Clinical Pharmacokinetics of Oral ALZ-801/Valiltramiprosate in a 2-Year Phase 2 Trial of APOE4 Carriers with Early Alzheimer's Disease

Abstract

Introduction: ALZ-801/valiltramiprosate is an oral, small-molecule inhibitor of β-amyloid (Aβ) oligomer formation in late-stage development as a potential disease-modifying therapy for Alzheimer's disease (AD). ALZ-801, a valine-conjugated prodrug, is rapidly converted to tramiprosate after oral dosing. Upon conversion to tramiprosate, it generates a single metabolite, 3-sulfopropanoic acid (3-SPA). Both tramiprosate and 3-SPA are active anti-Aβ oligomer agents that mediate ALZ-801's central mechanism of action (MOA). We summarize herein the pharmacokinetics (PK) of ALZ-801 in apolipoprotein ε4 (APOE4) carrier subjects with early AD from a phase 2 trial.

Methods: The ALZ-801 phase 2 study was designed to evaluate longitudinal effects of ALZ-801 (265 mg BID) on plasma, cerebrospinal fluid (CSF) and volumetric magnetic resonance imaging (MRI) AD biomarkers, and clinical outcomes over 104 weeks in APOE4 carriers with early AD. Eighty-four subjects (31 APOE4/4 homozygotes and 53 APOE3/4 heterozygotes) with positive CSF biomarkers of amyloid and tau pathology were enrolled. The phase 2 study included a substudy of 24 subjects to provide 8-h steady-state PK at 65 weeks. Sparse PK samples were also analyzed. The relationships between plasma PK exposure and clinical characteristics [i.e., sex, APOE genotype, age, body mass index (BMI), estimated glomerular filtration rate (eGFR), concomitant acetylcholinesterase inhibitor (AChEI) use, and tablet lot] were evaluated.

Results: The steady-state plasma PK results were closely aligned with the previous 2-week PK in the ALZ-801 phase 1b study in APOE4 carrier subjects with AD, as well as a phase 1 7-day PK study in heathy elderly volunteers. Following oral dosing, ALZ-801 was rapidly converted to the active moieties, tramiprosate and 3-SPA. The intersubject variability in plasma drug levels was low, confirming the superior performance of ALZ-801 versus oral tramiprosate tablet (150 mg BID) from the earlier tramiprosate phase 3 trials. Correlation analysis versus clinical characteristics showed that plasma exposures (Cmax and AUC8h) for ALZ-801, tramiprosate, and 3-SPA were not affected by sex, APOE genotype, age, BMI, concomitant AChEI use, or tablet lot. Plasma exposures of both tramiprosate and 3-SPA, but not ALZ-801, were inversely correlated with eGFR, in line with renal excretion as the primary route of elimination. ALZ-801 was well tolerated without new safety signals or events of amyloid-related imaging abnormalities (ARIA).

Conclusions: The steady-state PK profile of oral ALZ-801 in subjects with early AD was not affected by sex, APOE genotype, age, BMI, concomitant use of AChEI, or tablet lot. The inverse relationship of plasma exposures of tramiprosate and 3-SPA, but not ALZ-801, versus eGFR is consistent with renal clearance as the primary route of elimination for tramiprosate and 3-SPA (active moieties), and with the efficient conversion of ALZ-801 prodrug to the active moieties after dosing. These results demonstrate that ALZ-801 displays favorable PK properties without evidence of interactions with demographic characteristics and support its development as an oral disease-modifying treatment for AD.

Trial registration: https://clinicaltrials.gov/study/NCT04693520 .

