Synonyms: NRM-8499, homotaurine, 3-APS
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: Alzheon Inc.
This is a prodrug of homotaurine, a modified amino acid previously developed under the names tramiprosate and Alzhemed™. ALZ-801 is converted to homotaurine in vivo, but is more easily absorbed and lasts longer in the blood than tramiprosate.
Tramiprosate inhibits Aβ42 aggregation into toxic oligomers (Gervais et al., 2007; Kocis et al., 2017). Both ALZ-801 and tramiprosate are metabolized to 3-sulfopranpanoic acid (3-SPA), which is normally found in brain and also inhibits Aβ42 aggregation (Hey et al., 2018).
After tramiprosate failed in Phase 3, its maker, NeuroChem, marketed it as a nutritional supplement. Years later, a subgroup analysis of the trial data indicated positive effects in participants who carried two copies of ApoE4 (Absuhakra et al., 2016; Abushakra et al., 2017). Alzheon licensed ALZ-801 from NeuroChem and is developing it for Alzheimer’s disease.
Alzheon published results of a Phase 1 study of safety, tolerability, and pharmacokinetics of single and multiple doses of ALZ-801 in 127 healthy, old volunteers (Hey et al., 2018). The prodrug caused mild nausea and vomiting, which were not dose-related and went away after a week on drug or when taking the drug with food. Other common side effects were headaches, dizziness, and falls, also not dose-related. The drug had a longer half-life and less variability in blood levels between people than tramiprosate, and could be taken with food without affecting plasma concentrations. A dose of 265 mg of ALZ-801 twice daily achieved the same blood exposure as the 150 mg dose twice daily used in the Phase 3 tramiprosate trials, and brain levels five to 15 times higher than required to inhibit Aβ42 aggregation in vitro.
In October 2017, the U.S. Food and Drug Administration granted ALZ-801 Fast Track designation for the treatment of Alzheimer’s disease. According to Alzheon’s website, the company plans to run a Phase 3 trial in people homozygous for ApoE4 with early to mild AD, who will receive 265 mg of ALZ-801 twice a day for 18 months. The primary endpoint will be change in ADAS-COG; secondary endpoints include disability assessment for dementia (DAD), CDR-SB, and MMSE. The trial will also include biomarker endpoints such as hippocampal volume and cortical thickness MRI, as well as CSF and plasma measures of neurofilament light and p-Tau. The company will also reportedly monitor CSF Aβ oligomer concentration (Tolar et al., 2019).
On December 2, 2019, Alzheon issued a press release stating that their analysis of ADNI and tramiprosate trial data showed cortical thickness differences between ApoE3/3 and ApoE4/4 carriers with mild AD, and announcing that cortical thickness would be a secondary outcome in the planned trial (company press release).
For all ALZ-801 trials, see clinicaltrials.gov.
Last Updated: 04 Dec 2019
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