PMID- 29063518 OWN - NLM STAT- MEDLINE DCOM- 20190610 LR - 20190619 IS - 1179-1926 (Electronic) IS - 0312-5963 (Print) IS - 0312-5963 (Linking) VI - 57 IP - 3 DP - 2018 Mar TI - Clinical Pharmacokinetics and Safety of ALZ-801, a Novel Prodrug of Tramiprosate in Development for the Treatment of Alzheimer's Disease. PG - 315-333 LID - 10.1007/s40262-017-0608-3 [doi] AB - BACKGROUND: ALZ-801 is an orally available, valine-conjugated prodrug of tramiprosate. Tramiprosate, the active agent, is a small-molecule beta-amyloid (Abeta) 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 beta-amyloid oligomer formation by a multi-ligand enveloping mechanism of action that stabilizes Abeta42 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. FAU - Hey, John A AU - Hey JA AD - Alzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA, 01701, USA. john.hey@alzheon.com. FAU - Yu, Jeremy Y AU - Yu JY AD - Alzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA, 01701, USA. FAU - Versavel, Mark AU - Versavel M AD - Alzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA, 01701, USA. FAU - Abushakra, Susan AU - Abushakra S AD - Alzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA, 01701, USA. FAU - Kocis, Petr AU - Kocis P AD - Alzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA, 01701, USA. FAU - Power, Aidan AU - Power A AD - Alzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA, 01701, USA. FAU - Kaplan, Paul L AU - Kaplan PL AD - Alzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA, 01701, USA. FAU - Amedio, John AU - Amedio J AD - Alzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA, 01701, USA. FAU - Tolar, Martin AU - Tolar M AD - Alzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA, 01701, USA. LA - eng PT - Clinical Trial, Phase I PT - Comparative Study PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PL - Switzerland TA - Clin Pharmacokinet JT - Clinical pharmacokinetics JID - 7606849 RN - 0 (Capsules) RN - 0 (Prodrugs) RN - 0 (Tablets) RN - 1EQV5MLY3D (Taurine) RN - 5K8EAX0G53 (tramiprosate) RN - GHG2B47067 (ALZ-801) RN - HG18B9YRS7 (Valine) SB - IM MH - Administration, Oral MH - Adult MH - Aged MH - Alzheimer Disease/drug therapy MH - Area Under Curve MH - Capsules MH - Dose-Response Relationship, Drug MH - Double-Blind Method MH - Female MH - Half-Life MH - Humans MH - Male MH - Middle Aged MH - Prodrugs/administration & dosage/*adverse effects/*pharmacokinetics MH - Tablets MH - Taurine/administration & dosage/adverse effects/*analogs & derivatives/pharmacokinetics MH - Valine/administration & dosage/adverse effects/*analogs & derivatives/pharmacokinetics MH - Young Adult PMC - PMC5814546 COIS- 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. EDAT- 2017/10/25 06:00 MHDA- 2019/06/14 06:00 PMCR- 2017/10/23 CRDT- 2017/10/25 06:00 PHST- 2017/10/25 06:00 [pubmed] PHST- 2019/06/14 06:00 [medline] PHST- 2017/10/25 06:00 [entrez] PHST- 2017/10/23 00:00 [pmc-release] AID - 10.1007/s40262-017-0608-3 [pii] AID - 608 [pii] AID - 10.1007/s40262-017-0608-3 [doi] PST - ppublish SO - Clin Pharmacokinet. 2018 Mar;57(3):315-333. doi: 10.1007/s40262-017-0608-3.