Fig. 1

ALZ-801 phase 2 biomarker study design, activities, and PK sampling visits. A-IADL Amsterdam Instrumental Activities of Daily Living, BID twice daily, CDR Clinical Dementia Rating, CSF cerebrospinal fluid, DSST Digit Symbol Substitution Test, ECG electrocardiogram, FU follow-up, INR international normalized ratio for assessment of prothrombin time, MMSE Mini-Mental State Exam, MRI magnetic resonance imaging, PET positron emission tomography, PK pharmacokinetics, QD once daily, RAVLT Rey Auditory Verbal Learning Test, Tel telephone, V visit, W week

Fig. 2

Mean temporal plasma concentrations of ALZ-801, tramiprosate, and 3-SPA at week 65 following ALZ-801 tablet 265 mg BID treatment in subjects with AD in the ALZ-801-201ADBM phase 2 study. Data are shown in reference to the ALZ-801-106ADPK phase 1b study. Values are expressed as mean ± SD with n = 24 and 7 for the ALZ-801-201ADBM study and the ALZ-801-106ADPK study, respectively. The ALZ-801-201ADBM 8h PK substudy used tablet lot 20242 and 21172. The ALZ-801-106ADPK study used tablet lot 18064. Note that the ALZ-801 phase 2 study did not include a 30-min sampling time point as did the ALZ-801-106ADPK study. ALZ-801-106ADPK study was sampled for 24 h post-dose, and only 12-h data are shown

Fig. 3

Individual plasma PK profiles for ALZ-801, tramiprosate, and 3-SPA at week 65 following ALZ-801 tablet 265 mg BID treatment in 24 subjects with AD in the ALZ-801-201ADBM phase 2 study. See keys in Fig. 2

Fig. 4

Comparison of the steady-state plasma PK profiles for ALZ-801, tramiprosate, and 3-SPA by sex at week 65 following ALZ-801 tablet 265 mg BID treatment in 24 subjects with AD in the ALZ-801-201ADBM phase 2 study. Values are expressed as mean ± SD with n = 16 for males and n = 8 for females

Fig. 5

Comparison of the steady-state plasma PK profiles for ALZ-801, tramiprosate, and 3-SPA by APOE genotype at week 65 following ALZ-801 tablet 265 mg BID treatment in 24 subjects with AD in the ALZ-801-201ADBM phase 2 study. Values are expressed as mean ± SD with n = 13 for APOE3/4 and n = 11 for APOE4/4

Fig. 6.

Relationship of the steady-state plasma Cmax (left) and AUC8h (right) for ALZ-801, tramiprosate, and 3-SPA versus age at week 65 following ALZ-801 tablet 265 mg BID treatment in 24 subjects with AD in the ALZ-801-201ADBM phase 2 study. Data were analyzed by Pearson correlation. R, correlation coefficient

Fig. 7.

Relationship of the steady-state plasma Cmax (left) and AUC8h (right) for ALZ-801, tramiprosate, and 3-SPA versus BMI at week 65 following ALZ-801 tablet 265 mg BID treatment in 24 subjects with AD in the ALZ-801-201ADBM phase 2 study. Data were analyzed by Pearson correlation. R, correlation coefficient

Fig. 8

Relationship of the steady-state plasma Cmax (left) and AUC8h (right) for ALZ-801, tramiprosate, and 3-SPA at week 65 versus week 52 eGFR following ALZ-801 tablet 265 mg BID treatment in 24 subjects with AD in the ALZ-801-201ADBM phase 2 study. Data were analyzed by Pearson correlation. Cmax: p = 0.44, 0.004, and 0.016 for ALZ-801, tramiprosate, and 3-SPA, respectively (two-tailed). AUC8h: p = 0.13, 0.0006, and 0.0014 for ALZ-801, tramiprosate, and 3-SPA, respectively (two-tailed). R, correlation coefficient

Fig. 9

Comparison of the steady-state plasma PK profiles for ALZ-801, tramiprosate, and 3-SPA at week 65 by the status of concomitant AChEI use following ALZ-801 tablet 265 mg BID treatment in 24 subjects with AD in the ALZ-801-201ADBM phase 2 study. Data were expressed as mean ± SD with n = 17 for without AChEI use and n = 7 for with AChEI use

Fig. 10

Steady-state plasma concentrations of ALZ-801, tramiprosate, and 3-SPA sampled at week 78 (left, n = 74) and 104 (right, n = 70) following ALZ-801 tablet 265 mg BID treatment in subjects with AD in the ALZ-801-201ADBM phase 2 study. Lower band: lowest concentrations of the ALZ-801-106ADPK phase 1b study (n = 7). Higher band: highest concentrations of the ALZ-801-106ADPK study (n = 7)