Clinical Pharmacokinetics and Safety of ALZ-801, a Novel Prodrug of Tramiprosate in Development for the Treatment of Alzheimer's Disease

Abstract

Background: ALZ-801 is an orally available, valine-conjugated prodrug of tramiprosate. Tramiprosate, the active agent, is a small-molecule β-amyloid (Aβ) anti-oligomer and aggregation inhibitor that was evaluated extensively in preclinical and clinical investigations for the treatment of Alzheimer's disease (AD). Tramiprosate has been found to inhibit β-amyloid oligomer formation by a multi-ligand enveloping mechanism of action that stabilizes Aβ42 monomers, resulting in the inhibition of formation of oligomers and subsequent aggregation. Although promising as an AD treatment, tramiprosate exhibited two limiting deficiencies: high intersubject pharmacokinetic (PK) variability likely due to extensive gastrointestinal metabolism, and mild-to-moderate incidence of nausea and vomiting. To address these, we developed an optimized prodrug, ALZ-801, which retains the favorable efficacy attributes of tramiprosate while improving oral PK variability and gastrointestinal tolerability. In this study, we summarize the phase I bridging program to evaluate the safety, tolerability and PK for ALZ-801 after single and multiple rising dose administration in healthy volunteers.

Methods: Randomized, placebo-controlled, phase I studies in 127 healthy male and female adult and elderly volunteers included [1] a single ascending dose (SAD) study; [2] a 14-day multiple ascending dose (MAD) study; and [3] a single-dose tablet food-effect study. This program was conducted with both a loose-filled capsule and an immediate-release tablet formulation, under both fasted and fed conditions. Safety and tolerability were assessed, and plasma and urine were collected for liquid chromatography-mass spectrometry (LC-MS) determination and non-compartmental PK analysis. In addition, we defined the target dose of ALZ-801 that delivers a steady-state plasma area under the curve (AUC) exposure of tramiprosate equivalent to that studied in the tramiprosate phase III study.

Results: ALZ-801 was well tolerated and there were no severe or serious adverse events (AEs) or laboratory findings. The most common AEs were transient mild nausea and some instances of vomiting, which were not dose-related and showed development of tolerance after continued use. ALZ-801 produced dose-dependent maximum plasma concentration (C max) and AUC exposures of tramiprosate, which were equivalent to that after oral tramiprosate, but with a substantially reduced intersubject variability and a longer elimination half-life. Administration of ALZ-801 with food markedly reduced the incidence of gastrointestinal symptoms compared with the fasted state, without affecting plasma tramiprosate exposure. An immediate-release tablet formulation of ALZ-801 displayed plasma exposure and low variability similar to the loose-filled capsule. ALZ-801 also showed excellent dose-proportionality without accumulation or decrease in plasma exposure of tramiprosate over 14 days. Based on these data, 265 mg of ALZ-801 twice daily was found to achieve a steady-state AUC exposure of tramiprosate equivalent to 150 mg twice daily of oral tramiprosate in the previous phase III trials.

Conclusions: ALZ-801, when administered in capsule and tablet forms, showed excellent oral safety and tolerability in healthy adults and elderly volunteers, with significantly improved PK characteristics over oral tramiprosate. A clinical dose of ALZ-801 (265 mg twice daily) was established that achieves the AUC exposure of 150 mg of tramiprosate twice daily, which showed positive cognitive and functional improvements in apolipoprotein E4/4 homozygous AD patients. These bridging data support the phase III development of ALZ-801in patients with AD.

Conflict of interest statement

Funding

The studies summarized in this report were supported by Alzheon, Inc.

Conflict of interest

John A. Hey, Susan Abushakra, Petr Kocis, Aidan Power, Paul L. Kaplan, and Martin Tolar are employees of Alzheon, Inc. Jeremy Y. Yu, Mark Versavel, and John Amedio have served as consultants or advisors to Alzheon, Inc., and may own Alzheon stock options.

Figures

Fig. 1

Chemical structure of ALZ-801

Fig. 2

Schematic illustration of the oral absorption, conversion to tramiprosate, distribution and elimination characteristics of ALZ-801 prodrug. GI gastrointestinal

Fig. 3

a Plasma concentrations of ALZ-801 (prodrug) and tramiprosate (active drug) over time after single ascending oral administration of ALZ-801 loose-filled capsules at 100, 172, and 300 mg/kg in healthy volunteers (mean + SD, n = 11–16; Study 1 in Table 1). b Tramiprosate exposure (Cmax and AUCt) versus dose relationship indicates dose linearity. Cmax maximum concentration, AUCt area under the concentration–time curve from time zero to time t, SD standard deviation

Fig. 4

Mean pharmacokinetic time course for ALZ-801 phase I multiple ascending dose studies in healthy human volunteers under fasted and fed conditions (Study 2 in Table 1)

Fig. 5

Plasma tramiprosate exposure versus dose relationships after an oral ALZ-801 tablet and capsule in healthy humans show strong dose-exposure proportionality under all conditions (Studies 2 and 3 in Table 1). AUC area under the concentration–time curve, AUC12 AUC from time zero to 12 h

Fig. 6

Mean pharmacokinetic curves for the ALZ-801 immediate-release tablet in phase I, single-dose studies in healthy human volunteers (Study 3 in Table 1)

Fig. 7

Individual ALZ-801 and tramiprosate plasma time course graphs illustrating low intersubject variability after oral administration of the ALZ-801 tablet to healthy human subjects (Study 3 in Table 1)

Fig. 8

Comparison of the pharmacokinetic curves and variability for plasma tramiprosate in fasted healthy volunteers following a single oral dose of 171 mg ALZ-801 tablet versus loose capsule, and versus a single equivalent oral dose of 100 mg tramiprosate modified-release tablet. MR modified-release

Fig. 9

Comparison of pharmacokinetic variability of plasma tramiprosate following ALZ-801 tablet in the present phase I study versus tramiprosate tablet in an earlier phase II trial. bid twice daily

Fig. 10

Urinary clearance of ALZ-801, tramiprosate, and NRM5074 following oral administration of ALZ-801 immediate-release tablet (Cohort D of Study 2: day 1, 265 mg once daily; days 2–6, 265 mg twice daily; and day 7, 265 mg once daily) in healthy human subjects. Data are summarized in Table 8. CLr renal clearance