Table 1.
Recent clinical trials for disease-modification in AD.
| Drug name | Mechanism of action | Population (disease stage) | Dose and administration route | Sample size | Clinical outcomes | Biomarkers measured | Results | Comments |
|---|---|---|---|---|---|---|---|---|
| Aducanumab ENGAGE (NCT02477800) EMERGE (NCT02484547) |
Monoclonal antibody that binds soluble forms of amyloid | Mild AD | 3, 6 mg/kg, or placebo; Monthly IV | ENGAGE: 1,647 EMERGE: 1,638 |
Primary: CDR-SB score Secondary: MMSE, ADAS-Cog 13, ADCS-ADL-MCI |
Amyloid PET | Terminated for futility | ~35% of participants developed ARIA-E |
| Atabecestat (JNJ-54861911) (29) | BACE-1 inhibitor | Pre-clinical | 5, 25 mg, or placebo; oral | 557 | PACC, RBANS | Greater cognitive deterioration in the intervention groups in comparison to placebo | Hepatic toxicity | |
| Avagacestat (30) | γ-secretase inhibitor | Prodromal | 50 mg escalating to 25 mg, or placebo; oral | 263 | ADAS-cog, ADCS-ADL, CDR-SB, MMSE, free and cued selective reminding test | Total tau, phosphorylated tau, Aβ1−42 in CSF; Brain MRI; Amyloid PET in a subset of participants | Terminated early. Minimal reductions in CSF amyloid and no significant treatment differences in the avagacestat arm vs. placebo | Adverse events: gastrointestinal tract adverse events, increases in non-melanoma skin cancer and reversible renal tubule effects |
| Bapineuzumab (31) | Monoclonal antibody directed at amyloid plaques and oligomers | Mild to moderate | 0.5, 1.0, 2.0 mg/kg, or placebo; IV every 13 weeks | Study 1: 1,121 APOE ε4 allele carriers Study 2: 1,331 non-carriers |
ADAS-cog; DAD | Amyloid PET, phosphorylated tau in CSF | No efficacy | Amyloid-related imaging abnormalities with edema among patients receiving bapineuzumab |
| Donanemab (32) | Anti-Aβ IgG1 targeting established amyloid plaques | Early, prodromal AD | 700 mg for the first three doses, followed by 1,400 mg, intravenously, every 4 weeks up to 72 weeks | 272 | Primary: iADRS. Secondary: CDR-SB, ADAS-Cog, ADCS-iADL, MMSE | Amyloid PET, Tau PET, volumetric MRI | Small reduction of cognitive decline measured by primary outcome in the intervention group, but mixed results in secondary outcomes | ARIA-E occurred in of participants receiving the intervention |
| Gantenerumab (33) | Anti-Aβ monoclonal antibody that binds with high affinity to aggregated Aβ and promotes its removal by Fc receptor-mediated phagocytosis | Scarlet Road trial: Prodromal | 105 mg, 225 mg, or placebo, subcutaneous every 4 weeks | 797 | Primary: CDR-SB score. Secondary: ADAS-Cog 13, MMSE, Cambridge Neuropsychological Test Automated Battery (CANTAB), FCSRT. Behavioral: NPI-Q, FAQ | Amyloid PET, brain volumes by MRI, CSF Aβ1−42, total tau, phosphorylated tau, and neurogranin | No differences between groups in the primary or secondary clinical endpoints were observed | The incidence of generally asymptomatic amyloid-related imaging abnormalities increased in a dose- and APOE ε4 genotype-dependent manner |
| Gantenerumab (33) | Anti-Aβ monoclonal antibody that binds with high affinity to aggregated Aβ and promotes its removal by Fc receptor-mediated phagocytosis | Scarlet Road trial: Prodromal | 105 mg, 225 mg, or placebo, subcutaneous every 4 weeks | 797 | Primary: CDR-SB score. Secondary: ADAS-Cog 13, MMSE, Cambridge Neuropsychological Test Automated Battery (CANTAB), FCSRT. Behavioral: NPI-Q, FAQ | Amyloid PET, brain volumes by MRI, CSF Aβ1−42, total tau, phosphorylated tau, and neurogranin | No differences between groups in the primary or secondary clinical endpoints were observed | The incidence of generally asymptomatic amyloid-related imaging abnormalities increased in a dose- and APOE ε4 genotype-dependent manner |
| Intravenous immunoglobulin (IVIg) (34) | Intravenous immunoglobulin used in autoimmune disorder and immunodeficiency | Mild to moderate | IV at doses of 0.2 or 0.4 g/kg every 2 weeks or placebo-albumin | 390 | ADAS-Cog and ADCS-ADL | Volumetric T1-weighted MRI sequences (NeuroQuant). Blood total immunoglobulin; Ab-40 and Ab-42. CSF anti-monomer and anti-oligomer AB assays | No beneficial effects were observed in the dual primary outcome measures | Intervention group had more systemic reactions (chills, rashes) but fewer respiratory infections than participants receiving placebo |
