Therapeutics

AZP2006

Overview

Name: AZP2006
Synonyms: AZP-2006
Chemical Name: N-[3-[4-[3-[bis(2-methylpropyl)amino]propyl]piperazin-1-yl]propyl]-1H-benzimidazol-2-amine
Therapy Type: Small Molecule (timeline)
Target Type: Tau (timeline), Inflammation (timeline), Other (timeline)
Condition(s): Progressive Supranuclear Palsy, Alzheimer's Disease
U.S. FDA Status: Progressive Supranuclear Palsy (Phase 2), Alzheimer's Disease (Phase 1)
Company: AlzProtect

Background

This small molecule is said to increase levels of the neurotrophic factor progranulin. According to information from its maker, AZP2006 binds to prosaposin, a cofactor for progranulin processing. Prosaposin and progranulin are lysosomal proteins that are genetically implicated in Parkinson’s risk (e.g., Valdez et al., 2010Oji et al., 2020). Prosaposin regulates progranulin, and increased levels of both have been associated with AD neuropathology (Nicholson et al., 2016Mendsaikhan et al., 2019). 

AZP2006 stabilizes the prosaposin-progranulin complex. The drug-development rationale is that this stabilization prevents progranulin cleavage and increases progranulin secretion. Previously, an effect blocking tau phosphorylation had been claimed (Medina, 2018Jadhav et al., 2019).

The drug is being developed for the treatment of Alzheimer’s disease and progressive supranuclear palsy, a rapidly progressing tauopathy that strikes in mid-life. 

No preclinical data has been published for AZP2006. At the 2020 AAT-AD/PD Focus meeting, the company presented results from cell and animal models. In primary rat neuron/microglia co-cultures exposed to Aβ42, the compound reportedly promoted neuron survival and prevented neurite loss. It increased progranulin secretion, inhibited microglial activation and proinflammatory cytokine production, and decreased tau phosphorylation. In a naturally occurring mouse model of accelerated aging, called SamP8, AZP2006 reportedly prevented or reversed cognitive deficits, while decreasing phosphorylated tau, Aβ, oxidative stress, and neuroinflammation. In tau-overexpressing mice, AZP2006 was reported to decrease tau phosphorylation.

Findings

At AAT-AD/PD, the company presented on three Phase 1 studies conducted between 2015 and 2017 in France. The trials tested eight single doses from 3 to 500 mg, or multiple doses of 30, 60, or 120 mg daily for 10 days, in 88 healthy men. The trials revealed no safety issues. 

In July 2019, the company registered a Phase 2 trial in patients with progressive supranuclear palsy (PSP). This biomarker-driven study will enroll 36 men and women age 40 to 80 with probable or possible PSP according to clinical criteria, at two hospitals in Paris and Lille. Participants will be randomized to three equal groups and receive 60 mg AZP2006 for 12 weeks; 80 mg for 10 days followed by 50 mg for 12 weeks; or placebo, taken as an oral solution once daily. The primary outcomes are safety and tolerability. Secondary and exploratory outcomes include CSF tau, phosphorylated tau, Aβ, progranulin, as well as biomarkers of oxidative stress, inflammation, and neurodegeneration. Recruitment is scheduled to begin in June 2020, and the trial will run through October 2021.

AZP2006 received orphan drug designation for PSP in Europe in 2015 and in the United States in 2017. 

For details on AZP2006 trials, see clinicaltrials.gov.

Last Updated: 11 May 2020

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Research Models Citations

  1. Senescence Accelerated Mouse (SAMP8)

Paper Citations

  1. . Progranulin mutations result in impaired processing of prosaposin and reduced glucocerebrosidase activity. Hum Mol Genet. 2020 Mar 27;29(5):716-726. PubMed.
  2. . Variants in saposin D domain of prosaposin gene linked to Parkinson's disease. Brain. 2020 Apr 1;143(4):1190-1205. PubMed.
  3. . Prosaposin is a regulator of progranulin levels and oligomerization. Nat Commun. 2016 Jun 30;7:11992. PubMed.
  4. . Characterization of lysosomal proteins Progranulin and Prosaposin and their interactions in Alzheimer's disease and aged brains: increased levels correlate with neuropathology. Acta Neuropathol Commun. 2019 Dec 21;7(1):215. PubMed.
  5. . An Overview on the Clinical Development of Tau-Based Therapeutics. Int J Mol Sci. 2018 Apr 11;19(4) PubMed.
  6. . A walk through tau therapeutic strategies. Acta Neuropathol Commun. 2019 Feb 15;7(1):22. PubMed.

External Citations

  1. in Europe
  2. United States
  3. clinicaltrials.gov

Further Reading