Donanemab is an immunoglobulin gamma 1 (IgG1) monoclonal antibody with high affinity for a modified, N-terminal truncated form of amyloid beta (N3pE Aβ). N3pE Aβ is present in brain amyloid plaques at low levels, and not detected in plasma and CSF. Donanemab binds to N3pE Aβ and aids plaque removal through microglial-mediated phagocytosis.
The percentage of donanemab treated patients who achieved amyloid clearance (that is, less than 24.1 Centiloids) in Study TRAILBLAZER-ALZ 2 was 32.5% at week 24, 69.5% at week 52 and 80.8% at week 76 in the indicated population.
In study TRAILBLAZER-ALZ 2, the difference between donanemab and placebo in the change from baseline amyloid level at week 76 was statistically significant in the indicated population (-89.24 Centiloids).
In Study TRAILBLAZER-ALZ 6, similar amyloid plaque reduction was observed at week 24 for the dosing regimen of 350/700/1 050 mg, then 1 400 mg every 4 weeks thereafter, when compared with the dosing regimen of 700 mg for the first three infusions, then 1 400 mg every 4 weeks thereafter, studied in the pivotal study.
Donanemab exposure decreased with increasing ADA titre. Amyloid beta reduction was found irrespective of ADA titre. No association was observed between the presence of ADA and outcomes on the iADRS and CDR-SB.
Donanemab is for intravenous administration only.
Following intravenous dosing, donanemab undergoes biphasic elimination. The central volume of distribution is 3.36 L with 18.7% inter-individual variability. Peripheral volume of distribution is 4.83 L, with 93.9% inter-individual variability. In a clinical pharmacology study, the ratio of cerebrospinal fluid to serum concentration was observed at approximately 0.2%.
Donanemab is a monoclonal antibody and is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as an endogenous IgG, hence there is no metabolic inhibition or induction of enzymatic pathways. Donanemab is not expected to be metabolized by the cytochrome P450 families of drug-metabolizing enzymes responsible for metabolism and elimination of small molecules and would, therefore, not produce any active metabolites.
The half-life of donanemab is approximately 12.1 days. Donanemab clearance was 0.0255 L/h (24.9% inter-individual variability).
Donanemab showed dose proportional increase and time linearity in serum exposure in dose range 350 mg to 1 400 mg.
The PK of donanemab was not affected by age (54-88), sex (55.0% female), or race (89.9% White, 6.3% Asian, 2.9% Black and 0.3% American Indian or Other), based on a population PK analysis. While body weight (range 39 to 157 kg, mean of 74 kg) was found to influence both clearance and volume of distribution, the resulting changes do not suggest a need for dose adjustment.
Donanemab clearance increased linearly with log (ADA titre). This increase in clearance with titre resulted in a 17% decrease in AUCτ,ss, and a 31% decrease in drug concentration before the next dose (Ctrough,ss). Although donanemab exposure decreased with increasing ADA titer, the development of ADA was not associated with loss of clinical efficacy of donanemab.
Renal and hepatic impairment did not affect the PK of donanemab based on population PK analysis. No dose adjustment is necessary in patients with renal or hepatic impairments.
Model based exposure-response analyses demonstrated that donanemab treatment was 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.
In addition, model based association between donanemab treatment and ARIA-E was demonstrated and identified risk factors such as ApoE ε4 genotype, number of baseline microhaemorrhages and presence of superficial siderosis at baseline.
During an off-treatment period, amyloid PET values began to increase with a median rate of 2.80 Centiloids/year.
In single doses from 350 to 2 800 mg (approximately 2 times the dosage of 1 400 mg for 70 kg of body weight studied in the pivotal study), and multiple 350 to 1 400 mg doses, exposures (Cmax and AUC) increased proportionally. Similar exposure was observed for the donanemab dosing regimen of 350/700/1 050 mg, then 1 400 mg every 4 weeks thereafter, compared with the dosing regimen of 700 mg for the first three infusions, then 1 400 mg every 4 weeks thereafter, that established clinical efficacy in the pivotal study.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and repeated dose toxicity. No animal studies have been performed to test donanemab for potential of carcinogenicity, genotoxicity, reproductive toxicity or fertility impairment.
A weight-of-evidence assessment of all data, including evaluation of the target biology (residing in deposited Aβ plaques only), the nature of the product (high specificity of the monoclonal antibody molecule for the target and composition of naturally occurring amino acids and monosaccharides), the mechanism of action (phagocytic removal of amyloid plaque in the CNS) and the lack of effects in the toxicology studies, suggest a low potential for risk of reproductive toxicity or carcinogenicity.
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