Donanemab is a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against insoluble N-truncated pyroglutamate amyloid beta. The accumulation of amyloid beta plaques in the brain is a defining pathophysiological feature of Alzheimer’s disease. Donanemab-azbt reduces amyloid beta plaques, as evaluated in Study 1.
The effect of donanemab on amyloid beta plaque levels in the brain was evaluated using amyloid Positron Emission Tomography (PET) imaging (18F-florbetapir tracer). The PET signal was quantified using the Standard Uptake Value Ratio (SUVR) method to estimate brain levels of amyloid beta plaque in composites of brain areas expected to be widely affected by Alzheimer’s disease pathology (precuneus, frontal, anterior cingulate, posterior cingulate, parietal, and temporal cortices), compared to a brain region expected to be spared of such pathology (cerebellum). Results of amyloid PET were also expressed on the Centiloid scale.
In Study 1, donanemab reduced amyloid beta plaque levels in the brain in a time-dependent manner, starting at Week 24, and continuing through Week 76 (p<0.0001), compared to placebo. In clinical pharmacology studies, donanemab demonstrated a dose- and time-dependent reduction in amyloid beta plaque, with the decrease observed starting at Week 12.
During an off-treatment period, amyloid PET values began to increase with a median rate of 2.80 Centiloids/year.
A reduction in plasma p-tau217 was observed with donanemab compared to placebo in Study 1.
Biomarker results of donanemab in Study 1 (AACI):
| Biomarker Endpoint at Week 76 | Donanemab | Placebo |
|---|---|---|
| Amyloid Beta PET SUVR | N=712 | N=754 |
| Mean baseline | 1.53 | 1.52 |
| Adjusted mean change from baseline | -0.47 | -0.00 |
| Difference from placebo | -0.47, p<0.0001 | |
| Amyloid Beta PET Centiloid | N=765 | N=812 |
| Mean baseline | 104.0 | 101.8 |
| Adjusted mean change from baseline | -87.0 | -0.7 |
| Difference from placebo | -86.4, p<0.0001 | |
| Plasma p-tau217 (log10 transformed)a | N=758 | N=786 |
| Mean baseline | 0.67 | 0.66 |
| Adjusted mean change from baseline | -0.19 | 0.03 |
| Difference from placebo | -0.22, p<0.0001 |
N is the number of patients with baseline value.
a Results should be interpreted with caution due to the uncertainties in bioanalysis.
Model based exposure-response analyses for Study 1 demonstrated that exposures to donanemab were associated with a reduction in clinical decline on iADRS and CDR-SB. An association between reduction in amyloid beta plaque from baseline and clinical decline on iADRS and CDR-SB was also observed.
The pharmacokinetics (PK) of donanemab were characterized using a population PK analysis with concentration data collected from 2131 patients with Alzheimer’s disease who received donanemab in single or multiple doses. Accumulation of <1.3-fold occurs with every-4-week dosing; steady-state exposures are achieved after a single dose. In single doses from 10 to 40 mg/kg (~2 times the approved recommended dosage of 1400 mg for 70 kg of body weight), and multiple 10 and 20 mg/kg doses, exposures (Cmax and AUC) increased proportionally.
The central volume of distribution is 3.36 L.
Donanemab is expected to be degraded by proteolytic enzymes in the same manner as endogenous IgG. The mean terminal half-life of donanemab-azbt is approximately 12.1 days. Donanemab-azbt clearance is 0.0255 L/h.
Age, sex, or race were not found to affect the pharmacokinetics of donanemab-azbt. While body weight was found to influence both clearance and volume of distribution, the resulting changes were not clinically significant.
No clinical studies were conducted to evaluate the pharmacokinetics of donanemab-azbt in patients with renal or hepatic impairment. Donanemab-azbt is degraded by proteolytic enzymes and is not expected to undergo renal elimination or metabolism by hepatic enzymes.
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