Synonyms: ANVS-401, 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, Parkinson's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2), Parkinson's Disease (Phase 1/2)
Company: Annovis Bio
Posiphen, also known as ANVS-401, is the pure (+) enantiomer, i.e. mirror image, of phenserine. Both compounds derive from the intramural research program at NIH and were licensed to Axonyx, Inc., which developed both enantiomers into the clinic. Axonyx merged with Torrey Pines Therapeutics, which licensed posiphen to QR Pharma in 2008.
Both posiphen and phenserine reduce production of amyloid precursor protein by blocking translation of its mRNA (Shaw et al., 2001). Phenserine also inhibits acetylcholinesterase, while posiphen does not. Both are dosed by mouth and enter the brain. Posiphen and phenserine are considered separate therapeutics, as there is no chiral switching between the two, or between their metabolites. Posiphen and phenserine, and their respective metabolites, differ in their pharmacokinetics.
They share a number of common actions and, additionally, have separate actions. Posiphen and phenserine act on iron-response element sequences in the 5' untranslated region of APP mRNA to inhibit APP protein synthesis. They reduced APP and Aβ in neuronal cultures and brains of wild-type and AD transgenic mice (Lahiri et al., 2007; Marutle et al., 2007). Both drugs were reported to be neuroprotective and neurotrophic in AD mouse models (Lilja et al., 2013; Lilja et al., 2013), and posiphen was reported to normalize memory impairment, learning, and synaptic function (Teich et al., 2018). Posiphen was also tested in the APP-overexpressing Ts65DN mouse model of Down's syndrome, where 50 mg/kg for 26 days lowered expression of APP and its C-terminal fragments, corrected deficits in axonal transport, and normalized neurotrophin signaling (Chen et al., 2021).
Posiphen and phenserine reportedly also block translation of α-synuclein mRNA, implying potential application in Parkinson’s disease (Rogers et al., 2011; Mikkilineni et al., 2012; Yu et al., 2013). Posiphen 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 statistically significant reductions in CSF of APP cleavage fragments sAPPα and β, as well as of both total- and phosphorylated-tau, and the inflammation markers YKL-40, complement C3, and MCP-1. A trend for reduction was evident in CSF levels of Aβ42 (-51.4%, p=0.0533).
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 three 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). The Alzheimer Disease Cooperative Study group is running the trial at six academic medical centers in the U.S. As of February 2020, 11 participants had enrolled, and no adverse effects were reported (company press release). The trial was paused from March to October 2020 due to COVID19, and is expected to finish in December 2021.
In 2019, QR Pharma became Annovis Bio.
In August 2020, Annovis began a Phase 1/2 dose-finding biomarker study in early AD and Parkinson’s disease patients. In Part 1, 14 AD and 14 PD patients were to be randomized roughly 2:1 to 80 mg posiphen or placebo, taken daily for 23 to 27 days. At the last dose, participants undergo blood and CSF sampling. In Part 2 of the study, 40 PD patients will receive 5, 10, 20, or 40 mg posiphen, under the same design as in Part 1. The primary outcome is adverse events. Other endpoints include pharmacokinetic, functional, and cognitive endpoints. A panel of CSF biomarkers to be measured spans amyloid and tau pathology, inflammation, and neuronal death.
Part 1 finished in early 2021, and Annovis presented results at the 2021 AAIC on July 28. There were no serious adverse events. On exploratory efficacy measures, the company claimed a statistically significant within-subject improvement in the ADAS-Cog11 from baseline to 25 days, but the comparison with placebo group fell short of significance. Posiphen-treated PD patients improved on the WAIS coding task, a paper-and-pencil test measuring motor dexterity and cognitive speed compared to placebo. The AD patients had a decrease in all amyloid/tau biomarkers, with a 12 percent reduction in pTau, and improvement in the Aβ42/40 ratio. The neurodegeneration biomarker NfL had 13 percent lower levels in AD and 9 percent in PD, but the change was not statistically significant. The company reported significant reductions by 43 and 28 percent in inflammatory markers sTREM2 and GFAP in treated PD patients; a 55 percent YKL40 reduction did not meet statistical significance. The study is expected to finish in September 2021.
For details on posiphen trials, see clinicaltrials.gov.
Last Updated: 30 Jul 2021
- Maccecchini ML, Chang MY, Pan C, John V, Zetterberg H, Greig NH. 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.
