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)
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., 2010; 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 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.
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.
For details on AZP2006 trials, see clinicaltrials.gov.
Last Updated: 11 May 2020
Research Models Citations
- 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.
- 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.
- 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.
- 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.
- Medina M. An Overview on the Clinical Development of Tau-Based Therapeutics. Int J Mol Sci. 2018 Apr 11;19(4) PubMed.
- 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.
- Chitramuthu BP, Bennett HP, Bateman A. Progranulin: a new avenue towards the understanding and treatment of neurodegenerative disease. Brain. 2017 Dec 1;140(12):3081-3104. PubMed.
- Van Damme P. Another piece in the progranulin puzzle: special binding between progranulin and prosaposin creates additional lysosomal access: An Editorial Comment for 'The interaction between progranulin and prosaposin is mediated by granulins and the linker region be. J Neurochem. 2017 Aug 4; PubMed.
- Zhou X, Sun L, Bastos de Oliveira F, Qi X, Brown WJ, Smolka MB, Sun Y, Hu F. Prosaposin facilitates sortilin-independent lysosomal trafficking of progranulin. J Cell Biol. 2015 Sep 14;210(6):991-1002. PubMed.