Therapeutics

Ezeprogind

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Overview

Name: Ezeprogind
Synonyms: AZP2006 , 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
U.S. FDA Status: Progressive Supranuclear Palsy (Phase 2)
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., 2020; Oji et al., 2020). Prosaposin regulates progranulin, and increased levels of both have been associated with AD neuropathology (Nicholson et al., 2016; Mendsaikhan 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, 2018; Jadhav et al., 2019).

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

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. A subsequent peer-reviewed publication included these results, and also reported reductions in phosphotau181 and markers of inflammation, along with improved learning and memory behaviors, in mice injected with Aβ (Callizot et al., 2021).

At the 2023 AD/PD conference, the company presented preclinical data in a Parkinson’s disease cell model. AZP2006 was claimed to normalize lysosome function and protect against α-synuclein toxicity in neurons bearing a Parkinson’s-associated mutation in the glucocerebrosidase gene GBA.

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.

In June 2020, the company began a Phase 2 trial in patients with progressive supranuclear palsy. This biomarker-driven study enrolled 36 men and women age 40 to 80 with probable or possible PSP according to clinical criteria, at three hospitals in Paris and Lille. Participants were randomized to three equal groups and received 60 mg AZP2006 daily for 12 weeks; 80 mg for 10 days followed by 50 mg for 12 weeks; or placebo, taken as an oral solution once daily. Primary outcomes were safety and tolerability. Secondary and exploratory outcomes included CSF tau, phosphorylated tau, Aβ, progranulin, as well as markers of oxidative stress, inflammation, and neurodegeneration. The company presented results at the 2023 AD/PD conference. AZP2006 was well tolerated at the 60 mg dose, with no serious drug-related adverse events. Blood levels reached steady state four to six weeks after the start of dosing. Half-life was 30 days, and CSF concentrations reached about 3 percent of plasma levels. The treatment group had elevated plasma progranulin relative to baseline, and less decline in CSF progranulin than the placebo group. AZP2006 reduced total tau and phosphotau181 compared to baseline; no changes in other markers of neurodegeneration or inflammation were seen. The company reported numerical improvements in exploratory clinical endpoints of the PSP-Rating Scale score and gait score. The trial is continuing through July 2024 with an open-label extension treating 20 patients with 60 mg daily. The company is planning a 12-month, Phase 2/3 study in Europe and the U.S., to begin in 2024.

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: 22 Nov 2023

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References

Research Models Citations

  1. Senescence Accelerated Mouse (SAMP8)

Paper Citations

  1. Valdez C, Ysselstein D, Young TJ, Zheng J, Krainc D. Progranulin mutations result in impaired processing of prosaposin and reduced glucocerebrosidase activity. Hum Mol Genet. 2020 Mar 27;29(5):716-726. PubMed.
  2. Oji Y, Hatano T, Ueno SI, Funayama M, Ishikawa KI, Okuzumi A, Noda S, Sato S, Satake W, Toda T, Li Y, Hino-Takai T, Kakuta S, Tsunemi T, Yoshino H, Nishioka K, Hattori T, Mizutani Y, Mutoh T, Yokochi F, Ichinose Y, Koh K, Shindo K, Takiyama Y, Hamaguchi T, Yamada M, Farrer MJ, Uchiyama Y, Akamatsu W, Wu YR, Matsuda J, Hattori N. Variants in saposin D domain of prosaposin gene linked to Parkinson's disease. Brain. 2020 Apr 1;143(4):1190-1205. PubMed.
  3. Nicholson AM, Finch NA, Almeida M, Perkerson RB, van Blitterswijk M, Wojtas A, Cenik B, Rotondo S, Inskeep V, Almasy L, Dyer T, Peralta J, Jun G, Wood AR, Frayling TM, Fuchsberger C, Fowler S, Teslovich TM, Manning AK, Kumar S, Curran J, Lehman D, Abecasis G, Duggirala R, Pottier C, Zahir HA, Crook JE, Karydas A, Mitic L, Sun Y, Dickson DW, Bu G, Herz J, Yu G, Miller BL, Ferguson S, Petersen RC, Graff-Radford N, Blangero J, Rademakers R. Prosaposin is a regulator of progranulin levels and oligomerization. Nat Commun. 2016 Jun 30;7:11992. PubMed.
  4. Mendsaikhan A, Tooyama I, Bellier JP, Serrano GE, Sue LI, Lue LF, Beach TG, Walker DG. 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. Medina M. An Overview on the Clinical Development of Tau-Based Therapeutics. Int J Mol Sci. 2018 Apr 11;19(4) PubMed.
  6. Jadhav S, Avila J, Schöll M, Kovacs GG, Kövari E, Skrabana R, Evans LD, Kontsekova E, Malawska B, de Silva R, Buee L, Zilka N. A walk through tau therapeutic strategies. Acta Neuropathol Commun. 2019 Feb 15;7(1):22. PubMed.
  7. Callizot N, Estrella C, Burlet S, Henriques A, Brantis C, Barrier M, Campanari ML, Verwaerde P. AZP2006, a new promising treatment for Alzheimer's and related diseases. Sci Rep. 2021 Aug 19;11(1):16806. PubMed.

External Citations

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

Further Reading