- Paterson RW, Gabelle A, Lucey BP, Barthélemy NR, Leckey CA, Hirtz C, Lehmann S, Sato C, Patterson BW, West T, Yarasheski K, Rohrer JD, Wildburger NC, Schott JM, Karch CM, Wray S, Miller TM, Elbert DL, Zetterberg H, Fox NC, Bateman RJ. 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.
- Shaw KT, Utsuki T, Rogers J, Yu QS, Sambamurti K, Brossi A, Ge YW, Lahiri DK, Greig NH. Phenserine regulates translation of beta -amyloid precursor protein mRNA by a putative interleukin-1 responsive element, a target for drug development. Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7605-10. PubMed.
- Lahiri DK, Chen D, Maloney B, Holloway HW, Yu QS, Utsuki T, Giordano T, Sambamurti K, Greig NH. 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.
- Marutle A, Ohmitsu M, Nilbratt M, Greig NH, Nordberg A, Sugaya K. 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.
- Lilja AM, Luo Y, Yu QS, Röjdner J, Li Y, Marini AM, Marutle A, Nordberg A, Greig NH. Neurotrophic and neuroprotective actions of (-)- and (+)-phenserine, candidate drugs for Alzheimer's disease. PLoS One. 2013;8(1):e54887. PubMed.
- Lilja AM, Röjdner J, Mustafiz T, Thomé CM, Storelli E, Gonzalez D, Unger-Lithner C, Greig NH, Nordberg A, Marutle A. Age-dependent neuroplasticity mechanisms in Alzheimer Tg2576 mice following modulation of brain amyloid-β levels. PLoS One. 2013;8(3):e58752. PubMed.
- Teich AF, Sharma E, Barnwell E, Zhang H, Staniszewski A, Utsuki T, Padmaraju V, Mazell C, Tzekou A, Sambamurti K, Arancio O, Maccecchini ML. 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.
- Chen XQ, Salehi A, Pearn ML, Overk C, Nguyen PD, Kleschevnikov AM, Maccecchini M, Mobley WC. Targeting increased levels of APP in Down syndrome: Posiphen-mediated reductions in APP and its products reverse endosomal phenotypes in the Ts65Dn mouse model. Alzheimers Dement. 2021 Feb;17(2):271-292. Epub 2020 Sep 25 PubMed.
- Rogers JT, Mikkilineni S, Cantuti-Castelvetri I, Smith DH, Huang X, Bandyopadhyay S, Cahill CM, Maccecchini ML, Lahiri DK, Greig NH. 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.
- Mikkilineni S, Cantuti-Castelvetri I, Cahill CM, Balliedier A, Greig NH, Rogers JT. 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.
- Yu QS, Reale M, Kamal MA, Holloway HW, Luo W, Sambamurti K, Ray B, Lahiri DK, Rogers JT, Greig NH. 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.
- Kuo YM, Nwankwo EI, Nussbaum RL, Rogers J, Maccecchini ML. 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.
- Yu SJ, Wu KJ, Bae E, Wang YS, Chiang CW, Kuo LW, Harvey BK, Greig NH, Wang Y. Post-treatment with Posiphen Reduces Endoplasmic Reticulum Stress and Neurodegeneration in Stroke Brain. iScience. 2020 Feb 21;23(2):100866. Epub 2020 Jan 28 PubMed.
- Turcato F, Kim P, Barnett A, Jin Y, Scerba M, Casey A, Selman W, Greig NH, Luo Y. Sequential combined Treatment of Pifithrin-α and Posiphen Enhances Neurogenesis and Functional Recovery After Stroke. Cell Transplant. 2018 Apr;27(4):607-621. Epub 2018 Jun 5 PubMed.
- Kisby B, Jarrell JT, Agar ME, Cohen DS, Rosin ER, Cahill CM, Rogers JT, Huang X. Alzheimer's Disease and Its Potential Alternative Therapeutics. J Alzheimers Dis Parkinsonism. 2019;9(5) Epub 2019 Sep 13 PubMed.
- Bandyopadhyay S, Cahill C, Balleidier A, Huang C, Lahiri DK, Huang X, Rogers JT. 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.
- Klein J. Phenserine. Expert Opin Investig Drugs. 2007 Jul;16(7):1087-97. PubMed.