Table 2.
Adverse events in Aß-targeted clinical trials.
| Drug (Mechanism) | Aß endpoints | Relevant adverse effects | References |
|---|---|---|---|
| Aducanumab (Anti-Aß immunization, Passive) |
↓ Aß plaques | ARIA ↑ Urinary tract infection ↑ Upper respiratory tract infection |
AlzForum (n.d.-a); Ferrero et al., 2016; Sevigny et al., 2016 |
| Affitope AD02 (Anti-Aß immunization, Active) |
↓ Aß plaques | ↑ Atrophy and worsened cognition compared to unexpectedly beneficial placebo | AlzForum (n.d.-b); Schneeberger et al., 2009; AlzForum, 2014b |
| Alzhemed (Aß-binding) |
↓ CSF Aß | ↑ Hippocampal atrophy ↑ GI reactions |
Aisen et al., 2006, 2007; Gauthier et al., 2009; Saumier et al., 2009 |
| AN-1792 (Anti-Aß immunization, Active) |
↓ Focal plaques NE total Aß NE/↑ vascular Aß ↑ Soluble Aß in gray matter ↑↑↑ Aß in white matter |
↑ Atrophy transiently NE/↑ Atrophy on follow-up 6% meningoencephalitis 8 deaths with “virtually complete plaque removal” |
AlzForum (n.d.-c) Nicoll et al., 2003; Ferrer et al., 2004; Fox et al., 2005; Masliah et al., 2005; Patton et al., 2006; Holmes et al., 2008; Kokjohn and Roher, 2009; Vellas et al., 2009; Boche et al., 2010 |
| Avagacestat (γ-secretase inhibitor) |
↓ Aß slightly in CSF | NE/worsened cognition ↑ Atrophy ↑ ARIA ↑↑ Skin cancer Skin/GI reactions |
Coric et al., 2012, 2015 |
| Bapineuzumab (Anti-Aß immunization, Passive) |
↓ Fibrillar Aß | ARIA (~33% in APOE4/4, 7% APOE4/X, 4% non-APOE4), ↑ Seizures ↑ Paranoia ↑ Skin/GI/cardiovascular reactions |
Salloway et al., 2009; Black et al., 2010; Rinne et al., 2010; AlzForum, 2012a,b; AlzForum (n.d.-e); Pfizer, 2008, 2013; AlzForum, 2013; Hu et al., 2015; Ketter et al., 2017 |
| BI1181181 (BACE-inhibitor) | ↓ CSF Aß ~80% | ↑ Skin reactions | AlzForum (n.d.-f) |
| CAD106 (Anti-Aß immunization, Active) |
↓ Brain Aß NE CSF Aß ↑ Plasma Aß 2-5X |
↑ ARIA in strong responders ~8% Attrition for safety concerns ↑ Acute psychosis ↑ Skin/cardiovascular reactions |
AlzForum (n.d.-g); AlzForum, 2014a |
| E2609 (BACE-inhibitor) |
↓ Plasma Aß ↓ CSF Aß ~80% |
↑ Infections ↑ Relapse of orolabial herpes |
AlzForum (n.d.-h) |
| ELND005 (Aß-binding) |
↓ CSF Aß | ↑ Ventricular volume ↑ Infections 9 deaths at high doses |
AlzForum (n.d.-i); Transition Therapeutics Ireland Limited, 2007, 2009; AlzForum, 2009; Salloway et al., 2011; Ma et al., 2012 |
| Gantenerumab (Anti-Aß immunization, Passive) |
↓ Aß ~11% | ↑ ARIA (temporary and in areas with the most Aß reduction) “Futility” |
AlzForum (n.d.-j);Ostrowitzki et al., 2012, 2017; Roche, 2014 |
| LY2886721 (BACE-inhibitor) |
↓ BACE activity 50–75% ↓ Aß42 ~72%, |
↑ Abnormal liver biochemistry | AlzForum (n.d.-k) |
| RG7129 (BACE-inhibitor) |
↑ Liver toxicity | AlzForum (n.d.-l) | |
| Semagacestat (γ-secretase inhibitor) |
NE/↓ CSF Aß ↓ Plasma Aß40 38–72% |
NE/worsened cognition ↑ Infections ↑ Skin cancer, skin reactions |
AlzForum (n.d.-m); Siemers et al., 2006, 2007; Eli Lilly Company, 2008; Fleisher et al., 2008; Bateman et al., 2009; Doody et al., 2013 |
Documented negative outcomes from clinical trials that have targeted Aß. Not all results are reported. Only drugs with reported effects or side-effects outside of Aß modulation are included on this table. ARIA, Amyloid-related imaging abnormalities; APOE, apolipoprotein; NE, no effect.