Overview

Name: Emtricitabine
Chemical Name: 2',3'-dideoxy-5-fluoro-3'-thiacytidine
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: Gilead Sciences, Inc.

Background

This nucleoside analog reverse transcriptase inhibitor is used for the prevention and treatment of HIV infection. It is taken as capsules or an oral solution, and is always combined with other antiretrovirals. It is well tolerated, with mild to moderate diarrhea, headache, nausea, and rash being the most common side effects.

Interest in repurposing reverse transcriptase inhibitors (RTIs) to treat Alzheimer’s disease arose from studies implicating DNA retrotransposon activity in aging and neurodegeneration. Increasing retrotransposon activity with age leads to the accumulation of nuclei acids in the cytosol of cells. There, they activate the immune system and promote inflammation, a causative factor in age-associated diseases including neurodegeneration. Nucleoside RTIs have been shown to reduce inflammation in animal models and in human clinical trials (e.g. De Cecco et al. 2019; Rice et al., 2018). One study reported intrinsic anti-inflammatory activity of nucleoside RTIs, independent of reverse transcriptase (Fowler et al., 2014). Other RTIs are in trials for AD, amyotrophic lateral sclerosis/frontotemporal dementia, and progressive supranuclear palsy, due to their ability to quiet inflammation (TPN-101), or to modulate cholesterol metabolism (Efavirenz).

Findings

In December 2021, a Phase 1 safety study of emtricitabine began at Butler Hospital in Providence, Rhode Island. It is enrolling 25 people with biomarker-confirmed mild cognitive impairment or mild to moderate dementia due to AD to receive six months of either placebo or the standard HIV dose of 200 mg daily emtricitabine. The primary outcome is the number of people with adverse events due to treatment; secondary outcomes include levels of inflammatory biomarkers in blood, cognitive and functional scales, and CSF phospho-tau and Aβ42. The trial will run until March 2024.

For details on this trial, see clinicaltrials.gov.

Last Updated: 15 Sep 2023

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References

Therapeutics Citations

Paper Citations

De Cecco M, Ito T, Petrashen AP, Elias AE, Skvir NJ, Criscione SW, Caligiana A, Brocculi G, Adney EM, Boeke JD, Le O, Beauséjour C, Ambati J, Ambati K, Simon M, Seluanov A, Gorbunova V, Slagboom PE, Helfand SL, Neretti N, Sedivy JM. L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature. 2019 Feb;566(7742):73-78. Epub 2019 Feb 6 PubMed.
Rice GI, Meyzer C, Bouazza N, Hully M, Boddaert N, Semeraro M, Zeef LA, Rozenberg F, Bondet V, Duffy D, Llibre A, Baek J, Sambe MN, Henry E, Jolaine V, Barnerias C, Barth M, Belot A, Cances C, Debray FG, Doummar D, Frémond ML, Kitabayashi N, Lepelley A, Levrat V, Melki I, Meyer P, Nougues MC, Renaldo F, Rodero MP, Rodriguez D, Roubertie A, Seabra L, Uggenti C, Abdoul H, Treluyer JM, Desguerre I, Blanche S, Crow YJ. Reverse-Transcriptase Inhibitors in the Aicardi–Goutières Syndrome. N Engl J Med. 2018 Dec 6;379(23):2275-7. PubMed.
Fowler BJ, Gelfand BD, Kim Y, Kerur N, Tarallo V, Hirano Y, Amarnath S, Fowler DH, Radwan M, Young MT, Pittman K, Kubes P, Agarwal HK, Parang K, Hinton DR, Bastos-Carvalho A, Li S, Yasuma T, Mizutani T, Yasuma R, Wright C, Ambati J. Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity. Science. 2014 Nov 21;346(6212):1000-3. PubMed.

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