| Lanabecestat (35) | BACE-1 inhibitor | Mild | 20 mg, 50 mg or placebo; oral | AMARANTH trial: 2,218DAYBREAK-ALZ trial: 1,722 | ADAS-Cog, ADCS-iADL, FAQ iADRS, CDR-SB, NPI, MMSE | MRI Hippocampal volume, amyloid PET, CSF Aβ1−42 and Aβ1−40, total tau, phosphorylated tau and soluble Aβ precursor pro- tein (sAPPα and sAPPβ) | Both studies were terminated early after futility analysis | Psychiatric adverse events, weight loss, and hair color changes were reported in a higher percentage of patients receiving lanabecestat |
| Methylthioninium moiety [leuco-methylthioninium bis (hydromethanesulfonate); LMTM] (36) |
Selective inhibitor of tau protein aggregation | Mild to moderate | 75 or 125 mg twice daily or 4 mg twice daily (control dose) for blinding urine or fecal discolouration; Oral | 891 | ADAS-Cog and ADCS-ADL | Volumetric Brain MRI, 18F-FDG-PET. CSF total tau, phospho-tau, and amyloid-β1−42 | No treatment benefit at either of the doses tested for the coprimary outcomes | Gastrointestinal and urinary effects were the most common adverse events with both high doses of LMTM, and the most common causes for discontinuation |
| Nilvadipine (37) | Dihydropyridine (DHP) calcium channel blocker | Mild to moderate | 8 mg sustained release nilvadipine or matched placebo | 511 | ADAS-Cog 12, CDR-SB as a gated co-primary outcome | The prespecified primary analyses failed to show any treatment benefit | Higher counts of adverse events on nilvadipine | |
| Verubecestat (38) | BACE-1 inhibitor | Mild to Moderate | 12, 40 mg or placebo; oral | 1,958 | ADAS-cog and ADCS-ADL); MMSE, CDR-SB | MRI hippocampal volume, amyloid PET, CSF total tau | Stopped for futility | |
| Verubecestat (39) | BACE-1 inhibitor | Prodromal | 12, 40 mg or, placebo; oral | 1,454 | CDR-SB; Progression to the diagnosis of ADdementia | MRI hippocampal volume, amyloid PET, CSF total tau | Stopped for futility | Trend for worse performance in the high dose verubecestat group |
| Semagecestatv (40) | γ-secretase inhibitor | Mild to moderate | 100, 140 mg, or placebo; oral | 1,537 | ADAS-cog, ADCS-ADL, CDR-SB, NPI, RUD-Lite, EQ-5D, MMSE | CSF Aβ and tau protein, volumetric MRI, amyloid PET | Terminated early. No improvement. Greater cognitive deterioration in the group receiving higher dose | Adverse events: Worsening of cognition, increased rates of skin cancer and infection 76 weeks |
| Solanezumab (41) | Monoclonal antibody that binds soluble forms of amyloid | Mild to moderate | 400 mg every 4 weeks | EXPEDITION 1:1,012EXPEDITION 2:1,040 | ADAS-cog; ADCS-ADL | Plasma Aβ1−40 and Aβ1−42 levels, amyloid PET, CSF total tau and phosphorylated-tau. Volumetric MRI | Neither study showed significant improvement in the primary outcomes | ARIA-E and hemorrhage slightly more frequent with solanezumab |
| Solanezumab (42) | Monoclonal antibody that binds soluble forms of amyloid | Mild AD | 400 mg or placebo; IV every 4 weeks | 2,129 | ADAS-cog, MMSE, ADCS-ADL, ADCS-iADL, CDR-SB, FAQ, iADRS | Plasma Aβ1−40 and Aβ1−42 levels, amyloid PET, CSF total tau and phosphorylated-tau. Volumetric MRI | No efficacy | |
| Tarenflurbil (43) | γ-secretase inhibitor | Mild AD | 800 mg or placebo | 1,649 | Co primary ADAS-cog ADCS-ADL; CDR-SB, Neuro-quality of life scale (QOL-AD), MMSE | Plasma concentrations of S-flurbiprofen | No efficacy |
PACC: ADCS-ADL-MCI, Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory; APOE, Apolipoprotein E; ARIA, amyloid-related imaging abnormalities; CDR-SB, Clinical Dementia Rating–Sum of Boxes; CANTAB, Cambridge Neuropsychological Test Automated Battery; DAD, Disability Assessment for Dementia; FAQ, Functional Activities Questionnaire; iADRS, Integrated Alzheimer's Disease Rating Scale; MMSE, Mini-Mental State; NPI-Q, Neuropsychiatric Inventory Questionnaire; PACC, Pre-clinical Alzheimer's Cognitive Composite; RUD-Lite, Resource Utilization in Dementia Lite scale.