Aducanumab, gantenerumab, BAN2401, and ALZ-801—the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval
Some quotes may be especially applicable to those with early AD, MCI or who have ApoE 4/4 and are 60 or older. None of this research ignores the importance of maintaining cognitive health through our individual decisions. Some, however, are likely to need an additional treatment option. [Emphasis added]
This analysis focused on anti-amyloid agents that fulfilled the following criteria: (1) completed phase 3 or phase 2 trials in symptomatic AD patients; (2) demonstrated acceptable safety with treatment duration ≥ 12 months, the regulatory standard for long-term safety; (3) reported significant effects on clinical outcomes or on AD imaging or fluid biomarkers; (4) published mechanisms of action (MOA) and pharmacokinetic (PK) profiles; and (5) in active clinical development.
Major progress has been achieved in AD drug development, with several anti-amyloid agents recently reporting promising clinical and biomarker effects in late-stage trials. The three antibodies aducanumab, gantenerumab, and BAN2401, and the small molecule ALZ-801, [tramiprosate] have also shown acceptable long-term safety. Therefore, confirmation of their efficacy may lead to the approval and marketing of this first wave of disease-modifying treatments over the next 3 to 5 years.
...The common characteristic shared by these agents is their ability to target neurotoxic soluble Aβ oligomers . Aducanumab and gantenerumab preferentially target insoluble amyloid plaques and fibrils and engage oligomers only partially, while BAN2401 preferentially targets oligomers over plaques , and ALZ-801 selectively blocks the formation of Aβ oligomers without binding amyloid plaque .
APOE4 carriers, who are at higher risk of early AD progression and constitute ~ 65% of AD patients, provide an optimal group for clinical efficacy studies and initial approval for drugs targeting neurotoxic soluble Aβ oligomers, since these patients carry a several-fold higher burden of Aβ oligomers compared to noncarriers . APOE4 carriers also have higher levels of insoluble amyloid deposits in brain vessels, which increases their risk of ARIA-E and ARIA-H when treated with anti-amyloid antibodies . Therefore, careful evaluation of efficacy and safety of anti-amyloid agents in APOE4 carriers is important to determine the benefit-risk profile in this large subgroup of AD patients with increased risk and earlier onset of the disease. Due to the rapid removal of amyloid plaque deposits from brain vessels, treatment with antibodies aducanumab, gantenerumab, and BAN2401 is associated with a substantial risk of ARIA-E in APOE4 carriers. While the efficacy of aducanumab in APOE4 carriers has not yet been disclosed, the incidence of ARIA-E in APOE4 carriers was ~ 42% in this group versus ~ 35% in the overall population [11, 19]. BAN2401 showed more robust clinical efficacy in APOE4 carriers [23]; however, this was associated with a higher incidence of ARIA-E of ~ 15% versus 10% in the overall study population.
In APOE4/4 homozygotes, ALZ-801/tramiprosate showed substantial cognitive and functional benefits with no events of ARIA-E and may offer an optimal benefit-risk profile in APOE4 carriers....ALZ-801 is an oral agent, which efficiently crosses the blood-brain barrier... and blocks the formation of neurotoxic soluble Aβ oligomers in a dose-dependent manner, without affecting insoluble amyloid plaques or fibrils. ALZ-801 is a prodrug of tramiprosate with improved gastrointestinal absorption and tolerability... ALZ-801 is ready to enter phase 3 based on a large body of clinical data in AD patients, including (1) favorable safety profile from tramiprosate safety database of > 2000 AD patients treated for 18 months; (2) well-defined target clinical dose that fully blocks the formation of Aβ oligomers in the brain based on clinical data from the phase 3 AD trials and from an in vitro Aβ oligomer inhibition assay; and (3) precision medicine approach initially focusing on high-risk homozygous APOE4/4 patients with early AD [1]. Oral ALZ-801 provides convenient at-home dosing for elderly patients and their caregivers, as well as potential preventive treatment of presymptomatic subjects with high risk for AD.