The body of evidence suggesting a causative, initiating role of
beta amyloid (Aβ) in the pathogenesis of
Alzheimer's disease (AD) is substantial. Yet, only a few anti-
amyloid agents have shown meaningful efficacy in clinical trials. We evaluated the unifying characteristics of anti-
amyloid agents with positive clinical or
biomarker effects in long-duration trials and analyzed how pharmacological characteristics determine their clinical product profiles. Four agents with the potential for near term approval fulfill these criteria: the
injectable antibodies,
aducanumab,
gantenerumab, and
BAN2401, and a small molecule oral agent,
ALZ-801.
Aducanumab and
BAN2401 showed significant efficacy on both clinical and
biomarker outcomes;
gantenerumab showed significant
biomarker effects, with no clinical efficacy reported to date; and
ALZ-801 showed significant clinical effects in the high-risk population of patients homozygous for the ε4 allele of
apolipoprotein E gene (
APOE4) and a dose-dependent preservation of hippocampal volume. We explored how the pharmacological properties of these agents, namely selectivity for Aβ oligomers, plasma half-life, brain penetration, and time to peak brain exposure, determine their clinical profiles. A crucial characteristic shared by these agents is their ability to engage neurotoxic soluble Aβ oligomers, albeit to various degrees.
Aducanumab and
gantenerumab partially target oligomers, while mostly clearing insoluble
amyloid plaques;
BAN2401 preferentially targets soluble protofibrils (large oligomers) over plaques; and
ALZ-801 blocks the formation of oligomers without binding to plaques. The degree of selectivity for Aβ oligomers and brain exposure drive the magnitude and onset of clinical efficacy, while the clearance of plaques is associated with
vasogenic brain edema. Only the highest doses of
aducanumab and
BAN2401 show modest efficacy, and higher dosing is limited by increased risk of vasogenic
edema, especially in
APOE4 carriers. These limitations can be avoided, and efficacy improved by small molecule agents that selectively inhibit the formation or block the toxicity of Aβ oligomers without clearing
amyloid plaques. The most advanced selective anti-oligomer agent is
ALZ-801, an optimized oral
prodrug of
tramiprosate, which demonstrated efficacy in homozygous
APOE4/4 AD subjects.
ALZ-801 selectively and fully inhibits the formation of Aβ42 oligomers at the clinical dose, without evidence of vasogenic
edema, and will be evaluated in a phase 3 trial in homozygous
APOE4/4 patients with early AD. In addition to clinical measures, the phase 3 trial will include cerebrospinal fluid, plasma, and imaging
biomarkers to gain further insights into the role of soluble Aβ oligomers in the pathogenesis of AD and their impact on
disease progression.