Aducanumab-avwa is the generic name of Aduhelm. It has been recently given accelerated FDA approval based on its effect on reducing beta-amyloid plaques in patients with Alzheimer’s disease.
Aducanumab MOA – How does the drug act?
Alzheimer’s disease is characterized by the aggregation of beta-amyloid plaques in the brain. Aducanumab is a human monoclonal IgG1 antibody that is directed against the amyloid plaques in the brain in their soluble as well as insoluble forms.
In clinical studies, Aducanumab resulted in a reduction in the beta-amyloid plaques at week 78 as detected by MR imaging and PET scanning.
The drug is eliminated by degradation into peptides and amino acids. When administered intravenously at an interval of four weeks, the steady-state concentration is reached after 16 weeks. It has a half-life elimination of 24.8 days.
What are the important side effects of Aducanumab?
Aducanumab (Aduhelm) Injection caused very serious side effects that resulted in controversies regarding its approval (including controversies among the FDA members). The two major side effects related to the drug infusion are:
- ARIA-E (Amyloid-related imaging abnormalities-edema). ARIA-E was more common in apolipoprotein E ε4 carriers vs non-carriers (42% vs 20% respectively).
- ARIA-H (amyloid-related imaging abnormalities-hemosiderin deposition). ARIA-H is further divided into ARIA-H (superficial siderosis) and ARIA-H (microhemorrhages).
The incidence of these two adverse drug reactions was very common in patients who received the drug compared to those who received a placebo.
ARIA-E with or without hemorrhages was observed in 41% of the patients who got treated compared to only 10% of the patients in the placebo group. ARIA-E was observed in 35% of the patients compared to only 3% in the placebo group.
ARIA-H was not seen alone, however, in the setting of ARIA-E, ARIA-H was observed in 21% of the patients compared to only 1% in the placebo group.
Clinical symptoms related to the adverse effects of the drug were observed in 24% of the patients. These symptoms primarily included headaches, falls, diarrhea, and mental confusion, delirium, drowsiness, or disorientation.
What is the dosing regimen used to treat patients with Alzheimer’s disease?
Aducanumab is available as injection formulations containing 170 mg per 1.7 ml and 300 mg per 3 ml vials each (equivalent to 100 mg/ml).
The drug is administered intravenously over one hour every four weeks. The treatment is initiated in a low dose and titrated upwards to the usual maintenance dose. The dosing titration and dosing schedule are given in the following table:
| IV Infusion Schedule | ADUHELM Dosage |
| Infusion No. 1 and 2 | 1 mg/kg |
| Infusion No. 3 and 4 | 3 mg/kg |
| Infusion No. 5 and 6 | 6 mg/kg |
| Infusion No. 7 and beyond | 10 mg/kg |
How effective is the Aducanumab?
Two clinical trials evaluated the role of Aducanumab in patients with Alzheimer’s disease while one clinical trial evaluated the drug in different dosages.
In the first two clinical trials, Aducanumab was administered in the following doses every four weeks for 18 months:
- Group 1:
- 3 mg/kg in ApoE ε4 carriers
- 6 mg/kg in ApoE ε4 non-carriers
- Group 2:
- 10 mg/kg
- Group 3:
- Placebo
All patient who had Alzheimer’s disease with or without concomitant treatments like cholinesterase inhibitors or NMDA antagonist (memantine) and with the following scores were enrolled:
- Clinical Dementia Rating (CDR) global score of 0.5,
- a Repeatable Battery for Assessment of Neuropsychological Status (RBANS) delayed memory index score of 85 or less, and
- a Mini-Mental State Examination (MMSE) score of 24-30.
The results of the study-1 are tabulated here [Ref]:
| Biomarker endpoint at week 78 | Biomarker at baseline and after 78 weeks | Aduhelm high Dose | Placebo |
| Amyloid-Beta PET Composite SUVR | At Baseline | 1.383 | 1.375 |
| Change from baseline | -0.264 | 0.014 | |
| Amyloid-Beta PET Centiloid | At Baseline | 85.3 | 83.5 |
| Change from baseline | -60.8 | 3.4% | |
| CSF p-Tau (pg/mL) | At Baseline | 100.11 | 72.55 |
| Change from baseline | -22.93 | -0.49 | |
| CSF t-Tau (pg/mL) | At Baseline | 686.65 | 484.00 |
| Change from baseline | -112.44 | -0.39 |
The improvement in the biomarkers of study No.2 are tabulated here [Ref]:
| Biomarker endpoint at week 78 | Biomarker at baseline and after 78 weeks | Aduhelm high Dose | Placebo |
| Amyloid-Beta PET Composite SUVR | At Baseline | 1.407 | 1.376 |
| Change from baseline | -0.235 | 0.003 | |
| Amyloid-Beta PET Centiloid | At Baseline | 90.8 | 83.8 |
| Change from baseline | -54.0 | -0.5 | |
| CSF p-Tau (pg/mL) | At Baseline | 121.81 | 94.53 |
| Change from baseline | -13.19 | -2.24 | |
| CSF t-Tau (pg/mL) | At Baseline | 618.50 | 592.57 |
| Change from baseline | -102.51 | -33.26 |
In Summary:
Aducanumab (Aduhelm) is a novel drug with a different mechanism of action. The drug resulted in radiographic regression of the changes associated with Alzheimer’s disease. However, the rates of serious adverse events were high too affecting almost 50% of the study patients in the treatment arm.