Synonyms: ANVS-401, (+)-phenserine, Posiphen tartrate
Chemical Name: (3aR)-1, 3a, 8-trimethyl-1, 2, 3, 3a, 8, 8a-hexahydropyrrolo (2, 3-b) indol-5-yl phenyl-carbamate tartrate
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline), alpha-synuclein
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Annovis Bio
Posiphen, also known as ANVS-401, is the pure (+) enantiomer of phenserine. Both compounds were originally developed by Torrey Pines Therapeutics and licensed to QR Pharma in 2008. Both Posiphen and phenserine reduce production of amyloid precursor protein by blocking translation of its mRNA. Phenserine also inhibits acetylcholinesterase, while Posiphen does not. It is dosed by mouth and enters the brain.
Posiphen acts on iron-response element sequences in the 5' untranslated region of APP mRNA to inhibit protein synthesis. It reduced APP and Aβ in neuronal cultures and brains of wild-type and AD transgenic mice (Lahiri et al., 2007; Marutle et al., 2007). The drug was reported to be neuroprotective and neurotrophic in AD mouse models (Lilja et al., 2013; Lilja et al., 2013), and to normalize memory impairment, learning, and synaptic function (Teich et al., 2018).
Posiphen reportedly also blocks translation of α-synuclein mRNA, implying potential application in Parkinson’s disease (Rogers et al., 2011; Mikkilineni et al., 2012; Yu et al., 2013). The compound reduced α-synuclein expression in brain and gut, and improved intestinal function in the A53T α-synuclein transgenic mouse model of PD (Kuo et al., 2019).
Results of three Phase 1 studies of Posiphen are published (Maccecchini et al., 2012). They include single and multiple dosing in 120 healthy adults and a small proof-of-concept study in five people with MCI. Most common side effects were dizziness, nausea, and vomiting that increased with dose. Adverse effects did not increase significantly at doses of up to 60 mg four times a day for 10 days, at which point Posiphen reached brain concentrations presumed sufficient to inhibit APP production. Ten days of treatment in people with MCI led to reductions in CSF of APP cleavage fragments sAPPα and β, and Aβ42, total tau, and phosphorylated tau, and the inflammation markers YKL-40, complement C3, and MCP-1.
In March 2017, QR Pharma started a Phase 1/2 trial to study the effect of Posiphen on APP synthesis in people with early AD. The study is recruiting 24 participants with a diagnosis of amnestic MCI or probable mild AD, and CSF levels of Aβ42 consistent with AD. They are randomized to receive 60, 120, or 180 mg daily, divided into four doses, or placebo for 23 to 25 days. Primary endpoints are safety, pharmacokinetics in plasma and CSF, and the rate of turnover of CSF Aβ40 using the stable isotope labeling kinetics (SILK) technique (see Paterson et al., 2019). As of February 2020, 11 participants had enrolled, and no adverse effects were reported (company press release). The Alzheimer Disease Cooperative Study group is running the trial at six academic medical centers in the U.S. It is expected to finish in the spring of 2021.
In 2019, QR Pharma became Annovis Bio. After going public in 2020, the company announced it would begin a Phase 2 study in 68 participants with Parkinson’s disease or AD (see press release), but no trial has been registered.
For details on Posiphen trials, see clinicaltrials.gov.
Last Updated: 19 Jun 2020
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