Stable Isotope Labelling Kinetics: Models and methods to evaluate APP production rates with Posiphen treatment in the DISCOVER clinical trial

• Published in: Alzheimer's & dementia Vol. 19; no. S21
• Main Authors: Elbert, Donald L, Galasko, Douglas R., Farlow, Martin R., Aslanyan, Vahan, Pa, Judy, Lucey, Brendan, Honig, Lawrence S., Moghekar, Abhay, Bateman, Randall J., Momper, Jeremiah, Rissman, Robert A, Balasubramanian, Archana, Maccecchini, Maria L., Feldman, Howard H.
• Format: Journal Article
• Language: English
• Published: 01.12.2023
• ISSN: 1552-5260; 1552-5279
• DOI: 10.1002/alz.077287

Background Posiphen has been reported to decrease translation of beta amyloid precursor protein (APP) mRNA, resulting in decreased production of Aβ.1 The pharmacodynamics of Posiphen require further clarification to better assess its therapeutic potential. Method The DISCOVER phase 1b placebo controlled RCT enrolled patients with MCI or mild AD dementia (age 55‐89, MMSE 17‐30, CDR = 0.5‐1.0, CSF Aβ42/40 < 0.131 by mass spectrometry) at five centers.2,3 Patients were randomized to sequential dose cohorts of oral Posiphen (60 mg; once (QD), twice (BID) or three times (TID) per day for 21 days) or placebo. SILK studies were performed during a confinement on day 22. Lumbar and venous catheters were placed and 13C6‐leucine infused for 9 hours with dosing of placebo or Posiphen according to assigned study arm. CSF and venous blood were collected every two hours over 36 hours. Pharmacodynamics of APP were evaluated via a recently described mathematical model of APP and Aβ kinetics.4 Result APP production rate was calculated for a total of 14 subjects (less than study design due to COVID) by the model in Figure 1. Nonparametric analysis of group differences was not significant (p = 0.08) with n = 1‐5 per group (Figure 2A). A trend towards lower CSF Aβ40 concentrations (indicative of lower intrinsic APP production rates) prior to drug exposure was noted in the higher dose groups (Figure 2B). The calculated APP production rate was thus controlled for pre‐drug CSF Aβ40 concentrations, which showed a downward trend with increasing dose (95%CI:(‐2209.58, 147.79, p = 0.08; Figure 3) but was not significant. Conclusion This study provides preliminary evidence that the rate of production of APP may be measured by the SILK method in Aβ lowering drug trials. Variability in APP productions rates in the population suggest that CSF Aβ concentration should be considered as part of study randomization.