab and Crenezumab did not improve any clinical outcomes, but Bapineuzumab and Gantenerumab decreased CSF p181-tau. All drugs except Solanezumab increased ARIA risk.

Conclusions

The increased power of this meta-analysis allowed us to detect small clinical and large biomarker improvements induced by anti-Aβ monoclonal antibodies. These findings support the view that Aβ remains a rational target for AD drug development and provide moderate support for the continuous development of anti-Aβ monoclonal antibodies as a treatment for AD.