Characterization of exposure–Clinical Dementia Rating–Sum of Boxes relationship in subjects with early Alzheimer’s disease from the aducanumab Phase 3 trials

• Published in: Journal of pharmacokinetics and pharmacodynamics Vol. 50; no. 1; pp. 45 - 62
• Main Authors: Muralidharan, Kumar Kandadi, Kowalski, Kenneth G., Tong, Xiao, Haeberlein, Samantha Budd, Rajagovindan, Rajasimhan, Nestorov, Ivan
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.02.2023; Springer Nature B.V
• Subjects: Alzheimer Disease - drug therapy; Alzheimer's disease; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Clinical trials; Dementia; Dementia disorders; Disease Progression; Humans; Mental Status and Dementia Tests; Monoclonal antibodies; Neurodegenerative diseases; Original Paper; Pharmacology/Toxicology; Pharmacy; Veterinary Medicine/Veterinary Science; Mixture model; Aducanumab; Alzheimer’s disease; Disease progression; Exposure–response
• ISSN: 1567-567X; 1573-8744; 1573-8744
• DOI: 10.1007/s10928-022-09839-3

Clinical Dementia Rating–Sum of Boxes (CDR–SB) assessments from two Phase 3 studies (ENGAGE and EMERGE) of aducanumab in subjects with early Alzheimer’s disease (AD) were pooled to develop an exposure–response (ER) model. A linear model in the logit-transformed scaled CDR–SB best characterized the time profile for placebo- and aducanumab-treated subjects, with concentration as the exposure metric. The model allowed delineation of slow (4%), typical (86%), and fast (10%) progressing subpopulations in the data. The estimated drug effect on the disease progression rate was significant, 2.05 L/(g·year), with a 95% confidence interval (1.60, 2.50) that did not include zero. Following an evaluation of a series of ER model forms including differential drug and null effects either between the studies or among the three progression classes, the final ER model with a common (pooled) estimate of the drug effect between the studies and among the three progression classes was considered parsimonious. The final model provides supportive evidence that the two studies demonstrate a common intrinsic pharmacology. None of the identified covariates (Mini-Mental State Examination–BL score and Asian race) were clinically meaningful. Finally, simulations demonstrated that the intrinsic pharmacology remained consistent between the two Phase 3 studies.