Therapeutics

Posiphen

Overview

Name: Posiphen
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

Background

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., 2011Mikkilineni 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).

Findings

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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References

Therapeutics Citations

  1. Phenserine

Paper Citations

  1. . Posiphen as a candidate drug to lower CSF amyloid precursor protein, amyloid-β peptide and τ levels: target engagement, tolerability and pharmacokinetics in humans. J Neurol Neurosurg Psychiatry. 2012 Sep;83(9):894-902. PubMed.
  2. . SILK studies - capturing the turnover of proteins linked to neurodegenerative diseases. Nat Rev Neurol. 2019 Jul;15(7):419-427. Epub 2019 Jun 20 PubMed.
  3. . The experimental Alzheimer's disease drug posiphen [(+)-phenserine] lowers amyloid-beta peptide levels in cell culture and mice. J Pharmacol Exp Ther. 2007 Jan;320(1):386-96. PubMed.
  4. . Modulation of human neural stem cell differentiation in Alzheimer (APP23) transgenic mice by phenserine. Proc Natl Acad Sci U S A. 2007 Jul 24;104(30):12506-11. PubMed.
  5. . Neurotrophic and neuroprotective actions of (-)- and (+)-phenserine, candidate drugs for Alzheimer's disease. PLoS One. 2013;8(1):e54887. PubMed.
  6. . Age-dependent neuroplasticity mechanisms in Alzheimer Tg2576 mice following modulation of brain amyloid-β levels. PLoS One. 2013;8(3):e58752. PubMed.
  7. . Translational inhibition of APP by Posiphen: Efficacy, pharmacodynamics, and pharmacokinetics in the APP/PS1 mouse. Alzheimers Dement (N Y). 2018;4:37-45. Epub 2018 Jan 18 PubMed.
  8. . The alpha-synuclein 5'untranslated region targeted translation blockers: anti-alpha synuclein efficacy of cardiac glycosides and Posiphen. J Neural Transm. 2011 Mar;118(3):493-507. PubMed.
  9. . The anticholinesterase phenserine and its enantiomer posiphen as 5'untranslated-region-directed translation blockers of the Parkinson's alpha synuclein expression. Parkinsons Dis. 2012;2012:142372. PubMed.
  10. . Synthesis of the Alzheimer drug Posiphen into its primary metabolic products (+)-N1-norPosiphen, (+)-N8-norPosiphen and (+)-N1, N8-bisnorPosiphen, their inhibition of amyloid precursor protein, α-synuclein synthesis, interleukin-1β release, and cholinergi. Antiinflamm Antiallergy Agents Med Chem. 2013 Jan 22; PubMed.
  11. . Translational inhibition of α-synuclein by Posiphen normalizes distal colon motility in transgenic Parkinson mice. Am J Neurodegener Dis. 2019;8(1):1-15. Epub 2019 Feb 15 PubMed.

External Citations

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

Further Reading

Papers

  1. . Alzheimer's Disease and Its Potential Alternative Therapeutics. J Alzheimers Dis Parkinsonism. 2019;9(5) Epub 2019 Sep 13 PubMed.
  2. . Novel 5' untranslated region directed blockers of iron-regulatory protein-1 dependent amyloid precursor protein translation: implications for down syndrome and Alzheimer's disease. PLoS One. 2013;8(7):e65978. PubMed.
  3. . Phenserine. Expert Opin Investig Drugs. 2007 Jul;16(7):1087-97. PubMed.