Therapeutics

ALZ-801

Overview

Name: ALZ-801
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 3)
Company: Alzheon Inc.

Background

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 was reported to inhibit 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 a potential positive effect in participants who carried two copies of ApoE4 (Abushakra et al., 2016; Abushakra et al., 2017). Alzheon licensed ALZ-801 from NeuroChem and is developing it for Alzheimer’s disease.

Findings

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. 

In December 2019, Alzheon announced that its analysis of ADNI and tramiprosate trial data showed differences in cortical thickness between ApoE3/3 and ApoE4/4 carriers with mild AD, and that cortical thickness would be a secondary outcome in a planned Phase 3 trial (company press release; also see Abushakra et al., 2020). In August 2020, Alzheon announced that the U.S. National Institute on Aging will fund this trial (press release).

In September 2020, the company began a Phase 2, open-label biomarker study enrolling 80 people with early stage AD dementia and one or two copies of ApoE4. Participants receive 265 mg of drug twice daily for two years, with primary outcomes being change from baseline in CSF p-Tau181 and adverse events. Secondary measures include CSF and plasma biomarkers neurodegeneration, amyloid load, and microglial activation, plus hippocampal volume and cortical thickness MRI. The study also assesses cognition and activities of daily living. Taking place in Czechia and the Netherlands, it is expected to finish in June 2023.

The Phase 3 trial, dubbed APOLLOE4, began in May 2021 (press release). It plans to enroll 300 ApoE4 homozygotes with early to mild AD, who will receive 265 mg of ALZ-801 or placebo 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 includes biomarker endpoints such as hippocampal volume MRI, as well as CSF and plasma measures of neurofilament light and p-Tau. The company will also monitor the concentration in the CSF of Aβ oligomers, which it argues are a major target of ALZ-801 (Tolar et al., 2019, Tolar et al., 2021). Running at approximately 85 sites in the U.S., Canada, and Europe, this trial is slated to be complete by May 2024.

For all ALZ-801 trials, see clinicaltrials.gov.

Last Updated: 20 Jul 2021

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References

Therapeutics Citations

  1. Alzhemed™

Paper Citations

  1. . Clinical Pharmacokinetics and Safety of ALZ-801, a Novel Prodrug of Tramiprosate in Development for the Treatment of Alzheimer's Disease. Clin Pharmacokinet. 2018 Mar;57(3):315-333. PubMed.
  2. . APOE ε4/ε4 homozygotes with early Alzheimer's disease show accelerated hippocampal atrophy and cortical thinning that correlates with cognitive decline. Alzheimers Dement (N Y). 2020;6(1):e12117. Epub 2020 Dec 4 PubMed.
  3. . The path forward in Alzheimer's disease therapeutics: Reevaluating the amyloid cascade hypothesis. Alzheimers Dement. 2020 Jan 3; PubMed.
  4. . Neurotoxic Soluble Amyloid Oligomers Drive Alzheimer's Pathogenesis and Represent a Clinically Validated Target for Slowing Disease Progression. Int J Mol Sci. 2021 Jun 14;22(12) PubMed.
  5. . Targeting soluble Abeta peptide with Tramiprosate for the treatment of brain amyloidosis. Neurobiol Aging. 2007 Apr;28(4):537-47. PubMed.
  6. . Elucidating the Aβ42 Anti-Aggregation Mechanism of Action of Tramiprosate in Alzheimer's Disease: Integrating Molecular Analytical Methods, Pharmacokinetic and Clinical Data. CNS Drugs. 2017 Jun;31(6):495-509. PubMed.
  7. . Discovery and Identification of an Endogenous Metabolite of Tramiprosate and Its Prodrug ALZ-801 that Inhibits Beta Amyloid Oligomer Formation in the Human Brain. CNS Drugs. 2018 Sep;32(9):849-861. PubMed.
  8. . Clinical Benefits of Tramiprosate in Alzheimer's Disease Are Associated with Higher Number of APOE4 Alleles: The "APOE4 Gene-Dose Effect". J Prev Alzheimers Dis. 2016;3(4):219-228. PubMed.
  9. . Clinical Effects of Tramiprosate in APOE4/4 Homozygous Patients with Mild Alzheimer's Disease Suggest Disease Modification Potential. J Prev Alzheimers Dis. 2017;4(3):149-156. PubMed.

External Citations

  1. company press release
  2. press release
  3. press release
  4. clinicaltrials.gov

Further Reading

Papers

  1. . Aducanumab, gantenerumab, BAN2401, and ALZ-801-the first wave of amyloid-targeting drugs for Alzheimer's disease with potential for near term approval. Alzheimers Res Ther. 2020 Aug 12;12(1):95. PubMed.
  2. . The path forward in Alzheimer's disease therapeutics: Reevaluating the amyloid cascade hypothesis. Alzheimers Dement. 2020 Jan 3; PubMed.